Method for producing a mixed liquid, the mixed liquid, and the solid composition

Abstract

A method for producing a liquid mixture, comprising a first mixing step, in which fine particles are mixed with a hydroxy compound to obtain the hydroxy compound coated with the fine particles, and a second mixing step, in which the hydroxy compound coated with the fine particles is mixed with a solvent to obtain a liquid mixture in which the fine particles coated with the hydroxy compound are dispersed in the solvent.

Description

Technical Field

[0001] The present invention relates to a method for producing a mixed liquid, a mixed liquid, and a solid composition. This application claims priority based on Japanese Patent Application No. 2021-166788 filed in Japan on October 11, 2021, and incorporates the content herein by reference.

Background Art

[0002] In the fields of pharmaceuticals, foods, cosmetics, paints, etc., from the viewpoint of improving scratch resistance, surface hardness, durability, heat resistance, light resistance, weather resistance, ultraviolet shielding property, conductivity, etc., attempts have been made to coat fine particles (sub-particles) on the surface of mother particles to impart new physical properties. Specifically, in the pharmaceutical field, attempts have been made to coat tablets with metal oxides such as fine particle titanium oxide and fine particle iron oxide to improve the photo stability of the active ingredients contained in the tablets. Also, in the cosmetic field, attempts have been made to coat feel modifiers such as nylon resins and silicone resins with fine particle titanium oxide to improve ultraviolet shielding property without impairing the feel.

[0003] In recent years, from the viewpoint of further improving functions, it has been required to uniformly coat fine particles on the surface of mother particles. However, for fine particles of about several tens of μm or less, intermolecular forces such as the attractive force acting between particles (for example, van der Waals force, etc.) are larger than the gravitational force applied to the particles, so they become highly cohesive adhesive particles, and it is difficult to uniformly coat the fine particles on the surface of the mother particles.

[0004] Examples of methods for coating fine particles on the surface of mother particles include a method in which fine particles are dispersed in a solution to prepare a coating solution, and the coating solution is coated on the mother particles. In order to uniformly coat fine particles on the surface of the mother particles, for example, additives such as a dispersant are added to the coating solution to suppress aggregation of the fine particles.

[0005] For example, Patent Document 1 discloses a coating agent comprising metal nanoparticles, a dispersion medium, a metal nanoparticle dispersant, and a binder, wherein the metal nanoparticles are metal oxide nanoparticles, the metal nanoparticle dispersant contains two or more active energy curing groups and a monomer or oligomer having at least one carboxyl group, and the binder contains a (meth)acrylic resin binder having (meth)acryloyl groups in its side chains. The disclosure states that this coating agent offers excellent dispersibility and dispersion stability of metal nanoparticles, and can improve the transparency, adhesion, hardness, and durability (alkali resistance, light resistance) of the coating film. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Patent No. 6186032 [Overview of the project] [Problems that the invention aims to solve]

[0007] However, conventional mixtures (typically coating solutions) do not sufficiently improve the dispersibility and dispersion stability of fine particles, and even when mother particles are coated with such mixtures, there is room for improvement in the uniformity of fine particles on the mother particle surface. Furthermore, even if smaller particle sizes are used as raw materials, these particles can aggregate during the manufacturing process of the mixture, resulting in a problem where the particle size of the particles in the mixture actually becomes larger than when larger particle sizes are used as raw materials.

[0008] The present invention has been made in view of these circumstances, and aims to provide a method for producing a mixed liquid with good dispersibility and dispersion stability of fine particles, a mixed liquid obtained by the production method, a solid composition coated with the mixed liquid, and a solid composition made from the mixed liquid. [Means for solving the problem]

[0009] The inventors of the present invention conducted thorough research on fine particles and dispersants to solve the above problems. As a result, they discovered that instead of simply mixing each raw material to produce a mixed solution, by pre-mixing fine particles with a specific dispersant (hydroxy compound) to create composite particles, and then dissolving the dispersant of these composite particles in a solvent to produce a mixed solution, it is possible to produce a mixed solution with dramatically improved dispersibility and dispersion stability of the fine particles, thus completing the present invention.

[0010] In other words, the present invention has the following aspects. [1] A method for producing a mixed liquid, comprising: a first mixing step of mixing fine particles with a hydroxy compound to obtain a hydroxy compound coated with fine particles; and a second mixing step of mixing the hydroxy compound coated with the fine particles with a solvent to obtain a mixed liquid in which the fine particles coated with the hydroxy compound are dispersed in the solvent. [2] The method for producing the mixture according to [1], wherein the hydroxy compound is one or more compounds selected from sugars, vitamin P derivatives, and salts of vitamin P derivatives. [3] A method for producing a mixed solution according to [1] or [2], wherein a high molecular weight dispersant is further mixed in the second mixing step.

[0011] [4] A method for producing a mixed liquid according to any one of [1] to [3], wherein the average particle size D50 of the fine particles in the first mixing step is 1 nm or more and 900 nm or less, and the average particle size D50 of the hydroxy compound is 30 μm or more and 300 μm or less. [5] The method for producing a mixed liquid according to any one of [1] to [4], wherein the average particle size D50 of the fine particles in the second mixing step is 410 nm or less. [6] The method for producing a mixed liquid according to any one of [1] to [5], wherein in the first mixing step, the amount of the hydroxy compound used is 200 parts by mass or more and 2500 parts by mass or less per 100 parts by mass of the fine particles.

[0012] [7] A mixture in which fine particles coated with a hydroxy compound are dispersed in a solvent, wherein the hydroxy compound is D-mannitol, α-cyclodextrin, HP-β-cyclodextrin, methyl hesperidin, and sucralose. A solid composition coated with the mixture described in [8] and [7]. A solid pharmaceutical composition coated with the mixture described in [9] and [7]. A solid composition prepared by the mixture described in

[10] [7].

[11] A mixture containing a hydroxy compound and fine particles, wherein the average particle size D50 of the fine particles is 200 nm or less, and the span value of the fine particles is 9 or less. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a method for producing a mixed liquid with good dispersibility and dispersion stability of fine particles, a mixed liquid obtained by the production method, a solid composition coated with the mixed liquid, and a solid composition made from the mixed liquid. [Brief explanation of the drawing]

[0014] [Figure 1] This graph shows the results of the photostability evaluation of the solid compositions of the examples and comparative examples. [Figure 2] This graph shows the results of the photostability evaluation of the solid compositions of the examples and comparative examples. [Modes for carrying out the invention]

[0015] (Method for producing the mixed solution) The method for producing the mixed solution of this embodiment comprises a first mixing step (hereinafter referred to as the "first mixing step") in which fine particles and a hydroxy compound are mixed to obtain a hydroxy compound coated with fine particles, and a second mixing step (hereinafter referred to as the "second mixing step") in which the hydroxy compound coated with the fine particles and a solvent are mixed to obtain a mixed solution in which the fine particles coated with the hydroxy compound are dispersed in the solvent.

[0016] <First mixing step> In the first mixing step in the method for producing the mixed solution of the present embodiment, fine particles and a hydroxy compound are mixed to obtain a hydroxy compound coated with the fine particles. Here, the "hydroxy compound coated with fine particles" means that part or all of the surface of the solid hydroxy compound is covered with fine particles.

[0017] ≪Fine particles≫ In this specification, "fine particles" means particles having an average particle diameter D50 measured by the laser diffraction method of less than 1 μm.

[0018] In this specification, the average particle diameter D50 can be measured by the following method. First, 100 mg of fine particles is dispersed in ethanol. Next, for the fine particles dispersed in ethanol, a laser diffraction / scattering type particle size distribution measuring device (for example, "LA-950" manufactured by Horiba, Ltd.) is used to obtain the particle size distribution of the fine particles. Based on the cumulative volume distribution diagram of the obtained particle size distribution of the fine particles, the average particle diameter D50 is calculated by obtaining the particle diameter at a cumulative percentage of 50% from the small diameter side.

[0019] The average particle diameter D50 of the fine particles in the mixed solution can be measured by the following method. Since the components other than the fine particles in the mixed solution exist in a state dissolved in the solvent, the mixed solution is diluted to an appropriate concentration, and a laser diffraction type particle size distribution measuring device (for example, "LA-950" manufactured by Horiba, Ltd.) is used to obtain the particle size distribution of the fine particles. Based on the cumulative volume distribution diagram of the obtained particle size distribution of the fine particles, the average particle diameter D50 is calculated by obtaining the particle diameter at a cumulative percentage of 50% from the small diameter side. In addition, when two or more types of fine particles are contained in the mixed solution, for all the fine particles, the average particle diameter D50 measured by the above method may be within the preferable range described later, but it is sufficient that the average particle diameter D50 of at least one type of fine particles is within the preferable range described later. One method for separating one type of particle from two or more types is to use sieving if the particle sizes of the particles differ significantly. Separation can also be achieved by utilizing differences in sedimentation velocity or specific gravity.

[0020] From the viewpoint of obtaining the effects of the present invention to the greatest extent, the fine particles used in the first step preferably have an average particle diameter D50 of 1 nm to 900 nm, more preferably 1 nm to 600 nm, even more preferably 10 nm to 150 nm, and particularly preferably 10 nm to 50 nm.

[0021] The fine particles used in the first step can be either organic or inorganic. Furthermore, the fine particles may be surface-treated, or they may be composite particles such as microencapsulated fine particles.

[0022] ·Organic fine particles Examples of organic microparticles include polymer microparticles obtained by emulsion polymerization, microemulsion polymerization, soap-free polymerization, seed polymerization, dispersion polymerization, suspension polymerization, etc. (e.g., powders, latex, or emulsion-type polymer microparticles of polyethylene, polypropylene, polystyrene, polyacrylate, polyamide, silicone resin, phenolic resin, natural polymers, etc.); and organic pigments (e.g., azo lakes, insoluble azo pigments, condensed azo pigments, chelated azo pigments, phthalocyanine pigments, perylene pigments, perinone pigments, quinacridone pigments, thio Examples include indigo pigments, isoindolinone pigments, quinoflarone pigments, dioxazine pigments, anthraquinone pigments, nitro pigments, nitroso pigments, aniline black, etc.); foods; and drugs (amlodipine, ebastine, selegiline, brotizolam, ramosetron, midodrine, montelukast, azulene sulfonic acid, etizolam, bromperidol, mecobalamin, alfacalcidol, bromocriptine, pramipexole, rosuvastatin, silodosin, nifedipine, and their pharmacologically acceptable salts or solvates, etc.).

[0023] More specifically, examples of organic pigments include Red 202, Red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1, Green 201, Purple 201, Red 204, etc., which may be lake-formed.

[0024] ·Inorganic fine particles Examples of inorganic fine particles include metal oxides such as iron oxide (red iron oxide, yellow iron oxide, black iron oxide), silicon dioxide (silica), titanium dioxide, zinc oxide, aluminum oxide, cobalt oxide, and thallium oxide; silicate minerals such as mica, talc, sericite, kaolin, and synthetic mica; metal carbonates such as calcium carbonate and magnesium carbonate; metal sulfates such as barium sulfate; metal particles such as copper, silver, gold, nickel, palladium, platinum, and cobalt; composite powders such as titanium mica; boron nitride; lead white; carbon black; cadmium red; lead yellow; ultramarine; cobalt blue; cobalt violet; and zinc chromate.

[0025] In this embodiment, the fine particles are preferably inorganic fine particles, more preferably metal oxides, and even more preferably iron oxide or titanium dioxide, because they have higher cohesiveness and are more likely to produce the effects of the present invention.

[0026] In this embodiment, one type of fine particle may be used alone, or two or more types may be used in combination.

[0027] ≪Hydroxy compounds≫ In this specification, "hydroxy compound" refers to a compound different from the "fine particles" described above, and means a compound having one or more hydroxyl groups. Furthermore, in this specification, "hydroxy compound" refers to a compound that is solid at 25°C.

[0028] The hydroxy compound used in the first step is not particularly limited, as long as it is a compound that is solid at 25°C and dissolves in the solvent in the second mixing step described later.

[0029] More specifically, examples of hydroxy compounds used in the first step include polyhydric alcohols and vitamin derivatives.

[0030] • Polyhydric alcohols Examples of polyhydric alcohols include trihydric alcohols such as trimethylolethane and trimethylolpropane; tetrahydric alcohols such as pentaerythritol and erythritol; pentahydric alcohols such as arabitol and xylitol; hexahydric alcohols such as dipentaerythritol, sorbitol, mannitol, isitol, inositol, talose, and allose; or derivatives of these polyols in which some or all of the hydrogen atoms in these compounds are substituted with other substituents. To explain using inositol as an example, inositol has nine stereoisomers: cis-inositol, epi-inositol, allo-inositol, myo-inositol, muco-inositol, neo-inositol, chiro-inositol (which exists in D and L forms), and scyllo-inositol. Similarly, other compounds may use only one isomer, or two or more isomers in combination.

[0031] Among polyhydric alcohols, a sugar is more preferable as the hydroxy compound used in the first step.

[0032] ·sugar The sugar may be a monosaccharide or an oligosaccharide. Here, a monosaccharide refers to a sugar that cannot be further hydrolyzed and is a compound that forms the building blocks of a polysaccharide. A monosaccharide can also be said to be the smallest unit of sugars. An oligosaccharide is a sugar oligomer in which multiple monosaccharides are linked together by glycosidic bonds.

[0033] · · Monosaccharide Examples of monosaccharides include glucose, fructose, galactose, sucralose, ribose, xylose, mannitol, sorbitol, xylitol, erythritol, and pentaerythritol.

[0034] Oligosaccharides Oligosaccharides specifically include disaccharides such as sucrose, lactose, maltose, isomaltose, trehalose, cellobiose, and maltitol; trisaccharides such as raffinose, melegitose, and maltotriose; tetrasaccharides such as stachyose; hexasaccharides such as α-cyclodextrin; heptasaccharides such as β-cyclodextrin; and octasaccharides such as γ-cyclodextrin. The oligosaccharide may also be an oligosaccharide derivative. Specific examples of oligosaccharide derivatives include 2-hydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin), in which the hydroxyl group of β-cyclodextrin is modified to 2-hydroxypropyl.

[0035] Other sugars Furthermore, other sugars may be used as the sugar, such as heptose, deoxy sugars, amino sugars, thio sugars, seleno sugars, aldonic acid, uronic acid, sugar acid, ascorbic acid, ketoaldonic acid, anhydro sugars, unsaturated sugars, sugar esters, sugar ethers, glycosides, etc., and hydrolyzed polysaccharides such as starch, glycogen, and cellulose may also be used.

[0036] • Vitamin derivatives Examples of vitamin derivatives include vitamin C derivatives or salts thereof, vitamin E derivatives or salts thereof, and vitamin P derivatives or salts thereof.

[0037] • Vitamin C derivatives or their salts Examples of vitamin C derivatives include ascorbic acid derivatives in which at least one hydroxyl group of ascorbic acid has been derivatized. More specifically, examples of the ascorbic acid derivatives include ascorbyl phosphate, which is obtained by phosphate esterification of any of the hydroxyl groups of ascorbic acid; ethyl ascorbic acid, which is obtained by ethoxylation of any of the hydroxyl groups of ascorbic acid; ascorbic acid glucoside, which is obtained by glucosidering any of the hydroxyl groups of ascorbic acid; acylated ascorbic acid, which is obtained by acylation of any of the hydroxyl groups of ascorbic acid; and glyceryl ascorbic acid, which is obtained by substituting any of the hydroxyl groups of ascorbic acid with glycerin.

[0038] Examples of salts of ascorbic acid derivatives include salts of ascorbic acid derivatives with inorganic bases and salts of ascorbic acid derivatives with organic bases. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts; and zinc salts. Examples of salts with organic bases include alkylammonium salts and salts with basic amino acids.

[0039] Vitamin E derivatives or their salts Examples of vitamin E derivatives include tocopherol phosphate ester or its salts. Examples of salts of tocopherol phosphate ester include salts of tocopherol phosphate ester with an inorganic base, and salts of tocopherol phosphate ester with an organic base. Examples of inorganic and organic bases include those similar to those described above for ascorbic acid derivatives.

[0040] • Vitamin P derivatives or their salts Examples of vitamin P derivatives include methylhesperidin, which is obtained by methylating hesperidin. The methylhesperidin is preferably in a form that is solubilized in water.

[0041] Methyl hesperidin is known to exist primarily in two forms: chalcone-type compounds (chalcone methyl hesperidin) and flavanone-type compounds (flavanone methyl hesperidin), but it is not limited to these two forms.

[0042] Methyl hesperidin can be produced by known methods, for example, by dissolving hesperidin produced from citrus peels in an aqueous sodium hydroxide solution, reacting the alkaline solution with a corresponding amount of dimethyl sulfuric acid, neutralizing the reaction mixture with sulfuric acid, extracting with n-butyl alcohol, removing the solvent by distillation, and then recrystallizing with isopropyl alcohol.

[0043] In this embodiment, among the above, the hydroxy compound is preferably one with a hydroxy equivalent (molecular weight of the hydroxy compound / number of hydroxyl groups in the hydroxy compound) of 10 to 500, more preferably 10 to 300, even more preferably 10 to 100, particularly preferably 30 to 85, and most preferably 50 to 85.

[0044] In this embodiment, the hydroxy compound is preferably a sugar, a vitamin P derivative, or a salt thereof. More specifically, the hydroxy compound is preferably one or more compounds selected from mannitol, oligosaccharides, vitamin P derivatives, and salts of vitamin P derivatives; more preferably one or more compounds selected from mannitol, sucralose, α-cyclodextrin, β-cyclodextrin, α-cyclodextrin derivatives, β-cyclodextrin derivatives, and methylhesperidin; even more preferably one or more compounds selected from D-mannitol, sucralose, α-cyclodextrin, HP-β-cyclodextrin, and methylhesperidin; and particularly preferably sucralose or α-cyclodextrin.

[0045] The hydroxy compound used in the first step may be used alone or in combination of two or more types.

[0046] In the first mixing step of this embodiment, the amount of hydroxy compound used is preferably 200 parts by mass or more, more preferably 500 parts by mass or more, and even more preferably 800 parts by mass or more, per 100 parts by mass of fine particles. Furthermore, the amount of hydroxy compound used in the first mixing step of this embodiment is preferably 2,500 parts by mass or less, more preferably 2,200 parts by mass or less, and even more preferably 2,000 parts by mass or less, per 100 parts by mass of fine particles. For example, the amount of hydroxy compound used in the first mixing step of this embodiment is preferably 200 parts by mass or more and 2500 parts by mass or less, more preferably 500 parts by mass or more and 2200 parts by mass or less, and even more preferably 800 parts by mass or more and 2000 parts by mass or less, per 100 parts by mass of fine particles.

[0047] If the amount of hydroxy compound used in the first mixing step of this embodiment is within the above preferred range, the surface of the hydroxy compound can be more uniformly coated with fine particles.

[0048] From the viewpoint of obtaining the effects of the present invention, the average particle size D50 of the hydroxy compound used in the first mixing step of this embodiment is preferably 0.2 μm or more and 300 μm or less, more preferably 1 μm or more and 250 μm or less, even more preferably 10 μm or more and 200 μm or less, and particularly preferably 30 μm or more and 150 μm or less.

[0049] In the first mixing step of this embodiment, the ratio of the average particle size D50 of the hydroxy compound to the average particle size D50 of the fine particles (average particle size D50 of the hydroxy compound / average particle size D50 of the fine particles) is preferably 10 to 10000, more preferably 50 to 7500, even more preferably 100 to 6000, and particularly preferably 1000 to 4500, from the viewpoint of obtaining the effects of the present invention to the greatest extent possible.

[0050] Furthermore, if the mixture contains two or more types of fine particles and two or more types of hydroxy compounds, the ratio of the average particle size D50 measured for all hydroxy compounds to the average particle size D50 measured for all fine particles may be within the above preferred range, but it is sufficient if the ratio of the average particle size D50 of at least one type of hydroxy compound to the average particle size D50 of at least one type of fine particle is within the above preferred range.

[0051] In the method for producing the mixed liquid of this embodiment, the first mixing step may be a chemical surface modification method that causes a chemical reaction to attach fine particles to the hydroxy compound, or a physical surface modification method that applies physical energy to attach fine particles to the hydroxy compound, but a physical surface modification method is preferred.

[0052] Specifically, from the viewpoint of dispersing finer particles, a mechanical surface modification method (mechanochemical method) is more preferable as a physical surface modification method. Mechanical surface modification is a method that involves repeatedly applying compression, shearing, or impact to two or more types of particles with different particle sizes and compositions, thereby immobilizing or forming a film of fine particles (sub-particles) on the surface of a core particle (mother particle).

[0053] The mixing apparatus used for the first mixing step in the method for producing the mixed liquid of this embodiment is not particularly limited, and any known mixing apparatus can be used. When a mechanical surface modification method is performed as the first mixing step, the following can be used as the apparatus for performing the mechanical surface modification method: planetary ball mill (manufactured by Fritsch), hybridization system (manufactured by Nara Machine Works), Mechanofusion® system (manufactured by Hosokawa Micron Corporation), Novilta® (manufactured by Hosokawa Micron Corporation), Nanocura® (manufactured by Hosokawa Micron Corporation), Mechanomill® (manufactured by Okada Seikou Co., Ltd.), Theta Composer® (manufactured by Tokuju Kogyo Co., Ltd.), Nanosonic Mill (manufactured by Inoue Seisakusho Co., Ltd.), kneader (manufactured by Inoue Seisakusho Co., Ltd.), Supermascolloider (manufactured by Masukou Sangyo Co., Ltd.), Nanomec Reactor (manufactured by Techno-i Co., Ltd.), Cornell Despa (manufactured by Asada Iron Works Co., Ltd.), etc.

[0054] In the first mixing step, it is preferable to set the mixing conditions such that the power load on the fine particles and the hydroxyl compound is preferably 1 W / g or more, more preferably 3 W / g or more, and even more preferably 5 W / g or more.

[0055] Here, the power P (kW) can be calculated using the following equation (1). Power P (kW) = (Current × Voltage × Efficiency × Power Factor) / 1000 ... (1)

[0056] The upper limit of the load power is not particularly limited and is set to an extent that the hydroxyl compound is not excessively crushed. For example, the upper limit of the load power may be 100 W / g or less, 50 W / g or less, or 10 W / g or less.

[0057] The mixing temperature in the first mixing step is not particularly limited as long as the components do not degrade, and is, for example, 5 to 100°C. The mixing time for the first mixing step is not particularly limited, as long as the components do not deteriorate, and can be, for example, 1 to 30 minutes.

[0058] <Second mixing process> The second mixing step in the method for producing the mixed solution of this embodiment is a step of mixing a hydroxy compound coated with fine particles with a solvent to obtain a mixed solution in which the fine particles coated with the hydroxy compound are dispersed in the solvent. In the first mixing step, the hydroxy compound was coated with fine particles, but in the second mixing step, most of the hydroxy compound dissolves in the solvent, causing the mother particles and daughter particles to reverse positions, and fine particles coated with the hydroxy compound are produced. Here, "fine particles coated with a hydroxy compound" refers to fine particles in which part or all of the surface is covered with a hydroxy compound. The amount of hydroxy compound coating the fine particles can be controlled, for example, by the amount of hydroxy compound used per 100 parts by mass of fine particles in the first mixing step described above.

[0059] The average particle size D50 of the fine particles in the mixed liquid obtained by the second mixing step is preferably 410 nm or less, more preferably 5 nm to 200 nm, even more preferably 30 nm to 100 nm, particularly preferably 40 nm to 95 nm, and most preferably 50 nm to 90 nm.

[0060] Solvent Examples of solvents in this embodiment include water, organic solvents, and mixed solvents thereof. Examples of organic solvents include ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents, amide solvents, sulfoxide solvents, fluorine-based inert liquids, hydrocarbon solvents, and silicone solvents.

[0061] Ester-based solvents Ester solvents are organic solvents that contain (-C(=O)-O-) in their structure. Examples of ester solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, amyl acetate, isoamyl acetate, ethyl methoxyethyl acetate, ethyl ethoxyethyl acetate, 2-methoxybutyl acetate, 3-methoxybutyl acetate, 4-methoxybutyl acetate, 3-methoxy-3-methylbutyl acetate, 3-ethyl-3-methoxybutyl acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monopropyl ether acetate, ethylene glycol monobutyl ether acetate, ethylene glycol monophenyl ether acetate, diethylene glycol monomethyl ether acetate, diethylene glycol monoethyl ether acetate, diethylene glycol monopropyl ether acetate, diethylene glycol monobutyl ether acetate, diethylene glycol monophenyl ether acetate, and propylene glycol monomethyl ether acetate. (PGMEA), propylene glycol monoethyl ether acetate, propylene glycol monopropyl ether acetate, 2-ethoxybutyl acetate, 4-ethoxybutyl acetate, 4-propoxybutyl acetate, 2-methoxypentyl acetate, 3-methoxypentyl acetate, 4-methoxypentyl acetate, 2-methyl-3-methoxypentyl acetate, 3-methyl-3-methoxypentyl acetate, 3-methyl-4-methoxypentyl acetate, 4-methyl-4-methoxypentyl acetate, propylene Glycol diacetate, methyl formate, ethyl formate, propyl formate, butyl formate, ethyl lactate (EL), propyl lactate, butyl lactate, ethyl carbonate, propyl carbonate, butyl carbonate, methyl pyruvate, ethyl pyruvate, propyl pyruvate, butyl pyruvate, methyl acetoacetate, ethyl acetoacetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, methyl 2-hydroxypropionate, ethyl 2-hydroxypropionate, methyl-3-methoxypropionate, ethyl-3-methoxypropionate,Examples include ethyl-3-ethoxypropionate and propyl-3-methoxypropionate.

[0062] Ketone-based solvents Ketone solvents are organic solvents that have a carbonyl group (ketone: -C(=O)-) other than an ester bond. Examples of ketone solvents include acetone, 1-hexanone, 2-hexanone, 4-heptanone, 2-heptanone (methyl amyl ketone), 1-octanone, 2-octanone, 1-nonanone, 2-nonanone, diisobutyl ketone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, acetonylacetone, phenylacetone, acetophenone, methyl naphthyl ketone, cyclohexanone (CHN), methylcyclohexanone, ionone, isophorone, diacetonyl alcohol, diacetone alcohol, and acetylcarbinol.

[0063] Ether-based solvents Ether-based solvents are organic solvents that have ether bonds (-O-) other than ester bonds. Examples of ether-based solvents include alkylene glycol monoalkyl ethers such as propylene glycol monomethyl ether (PGME), ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monohexyl ether, ethylene glycol monophenyl ether, ethylene glycol mono-2-ethylbutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, and propylene glycol monobutyl ether; and polyhydric alcohol partial ethers such as ether group-containing alkylene glycol monoalkyl ether compounds such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether.

[0064] Alcohol-based solvents Alcohol-based solvents are organic solvents that contain an alcoholic hydroxyl group in their structure. An "alcoholic hydroxyl group" refers to a hydroxyl group bonded to a carbon atom of an aliphatic hydrocarbon group. In this specification, alcohol-based solvents are not included in ester-based solvents, ketone-based solvents, or ether-based solvents. Examples of alcohol-based solvents include monoalcohols such as methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, sec-butanol, t-butanol, n-pentanol, 4-methyl-2-pentanol (methyl isobutylcarbinol), and 2-methylbutyl alcohol; and polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol, and dipropylene glycol.

[0065] ≪Nitrile-based solvents≫ Nitrile solvents are organic solvents that contain a nitrile group (-C≡N) in their structure. Examples of nitrile solvents include acetonitrile, propionitol, valeronitrile, and butyronitrile.

[0066] ≪Amid-based solvents≫ Amide solvents are organic solvents that contain an amide group in their structure. Examples of amide solvents include N,N-dimethylformamide, N-methylformamide, N,N-dimethylacetamide, N-methylacetamide, and N,N-diethylacetamide.

[0067] Sulfoxide-based solvents Sulfoxide solvents are organic solvents that contain a sulfinyl group (-S(=O)-) with two alkyl groups bonded to it in their structure. Examples of sulfoxide-based solvents include dimethyl sulfoxide.

[0068] Hydrocarbon solvents Examples include hexane, heptane, octane, dodecane, cyclohexane, methylcyclohexane, isooctane, and hydrogenated triisobutylene.

[0069] ≪Silicone-based solvents≫ Examples include octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), hexamethyldisiloxane, octamethyltrisiloxane, and polydimethylsiloxane (1cs, 6cs, etc.).

[0070] In this embodiment, the solvent is preferably one that can adequately dissolve the hydroxy compound described above, and more preferably a solvent containing water or an alcohol-based solvent, and even more preferably water alone or an alcohol-based solvent alone.

[0071] The solvent in this embodiment may be used alone or in combination of two or more types.

[0072] ≪Optional ingredients≫ In the second mixing step of this embodiment, the hydroxy compound coated with the fine particles obtained in the first mixing step described above, and any other component other than the solvent may be added and mixed. Optional components include, specifically, plasticizers, high molecular weight dispersants; antioxidants such as phenolic antioxidants, hindered amine antioxidants, phosphorus antioxidants, sulfur antioxidants, benzotriazole antioxidants, benzophenone antioxidants, hydroxyamine antioxidants, salicylic acid ester antioxidants, and triazine antioxidants; and corrosion inhibitors such as benzotriazole or its derivatives, thiadiazole, and benzothiazole.

[0073] In the second mixing step of this embodiment, from the viewpoint of further improving the dispersibility and dispersion stability of the fine particles, it is preferable to mix a high molecular weight dispersant in addition to the hydroxy compound coated with fine particles and the solvent.

[0074] ≪High molecular weight dispersants≫ High molecular weight dispersants are surfactants that structurally have hydrophilic and lipophilic parts, and are polymer compounds with a molecular weight of approximately 2000 or more, formed by a chain of monomers. Furthermore, some high molecular weight dispersants fall under the category of hydroxy compounds mentioned above. In other words, in the second mixing step of this embodiment, the hydroxy compound in the hydroxy compound coated with fine particles and the separately added high molecular weight dispersant may be the same or different. Among these, it is preferable that the hydroxy compound in the hydroxy compound coated with fine particles and the separately added high molecular weight dispersant are different, and it is even more preferable that the hydroxy compound is a compound that does not correspond to the high molecular weight dispersant.

[0075] Examples of high molecular weight dispersants include anionic high molecular weight dispersants, nonionic high molecular weight dispersants, and cationic high molecular weight dispersants.

[0076] • Anionic high molecular weight dispersant More specifically, examples of anionic high molecular weight dispersants include styrene-maleic anhydride copolymers; formalin-bound naphthalene sulfonates; polyacrylates; carboxymethylcellulose; olefin-maleic anhydride copolymers; polystyrene sulfonates; acrylamide-acrylic acid copolymers; and sodium alginate (natural).

[0077] • Nonionic high molecular weight dispersant More specifically, nonionic high molecular weight dispersants include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer; hydroxypropyl cellulose; hydroxypropyl methylcellulose; polyvinyl alcohol; polyoxyethylene alkyl ether; polyalkylene polyamine; polyacrylamide; polyoxypropylene / polyoxyethylene block; and polymerized starch (natural).

[0078] • Cationic high molecular weight dispersant More specifically, examples of cationic high molecular weight dispersants include polyethyleneimine, aminoalkyl (meth)acrylate copolymer, polyvinylimidazoline, and satkinsan (natural).

[0079] Among the high molecular weight dispersants mentioned above, nonionic high molecular weight dispersants are preferred from the viewpoint of further improving the dispersibility and dispersion stability of fine particles. Specifically, it is more preferable to use one or more nonionic high molecular weight dispersants selected from the group consisting of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0080] In this embodiment, the high molecular weight dispersant may be used alone or in combination of two or more types. In the second mixing step of this embodiment, the amount of high molecular weight dispersant used is preferably 200 parts by mass or more, more preferably 300 parts by mass or more, and even more preferably 400 parts by mass or more, per 100 parts by mass of fine particles. Furthermore, the amount of high molecular weight dispersant used in the second mixing step of this embodiment is preferably 2,000 parts by mass or less, more preferably 1,500 parts by mass or less, and even more preferably 1,000 parts by mass or less, per 100 parts by mass of fine particles. For example, the amount of high molecular weight dispersant used in the second mixing step of this embodiment is preferably 200 parts by mass or more and 2000 parts by mass or less, more preferably 300 parts by mass or more and 1500 parts by mass or less, and even more preferably 400 parts by mass or more and 1000 parts by mass or less, per 100 parts by mass of fine particles.

[0081] If the amount of high molecular weight dispersant used in the second mixing step of this embodiment is within the above preferred range, the dispersibility and dispersion stability of the fine particles can be further improved.

[0082] In the second mixing step of this embodiment, when adding optional components, the order in which each component is added is not particularly limited. All components may be added and then mixed, some components may be added sequentially while mixing, or all components may be added sequentially while mixing.

[0083] The second mixing step in the method for producing the mixed liquid of this embodiment is not particularly limited, as long as it is a general method of mixing a solid and a liquid. Specifically, mixing can be appropriately selected from known methods such as: mixing by rotating a stirring bar or impeller; mixing using a mixer, three-roll mill, kneader or bead mill, etc.; or mixing by applying ultrasonic waves.

[0084] The mixing apparatus used for the second mixing step in the method for producing the mixed liquid of this embodiment is not particularly limited, and any known mixing apparatus can be used. Specifically, an ultrasonic homogenizer (product name: UD-200, manufactured by Tommy Seiko Co., Ltd.) can be used.

[0085] The mixing temperature in the second mixing step is not particularly limited as long as the components do not degrade, and is, for example, 5 to 100°C. The mixing time in the second mixing step is not particularly limited as long as the components do not deteriorate, and can range from, for example, 1 minute to 1 hour.

[0086] The method for producing the mixed liquid according to this embodiment, as described above, comprises a first mixing step of mixing fine particles with a hydroxy compound to obtain a hydroxy compound coated with fine particles, and a second mixing step of mixing the hydroxy compound coated with fine particles with a solvent to obtain a mixed liquid in which the fine particles coated with the hydroxy compound are dispersed in the solvent. This dramatically improves the dispersibility and dispersion stability of the fine particles compared to conventional methods of simply mixing each raw material to produce a mixed liquid. This is presumed to be because, in the first mixing step, the aggregated and broken-down fine particles uniformly adhere to the surface of the hydroxy compound, and then, in the second mixing step, the hydroxy compound coated with the fine particles is mixed with the solvent, causing the aggregated fine particles to break down and the hydroxy compound to dissolve.

[0087] (mixed liquid) The mixture of this embodiment is a mixture in which fine particles coated with a hydroxy compound are dispersed in a solvent, and the hydroxy compound is one or more compounds selected from D-mannitol, α-cyclodextrin, HP-β-cyclodextrin, methyl hesperidin, and sucralose.

[0088] The mixture in this embodiment is typically a mixture produced by the method for producing the mixture described above.

[0089] The hydroxy compound, fine particles, solvent, and optional components added as needed in the mixture of this embodiment are the same as those in the method for producing the mixture described above.

[0090] The hydroxy compound content in the mixture of this embodiment is preferably 200 parts by mass or more and 2000 parts by mass or less, more preferably 500 parts by mass or more and 1500 parts by mass or less, and even more preferably 800 parts by mass or more and 1200 parts by mass or less, per 100 parts by mass of fine particles.

[0091] From the viewpoint of obtaining the effects of the present invention, the average particle diameter D50 of the fine particles in the mixed liquid of this embodiment is preferably 410 nm or less, more preferably 5 nm to 200 nm, even more preferably 30 nm to 100 nm, particularly preferably 40 nm to 95 nm, and most preferably 50 nm to 90 nm.

[0092] In this embodiment, the average particle size D50 of the fine particles in the mixed liquid is preferably within the above preferred range, and the span value of the fine particles in the mixed liquid is preferably 58 or less, more preferably 10 or less, even more preferably 9 or less, even more preferably 8 or less, even more preferably 6.5 or less, and most preferably 1 or less. Here, the "span value" is an indicator of the sharpness of the particle size distribution and can be calculated using the formula (D90-D10) / D50. A smaller span value indicates a sharper particle size distribution. D10 represents the particle size at which the cumulative volume distribution from the smallest diameter is 10%, based on the cumulative volume distribution diagram of the particle size distribution of the fine particles, and D90 represents the particle size at which the cumulative volume distribution from the smallest diameter is 90%, based on the cumulative volume distribution diagram of the particle size distribution of the fine particles. Both D10 and D90 can be measured in the same way as D50 described above.

[0093] Furthermore, if the mixed solution contains two or more types of fine particles, the average particle size D50 of all fine particles may be within the above preferred range, and the span value may also be within the above preferred range. However, it is sufficient if the average particle size D50 of at least one type of fine particle is within the above preferred range and the span value is within the above preferred range.

[0094] The mixture of this embodiment can be used as a coating agent, paint, or granulating liquid. Furthermore, by adding paste oils, waxes, etc., it can also be used as a cream (semi-solid preparation) for pharmaceutical and cosmetic purposes. The mixture of this embodiment is particularly useful as a coating agent for tablets and the like among the above.

[0095] In the mixture of this embodiment described above, the fine particles are coated with a hydroxy compound, and therefore the fine particles are well dispersed in the solvent. Therefore, for example, when the mixture of this embodiment is used as a coating agent, fine particles can be uniformly attached to the surface of the object to be coated.

[0096] Furthermore, the mixed solution of one embodiment contains a hydroxy compound and fine particles, wherein the average particle size D50 of the fine particles is 200 nm or less, and the span value of the fine particles is 9 or less.

[0097] The preferred embodiments of the hydroxy compound and fine particles in the mixture of this embodiment are as described above.

[0098] The average particle size D50 of the fine particles in the mixed liquid of this embodiment is 200 nm or less, preferably 5 nm to 200 nm, more preferably 30 nm to 100 nm, even more preferably 40 nm to 95 nm, and particularly preferably 50 nm to 90 nm.

[0099] The span value of the fine particles in the mixed liquid of this embodiment is 9 or less, preferably 8 or less, more preferably 6.5 or less, and even more preferably 1 or less.

[0100] (solid composition) Specific examples of the solid composition in this embodiment include a solid composition coated with the above-described mixed liquid and a solid composition prepared using the above-described mixed liquid. More specifically, examples of solid compositions include solid pharmaceutical compositions, solid cosmetics, and solid foods.

[0101] ≪Solid composition coated with a mixed solution≫ In this specification, "solid composition coated with a mixed liquid" specifically means a solid composition having a coating layer formed by a mixed liquid on its surface. That is, "solid composition coated with a mixed liquid" is not limited to simply applying a mixed liquid to a solid composition, drying the solvent, and forming a coating layer on the surface of the solid composition. For example, a gelling agent may be further added to the mixed liquid to form a film, and the solid composition may be coated with the film. Alternatively, capsules may be made from the mixed liquid by a rotary or seamless method, and the solid composition may be coated with these capsules.

[0102] Typical examples of solid compositions coated with a mixture include solid pharmaceutical compositions coated with a mixture and solid cosmetic compositions coated with a mixture.

[0103] • Solid pharmaceutical composition coated with a mixture The dosage form of the solid pharmaceutical composition coated with the mixture is not particularly limited and includes, for example, tablets, pills, powders, granules, etc.

[0104] The solid pharmaceutical composition contains a drug and a pharmaceutically acceptable carrier. Examples of drugs include amlodipine, ebastine, selegiline, brotizolam, ramosetron, midodrine, montelukast, azulene sulfonic acid, etizolam, bromperidol, mecobalamin, alfacalcidol, bromocriptine, pramipexole, rosuvastatin, silodosin, nifedipine, and their pharmacologically acceptable salts or solvates. Amlodipine besylate is a specific example of a pharmacologically acceptable salt of the above-mentioned drug.

[0105] There are no particular restrictions on pharmaceutically acceptable carriers, and carriers commonly used in pharmaceuticals can be used. For example, common raw materials listed in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards for Non-Pharmacopoeial Drugs, Pharmaceutical Excipients Standards 2018 (Yakuji Nippo Co., Ltd., 2018), Dictionary of Pharmaceutical Excipients 2021 (edited by the Japan Pharmaceutical Excipients Association, Yakuji Nippo Co., Ltd., 2021), Handbook of Pharmaceutical Excipients, 7th edition (Pharmaceutical Press, 2012), etc., can be used. A pharmaceutically acceptable carrier may be used alone or in combination of two or more types.

[0106] Pharmaceutically acceptable carriers include, more specifically, excipients, disintegrants, binders, fragrances, colorants, lubricants, and the like.

[0107] Examples of excipients include starches such as corn starch and potato starch, microcrystalline cellulose, talc, and mannitol.

[0108] Examples of disintegrants include partially pregelatinized starch, carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and carboxymethyl starch sodium.

[0109] Examples of binders include polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, acacia gum powder, gelatin, pullulan, carmellose sodium, ethylcellulose, and aminoalkyl metallate copolymer.

[0110] Examples of flavoring agents include aspartame, sucralose, sodium saccharin, dipotassium glycyrrhizin, stevia, thaumatin, and citric acid.

[0111] Specifically, the flavorings include menthol, peppermint micron, lemon, lemon-lime, orange, peppermint oil, and various other flavors.

[0112] Examples of coloring agents include iron oxide, tar-based dyes, turmeric extract, caramel, carotene solution, beta-carotene, copper chlorophyll, and riboflavin.

[0113] Examples of lubricants include surfactants such as magnesium stearate, polyethylene glycol, liquid paraffin, silicone, and long-chain fatty acid esters; and waxes such as beeswax, carnauba wax, and paraffin.

[0114] • Solid cosmetic coated with a mixture The form of the solid cosmetic coated with the mixture is not particularly limited and includes base makeup cosmetics such as foundation and makeup base; and point makeup cosmetics such as eyeshadow, lipstick, lip gloss, and blush.

[0115] The ingredients contained in solid cosmetics are not particularly limited, and general cosmetic ingredients can be used. For example, general ingredients listed in the Second Edition Commentary on the Standards for Cosmetic Ingredients (edited by the Japan Compendium of Cosmetic Ingredients Association, Yakuji Nippo Co., Ltd., 1984), Standards for Ingredients Outside the Standards for Cosmetic Ingredients (supervised by the Examination Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nippo Co., Ltd., 1993), Supplement to the Standards for Ingredients Outside the Standards for Cosmetic Ingredients (supervised by the Examination Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nippo Co., Ltd., 1993), Standards for Approval of Cosmetic Types (supervised by the Examination Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nippo Co., Ltd., 1993), Dictionary of Cosmetic Ingredients (Nikko Chemicals Co., Ltd., 1991), International Cosmetic Ingredient Dictionary and Handbook 2002 Ninth Edition Vol.1~4, by CTFA, etc., can be used.

[0116] A solid composition coated with the mixed solution can be coated with the mixed solution by known methods. For example, spin coating, dipping, spraying, etc., can be used.

[0117] The spin coating method is a method in which a solid composition is rotated using a spin coater or the like, and a mixed liquid is dropped or sprayed onto the rotating solid composition. The dipping method is a method of immersing a solid composition in a mixed liquid. The spray method is a method of transporting a solid composition in a predetermined direction and spraying a mixed liquid into that space.

[0118] Alternatively, gelling agents such as gelatin, agar, carrageenan, pectin, locust bean gum, xanthan gum, guar gum, gum arabic, taraya gum, karaya gum, alginic acid, tara gum, and starch may be added to the mixture, a film may be prepared from the mixture by a known method, and the solid composition may be coated with the film. Alternatively, a mixture containing a gelling agent may be used to soften the mixture using a known rotary or seamless method, thereby coating the solid composition.

[0119] For example, a fluidized bed granulator (product name: MP-01, manufactured by Powrec) and a film coating apparatus (product name: HCT-LABO, manufactured by Freund Industrial Co., Ltd.) can be used to produce a solid composition coated with a mixed liquid.

[0120] ≪Solid composition prepared from a mixed solution≫ Examples of solid compositions produced by the mixed liquid include resin films and the like. The resin film contains the mixture of the above-described embodiment, a thermoplastic resin, and other components as needed.

[0121] The thermoplastic resins include polyolefin resins such as polyethylene, polypropylene, and polybutadiene; polyester resins such as polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, and polytrimethylene terephthalate; and polyamide 6 (nylon 6), polyamide 66 (nylon 66), polyamide 11 (nylon 11), polyamide 12 (nylon 12), polyamide 46 (nylon 46), polyamide 610 (nylon 610), polytetramethylene terephthalamide (nylon 4T), polyhexamethylene terephthalamide (nylon 6T), polymetaxylene adipamide (nylon MXD6), polynonameethylene terephthalamide (nylon 9T), and polydecamethylene terephthalamide (nylon 10T). Examples include: mid-type resins; vinyl resins such as vinyl chloride, vinylidene chloride vinyl acetate, and polyvinyl alcohol; polystyrene resins such as polystyrene, acrylonitrile-styrene resin (AS resin), and acrylonitrile-butadiene-styrene resin (ABS resin); polysulfone resins such as modified polysulfone, polyethersulfone, polysulfone, and polyphenylsulfone; polyphenylene sulfides such as linear polyphenylene sulfide, crosslinked polyphenylene sulfide, and semi-crosslinked polyphenylene sulfide; polyether ketones such as polyether ketone, polyether ether ketone, and polyether ketone ketone; polycarbonate; polyphenylene ether; and polyimide resins such as thermoplastic polyimide, polyamide imide, and polyether imide.

[0122] Other components include conductive agents, ultraviolet absorbers, antioxidants, antibacterial agents, insecticides, deodorants, color inhibitors, heat stabilizers, mold release agents, antistatic agents, plasticizers, lubricants, colorants, pigments, dyes, foaming agents, antifoaming agents, viscosity modifiers, surfactants, and the like.

[0123] The resin film can be manufactured, for example, by melt-kneading the mixture of the above-described embodiment, a thermoplastic resin, and other components as needed in a melt-extruder, extruding it from the discharge port of an extruder die, and then undergoing a cooling process. Furthermore, the method for manufacturing the resin film is not particularly limited, and known methods such as the inflation method, T-die method, melt extrusion molding method, solution casting method, and calendering method can be used.

[0124] The solid composition of this embodiment described above is coated with the above-mentioned mixed liquid. Therefore, for example, if the solid composition is a solid pharmaceutical composition and the contained fine particles have a light scattering effect, the fine particles are uniformly attached to the surface of the solid pharmaceutical composition. As a result, the light scattering and absorption effect of the fine particles makes it difficult for light to reach the drug contained in the solid pharmaceutical composition, thereby improving the photostability of the solid pharmaceutical composition. [Examples]

[0125] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to the following examples.

[0126] [Preparation of the mixed liquid 1] (Examples 1-5) First mixing step: 0.1 g of ultrafine iron(III) oxide (product name: ultrafine iron(III) oxide, manufactured by Ioritech, average particle size D50: 20-40 nm) and 0.9 g of each hydroxy compound shown in Table 1 below were subjected to dry compounding treatment using a dry compounding apparatus (product name: Novilta® Mini, manufactured by Hosokawa Micron Corporation) to obtain hydroxy compounds coated with ultrafine iron(III) oxide (compounded powder A).

[0127] Second mixing step: 1 g of composite powder A, 1 g of high molecular weight dispersant A (product name: POVACOAT, manufactured by Daido Chemical Industries, Ltd., compound name: polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer), and 19 g of water were mixed using an ultrasonic homogenizer (product name: UD-200, manufactured by Tommy Seiko Co., Ltd.) to obtain the mixed solutions of Examples 1 to 5, in which ultrafine iron(III) oxide coated with a hydroxy compound was dispersed in water.

[0128] (Comparative Example 1) 0.1 g of ultrafine iron(III) oxide, 1 g of high molecular weight dispersant A, and 19 g of water were mixed using an ultrasonic homogenizer to obtain the mixture of Comparative Example 1.

[0129] (Comparative Example 2) 0.1 g of ultrafine iron(III) oxide, 0.9 g of D-mannitol (product name: PEARLITOL 50C, manufactured by Rocket Co.), 1 g of high molecular weight dispersant A, and 19 g of water were mixed in an ultrasonic homogenizer to obtain the mixture of Comparative Example 2.

[0130] (Comparative Examples 3-5) In the preparation of the mixtures of Examples 1 to 5 described above, the mixtures of Comparative Examples 3 to 5 were obtained using the same method as the preparation of the mixtures of Examples 1 to 5, except that each hydroxy compound shown in Table 1 below was replaced with each compound without a hydroxyl group shown in Table 2 below.

[0131] [Measurement of particle size of fine particles] The average particle sizes D10, D50, and D90 of the ultrafine iron(III) oxide mixtures in each example were measured using a laser diffraction particle size analyzer (product name: LMS-2000, manufactured by Seishin Corporation). The results, denoted as "D50," are shown in Tables 1, 2, 5-7. The "span value," which can be obtained using (D90-D10) / D50, was also calculated and is shown in Tables 1, 2, 5-7.

[0132] [Table 1]

[0133] [Table 2]

[0134] Tables 1 and 2 have the following meanings, respectively. The values ​​in the tables represent the amount of each ingredient (g). Ultrafine iron(III) oxide (product name: Ultrafine iron(III) oxide, manufactured by Ioritech, average particle size D50: 20-40 nm).

[0135] D-mannitol: D-mannitol (trade name: PEARLITOL 50C, manufactured by Rocket, average particle size D50: 38 μm). α-CyD: α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm). Methylhesperidin: Methylhesperidin (product name: Methylhesperidin, manufactured by Alps Foods Industry Co., Ltd., average particle size D50: 30.3 μm). HP-β-CyD: Hydroxypropylated β-cyclodextrin (Trade name: Celldex HP-β-CD, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 47 μm). Sucralose: (Product name: SU-600, manufactured by Tsuruya Chemical Industries, average particle size D50: 57 μm).

[0136] Acesulfame potassium: (Trade name: Sanet, manufactured by Mitsubishi Corporation Life Sciences, average particle size D50: 36 μm). Sodium lauryl sulfate: (Trade name: SLS, manufactured by Nikko Chemicals Co., Ltd., average particle size D50: 72 μm). Sodium triphosphate: (Product name: Sodium tripolyphosphate, manufactured by Taihei Chemical Industry Co., Ltd., average particle size D50: 30 μm).

[0137] Povacoat: (Product name: POVACOAT, manufactured by Daido Chemical Industries, Ltd., compound name: polyvinyl alcohol, acrylic acid, methyl methacrylate copolymer).

[0138] As shown in Tables 1 and 2, the mixture of the examples had a smaller average particle size D50 and span value for the ultrafine iron(III) oxide compared to the mixture of the comparative examples, confirming that the ultrafine iron(III) oxide was well dispersed.

[0139] The mixtures in Comparative Examples 1 and 2 were simply prepared by mixing each raw material with an ultrasonic homogenizer. As a result, the aggregation of ultrafine iron(III) oxide was not disrupted, and the average particle size D50 of ultrafine iron(III) oxide was large. Although the mixture in Comparative Example 3 did not contain hydroxyl compounds, thus reducing the average particle size D50 of the ultrafine iron(III) oxide, its large span value resulted in a broader particle size distribution and poorer dispersibility of the ultrafine iron(III) oxide. Comparative Examples 4 and 5 did not contain hydroxyl compounds, and therefore could not break down the aggregates of ultrafine iron(III) oxide, resulting in a large average particle size D50 of the ultrafine iron(III) oxide.

[0140] [Manufacturing of Solid Pharmaceutical Composition 1] (Examples 1a-1c) Using the mixture from Example 1, the uncoated tablets of the formulation shown in Table 3 were coated using a film coating apparatus (product name: HCT-LABO, manufactured by Freund). A solid pharmaceutical composition of Example 1a was obtained with a coating film weight of 0.54 mg, a solid pharmaceutical composition of Example 1b was obtained with a coating film weight of 2 mg, and a solid pharmaceutical composition of Example 1c was obtained with a coating film weight of 5.4 mg.

[0141] (Comparative Examples 2a-2c) Using the mixture from Comparative Example 2, the uncoated tablets with the formulations shown in Table 3 were coated using the film coating apparatus described above. A solid pharmaceutical composition of Comparative Example 2a was obtained with a coating film weight of 0.54 mg, a solid pharmaceutical composition of Comparative Example 2b was obtained with a coating film weight of 2 mg, and a solid pharmaceutical composition of Comparative Example 2c was obtained with a coating film weight of 5.4 mg.

[0142] [Table 3]

[0143] [Evaluation of photostability 1] The photostability of each example of solid pharmaceutical composition was evaluated using the following method, and the results are shown in Figure 1. Each example of a solid pharmaceutical composition was placed in a photostabilization apparatus and exposed to light with a total illuminance of 1,200,000 lux·hr at 25°C using a xenon lamp as the light source. After that, each example of a solid pharmaceutical composition was removed from the test apparatus. Subsequently, a mixture of potassium dihydrogen phosphate aqueous solution (4.1→1000) and acetonitrile (volume ratio 4:1) was added to each example of a solid pharmaceutical composition to dissolve the contents and prepare the respective sample solutions.

[0144] The related substance (decomposition product I) represented by the following chemical formula (1) in each sample solution was measured by HPLC.

[0145] [ka]

[0146] The conditions for the HPLC method are as follows: <Measurement Conditions> Detector: UV absorbance spectrophotometer (measurement wavelength: 237 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with 3 μm octylsilylated silica gel for liquid chromatography. Mobile phase flow rate: 1.0 mL per minute Sample injection volume: 10 μL Mobile phase: Consists of solutions A and B. Solution A: Potassium dihydrogen phosphate aqueous solution (4.1 → 1000) Solution B: Acetonitrile mixture Mobile phase delivery: The concentration gradient was controlled by varying the mixing ratio of solution A and solution B as shown in Table 4.

[0147] [Table 4]

[0148] As shown in Figure 1, the solid pharmaceutical composition of the example was found to have a lower amount of degradation product I and better photostability compared to the solid pharmaceutical composition of the comparative example.

[0149] [Manufacturing of Solid Pharmaceutical Compositions 2] (Example 2a) Using the mixture from Example 2, the uncoated tablets of the formulation shown in Table 3 were coated using a film coating apparatus (product name: HCT-LABO, manufactured by Freund). A solid pharmaceutical composition of Example 2a was obtained, in which the weight of the coating film was 2 mg.

[0150] (Comparative Example 6a) 0.1 g of iron(III) oxide (product name: iron(III) oxide, manufactured by Kiseki Kasei Co., Ltd., average particle size D50: 460 nm), 0.9 g of α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm), 1 g of high molecular weight dispersant A, and 19 g of water were mixed in an ultrasonic homogenizer to obtain the mixture of Comparative Example 6. Using the obtained mixture, the uncoated tablets of the formulation shown in Table 3 were coated using a film coating apparatus (product name: HCT-LABO, manufactured by Freund). A solid pharmaceutical composition of Comparative Example 6a was obtained, in which the weight of the coating film was 2 mg.

[0151] [Evaluation of photostability 2] Using the same method as described in [Evaluation of Photostability 1] above, related substances (decomposition product I) were measured by HPLC, and the photostability of the solid pharmaceutical compositions of Example 2a and Comparative Example 6a described above was evaluated. Furthermore, evaluations were conducted not only after exposure to a total illuminance of 1.2 million lux·hr, similar to [Evaluation of Photostability 1], but also after exposure to a total illuminance of 300,000 lux·hr and 600,000 lux·hr. The results are shown in Figure 2.

[0152] As shown in Figure 2, the solid pharmaceutical composition of the example was found to have a lower amount of degradation product I and better photostability compared to the solid pharmaceutical composition of the comparative example.

[0153] From the above, it was confirmed that the method for producing the mixture in the examples yields a mixture with good dispersibility and dispersion stability of fine particles. Furthermore, it was confirmed that the solid pharmaceutical composition coated with the mixture exhibits good photostability.

[0154] [Production of the mixed solution 2] (Examples 6-8) In the above-described [Production of Mixture 1], the mixtures of Examples 6 to 8 were obtained in the same manner as in the example of [Production of Mixture 1], except that the high molecular weight dispersant A used in the second mixing step was changed to the high molecular weight dispersant shown in Table 5.

[0155] [Table 5]

[0156] In Table 5, each term has the following meaning. The values ​​in the table represent the amount of each ingredient (g). Ultrafine iron(III) oxide (product name: Ultrafine iron(III) oxide, manufactured by Ioritech, average particle size D50: 20-40 nm).

[0157] α-CyD: α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm). Sucralose: (Product name: J-600, manufactured by Tsuruya Chemical Industries, average particle size D50: 134 μm).

[0158] HPC-SSL: Hydroxypropylcellulose (Product name: NISSO HPC-SSL, manufactured by Nippon Soda Co., Ltd.). HPMC: Hydroxypropyl methylcellulose (product name: TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.). PVP K25: Polyvinylpyrrolidone (product name: Coridon 25, manufactured by BASF).

[0159] As shown in Tables 1 and 5, a comparison between the mixture of Example 2 and the mixtures of Examples 6 and 7, and a comparison between the mixture of Example 5 and the mixture of Example 8, indicates that using any of the high molecular weight dispersants made it possible to reduce the average particle size D50 and span value of the ultrafine iron(III) oxide, and to disperse the ultrafine iron(III) oxide well.

[0160] [Production of the mixed solution 3] (Example 9) In the example of [Production of Mixture 1] described above, the mixture of Example 9 was produced using the same manufacturing method as in the example of [Production of Mixture 1], except that the hydroxy compound used in the first mixing step was changed to the hydroxy compound shown in Table 6 below.

[0161] [Table 6]

[0162] In Table 6, each term has the following meaning. The values ​​in the table represent the amount of each ingredient (g). Ultrafine iron(III) oxide (product name: Ultrafine iron(III) oxide, manufactured by Ioritech, average particle size D50: 20-40 nm).

[0163] Sucralose 134μm: (Product name: J-600, manufactured by Tsuruya Chemical Industries, average particle size D50: 134μm).

[0164] Povacoat: (Product name: POVACOAT, manufactured by Daido Chemical Industries, Ltd., compound name: polyvinyl alcohol, acrylic acid, methyl methacrylate copolymer)

[0165] As shown in Tables 1 and 6, a comparison of the mixture from Example 5 and the mixture from Example 9 revealed that the average particle size D50 of sucralose affects the average particle size D50 and span value of the ultrafine iron(III) oxide. Specifically, it was found that using sucralose with an average particle size D50 of 134 μm resulted in better dispersion of the ultrafine iron(III) oxide than using sucralose with an average particle size D50 of 57 μm.

[0166] [Production of the mixed solution 4] (Example 10) In the method for producing the mixed solution of Example 2 described above in [Production of Mixed Solution 1], the mixed solution of Example 10 was obtained by the same method as the method for producing the mixed solution of Example 2, except that the ultrafine iron(III) oxide was replaced with yellow iron(III) oxide (product name: yellow iron(III) oxide, manufactured by Kiseki Kasei Co., Ltd., average particle size D50: 100-500 nm).

[0167] (Comparative Example 7) 0.1 g of yellow iron(III) oxide (product name: Yellow Iron(III) oxide, manufactured by Kiseki Kasei Co., Ltd., average particle size D50: 100-500 nm), 0.9 g of α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm), 1 g of high molecular weight dispersant A, and 19 g of water were mixed in an ultrasonic homogenizer to obtain the mixture of Comparative Example 7.

[0168] [Table 7]

[0169] In Table 7, each term has the following meaning. The values ​​in the table represent the amount (g) of each ingredient. Yellow iron(III) oxide (product name: Yellow Iron(III) oxide, manufactured by Kiseki Kasei Co., Ltd., average particle size D50: 300 nm). α-CyD: α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm). Povacoat: (Product name: POVACOAT, manufactured by Daido Chemical Industries, Ltd., compound name: polyvinyl alcohol, acrylic acid, methyl methacrylate copolymer)

[0170] As shown in Table 7, the mixture of the examples had a smaller average particle size D50 and span value of yellow iron(III) oxide compared to the mixture of the comparative examples, confirming that the yellow iron(III) oxide was well dispersed.

[0171] [5. Manufacturing of the mixed liquid] (Example 11) First mixing step: 0.1 g of titanium dioxide (product name: Titanium Dioxide FG, manufactured by Freund Industrial Co., Ltd., average particle size D50: 550 nm) and 0.9 g of α-CyD: α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm) were subjected to dry compounding treatment using a dry compounding apparatus (product name: Novilta® Mini, manufactured by Hosokawa Micron Corporation) to obtain α-CyD coated with titanium dioxide (compounded powder B).

[0172] Second mixing step: 1 g of composite powder B, 1 g of high molecular weight dispersant A (product name: POVACOAT, manufactured by Daido Chemical Industries, Ltd., compound name: polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer), and 19 g of water were mixed using an ultrasonic homogenizer (product name: UD-200, manufactured by Tommy Seiko Co., Ltd.) to obtain the mixed solution of Example 11, in which titanium dioxide coated with α-CyD was dispersed in water.

[0173] (Comparative Example 8) 0.1 g of titanium dioxide (product name: Titanium Dioxide FG, manufactured by Freund Industrial Co., Ltd., average particle size D50: 550 nm), 0.9 g of α-CyD:α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm), 1 g of high molecular weight dispersant A, and 19 g of water were mixed in an ultrasonic homogenizer to obtain the mixture of Comparative Example 8.

[0174] [Measurement of particle size of fine particles] The average particle sizes D10, D50, and D90 of titanium dioxide in the mixed solutions of each example were measured using a laser diffraction particle size analyzer (product name: LMS-2000, manufactured by Seishin Corporation). The results are shown in Table 8 as "D50". The "span value" obtainable from (D90-D10) / D50 was also calculated and is shown in Table 8.

[0175] [Table 8]

[0176] As shown in Table 8, the mixture of the examples had a smaller average particle size D50 and span value of titanium dioxide compared to the mixture of the comparative examples, confirming that the titanium dioxide was well dispersed.

[0177] In Comparative Example 8, the mixture was simply prepared by mixing each raw material with an ultrasonic homogenizer. As a result, the aggregation of titanium dioxide was not disrupted, and the average particle size D50 of titanium dioxide was large.

[0178] [6. Manufacturing of the mixed solution] (Examples 12-16) The mixtures of Examples 12 to 16 were obtained in the same manner as the mixture of Example 2, except that the content of ultrafine iron(III) oxide (product name: ultrafine iron(III) oxide, manufactured by Ioritech, average particle size D50: 20-40 nm), α-CyD: α-cyclodextrin (product name: Celldex A-100, manufactured by Nippon Shokuhin Kako Co., Ltd., average particle size D50: 36 μm), Povacoat: (product name: POVACOAT, manufactured by Daido Kasei Kogyo Co., Ltd., compound name: polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer), and water was changed as shown in Table 9.

[0179] [Measurement of particle size of fine particles] The average particle sizes D10, D50, and D90 of the ultrafine iron(III) oxide mixtures in each example were measured using a laser diffraction particle size analyzer (product name: LMS-2000, manufactured by Seishin Corporation). The results are shown in Table 9 as "D50". The "span value" obtainable from (D90-D10) / D50 was also calculated and is shown in Table 9. Furthermore, for easier comparison, the mixture of Example 2 shown in Table 1 above is shown again in Table 9.

[0180] [Table 9]

[0181] As shown in Table 9, even when the content of each component was changed, the average particle size D50 and span value of the ultrafine iron(III) oxide in the mixture of the examples were small, confirming that the ultrafine iron(III) oxide was well dispersed. Furthermore, among these, the mixtures of Examples 2, 12, and 15 showed particularly small average particle sizes D50 and span values ​​for ultrafine iron(III) oxide, confirming that the ultrafine iron(III) oxide was better dispersed.

[0182] While preferred embodiments of the present invention have been described above, the present invention is not limited to these embodiments. Additions, omissions, substitutions, and other modifications are possible without departing from the spirit of the invention. The present invention is not limited by the foregoing description, but only by the scope of the appended claims.

Claims

1. A first mixing step involves mixing fine particles with a hydroxy compound to obtain a hydroxy compound coated with fine particles, The process includes a second mixing step of mixing a hydroxy compound coated with the aforementioned fine particles with a solvent and a high molecular weight dispersant to obtain a mixed solution in which the fine particles coated with the hydroxy compound are dispersed in the solvent. The hydroxy compound is one or more compounds selected from monosaccharides, oligosaccharides, 2-hydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin), methylhesperidin, and salts of methylhesperidin. The hydroxy equivalent (molecular weight of the hydroxy compound / number of hydroxyl groups in the hydroxy compound) of the hydroxy compound is 10 or more and 500 or less. A method for producing a mixed liquid, wherein the average particle size D50 of the fine particles in the first mixing step is 1 nm or more and 900 nm or less, and the average particle size D50 of the hydroxy compound is 30 μm or more and 300 μm or less.

2. The method for producing the mixture according to claim 1, wherein the hydroxy compound is one or more compounds selected from D-mannitol, α-cyclodextrin, HP-β-cyclodextrin, methylhesperidin, and sucralose.

3. The method for producing a mixed liquid according to claim 1 or 2, wherein the fine particles are inorganic fine particles.

4. The method for producing the mixed liquid according to claim 1 or 2, wherein the fine particles are a metal oxide.

5. The method for producing a mixed liquid according to claim 1 or 2, wherein the average particle size D50 of the fine particles in the second mixing step is 410 nm or less.

6. The method for producing a mixed liquid according to claim 1 or 2, wherein in the first mixing step, the amount of the hydroxy compound used is 200 parts by mass or more and 2,500 parts by mass or less per 100 parts by mass of the fine particles.

7. It contains a hydroxy compound, fine particles, and a high molecular weight dispersant. The hydroxy compound is one or more compounds selected from monosaccharides, oligosaccharides, 2-hydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin), methylhesperidin, and salts of methylhesperidin. The hydroxy equivalent (molecular weight of the hydroxy compound / number of hydroxyl groups in the hydroxy compound) of the hydroxy compound is 10 or more and 500 or less. The average particle size D50 of the aforementioned fine particles is 200 nm or less. A coating agent or granulating liquid in which the span value of the fine particles is 9 or less.

8. It contains a hydroxy compound, fine particles, and a high molecular weight dispersant. The hydroxy compound is one or more compounds selected from monosaccharides, oligosaccharides, 2-hydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin), methylhesperidin, and salts of methylhesperidin. The hydroxy equivalent (molecular weight of the hydroxy compound / number of hydroxyl groups in the hydroxy compound) of the hydroxy compound is 10 or more and 500 or less. The average particle size D50 of the aforementioned fine particles is 200 nm or less. A coating agent for tablet coating, wherein the span value of the fine particles is 9 or less.

9. A solid composition coated with the coating agent or granulating liquid described in claim 7.

10. A solid pharmaceutical composition coated with the coating agent or granulating solution described in claim 7.

11. This is a mixture in which fine particles coated with a hydroxy compound are dispersed in a solvent and a high molecular weight dispersant. The hydroxy compound is one or more compounds selected from D-mannitol, α-cyclodextrin, HP-β-cyclodextrin, methylhesperidin, and sucralose. The aforementioned fine particles are iron oxide or titanium dioxide, and the coating agent or granulating liquid is used.

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