Composition for external preparation for skin, containing composite microneedle containing polymer active ingredient

Abstract

Provided is a novel means for delivering an active ingredient into the skin. An external preparation composition for the skin, which is characterized by containing composite microneedle-like crystals in which a polymer active ingredient is included in crystals of a biosoluble substance; a method for producing a taurine composite microneedle-like crystal in which a polymer active ingredient is encapsulated in a crystal, the method being characterized by comprising a step for inducing crystal growth in an environment in which an aqueous solution (A) in which taurine, which is a biosoluble substance, is dissolved in water, and a liquid substance (B) having a low solubility in taurine are mixed or brought into contact with each other, by dissolving or dispersing a polymer active ingredient in the aqueous solution (A) or the liquid substance (B), the polymer active ingredient is enclosed in the crystal along with the growth of the crystal.

Description

Technical Field

[0001] This invention relates to a topical skin composition, and more particularly to a composite microneedle-shaped crystal containing a high molecular weight active ingredient in a biologically soluble substance crystallization, and a topical skin composition containing the composite microneedle-shaped crystal. Background Technology

[0002] To date, various methods have been employed to enhance the skin permeability of active ingredients. Most active ingredients, such as vitamins, amino acids, and peptides, are unstable in their water-soluble state and are easily decomposed by oxidation or temperature, making them difficult to mix stably in compositions. Therefore, these active ingredients typically require stabilization treatment before use. For example, in Patent Document 1, crystallization and mixing of calcium pantothenate and ascorbic acid showed improved stability compared to an uncrystallized mixture of calcium pantothenate and ascorbic acid. Furthermore, Patent Document 2 describes a method for obtaining a stable liquid formulation by adding water-soluble vitamins to edible oils such as sunflower oil, corn oil, or cottonseed oil. Further, Patent Document 3 shows a lipstick composition containing a crystalline vitamin B3 compound.

[0003] However, the compositions described in Patent Documents 1-3 are all powder mixtures without anhydrous or other polar solvents. These compositions are substances in which the active ingredient is dispersed in oils without polar solvents, and their use is limited to applications under anhydrous conditions. Therefore, these compositions are not topical skin preparations composed of active ingredients crystallized in aqueous media such as emulsions or creams.

[0004] On the other hand, water-soluble polymers such as hyaluronic acid and its salts, chondroitin sulfate and its salts, proteoglycans, and collagen have excellent moisturizing functions, can retain moisture in the body, and improve skin elasticity. Therefore, it is best to deliver them into the skin in a polymeric state. However, due to the skin barrier function, polymeric components cannot penetrate the skin by simply applying them. To overcome these problems, various methods have been developed, such as methods using phospholipid vesicles or penetration enhancers. Patent documents 4 and 5 describe methods of encapsulating hyaluronic acid in multilayer lipid vesicles and allowing it to penetrate into the skin. Furthermore, patent document 6 describes a method using a skin penetration enhancer containing peptides, and achieves penetration by binding hyaluronic acid to peptides.

[0005] Existing technical documents

[0006] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 2005-325080

[0008] [Patent Document 2] Japanese Patent Publication No. 2004-500392

[0009] [Patent Document 3] Japanese Patent Publication No. 2002-536391

[0010] [Patent Document 4] Japanese Patent Publication No. 2024-511804

[0011] [Patent Document 5] Japanese Patent Publication No. 2024-511215

[0012] [Patent Document 6] Japanese Patent Publication No. 2016-527188 Summary of the Invention

[0013] [The problem the invention aims to solve]

[0014] In methods of encapsulating polymeric components within phospholipid vesicles, the formation of phospholipid vesicles is sometimes impossible depending on the type of polymeric component, thus limiting the types of polymeric components that can be encapsulated. As described in Patent Document 6, the types of polymeric components that can be combined with a penetration enhancer are also limited. Furthermore, while it has been studied to reduce the molecular weight of polymeric components such as hyaluronic acid and collagen to a level that allows them to penetrate the skin, these components, once reduced to a lower molecular weight, often fail to achieve the desired water-retention and elasticity-improving functions. Therefore, there has been a persistent desire to develop a method that allows the polymeric component to penetrate the skin while maintaining its original state.

[0015] The purpose of this invention is to provide a topical skin composition in which a biosoluble substance (active substance) is crystallized and stably dispersed in an oily medium, an aqueous medium, or an emulsion medium of both, and the crystallized active substance is absorbed by the skin; and, in addition to the crystallized active substance, an active ingredient as a polymer (polymeric active ingredient) is encapsulated or attached to the surface, thereby forming a composite microneedle-like crystal, and to provide a topical skin composition with the composite microneedle-like crystal as the main component.

[0016] The means used to solve the problem.

[0017] Through repeated and in-depth research, the inventors discovered that when the crystalline component of a water-soluble active ingredient is dissolved in an aqueous solution at a concentration not less than its saturation solubility, and the active ingredient is crystallized in the presence of a polar solvent to form microspicules, a composite crystalline microspicule can be prepared by coexisting with a polymeric active ingredient. This allows the active ingredient to be encapsulated within the microspicules or attached to their surface. Furthermore, these microspicules can be incorporated into polar solvent systems, non-polar solvent systems, and mixtures thereof, thereby providing a topical skin formulation with good application properties. Based on this, the present invention was completed.

[0018] Generally, besides oil-soluble components, substances such as amino acids, vitamins, and peptides can be crystallized through recrystallization and can be used as the active ingredients in this invention. Utilizing this property, aqueous solutions with concentrations higher than the saturation solubility can typically be prepared and placed at low temperatures to allow crystals to precipitate. However, under these conditions, crystals tend to overgrow, making it difficult to obtain fine crystals. In this invention, by mixing or contacting a high-concentration solution containing the active ingredient with a low-solvent solvent that has a low solubility for that active ingredient, an environment of extremely low solubility is created at the interface between the solution containing the active ingredient and the low-solvent solvent, thereby allowing fine crystals to precipitate.

[0019] In this process, in addition to the active ingredient, an appropriate amount of high-molecular-weight active ingredient is uniformly dissolved or dispersed. This allows the active ingredient to be crystallized and contained within the active ingredient during crystallization, or to precipitate onto the outer surface of the crystals. The active ingredient, dissolved at a concentration higher than its saturation solubility, is added to the aqueous phase, and an appropriate amount of surfactant is prepared and emulsified with the oil phase to prepare a skin topical formulation in a crystalline state. In this invention, the active ingredient is contained within the needle-like crystals of the active ingredient and / or exists on its outer surface.

[0020] The present invention is as follows:

[0021] [1] A skin topical preparation composition, characterized in that it contains composite micro-needle-shaped crystals in which a high molecular weight active ingredient is contained in a biologically soluble substance crystallization.

[0022] [2] The skin topical composition according to [1] is characterized in that the composite microneedle-like crystals are at least partially contained in a dispersed state.

[0023] [3] The skin topical composition according to [1] or [2] is characterized in that the composite microneedle-shaped crystals have a space and contain a polymeric active ingredient within the space.

[0024] [4] The skin topical composition according to any one of [1] to [3] is characterized in that the diameter of the composite microneedle crystals does not exceed 150 micrometers and the length does not exceed 3000 micrometers.

[0025] [5] The topical skin composition according to any one of [1] to [4] is characterized in that the biosoluble substance is selected from the group consisting of amino acids, peptides and vitamins.

[0026] [6] The skin topical composition according to any one of [1] to [5] is characterized in that the biosoluble substance is taurine.

[0027] [7] The skin topical composition according to any one of [1] to [6] is characterized in that the biosoluble substance is taurine, and the content of the high molecular weight active ingredient in the taurine crystals is 0.001% to 30%.

[0028] [8] The skin topical composition according to any one of [1] to [5] is characterized in that the biosoluble substance is p-cymene-5-ol.

[0029] [9] The skin topical composition according to any one of [1] to [5] is characterized in that the biosoluble substance is gallic acid.

[0030]

[10] The topical skin composition according to any one of [1] to [8] is characterized in that the polymeric active ingredient is selected from one or more of the following groups: hyaluronic acid and its salts, hydrolyzed hyaluronic acid and its salts, acetylated hyaluronic acid and its salts, acylated hyaluronic acid and its salts, other hyaluronic acid derivatives and their salts, chondroitin sulfate and its salts, chondroitin sulfate derivatives and their salts, elastin, hydrolyzed elastin, water-soluble collagen, determinated collagen, isostearyl hydrolyzed collagen, succinylated determinated collagen, water-soluble collagen cross-linked polymer, water-soluble elastin, water-soluble proteoglycan, heparin-like substances, 2-methacryloyloxyethyl phosphorocholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl phosphorocholine-stearyl methacrylate copolymer, glyceryl-N-(2-methacryloyloxyethyl)carbamate-stearyl methacrylate copolymer, dextran, carboxymethyl dextran and its salts, and Suizenji nori polysaccharide.

[0031]

[11] The skin topical composition according to any one of [1] to

[10] is characterized in that one or more polymeric active ingredients are dissolved or dispersed in the medium of the skin topical composition.

[0032]

[12] A method for manufacturing taurine crystals, characterized in that the taurine crystals contain composite micro-needle-shaped crystals of a high molecular weight active ingredient, the method comprising: a step of inducing crystal growth by mixing or contacting an aqueous solution (A) obtained by dissolving taurine, which is a biosoluble substance, in water with a liquid substance (B) with low taurine solubility; and by dissolving or dispersing the high molecular weight active ingredient in the aqueous solution (A) or the liquid substance (B), so that it is contained in the crystals as they grow.

[0033]

[13] The manufacturing method according to

[12] is characterized in that the liquid substance (B) is a water-soluble organic solvent.

[0034]

[14] The manufacturing method according to

[13] is characterized in that the water-soluble organic solvent is selected from one or more of the following groups: ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, glycerol, diglycerol, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerol, and ethylhexylglycerol.

[0035]

[15] The manufacturing method according to any one of

[12] to

[14] is characterized in that the concentration of the effective polymeric component in the aqueous solution (A) or the liquid substance (B) is 0.001% by mass or more.

[0036]

[16] The manufacturing method according to any one of

[12] to

[15] is characterized in that the concentration of taurine in the aqueous solution (A) is 3 to 28% by mass.

[0037]

[17] The manufacturing method according to any one of

[12] to

[16] is characterized in that the proportion of the liquid substance (B) is 50% by mass or less relative to the total amount of the aqueous solution (A).

[0038]

[18] A method for manufacturing a skin topical agent composition, characterized in that the composition contains composite micro-needle-shaped crystals in which a polymeric active ingredient is included in the crystallization; the method includes: inducing crystal growth under conditions of mixing or contacting an aqueous solution (A) obtained by dissolving taurine, which is a biosoluble substance, in water with a liquid substance (B) with low taurine solubility; and dissolving or dispersing the polymeric active ingredient in the aqueous solution (A) or the liquid substance (B) so that it is included in the crystallization during crystal growth; and includes a step of formulating the composite micro-needle-shaped crystals obtained in the crystal growth step into the skin topical agent composition.

[0039]

[19] The manufacturing method according to

[18] is characterized in that the concentration of the effective polymeric component in the aqueous solution (A) or the liquid substance (B) is 0.001% by mass or more.

[0040]

[20] The manufacturing method according to

[18] or

[19] is characterized in that the concentration of taurine in the aqueous solution (A) is 3 to 28% by mass.

[0041]

[21] The manufacturing method according to any one of

[18] to

[20] is characterized in that the proportion of the liquid substance (B) is 50% by mass or less relative to the total amount of the aqueous solution (A).

[0042]

[22] The manufacturing method according to any one of

[18] to

[21] is characterized in that the liquid substance (B) is a water-soluble organic solvent, and the water-soluble organic solvent is selected from one or more of the following group: ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentylene glycol, diethylene glycol,

[0043] Dipropylene glycol, glycerin, diglycerin, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerin, ethylhexylglycerin.

[0044] [Invention Effects]

[0045] According to the present invention, a topical skin composition having a microspicule-like sensation on the skin can be prepared using either polar or non-polar solvents. Furthermore, although the crystalline component (active substance) exists in a crystalline state in the topical skin composition, the crystals dissolve and are absorbed by the skin during application and integration, thus providing a topical skin composition with a pleasant feel, gentleness, and no skin irritation, offering an unprecedented tactile experience. In addition, after the topical skin composition is applied to the skin, the high-molecular-weight active ingredient contained in or attached to the surface of the active substance crystals is also absorbed and dissolved within the skin, thereby achieving a significantly greater effect compared to applying the active ingredient to the skin alone.

[0046] This invention provides a novel delivery method for delivering active substances and high molecular weight active ingredients into the skin, and can improve the stability of the contained high molecular weight active ingredients.

[0047] The preparation method of the present invention is roughly as follows: a solution containing a polymeric active ingredient and a crystalline active substance is introduced into or brought into contact with a solvent with low solubility for the crystalline active substance, thereby creating an environment with extremely low solubility for the crystalline active substance. As the active substance crystallizes, the polymeric active ingredient is contained within the crystal. Attached Figure Description

[0048]

Figure 1

[0049]

Figure 2

[0050]

Figure 3

[0051]

Figure 4

[0052]

Figure 5

[0053] The topical skin composition of this invention contains composite microneedle-shaped crystals in which a high molecular weight active ingredient is included in the crystallization of the active substance. The topical skin composition of this invention contains composite microneedle-shaped crystals in which a high molecular weight active ingredient is included in the crystallization of the active substance.

[0054] The effective substance for forming complex micro-needle-like crystals is a biosoluble substance. Examples of biosoluble substances include amino acids, peptides, and vitamins. Preferably, the biosoluble substance is selected from the group consisting of amino acids, peptides, and vitamins.

[0055] The amino acids that can be used in this invention include: essential amino acids such as isoleucine, leucine, valine, histidine, lysine, methionine, tryptophan, phenylalanine, and threonine; non-essential amino acids such as asparagine, aspartic acid, alanine, arginine, cysteine, cystine, glutamine, glutamic acid, glycine, proline, serine, and tyrosine; and free amino acids that do not constitute proteins, such as theanine, ornithine, citrulline, taurine, and γ-aminobutyric acid. Furthermore, modified amino acids such as methylated and acetylated amino acids can also be used as amino acids. Examples of modified amino acids include hydroxyproline.

[0056] Among amino acids, those with a saturated solubility of 1–10 g in 100 g of water at 25°C are most suitable, including asparagine, glutamine, histidine, methionine, valine, isoleucine, leucine, phenylalanine, tryptophan, and taurine. When the above-mentioned active ingredient (biosoluble substance) is taurine, it is best to have it in a state where it exists both dissolved and crystalline in the topical skin formulation.

[0057] The peptides that can be used in this invention include dipeptides composed of two amino acids, tripeptides composed of three amino acids, and oligopeptides composed of multiple amino acids. As dipeptides, even those consisting solely of the amino acids that make up proteins number at least 20, resulting in over 400 possible combinations. Among these dipeptides, glycylglycine, carnosine (composed of β-alanine and histidine), anserine (composed of β-alanine and 1-methylhistidine), balenine (composed of β-alanine and 3-methylhistidine), and aspartame (composed of phenylalanine and aspartic acid) are particularly suitable. As tripeptides, although various types exist, glutathione (composed of glutamic acid, cysteine, and glycine) is the most suitable.

[0058] To further explain peptides, hydrolyzed peptides can also be obtained by hydrolyzing plant proteins such as soybeans, corn, and wheat through enzymes or acids; hydrolyzed peptides can be obtained by hydrolyzing animal proteins such as milk proteins and gelatin through enzymes or acids; and hydrolyzed peptides can be obtained by hydrolyzing silk, wool, etc. through enzymes or acids.

[0059] The vitamins that can be used in this invention include water-soluble vitamins. Examples of water-soluble vitamins include: vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid), vitamin B12 (cyanocobalamin), and vitamin C.

[0060] To further explain, as water-soluble vitamins, their derivatives can also be utilized, such as: thiamine monophosphate, thiamine diphosphate, thiamine triphosphate, flavin mononucleotide, flavin adenine dinucleotide, riboflavin phosphate, nicotinamide adenine dinucleotide phosphate, pyridoxine cyclic phosphate, hydroxycobalamin, deoxyadenosylcobalamin, ascorbate glucoside, sodium ascorbate phosphate, 3-O-ethyl ascorbic acid, etc.

[0061] In addition to the above, the effective substances (biosoluble substances) that can be used in this invention include, for example, p-cymene-5-ol and gallic acid. The aforementioned effective substances (biosoluble substances) can be either p-cymene-5-ol or gallic acid.

[0062] The topical skin composition of this invention contains composite microneedle-shaped crystals, but may also include composite microcolumnar crystals (i.e., columnar crystals containing high-molecular-weight active ingredients in the crystallization of the active substance). Needle-shaped crystals refer to crystals whose major axis is more than three times their minor axis, while columnar crystals refer to crystals whose major axis is less than three times their minor axis. Preferably, the composite microneedle-shaped crystals have a minor axis not exceeding 150 micrometers and a major axis not exceeding 3000 micrometers; more preferably, a minor axis not exceeding 150 micrometers and a major axis of 100–3000 micrometers; even more preferably, a minor axis not exceeding 100 micrometers and a major axis of 100–2000 micrometers; and most preferably, a minor axis not exceeding 80 micrometers and a major axis of 150–2000 micrometers.

[0063] Here, the thickness and length of the crystals are measured using a digital microscope (Keyence VHX-7000 digital microscope). The short diameter refers to the length of the short side of the crystal, while the long diameter refers to the length of the long side of the crystal.

[0064] In a topical skin composition, the composite microneedle-like crystals are preferably at least partially contained in a dispersed state. At least a portion of the composite microneedle-like crystals are preferably contained in a dispersed state in the topical skin composition.

[0065] The composite microneedle-shaped crystals preferably have a space, and the effective polymer components are encapsulated within the space.

[0066] In this invention, the specific recrystallization (crystallization growth) process refers to the process of mixing or contacting an aqueous solution (A) containing the effective substance with a liquid substance (B) to which the effective substance has low solubility, thereby inducing crystal growth in an environment where the effective substance has extremely low solubility.

[0067] The effective substance used for recrystallization (crystal growth) is a liquid substance (B) with low solubility. Since the effective substance in this invention is a biosoluble and water-soluble substance, organic solvents can be cited as examples. Liquid substance (B) is not particularly limited, and examples include: polar organic solvents such as acetone, methyl ethyl ketone, dimethyl sulfoxide, dimethylformamide, ethyl acetate, isopropyl myristate, methyl heptyl laurate, and jojoba oil; non-polar organic solvents such as dodecane, isododecane, liquid paraffin, squalane, hydrogenated polyisobutylene, and olefin oligomers; monohydric alcohols such as ethanol and 1-propanol; and polyhydric alcohols such as 1,3-butanediol, glycerol, and 1,2-pentanediol. Liquid substance (B) with a solubility of 1% by mass or more in water at 25°C (water-soluble organic solvent) is particularly preferred because it can significantly reduce the solubility of the effective substance. Specifically, the preferred ingredients are one or more of the following: ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, ethylene glycol, diethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, glycerol, diglycerol, 1,2-pentanediol, 1,2-hexanediol, acetone, methyl ethyl ketone, dimethyl sulfoxide, dimethylformamide, cyclohexylglycerol, and ethylhexylglycerol. Based on the viewpoint of using the obtained fine needle-like crystals as an ingredient in a topical skin preparation, the most preferably water-soluble organic solvent for the liquid substance (B) is selected from one or more of the group consisting of ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, glycerin, diglycerin, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerin, and ethylhexylglycerin. When using two or more solvents, a mixed solvent is preferred.

[0068] If the liquid substance (B) is not used, the crystals will not form fine needle-like crystals, resulting in a rough feel when mixed into the skin topical formulation, which is not ideal.

[0069] From the viewpoint that the concentration of the effective substance in the aqueous solution (A) where the effective substance is dissolved in water induces the growth of fine needle-like crystals when mixed with a solvent with low solubility of the effective substance, it is preferably 40% by mass or more and 300% by mass or less of the saturated concentration of the effective substance at the crystallization precipitation temperature. When the concentration is below 40% by mass, crystallization will not occur unless more than 100% by mass of liquid substance (B) is added to the aqueous solution (A), and a sufficient amount of crystals cannot be obtained, which is impractical in terms of cost and yield. When the concentration exceeds 300% by mass, the dissolution of the effective substance becomes difficult even when heated to above 80°C, so the recrystallization process is also impractical. Therefore, it is preferable that the concentration of the effective substance in the aqueous solution (A) is 50 to 200% by mass of the saturated concentration, more preferably 60 to 180% by mass, and most preferably 70 to 170% by mass.

[0070] When the aqueous solution (A) in which the effective substance used for recrystallization is dissolved is an aqueous solution, one or more water-soluble organic solvents with low solubility for the effective substance can be added as liquid substance (B) to reduce the saturation concentration. In this case, the preferred water-soluble organic solvents are glycerol, 1,3-propanediol, ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, diglycerol, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerol, ethylhexylglycerol, etc. The concentration of liquid substance (B) (water-soluble organic solvent) relative to the total amount of aqueous solution (A) is preferably 50% by mass or less, more preferably 30% by mass or less, and most preferably 25% by mass or less. When it exceeds 50% by mass, if the effective substance is taurine, the solubility of taurine will be too low, and a sufficient amount of crystals cannot be obtained, which is impractical in terms of cost and yield.

[0071] In this invention, the key feature is that the active polymeric component is contained in or attached to the fine needle-like crystals of the active substance.

[0072] The active polymeric components are not particularly limited, but those with high biocompatibility are preferred. Examples of naturally derived active polymeric components include: hyaluronic acid and its salts, hydrolyzed hyaluronic acid and its salts, acetylated hyaluronic acid and its salts, acylated hyaluronic acid and its salts, other hyaluronic acid derivatives and their salts, chondroitin sulfate and its salts, chondroitin sulfate derivatives and their salts, elastin, hydrolyzed elastin, water-soluble collagen, determinate collagen, acylated hydrolyzed collagen, succinyl determinate collagen, succinyl determinate collagen, water-soluble collagen cross-linked polymers, water-soluble elastin, water-soluble proteoglycans, heparin-like substances, dextran, carboxymethyl dextran and their salts, and polysaccharides from *Porphyra yezoensis*, etc.

[0073] Examples of high-molecular-weight active ingredients that can be synthesized include: 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl phosphorylcholine-stearyl methacrylate copolymer, glyceryl-N-(2-methacryloyloxyethyl)carbamate-stearyl methacrylate copolymer, etc.

[0074] Preferred active polymeric components are selected from one or more of the following groups: hyaluronic acid and its salts, hydrolyzed hyaluronic acid and its salts, acetylated hyaluronic acid and its salts, acylated hyaluronic acid and its salts, other hyaluronic acid derivatives and their salts, chondroitin sulfate and its salts, chondroitin sulfate derivatives and their salts, elastin, hydrolyzed elastin, water-soluble collagen, determinated collagen, acylated hydrolyzed collagen, succinylated determinated collagen, succinylated determinated collagen, water-soluble collagen cross-linked polymer, water-soluble elastin, water-soluble proteoglycans, heparin-like substances, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl phosphorylcholine-stearyl methacrylate copolymer, glyceryl-N-(2-methacryloyloxyethyl)carbamate-stearyl methacrylate copolymer, dextran, carboxymethyl dextran and its salts, and Suizenji nori polysaccharide.

[0075] The inclusion rate of the polymeric active ingredient in the composite microneedle crystals is preferably 0.001% to 30% by mass. When the above-mentioned biosoluble substance is taurine, the inclusion rate of the polymeric active ingredient in the taurine crystals is preferably 0.001% to 30% by mass.

[0076] Furthermore, the composite microneedle-shaped crystals can also contain two or more high-molecular-weight active ingredients, or simultaneously contain both high-molecular-weight and low-molecular-weight active ingredients. For example, by simultaneously encapsulating high-molecular-weight active ingredients such as hyaluronic acid and collagen (high-molecular-weight active ingredients) and low-molecular-weight functional ingredients such as moisturizers and whitening agents (low-molecular-weight active ingredients) within the composite microneedle-shaped crystals, the skin permeability of these ingredients can be improved, and a higher skin care effect can be expected.

[0077] The included polymeric active ingredient can be used in a dissolved or dispersed state in an aqueous solution (A) or in a liquid substance (B) where the active ingredient has low solubility. There is no upper limit to the concentration of the polymeric active ingredient in the aqueous solution (A) or the liquid substance (B), but from the perspective of the amount of encapsulated component contained within the active ingredient crystals, it is preferably 0.001% by mass or more.

[0078] The obtained composite microneedle-like crystals can be filtered, dried, and then formulated into topical skin formulations, or the crystallized solution can be used directly. Furthermore, the polymeric active ingredient can exist not only in the active substance crystals but also dissolved or dispersed in the topical skin formulation. In this case, the polymeric active ingredient contained in the active substance crystals and the polymeric active ingredient contained in the topical skin formulation may be of different types.

[0079] The topical skin formulations of the present invention can be used primarily as topical compositions for cosmetics, quasi-drugs, and pharmaceuticals. The dosage form of the topical skin formulations of the present invention is not particularly limited, and examples include solutions, lotions, oils, emulsions, creams, aqueous gels, and ointments. These formulations can be prepared using conventional methods.

[0080] For solutions, lotions, emulsions, creams, and water-based gels, formulations can be prepared while maintaining the composite micro-needle-shaped crystals by keeping the concentration of the active ingredients in the aqueous phase above the saturation concentration.

[0081] For cosmetic oils and ointments, it is formulated by mixing, filtering and drying composite micro-needle-shaped crystals.

[0082] Furthermore, in the topical skin formulation of the present invention, without impairing the effects of the present invention described above, one or more of the following ingredients commonly used in cosmetics, quasi-drugs, and topical pharmaceutical preparations may be appropriately added: water, oils, surfactants, gelling agents, powders, nanoparticles, alcohols, water-soluble polymers, film-forming agents, resins, ultraviolet protectants, inclusion compounds, antibacterial agents, fragrances, deodorants, salts, pH adjusters, cooling agents, animal or microbial extracts, plant extracts, blood circulation promoters, astringents, anti-seborrheic agents, whitening agents, anti-inflammatory agents, moisturizers, anti-glycation agents, keratolytic agents, colorants (including natural pigments), enzymes, hormones, and vitamins.

[0083] The water contained in the topical skin composition of the present invention is not particularly limited, and may include, for example, purified water, ion-exchanged water, tap water, etc.

[0084] Examples of water-soluble alcohols include: lower alcohols, polyols, polyol polymers, divalent alcohol alkyl ethers, divalent alcohol alkyl ethers, divalent alcohol ether esters, glycerol monoalkyl ethers, sugar alcohols, monosaccharides, oligosaccharides, polysaccharides and their derivatives.

[0085] Examples of lower alcohols include ethanol, propanol, isopropanol, isobutanol, and tert-butanol.

[0086] Examples of polyols include: divalent alcohols (e.g., dipropylene glycol, 1,3-butanediol, ethylene glycol, trimethylene glycol, 1,2-butanediol, tetramethylene glycol, 2,3-butanediol, pentamethylene glycol, 2-buten-1,4-diol, hexanediol, octanediol, etc.), trivalent alcohols (e.g., glycerol, trimethylpropane, etc.), tetravalent alcohols (e.g., diglycerol, 1,2,6-hexanetriol, and pentaerythritol, etc.), pentavalent alcohols (e.g., xylitol, triglycerides, etc.), hexavalent alcohols (e.g., sorbitol, mannitol, etc.), and polyol polymers (e.g., diethylene glycol, etc.). Alcohols, dipropylene glycol-triethylene glycol, polypropylene glycol, tetraethylene glycol, diglycerol-triglycerol, tetraglycerol, polyglycerol, etc.), divalent alcohol alkyl ethers (e.g., ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monohexyl ether, ethylene glycol mono-2-methylhexyl ether, ethylene glycol isopentyl ether, ethylene glycol benzyl ether, ethylene glycol isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, etc.), divalent alcohol alkyl ethers (e.g., diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether). Diethylene glycol butyl ether, diethylene glycol methyl ethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, propylene glycol isopropyl ether, dipropylene glycol methyl ether, dipropylene glycol ethyl ether, dipropylene glycol butyl ether, etc.), divalent alcohol ether esters (e.g., ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate, ethylene glycol monophenyl ether acetate, ethylene glycol diadipate, ethylene glycol disuccinate, diethylene glycol monoethyl ether acetate, diethylene glycol monobutyl ether acetate, propylene glycol monomethyl ether acetate, propylene glycol monoethyl ether... Glycerides such as esters, propylene glycol monopropyl ether acetate, propylene glycol monophenyl ether acetate, etc.), glycerol monoalkyl ethers (e.g., hexadecyl alcohol, octadecyl alcohol, octadecyltrienol, etc.), sugar alcohols (e.g., maltotriose, mannitol, sucrose, erythritol, glucose, fructose, starch-degrading sugar, maltose, starch-degrading sugar reducing alcohol, etc.), glycerol condensates, tetrahydrofurfuryl alcohol, POE-tetrahydrofurfuryl alcohol, POP-butyl ether, POP·POE-butyl ether, trioxypropylene glycerol ether, POP-glycerol ether, POP-glycerol ether phosphate, POP·POE-pentaerythritol ether, polyglycerol, etc.

[0087] Examples of monosaccharides include: trioses (e.g., D-glyceraldehyde, dihydroxyacetone, etc.), tetraoses (e.g., D-erythrose, D-thulose, D-sorghumose, erythritol, etc.), pentoses (e.g., L-arabinose, D-xylose, L-lysose, D-arabinose, D-ribose, D-ribulose, D-xylulose, L-xylulose, etc.), and hexoses (e.g., D-glucose, D-tarose, D-buxicosose, D-galactose, D-fructose, L-galactose, L-mannose). Sugars include: D-tagatose, heptose (e.g., heptose, heptulose), octose (e.g., octulose), deoxy sugars (e.g., 2-deoxy-D-ribose, 6-deoxy-L-galactose, 6-deoxy-L-mannose), amino sugars (e.g., D-glucosamine, D-galactosamine, sialic acid, glucuronic acid, muramic acid), and uronic acids (e.g., D-glucuronic acid, D-mannuronic acid, L-gulonic acid, D-galacturonic acid, L-iduronic acid).

[0088] Examples of oligosaccharides include: sucrose, sanguine, umbelliferose, lactose, plant sugars, isoprunose, α,α-trehalose, raffinose, plumose, umbelliferose, muscariaose, and purslane sugars.

[0089] Examples of polysaccharides include: cellulose, pear seed, starch, galactomannan, dermatan sulfate, glycogen, gum arabic, heparin sulfate-astragalus gum, keratin sulfate, chondroitin, xanthan gum, guar gum, dextran, keratin sulfate, sophora bean gum, and succinyl glucan.

[0090] Examples of anti-inflammatory agents include: plant-derived components, allantoin and its derivatives, glycyrrhetinic acid and its derivatives, glycyrrhizic acid and its salts or derivatives, salicylic acid derivatives, aminocaproic acid, azulene and its derivatives, etc.

[0091] Examples of gelling agents (thickeners) include: gum arabic, carrageenan, tragacanth gum, kaempferia gum, quince seed, casein, dextrin, gelatin, sodium pectate, sodium alginate, methylcellulose, ethylcellulose, CMC, hydroxyethylcellulose, hydroxypropylcellulose, PVA, PVM, PVP, sodium polyacrylate, carboxyvinyl polymer, locust bean gum, guar gum, tamarind gum, dialkyldimethylammonium sulfate cellulose, xanthan gum, magnesium aluminum silicate, bentonite, bentonite, AlMg silicate (magnesium aluminum silicate), lithium magnesium silicate, anhydrous silicic acid, etc.

[0092] Examples of natural water-soluble polymers include: plant-based polymers (e.g., gum arabic, tragacanth, galactomannan, guar gum, carob gum, carrageenan, pectin, agar, quince seed, algal colloids (brown algae extract), starch (rice, corn, potato, wheat), glycyrrhizic acid), microbial polymers (e.g., xanthan gum, dextran, succinyl glucan, pullulan, etc.), and animal-based polymers (e.g., collagen, casein, albumin, gelatin, etc.).

[0093] Examples of semi-synthetic water-soluble polymers include: starch-based polymers (e.g., carboxymethyl starch, methyl hydroxypropyl starch, etc.), cellulose-based polymers (methyl cellulose, ethyl cellulose, methyl hydroxypropyl cellulose, hydroxyethyl cellulose, sodium cellulose sulfate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, microcrystalline cellulose, etc.), and alginate-based polymers (e.g., sodium alginate, propylene glycol alginate, etc.).

[0094] Examples of synthetic water-soluble polymers include: vinyl polymers (e.g., polyvinyl alcohol, polyvinyl methyl ether, polyvinylpyrrolidone, carboxyvinyl polymers, etc.), polyoxyethylene polymers (e.g., polyethylene glycol 20000, 40000, 60000, etc.), acrylic polymers (e.g., sodium polyacrylate, ethyl polyacrylate, polyacrylamide, etc.), polyethyleneimine, cationic polymers, etc.

[0095] Examples of moisturizers include: chondroitin sulfate, hyaluronic acid and its derivatives, hyaluronic acid cross-linkers, mucopolysaccharide sulfate, carboxylic acid, determinate collagen, cholesterol-12-hydroxystearate, sodium lactate, bile salts, DL-pyrrolidone carboxylate, short-chain soluble collagen, diglyceride (EO)PO adduct, rose extract, yarrow extract, lemon balm extract, etc.

[0096] Examples of skin-whitening agents (whitening ingredients) include: tranexamic acid, ascorbic acid and its salts, ascorbic acid derivatives and other vitamin C derivatives (sodium ascorbate phosphate, magnesium ascorbate phosphate, tetraisopalmitate ascorbate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbate glucoside, etc.), arbutin, kojic acid, placental extract, ellagic acid, niacinamide, hydroquinone, linoleic acid and its derivatives, astaxanthin, etc.

[0097] Examples of keratolytic agents (keratolytic softening ingredients) include: lactic acid, salicylic acid, gluconic acid, glycolic acid, citric acid, malic acid, fruit acid, phytic acid, urea, sulfur, etc.

[0098] Examples of anti-aging ingredients include: hydrolyzed soy protein, vitamin A-like substances (retinol and its derivatives, retinoic acid and retinal, etc.), kinetin, adenosine, NMN (nicotinamide mononucleotide), AMP (adenosine monophosphate), ADP (adenosine diphosphate), ATP (adenosine triphosphate), oleanolic acid, turmeric extract, sphingosine derivatives, mevalonate lactone, etc.

[0099] Examples of anti-glycation agents (anti-glycation components) include: plant extracts such as leaf extract of Buddleja axillaris (a plant in the Loganiaceae family), evening primrose oil, Phyllanthus emblica fruit, juice or its extract, L-arginine, L-lysine, hydrolyzed casein, hydrolyzed tannins, carnosine, etc.

[0100] Examples of plant-derived components that promote blood circulation include: ginseng, Ashitaba, arnica, ginkgo, fennel, euphorbia, oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, ginger, hawthorn, juniper, chuanxiong, senecio scandens, thyme, clove, dried tangerine peel, chili pepper, angelica, peach kernel, juniper, ginseng, garlic, butcher's broom, grape, peony, horse chestnut, lemon balm, grapefruit, coix seed, green tea, rosemary, rosehip, dried tangerine peel, angelica, juniper, peach, apricot, walnut, corn, golden chamomile, cod liver oil phenol, cantharides tincture, lycorine, etc.; as well as γ-oryzanol, nicotinic acid tocopherol, glucosyl hesperidin, etc.

[0101] Polyphenols include curcumin, flavanones, styrene, polymethoxyflavones, flavonols, flavonones, chalcones, lignins, flavanols, isoflavones, etc., which belong to the flavonoid polyphenols.

[0102] Examples of metal ion chelating agents include: 1-hydroxyethane-1,1-diphosphonic acid, tetrasodium 1-hydroxyethane-1,1-diphosphonic acid, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, succinic acid, ethylenediaminetetraacetic acid, and trisodium ethylenediaminehydroxyethyltriacetate.

[0103] Examples of UV protectants (water-soluble UV absorbers) include: 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, and 4-phenylbenzophenone. Benzophenone, 2-ethylhexyl-4'-phenyl-benzophenone-2-carboxylic acid ester, 2-hydroxy-4-n-octyloxybenzophenone, 4-hydroxy-3-carboxybenzophenone and other benzophenone-based ultraviolet absorbers; phenylbenzimidazole-5-sulfonic acid and its salts, phenylene-bis-benzimidazole-tetrasulfonic acid and its salts and other benzimidazole-based ultraviolet absorbers; 3-(4'-methylbenzyl)-d,l-camphor, 3-benzyl-d,l-camphor, allantoic acid, ethyl allantoic acid, etc.

[0104] Examples of powders (powder components) and nanoparticles include: inorganic powders (e.g., talc, kaolin, mica, sericite, muscovite, phlogopite, synthetic mica, red mica, biotite, vermiculite, magnesium carbonate, calcium carbonate, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, tungstate metal salts, magnesium, silicon dioxide, zeolite, barium sulfate, calcined calcium sulfate (calcined gypsum), calcium phosphate, fluorapatite, hydroxyapatite, ceramic powders, metal soaps (e.g., zinc myristate, calcium palmitate, aluminum stearate), boron nitride, etc.) Organic powders (e.g., polyamide resin powder (nylon powder), polyethylene powder, polymethyl methacrylate powder, polystyrene powder, styrene-acrylic acid copolymer resin powder, phenylguanidine resin powder, polytetrafluoroethylene powder, cellulose powder, etc.); inorganic white pigments (e.g., titanium dioxide, zinc oxide, etc.); inorganic red pigments (e.g., iron oxide (ochre), ferritic acid, etc.); inorganic brown pigments (e.g., γ-iron oxide, etc.); inorganic yellow pigments (e.g., yellow iron oxide, loess, etc.); inorganic black pigments (e.g., black iron oxide, low... Inorganic pigments include: titanium dioxide, etc.; inorganic purple pigments (e.g., manganese violet, cobalt violet, etc.); inorganic green pigments (e.g., chromium oxide, chromium hydroxide, cobalt titanate, etc.); inorganic blue pigments (e.g., ultramarine, Prussian blue, etc.); pearlescent pigments (e.g., titanium dioxide coated mica, titanium dioxide coated bismuth oxychloride, titanium dioxide coated talc, colored titanium dioxide coated mica, bismuth oxychloride, fish scale foil, etc.); metallic powder pigments (e.g., aluminum powder, copper powder, etc.); organic pigments such as zirconium, barium, or aluminum lake (e.g., Red 201, Red 202, Red 204, etc.). Organic pigments such as Red 205, Red 220, Red 226, Red 228, Red 405, Orange 203, Orange 204, Yellow 205, Yellow 401, and Blue 404; and natural pigments such as Red 3, Red 104, Red 106, Red 227, Red 230, Red 401, Red 505, Orange 205, Yellow 4, Yellow 5, Yellow 202, Yellow 203, Green 3, and Blue 1; and natural pigments such as chlorophyll and beta-carotene.

[0105] Examples of enzymes include: hydrolases (proteases, amylases, saccharifying enzymes, dextranases, lipases, cellulases, lysozymes), and oxidoreductases (laccases, peroxidases, catalases, lactate oxidases, glucose oxidases, galactose oxidases, pyruvate oxidases, aldehyde oxidases, monoamine oxidases, uricase oxidases).

[0106] The protein-degrading enzymes used in this invention are primarily intended to effectively remove dead skin cells. Any enzyme that fulfills this purpose and can be formulated into cosmetics can be used. Specifically, examples include proteases derived from microorganisms such as Bacillus subtilis and Actinomycetes, which exist in forms suitable for cosmetic formulation. Papain can also be used.

[0107] Examples of vitamins include: vitamins A, B1, B2, B6, C, E and their derivatives, pantothenic acid and its derivatives, biotin, etc.

[0108] Examples of antioxidants include tocopherols, butylated hydroxytoluene, butylated hydroxyanisole, and gallic acid esters.

[0109] Examples of pH adjusters include: lactic acid-sodium lactate, citric acid-sodium citrate, succinic acid-sodium succinate, and other buffers.

[0110] Examples of oil-based formulations (oil phase components) include liquid oils, solid oils, waxes, hydrocarbon oils, higher fatty acids, synthetic ester oils, and silicone oils, which are commonly used in cosmetics and quasi-drug products. By combining these oil phase components with the aforementioned aqueous phase components and adding appropriate surfactants, skin-use compositions can be formulated.

[0111] Examples of liquid oils include: avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, peach kernel oil, wheat germ oil, tea seed oil, castor oil, flaxseed oil, safflower seed oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, torreya nut oil, rice bran oil, pine oil, Japanese tung oil, jojoba oil, germ oil, triglycerides, etc.

[0112] Examples of solid fats include: cocoa butter, coconut oil, horse fat, hydrogenated coconut oil, palm oil, beef tallow, mutton tallow, hydrogenated beef tallow, palm kernel oil, lard, beef bone fat, wood wax kernel oil, hydrogenated oil, beef hoof oil, wood wax, hydrogenated castor oil, etc.

[0113] Examples of waxes include: beeswax, candelilla wax, cotton wax, carnauba wax, bayberry wax, wood wax, whale wax, montan wax, rice bran wax, lanolin, kapok wax, lanolin acetate, liquid lanolin, sugarcane wax, lanolin fatty acid isopropyl ester, hexyl laurate, reduced lanolin, jojoba wax, hard lanolin, shellac wax, polyoxyethylene lanolin alcohol ether, polyoxyethylene lanolin alcohol acetate, polyoxyethylene cholesterol ether, lanolin fatty acid polyethylene glycol, polyoxyethylene hydrogenated lanolin alcohol ether, hexadecyl palmitate, etc.

[0114] Examples of hydrocarbon oils include: flowing paraffin, ceresin, squalane, isoprene, paraffin, ceresin, squalene, petrolatum, microcrystalline wax, etc.

[0115] Examples of high-grade fatty acids include: lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, undecenoic acid, rosin acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

[0116] Examples of synthetic ester oils include: cetyl octanoate, myristyl octanoate, triglyceride (ethylhexanoate), pentaerythritol tetra(2-ethylhexanoate), dioctyl octanoate, and tripropylene glycol dineoproteroides.

[0117] Examples of silicone oils include: linear polysiloxanes (e.g., dimethyl polysiloxane, methylphenyl polysiloxane, diphenyl polysiloxane, etc.); cyclic polysiloxanes (e.g., octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecylcyclohexasiloxane, etc.); silicone resins and silicone rubbers that form a three-dimensional network structure; various modified polysiloxanes (amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, fluorinated polysiloxanes, etc.); and acrylic siloxanes, etc.

[0118] Examples of amino acids include: neutral amino acids such as glycine, alanine, valine, leucine, and isoleucine; hydroxyl amino acids among aliphatic amino acids such as serine and threonine; sulfur-containing amino acids among aliphatic amino acids such as cysteine, cystine, and methionine; acidic amino acids such as glutamic acid and aspartic acid; amino acids containing amide groups such as glutamine and asparagine; basic amino acids such as arginine; aromatic amino acids such as phenylalanine and tyrosine; and amino acids containing imino groups such as proline and hydroxyproline.

[0119] The method for manufacturing the topical skin composition of the present invention is characterized by comprising the following steps:

[0120] A process of inducing crystal growth in an aqueous solution (A) containing a dissolved biosoluble substance (active substance) in an environment of mixing or contacting with a liquid substance (B) with low solubility in the biosoluble substance, wherein, due to the dissolution or dispersion of the biosoluble substance in the aqueous solution (A) or the liquid substance (B), the polymeric active ingredient is contained in the active substance crystals as the crystals grow; and a process of formulating the composite microneedle-shaped crystals containing the polymeric active ingredient obtained in the crystal growth process into a topical skin agent composition.

[0121] The following example uses taurine as the biologically soluble (active) substance.

[0122] Method for manufacturing taurine complex micro needle-like crystals

[0123] A method for manufacturing taurine composite micro-needle crystals includes a step of inducing crystal growth in an environment where an aqueous solution (A) of dissolved taurine is mixed or contacted with a liquid substance (B) with low taurine solubility (crystal growth step). In this step, because the polymeric active ingredient is dissolved or dispersed in the aqueous solution (A) or the liquid substance (B), the polymeric active ingredient is included in the crystal as it grows.

[0124] The liquid substance (B) is preferably a water-soluble organic solvent, and preferably one or more of the following: ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, glycerol, diglycerol, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerol, and ethylhexylglycerol.

[0125] In the crystal growth process, the concentration of the active polymer component is preferably 0.001% by mass or more in the aqueous solution (A) or liquid substance (B), and the concentration of taurine in the aqueous solution (A) is preferably 3 to 28% by mass.

[0126] When the aqueous solution (A) is mixed or in contact with the liquid substance (B), the total amount of the liquid substance (B) relative to the aqueous solution (A) is preferably 50% by mass or less.

[0127] Method for manufacturing a topical skin formulation containing taurine complex microneedle-like crystals

[0128] A method for manufacturing a topical skin agent composition containing taurine complex microneedle-like crystals includes a step of inducing crystal growth (crystal growth step) by mixing or contacting an aqueous solution (A) containing taurine with a liquid substance (B) having low solubility for taurine. In this step, the active ingredient is incorporated into the crystals as they grow because the polymeric active ingredient is dissolved or dispersed in the aqueous solution (A) or the liquid substance (B).

[0129] The method for manufacturing a skin topical agent composition containing taurine complex microneedle crystals further includes the step of adding the taurine complex microneedle crystal formulation containing high molecular weight active ingredients obtained through the above-mentioned crystal growth process to the skin topical agent composition.

[0130] In the method for manufacturing a skin topical agent composition containing taurine complex microneedle crystals, the preferred configuration of the crystal growth step described above is the same as the preferred configuration of the crystal growth step in the method for manufacturing taurine complex microneedle crystals described above.

[0131] Various topical skin formulations can be prepared by maintaining the concentration of the active ingredient in the aqueous phase above saturation during the manufacturing process to preserve the composite micro-needle-like crystals, or by obtaining composite micro-needle-like crystals through recrystallization, followed by filtration, drying, and formulation. They can also be prepared using various manufacturing methods. For details, please refer to the formulation examples below.

[0132]

Example

[0133] The present invention will be further described in detail below through the following embodiments. These embodiments are only for illustrating examples of the present invention, and the scope of the present invention is not limited to these embodiments. Unless otherwise specified, the formulation amounts in the following embodiments are all by mass%, and the units for thickness and length are micrometers.

[0134] Comparative Example 1

[0135] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 100,000 to 300,000) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered, washed with 10.0 mL of ethanol, and dried to obtain the crystalline product. No fluorescent substance was found in the crystals when observed under a fluorescence microscope.

[0136] Comparative Example 2

[0137] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 1.2 million to 1.6 million) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered, washed with 10.0 mL of ethanol, and dried to obtain the crystalline product. No fluorescent substance was found in the crystals when observed under a fluorescence microscope.

[0138] Comparative Example 3

[0139] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled chondroitin C sulfate sodium (manufactured by PG Research Co., Ltd.) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered, washed with 10.0 mL of ethanol, and dried to obtain the crystalline product. No fluorescent substance was found in the crystals when observed under a fluorescence microscope.

[0140] Comparative Example 4

[0141] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled heparin sulfate sodium (manufactured by PG Research Co., Ltd.) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated, washed with ethanol, and dried to obtain the crystalline product. No fluorescent substance was found in the crystals when observed under a fluorescence microscope.

[0142] Comparative Example 5

[0143] One mL of an aqueous solution containing 10% taurine and 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-200, average molecular weight 1.8 million to 2.2 million) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0144] Comparative Example 6

[0145] One mL of an aqueous solution containing 10% taurine and 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-80, average molecular weight 600,000 to 1,000,000) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0146] Comparative Example 7

[0147] One mL of an aqueous solution containing 10% by mass taurine and 0.1% by mass sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-SU, average molecular weight 50,000 to 110,000) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0148] Comparative Example 8

[0149] One mL of an aqueous solution containing 10% taurine and 0.1% water-soluble proteoglycan (manufactured by Renaiss Corporation, product name: Proteoglycan-LS, average molecular weight 900,000 to 1,400,000) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0150] Comparative Example 9

[0151] One mL of an aqueous solution containing 10% taurine and 0.1% sodium chondroitin sulfate (manufactured by Maruha Nichiro Co., Ltd., product name: Exogenous Chondroitin Sulfate Sodium) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0152] Comparative Example 10

[0153] One mL of an aqueous solution containing 10% taurine and 0.1% water-soluble collagen (manufactured by Co-op Agri Co., Ltd., product name: Seagem Collagen) was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0154] Comparative Example 11

[0155] One mL of an aqueous solution containing 10% taurine, 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-200, average molecular weight 1.8 million to 2.2 million), and 5.0% trimethylglycine was heated to 50°C to dissolve the solution uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0156] Comparative Example 12

[0157] One mL of an aqueous solution containing 10% taurine, 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-200, average molecular weight 1.8 million to 2.2 million), and 5.0% sodium pyrrolidone carboxylate was heated to 50°C to dissolve it uniformly. After cooling to room temperature and standing for 24 hours, the precipitated crystals were filtered and separated. The crystals were washed with 10.0 mL of ethanol and dried to obtain the crystalline product.

[0158] Example 1

[0159] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 100,000 to 300,000) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were separated by filtration, washed with 10.0 mL of ethanol, and dried to obtain slightly yellowish-white needle-like crystals. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals.

[0160] Example 2

[0161] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 1.2 million to 1.6 million) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were filtered and separated. After washing with 10.0 mL of ethanol and drying, slightly yellowish-white needle-like crystals were obtained. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals. Quantification of the fluorescein-labeled sodium hyaluronate by fluorescence intensity confirmed that the crystals contained 0.004% fluorescein-labeled sodium hyaluronate.

[0162] Example 3

[0163] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled chondroitin C sulfate sodium (manufactured by PG Research Co., Ltd.) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were separated by filtration, washed with 10.0 mL of ethanol, and dried to obtain slightly yellowish-white needle-like crystals. Fluorescence microscopy confirmed the presence of fluorescence generated by fluorescein-labeled chondroitin C sulfate sodium within the crystals.

[0164] Example 4

[0165] One mL of an aqueous solution containing 10% taurine and 0.1% fluorescein-labeled heparin sulfate sodium (manufactured by PG Research Co., Ltd.) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were filtered and separated. After washing with 10.0 mL of ethanol and drying, slightly yellowish-white needle-like crystals were obtained. Fluorescence microscopy confirmed the presence of fluorescence generated by fluorescein-labeled heparin sulfate sodium within the crystals.

[0166] Example 5

[0167] One mL of an aqueous solution containing 23% by mass pyridoxine hydrochloride and 0.1% by mass fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 100,000 to 300,000) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were separated by filtration, washed with 10.0 mL of ethanol, and dried to obtain slightly yellowish-white needle-like crystals. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals.

[0168] Example 6

[0169] One mL of an aqueous solution containing 15% glycylglycine and 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 100,000 to 300,000) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were separated by filtration, washed with 10.0 mL of ethanol, and dried to obtain slightly yellowish-white needle-like crystals. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals.

[0170] Example 7

[0171] One mL of an aqueous solution containing 15% glutathione and 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 100,000 to 300,000) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were filtered and separated. After washing with 10.0 mL of ethanol and drying, slightly yellowish-white needle-like crystals were obtained. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals.

[0172] Example 8

[0173] In 1.0 mL of an ethanol solution containing 5% p-cymene-5-ol, 10 mL of an aqueous solution containing 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., average molecular weight 100,000–300,000) was slowly and quietly added dropwise. The precipitated crystals were filtered, washed with 10.0 mL of purified water, and dried to obtain slightly yellowish-white needle-like crystals. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals.

[0174] Example 9

[0175] In a 1.0 mL ethanol solution containing 5% gallic acid by mass, 1 mL of an aqueous solution containing 0.1% fluorescein-labeled sodium hyaluronate (manufactured by PG Research Co., Ltd., with an average molecular weight of 100,000 to 300,000) was slowly and quietly added dropwise. The precipitated crystals were filtered, washed with 10.0 mL of purified water, and dried to obtain slightly yellowish-white needle-like crystals. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein-labeled sodium hyaluronate within the crystals.

[0176] Example 10

[0177] A 100 mL aqueous solution containing 10% taurine and 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: Hyaluronic Acid FCH-200, average molecular weight 1.8 million to 2.2 million) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0178] Example 11

[0179] A 100 mL aqueous solution containing 10% taurine and 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-80, average molecular weight 600,000 to 1,000,000) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0180] Example 12

[0181] A 100 mL aqueous solution containing 10% taurine and 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-SU, average molecular weight 50,000 to 110,000) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0182] Example 13

[0183] A 100 mL aqueous solution containing 10% taurine and 0.1% water-soluble proteoglycan (manufactured by Renaiss Corporation, product name: Proteoglycan-LS, average molecular weight 900,000 to 1,400,000) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0184] Example 14

[0185] A 100 mL aqueous solution containing 10% taurine and 0.1% sodium chondroitin sulfate (manufactured by Maruha Nichiro Co., Ltd., product name: Exogenous Chondroitin Sulfate Sodium) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0186] Example 15

[0187] A 100 mL aqueous solution containing 10% taurine and 0.1% water-soluble collagen (manufactured by Co-op Agri Co., Ltd., product name: Seagem Collagen) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0188] Example 16

[0189] A 1 mL aqueous solution containing 10% taurine and 0.1% fluorescein isothiocyanate-labeled dextran (Merck, average molecular weight 4,000) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were filtered and separated. After washing with 10.0 mL of ethanol and drying, slightly yellowish-white needle-like crystals were obtained. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein isothiocyanate-labeled dextran within the crystals. Quantification of fluorescein isothiocyanate-labeled sodium hyaluronate by fluorescence intensity confirmed the presence of 0.18% (w / w) fluorescein isothiocyanate-labeled dextran in the crystals.

[0190] Example 17

[0191] A 1 mL aqueous solution containing 10% taurine and 0.1% fluorescein isothiocyanate-labeled dextran (Merck, average molecular weight 150,000) was heated to 50°C to dissolve it uniformly. Then, 1.0 mL of ethanol solution was slowly and quietly added dropwise. Crystals precipitated at the interface between the two phases were filtered and separated. After washing with 10.0 mL of ethanol and drying, slightly yellowish-white needle-like crystals were obtained. Fluorescence microscopy confirmed the presence of fluorescence generated by the fluorescein isothiocyanate-labeled dextran within the crystals. Quantification of fluorescein isothiocyanate-labeled sodium hyaluronate by fluorescence intensity confirmed the presence of 0.058% (w / w) fluorescein isothiocyanate-labeled dextran in the crystals.

[0192] Example 18

[0193] A 100 mL aqueous solution containing 10% taurine and 0.1% sodium carboxymethyl dextran (manufactured by Meisang Industry Co., Ltd., with an average molecular weight of 1 million) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0194] Example 19

[0195] A 100 mL aqueous solution containing 10% taurine, 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-200, average molecular weight 1.8 million to 2.2 million), and 5.0% trimethylglycine was heated to 50°C to dissolve the hyaluronic acid evenly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0196] Example 20

[0197] A 100 mL aqueous solution containing 10% taurine, 0.1% sodium hyaluronate (manufactured by Kikkoman Chemical Co., Ltd., product name: hyaluronic acid FCH-200, average molecular weight 1.8 million to 2.2 million), and 5.0% sodium pyrrolidone carboxylate was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0198] Example 21

[0199] A 100 mL aqueous solution containing 10% taurine and 0.1% sodium hyaluronate (manufactured by Nippon Shinyaku Co., Ltd., product name: Hyaluronic Acid 3000CS, average molecular weight 3,000) was heated to 50°C to dissolve it uniformly. Then, 50 mL of ethanol solution was slowly and quietly added dropwise in 5 portions. The crystals that precipitated at the interface between the two phases were filtered and separated. After washing with 200 mL of ethanol and drying, white needle-like crystals were obtained.

[0200] Microscopic observation was performed on the crystals obtained in Comparative Examples 1-4 and Examples 1-9 to confirm the crystal morphology, the short axis and long axis of the largest crystal. Simultaneously, fluorescence microscopy was performed to observe the presence of fluorescent substances within the crystals, and the results are shown in Table 1.

[0201] Table 1

[0202] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Crystal shape columnar columnar columnar columnar Maximum particle size (short diameter) μm 664 769 534 620 Maximum particle size (major diameter) μm 2540 3247 2386 3257 Does the crystal contain fluorescence? none none none none

[0203] Table 2

[0204] Example 1 Example 2 Example 3 Example 4 Crystal shape acicular acicular acicular acicular Maximum particle size (short diameter) μm 54 47 60 35 Maximum particle size (major diameter) μm 782 621 483 834 Does the crystal contain fluorescence? have have have have

[0205] Table 3

[0206] Example 5 Example 6 Example 7 Example 8 Crystal shape granular granular granular acicular Maximum particle size (short diameter) μm 32 24 41 87 Maximum particle size (major diameter) μm 84 51 73 478 Does the crystal contain fluorescence? have have have have

[0207] Table 4

[0208] Example 9 Crystal shape acicular Maximum particle size (short diameter) μm 47 Maximum particle size (major diameter) μm 2487 Does the crystal contain fluorescence? have

[0209] Next, the crystals obtained from Comparative Examples 5-10 and Examples 10-15 were formulated into the emulsion formulations shown in Table 5 and the cosmetic oil formulations shown in Table 6, respectively. Five evaluators evaluated their user experience and scored them according to the ratings recorded in Table 7, and the average score was calculated. The presence of moisturizing sensation after 2 hours of use was also evaluated. The results are shown in Tables 8 and 9.

[0210] Regarding the emulsion, the taurine concentration in phase A was set to saturation at 25°C. Phase B was gradually added to phase A, which was heated to 80°C, while mixing with a stirrer (high-speed stirrer). After cooling to 25°C, phase C was mixed. The resulting composition was then mixed with the taurine crystals in layer D to prepare an emulsion containing crystals.

[0211] Regarding cosmetic oils, phase A is heated to 100°C and mixed, then cooled to 25°C and mixed with taurine crystals from layer B to prepare a cosmetic oil containing crystals.

[0212] Table 5

[0213]

[0214] Table 6

[0215]

[0216] Table 7

[0217] 0:00 I always felt a strong rough texture. 2 o'clock I always felt a slightly rough texture. 4 o'clock Sometimes I can feel a slightly rough texture. 6 o'clock Occasionally, a slightly rough texture can be felt. 8 o'clock Feels smooth to the touch 10 o'clock It feels very smooth to the touch.

[0218] Table 8

[0219] Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Crystal shape columnar columnar columnar columnar columnar columnar Maximum particle size (short diameter) μm 1024 782 841 985 642 574 Maximum particle size (major diameter) μm 5048 3794 4216 4823 4287 3674 Emulsion rating 0.0 0.0 0.0 0.0 0.0 0.0 Cosmetic oil rating 0.0 0.0 0.0 0.0 0.0 .0 Does it moisturize? none none none none none none

[0220] Table 9

[0221] Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Crystal shape acicular acicular acicular acicular acicular columnar Maximum particle size (short diameter) μm 32 24 45 57 37 128 Maximum particle size (major diameter) μm 485 671 379 879 412 312 Emulsion rating 8.8 9.6 9.6 9.2 10.0 8.4 Cosmetic oil rating 9.6 10.0 9.6 9.2 10.0 8.0 Does it moisturize? have have have have have have

[0222] As shown in Tables 8 and 9, the crystals obtained by the manufacturing method of the present invention form fine needle-like or columnar crystals, and by controlling the crystal size, it is confirmed that there is no roughness in the use of the formulated product, and the use experience is significantly improved.

[0223] After being prepared according to the beauty serum formulas shown in Tables 10, 11, and 12, its moisturizing properties were evaluated by five evaluators. The evaluation was conducted according to the scoring system recorded in Table 13, and the average score was calculated. The results are shown in Table 14.

[0224] Table 10

[0225]

[0226] Table 11

[0227]

[0228] Table 12

[0229]

[0230] Table 13

[0231] 0:00 I don't feel moisturized 2 o'clock It feels slightly moisturized 4 o'clock It feels moisturized 6 o'clock It feels very moisturizing

[0232] Table 14

[0233] score The composition of Comparative Example 13 2.0 The composition of Comparative Example 14 0.8 The composition of Comparative Example 15 2.4 The composition of Comparative Example 16 0.8 The composition of Comparative Example 17 0.8 The composition of Comparative Example 18 1.2 Composition of Example 21 4.0 Composition of Example 22 5.6 Composition of Example 23 4.4 Composition of Example 24 6.0 Composition of Example 25 4.0 Composition of Example 26 3.2

[0234] As shown in Table 14, the moisturizing properties of Examples 21-26, which incorporated crystals obtained by the manufacturing method of the present invention, were significantly improved. In particular, as shown in the results of Examples 22 and 24, higher moisturizing properties can be obtained by simultaneously encapsulating both a water-soluble polymer and a low-molecular-weight moisturizer within the microneedle-shaped crystals, thus confirming the advantages of encapsulating the active ingredients within the microneedle-shaped crystals.

[0235] Example 27 and Comparative Example 19

[0236] The amount of fluorescein-labeled sodium hyaluronate penetrating into the skin was determined using the microneedle-like crystals obtained in Example 2.

[0237] A composition containing 20% ​​by mass of the fine needle-like crystals obtained in Example 2, as shown in the table below, was prepared, along with a composition prepared by dissolving fluorescein-labeled sodium hyaluronate to the same concentration as a comparative example. The amount of fluorescein-labeled sodium hyaluronate penetrating the skin when the obtained compositions were applied was compared.

[0238] Table 15

[0239]

[0240] The evaluation of skin penetration was conducted using a vertical Franz diffusion cell with an effective diameter of 2.0 cm, an area of ​​3.14 square centimeters, and a receiving cell volume of 2.4 mL. Each sample was applied to the surface of isolated human skin at a dosage of 100.0 mg / square centimeter.

[0241] Four hours later, the stratum corneum of the sample skin was separated from the epidermis and dermis using an adhesive tape peeling method, and the fluorescence intensity was used to quantify the fluorophore-labeled sodium hyaluronate contained in the stratum corneum, epidermis, dermis, and receiving solution.

[0242] like Figure 4As shown, in the composition of Example 27, fluorescein-labeled sodium hyaluronate was confirmed to penetrate into the stratum corneum, epidermis, and dermis, while in the composition of Comparative Example 19, no penetration of fluorescein-labeled sodium hyaluronate was confirmed. This confirms that by encapsulating the active ingredient in microneedle-like crystals, the active ingredient can penetrate into the epidermis, dermis, and receiving fluid.

[0243] Example 28 and Comparative Example 20

[0244] The amount of fluorescein isothiocyanate-labeled dextran in the skin was determined using the microneedle-shaped crystals obtained in Example 17.

[0245] Compositions containing the fine needle-like crystals obtained in Example 17, as shown in the table below, were formulated to achieve a fluorescein isothiocyanate-labeled dextran content of 0.01% by mass. Comparative composition for dissolving fluorescein isothiocyanate-labeled dextran was also formulated. The penetration amount of fluorescein isothiocyanate-labeled dextran into the skin when the obtained compositions were applied was compared.

[0246] Table 16

[0247]

[0248] The evaluation of skin penetration was conducted using a vertical Franz diffusion cell with an effective diameter of 2.0 cm, an area of ​​3.14 square centimeters, and a receiving cell volume of 2.4 mL. Each sample was applied to the surface of isolated human skin at a dosage of 30.0 mg / square centimeter.

[0249] Four hours later, the stratum corneum of the sample skin was separated from the epidermis and dermis using an adhesive tape peeling method, and the fluorescein isothiocyanate-labeled dextran contained in the stratum corneum, epidermis, dermis, and receiving solution was quantified by fluorescence intensity.

[0250] like Figure 5 As shown, in the composition of Example 28, fluorescein isothiocyanate-labeled dextran was confirmed to penetrate into the stratum corneum, epidermis, and dermis, while in the composition of Comparative Example 20, no penetration of fluorescein isothiocyanate-labeled dextran was confirmed. This confirms that by encapsulating the active ingredient in microneedle-like crystals, the active ingredient can penetrate into the epidermis, dermis, and receiving fluid.

[0251] Examples of formulations are shown below, but the invention is not limited to these examples.

[0252] [Toner]

[0253] [A]

[0254]

[0255] [B]

[0256] 10.00% by mass of dipropylene glycol

[0257] 1,2-Pentanediol 2.50% by mass

[0258] [C]

[0259] 0.45% by mass of (acrylate / cetyl methacrylate-20) copolymer

[0260] Purified water 1.05% by mass

[0261] [D]

[0262] The crystals obtained in Example 12 were 0.30% by mass.

[0263] Phase A, heated to 80°C and homogeneously dissolved, was cooled to 35°C. Phase B was then added with stirring and stirred at 35°C for 10 minutes. Phase C was then added and stirred with a high-speed mixer for 10 minutes to ensure homogeneity. Finally, the crystals of Phase D were added and stirred for 5 minutes to obtain the cosmetic lotion composition.

[0264] The taurine microcrystals in the obtained composition are needle-shaped, with a maximum particle size (short axis) of 45 micrometers and a maximum particle size (long axis) of 379 micrometers. The composition has a smooth feel and a good user experience.

[0265] [Aqueous Gel]

[0266] [A]

[0267]

[0268] [B]

[0269] 10.00% by mass of dipropylene glycol

[0270] 1,2-Pentanediol 2.50% by mass

[0271] [C]

[0272] Polyacrylate crosspolymer-6 2.00% by mass

[0273] [D]

[0274] The crystals obtained in Example 11 were 0.30% by mass.

[0275] Phase A, heated to 80°C and homogeneously dissolved, was cooled to 35°C. Phase B was then added with stirring, and the mixture was stirred at 35°C for 10 minutes to allow fine needle-like crystals of taurine to precipitate. Subsequently, Phase C was added, and the mixture was stirred at a high speed for 10 minutes to ensure homogeneity. Then, the crystals of Phase D were added, and the mixture was stirred for 5 minutes to obtain an aqueous gel composition.

[0276] The taurine microcrystals in the obtained composition are needle-shaped, with a maximum particle size (short axis) of 24 micrometers and a maximum particle size (long axis) of 671 micrometers. The obtained composition has a smooth feel and is a composition with a good user experience.

[0277] [Emulsion]

[0278] [A]

[0279]

[0280] [B]

[0281]

[0282] [C]

[0283] 0.75% by mass of (hydroxyethyl acrylic acid / sodium acryloyl dimethyl taurate) copolymer

[0284] Isohexadecane 0.45% by mass

[0285] Polysorbate 80 0.15% by mass

[0286] 0.65% by mass of purified water

[0287] [D]

[0288] Squalane 5.00% by mass

[0289] Phase A, heated to 80°C and homogeneously dissolved, was cooled to 35°C. Phase B was then added with stirring, and the mixture was stirred at 35°C for 10 minutes to allow fine needle-like crystals of taurine to precipitate. Subsequently, the mixture of phase C was added, and the mixture was stirred at high speed for 5 minutes to ensure homogeneity. Then, phase D was added, and the mixture was stirred at high speed for 10 minutes to emulsify, yielding the emulsion composition.

[0290] The taurine microcrystals in the obtained composition were needle-shaped, with a maximum particle size (short axis) of 30 μm and a maximum particle size (long axis) of 250 μm. Analysis of the crystals extracted from the obtained composition, performed by high-performance liquid chromatography (HPLC), confirmed the presence of 3-O-ethyl ascorbic acid. Fluorescence microscopy confirmed the presence of fluorescein-labeled sodium hyaluronate within the crystals. The obtained composition had a smooth feel, resulting in a composition with a good user experience.

[0291] [O / W type cream]

[0292] [A]

[0293]

[0294] [B]

[0295] 1,3-Propanediol 15.00% by mass

[0296] 1.50% by mass of pentanediol

[0297] Phenoxyethanol 0.30% by mass

[0298] [C]

[0299] 0.75% by mass of (hydroxyethyl acrylic acid / sodium acryloyl dimethyl taurate) copolymer

[0300] Polysorbate 80 0.15% by mass

[0301] 0.65% by mass of purified water

[0302] [D]

[0303] 0.65% by mass of squalane

[0304] Phase A, heated to 80°C and homogeneously dissolved, was cooled to 35°C. Phase B was then added with stirring, and the mixture was stirred at 35°C for 10 minutes to allow fine needle-like crystals of taurine to precipitate. Subsequently, the mixture of phase C was added, and the mixture was stirred at a high speed for 5 minutes to ensure homogeneity. Then, phase D was added, and the mixture was stirred at a high speed for 10 minutes to emulsify, yielding an O / W type cream composition.

[0305] The taurine microcrystals in the obtained composition were needle-shaped, with a maximum particle size (short axis) of 30 μm and a maximum particle size (long axis) of 250 μm. Analysis of the crystals extracted from the obtained composition, performed by high-performance liquid chromatography (HPLC), confirmed the presence of nicotinamide. Fluorescence microscopy confirmed the presence of fluorescein-labeled chondroitin C sulfate sodium within the crystals. The obtained composition had a smooth feel, resulting in a composition with a good user experience.

[0306] [W / O type cream]

[0307] [A]

[0308]

[0309] [B]

[0310] 1,3-Propanediol 9.00% by mass

[0311] 1,2-Hexanediol 0.70% by mass

[0312] Phenoxyethanol 0.30% by mass

[0313] [C]

[0314]

[0315] Phase A, heated to 80°C and homogeneously dissolved, was cooled to 35°C. Phase B was then added with stirring, and the mixture was stirred at 35°C for 10 minutes to allow fine needle-like crystals of taurine to precipitate. This mixture was then added to the homogeneously mixed Phase C within 5 minutes using a high-speed mixer, followed by another 10 minutes of high-speed stirring to emulsify and obtain a W / O cream composition.

[0316] The taurine microcrystals in the obtained composition were needle-shaped, with a maximum particle size (short axis) of 25 μm and a maximum particle size (long axis) of 200 μm. Analysis of the crystals extracted from the obtained composition, performed by high-performance liquid chromatography (HPLC), confirmed the presence of L-ascorbic acid-2-glucosinolate. Fluorescence microscopy confirmed the presence of fluorescein amine-labeled heparin sulfate sodium within the crystals. The obtained composition had a smooth feel, resulting in a composition with a good user experience.

[0317] [Cosmetic Oil]

[0318] [A]

[0319]

[0320] [B]

[0321] 0.50% by mass of taurine micro-needle crystals obtained in Example 13

[0322] Phase A is heated to 100°C and stirred until homogeneous, then cooled to 35°C. Phase B is added and stirred until evenly dispersed to obtain the cosmetic oil composition.

[0323] The taurine microcrystals in the obtained composition are needle-shaped, with a maximum particle size (short axis) of 57 micrometers and a maximum particle size (long axis) of 879 micrometers. The obtained composition has a smooth feel and is a composition with a good user experience.

[0324] Examples of fluorescence micrographs of the crystals obtained in this invention are shown in the figure. Figures 1-3 This crystal was obtained through Example 2.

Claims

1. A topical skin preparation composition, characterized in that, A composite micro-needle-shaped crystal containing high molecular weight active ingredients within a crystal of biologically soluble substances.

2. The topical skin composition according to claim 1, characterized in that, The composite microneedle-shaped crystals are at least partially contained in a dispersed state.

3. The topical skin composition according to claim 1 or 2, characterized in that, The composite microneedle-shaped crystals have a space, and the effective polymer components are encapsulated within this space.

4. The topical skin composition according to any one of claims 1 to 3, characterized in that, The composite microneedle-shaped crystals have a diameter of less than 150 micrometers and a length of less than 3000 micrometers.

5. The topical skin composition according to any one of claims 1 to 4, characterized in that, The biosoluble substances are selected from a group consisting of amino acids, peptides, and vitamins.

6. The topical skin composition according to any one of claims 1 to 5, characterized in that, The biosoluble substance is taurine.

7. The topical skin composition according to any one of claims 1 to 6, characterized in that, The inclusion rate of the polymeric active ingredient in taurine crystals is 0.001% to 30%.

8. The topical skin composition according to any one of claims 1 to 5, characterized in that, The biosoluble substance is p-cymene-5-ol.

9. The topical skin composition according to any one of claims 1 to 5, characterized in that, The biosoluble substance is gallic acid.

10. The topical skin composition according to any one of claims 1 to 8, characterized in that, The active polymeric components are selected from one or more of the following groups: hyaluronic acid and its salts, hydrolyzed hyaluronic acid and its salts, acetylated hyaluronic acid and its salts, acylated hyaluronic acid and its salts, other hyaluronic acid derivatives and their salts, chondroitin sulfate and its salts, chondroitin sulfate derivatives and their salts, elastin, hydrolyzed elastin, water-soluble collagen, determinated collagen, acylated hydrolyzed collagen, succinylated determinated collagen, succinylated determinated collagen, water-soluble collagen cross-linked polymer, water-soluble elastin, water-soluble proteoglycans, heparin-like substances, 2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer, 2-methacryloyloxyethyl phosphorylcholine-stearyl methacrylate copolymer, glyceryl-N-(2-methacryloyloxyethyl)carbamate-stearyl methacrylate copolymer, dextran, carboxymethyl dextran and its salts, and Suizenji nori polysaccharides.

11. Further description: The topical skin composition according to any one of claims 1 to 10 is characterized in that, One or more of the polymeric active ingredients are dissolved or dispersed in the medium of the topical skin composition.

12. A method for manufacturing taurine composite microneedle-like crystals containing a high molecular weight active ingredient in the crystal, characterized in that, Crystal growth is induced under conditions where an aqueous solution (A) of taurine, a biosoluble substance, dissolved in water is mixed or contacted with a liquid substance (B) with low taurine solubility. This is achieved by dissolving or dispersing the active polymeric component in the aqueous solution (A) or the liquid substance (B), and by including the active polymeric component in the crystal as it grows.

13. The manufacturing method according to claim 12, characterized in that, The liquid substance (B) is a water-soluble organic solvent.

14. The manufacturing method according to claim 13, characterized in that, The water-soluble organic solvent is selected from one or more of the following groups: ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, glycerol, diglycerol, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerol, and ethylhexylglycerol.

15. The manufacturing method according to any one of claims 12 to 14, characterized in that, The concentration of the effective polymeric component in the aqueous solution (A) or the liquid substance (B) is 0.001% by mass or more.

16. The manufacturing method according to any one of claims 12 to 15, characterized in that, The concentration of taurine in the aqueous solution (A) is 3–28% by mass.

17. The manufacturing method according to any one of claims 12 to 16, characterized in that, The proportion of the liquid substance (B) relative to the total amount of the aqueous solution (A) is less than 50% by mass.

18. A method for manufacturing a topical skin composition, characterized in that, The topical skin composition contains composite microneedle-shaped crystals in which a polymeric active ingredient is contained within the crystals. The method includes the following steps: inducing crystal growth under conditions where an aqueous solution (A) formed by dissolving taurine in water is mixed or contacted with a liquid substance (B) with low taurine solubility; wherein the polymeric active ingredient dissolved or dispersed in the aqueous solution (A) or the liquid substance (B) is contained in the crystals along with the crystal growth; and the composite microneedle-shaped crystals obtained in the crystal growth step are formulated into the topical skin composition.

19. The manufacturing method according to claim 18, characterized in that, The concentration of the effective polymeric component in the aqueous solution (A) or the liquid substance (B) is 0.001% by mass or more.

20. The manufacturing method according to claim 18 or 19, characterized in that, The concentration of taurine in the aqueous solution (A) is 3–28% by mass.

21. The manufacturing method according to any one of claims 18 to 20, characterized in that, The proportion of the liquid substance (B) relative to the total amount of the aqueous solution (A) is less than 50% by mass.

22. The manufacturing method according to any one of claims 18 to 21, characterized in that, The liquid substance (B) is a water-soluble organic solvent selected from one or more of the following groups: ethanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, isopentyl glycol, diethylene glycol, dipropylene glycol, glycerol, diglycerol, 1,2-pentanediol, 1,2-hexanediol, cyclohexylglycerol, and ethylhexylglycerol.

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