Substance-encapsulated particle dispersion oil

Abstract

To provide a substance-involving particle dispersion oily medicine that involves not only water and a water-soluble component, but also an oil-soluble component.SOLUTION: Provided is a dispersion oily medicine of particles in which a hydrophilic substance is involved in a dehydrated region within a hydrophilic moiety association structure formed by amphipathic molecules, the hydrophilic substance comprising a reduced product of water and / or water-soluble component, and a hydrophilized form of an oil-soluble component, a substance to be involved. Furthermore, the hydrophilized form of the oil-soluble component is a liposome or an exosome that retains the oil-soluble component in a hydrophobic moiety association region within a lipid bilayer, or a micelle in which the oil-soluble component is involved in a hydrophobic moiety association structure formed by amphipathic molecules.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to an oil agent in which substance-containing particles are dispersed.

Background Art

[0002] Conventionally, in the field of pharmaceuticals, in order to efficiently actuate a predetermined component on a desired site, products applying the concept of a drug delivery system (DDS) for controlling drug distribution in the body quantitatively, spatially, and temporally have been variously proposed.

[0003] Moreover, in recent years, the concept of this drug delivery system is not limited to the field of pharmaceuticals, and its scope of application is gradually expanding to the fields of cosmetics and foods.

[0004] As means for realizing a drug delivery system, techniques such as applying an emulsion, techniques for making a sustained-release preparation, techniques using an antibody, etc. have been proposed so far. Among these, the technique of applying an emulsion can construct a component carrier relatively easily and at low cost, and is expected as a technique capable of imparting new functionality to cosmetics and foods.

[0005] For example, a technique for producing a solid dispersed in oil (hereinafter referred to as a solid dispersion technique) by subjecting a W / O emulsion containing a predetermined water-soluble molecule in an aqueous phase to heat dehydration or vacuum dehydration to remove water and precipitate the water-soluble molecule to make it in a solid state is a technique positioned on the extension line of the above emulsion application technique, and has attracted attention as a technique for solving the problem of micronization that the conventional emulsion application technique has (for example, refer to Patent Documents 1 to 3).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

[0007] However, conventional solid dispersion technologies have been limited to encapsulating water-soluble components and have not been able to disperse oil-soluble components into nanoparticles in oil.

[0008] In other words, even if an oil-soluble component is added, it cannot be kept within the nanoparticles. During the preparation of the W / O emulsion-type precursor, it would migrate into the oil phase.

[0009] The present invention has been made in view of these circumstances, and provides a substance-encapsulating particle dispersion oil agent that contains not only water and water-soluble components, but also oil-soluble components. [Means for solving the problem]

[0010] In order to solve the above conventional problems, the substance-encapsulated particle dispersion oil agent according to the present invention has the following characteristics: (1) A dispersion oil in which a hydrophilic substance is encapsulated in a dehydrated region within a hydrophilic group structure formed by amphiphilic molecules, wherein the hydrophilic substance comprises a water and / or water-soluble component water-reduced product and a hydrophilized form of the oil-soluble component to be encapsulated. Furthermore, the hydrophilized form of the oil-soluble component is a liposome or exosome in which the oil-soluble component is held in the hydrophobic association region within the lipid bilayer, or a micelle in which the oil-soluble component is encapsulated within a hydrophobic association structure formed by amphiphilic molecules. That's what we decided.

[0011] Furthermore, the substance-encapsulated particle dispersion oil agent according to the present invention also has the following features. (2 ) bao It has the function of improving the skin penetration of the target oil-soluble and / or water-soluble components. [Effects of the Invention]

[0012] According to the substance-encapsulating particle dispersion oil agent of the present invention, it is a dispersion oil agent of particles in which a hydrophilic substance is encapsulated in a dehydrated region within a hydrophilic part association structure formed by an amphiphilic molecule, and the hydrophilic substance includes a dehydrated product of water and / or a water-soluble component and a hydrophilized product of an oil-soluble component to be encapsulated. Furthermore, the hydrophilized form of the oil-soluble component is a liposome or exosome in which the oil-soluble component is held in the hydrophobic association region within the lipid bilayer, or a micelle in which the oil-soluble component is encapsulated within a hydrophobic association structure formed by amphiphilic molecules. Therefore, it is possible to provide a dispersion oil agent of substance-encapsulating particles in which an oil-soluble component is also encapsulated.

Brief Description of the Drawings

[0013] [Figure 1] It is an explanatory diagram showing a microscopic image of a permeation test of a substance-encapsulating particle dispersion oil agent using artificial skin.

Embodiments for Carrying Out the Invention

[0014] The present invention relates to a substance-encapsulating particle dispersion oil agent, and particularly provides a substance-encapsulating particle dispersion oil agent in which an oil-soluble component is also encapsulated.

[0015] In the present specification, the substance-encapsulating particle dispersion oil agent means an oil agent in which particles (substance-encapsulating particles) in which a plurality of hydrophilic substances are encapsulated in a dehydrated region within a hydrophilic part association structure formed by an amphiphilic molecule are dispersed.

[0016] Here, examples of the oil component (base oil agent described later) for dispersing the substance-encapsulating particles include fats and oils, waxes, hydrocarbons, fatty acids, alcohols, esters, silicone oils, and fluorine oils.

[0017] More specifically explaining the oil component, fats and oils can employ vegetable oils and animal oils.

[0018] As vegetable oils, for example, oil of Limnanthes alba, argan oil, kukui nut oil, cranberry seed oil, wheat germ oil, rice bran oil, avocado oil, almond oil, olive oil, sesame oil, rice oil, safflower oil, shea butter, evening primrose oil, pistachio seed oil, macadamia nut oil, mango seed butter, meadowfoam oil, rose hip oil, soybean oil, corn oil, rapeseed oil, persic oil, palm oil, palm kernel oil, castor oil, sunflower oil, grape seed oil, cottonseed oil, mink oil, coconut oil, linseed oil, peanut oil, camellia oil, sasanqua oil, cocoa butter, and other vegetable oils can be used.

[0019] As animal oils, for example, emu oil, hardened oil, horse oil, mink oil, egg yolk oil, beef tallow, lard, mutton fat, carp oil, tuna oil, menhaden oil, and other animal oils can be used.

[0020] As waxes, for example, carnauba wax, candelilla wax, rice bran wax, shellac, lanolin, jojoba oil, beeswax, montan wax, orange roughy oil, candelilla wax, sugarcane wax, insect white wax, palm wax, wool fat, and other waxes can be used.

[0021] As hydrocarbons, for example, petroleum-based hydrocarbons, naturally occurring mineral-based hydrocarbons, synthetic hydrocarbons, animal-based hydrocarbons, plant-based hydrocarbons, etc. can be used.

[0022] Petroleum-based materials include, for example, liquid paraffin, paraffin, microcrystalline wax, petrolatum, isoparaffins, and other petroleum-based hydrocarbons. Mineral-based materials include, for example, ozokerite, ceresin, and other naturally occurring mineral-based hydrocarbons. Synthetic materials include, for example, polyethylene, α-olefin oligomers, polybutene, synthetic squalane, fullerene, and other synthetic hydrocarbons. Animal-based materials include, for example, squalene, squalane, and other animal-derived hydrocarbons. Plant-based materials include, for example, plant-derived squalene, plant-derived squalane, farnesene, farnesane, limonene, turpentine oil, and other plant-derived hydrocarbons.

[0023] Examples of fatty acids that can be used include linear saturated fatty acids, linear monoenoic acid, acetyleneic acid, polyenoic acid, monoalkyl saturated fatty acids, and polyalkyl saturated fatty acids.

[0024] Examples of straight-chain saturated fatty acids that can be used include methaneic acid, ethaneic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nosanic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, and other straight-chain saturated fatty acids.

[0025] Examples of linear monoenoic acids that can be used include acrylic acid, acetaryl acid, caproleic acid, lindelic acid, tuzuic acid, zomarinic acid, petroseric acid, oleic acid, elaidic acid, basenic acid, codoic acid, gondouic acid, erucic acid, brassic acid, ceracoleic acid, other linear monoenoic acids, or isomers of these linear monoenoic acids.

[0026] Examples of acetylene acids that can be used include propic acid, tetrolic acid, pentic acid, hexic acid, heptic acid, octic acid, nonicic acid, decinic acid, undecinic acid, dodecinic acid, tridecinic acid, tetradecinic acid, hexadecinic acid, heptadecinic acid, octadecinic acid, nonadecinic acid, docosinic acid, docosadiic acid, tricosinic acid, other acetylene acids, or isomers of these acetylene acids.

[0027] Examples of polyenoic acids that can be used include pentadienoic acid, sorbic acid, linole-elaidic acid, alpha-linolenic acid, gamma-linolenic acid, linolene-elaidic acid, alpha-eleostearic acid, beta-eleostearic acid, punicic acid, stearidonic acid, parinaric acid, dihomo-gamma-linolenic acid, arachidonic acid, EPA, sardine acid, DHA, herring acid, other polyenoic acids, or isomers of these polyenoic acids.

[0028] Examples of monoalkyl saturated fatty acids that can be used include methylpropanoic acid, methylbutanoic acid, dimethylpropanoic acid, methylpentanoic acid, isocaproic acid, ethylpentanoic acid, propylpentanoic acid, methyldecanoic acid, propyloctanoic acid, methylhendecanoic acid, propylnonanoic acid, methyldodecanoic acid, propyldecanoic acid, methyltridecanoic acid, methyltetradecanoic acid, methylpentadecanoic acid, ethyltetradecanoic acid, methylhexadecanoic acid, propyltetradecanoic acid, ethylhexadecanoic acid, methylheptadecanoic acid, butyltetradecanoic acid, methyloctadecanoic acid, ethylheptadecanoic acid, methylnonadecanoic acid, ethyloctadecanoic acid, methylicosanoic acid, propyloctadecanoic acid, butyloctadecanoic acid, methyldocosanoic acid, pentyloctadecanoic acid, methyltricosanoic acid, ethyldocosanoic acid, other monoalkyl saturated fatty acids, or isomers of these monoalkyl saturated fatty acids.

[0029] Examples of polyalkyl saturated fatty acids that can be used include branched alkanes and other polyalkyl saturated fatty acids.

[0030] Furthermore, examples of alcohols that can be used include higher alcohols, aromatic alcohols and phenols, sterols, phytosterols and terpene alcohols.

[0031] Examples of higher alcohols that can be used include benzyl alcohol, lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol, oleyl alcohol, behenyl alcohol, ricinoleyl alcohol, and other higher alcohols.

[0032] Examples of aromatic alcohols and phenols that can be used include phenol, cresol, cyclohexanol, catechol, resorcinol, hydroquinone, benzyl alcohol, phenylethyl alcohol, naphthol, and other aromatic alcohols and phenols.

[0033] Examples of sterols, phytosterols, and terpene alcohols include cholesterol, cholestanol, campestanol, ergostanol, sitostanol, 22-dehydrostigmamanol, coprostanol, epicoprostanol, 22-dehydrocholesterol, desmosterol, campesterol, dihydrobrassicasterol, clinosterol, brassicasterol, 24-methylenecholesterol, codisterol, sitosterol, and clionasterol. Stigmasterol, polyferasterol, fucosterol, isofucosterol, clerosterol, 22-dehydroclerosterol, latosterol, fungisterol, episterol, schottenol, 22-dihydrochondriasterol, spinasterol, chondriasterol, anabesterol, 24β-ethyl-25-dehydrolatosterol, 25-dehydrochondriasterol, thymosterol, ascosterol, fecosterol, 7-dehydrocholesterol 22-Dihydroergosterol, Ergosterol, 24(24)-Dehydroergosterol, 7-Dehydropolypheresterol, Vernosterol, 14-Dehydroergosterol, Polynastanol, 24-Methylenepolinasterol, Lophenol, Gramysterol, Citrostadienol, Obtusifoliol, Cyclooicarenol, 4,4-Dimethylthymosterol, Lanosterol, Parceol, Cycloartanol, Cycloartenol, Cyclosadol 24-Methi Lencycloartanol, cyclobranol, cyclolaudenol, butyrospermol, euphor, tilcarol, 10α-cucurbitadienol, lupeol, amylin, germanicol, taraxerol, multiflourenol, isomaltlurourenol, glutinol, friederanol, taraxasterol, bauelenol, fernerol, isoarborinol, simialenol, other sterols, phytosterols, and terpene alcohols can be used.

[0034] Furthermore, as esters, for example, esters of linear fatty acids and lower alcohols, esters of linear fatty acids and linear higher alcohols, esters of linear fatty acids and branched higher alcohols, esters of linear fatty acids and polyhydric alcohols, esters of branched fatty acids and lower alcohols, esters of branched fatty acids and linear higher alcohols, esters of branched fatty acids and branched higher alcohols, esters of branched fatty acids and polyhydric alcohols, esters of fatty acids with hydroxyl groups and alcohols, esters of dibasic acids and alcohols, and esters of fatty acids and sterols can be used.

[0035] Examples of esters of linear fatty acids and lower alcohols that can be used include ethyl oleate, isopropyl myristate, isopropyl palmitate, and other esters of linear fatty acids and lower alcohols.

[0036] Examples of esters of linear fatty acids and linear higher alcohols include cetyl palmitate, myristyl myristate, and other esters of linear fatty acids and linear higher alcohols.

[0037] Examples of esters of straight-chain fatty acids and branched higher alcohols include octyldodecyl myristate, octyldodecyl oleate, and other esters of straight-chain fatty acids and branched higher alcohols.

[0038] Examples of esters between straight-chain fatty acids and polyhydric alcohols include medium-chain fatty acid triglycerides and other esters between straight-chain fatty acids and branched higher alcohols.

[0039] Examples of esters of branched fatty acids and lower alcohols include isopropyl isostearate, ethyl isostearate, and other esters of branched fatty acids and lower alcohols.

[0040] Examples of esters of branched fatty acids and linear higher alcohols include cetyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, and other esters of branched fatty acids and linear higher alcohols.

[0041] Examples of esters of branched fatty acids and branched higher alcohols include isocetyl isostearate, octyldodecyl dimethyloctanoate, and other esters of branched fatty acids and branched higher alcohols.

[0042] Examples of esters of branched fatty acids and polyhydric alcohols include esters of branched fatty acids with glycerin, trimethylolpropane, pentaerythritol, and other esters of branched fatty acids with polyhydric alcohols.

[0043] Examples of esters of fatty acids containing hydroxyl groups with alcohols include myristyl lactate, cetyl lactate, trioctyldodecyl citrate, diisostearyl malate, and other esters of fatty acids containing hydroxyl groups with alcohols.

[0044] Examples of esters of dibasic acids and alcohols that can be used include diisopropyl adipate, diethyl sebacate, and other esters of dibasic acids and alcohols.

[0045] Examples of esters between fatty acids and sterols include phytosteryl hydroxystearate, phytosteryl isostearate, and other esters between fatty acids and sterols.

[0046] Furthermore, as silicone oils, for example, straight silicone oils such as dimethyl silicone oil, methylphenyl silicone oil, cyclic silicone oil, methyl hydrogen silicone oil, and other straight silicone oils can be used, and as modified silicone oils, alcohol-modified silicone oil, alkyl-modified silicone oil, polyether-modified silicone oil, amino-modified silicone oil, and other modified silicone oils can be used.

[0047] Furthermore, as the fluorinated oil, for example, perfluoropolyether or other fluorinated oils can be used.

[0048] The amphiphilic molecules constituting the substance-encapsulating particles are molecules that possess a surfactant effect, having both a hydrophilic part and a hydrophobic (lipophilic) part within the molecule. Preferably, amphiphilic molecules widely used as surfactants can be utilized.

[0049] Examples of such amphiphilic molecules include phospholipids, sphingophospholipids, and sterols.

[0050] Examples of phospholipids include phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol, lysophosphatidic acid, lysophosphatidylcholine, egg yolk phosphatidylcholine, brain phosphatidylserine, cardiolipin, and their derivatives.

[0051] Examples of sphingophospholipids include sphingomyelin, brain sphingomyelin, cerebrosides, gangliosides, and their derivatives.

[0052] Examples of sterols include cholesterol, ergocalciferol, cholecalciferol, and their derivatives.

[0053] In addition, as amphiphilic molecules other than those mentioned above, it is also possible to use substances that exhibit amphiphilicity capable of forming substance-encapsulating particles in relation to the aforementioned oil component used as the base oil and the aqueous phase containing the substance to be encapsulated, as described later. These substances include glycolipids, steroid hormones, prostaglandins, bile acids, vitamin A compounds, vitamin K compounds, plant growth hormones, biotin, ubiquinone, vitamin C derivatives, riboflavin derivatives, vitamin E compounds, carotenoids, cardiac glycosides, ratonaside, alcohols, mycosides, antibiotics, etc.

[0054] The hydrophilic aggregate structure of substance-encapsulated particles is a structure formed by the aggregation of multiple amphiphilic molecules as described above, and in particular, it is an inverse micelle-like structure formed by the aggregation of hydrophilic parts of the molecular structure of amphiphilic molecules.

[0055] Furthermore, the encapsulated particles consist of a region where part or all of the hydrophilic aggregate structure is dehydrated.

[0056] This dehydrated region is formed by subjecting the dispersion-encapsulated reverse micelles, which will be described later, as precursor particles of the substance-encapsulated particles to dehydration. The dehydration method is not particularly limited as long as the hydrophilic aggregate structure is not crushed or broken down, and methods such as heat dehydration or vacuum dehydration can be employed. For example, when using vacuum dehydration, commercially available equipment such as an evaporator that can dehydrate while adjusting the temperature and vacuum level can be used. Also, if the oil is liquid at temperatures below 0°C, so-called freeze-drying can be used, in which the frozen aqueous phase is degassed under vacuum, resulting in sublimation and dehydration.

[0057] The dehydrated regions within the hydrophilic aggregate structure of the substance-encapsulated particles contain significantly less water than the hydrophilic aggregate structure of the inverse micelles encapsulated in the dispersion. For example, the amount of water removed is less than the amount of water that causes water-soluble molecules dissolved in the dispersion to precipitate.

[0058] Furthermore, multiple hydrophilic substances are encapsulated in the dehydrated regions within the hydrophilic aggregate structure of the substance-encapsulated particles. The substance-encapsulated particle-dispersed oil according to this embodiment is formed by dispersing such substance-encapsulated particles in a base oil.

[0059] Herein, a characteristic of the substance-encapsulated particle dispersion oil agent according to this embodiment is that, as the aforementioned multiple hydrophilic substances, at least the water-reduced product of an aqueous solution of a water-soluble component and the hydrophilized form of an oil-soluble component are present.

[0060] The water-reduced product of an aqueous solution contains the water-soluble component that is encapsulated by the substance-encapsulating particles. To give an example of what is encapsulated, if substance-encapsulating particles are used as a means of penetrating components into the skin, the component that is to be delivered into the skin is the component that is encapsulated.

[0061] Furthermore, the water-reducing products of aqueous solutions include not only pure water-soluble components, but also water-soluble components that contain some water.

[0062] The water-soluble component is not particularly limited as long as it is a molecule that can dissolve in water, and may be either an organic or inorganic compound. It may also be a protein or peptide such as an enzyme, or a mixture thereof. For example, as an enzyme, examples include water-soluble enzymes with EC numbers (Enzyme Commission numbers) classified by the International Union of Biochemistry and Molecular Biology (formerly the International Biochemical Union) as EC 1.XXX: oxidoreductases, EC 2.XXX: transferases, EC 3.XXX: hydrolases, EC 4.XXX: addition-elimination enzymes, EC 5.XXX: isomerases, EC 6.XXX: ligases (X is a number). It may also be a water-soluble protein or peptide (hereinafter referred to as water-soluble cytokines) that exhibit immune, antitumor, antiviral, cell proliferation, or differentiation effects, or extracts such as placenta or stem cell culture medium containing water-soluble cytokines, or water-soluble vitamins such as ascorbic acid and their salts and derivatives, or water-soluble viscous substances such as hyaluronic acid.

[0063] The hydrophilized form of the oil-soluble component contains the oil-soluble component that is the target of the substance-encapsulating particles.

[0064] Furthermore, a hydrophilic form of an oil-soluble component refers to a structure in which the oil-soluble component is encapsulated by multiple amphiphilic molecules that have associated together, allowing it to disperse in water.

[0065] Examples of hydrophilized oil-soluble components include liposomes, exosomes, or bilayer sheets that hold the oil-soluble component in the hydrophobic association region within the lipid bilayer, or micelles in which the oil-soluble component is encapsulated within a hydrophobic association structure formed by amphiphilic molecules.

[0066] Examples of oil-soluble components include glycolipids, steroid hormones, prostaglandins, bile acids, vitamin A compounds, vitamin K compounds, plant growth hormones, biotin, ubiquinone, vitamin C derivatives, riboflavin derivatives, vitamin E compounds, carotenoids, cardiac glycosides, ratonaside, alcohols, mycosides, antibiotics, fatty acids, and vegetable oils. While some of the oil-soluble components listed below exhibit amphiphilicity, they are classified here as oil-soluble components because they also show affinity for oil.

[0067] Examples of glycolipids include plasmalogens and their derivatives.

[0068] Examples of steroid hormones include corticosterone, andosterone, hydrocortisone, estrone, β-estradiol, testosterone, progesterone, and their derivatives.

[0069] Examples of prostaglandins include prostanic acid, prostaglandin E1, prostaglandin F1α, prostaglandin F2α, and their derivatives.

[0070] Examples of bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, and their derivatives.

[0071] Examples of vitamin A include vitamin A1, vitamin A2, and their derivatives.

[0072] Examples of vitamin K compounds include vitamin K1, vitamin K2, vitamin K3, and their derivatives.

[0073] Examples of plant growth hormones include auxin a, auxin b, and their derivatives.

[0074] Examples of vitamin C derivatives include ascorbyl tetra-2-hexyldecanoate.

[0075] Examples of riboflavin derivatives include riboflavin tetrabutyrate.

[0076] Examples of vitamin E include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and their derivatives.

[0077] Examples of carotenoids include β-carotene, α-carotene, γ-carotene, zeaxanthin, cryptoxanthin, echinonene, astaxanthin, lutein, lycopene, canthaxanthin, bixin, crocetin, crocin, cycloxin, enanthoxin, violaxanthin, xanthophyll, and their derivatives.

[0078] Examples of cardiac glycosides include saponins, ouabain, ouabagenin, oleandrin, proscylaridine, cerbeloside, cerveline, carotropin, digitoxin, digitonin, digonin, digitanin, adonitoxin, α-antialin, dioscin, asiaticoside, and their derivatives.

[0079] Examples of ratonaside include ratonaside A, ratonaside B, ratonaside C, strophantidine, strophanthin, strophantoside, simin, silarenin, silarene, siloside, prossilazine, covalatoxin, herebrin, eczin, funthumin, tebetin, periprosin, escin, chlorgenin, colosintin, and their derivatives.

[0080] Examples of alcohols include laccol, 3-pentadecylcatel, menthol, borneol, nerol, and their derivatives.

[0081] Examples of micosides include micosides A, B, C2, Cm, Cb, C3, and G, as well as their derivatives.

[0082] Examples of antibiotics include fumigacin, chartzulcin, pimaricin (nystatin, etruscomycin, amphotericin B, philipin, trichomycin, candidine, fungichromin, etc.), frequentin, myceliaamide, mycomycin, surfactin, and their derivatives.

[0083] Examples of fatty acids include saturated fatty acids and unsaturated fatty acids, with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) being representative examples of the latter.

[0084] As for vegetable oils, in addition to oils rich in unsaturated fatty acids such as olive oil, perilla oil, and linseed oil, various oils commonly used for cooking, such as soybean oil, cottonseed oil, corn oil, safflower oil, and rapeseed oil, can be used.

[0085] Furthermore, this application provides a method for producing a substance-encapsulated particle dispersion oil agent that contains not only water-soluble components but also oil-soluble components.

[0086] To be more specific, the method for producing a substance-encapsulated particle dispersion oil according to this embodiment comprises the steps of: preparing a W / O emulsion using an aqueous phase containing a water-soluble component and a hydrophilized form of an oil-soluble component (hereinafter also referred to as the encapsulation target substance); and dehydrating the W / O emulsion to prepare a dispersion oil containing the encapsulation target substance.

[0087] To explain each step, first, the step of preparing a W / O emulsion using an aqueous phase containing the substance to be encapsulated refers to, for example, emulsifying a dispersion in which a hydrophilic form of the oil-soluble component to be encapsulated is dispersed in an aqueous solution of the water-soluble component to be encapsulated with a base oil in the presence of amphiphilic molecules, thereby creating a state in which micelles containing the dispersion are dispersed in the base oil.

[0088] Next, the step of dehydrating the W / O emulsion to prepare a dispersed oil containing the substance to be encapsulated refers to, for example, subjecting the W / O emulsion to a vacuum dehydration apparatus to dehydrate the water inside the micelles containing the dispersion while boiling, thereby creating a state in which particles containing the water-reduced product of the aqueous solution of the water-soluble component and the hydrophilized form of the oil-soluble component are dispersed in the oil.

[0089] The size of the substance-encapsulated particles is not particularly limited, but for example, by the method described above, in which the water inside the micelles containing the dispersion is boiled and dehydrated, substance-encapsulated particles with a relatively uniform particle size of 1 μm or less on average are dispersed in the oil. In this invention, the average particle size refers to the particle size corresponding to 50% by volume in the cumulative volume particle size distribution (D50), and can generally be measured by a dynamic light scattering photometer, a laser diffraction / scattering particle size analyzer, etc.

[0090] Here, a dispersion is, as mentioned above, a liquid in which a hydrophilic form of an oil-soluble component is dispersed in an aqueous solution of a water-soluble component. The hydrophilic form of the oil-soluble component can be micelles, liposomes, bilayer sheets, or exosomes.

[0091] As a hydrophilized form of an oil-soluble component, a micelle can be used in which the oil-soluble component is encapsulated within the hydrophobic association region of an amphiphilic molecule. Such a micelle can be obtained by emulsifying an oily liquid containing an oil-soluble component in an aqueous solution of a water-soluble component in the presence of an amphiphilic molecule.

[0092] Here, an oily liquid containing an oil-soluble component refers not only to a liquid in which the oil-soluble component to be encapsulated is dissolved in the aforementioned oils and fats, waxes, hydrocarbons, fatty acids, alcohols, esters, silicone oils, and fluorinated oils, but also to oil-soluble components that are liquid themselves. For example, oil-soluble components that are liquid at room temperature (e.g., 10-30°C), such as the unsaturated fatty acid docosahexaenoic acid, or vegetable oils like olive oil and tocopherol, are considered oily liquids in themselves.

[0093] Furthermore, liposomes and bilayer sheets can be used that are obtained by emulsifying an oily liquid containing an oil-soluble component in an aqueous solution of a water-soluble component in the presence of a surfactant, thereby retaining the oil-soluble component within the hydrophobic association region of the lipid bilayer.

[0094] Furthermore, exosomes obtained from specific eukaryotic cells can be used as hydrophilized forms of oil-soluble components. Similar to liposomes, the oil-soluble components are retained within the hydrophobic association region of the lipid bilayer in exosomes.

[0095] Furthermore, according to the method for producing a substance-encapsulated particle dispersion oil according to this embodiment, it is possible to provide a method for producing a substance-encapsulated particle dispersion oil that contains not only water-soluble components but also oil-soluble components.

[0096] Incidentally, human skin has the characteristic of having more moisture as you go deeper into it. The deeper layers of the stratum corneum contain the same amount of moisture as the rest of the body, but as you move towards the surface, the amount of moisture gradually decreases to about 20-30%, and this moisture gradient creates a barrier structure where the surface of the skin is relatively oilier.

[0097] Therefore, when the substance to be delivered into the skin is a water-soluble component, it is often used in combination with oil to ensure it penetrates the stratum corneum as smoothly as possible.

[0098] For example, as previously proposed by the applicants, if the oil formulation consists of a water-reduced aqueous solution of a water-soluble component arranged in an inverse micelle structure dispersed in a base oil, the water-soluble component can be delivered to deeper layers of the stratum corneum by penetrating it.

[0099] In contrast, oil-soluble components penetrate the surface of the stratum corneum relatively easily. Therefore, if an oil-soluble component is included in the base oil, it is possible to allow it to penetrate the surface of the stratum corneum.

[0100] However, due to the aforementioned moisture gradient in the skin, it is difficult to allow oil-soluble components to penetrate deeper into the skin.

[0101] In this regard, the technology proposed in this application, namely, a dispersion oil in which the water-reduced product of the aqueous solution of water or water-soluble components to be encapsulated and the hydrophilized form of the oil-soluble component to be encapsulated are contained as hydrophilic substances in the dehydrated region within the hydrophilic association structure of amphiphilic molecules, makes it possible to allow the oil-soluble components to reach deeper into the base oil along with the water-soluble components compared to simply adding the oil-soluble components to the base oil.

[0102] Furthermore, this invention also includes a technology for delivering oil-soluble components to the deeper layers of the skin, regardless of the presence or absence of water-soluble components.

[0103] In other words, this technology is characterized by the fact that by making the oil-soluble component a hydrophilic form and encapsulating it within inverse micelles, it allows the oil to permeate the surface of the stratum corneum as an oil, and as the moisture content increases, the hydrophilic form of the oil-soluble component contained within the inverse micelles penetrates further into the stratum corneum. In the following description, a form in which only an oil-soluble component is encapsulated without a water-soluble component is referred to as the oil-soluble component-only form, and a form in which both a water-soluble component and an oil-soluble component are encapsulated is referred to as the oil-soluble / water-soluble combined form.

[0104] This configuration allows the oil-soluble component to reach deeper into the skin compared to simply adding it to the base oil. Furthermore, for example, the above-described method for producing a substance-encapsulated particle dispersion oil involves emulsifying a dispersion of the hydrophilized oil-soluble component (to be encapsulated) in an aqueous solution of the water-soluble component (to be encapsulated) with the base oil in the presence of amphiphilic molecules, and preparing an emulsion in which micelles encapsulating the dispersion are dispersed in the base oil; and subjecting the emulsion to a vacuum dehydration apparatus to dehydrate the water inside the micelles encapsulating the dispersion while boiling, thereby reducing the water content of the aqueous solution of the water-soluble component and hydrophilizing the oil-soluble component. A method for producing a substance-encapsulated particle dispersion oil containing an oil-soluble component and a water-soluble component, comprising the steps of preparing an oil solution in which particles containing an oil-soluble component are dispersed, wherein the dispersion is a liquid in which at least one selected from (a) micelles, (b) liposomes or bilayer sheets, and (c) exosomes is dispersed in an aqueous solution of the water-soluble component as a hydrophilized form of the oil-soluble component, thus providing a method for producing a substance-encapsulated particle dispersion oil containing an oil-soluble component as well.

[0105] Furthermore, this application also provides a technology for adjusting (controlling) the penetration depth of oil-soluble components in the skin, and more specifically, a technology for delivering a predetermined oil-soluble component to a desired depth in the skin, which will be explained below.

[0106] This depth adjustment technology can be achieved, for example, by adjusting the polarity of the base oil. Oil-soluble components are generally classified into polar components (polar oils) and nonpolar components (nonpolar oils) based on their properties. For example, hydrocarbon oils are mostly nonpolar oils, and mineral oil is also a hydrocarbon oil and can be considered a nonpolar component (nonpolar oil). On the other hand, β-caryophyllene, for example, is a polar component (polar oil) with an uneven distribution of charge within its molecule.

[0107] When a nonpolar oil is used as the base oil in a substance-encapsulating particle dispersion oil, the oil-soluble component encapsulated within the reverse micelle due to the moisture gradient in the skin can penetrate to a relatively shallower depth compared to when a polar oil is used, as described later. Conversely, when a polar oil is used as the base oil, it has a slightly more affinity for water than the nonpolar oil mentioned above, making it possible to penetrate to a greater depth.

[0108] In this way, by selecting the polarity of the base oil, the penetration depth of the oil-soluble component to be encapsulated can be adjusted.

[0109] Furthermore, regardless of whether or not the penetration depth of oil-soluble components is adjusted by adjusting the polarity of the base oil, the depth to which the oil-soluble components reach the encapsulated components may be adjusted by adjusting the polarity of the oil-soluble components themselves.

[0110] In other words, if it is possible to select from several oil-soluble components to be encapsulated in order to achieve a predetermined purpose, the penetration depth of the oil-soluble component can be adjusted by selecting the strength of polarity of that component.

[0111] Furthermore, the oil-soluble component to be encapsulated may include a first oil-soluble component for achieving a predetermined purpose and a second oil-soluble component for adjusting the penetration depth of the first oil-soluble component.

[0112] In such cases, even if the first oil-soluble component is nonpolar and cannot be substituted with other components, the penetration depth can be adjusted by the second oil-soluble component. Furthermore, this second oil-soluble component may be added for purposes other than adjusting the penetration depth.

[0113] Furthermore, instead of adjusting the polarity of the oil-soluble components, it is also possible to adjust the penetration depth by adjusting the HLB (Hydrophilic-Lipophilic Balance) value of the amphiphilic molecules used in reverse micelles.

[0114] The HLB value represents the degree of affinity of a surfactant to water and oil (water-insoluble organic compounds), and in the Griffin method, the HLB value can be adjusted within a range of approximately 1 to 7. The closer the HLB value is to 1, the shallower the penetration depth, and the closer the HLB value is to 7, the deeper the penetration can be.

[0115] The substance-encapsulated particle dispersion oil and the method for producing the substance-encapsulated particle dispersion oil according to this embodiment will be further described below with reference to examples.

[0116] [1. Manufacturing of substance-encapsulated particle dispersion oils] As examples of the substance-encapsulated particle dispersion oils and their production according to this embodiment, three substance-encapsulated particle dispersion oils will be described: a micelle-type substance-encapsulated particle dispersion oil, a liposome-type substance-encapsulated particle dispersion oil, and an exosome-type substance-encapsulated particle dispersion oil.

[0117] (1-1. Micelle-type substance-encapsulated particle dispersion oil agent) This oil-based formulation is an example in which micelles, which encapsulate the oil-soluble component within the hydrophobic association region of the amphiphilic molecule, are used as hydrophilic forms of the oil-soluble component. This is achieved by emulsifying an oily liquid containing an oil-soluble component in an aqueous solution of a water-soluble component in the presence of amphiphilic molecules.

[0118] One part by weight of nicotinamide mononucleotide (hereinafter also referred to as NMN) was added to 99 parts by weight of water to prepare a 1 w / w% NMN aqueous solution. Next, 3 parts by weight of PPG-6 decyltetradeceth-30 and 0.5 parts by weight of lutein were added to 100 parts by weight of this 1 w / w% NMN aqueous solution, and the mixture was emulsified at room temperature for 10 minutes using a 600 rpm motor to prepare a dispersion. This dispersion is a dispersion in which micelles (hydrophilic forms of oil-soluble components) that encapsulate the oil-soluble component within the hydrophobic association region of an amphiphilic molecule are dispersed in an aqueous solution of the water-soluble component.

[0119] Next, the dispersion was mixed with 91.5 parts by weight of ethylhexyl palmitate as a base oil and 5 parts by weight of polyglycerin condensed ricinoleate ester as an amphiphilic molecule. The mixture was then emulsified at room temperature for 1 minute using a homogenizer set to 24,000 rpm to prepare an emulsion in which micelles containing the dispersion were dispersed in the base oil.

[0120] Next, a predetermined amount of the prepared emulsion was placed in a container and subjected to an evaporator, where dehydration was carried out for 40 minutes under reduced pressure of approximately 1 / 10 of atmospheric pressure while heating to 60°C and boiling. After the dehydration treatment, the liquid remaining in the container was obtained as a substance-encapsulated particle dispersion oil according to this embodiment, that is, an oil in which particles encapsulating a water-reduced aqueous solution of a water-soluble component and a hydrophilic form of an oil-soluble component are dispersed. Hereinafter, this oil, in which particles encapsulated as hydrophilic substances in a dehydrated region within a hydrophilic assembly structure of polyglycerin condensed ricinoleic acid ester, an amphiphilic molecule, containing a water-reduced aqueous solution of NMN as a water-soluble component and a hydrophilic form of lutein, an oil-soluble component, encapsulated within a hydrophobic assembly structure of a micelle of the amphiphilic molecule PPG-6 decyltetradeceth-30, is dispersed in ethylhexyl palmitate as a base oil, will be referred to as micelle-type substance-encapsulated particle dispersion oil A.

[0121] (1-2. Liposome-type substance-encapsulated particle dispersion oil agent) This oil-based formulation is an example in which liposomes, which hold the oil-soluble components within the hydrophobic association region of a lipid bilayer, are used as hydrophilic forms of the oil-soluble components. This is achieved by emulsifying an oily liquid containing oil-soluble components in an aqueous solution of water-soluble components in the presence of a surfactant.

[0122] One part by weight of NMN, the water-soluble component to be encapsulated, was added to 99 parts by weight of water to prepare a 1 w / w% NMN aqueous solution. Next, 0.1 parts by weight of hydrogenated lecithin, 0.3 parts by weight of 1,3-butylene glycol, and 0.5 parts by weight of lutein, the oil-soluble component to be encapsulated, were added to 100 parts by weight of this 1 w / w% NMN aqueous solution, and the mixture was emulsified at 60°C for 10 minutes in a homogenizer set to 5000 rpm to prepare a dispersion. This dispersion is a dispersion in which liposomes (hydrophilic forms of oil-soluble components) that hold oil-soluble components in the hydrophobic association region within the lipid bilayer layer are dispersed in an aqueous solution of water-soluble components.

[0123] Next, the dispersion was mixed with 94.1 parts by weight of ethylhexyl palmitate as a base oil and 5 parts by weight of polyglycerin condensed ricinoleate ester as an amphiphilic molecule. The mixture was then emulsified at room temperature for 1 minute using a homogenizer set to 24,000 rpm to prepare an emulsion in which micelles containing the dispersion were dispersed in the base oil.

[0124] Next, a predetermined amount of the prepared emulsion was placed in a container and subjected to an evaporator. Dehydration was carried out for 40 minutes under reduced pressure of approximately 1 / 10 of atmospheric pressure, while heating to 60°C and boiling. After the dehydration treatment, the liquid remaining in the container was obtained as the substance-encapsulated particle dispersion oil according to this embodiment. Hereinafter, this oil, in which particles containing a hydrophilic substance encapsulated as a hydrophilic substance in the dehydrated region of a hydrophilic region within a hydrophilic region of a polyglycerol condensed ricinoleic acid ester, an amphiphilic molecule, are dispersed in ethylhexyl palmitate as a base oil, is referred to as liposome-type substance-encapsulated particle dispersion oil B.

[0125] (1-3. Exosome-type substance-encapsulated particle dispersion oil agent) This oil formulation is an example in which exosomes obtained from specified cells, etc., are used as hydrophilic bodies of oil-soluble components.

[0126] A 1 w / w% NMN aqueous solution was prepared by adding 1 part by weight of NMN to 99 parts by weight of water as the water-soluble component to be encapsulated. Next, 1 part by weight of an exosome-containing extract containing the desired oil-soluble component was added to 100 parts by weight of this 1 w / w% NMN aqueous solution, and the mixture was emulsified at room temperature for 10 minutes using a 600 rpm three-one motor to prepare a dispersion. This dispersion is a dispersion in which exosomes (hydrophilic forms of oil-soluble components) that hold oil-soluble components in the hydrophobic association regions within the lipid bilayer layer are dispersed in an aqueous solution of water-soluble components. Alternatively, a liposome solution containing the desired oil-soluble component can be added instead of the exosome-containing extract.

[0127] Next, the dispersion was mixed with 95 parts by weight of ethylhexyl palmitate as a base oil and 5 parts by weight of polyglycerin condensed ricinoleate ester as an amphiphilic molecule. The mixture was then emulsified at room temperature for 1 minute in a homogenizer set to 24,000 rpm to prepare an emulsion in which micelles containing the dispersion were dispersed in the base oil.

[0128] Next, a predetermined amount of the prepared emulsion was placed in a container and subjected to an evaporator. Dehydration was carried out for 40 minutes under reduced pressure of approximately 1 / 10 of atmospheric pressure, while heating to 60°C and boiling. After the dehydration treatment, the liquid remaining in the container was obtained as the substance-encapsulated particle dispersion oil according to this embodiment. Hereinafter, this oil, in which particles encapsulated as hydrophilic substances in the dehydrated region of a hydrophilic region within a polyglycerol condensed ricinoleic acid ester, an amphiphilic molecule, are dispersed in ethylhexyl palmitate as a base oil, and the exosome, which is formed by the dehydration of an aqueous solution of NMN as a water-soluble component and an exosome that holds a desired oil-soluble component in the hydrophobic region within the lipid bilayer, are dispersed in ethylhexyl palmitate as a base oil, will be referred to as exosome-type substance-encapsulated particle dispersion oil C.

[0129] [2. Permeation test of substance-encapsulated particle-dispersed oils using artificial skin] Next, with respect to the substance-encapsulated particle dispersion oil produced in the above-mentioned [1. Production of substance-encapsulated particle dispersion oil], liposome-type substance-encapsulated particle dispersion oil B, as shown in (1-2. Liposome-type substance-encapsulated particle dispersion oil), was applied as a test solution to the surface of artificial skin, and the permeability was checked after 3 hours or 16 hours. In addition, a mixture of lutein and ethylhexyl palmitate (IOP) (hereinafter also referred to as comparator Y) was subjected to the same test as a control.

[0130] (2-1. Preparation of artificial skin by applying the test solution) The experiment was conducted using three-dimensional cultured skin. The three-dimensional cultured skin used was LabCyte EPI-MODEL12, purchased from Japan Tissue Engineering Co., Ltd. 1 ml of phosphate buffer warmed to 32°C was added to each well of a 12-well plate. After placing the insert cups of LabCyte EPI-MODEL12, which had the three-dimensional cultured skin pre-formed, into the wells, the plate was pre-incubated at 32°C for 30 minutes.

[0131] Next, 100 μL of either liposome-type substance-encapsulated particle dispersion oil B or comparator Y was dropped onto the surface of three-dimensional cultured skin as the test solution, and the mixture was incubated at 32°C for 3 hours or 16 hours while shaking at 25 rpm.

[0132] After 3 or 16 hours, the test solution was removed from the surface of the three-dimensional cultured skin using a micropipette, and the surface of the three-dimensional cultured skin was washed with 200 μL of IOP. This washing procedure with IOP was repeated three times, followed by the removal of 200 μL of phosphate buffer three more times, and any remaining moisture on the surface of the three-dimensional cultured skin was removed with a paper cloth. Finally, the three-dimensional cultured skin was collected from the insert cup along with the membrane filter using tweezers, and it was frozen for storage.

[0133] (2-2. Qualitative test: Observation of three-dimensional cultured skin sections using a fluorescence microscope) Frozen three-dimensional cultured skin was embedded in a cryo-sectioning device (CryoStar NX70, PHC Corporation) using a compound, and 10 μm sections were prepared using a cryostat. Phase contrast images and images using a BZ-X filter GFP (excitation wavelength 470 / 40, absorption wavelength 525 / 50) were then captured using an all-in-one fluorescence microscope BZ-X810 (Keyence Corporation).

[0134] (2-3. Quantitative test: Calculation of the amount of lutein that penetrated into three-dimensional cultured skin) Frozen three-dimensional cultured skin was thawed at room temperature (25°C) for 30 minutes. 500 μL of isopropanol was added to a 1.5 mL microtube, the three-dimensional cultured skin was immersed in it, and the mixture was stirred for 1 minute. The mixture was then left to stand overnight at room temperature (25°C) to extract the lutein that had penetrated into the three-dimensional cultured skin.

[0135] Next, 200 μL of isopropanol in which lutein had been eluted was transferred to a 96-well plate, and absorbance measurements were performed at a wavelength of 440 nm using a microplate reader ARVO MX-fla (PerkinElmer Japan Co., Ltd.). The amount of lutein that penetrated into the three-dimensional cultured skin was calculated by comparing the obtained absorbance values ​​with a calibration curve, and the penetration increase rate of liposome-type substance-encapsulated particle-dispersed oil B relative to comparator Y was determined using the following formula. Penetration Increase Rate (%) = [(Amount of Liposome-Type Substance-Encapsulated Particle Dispersed Oil Agent B Penetrating into Three-Dimensional Cultured Skin / Amount of Comparator Agent Y Penetrating into Three-Dimensional Cultured Skin) - 1] × 100

[0136] (2-4. Review of test results) Figure 1 shows microscopic images of three-dimensional cultured skin sections 16 hours after applying the test solution. Figure 1(a) shows the results for comparison agent Y, and Figure 1(b) shows the results for liposome-type substance-encapsulated particle-dispersed oil agent B.

[0137] Referring to the fluorescence images, lutein was detected on the stratum corneum surface of the three-dimensional cultured skin in comparison agent Y, as shown in Figure 1(a). On the other hand, in comparison agent B, lutein was observed to have penetrated throughout the entire three-dimensional cultured skin, as shown in Figure 1(b).

[0138] Furthermore, quantitative testing of lutein showed that the penetration increase rate of liposome-type substance-encapsulated particle-dispersed oil B compared to comparator Y was 22%, demonstrating the improvement in skin penetration according to the present invention.

[0139] [3. Qualitative permeability test of substance-encapsulated particle-dispersed oils using a filter for skin permeability testing] Regarding the substance-encapsulated particle dispersion oil manufactured in [1. Manufacturing of Substance-Encapsulated Particle Dispersion Oil], a qualitative permeability test of liposome-type substance-encapsulated particle dispersion oil B was performed using a skin permeability test filter to confirm that it reaches deep into the skin when applied, even when the types of oil-soluble and water-soluble components encapsulated are changed. In addition, a mixture of lutein, fluorescently labeled nicotinamide mononucleotide (fluorescently labeled NMN), and ethylhexyl palmitate (IOP) (hereinafter also referred to as comparator Z) was subjected to the same test as a comparison.

[0140] (3-1. Selection of oil-soluble components) The following oil-soluble components were selected: First, ceramide and glycolipids were selected as representative lipids. Second, ubiquinone was selected as a representative enzyme or coenzyme. Third, astaxanthin and lutein were selected as representative carotenoids. Fourth, tocopherol was selected as a representative lipid-soluble tocopherol. Few fourth, ferulic acid was selected as a representative phenol.

[0141] (3-2. Selection of water-soluble components) The following water-soluble components were selected: First, β-nicotinamide mononucleotide was selected as a representative of vitamins. Second, sodium hyaluronate was selected as a representative of peptides. Third, epidermal growth factor (EGF) was selected as a representative of proteins. Fourth, L-ascorbic acid 2-glucoside (AA2G) was selected as a representative of vitamin derivatives.

[0142] (3-3. Sample collection for transmission and qualitative tests using a static diffusion cell) For the permeability test using a static diffusion cell, we used the "Strat-M" skin permeability test membrane (Merck KGaA), which is a filter for skin permeability testing.

[0143] Strat-M was pre-treated by immersing it in phosphate-buffered saline, used as the receptor solution, for 1 hour and then immobilized in a static diffusion cell with refluxing water at 37°C. The reservoir side was filled with phosphate-buffered saline as the receptor solution. 500 μL of a substance-encapsulating particle dispersion oil containing the above-mentioned water-soluble and oil-soluble components was dropped onto the top of the Strat-M (donor side) as the test solution. After 30 minutes, 400 μL of the receptor solution was sampled and used as the qualitative test sample.

[0144] Subsequently, the permeability of each test solution to a skin permeability test filter was confirmed by qualitative testing.

[0145] (3-4. Qualitative test: Confirmation of the presence or absence of oil-soluble and water-soluble components that have permeated through the skin permeability test filter) Table 1 shows the test methods and confirmation procedures used to determine the presence or absence of oil-soluble and water-soluble components that permeated the skin permeability test filter. [Table 1]

[0146] (3-5. Qualitative test results) The qualitative test results are shown in Table 2. Note that whether or not permeability was detected is indicated by ○ (yes) for successful permeability and × (no) for unsuccessful permeability. [Table 2]

[0147] As shown in Table 2, qualitative tests of each sample confirmed that liposome-encapsulated particle dispersion oil B exhibited higher permeability than comparator Z for both oil-soluble and water-soluble components.

[0148] [4. Quantitative Permeability Test of Substance-Encapsulating Particle-Dispersed Oils Using a Filter for Skin Permeability Testing] Next, regarding the substance-encapsulated particle dispersion oil produced in the above-mentioned [1. Production of substance-encapsulated particle dispersion oil], a permeation test was conducted using a static diffusion cell to confirm the amount of permeation, with liposome-type substance-encapsulated particle dispersion oil B, shown in (1-2. Liposome-type substance-encapsulated particle dispersion oil), as a representative example. Similarly, the above-mentioned comparative agent Z was also subjected to the same test as a comparison.

[0149] (4-1. Sample collection for transmission and quantitative tests using static diffusion cells) For the permeability test using a static diffusion cell, we used the "Strat-M" skin permeability test membrane (Merck KGaA), which is a filter for skin permeability testing.

[0150] Strat-M was pre-treated by immersing it in phosphate-buffered saline (used as the receptor solution) for 1 hour and then immobilized in a static diffusion cell with refluxed water at 37°C. The reservoir side was filled with phosphate-buffered saline as the receptor solution. 500 μL of liposome-encapsulated particle dispersion oil B or comparator Z was dropped onto the top of the Strat-M (donor side) as the test solution, and 400 μL of the receptor solution was sampled at 0, 0.5, and 1 hour to obtain quantitative test samples.

[0151] (4-2. Quantitative test: Calculation of lutein and fluorescently labeled NMN amounts that pass through the skin permeability test filter) Next, 90 μL of the quantitative test sample was transferred to a 96-well plate, 10 μL of dimethyl sulfoxide was added, and the plate was shaken at 600 rpm at room temperature (25°C) for 5 minutes in the dark.

[0152] Subsequently, absorbance measurements at a wavelength of 442 nm and fluorescence intensity measurements at excitation wavelengths of 380 nm and 580 nm were performed using the Infinite® 200 PRO microplate reader (Tecan Japan Co., Ltd.).

[0153] The obtained values ​​were compared with a calibration curve to calculate the concentrations of lutein and fluorescently labeled NMN in the quantitative test sample. Furthermore, the amounts of lutein and fluorescently labeled NMN that passed through the skin permeability test filter were determined using the following formulas. Cumulative permeation amount (μg / cm 2 ) = CV / S C: Concentrations of lutein and fluorescently labeled NMN in the quantitative test sample (μg / mL) V: Volume of receptor solution (mL) S: Effective area (cm²) of the filter for skin permeability testing 2 )

[0154] (4-3. Quantitative Test Results) Cumulative lutein permeation (μg / cm³) 2 Table 3 shows the cumulative transmission amount of fluorescently labeled NMN (μg / cm³). 2 The results are shown in Table 4. [Table 3] [Table 4]

[0155] In this embodiment, as shown in Table 3, the cumulative permeation of lutein was 2.6 times higher for liposome-encapsulated particle dispersion oil B than for comparator Z at 0.5 hours of sampling, and 2.3 times higher at 1 hour of sampling.

[0156] Similarly, as shown in Table 4, the cumulative transmission amount of fluorescently labeled NMN was 2.1 times higher for liposome-encapsulated particle dispersion oil B than for comparator Z at 0.5 hours of sampling, and 3.8 times higher at 1 hour of sampling.

[0157] Based on the above, it was suggested that liposome-type substance-encapsulated particle dispersion oil agent B increased the permeability of oil-soluble and water-soluble components compared to comparator Z, i.e., that penetration was promoted.

[0158] These results demonstrate that, according to the substance-encapsulated particle dispersion oil agent of this embodiment, the encapsulated water-soluble and oil-soluble components can reach deeper into the skin compared to the conventional comparative agent Y. Furthermore, based on the above results, NMN, a water-soluble substance, can be efficiently penetrated into the skin. Therefore, it is possible to provide cosmetics, pharmaceuticals, foods, etc., that allow for efficient transdermal or oral intake of NMN. In addition, by using oil-soluble vitamins as the oil-soluble component, oxidized nicotinamide adenine dinucleotide (NAD) can be continuously absorbed into the body along with NMN. + By increasing the amount of fat-soluble vitamins, and by supporting the activated activity of living cells, a more synergistic effect can be obtained, such as the sustained healthy bodily functions.

[0159] As described above, the substance-encapsulated particle dispersion oil according to this embodiment is a particle dispersion oil in which a plurality of hydrophilic substances are encapsulated in a dehydrated region within a hydrophilic group structure formed by amphiphilic molecules. Since the plurality of hydrophilic substances include a water-reduced product of an aqueous solution of the water-soluble component to be encapsulated and a hydrophilized form of the oil-soluble component to be encapsulated, it is possible to provide a substance-encapsulated particle dispersion oil that encapsulates not only water-soluble components but also oil-soluble components.

[0160] Finally, the above-described embodiments are merely examples of the present invention, and the present invention is not limited to the embodiments described above. Therefore, it goes without saying that various modifications can be made to embodiments other than those described above, as long as they do not depart from the technical spirit of the present invention, depending on the design and other factors.

Claims

1. A dispersion oil for particles in which a hydrophilic substance is encapsulated in a dehydrated region within a hydrophilic associate structure formed by amphiphilic molecules, The hydrophilic substance comprises a water-reduced product of water and / or a water-soluble component, and a hydrophilized form of the oil-soluble component to be encapsulated. A substance-encapsulated particle dispersion oil characterized in that the hydrophilic form of the oil-soluble component is a liposome or exosome in which the oil-soluble component is held in the hydrophobic association region within the lipid bilayer, or a micelle in which the oil-soluble component is encapsulated within a hydrophobic association structure formed by amphiphilic molecules.

2. The substance-encapsulating particle dispersion oil according to claim 1, characterized in that it has the function of improving the skin penetration of the oil-soluble component and / or water-soluble component that are to be encapsulated.

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