Method for producing the composition and liposome-containing composition

Abstract

To provide a novel agent applicable to human skin. [Solution] The composition of the present disclosure comprises liposomes and a dispersion medium for dispersing the liposomes, wherein the liposomes comprise an amphoteric surfactant, an anionic substance, a complex lipid, and sterols, and the content of the amphoteric surfactant is 1 to 20% by mass based on the total mass of the liposomes.

Description

[Technical Field]

[0001] This disclosure relates to compositions and methods for producing liposome-containing compositions. [Background technology]

[0002] In the pharmaceutical and cosmetic fields, liposomes, which encapsulate target substances such as drugs or active ingredients, are used as a delivery technology (drug delivery system: DDS) to deliver these target substances into the human body. As an application of these liposomes, research is being conducted on the development of, for example, pH-responsive liposomes. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2019 / 045097 [Overview of the project] [Problems that the invention aims to solve]

[0004] The inventors attempted to develop pH-responsive liposomes and found that lauryl betaine was effective as a substance that imparts the aforementioned pH responsiveness. However, concerns arose regarding the irritation caused by lauryl betaine when using liposomes containing lauryl betaine on the skin.

[0005] Therefore, this disclosure aims to provide, for example, a novel composition applicable to human skin that has reduced irritancy. [Means for solving the problem]

[0006] To achieve the above objective, the composition of the present disclosure comprises liposomes and a dispersion medium for dispersing the liposomes, wherein the liposomes comprise an amphoteric surfactant, an anionic substance, a complex lipid, and sterols, and the content of the amphoteric surfactant is 1 to 20% by mass based on the total mass of the liposomes.

[0007] The method for producing the liposome-containing composition of this disclosure includes a production step of generating liposomes from an amphoteric surfactant, an anionic substance, a complex lipid, and sterols, wherein the content of the amphoteric surfactant is 1 to 20% by mass, based on the total mass of the liposomes. [Effects of the Invention]

[0008] According to this disclosure, for example, it is possible to provide novel compositions that are less irritating and applicable to human skin. [Modes for carrying out the invention]

[0009] <Definition> In this specification, "liposome" means a vesicle having a lipid bilayer dispersed in an aqueous solvent. In the liposome, a structure in which the lipid bilayer is single is called a single-lamellar structure, and a structure in which the lipid bilayer is multiple is called a multi-lamellar structure.

[0010] In this specification, "surfactant" means a compound having a hydrophilic group and a hydrophobic (lipophilic) group. Examples of surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants. Anionic surfactants mean surfactants that dissociate into anions in aqueous solution. Cationic surfactants mean surfactants that dissociate into cations in aqueous solution. Amphoteric surfactants mean surfactants that dissociate into cations or anions in aqueous solution depending on the pH of the aqueous solution. Nonionic surfactants mean surfactants that do not dissociate into ions in aqueous solution.

[0011] In this specification, "anionic substance" means a substance that acquires a negative charge when dissolved in water.

[0012] In this specification, "sterols" means compounds containing a cyclopentanophenanthrene carbon skeleton.

[0013] The following explanation of this disclosure will be based on examples, but this disclosure is not limited to the following examples and can be modified and implemented as desired. Furthermore, the descriptions in this disclosure and each embodiment are interchangeable unless otherwise specified. In this specification, the expression "~" is used to mean including the numerical or physical values ​​before and after it. Also, in this specification, the expression "A and / or B" includes "A only," "B only," and "both A and B."

[0014] <Composition> In one embodiment, the Disclosure provides, for example, a composition applicable to human skin that is less irritating. The compositions of the Disclosure comprise liposomes and a dispersion medium for dispersing the liposomes, wherein the liposomes comprise an amphoteric surfactant, anionic substances, complex lipids, and sterols, and the content of the amphoteric surfactant is 1 to 20% by mass based on the total mass of the liposomes. In the following description, unless otherwise specified, the descriptions of the agents of the Disclosure may be incorporated into the descriptions of the corresponding compositions.

[0015] As a result of diligent research, the present inventors have found that by adjusting the content of the amphoteric surfactant contained in the liposomes in the composition to 1 to 20% by mass, the irritation when the composition is applied to the skin is improved, and the penetration into the skin when the composition is applied is also improved, leading to the establishment of this disclosure. It is presumed that the improvement in skin penetration is due to the reduction in the membrane strength of the liposomes, which makes the liposomes softer. However, this presumption does not limit this disclosure in any way. Therefore, the composition of this disclosure can provide, for example, a highly permeable composition that can suppress the occurrence of erythema caused by irritation when applied to the skin.

[0016] The amphoteric surfactant includes, for example, N-alkyl-N,N-dimethylamino acid betaines containing lauryldimethylaminoacetic acid betaine (lauryl betaine); fatty acid amide alkyl-N,N-dimethylamino acid betaines containing cocamidopropyl betaine and lauramidopropyl betaine; imidazoline type betaines containing sodium cocoamphoacetate and sodium lauroamphoacetate; alkyl sulfobetaines containing alkyldimethyltaurine; sulfate type betaines containing alkyldimethylaminoethanol sulfate ester; and phosphate type betaines containing alkyldimethylaminoethanol phosphate ester; etc.

[0017] The content of the amphoteric surfactant is, for example, 1 to 20% by mass, preferably 1 to 15% by mass, 2 to 18% by mass, 3 to 15% by mass, 3 to 10% by mass, or 5 to 6% by mass based on the total mass of the liposome. The content of the amphoteric surfactant may be, for example, the concentration of one kind of amphoteric surfactant or the total concentration of a plurality of kinds of amphoteric surfactants. By setting the content of the amphoteric surfactant in the composition of the present disclosure to 1 to 20% by mass (for example, by setting it to 1 to 6.9% by mass or 1 to 6.5% by mass), the emulsified state of the liposome in an aqueous solvent can be preferably maintained, and the occurrence of cloudiness, aggregation, or precipitation can be suppressed. Further, in the composition of the present disclosure, for example, by setting the content of the amphoteric surfactant to 1 to 20% by mass, the content of the amphoteric surfactant can be relatively reduced, so that the irritation when the composition of the present disclosure is applied to the skin can be suppressed.

[0018] The total mass of the liposome means the total mass of the components that can constitute the liposome. Specifically, the total mass of the liposome is, for example, the total mass of surfactants such as the amphoteric surfactant, anionic substances, and lipids such as complex lipids and sterols.

[0019] The anionic substance includes, for example, diacyl glycerol hemisuccinate, diacyl glycerol hemimalonate, diacyl glycerol hemiglutarate, diacyl glycerol hemialtate, diacyl glycerol hemicyclohexane-1,4-dicarboxylic acid, fatty acids, etc. Examples of the fatty acids include oleic acid, myristic acid, palmitic acid, stearic acid, nervonic acid, behenic acid, etc. The anionic substance is preferably a saturated fatty acid that is solid at room temperature (10°C to 30°C), and preferably palmitic acid.

[0020] The content of the anionic substance is, for example, 1 to 20% by mass based on the total mass of the liposome, preferably 1 to 15% by mass, 4 to 15% by mass, 5 to 10% by mass, or 6 to 9% by mass, and more preferably 8 to 9% by mass. By setting the content of the anionic substance to 20% by mass or less based on the total mass of the liposome, the composition of the present disclosure can preferably maintain the emulsified state of the liposome in the aqueous solvent and suppress the occurrence of cloudiness, aggregation, or precipitation.

[0021] In the liposome, the mass (M

[0022] , ) of the zwitterionic surfactant and the mass (M a ) of the anionic substance, the mass ratio (M z / M a ) is, for example, 0.2 to 1, 0.3 to 0.8.

[0022] The aforementioned complex lipid is a lipid containing phosphoric acid, sugar, sulfur, or a nitrogen-containing base in its molecule. The aforementioned complex lipid is not particularly limited and includes, for example, phospholipids, glycolipids, lipoproteins, sulfolipids, etc., and is preferably a phospholipid. The aforementioned phospholipid is not particularly limited as long as it is a lipid having a phosphate ester moiety in its molecular structure and capable of forming a bilayer film. The aforementioned phospholipid may be, for example, a natural product extracted or purified from plants or animals, a chemically synthesized product, or a product that has been processed by hydrogenation, hydroxylation, etc. Examples of the phospholipids include glycerophospholipids such as phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, and phosphatidic acid; sphingophospholipids such as sphingomyelin and ceramide citritin; lecithins such as soy lecithin and egg yolk lecithin; and hydrogenated lecithins such as hydrogenated soy lecithin and hydrogenated egg yolk lecithin. Preferably, phosphatidylcholine or hydrogenated phosphatidylcholine is used. The complex lipid may be one type or multiple types.

[0023] The content of the complex lipid is, for example, 50-95% by mass, 60-90% by mass, or 65-75% by mass, based on the total mass of the liposomes. The content of the complex lipid may be, for example, the concentration of one type of complex lipid or the total concentration of multiple types of complex lipids.

[0024] In the liposome, the (M) of the zwionic surfactant z ) and the mass (M) of the composite lipid. c ) and the mass ratio (M z / M c For example, these ranges are 0.02 to 0.1 and 0.03 to 0.09.

[0025] Examples of the sterols include plant sterols (phytosterols), animal sterols (zoosterols), etc. Examples of the plant sterols include sitosterol, stigmasterol, campesterol, brassicasterol, etc. Examples of the animal sterols include cholesterol; cholesterol derivatives such as dihydrocholesterol, dehydrocholesterol, cholesteryl oleate, cholesteryl isostearate, cholesteryl hydroxystearate, polyoxyethylene cholesteryl ether, etc.; etc., and preferably cholesterol. The sterols may be used, for example, singly or in combination of two or more.

[0026] The content of the sterols is, for example, 5 to 30% by mass, 10 to 20% by mass, or 15 to 20% by mass based on the total mass of the liposome. The content of the sterols may be, for example, the concentration of one type of sterols or the total concentration of two or more types of sterols.

[0027] In the liposome, the mass (M z ) of the zwitterionic surfactant and the mass (M s ) of the sterols, and the mass ratio (M z / M s ) are, for example, 0.10 to 0.50, 0.15 to 0.40.

[0028] The liposome preferably contains lauryldimethylaminoacetate betaine, palmitic acid, phosphatidylcholine or hydrogenated phosphatidylcholine, and cholesterol. The liposome contains, for example, 1 to 20% by mass of lauryldimethylaminoacetate betaine, 1 to 20% by mass of palmitic acid, 50 to 93% by mass of phosphatidylcholine and / or hydrogenated phosphatidylcholine, and 5 to 30% by mass of cholesterol based on the total mass of the liposome.

[0029] The dispersion medium is not particularly limited as long as it is a dispersion medium capable of dispersing the liposomes, and examples include aqueous solvents and organic solvents. Examples of aqueous solvents include tap water, natural water, hard water, soft water, seawater, deep-sea water, purified water, distilled water, ion-exchanged water, pure water, and ultrapure water (collectively referred to as "water"). Examples of organic solvents include butylene glycol and glycerin.

[0030] When the dispersion medium contains the aqueous solvent and the organic solvent, the combination of the aqueous solvent and the organic solvent is not particularly limited. Examples of such combinations include water and butylene glycol, water and glycerin, and so on.

[0031] When the combination of the aqueous solvent and the organic solvent is a combination of water and butylene glycol, the mass ratio (W:BG) of water (W) to butylene glycol (BG) is preferably 2:1 to 20:1, and more preferably 10:1 to 20:1. By setting the W:BG ratio to 2:1 to 20:1, the formation of sediment in the composition of the disclosure can be suppressed.

[0032] When the combination of the aqueous solvent and the organic solvent is a combination of water and glycerin, the mass ratio (W:G) of water (W) to glycerin (G) can be 2:1 to 20:1, 10:1 to 20:1, etc. By setting the W:G ratio to 2:1 to 20:1, the formation of sediment in the composition of this disclosure can be suppressed.

[0033] The liposome may, for example, encapsulate a target substance (in this case, the target substance is also referred to as the "encapsulation"). The encapsulation is not particularly limited and may include, for example, compounds used in pharmaceuticals, quasi-drugs, cosmetics, foods, etc. The encapsulation may include, for example, water-soluble substances, lipid-soluble substances, etc.The aforementioned inclusions include, for example, hyaluronic acid, glutathione, tranexamic acid, Sanguisorba officinalis extract, ascorbic acid, ascorbic acid stearate, sodium ascorbate disodium ascorbic acid sulfate, aspartic acid, aspartame, acetylglucosamine, acetylglutamic acid, acetylcysteine, acetylpantothenyl ethyl ester, adenosine triphosphate disodium, adenosine monophosphate disodium, ε-aminocaproic acid, γ-aminobutyric acid, allantoin, and allantoin-β-glycyrrhetinic acid. Albumin, inositol, erythritol, glucosamine hydrochloride, pyridoxine hydrochloride, oxyproline, orotic acid, hydrolyzed elastin, caffeine hydrate, chondroitin sulfate sodium, cyanocobalamin, water-soluble elastin, taurine, palmitoyl methyl taurate sodium, myristoyl methyl taurate sodium, thiamine hydrochloride, theanine, deoxyribonucleic acid, ascorbyl palmitate, pantothenyl alcohol, sodium pantothenate, calcium pantothenate, pyridoxine, phytic acid, placenta extract, Flavin adenine dinucleotide disodium dihydrate, anhydrous caffeine, riboflavin, riboflavin butyrate, riboflavin phosphate, resorcinol, levulinic acid, glycine, arginine, lysine solution, lauroyl lysine, aspartic acid, palmitoyl aspartic acid, cysteine, methionine, glutamic acid, threonine, serine, tyrosine, histidine, proline, salicylic acid, nicotinamide, retinyl palmitate, alginic acid, gamma-undecalactone, perilla oil, estradiol, estrone, ergocalcin Examples include ferol, β-carotene, glucosamine, cholecalciferol, tocopherol acetate, retinol acetate, salicylic acid, shikonin, ascorbyl dipalmitate, pyridoxine dipalmitate, natural vitamin E, α-tocopherol, horse oil, γ-nonalactone, bisabolol, vitamin A oil, hinokitiol, fumaric acid, powdered vitamin A, tocopherol linoleate, δ-tocopherol, tocopherol linoleate, isoleucine, phenylalanine, valine, leucine, and ascorbyl tetra-2-hexyldecanoate.

[0034] The content of the aforementioned encapsulants can be, for example, 0.5 to 10% by mass, 1 to 8% by mass, or 2 to 5% by mass, based on the total mass of the liposomes.

[0035] The compositions of this disclosure may further include, for example, a preservative. Examples of such preservatives include phenoxyethanol and methyl parahydroxybenzoate.

[0036] The compositions of this disclosure may further include, for example, a thickening agent. Examples of such thickening agents include xanthan gum, (acrylates / alkyl acrylate (C10-30)) crosspolymer, hydroxyethylcellulose, and the like. By including such thickening agents, the compositions of this disclosure can suppress the formation of sediment.

[0037] The compositions of this disclosure may further include, for example, a pH adjuster. Examples of such pH adjusters include sodium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate anhydrous, sodium hydroxide, citric acid, acetic acid, triethanolamine, and the like.

[0038] Preferably, the liposomes are pH-responsive liposomes. In this disclosure, "pH-responsive" means, for example, that the zeta potential of the liposomes shifts from positive to negative under any pH condition within a predetermined range. Specifically, when dispersed in an aqueous medium at a pH of 5 or lower, the zeta potential of the liposomes is positive; when dispersed in an aqueous medium at a pH of 8 or higher, the zeta potential of the liposomes is negative; and when dispersed in an aqueous solvent between pH 5 and 8, the zeta potential of the liposomes shifts from positive to negative as the pH value increases. Therefore, it is thought that the liposomes contained in the composition of this disclosure exist stably in an aqueous medium at a pH of 5 or lower, retaining bactiol, and become unstable under pH conditions where the zeta potential becomes zero in an aqueous medium between pH 5 and 8, undergoing membrane fusion and releasing the contents. Known methods can be used to measure the zeta potential. Specifically, examples of methods for measuring the zeta potential include electrophoretic light scattering (laser Doppler method).

[0039] The shape of the liposome is not particularly limited and may be a multilayer liposome or a monolayer liposome.

[0040] The average particle size of the liposomes is preferably 50 to 1100 nm, more preferably 50 to 200 nm or 50 to 100 nm. The average particle size of the liposomes can be measured by known methods, for example, dynamic light scattering. The average particle size of the liposomes can be adjusted as appropriate depending on the application. For example, when intended for administration into a living organism, it is preferable to adjust the average particle size of the liposomes to 200 nm or less. The average particle size of the liposomes can be adjusted, for example, by passing them through a filter with a small pore size using an extruder. When the average particle size of the liposomes is about 100 nm or less and the liposomes are single-layer liposomes, the liposomes are, for example, uniform in size and thermodynamically stable, and have good skin penetration even when used as cosmetics.

[0041] <Manufacturing method> In another embodiment, the Disclosure provides a method for producing a liposome-containing composition. The method of production of the Disclosure comprises a production step of generating liposomes from an amphoteric surfactant, an anionic substance, a complex lipid, and sterols, wherein the content of the amphoteric surfactant is 1 to 20% by mass, based on the total mass of the liposomes. The method of production of the Disclosure can be described by reference to the description of the composition of the Disclosure.

[0042] The manufacturing method of the present disclosure involves, for example, preparing a dispersion medium (first prepared solution) such as an aqueous solvent containing the encapsulated material, and a dispersion medium (second prepared solution) containing the components constituting the lipid membrane of the liposome.

[0043] The first prepared solution can be prepared, for example, by dispersing the encapsulated substance in the dispersion medium. The dispersion can be carried out by mixing the dispersion medium and the encapsulated substance. The first prepared solution may further contain, for example, a pH adjuster. The dispersion medium is preferably an aqueous solvent. The temperature during the dispersion is not particularly limited as long as it is a temperature at which the encapsulated substance can disperse in the dispersion medium, and examples include 50-90°C, 70-90°C, 75-85°C, etc. The time during the dispersion is not particularly limited as long as it is a time at which the encapsulated substance can disperse in the dispersion medium, and is preferably 3 minutes to 1 hour, more preferably 5 minutes to 30 minutes, or 10 minutes.

[0044] The second preparation solution can be prepared, for example, by mixing and homogenizing or dispersing components that impart pH responsiveness to the liposomes, such as the amphoteric surfactant and the anionic substance, and components that constitute the lipid membrane of the liposomes, such as the complex lipids and sterols, with the dispersion medium. For this reason, the preparation of the second preparation solution can be referred to as the production step. The dispersion medium is preferably an organic solvent. The mixing is preferably done by stirring without creating bubbles. The mixing temperature is not particularly limited as long as it is a temperature at which the components that impart pH responsiveness to the liposomes and the components that constitute the lipid membrane of the liposomes can be dispersed in the dispersion medium, for example, 70-90°C, 75-85°C, etc. The dispersion time is not particularly limited as long as it is a time at which the components that impart pH responsiveness to the liposomes and the components that constitute the lipid membrane of the liposomes can be dispersed in the dispersion medium, preferably 3 minutes to 1 hour, more preferably 5 minutes to 30 minutes, or 10 minutes.

[0045] The manufacturing method of the present disclosure may include a dispersion step of dispersing the liposomes produced in the production step in a dispersion medium. In the dispersion step, first, the first preparation solution and the second preparation solution are mixed. The temperature during the mixing is not particularly limited as long as it is a temperature at which the first preparation solution and the second preparation solution can be mixed, for example, 70 to 90°C, 75 to 85°C, etc. The time during the mixing is not particularly limited as long as it is a time at which the first preparation solution and the second preparation solution can be mixed, for example, 15 minutes to 1 hour, 30 minutes, etc. After the mixing, the dispersion step is performed to cool the mixture of the first preparation solution and the second preparation solution. The temperature during the cooling is not particularly limited as long as it is a temperature at which liposomes can be dispersed in the mixture, for example, 10 to 40°C, 15 to 30°C, etc.

[0046] The manufacturing method of the present disclosure may involve performing extruder treatment, sonication, French press treatment, homogenization treatment, etc., after the generation step or the dispersion step in order to adjust the particle size of the liposomes.

[0047] The manufacturing method of the present disclosure may further mix a third prepared solution containing a thickener and / or preservative with the mixture of the first and second prepared solutions. The third prepared solution can be prepared, for example, by mixing the thickener and / or preservative with the dispersion medium. The dispersion medium is preferably an aqueous solvent. The temperature at which the mixture of the first and second prepared solutions and the third prepared solution are mixed is not particularly limited, as long as the mixture and the third prepared solution can be mixed at that temperature, for example, 15 to 30°C. The time for mixing the mixture of the first and second prepared solutions and the third prepared solution is not particularly limited, as long as the mixture and the third prepared solution can be mixed at that time, for example, 12 to 36 hours, 18 to 24 hours, 20 to 25 hours, etc.

[0048] After mixing the mixture of the first and second preparations and the third preparation, the manufacturing method of the present disclosure may be sieved, for example, to remove foreign matter or to adjust the particle size of the liposomes. The sieving can be carried out, for example, using a sieve.

[0049] <Use> The conditions for use (administration conditions) of the compositions disclosed herein are not particularly limited, and the administration form, timing of administration, dosage, etc. can be appropriately set depending on the type of target to be administered, etc.

[0050] The preferred method of administration of the compositions of this disclosure is parenteral administration. Parenteral administration includes transdermal administration, application (contact) to the skin, etc. Application to the skin may also include application to the oral mucosa, i.e., application or contact to epithelial cells in the oral cavity. Furthermore, in addition to or instead of application to the skin surface, application to the skin may also include administration or injection into the skin or subcutaneously via the skin surface. Administration or injection into the skin via the skin surface can be carried out, for example, using a microneedle.

[0051] When the composition of this disclosure is used for transdermal administration or application to the skin (hereinafter also referred to as "topical skin preparation"), the form of the topical skin preparation may be an ampoule, capsule, powder, granules, liquid, gel, bubbles, emulsion, sheet, mist, spray, etc., depending on the form of use. Examples of the forms of use include pharmaceuticals; quasi-drugs; topical or systemic topical skin preparations; medicinal and / or cosmetic preparations for application to the scalp and hair; bath preparations for use in bathwater; other preparations; etc. Examples of topical or systemic skin preparations include basic cosmetics such as lotions, emulsions, creams, ointments, oils, and packs; facial cleansers or skin cleansers such as bar soaps, liquid soaps, and hand washes; massage agents, cleansing agents, depilatory agents, hair removal agents, shaving agents, aftershave lotions, preshave lotions, shaving creams; makeup cosmetics such as foundations, lipsticks, blushes, eyeshadows, eyeliners, and mascaras; perfumes; nail care products, nail polish, nail polish removers; poultices, plasters, tapes, sheets, patches, aerosols; and mouthwashes and other gargles. Examples of medicinal and / or cosmetic preparations applied to the scalp and hair include shampoos, conditioners, hair treatments, pre-hair treatments, permanent solutions, hair dyes, hair styling products, hair tonics, hair growth and nourishing products, poultices, plasters, tapes, sheets, aerosols, etc. Examples of other preparations include deodorants or antiperspirants, antiperspirants, sanitary products, sanitary cotton, wet wipes, etc. [Examples]

[0052] Next, examples of the present invention will be described. However, the present invention is not limited to the following examples. Unless otherwise specified, commercially available reagents were used according to their protocols. In these examples, the units % indicated for the amounts of various extracts, etc., mean %(w / v).

[0053] [Example 1] The composition of this disclosure was prepared, and its permeability to the substratum corneum was confirmed.

[0054] (1) Preparation of the composition Composition 1 of Example 1 was prepared by combining the various components listed in Table 1 below using the following method. Specifically, 392.5 g of purified water (dispersion medium) was heated to 75-85°C to obtain solution I. In addition, 48.375 g of 1,3-butylene glycol (solvent, butylene glycol, manufactured by Daicel Corporation, Nippon Refine Co., Ltd., or Higher Alcohol Industry Co., Ltd.) was heated to 75-85°C to obtain the heated 1,3-butylene glycol. Next, the following were added to the heated 1,3-butylene glycol in order, and the mixture was stirred and dissolved without creating foam to obtain solution II. • 2.3g of hydrogenated phosphatidylcholine (complex lipid, Phospholipon 90H, manufactured by H. Holstein Co., Ltd.) • 0.45g of cholesterol (sterols, Marine Cholesterol, manufactured by Nippon Suisan Kaisha, Ltd.) • 0.25g of palmitic acid (anionic substance, NAA-160, manufactured by NOF Corporation) • 0.25g of lauryl betaine (amphoionic surfactant, NIKKOL AM-301, manufactured by Nikko Chemicals Co., Ltd., containing 35% lauryl betaine) • 5g of polysorbate 60 (solubilizer, EMALEX TS-10V, manufactured by Nippon Emulsion Co., Ltd.) • 2.5g of bakuchiol (manufactured by BIB Corporation)

[0055] Subsequently, the above-mentioned solution II was added to 48.375 g of concentrated glycerin (dispersant, cosmetic-grade concentrated glycerin, manufactured by Iwaki Co., Ltd.) which was heated and stirred at 80-85°C, and homogenized to obtain solution III. After homogenization, solution I and solution III were mixed under heating and allowed to cool to obtain a mixture. The mixture was then filtered through a 0.4 μm membrane filter. After filtration, 250 g of purified water was mixed to obtain the composition of Example 1.

[0056] The composition of the composition of Example 1 is shown in Table 1 below, and the ratio of the components contained in the composition of Example 1 is shown in Table 2 below.

[0057] [Table 1]

[0058] [Table 2]

[0059] (2) Evaluation of stratum corneum permeability Next, the stratum corneum permeability of the composition from Example 1 was investigated. Specifically, a Strat-M™ membrane was attached to a static diffusion cell (Franz cell). The Strat-M™ membrane has a structure similar to human skin and is therefore commonly used to evaluate permeability to the stratum corneum. The receptor solution on the reservoir side was prepared by dissolving 0.9 g of sodium chloride and 0.1 g of polysorbate 60 in water, and then adding water to make a total volume of 100 g. 1.0 ml of the composition from Example 1 was used on the donor side. The entire Franz cell was kept at 32°C for 24 hours, after which the receiver solution was collected. The solution was then filtered through a 0.45 μm membrane filter, and the amount of bactiol filtration into the receiver solution was quantified by HPLC analysis, and the shaking rate was calculated. The procedure was the same as in Example 1, except that the control described in Table 1 above was used instead of the composition from Example 1.

[0060] (HPLC measurement conditions) HPLC system: SHIMADZU LC-20ADxr, SPD-M20A (manufactured by Shimadzu Corporation) Column: Mightysil RP-18GP 250 x 4.6 mm (particle size 5 μm) (manufactured by Kanto Chemical Co., Ltd.) Flow rate: 1.0mL / min Detector wavelength: 261nm Mobile phase: CH3CN:water = 70:30

[0061] As a result, the penetration rate of the composition of Example 1 was 0.069%, while the penetration rate of the control was 0.031%. These results indicate that the composition of Example 1 has higher permeability to the back of Strat-M (trademark) compared to the control.

[0062] [Manufacturing Example 1] The composition of this disclosure was prepared by combining the various components listed in Table 3 below using the following method. 398.97 g of purified water (dispersion medium) was mixed with 0.65 g of sodium dihydrogen phosphate (pH adjuster, manufactured by Taihei Chemical Industry Co., Ltd.), 0.30 g of sodium monohydrogen phosphate (pH adjuster, manufactured by Taihei Chemical Industry Co., Ltd.), 0.02 g of hyaluronic acid IW120 (inclusion), 0.02 g of acetylated hyaluronic acid (inclusion), 0.02 g of hydrolyzed hyaluronic acid hyalooligo (inclusion), and 0.02 g of glutathione (inclusion). The mixture was stirred and dissolved to obtain solution I. Next, 48.375 g of 1,3-butylene glycol (dispersion medium, butylene glycol) and 48.375 g of glycerin (dispersion medium, manufactured by Iwaki Corporation) were mixed and heated to 75-85°C. After heating, while confirming that the product temperature was 80-85°C when each raw material was added, 2.05 g of hydrogenated phosphastidylcholine (complex lipid, Phospholipon 90H, manufactured by H. Holstein Co., Ltd.), 0.45 g of cholesterol (sterols, Marine Cholesterol, manufactured by Nippon Suisan Kaisha, Ltd.), 0.25 g of palmitic acid (anionic substance, NAA-160, manufactured by NOF Corporation), and 0.5 g of lauryl betaine (amphoionic surfactant, NIKOL AM-301, 35% aqueous solution product, manufactured by Nikko Chemicals Co., Ltd.) were added in order, and the mixture was stirred and dissolved without creating foam to obtain solution II. Then, while confirming that the product temperature was 80-85°C, solution I and solution II were mixed. After mixing, the mixture was stirred under conditions of 75-85°C for 30 minutes. After stirring, the mixture was stirred and allowed to cool until the product temperature reached 15-30°C to obtain solution III. Subsequently, the aforementioned solution III was processed in an extruder to obtain solution IV. The extruder conditions were set to a processing pressure of 10-20 psi. Next, while stirring, 488 g of purified water (dispersion medium), 2 g of Nomcoat (xanthan gum, thickener, manufactured by Nisshin Oillio Group Ltd.), and 10 g of phenoxyethanol (preservative) were mixed and stirred until a clear, viscous liquid was obtained to obtain solution V. Then, equal amounts of solution IV and solution V were mixed and stirred overnight.After the stirring described above, the mixture was processed using a sieve equivalent to 100 mesh (equivalent to a mesh opening of 149 μm) or a strainer to obtain the composition of the example (Production Example 1). The water evaporated during these processes was replenished as needed.

[0063] [Table 3]

[0064] Table 4 below shows the ratio of each component in Production Example 1. Note that "liposome" in Table 4 refers to the total weight of the liposomes described above, specifically the sum of surfactants such as amphoteric surfactants (lauryl betaine in Table 4), anionic substances (palmitic acid in Table 4), complex lipids (hydrogenated phosphatidylcholine in Table 4), and lipids such as sterols (cholesterol, which is a sterol in Table 4). From the values ​​in Table 3, the total weight in Production Example 1 is 0.2925 (parts by mass). [Table 4]

[0065] [Formulation Examples 2-3] The compositions of this disclosure (Production Example 2-3) were prepared based on the formulations shown in Table 5 below.

[0066] [Table 5]

[0067] Table 6 below shows the ratios of each component in Production Examples 2-3. Note that "liposomes" in Table 6 refers to the total weight of the liposomes described above, specifically the sum of surfactants such as amphoteric surfactants (lauryl betaine in Table 5), anionic substances (palmitic acid in Table 5), complex lipids (hydrogenated phosphatidylcholine in Table 5), and lipids such as sterols (cholesterol, a sterol in Table 5). From the values ​​shown in Table 5, the total mass is 0.2925 (parts by mass) in Production Example 2 and 0.2925 (parts by mass) in Production Example 3.

[0068] [Table 6]

[0069] [Formulation Example 4] The composition of this disclosure (Production Example 4) was prepared based on the formulations shown in Table 7 below.

[0070] [Table 7]

[0071] Table 8 below shows the ratio of each component in Production Example 4. Note that "liposome" in Table 8 refers to the total weight of the liposomes described above, specifically the sum of surfactants such as amphoteric surfactants (lauryl betaine in Table 7), anionic substances (palmitic acid in Table 7), complex lipids (hydrogenated phosphatidylcholine in Table 7), and lipids such as sterols (cholesterol, which is a sterol in Table 7). From the values ​​shown in Table 7, the total mass in Production Example 4 is 0.2875 (parts by mass).

[0072] [Table 8]

[0073] While the present disclosure has been described above with reference to embodiments and examples, the present disclosure is not limited to the above embodiments and examples. Various modifications to the structure and details of the present disclosure are possible, as can be understood by those skilled in the art within the scope of the present disclosure.

[0074] <Note> Some or all of the above embodiments and examples may be described as follows, but are not limited to the following. <Composition> (Note 1) The media includes liposomes and a dispersion medium for dispersing the liposomes. The liposome comprises an amphoteric surfactant, an anionic substance, a complex lipid, and sterols. A composition in which the content of the zwitterionic surfactant is 1 to 20% by mass, based on the total mass of the liposomes. (Note 2) The composition according to Appendix 1, wherein the aforementioned biionic surfactant is at least one selected from the group consisting of N-alkyl-N,N-dimethylamino acid betaine, fatty acid amide alkyl-N,N-dimethylamino acid betaine, imidazoline-type betaine, alkyl sulfobetaine, sulfate-type betaine, and phosphate-type betaine. (Note 3) The composition according to Appendix 1 or 2, wherein the aforementioned biionic surfactant is at least one selected from the group consisting of lauryldimethylaminoacetic acid betaine (lauryl betaine), cocamidopropyl betaine, lauramidopropyl betaine, sodium cocoamphoacetate, sodium lauroamphoacetate, alkyldimethyl taurine, alkyldimethylaminoethanol sulfate, and alkyldimethylaminoethanol phosphate. (Note 4) The composition according to any one of the appendices 1 to 3, wherein the aforementioned biionic surfactant is lauryldimethylaminoacetic acid betaine (lauryl betaine). (Note 5) The composition according to any one of the appendices 1 to 4, wherein the anionic substance is palmitic acid. (Note 6) The composition according to any one of the appendices 1 to 5, wherein the content of the anionic substance is 1 to 20% by mass, based on the total mass of the liposomes. (Note 7) The composition according to any one of the appendices 1 to 6, wherein the dispersion medium is an aqueous solvent and / or an organic solvent. (Note 8) The composition described in Appendix 7, wherein the aqueous solvent is water. (Note 9) The composition according to Appendix 8, wherein the organic solvent is butylene glycol and / or glycerin. (Note 10) The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is butylene glycol, The composition according to any one of the appendices 7 to 9, wherein the mass ratio (W:BG) of water (W) to butylene glycol (BG) is 2:1 to 20:1. (Note 11) The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is glycerin, The composition according to any one of the appendices 7 to 9, wherein the mass ratio (W:G) of water (W) to glycerin (G) is 10:1 to 20:1. (Note 12) The composition according to any one of the appendices 1 to 11, wherein the complex lipid is a phospholipid, glycolipid, lipoprotein, and / or sulfolipid. (Note 13) The composition described in Appendix 12, wherein the complex lipid is a phospholipid. (Note 14) The composition according to Appendix 12 or 13, wherein the complex lipid is phosphatidylcholine. (Note 15) The composition according to any one of the appendices 1 to 14, wherein the content of the complex lipid is 60 to 90% by mass, based on the total mass of the liposomes. (Note 16) The composition according to any one of the appendices 1 to 15, wherein the sterols are cholesterol. (Note 17) The composition according to any one of the appendices 1 to 16, wherein the content of the sterols is 10 to 20% by mass, based on the total mass of the liposomes. (Note 18) The composition according to any one of the appendices 1 to 17, wherein the liposomes are pH-responsive liposomes. (Note 19) Furthermore, a composition according to any one of the appendices 1 to 18, which includes a preservative. (Note 20) Furthermore, a composition according to any one of the appendices 1 to 19, comprising a thickening agent. (Note 21) Furthermore, a composition according to any one of the appendices 1 to 20, comprising a pH adjuster. (Note 22) A composition for application to the skin, comprising any of the compositions described in Appendix 1 to 21. <Manufacturing method> (Note 23) The process includes a step of generating liposomes from amphoteric surfactants, anionic substances, complex lipids, and sterols. A method for producing a liposome-containing composition, wherein the content of the zwitterionic surfactant is 1 to 20% by mass, based on the total mass of the liposomes. (Note 24) The method for producing the product according to Appendix 23, wherein the aforementioned biionic surfactant is at least one selected from the group consisting of N-alkyl-N,N-dimethylamino acid betaine, fatty acid amide alkyl-N,N-dimethylamino acid betaine, imidazoline-type betaine, alkyl sulfobetaine, sulfate-type betaine, and phosphate-type betaine. (Note 25) The method for producing the antimicrobial agent according to Appendix 23 or 24, wherein the aforementioned zwionic surfactant is at least one selected from the group consisting of lauryldimethylaminoacetic acid betaine (lauryl betaine), cocamidopropyl betaine, lauramidopropyl betaine, sodium cocoamphoacetate, sodium lauroamphoacetate, alkyldimethyl taurine, alkyldimethylaminoethanol sulfate, and alkyldimethylaminoethanol phosphate. (Note 26) The method for producing the antimicrobial surfactant as described in any of Appendix 23 to 25, wherein the aforementioned biionic surfactant is lauryldimethylaminoacetic acid betaine (lauryl betaine). (Note 27) The method of production according to any one of the appendices 23 to 26, wherein the anionic substance is palmitic acid. (Note 28) A manufacturing method according to any one of the appendices 23 to 27, wherein the content of the anionic substance is 1 to 20% by mass, based on the total mass of the liposomes. (Note 29) The process includes a dispersion step of dispersing the liposomes generated in the above generation step into a dispersion medium, The manufacturing method according to any one of the appendices 23 to 28, wherein the dispersion medium is an aqueous solvent and / or an organic solvent. (Note 30) The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is butylene glycol, The manufacturing method described in Appendix 29, wherein the mass ratio (W:BG) of water (W) to butylene glycol (BG) is 2:1 to 20:1. (Note 31) The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is glycerin, The manufacturing method described in Appendix 29, wherein the mass ratio (W:G) of water (W) to glycerin (G) is 10:1 to 20:1. (Note 32) The manufacturing method according to any one of the appendices 23 to 31, wherein the complex lipid is a phospholipid, glycolipid, lipoprotein, and / or sulfolipid. (Note 33) The manufacturing method described in Appendix 32, wherein the composite lipid is a phospholipid. (Note 34) The manufacturing method according to Appendix 32 or 33, wherein the complex lipid is phosphatidylcholine. (Note 35) A manufacturing method according to any one of the appendices 23 to 34, wherein the content of the complex lipid is 60 to 90% by mass, based on the total mass of the liposomes. (Note 36) The manufacturing method according to any one of the appendices 23 to 35, wherein the sterols are cholesterol. (Note 37) A manufacturing method according to any one of the appendices 23 to 36, wherein the content of the sterols is 10 to 20% by mass, based on the total mass of the liposomes. (Note 38) The method of production according to any one of the appendices 23 to 37, wherein the liposomes are pH-responsive liposomes. [Industrial applicability]

[0075] As explained above, this disclosure provides a novel agent that is less irritating and applicable to human skin. For this reason, this disclosure is extremely useful, for example, in the field of cosmetics.

Claims

1. The media includes liposomes and a dispersion medium for dispersing the liposomes. The liposome comprises an amphoteric surfactant, an anionic substance, a complex lipid, and sterols. A composition in which the content of the amphoteric surfactant is 1 to 20% by mass, based on the total mass of the liposomes.

2. The composition according to claim 1, wherein the aforementioned biionic surfactant is at least one selected from the group consisting of N-alkyl-N,N-dimethylamino acid betaine, fatty acid amide alkyl-N,N-dimethylamino acid betaine, imidazoline-type betaine, alkyl sulfobetaine, sulfate-type betaine, and phosphate-type betaine.

3. The composition according to claim 1 or 2, wherein the aforementioned biionic surfactant is at least one selected from the group consisting of lauryldimethylaminoacetic acid betaine (lauryl betaine), cocamidopropyl betaine, lauramidopropyl betaine, sodium cocoamphoacetate, sodium lauroamphoacetate, alkyldimethyl taurine, alkyldimethylaminoethanol sulfate, and alkyldimethylaminoethanol phosphate.

4. The composition according to any one of claims 1 to 3, wherein the aforementioned biionic surfactant is lauryldimethylaminoacetic acid betaine (lauryl betaine).

5. The composition according to any one of claims 1 to 4, wherein the anionic substance is palmitic acid.

6. The composition according to any one of claims 1 to 5, wherein the content of the anionic substance is 1 to 20% by mass, based on the total mass of the liposomes.

7. The composition according to any one of claims 1 to 6, wherein the dispersion medium is an aqueous solvent and / or an organic solvent.

8. The composition according to claim 7, wherein the aqueous solvent is water.

9. The composition according to claim 8, wherein the organic solvent is butylene glycol and / or glycerin.

10. The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is butylene glycol, The composition according to any one of claims 7 to 9, wherein the mass ratio (W:BG) of water (W) to butylene glycol (BG) is 2:1 to 20:

1.

11. The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is glycerin, The composition according to any one of claims 7 to 9, wherein the mass ratio (W:G) of water (W) to glycerin (G) is 10:1 to 20:

1.

12. The composition according to any one of claims 1 to 11, wherein the complex lipid is a phospholipid, a glycolipid, a lipoprotein, and / or a sulfolipid.

13. The composition according to claim 12, wherein the complex lipid is a phospholipid.

14. The composition according to claim 12 or 13, wherein the complex lipid is phosphatidylcholine.

15. The composition according to any one of claims 1 to 14, wherein the content of the complex lipid is 60 to 90% by mass, based on the total mass of the liposomes.

16. The composition according to any one of claims 1 to 15, wherein the sterols are cholesterol.

17. The composition according to any one of claims 1 to 16, wherein the content of the sterols is 10 to 20% by mass, based on the total mass of the liposomes.

18. The composition according to any one of claims 1 to 17, wherein the liposomes are pH-responsive liposomes.

19. Furthermore, the composition according to any one of claims 1 to 18, further comprising a preservative.

20. Furthermore, the composition according to any one of claims 1 to 19, further comprising a thickening agent.

21. Furthermore, the composition according to any one of claims 1 to 20, comprising a pH adjuster.

22. A composition for application to the skin, comprising the composition according to any one of claims 1 to 21.

23. The process includes a step of generating liposomes from amphoteric surfactants, anionic substances, complex lipids, and sterols. A method for producing a liposome-containing composition, wherein the content of the amphoteric surfactant is 1 to 20% by mass, based on the total mass of the liposomes.

24. The method for producing a product according to claim 23, wherein the aforementioned zwionic surfactant is at least one selected from the group consisting of N-alkyl-N,N-dimethylamino acid betaine, fatty acid amide alkyl-N,N-dimethylamino acid betaine, imidazoline-type betaine, alkyl sulfobetaine, sulfate-type betaine, and phosphate-type betaine.

25. The method for producing a food product according to claim 23 or 24, wherein the aforementioned zwionic surfactant is at least one selected from the group consisting of lauryldimethylaminoacetic acid betaine (lauryl betaine), cocamidopropyl betaine, lauramidopropyl betaine, sodium cocoamphoacetate, sodium lauroamphoacetate, alkyldimethyl taurine, alkyldimethylaminoethanol sulfate, and alkyldimethylaminoethanol phosphate.

26. The manufacturing method according to any one of claims 23 to 25, wherein the aforementioned biionic surfactant is lauryldimethylaminoacetic acid betaine (lauryl betaine).

27. The manufacturing method according to any one of claims 23 to 26, wherein the anionic substance is palmitic acid.

28. The manufacturing method according to any one of claims 23 to 27, wherein the content of the anionic substance is 1 to 20% by mass, based on the total mass of the liposomes.

29. The process includes a dispersion step of dispersing the liposomes generated in the above generation step into a dispersion medium, The manufacturing method according to any one of claims 23 to 28, wherein the dispersion medium is an aqueous solvent and / or an organic solvent.

30. The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is butylene glycol, The manufacturing method according to claim 29, wherein the mass ratio (W:BG) of water (W) to butylene glycol (BG) is 2:1 to 20:

1.

31. The dispersion medium comprises the aqueous solvent and the organic solvent, The aqueous solvent is water. The aforementioned organic solvent is glycerin, The manufacturing method according to claim 29, wherein the mass ratio (W:G) of water (W) to glycerin (G) is 10:1 to 20:

1.

32. The manufacturing method according to any one of claims 23 to 31, wherein the complex lipid is a phospholipid, a glycolipid, a lipoprotein, and / or a sulfolipid.

33. The manufacturing method according to claim 32, wherein the composite lipid is a phospholipid.

34. The manufacturing method according to claim 32 or 33, wherein the complex lipid is phosphatidylcholine.

35. The manufacturing method according to any one of claims 23 to 34, wherein the content of the complex lipid is 60 to 90% by mass, based on the total mass of the liposomes.

36. The manufacturing method according to any one of claims 23 to 35, wherein the sterols are cholesterol.

37. The manufacturing method according to any one of claims 23 to 36, wherein the content of the sterols is 10 to 20% by mass, based on the total mass of the liposomes.

38. The manufacturing method according to any one of claims 23 to 37, wherein the liposomes are pH-responsive liposomes.

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