Composition

Abstract

Provided is a composition with which it is possible to enhance the percutaneous absorption of a crystalline water-soluble drug without temporarily irritating the skin as with an amphoteric surfactant.　The composition of the present disclosure contains water, a crystalline water-soluble drug, and porous particles, the composition being obtained by mixing the water, the crystalline water-soluble drug, and the porous particles to prepare a mixture, and the oil content of the mixture being 50 mass% or below relative to water.

Description

composition

[0001] The present disclosure relates to compositions.

[0002] BACKGROUND ART Various compositions are used in the fields of medicines, cosmetics, and the like.

[0003] Patent Document 1 discloses an external skin preparation that is composed of an ionic water-soluble drug and an amphoteric surfactant and that enhances the transdermal absorbability of the ionic water-soluble drug.

[0004] Patent Document 2 discloses a pharmaceutical composition containing mesoporous silica for sustained release, which encapsulates within its mesopores a physiologically active substance bound to a cell membrane-permeable vector.

[0005] JP 61-260027 A JP 2009-013142 A

[0006] For example, the stratum corneum, located at the outermost layer of the skin, has a barrier function that prevents foreign substances from entering from the outside, making it difficult for active ingredients applied to the skin to penetrate into the interior of the skin. Therefore, simply applying a drug to the skin tends to leave the drug's effects on the surface of the skin, and only exerts a short-term effect.

[0007] The technology described in Patent Document 1 uses an amphoteric surfactant to enhance the transdermal absorbability of ionic water-soluble drugs. Amphoteric surfactants are known to have the effect of temporarily disrupting the barrier properties of the stratum corneum, thereby weakening the barrier properties of the stratum corneum and enhancing the transdermal absorbability of ionic water-soluble drugs. However, since amphoteric surfactants cause temporary irritation to the skin, it has been difficult to employ such a technology when, for example, the skin of the subject to whom the drug is to be applied is sensitive.

[0008] In recent years, crystalline water-soluble drugs have been used, for example, as skin whitening agents. When a composition obtained by dissolving such drugs in water is applied to the skin, the drug crystallizes on the skin surface as the water evaporates, preventing the drug from penetrating into the skin. Therefore, among drugs, crystalline water-soluble drugs are drugs that are even more difficult to penetrate into the skin.

[0009] The technology described in Patent Document 2 is a technology for sustained release of a physiologically active substance bound to a cell membrane-permeable vector that easily permeates the cell membrane, and is completely opposite to the technology disclosed herein, which enhances the transdermal absorbability of crystalline water-soluble drugs and the like that are difficult to penetrate into the skin.

[0010] Therefore, an object of the present disclosure is to provide a composition that can enhance the transdermal absorption of crystalline water-soluble drugs without causing temporary irritation to the skin, as occurs with amphoteric surfactants.

[0011] Aspect 1: A composition comprising water, a crystalline water-soluble drug, and porous particles, obtained by mixing water, the crystalline water-soluble drug, and the porous particles to prepare a mixture, wherein the oil content in the mixture is 50% by mass or less relative to the water. Aspect 2: The composition according to Aspect 1, wherein the mass ratio of the porous particles to the crystalline water-soluble drug is 0.002 or more. Aspect 3: The composition according to Aspect 1 or 2, wherein the porous particles are spherical particles. Aspect 4: The porous particles are 100 ml or less. ２ The composition according to any one of Aspects 1 to 3, wherein the crystalline water-soluble drug is at least one selected from the group consisting of 4-methoxysalicylic acid, tranexamic acid, L-ascorbic acid, 4-methoxysalicylate, tranexamate, L-ascorbate, glycylglycine, nicotinamide, arbutin, L-ascorbic acid glucoside, 1-(2-hydroxyethyl)-2-imidazolidinone, adenosine, and a pyrimidylpyrazole compound represented by the following formula 1 and a salt thereof: In formula 1, R １ , R ３ , R ４ and R ６ are each independently an alkyl group having 1 to 3 carbon atoms, and R ２ and R ５are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. Aspect 6: The composition according to any one of Aspects 1 to 5, which is used as a transdermal absorption enhancer for a crystalline water-soluble drug. Aspect 7: A method for producing a composition, comprising mixing water, a crystalline water-soluble drug, and porous particles to prepare a mixture, wherein the oil content in the mixture is 50% by mass or less relative to the water. Aspect 8: The method according to Aspect 7, comprising mixing water, a crystalline water-soluble drug, and porous particles to prepare an aqueous phase part that is a mixture, preparing an oil phase part that contains an oil, and adding the oil phase part to the aqueous phase part to obtain an oil-in-water emulsion composition. Aspect 9: A cosmetic comprising the composition according to any one of Aspects 1 to 6.

[0012] According to the present disclosure, it is possible to provide a composition that can enhance the transdermal absorbability of a crystalline water-soluble drug without causing temporary irritation to the skin, as occurs with amphoteric surfactants.

[0013] Figure 1 is a diagram simulating the behavior of a crystalline water-soluble drug when a composition containing a crystalline water-soluble drug and water but not containing porous particles, and a composition according to one embodiment of the present disclosure (a single aqueous phase composition) are applied to the skin. Figure 2 is a diagram simulating the behavior of a crystalline water-soluble drug when a composition containing a crystalline water-soluble drug and water but not containing porous particles, and a composition according to another embodiment of the present disclosure (an oil-in-water emulsion composition) are applied to the skin. Figure 3 is a diagram simulating the behavior of a crystalline water-soluble drug when a composition containing a crystalline water-soluble drug and water but not containing porous particles, and a composition prepared by a method different from that of the present disclosure (an oil-in-water emulsion composition) are applied to the skin. Figure 4 is a graph showing the cumulative permeation amount of crystalline water-soluble drugs (potassium 4-methoxysalicylate and tranexamic acid) into a simulated skin membrane depending on the composition preparation method. FIG. 5 is a graph showing the amount of crystalline water-soluble drug (potassium 4-methoxysalicylate and tranexamic acid) adsorbed through the membrane 24 hours after applying compositions manufactured by different methods to a simulated skin membrane. FIG. 6 is a graph showing the cumulative permeation amount of a crystalline water-soluble drug (potassium 4-methoxysalicylate) into a simulated skin membrane when a composition containing no porous particles or a composition containing various porous particles is used. FIG. 7 is a graph showing the amount of crystalline water-soluble drug (potassium 4-methoxysalicylate) adsorbed through the membrane 24 hours after applying compositions containing no porous particles or a composition containing various porous particles to a simulated skin membrane. FIG. 8 is a graph showing the cumulative permeation amount of a crystalline water-soluble drug (potassium 4-methoxysalicylate) into a simulated skin membrane when compositions containing different porous particle contents are used. FIG. 9 is a graph showing the amount of crystalline water-soluble drug (potassium 4-methoxysalicylate) adsorbed through the membrane 24 hours after applying compositions containing different porous particle contents to a simulated skin membrane. Fig. 10 is a graph showing the cumulative permeation amount of a crystalline water-soluble drug (potassium 4-methoxysalicylate) into a simulated skin membrane when a composition containing or not containing a thickener was used. Fig. 11 is a graph showing the membrane adsorption amount of a crystalline water-soluble drug (potassium 4-methoxysalicylate) 24 hours after a composition containing or not containing a thickener was applied to a simulated skin membrane.Figure 12 is a graph showing the cumulative permeation amount of a crystalline water-soluble drug (nicotinamide) into a simulated skin membrane when a composition containing or not containing porous particles is used. Figure 13 is a graph showing the membrane adsorption amount of a crystalline water-soluble drug (nicotinamide) 24 hours after applying a composition containing or not containing porous particles to a simulated skin membrane. Figure 14 is a graph showing the sorption amount of a crystalline water-soluble drug (glycylglycine) in two layers of human skin when a composition containing or not containing porous particles is used. Figure 15 is a graph showing the total sorption amount of a crystalline water-soluble drug (glycylglycine) in six layers of human skin when a composition containing or not containing porous particles is used.

[0014] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present disclosure is not limited to the following embodiments, and various modifications can be made within the scope of the present invention.

[0015] The composition of the present disclosure is a composition comprising water, a crystalline water-soluble drug, and porous particles. This composition can be obtained by mixing water, the crystalline water-soluble drug, and the porous particles to prepare a mixture, and the oil content in the mixture is 50% by mass or less relative to the water.

[0016] Without being limited by theory, the principle of action by which the composition of the present disclosure can enhance the transdermal absorbability of crystalline water-soluble drugs without causing temporary irritation to the skin as occurs with amphoteric surfactants is believed to be as follows.

[0017] For example, when a composition prepared by simply dissolving a crystalline water-soluble drug in water is applied to the skin as shown on the left side of Figure 1, the dissolved crystalline water-soluble drug 11 can penetrate the skin to some extent. However, as the water 10 evaporates, the dissolved crystalline water-soluble drug 11 crystallizes. The crystallized crystalline water-soluble drug 12 cannot penetrate the skin and remains on the surface of the skin, so the drug's effects cannot be fully provided to the skin.

[0018] Furthermore, as described in Patent Document 2, it is known that when a drug that easily penetrates the skin is encapsulated in the pores of mesoporous silica, the drug exhibits sustained release properties and its ability to promote skin penetration is reduced. Therefore, it is generally believed that when a crystalline water-soluble drug that does not easily penetrate the skin is held in the pores of porous particles, the drug is difficult to release from the porous particles, and transdermal absorbability is actually worsened.

[0019] In light of this common general knowledge, the present inventors have discovered that when a composition is prepared by mixing water, a crystalline water-soluble drug, and porous particles with an oil content within a predetermined range, the dissolved crystalline water-soluble drug is more likely to be retained within the pores of the porous particles, and the transdermal absorbability of the drug is improved without deterioration. Here, the term "oil content within a predetermined range" also includes cases where no oil is included.

[0020] In the composition of the present disclosure, it is believed that the dissolved crystalline water-soluble drug is partially or entirely retained within the pores of the porous particles. As shown on the right side of Figure 1, when the composition in this state is applied to the skin, the porous particles 13 are positioned on the skin surface, covering the skin surface. As a result, it is believed that the porous particles 13 act as a barrier to water evaporation, thereby reducing or inhibiting evaporation of water 10 from the composition. This makes it easier for the crystalline water-soluble drug to remain dissolved, extending the drug penetration time into the skin, and therefore improving the transdermal absorption of the crystalline water-soluble drug compared to compositions that do not contain porous particles. Furthermore, even if the water around the porous particles evaporates, the pores of the porous particles are closed off from the external environment, creating an environment where water evaporation is more difficult, making it easier for the crystalline water-soluble drug to remain dissolved, and therefore the drug is believed to continue to be released from the porous particles without crystallizing.

[0021] Furthermore, crystalline water-soluble drugs generally crystallize on the surface of the skin as shown in Figure 1 when the water in the composition evaporates and the solubility reaches or exceeds the saturated solubility. The use of porous particles, due to some interaction with the drug, can reduce or delay such crystallization of crystalline water-soluble drugs on the skin surface compared to when porous particles are not used. It is believed that the effect of porous particles in reducing or delaying such crystallization also significantly contributes to transdermal absorbability.

[0022] The porous particles simply adhere to the skin surface and do not damage the stratum corneum of the skin to improve drug permeability, as do amphoteric surfactants. Therefore, it is believed that the composition of the present disclosure can be suitably used even if the subject to whom the drug is applied has sensitive skin.

[0023] Composition The composition of the present disclosure contains water, a crystalline water-soluble drug, and porous particles.

[0024] <Water> The water is not particularly limited as long as it can dissolve the crystalline water-soluble drug. For example, water used in cosmetics or quasi-drugs can be used. Examples of such water include ion-exchanged water, purified water, distilled water, ultrapure water, and tap water.

[0025] The amount of water is not particularly limited and can be appropriately adjusted depending on the formulation used in the composition (for example, a single aqueous phase, an oil-in-water emulsion). Specifically, the amount of water can be, for example, 40% by mass or more, 45% by mass or more, 50% by mass or more, 55% by mass or more, 60% by mass or more, 65% by mass or more, 70% by mass or more, 75% by mass or more, or 80% by mass or more, or less than 100% by mass, 99% by mass or less, 98% by mass or less, 95% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, or 60% by mass or less, based on the total amount of the composition.

[0026] <Crystalline Water-Soluble Drug> The crystalline water-soluble drug that can be incorporated into the composition of the present disclosure is not particularly limited. For example, such a crystalline water-soluble drug can be an ionic crystalline water-soluble drug. The crystalline water-soluble drug can be used alone or in combination of two or more kinds.

[0027] Specific examples of such crystalline water-soluble drugs include at least one selected from the group consisting of 4-methoxysalicylic acid, tranexamic acid, L-ascorbic acid, 4-methoxysalicylate, tranexamate, L-ascorbate, glycylglycine, nicotinamide, arbutin, L-ascorbic acid glucoside, 1-(2-hydroxyethyl)-2-imidazolidinone, adenosine, and pyrimidylpyrazole compounds represented by the following formula 1 and salts thereof. Here, the form of the salt is not particularly limited, and examples thereof include alkali metal salts (e.g., sodium salt, potassium salt, lithium salt), alkaline earth metal salts (e.g., magnesium salt, calcium salt), earth metal salts (e.g., aluminum salt), ammonium salt, amino acid salt, sulfate, hydrochloride, etc. In formula 1, R １ , R ３ , R ４ and R ６ are each independently an alkyl group having 1 to 3 carbon atoms, and R ２ and R ５ are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

[0028] Among the above-mentioned crystalline water-soluble drugs, 4-methoxysalicylic acid, 4-methoxysalicylate, glycylglycine, and nicotinamide (niacinamide) can be mixed with porous particles by the method of the present disclosure to more suitably enhance transdermal absorbability.

[0029] In some embodiments, the crystalline water-soluble drug that has penetrated into the skin via the composition of the present disclosure can remain in any of the stratum corneum, epidermis, and dermis that make up the skin for a long period of time (e.g., 24 hours or more), thereby improving the medicinal effects (e.g., moisturizing effect, whitening effect) of the drug on the skin.

[0030] The amount of the crystalline water-soluble drug is not particularly limited, and can be, for example, 0.01% by mass or more, 0.03% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.3% by mass or more, 0.5% by mass or more, 0.7% by mass or more, or 1.0% by mass or more relative to the total amount of the composition, and can be 10% by mass or less, 8.0% by mass or less, 5.0% by mass or less, or 3.0% by mass or less.

[0031] <Porous Particles> The porous particles that can be incorporated into the composition of the present disclosure are not particularly limited as long as they have pores at least on the surface of the particles. The porous particles may be solid particles or hollow particles. In the case of hollow particles, the pores on the particle surface may or may not be connected to the hollow portion inside the particle. The porous particles can be used alone or in combination of two or more types.

[0032] The shape of the porous particles is not particularly limited, and examples thereof include spherical, plate-like (leaf-like), needle-like, and polyhedral (e.g., tetrahedral, hexahedral) shapes. Among these, from the viewpoint of transdermal absorbability, spherical particles are preferred. Here, "spherical" includes true spheres, nearly spherical, and spheroids, and even if the surface is uneven, the particle falls under the "spherical" category in the present disclosure as long as the overall shape of the particle can be determined to be spherical. Specifically, the "spherical particles" in the present disclosure are not limited to true spheres, but may include particles whose minor axis / major axis ratio (ellipticity) is 1.5 or less, 1.2 or less, or 1.1 or less.

[0033] From the viewpoint of transdermal absorption, the porous particles are ２ / g or more, a pore volume of 0.1 mL / g or more, a pore diameter of 1 nm or more, a water absorption of 50 mL / 100 g or more, and an oil absorption of 50 mL / 100 g or more.

[0034] The specific surface area of ​​the porous particles is 100 m ２ / g or more, 150m ２ / g or more, 200m ２ / g or more, 250m ２ / g or more, 300m ２ / g or more, 350m ２ / g or more, 400m ２ / g or more, 450m ２ / g or more, 500m ２ / g or more, 550m ２ / g or more, 600m ２ / g or more, 620m ２ / g or more, 650m ２ / g or more, 670m ２ / g or more, or 700m ２ The upper limit of the specific surface area is not particularly limited, and can be, for example, 1,000 m ２ / g or less, 900m ２ / g or less, 800m ２ / g or less, or 750m ２ The specific surface area of ​​the porous particles can be measured by the BET method (nitrogen adsorption method).

[0035] The pore volume of the porous particles can be 0.1 mL / g or more, 0.5 mL / g or more, 1.0 mL / g or more, more than 1.0 mL / g, 1.2 mL / g or more, or 1.5 mL / g or more. There is no particular upper limit to the pore volume, and it can be, for example, 5.0 mL / g or less, 4.0 mL / g or less, 3.0 mL / g or less, or 2.5 mL / g or less. Here, the pore volume of the porous particles is measured by a gas adsorption method.

[0036] The pore diameter of the porous particles can be 1 nm or more, 3 nm or more, 5 nm or more, more than 5 nm, or 7 nm or more. There is no particular upper limit to the pore diameter, and the pore diameter can be, for example, 30 nm or less, 25 nm or less, 20 nm or less, or 15 nm or less. Here, the pore diameter of the porous particles is measured by a gas adsorption method.

[0037] The water absorption capacity of the porous particles can be 50 mL / 100 g or more, 70 mL / 100 g or more, 100 mL / 100 g or more, 150 mL / 100 g or more, 170 mL / 100 g or more, or 200 mL / 100 g or more. There is no particular upper limit to the water absorption capacity, and the water absorption capacity can be, for example, 500 mL / 100 g or less, 450 mL / 100 g or less, 400 mL / 100 g or less, 350 mL / 100 g or less, or 300 mL / 100 g or less. Here, the water absorption capacity of the porous particles can be measured in accordance with JIS K5101-13-2, using distilled water instead of boiled linseed oil.

[0038] The oil absorption of the porous particles can be 50 mL / 100 g or more, 100 mL / 100 g or more, 150 mL / 100 g or more, more than 150 mL / 100 g, 170 mL / 100 g or more, or 200 mL / 100 g or more. There is no particular upper limit to the oil absorption, and it can be, for example, 500 mL / 100 g or less, 450 mL / 100 g or less, 400 mL / 100 g or less, 350 mL / 100 g or less, or 300 mL / 100 g or less. Here, the oil absorption of the porous particles can be measured in accordance with JIS K5101-13-2.

[0039] The size (average particle diameter) of the porous particles can be, for example, 0.5 μm or more, 1.0 μm or more, 2.0 μm or more, 3.0 μm or more, 4.0 μm or more, or 5.0 μm or more, and can be 50 μm or less, 40 μm or less, 30 μm or less, 20 μm or less, 10 μm or less, or 8.0 μm or less. The average particle diameter of the porous particles can be obtained as a median diameter (D50) measured by laser diffraction. In addition to improving the transdermal absorbability of crystalline water-soluble drugs, the porous particles can also improve the whiteness, i.e., the whitening effect, when applied to the skin. From the viewpoint of the transdermal absorbability and whitening effect of the crystalline water-soluble drug, the average particle diameter of the porous particles is preferably 1.0 μm or more, more preferably 3.0 μm or more, and particularly preferably 5.0 μm or more. The composition of the present disclosure, which can also exhibit a whitening effect, can be suitably used as a whitening cosmetic.

[0040] The type of porous particles is not particularly limited, and examples thereof include inorganic particles, organic particles, and composite particles thereof. The porous particles can be used alone or in combination. Among them, inorganic particles are preferred from the viewpoint of transdermal absorbability of crystalline water-soluble drugs.

[0041] Examples of inorganic particles include silica-based particles, boron nitride particles, magnesium oxide particles, sericite particles, mica particles, barium sulfate particles, talc particles, and calcium carbonate particles. Among these, silica-based particles are preferred from the viewpoint of transdermal absorption of crystalline water-soluble drugs. Here, in the present disclosure, "silica-based particles" refers to particles formed using a material containing silica. Specifically, examples of silica-based particles include silica-containing composite oxide particles (e.g., silica alumina particles) containing silica as a constituent unit, in addition to silica particles. Among silica-based particles, silica particles are preferred from the viewpoint of transdermal absorption of crystalline water-soluble drugs, and silica particles other than mesoporous silica (e.g., spherical silica particles) are more preferred. The inorganic particles can be used alone or in combination of two or more types.

[0042] Examples of organic particles include biodegradable particles and non-biodegradable particles. The organic particles can be used alone or in combination of two or more kinds.

[0043] Examples of biodegradable particles include cellulose-based particles, polylactic acid particles, polycaprolactone particles, and polyhydroxybutyric acid particles.

[0044] Examples of cellulose-based particles include cellulose particles, cellulose ester particles (e.g., cellulose acetate, cellulose propionate, cellulose butyrate, cellulose sulfate, cellulose nitrocellulose, cellulose phosphate), cellulose ether particles (e.g., methyl cellulose, ethyl cellulose, carboxymethyl cellulose), and the like.

[0045] Examples of non-biodegradable particles include acrylic particles, polyolefin particles (eg, polyethylene particles), styrene particles, polyamide particles, silicone particles, and polyurethane particles.

[0046] The amount of the porous particles may be, for example, 0.5% by mass or more, 1.0% by mass or more, 1.5% by mass or more, 2.0% by mass or more, or 2.5% by mass or more, relative to the total amount of the composition. There is no particular upper limit to the amount, and the amount may be, for example, 20% by mass or less, 15% by mass or less, 10% by mass or less, 8.0% by mass or less, or 5.0% by mass or less.

[0047] The porous particles retain the dissolved crystalline water-soluble drug in their pores, and when the composition is applied to the skin, they can release the drug from the pores, and can reduce or delay the crystallization of the crystalline water-soluble drug. From the viewpoint of optimally exhibiting the retention and release performance of the dissolved crystalline water-soluble drug and the effect of reducing or delaying the crystallization of the crystalline water-soluble drug, the mass ratio of the porous particles to the crystalline water-soluble drug is preferably 0.002 or more, 0.01 or more, 0.05 or more, 0.1 or more, 0.5 or more, 1.0 or more, 1.5 or more, 2.0 or more, or 2.5 or more. The upper limit of this mass ratio is not particularly limited, and can be, for example, 10 or less, 9.0 or less, 8.0 or less, 7.0 or less, 6.0 or less, 5.0 or less, or 4.0 or less.

[0048] In addition, in the composition before application to the skin, the dissolved crystalline water-soluble drug may be entirely retained within the pores of the porous particles, or a portion may be retained within the pores of the porous particles, with the remainder existing outside the pores. Even if a portion of the dissolved crystalline water-soluble drug is present outside the pores of the porous particles, the composition of the present disclosure can use porous particles to reduce or delay the crystallization of the crystalline water-soluble drug, thereby improving the transdermal absorbability of the drug compared to a composition that does not contain porous particles.

[0049] <Optional Components> The composition of the present disclosure can be appropriately blended with various components as long as they do not adversely affect the effects of the present disclosure. Examples of various components include surfactants (e.g., anionic surfactants, nonionic surfactants), thickeners, moisturizers, dispersants, water-soluble polymers, film-forming agents, sequestering agents, lower alcohols (e.g., ethanol), polyhydric alcohols (e.g., ethylene glycol), higher alcohols, various extracts, sugars, amino acids, organic amines, polymer emulsions, chelating agents, UV absorbers, pH adjusters, skin nutrients, vitamins, pharmaceuticals, quasi-drugs, non-crystalline water-soluble drugs applicable to cosmetics, buffers, preservatives, antioxidants, stabilizers, propellants, refreshing agents, pigments, dyes, coloring materials, fragrances, oils, etc. The optional components can be used alone or in combination of two or more.

[0050] The composition of the present disclosure may contain an amphoteric surfactant, but the amphoteric surfactant is preferably blended in an amount of 1.0 mass % or less, 0.5 mass % or less, 0.1 mass % or less, 0.05 mass % or less, 0.01 mass % or less, or 0.005 mass % or less relative to the total amount of the composition. Alternatively, it is more preferable that no amphoteric surfactant is blended in the composition.

[0051] The composition of the present disclosure may contain oil, but as shown on the right side of Figure 2, the oil 24 is contained within the pores of the porous particles 23 or is disposed between the porous particles 23 and the skin. As a result, the proportion of dissolved crystalline water-soluble drug 21 retained within the pores of the porous particles may decrease, or the dissolved crystalline water-soluble drug 21 may be repelled by the oil 24 disposed between the porous particles 23 and the skin, inhibiting penetration of the drug into the skin. Therefore, from the viewpoint of improving the transdermal absorbability of the crystalline water-soluble drug, the oil is preferably incorporated in an amount of 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, relative to the total amount of the composition, and it is more preferable that no oil be incorporated in the composition.

[0052] In some embodiments, the compositions of the present disclosure include a thickener. The thickeners may be used alone or in combination. Although both aqueous and oil phase thickeners may be used as the thickener, aqueous phase thickeners are preferred.

[0053] The aqueous phase thickener can be one that is typically incorporated into cosmetics or pharmaceuticals to increase the viscosity of the aqueous phase. Specific examples include various hydrophilic thickeners such as natural water-soluble polymers, semi-synthetic water-soluble polymers, synthetic water-soluble polymers, and inorganic thickeners. Aqueous phase thickeners can be used alone or in combination of two or more.

[0054] Examples of natural water-soluble polymers include plant-derived polymers such as gum arabic, tragacanth gum, galactan, guar gum, carrageenan, pectin, quince seed extract, agar, and brown algae powder; microbial-derived polymers such as xanthan gum, dextran, pullulan, and succinoglycan; and animal-derived polymers such as collagen, casein, albumin, and gelatin.

[0055] Examples of semi-synthetic water-soluble polymers include starch-based polymers such as carboxymethyl starch and methylhydroxystarch; cellulose-based polymers such as methyl cellulose, nitrocellulose, ethyl cellulose, methylhydroxypropyl cellulose, hydroxyethyl cellulose, stearoxyhydroxypropylmethyl cellulose, cellulose sulfate, hydroxypropyl cellulose, carboxymethyl cellulose, and crystalline cellulose; and alginic acid-based polymers such as sodium alginate and propylene glycol alginate.

[0056] Examples of synthetic water-soluble polymers include vinyl polymers such as polyvinyl alcohol, polyvinyl acetate, polyvinyl methyl ether, polyvinylpyrrolidone, vinylpyrrolidone and vinyl acetate copolymers, and carboxyvinyl polymers; and acrylic polymers such as sodium polyacrylate, polyethyl acrylate, polyacrylamide, acrylic acid / alkyl methacrylate copolymers (e.g., (acrylates / alkyl acrylate (C10-30)) crosspolymer), polyacrylic acid alkanolamine, alkyl methacrylate and dimethylaminoethyl methacrylate copolymers, poly2-acrylamido-2-methylpropanesulfonic acid, polymethacryloyloxytrimethylammonium, (acryloyldimethyltaurate ammonium / VP) copolymer, and (dimethylacrylamide / acryloyldimethyltaurate Na) copolymer.

[0057] Examples of inorganic thickeners include bentonite, laponite, hectorite, aluminum magnesium silicate, and silicic anhydride.

[0058] The amount of thickener may be, for example, 0.1% by mass or more, 0.3% by mass or more, or 0.5% by mass or more, relative to the total amount of the composition, and may be 5.0% by mass or less, 4.0% by mass or less, 3.0% by mass or less, or 2.0% by mass or less.

[0059] In addition, when a thickener is used in the composition of the present disclosure, the crystalline water-soluble drug may be easily permeated through the stratum corneum.Therefore, for example, when it is desired to make the crystalline water-soluble drug remain in the stratum corneum and improve the medicinal effect in the skin (for example, moisturizing effect, whitening effect), the blending amount of the thickener is preferably 0.5% by mass or less, 0.3% by mass or less, 0.1% by mass or less, 0.05% by mass or less, or 0.01% by mass or less relative to the total amount of the composition, and it is more preferable that no thickener is blended in the composition.

[0060] <Transdermal absorbability of crystalline water-soluble drug> The transdermal absorbability of crystalline water-soluble drug in the composition of the present disclosure can be comprehensively evaluated, for example, from the results of the cumulative permeation test and membrane adsorption test described below using a simulated skin membrane.The simulated skin membrane has the performance similar to the stratum corneum of skin.Therefore, the cumulative permeation test can simulate the performance of drug permeating through the stratum corneum and being absorbed into skin, and the membrane adsorption test can simulate the performance of drug absorbed into the stratum corneum that constitutes skin.By comprehensively evaluating these two tests, the transdermal absorbability of crystalline water-soluble drug can be evaluated.That is, if at least one of the two tests, for example, the ratio of cumulative permeation amount and the ratio of membrane adsorption amount shown below are satisfied, the composition can be evaluated as having excellent transdermal absorbability.

[0061] (Ratio Relating to Cumulative Permeation Amount of Crystalline Water-Soluble Drug) In some embodiments, the composition of the present disclosure can achieve a ratio of the cumulative permeation amount of a composition containing porous particles to the cumulative permeation amount of a composition not containing porous particles, with respect to the cumulative permeation amount after 8 hours in such a cumulative permeation test, of 1.2 or more, 1.5 or more, 1.7 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, or 4.0 or more. The upper limit of such a ratio is not particularly limited, and can be, for example, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, or 10 or less. Herein, a "composition not containing porous particles" in the present disclosure refers to a composition prepared in the same manner as the composition of the present disclosure except that it does not contain porous particles, and the amount of water added to the composition is increased to account for the porous particles.

[0062] In some embodiments, the composition of the present disclosure can achieve a ratio of the cumulative permeation amount of a composition containing porous particles to the cumulative permeation amount of a composition not containing porous particles after 24 hours in such a cumulative permeation test of 1.1 or more, 1.3 or more, 1.5 or more, 1.7 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, or 4.0 or more. The upper limit of such ratio is not particularly limited and can be, for example, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, or 10 or less.

[0063] (Ratio of membrane adsorption amount of crystalline water-soluble drug) In some embodiments, in terms of membrane adsorption amount in this membrane adsorption test, the composition of the present disclosure can achieve the ratio of the membrane adsorption amount of the composition that comprises porous particles to the membrane adsorption amount of the composition that does not comprise porous particles of 1.1 or more, 1.2 or more, 1.3 or more, 1.4 or more, or 1.5 or more.The upper limit of this ratio is not particularly limited, and can be, for example, 5.0 or less, 4.5 or less, 4.0 or less, 3.5 or less, 3.0 or less, or 2.5 or less.

[0064] <<Method for Preparing Composition>> The composition of the present disclosure can be prepared by the following method. Note that the various materials that can be used in the method for preparing the composition, such as water, a crystalline water-soluble drug, porous particles, and optional components (e.g., a thickener), can be the same as those described above.

[0065] The composition of the present disclosure can be obtained by mixing water, a crystalline water-soluble drug, and porous particles to prepare a mixture. Here, the oil content in the mixture during the composition preparation stage is 50% by mass or less relative to the water. Porous particles generally have the ability to retain oil in their pores in addition to the dissolved crystalline water-soluble drug. Therefore, if a large amount of oil is contained during the preparation stage of the mixture, as shown on the right side of Figure 3, oil 34 is more likely to be retained in the pores of the porous particles 33, resulting in a reduced retention rate of the dissolved crystalline water-soluble drug 31, making it difficult to improve the transdermal absorption of the crystalline water-soluble drug. Furthermore, as described above, oil can also be located between the porous particles and the skin. As a result, the dissolved crystalline water-soluble drug is repelled by the oil located between the porous particles and the skin, inhibiting the drug's penetration into the skin.

[0066] The mixing of water, the crystalline water-soluble drug, and the porous particles may be carried out, for example, by mixing these three components simultaneously; by dissolving the crystalline water-soluble drug in water and then adding and mixing the porous particles; or by adding water to a mixture containing the crystalline water-soluble drug and the porous particles and then mixing the mixture.

[0067] In the composition of the present disclosure, the oil content is adjusted to a specific range during the step of mixing the dissolved crystalline water-soluble drug with the porous particles, so that the dissolved crystalline water-soluble drug can be favorably retained within the pores of the porous particles, thereby enhancing the transdermal absorbability of the crystalline water-soluble drug when the composition is applied to the skin.

[0068] From the viewpoint of transdermal absorbability of the crystalline water-soluble drug, the amount of oil relative to water in the preparation stage of the above mixture is preferably 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5.0% by mass or less, or 1.0% by mass or less, and it is more preferable that no oil is added in the preparation stage of the mixture.

[0069] The dosage form of the composition of the present disclosure is not particularly limited, but from the viewpoint of the transdermal absorption of crystalline water-soluble drugs, a single aqueous phase form or an oil-in-water emulsion form is preferred, and a single aqueous phase form is more preferred.Here, in the present disclosure, "single aqueous phase" refers to a single phase that is essentially composed of an aqueous phase.Furthermore, "substantially" refers to, for example, the fact that oil (e.g., an oil-soluble UV absorber) is solvated or solubilized by alcohol or the like and incorporated into the aqueous phase to a small extent, but does not include oil droplets (emulsified particles) emulsified by surfactants or the like, as contained in oil-in-water emulsion compositions.

[0070] The oil-in-water emulsion composition can be obtained by mixing water, a crystalline water-soluble drug, and porous particles to prepare an aqueous phase part, preparing an oil phase part containing an oil component, and adding the oil phase part to the aqueous phase part, where the oil component in the aqueous phase part mixture is 50% by mass or less relative to the water, as described above.

[0071] <<Uses of the Composition>> The composition of the present disclosure can be used in various applications. For example, the composition of the present disclosure can be suitably used as an agent to be applied to the skin, for example, an external skin preparation such as a cosmetic, a quasi-drug, or a pharmaceutical. In addition, the composition of the present disclosure has excellent transdermal absorbability of crystalline water-soluble drugs, and therefore can be suitably used, for example, as a transdermal absorption enhancer for crystalline water-soluble drugs.

[0072] When the composition of the present disclosure is used as a cosmetic, the product form is not particularly limited, and examples thereof include facial cosmetics such as lotion, serum, emulsion, and pack; makeup cosmetics such as foundation and eye shadow; sunscreen cosmetics (sunscreen agents); body cosmetics; skin cleansers such as makeup removers and body shampoos; hair cosmetics such as hair liquid, hair tonic, hair conditioner, shampoo, rinse, and hair growth agents; shaving cosmetics such as shaving cream, pre-shave lotion, and after-shave lotion; ointments, etc.

[0073] <<Application Site of Composition>> The composition of the present disclosure can be applied to any part of the body, for example, any part on the surface of the skin (body surface). Specifically, it can be appropriately applied to the skin surface of, for example, the face (lips, eyes, eyelids, cheeks, forehead, between the eyebrows, nose, etc.), head (scalp), ears, hands, arms, neck, legs, feet, chest, abdomen, back, etc. Here, the skin also includes nails, which have hardened due to changes in the keratin of the epidermis of the skin.

[0074] The present invention will be described in more detail below with reference to test examples and examples, but the present invention is not limited thereto. Unless otherwise specified, the blending amounts are expressed in mass %.

[0075] Test Examples 1 to 6 The compositions obtained by the manufacturing methods described below were used to carry out the various evaluations shown below, and the results are summarized in Tables 2 to 7 and Figures 4 to 15. The porous particles used in these examples and their physical properties are also shown in Table 1.

[0076]

[0077] <Evaluation of Compositions> (Cumulative Permeation Test) The permeability of various crystalline water-soluble drugs through simulated skin membranes was evaluated using a vertical Franz diffusion cell (hereinafter referred to as "Franz cell"), which allows sampling over time to determine the permeability of drugs and is also listed in the Japanese Pharmacopoeia.

[0078] For the Franz cell, it is 1.77 cm ２ A Franz cell with an effective permeation area of ​​100 μm was used. The pseudo-skin membrane, which is the permeable membrane placed in the Franz cell, was a Strat-M™ membrane (manufactured by Merck Millipore) cut with a punch to match the outer diameter of the donor cell constituting the Franz cell. The pseudo-skin membrane was immersed in physiological phosphate buffer solution (PBS) to fully hydrate it before being placed in the Franz cell.

[0079] The water bath and receiver cell jacket were connected to the Franz cell with a hose, and a thermostatic device system was assembled. The receiver cell was then filled with PBS. A cell clamp was used to firmly secure the simulated skin membrane between the receiver cell and the donor cell to prevent air from entering. The surface temperature of the simulated skin membrane was maintained at approximately 32°C, equivalent to the surface temperature of the skin, using a temperature regulator, and the PBS in the receiver cell was allowed to acclimate for at least one hour while stirring with a stirrer bar.

[0080] The sample was applied to the simulated skin membrane using a limited open application method that simulates actual use. The sample was applied at 2.65 μL / cm ２ The drug was applied uniformly to the simulated skin membrane for 30 seconds at a rate of 0, 1, 2, 4, 8, and 24 hours after application. The extract was collected from the receiver cell. The amount of drug in the collected extract was quantified using an HPLC system equipped with an LC-MS detector, and the cumulative permeation amount was calculated.

[0081] (Membrane adsorption test) Using the same equipment as in the cumulative permeation test, the sample was similarly applied to the simulated skin membrane. 24 hours after the sample was applied to the simulated skin membrane, the simulated skin membrane was removed from the Franz cell. The foamed soap solution was applied to a cotton swab, and the removed simulated skin membrane was wiped five times with the cotton swab, then wiped five times with purified water, and finally the surface moisture was absorbed.

[0082] The simulated skin membrane was then cut into small pieces, which were immersed in 2 mL of purified water while being subjected to ultrasonic irradiation for 15 minutes, and then stored overnight at 37°C to extract the drug from the simulated skin membrane. The amount of drug in the collected extract was quantified using an HPLC system equipped with an LC-MS detector, and the amount of drug adsorbed to the membrane was calculated.

[0083] (Stratum corneum sorptive property test) In the laboratory, the inside of both forearms of each subject was washed once with soap. After drying the washed area with a towel, the subject was allowed to stand in the laboratory for 15 minutes.

[0084] Each sample was applied to the inside of the forearm at 2 μL / cm ２The application sites were randomly rotated. Six hours after application of the samples, the application sites were washed once with soap to remove the samples adsorbed on the skin surface.

[0085] After the subjects were allowed to wait 15 minutes in the laboratory, the stratum corneum (six layers) at the application site was sampled six times by tape stripping. Of the six six-layer tapes, two tapes, each representing the top two layers, were removed. These two tapes were immersed in 2 mL of a solvent (a 1:1 mixture of water and methanol) and subjected to ultrasonic irradiation for 15 minutes. The drugs were then stored overnight at 37°C to extract the drugs from the tapes. Extracts were collected from the storage solution, and the drug amount was quantified using an Agilent G6120 HPLC system equipped with an LC-MS detector. The stratum corneum sorption amount for each of the two layers was calculated. The "total stratum corneum sorption amount" in the table refers to the sum of the stratum corneum sorption amounts for the six layers.

[0086] Test Example 1: Effect of differences in composition preparation method on transdermal absorbability In Test Example 1, the effect of differences in composition preparation method on the transdermal absorbability of a crystalline water-soluble drug was investigated. The results are summarized in Table 2 and Figures 4 and 5. Here, "O / W" in the table means the form of an oil-in-water emulsion. The values ​​for the cumulative permeation amount and membrane adsorption amount are the average values ​​obtained by measuring each composition three times.

[0087] Example 1 The water-soluble components in Table 2 were dissolved in ion-exchanged water, and then porous particles, Sunsphere™ H-52, were added and the mixture was stirred and mixed with a stirrer to prepare a single aqueous phase composition. Here, the amount of oil in the mixture during stirring and mixing was 0% by mass relative to the water.

[0088] Example 2 The water-soluble components other than the oil in Table 2 were added to ion-exchanged water and dissolved, and then porous particles, Sunsphere (trademark) H-52, were added and mixed with a stirrer to prepare an aqueous phase part. Next, oil was added to this aqueous phase part, and the mixture was stirred and mixed with a stirrer to prepare an oil-in-water emulsion composition. Here, the amount of oil in the mixture at the time of stirring and mixing the aqueous phase part was 0% by mass relative to the water.

[0089] Comparative Example 1 The water-soluble components other than the oil in Table 2 were added to ion-exchanged water and dissolved to prepare an aqueous phase part. Porous particles, Sunsphere (trademark) H-52, were added to the oil, and the mixture was stirred and mixed with a stirrer to prepare an oil phase part. Next, the oil phase part was added to the aqueous phase part, and the mixture was stirred and mixed with a stirrer to prepare an oil-in-water emulsion composition. In this case, the porous particles were mixed with the oil, forming a mixture of oil phase parts that did not contain water, and therefore this mixture did not satisfy the requirement that "the oil content in the mixture is 50% by mass or less relative to the water."

[0090]

[0091] (Results) When preparing a mixture by mixing water, a crystalline water-soluble drug, and porous particles, the compositions of Examples 1 and 2, which were prepared under the condition that "the oil content in the mixture is 50 mass% or less relative to the water," showed a greater cumulative permeation amount of the crystalline water-soluble drug than the composition of Comparative Example 1, which was not prepared under such conditions.

[0092] The composition of Example 1, which is in the form of a single aqueous phase containing no oil, was also found to be superior in terms of the amount of membrane adsorption after 24 hours. The amount of membrane adsorption after 24 hours for the composition of Example 2 was similar to that of the composition of Comparative Example 1, but the composition of Example 2 was superior in terms of the cumulative permeation amount. Therefore, judging comprehensively from the results of the cumulative permeation amount and the membrane adsorption amount, it can be said that the composition of Example 2 has superior transdermal absorbability of crystalline water-soluble drugs compared to the composition of Comparative Example 1.

[0093] Test Example 2: Effect of Differences in Porous Particles on Transdermal Absorbability In Test Example 2, the effect of differences in porous particles on the transdermal absorbability of a crystalline water-soluble drug was investigated. The results are summarized in Table 3 and Figures 6 and 7. Here, in the tables of the present disclosure, "ratio of cumulative permeation amount after 8 hours" and "ratio of cumulative permeation amount after 24 hours" refer to the ratio of the cumulative permeation amount of the composition of each Example containing porous particles to the cumulative permeation amount of the composition of Comparative Example 2 not containing porous particles, after 8 hours or 24 hours, respectively. "ratio of membrane adsorption amount" refers to the ratio of the membrane adsorption amount of the composition of each Example containing porous particles to the membrane adsorption amount of the composition of Comparative Example 2 not containing porous particles. Furthermore, each numerical value for cumulative permeation amount and membrane adsorption amount is the average of values ​​obtained by measuring each composition three times.

[0094] Comparative Example 2 Potassium 4-methoxysalicylate and ethanol were added to ion-exchanged water to dissolve the potassium 4-methoxysalicylate, thereby preparing a composition with a single aqueous phase that did not contain porous particles.

[0095] Example 3 Potassium 4-methoxysalicylate and ethanol were added to ion-exchanged water to dissolve the potassium 4-methoxysalicylate, and then porous particles, Godball (trademark) B-25C, were added and the mixture was stirred and mixed with a stirrer to prepare a composition with a single aqueous phase.

[0096] Examples 4 to 6 Single aqueous phase compositions of Examples 4 to 6 were prepared in the same manner as in Example 3, except that the porous particles shown in Table 3 were used.

[0097]

[0098] (Results) It was found that the compositions of Examples 3 to 6 containing porous particles had a greater cumulative permeation amount of the crystalline water-soluble drug than the composition of Comparative Example 2 containing no porous particles.

[0099] The compositions of Examples 3 to 5 were also found to be superior in terms of the amount of membrane adsorption after 24 hours. The amount of membrane adsorption after 24 hours for the composition of Example 6 was comparable to that for the composition of Comparative Example 2, but the composition of Example 6 was superior in terms of the cumulative permeation amount. Therefore, judging comprehensively from the results of the cumulative permeation amount and the membrane adsorption amount, it can be said that the composition of Example 6 has superior transdermal absorbability of crystalline water-soluble drugs compared to the composition of Comparative Example 2.

[0100] Test Example 3: Effect of different amounts of porous particles on transdermal absorbability In Test Example 3, the effect of different amounts of porous particles on the transdermal absorbability of a crystalline water-soluble drug was investigated. The results are summarized in Table 4 and Figures 8 and 9. The values ​​for the cumulative permeation amount and membrane adsorption amount are the average values ​​obtained by measuring each composition four times.

[0101] Examples 7 and 8 Single aqueous phase compositions of Examples 7 and 8 were prepared in the same manner as in Example 5, except that the blending amount of the porous particles was changed to the blending amount shown in Table 4.

[0102]

[0103] (Results) It was found that the cumulative permeation amount of the crystalline water-soluble drug increased with an increase in the amount of porous particles incorporated.

[0104] Test Example 4: Effect of incorporation of thickener on transdermal absorbability In Test Example 4, the effect of incorporation of a thickener on the transdermal absorbability of a crystalline water-soluble drug was investigated. The results are summarized in Table 5 and Figures 10 and 11. The values ​​for the cumulative permeation amount and membrane adsorption amount are the average values ​​obtained by measuring each composition four times.

[0105] (Example 9: No Thickener Included) The water-soluble components in Table 5 were added to ion-exchanged water and dissolved, and then porous particles, Sunsphere (trademark) H-52, were added and mixed by stirring with a stirrer to prepare a composition with a single aqueous phase.

[0106] (Example 10: Thickener included) Water-soluble components including the thickener in Table 5 were added to ion-exchanged water and dissolved, and then porous particles, Sunsphere (trademark) H-52, were added and mixed by stirring with a stirrer to prepare a composition with a single aqueous phase.

[0107]

[0108] (Results) It was found that the cumulative permeation amount was higher in the system containing a thickener than in the system without a thickener. On the other hand, it was found that the membrane adsorption amount was lower in the system containing a thickener than in the system without a thickener. These results show that the use of a thickener makes it easier for crystalline water-soluble drugs to permeate the stratum corneum.

[0109] Test Example 5: Effect of nicotinamide on transdermal absorbability In Test Example 5, the effect of nicotinamide (niacinamide) on transdermal absorbability was investigated when it was used as a crystalline water-soluble drug. The results are summarized in Table 6 and Figures 12 and 13. The cumulative permeation amount and membrane adsorption amount are the average values ​​obtained by measuring each composition three times.

[0110] Comparative Example 3 Nicotinamide and ethanol were added to ion-exchanged water to dissolve the nicotinamide, thereby preparing a composition having a single aqueous phase containing no porous particles.

[0111] Example 11 Nicotinamide and ethanol were added to ion-exchanged water to dissolve the nicotinamide, and then porous particles, Sunsphere (trademark) H-52, were added and the mixture was stirred and mixed with a stirrer to prepare a composition with a single aqueous phase.

[0112]

[0113] (Results) Even when nicotinamide was used as the crystalline water-soluble drug, the results of the cumulative permeation amount and membrane adsorption amount showed that Example 11, which contained porous particles, had superior transdermal absorbability of the crystalline water-soluble drug compared to the composition of Comparative Example 3, which did not contain porous particles.

[0114] Test Example 6: Effect of Glycylglycine on Transdermal Absorbability In Test Example 6, the effect of glycylglycine on transdermal absorbability was investigated when it was used as a crystalline water-soluble drug. The results are summarized in Table 7 and Figures 14 and 15. The cumulative permeation amount and membrane adsorption amount are the average values ​​obtained by measuring each composition three times.

[0115] Comparative Example 4 Glycylglycine and ethanol were added to ion-exchanged water to dissolve the glycylglycine, thereby preparing a composition having a single aqueous phase that did not contain porous particles.

[0116] Example 12 Glycylglycine and ethanol were added to ion-exchanged water to dissolve the glycylglycine, and then porous particles, Sunsphere (trademark) H-52, were added and the mixture was stirred and mixed with a stirrer to prepare a composition with a single aqueous phase.

[0117]

[0118] (Results) Even when glycylglycine was used as the crystalline water-soluble drug, it was found that Example 12, which contained porous particles, had superior transdermal absorption of the crystalline water-soluble drug compared to the composition of Comparative Example 4, which did not contain porous particles.

[0119] <<Formulation Examples of Compositions>> Formulation examples of the compositions of the present disclosure are listed below, but are not limited to these examples. Of the compositions with the formulations shown below, the compositions of Formulation Examples 1 and 2 are in the form of a single aqueous phase, and the compositions of Formulation Examples 3 and 4 are in the form of an oil-in-water emulsion. These were each prepared in the same manner as in Example 1 or 2, except that the ingredients and blending amounts were changed to those shown in Tables 8 to 10. Note that each of the compositions described in the following formulation examples also exhibited excellent transdermal absorbability of crystalline water-soluble drugs.

[0120] Formulation Examples 1-2: Single Aqueous Phase Compositions

[0121]

[0122] Formulation Example 3: Oil-in-water emulsion composition

[0123]

[0124] Formulation Example 4: Oil-in-water emulsion composition

[0125]

[0126] 10, 20, 30 Water 11, 21, 31 Dissolved crystalline water-soluble drug 12, 22, 32 Crystallized crystalline water-soluble drug 13, 23, 33 Porous particles 24, 34 Oil

Claims

1. A composition comprising water, a crystalline water-soluble drug, and porous particles, obtained by mixing water, a crystalline water-soluble drug, and porous particles to prepare a mixture, wherein the oil content in the mixture is 50% by mass or less with respect to water. Composition.

2. The composition according to claim 1, wherein the mass ratio of the porous particles to the crystalline water-soluble drug is 0.002 or more.

3. The composition according to claim 1 or 2, wherein the porous particles are spherical particles.

4. The porous particles have a specific surface area of 100 m ２ / g or more, a pore volume of 0.1 mL / g or more, a pore diameter of 1 nm or more, a water absorption of 50 mL / 100 g or more, and an oil absorption of 50 mL / 100 g or more, and the composition according to claim 1 or 2 having at least one selected from the group consisting of:

5. The crystalline water-soluble drug is at least one selected from the group consisting of 4-methoxysalicylic acid, tranexamic acid, L-ascorbic acid, 4-methoxysalicylate, tranexamate, L-ascorbate, glycylglycine, nicotinamide, arbutin, L-ascorbic acid glucoside, 1-(2-hydroxyethyl)-2-imidazolidinone, adenosine, and a pyrimidylpyrazole compound represented by the following formula 1 and salts thereof: 【Chemical Formula 1】 In formula 1, R １ 、R ３ 、R ４ and R ６ are each independently an alkyl group having 1 to 3 carbon atoms, and R ２ and R ５ are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

6. The composition according to claim 1 or 2, which is used as a percutaneous absorption promoter for a crystalline water-soluble drug.

7. A method for producing a composition, comprising mixing water, a crystalline water-soluble drug, and porous particles to prepare a mixture, wherein the oil content in the mixture is 50% by mass or less based on water.

8. Mixing water, a crystalline water-soluble drug, and porous particles to prepare an aqueous phase part which is a mixture, Preparing an oil phase part containing an oil content, Adding the oil phase part to the aqueous phase part to obtain an oil-in-water type emulsion composition, The production method according to claim 7.

9. A cosmetic containing the composition according to claim 1 or 2.

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