Skin permeation promoter and skin permeation promotion method

Abstract

To provide a skin permeation promoter that induces the permeation of physiologically active substances, is easily incorporated into aqueous formulations, and causes low irritation to the skin, as well as a skin permeation promotion method for physiologically active substances.SOLUTION: The present disclosure relates to a skin permeation promoter for the permeation of physiologically active substances, the promoter containing α-glucosylnaringin.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a skin permeation enhancer and a method for enhancing skin permeation. [Background technology]

[0002] The skin has attracted attention as an administration site for drugs (biologically active substances) that are expected to have not only local but also systemic effects, because the hepatic first-pass effect can be avoided, the administration method is simple, and it is also easy to discontinue administration. In order for an administered drug to have a pharmacological effect, it must penetrate the skin, and various attempts have been made to allow the drug to penetrate the skin. There are two routes of drug permeation through the skin: the transstratum corneum route, which permeates the gaps between keratinocytes in the stratum corneum or through keratinocytes, and the transappendage route, which permeates through appendages such as pores and sweat pores. The main route of drug permeation is the transstratum corneum route. The stratum corneum is a dense membrane with high lipid solubility overall, and functions as a barrier to protect the body from the outside world, so most drugs do not permeate the skin very much. In particular, the skin permeability of drugs with large molecular weights and water-soluble drugs is extremely low (Non-Patent Document 1).

[0003] As drug permeation enhancers, fatty alcohols, fatty acids and their esters, monoterpenes, essential oils, etc. are known, but these improve the skin permeability of drugs by acting on stratum corneum lipids and reducing their barrier function (Non-Patent Document 1), and therefore often have safety issues. In addition, depending on the drug, the skin permeability is often insufficient even when a permeation enhancer is used.

[0004] As a drug permeation enhancer with low skin irritation, it has been reported that the use of flavonoid compounds such as quercetin, apigenin, or myricetin enhances the skin permeation of drugs such as rofecoxib sodium, certain peptides, aspirin, imiquimod, and epinephrine (Patent Document 1).

[0005] It has been reported that α-glucosylnaringin, a type of glucosylated flavonoid compound, can improve the solubility of a specific poorly water-soluble substance in water compared to conventional methods, thereby improving its absorbability in the body and allowing a smaller amount of use to exert the desired medicinal effect (Patent Document 2). However, Patent Document 2 only predicts the absorbability of poorly water-soluble substances in the body, and it was completely unknown how α-glucosylnaringin acts on the skin permeation of drugs. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2015-163606 A [Patent Document 2] JP 2017-48127 A [Non-patent literature]

[0007] [Non-Patent Document 1] "Transdermal delivery of poorly absorbed drugs using chemical and physical absorption enhancement methods", Hiroaki Todo et al., Drug Delivery System, 27-3, 2012, pp. 156-163 Summary of the Invention [Problem to be solved by the invention]

[0008] Flavonoid compounds described in Patent Document 1, such as quercetin, apigenin, and myricetin, are poorly soluble in water, and therefore difficult to incorporate into aqueous preparations and the like. In view of the above circumstances, an object of the present invention is to provide a skin permeation enhancer and a method for enhancing skin permeation of a physiologically active substance, which allows permeation of a physiologically active substance, is easy to incorporate into aqueous preparations, etc., and is low in irritation to the skin. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the above problems can be solved by providing the following configuration, which has led to the completion of the present invention. The present invention relates to, for example, the following items [1] to [7]. [1] A skin permeation enhancer for delivering a physiologically active substance, comprising α-glucosylnaringin. [2] The skin permeation enhancer according to [1], wherein the α-glucosyl naringin comprises α-monoglucosyl naringin. [3] The skin permeation enhancer according to [2], wherein the content of the α-monoglucosyl naringin is 65% by mass or more in 100% by mass of the skin permeation enhancer. [4] The skin permeation enhancer according to any one of [1] to [3], wherein the physiologically active substance is at least one selected from the group consisting of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids. [5] The skin permeation enhancer according to [4], wherein the acidic nonsteroidal anti-inflammatory drug (NSAID) is an aromatic compound having two or more benzene rings. [6] The skin permeation enhancer according to any one of [1] to [4], wherein the physiologically active substance is at least one selected from the group consisting of mefenamic acid or a salt thereof, flavone, and hesperetin. [7] A method for enhancing skin permeation of a physiologically active substance, comprising the step of topically administering α-glucosylnaringin and the physiologically active substance to the skin. Effect of the Invention

[0010] According to the present invention, it is possible to provide a skin permeation enhancer that allows permeation of a physiologically active substance, is easily incorporated into aqueous preparations and the like, and is low in irritation to the skin, and a method for enhancing skin permeation of a physiologically active substance. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a graph showing the change in the amount of flavone permeated through the skin over time when α-glucosyl naringin, α-glucosyl rutin, α-glucosyl hesperidin, or naringin was added. [Diagram 2] FIG. 2 is a graph showing the change in the amount of flavone permeated through the skin over time when α-glucosylnaringin was added. [Diagram 3] FIG. 3 is a graph showing the change in the amount of hesperetin permeated through the skin over time when α-glucosylnaringin was added. [Figure 4] FIG. 4 is a graph showing the change over time in the amount of mefenamic acid permeated through the skin when α-glucosylnaringin was added. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Next, the present invention will be described in detail. Unless otherwise specified, the expression "A to B" regarding a numerical range means from A to B. Additionally, % means mass %.

[0013] <α-Glucosylnaringin> α-Glucosyl naringin (also called α-glucosyl naringin) is a general term for compounds in which one or more glucose molecules are added to the hydroxyl group of naringin. Naringin is a type of flavonoid having a structure in which neohesperidose (L-rhamnosyl-(α1→2)-D-glucose) is β-bonded to the hydroxyl group at the 7th position of the naringenin (5,7,4'-trihydroxyflavanone) skeleton. α-Glucosyl naringin has a structure in which one or more α-glucose molecules are bound to at least one of the hydroxyl group at the 3rd position (3'' position) of the glucose residue in the neohesperidose residue and the hydroxyl group at the 4th position (4' position) of the phenyl group in the naringenin skeleton. The α-glucosyl naringin of the present invention may be composed of one type of compound having such a structure alone or a mixture of two or more types.

[0014] α-Glucosylnaringin can be represented by the following formula (1). In formula (1), R 1 m and R 2The n's represent the number of α-glucose residues bonded to the 3' and 4' positions, respectively, and are mutually independent integers of 0 or more and usually 25 or less. However, in order for formula (1) to represent "α-glucosylnaringin", it is necessary that m+n≧1 is satisfied, that is, at least one molecule of α-glucose is bonded to naringin (when m=n=0, that is, R 1 , R 2 When both are -H, formula (1) represents "naringin".

[0015] [ka]

[0016] α-Glucosyl naringin is a compound contained as the main component in a material known as "enzyme-modified naringin" (sometimes called "transglycosylated naringin"). Of α-glucosyl naringin, naringin with only one glucose bond is called "α-monoglucosyl naringin", and naringin with two or more glucose bonds is called "α-polyglucosyl naringin".

[0017] Enzyme-treated naringin is, for example, a product (referred to as "first enzyme-treated naringin" in this specification) obtained by reacting a mixture of naringin and a sugar donor (e.g., dextrin) with a glycosyltransferase (e.g., cyclodextrin glucosyltransferase), and is a collection of various compounds in which one or more glucose molecules are added to the hydroxyl groups of naringin. Therefore, enzyme-treated naringin usually includes a mixture of compounds with different numbers of glucose molecules bound to naringin, for example, a mixture of α-monoglucosyl naringin and α-polyglucosyl naringin. In addition to α-glucosyl naringin, it may also include unreacted naringin and naringin derivatives other than α-glucosyl naringin, such as 7-glucosyl naringenin (also referred to as other naringin derivatives).

[0018] For a basic method for producing the first enzyme-treated naringin, see, for example, Japanese Patent Application Laid-Open No. 4-13691. If necessary, the first enzyme-treated naringin can be purified using, for example, a porous synthetic adsorbent and an appropriate elution solution to remove sugar donors and other impurities, and to obtain the first enzyme-treated naringin (purified α-glucosyl naringin) with a reduced content of naringin and an increased purity of α-glucosyl naringin.

[0019] As the α-glucosyl naringin, one α-glucose molecule is linked to the 3'' position of naringin and / or one α-glucose molecule is linked to the 4' position of naringin, i.e., at least one type of α-glucosyl naringin selected from 3''-α-monoglucosyl naringin (in formula (1) m=1, n=0), 4'-α-monoglucosyl naringin (same m=0, n=1), and 3''-4'-α-diglucosyl naringin (same m=1, n=1), is preferred, and among these, 3''-α-monoglucosyl naringin is more preferred. This is because the molecular weight of α-monoglucosyl naringin is smaller than that of α-polyglucosyl naringin, and therefore the number of molecules per unit mass is greater for α-monoglucosyl naringin, which is considered to be advantageous in terms of the skin permeation promoting effect. The α-glucosyl naringin preferably comprises α-monoglucosyl naringin.

[0020] Enzyme-treated naringin containing a large amount of the above three types of α-monoglucosyl naringin (referred to as "second enzyme-treated naringin" in this specification) can be obtained, for example, by treating the above-mentioned first enzyme-treated naringin with an enzyme having glucoamylase activity, and cleaving the sugar chain in which two or more molecules of α-glucose are linked by α-1,4 bonds, which have been transferred to the 3'' and / or 4'' positions of naringin by the glycosyltransferase, leaving only one molecule of α-glucose residue at the base. Furthermore, by treating the second enzyme-treated naringin with an enzyme having α-glucosidase activity and cleaving one molecule of α-glucose residue directly bonded to the hydroxyl group at the 4'' position, it is possible to obtain enzyme-treated naringin (referred to as "third enzyme-treated naringin" in this specification) that contains little or no 4'-α-monoglucosyl naringin and 3''-4'-α-diglucosyl naringin, while leaving 3''-α-monoglucosyl naringin. For the basic production method of the second and third enzyme-treated naringin, reference can be made to, for example, JP-A No. 2002-199896.

[0021] Furthermore, α-L-rhamnosidase is applied to the third enzyme-treated naringin to cleave the rhamnose contained in the rutinose units of naringin, thereby producing 7-glucosylnaringenin, and obtaining enzyme-treated naringin containing 7-glucosylnaringenin and α-monoglucosylnaringin (referred to as "fourth enzyme-treated naringin" in this specification).

[0022] In addition, since transglucosidase is an enzyme having both glucoamylase activity and α-glucosidase activity, by allowing transglucosidase to act on the first enzyme-treated naringin, the third enzyme-treated naringin rich in 3''-α-monoglucosyl naringin can be obtained in a single step instead of the two-step process described above. Furthermore, if necessary, an enzyme having β-glucosidase activity may be allowed to act on the third enzyme-treated naringin (or may be allowed to act simultaneously with transglucosidase on the first enzyme-treated naringin) to cleave the neohesperidose residue (not modified by glycosyltransferase) contained in the unreacted naringin dissolved in a small amount in the aqueous solution from its aglycone, naringenin. The naringenin produced by such a process has a lower solubility than naringin and can be easily removed from the aqueous solution as a precipitate, making it possible to recover 3''-α-monoglucosyl naringin from the aqueous solution with a higher purity.

[0023] In the present invention, taking into consideration the effects of the present invention, it is preferable to use enzyme-treated naringin, which is a composition containing α-glucosyl naringin, and any of the first enzyme-treated naringin, second enzyme-treated naringin, third enzyme-treated naringin, and fourth enzyme-treated naringin compositions may be used, but it is preferable to use the fourth enzyme-treated naringin.

[0024] Considering the effects of the present invention, the enzyme-treated naringin is preferably a mixture containing α-glucosylnaringin and at least one selected from the group consisting of naringin and 7-glucosylnaringenin.

[0025] The presence of various α-glucosyl naringin, naringin, and other components contained in enzyme-treated naringin can be confirmed by HPLC chromatograms, and the content of each component, or the purity of a desired specific component, can be calculated from the peak area of ​​the chromatogram.

[0026] The method for producing α-glucosyl naringin is not particularly limited, and known methods can be used. It is preferable to produce it by the enzyme treatment of naringin, since it has a good yield and is easy to produce. The method for obtaining and preparing naringin is not particularly limited, and it is possible to use a compound that is generally manufactured and sold as a reagent or purified product, or a compound prepared by extraction from a raw material such as the outer skin of citrus fruits (such as Natsumikan and grapefruit).

[0027] <Physiologically active substances> The physiologically active substance is not particularly limited as long as it is a substance known to have physiological activity. Examples of the physiologically active substances include anti-inflammatory drugs, antibacterial agents, hormone drugs, antihistamines, antiallergic drugs, blood flow improving agents, vasodilators, cardiac stimulants, antiarrhythmic drugs, antianginal drugs, antihypertensive drugs, insulin preparations, sequestering agents, vitamins, skin softeners, moisturizers, whitening agents, anti-wrinkle agents, astringents, ultraviolet absorbers, hair growth and hair care agents, antiperspirants, and deodorants.

[0028] The physiologically active substance is preferably a poorly water-soluble substance, more preferably a poorly water-soluble substance having two or more benzene rings, since this facilitates the skin permeation enhancing effect of α-glucosylnaringin.

[0029] More specifically, the anti-inflammatory drug includes steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs (NSAIDs), preferably non-steroidal anti-inflammatory drugs, more preferably acidic non-steroidal anti-inflammatory drugs (NSAIDs).

[0030] Examples of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) include salicylic acid drugs such as aspirin, ethenzamide, diflucinal (diflunisal), and methyl salicylate; propionic acid drugs such as ibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen; acetic acid drugs such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, and diclofenac; oxicam drugs such as piroxicam, meloxicam, tenoxicam, lornoxicam, and isoxicam; fenamic acid drugs such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid; and salts thereof.

[0031] The salt may be any pharma- ceutically acceptable salt, and examples thereof include inorganic salts containing metals such as sodium, potassium, magnesium, calcium, aluminum, and lithium; organic salts such as methylamine, ethylamine, ethanolamine, and lysine; phosphate salts; and ammonium salts.

[0032] Among these, aromatic compounds having two or more benzene rings are preferred because they are more likely to exhibit the skin permeation enhancing effect of α-glucosyl naringin. Examples of aromatic compounds having two or more benzene rings include diflusinal (diflunisal), naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, diclofenac, piroxicam, mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid, and fenamic acid-based compounds such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid are preferred.

[0033] More specifically, examples of the blood flow improver include flavonoids, tocopherol or its derivatives, heparinoids, dl-camphor, ginkgo leaf extract, ginger rhizome extract, capsicum fruit extract, ginger extract, cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxine mesylate, tolazoline hydrochloride, hepronicate, Shimotsuto extract, etc. Among these, flavonoids are preferred because they are more likely to exhibit the skin permeation promoting effect of α-glucosylnaringin.

[0034] Examples of flavonoids include flavones such as flavone, apigenin, luteolin, tangeretin, diosmin, nobiletin, and flavoxate; isoflavones such as daidzein, daidzin, and genistein; flavonols such as kaempferol, myricetin, quercetin, and rutin; flavanones such as eriodictyol, hesperetin, hesperidin, homoeriodictyol, and naringenin; flavanols such as catechin, epicatechin, and epigallocatechin; flavanonols such as dihydroquercetin; and anthocyanidins such as cyanidin, anthocyanin, delphinidin, malvidin, pelargonidin, and peonidin. Among these, flavonols, flavones, and flavanones are preferred because they are more likely to exhibit the skin permeation enhancing effect of α-glucosylnaringin, with rutin, quercetin, hesperidin, flavone, and hesperetin being more preferred, and flavone and hesperetin being even more preferred.

[0035] The physiologically active substance is preferably at least one selected from the group consisting of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids, since this is likely to produce the skin permeation enhancing effect of α-glucosylnaringin. Since the skin permeation enhancing effect of α-glucosylnaringin is easily achieved, the physiologically active substance is preferably at least one selected from the group consisting of mefenamic acid or a salt thereof, flavone, and hesperetin.

[0036] <Skin permeation enhancer> A skin permeation enhancer in one embodiment of the present invention contains α-glucosylnaringin and enhances skin permeation of a physiologically active substance.

[0037] The method for evaluating the effect of promoting skin permeation is not particularly limited, and known methods can be used. For example, if the degree of skin permeation of a physiologically active substance when the test substance is added is higher than the degree of skin permeation of a physiologically active substance when the test substance is not added, the test substance can be evaluated as having an effect of promoting skin permeation.

[0038] The degree of skin permeation of a physiologically active substance may be evaluated at a certain time point, or at different times, i.e., over time. The time point at which the degree of skin permeation of a physiologically active substance is evaluated is not particularly limited, but is preferably 4 hours or more after the start of the test, more preferably 6 hours or more after the start of the test, even more preferably 8 hours or more after the start of the test, and particularly preferably 12 hours or more after the start of the test.

[0039] The degree of skin permeation of a physiologically active substance can be measured by a known method, but is preferably measured by a method using a Franz diffusion cell. The permeation membrane of the Franz diffusion cell can be a known one, for example, skin derived from animals such as humans, guinea pigs, and mice, three-dimensional cultured skin, and artificial membranes for skin permeability tests such as Permea Pad Barrier and Strat-M membrane.

[0040] The degree of skin permeation promotion is not particularly limited as long as the skin permeation of a physiologically active substance when α-glucosylnaringin is used is greater than 100%, assuming that the skin permeation of the physiologically active substance when α-glucosylnaringin is not used is 100%, and may be, for example, 110% or more, 120% or more, 130% or more, 140% or more, 150% or more, 200% or more, 250% or more, 300% or more, 350% or more, 400% or more, 450% or more, or 500% or more.

[0041] The amount of α-glucosyl naringin contained in the skin permeation enhancer is not particularly limited. For example, the lower limit of the amount of α-glucosyl naringin contained in the skin permeation enhancer of the present invention may be, for example, 30% by mass, 40% by mass, 45% by mass, 50% by mass, 60% by mass, 70% by mass, or 80% by mass. The upper limit of the amount of α-glucosyl naringin contained in the skin permeation enhancer of the present invention may be, for example, 100% by mass, 99% by mass, 98% by mass, 95% by mass, 90% by mass, or 85% by mass. The range of the amount of α-glucosyl naringin contained in the skin permeation enhancer of the present invention may be set arbitrarily to a range that arbitrarily combines the lower limit and the upper limit, and may be set to, for example, 30 to 100% by mass, 60 to 100% by mass, 60 to 90% by mass, or the like. From the viewpoint of the skin permeation enhancing effect, the content of α-glucosyl naringin is preferably 65% ​​by mass or more in 100% by mass of the skin permeation enhancer, and more preferably the content of α-monoglucosyl naringin is 70% by mass or more in 100% by mass of the skin permeation enhancer.

[0042] The skin permeation enhancer may be any one that contains α-glucosyl naringin, and may be composed of only α-glucosyl naringin, or may further contain known optional components such as excipients, stabilizers, moisturizers, emulsifiers, etc., so long as the skin permeation enhancing effect of α-glucosyl naringin is not hindered. The skin permeation enhancer may also be an enzyme-treated naringin, which is a composition containing α-glucosyl naringin.

[0043] The mechanism by which α-glucosylnaringin promotes skin permeation of physiologically active substances is not clear, but the present inventors speculate as follows. It is generally known that the skin is made up of lipids, so the permeability of water-soluble drugs through the skin is extremely low, and the higher the lipid solubility, the easier it is to distribute through the skin and the faster the skin permeation rate. In other words, it is common technical knowledge that if a poorly water-soluble substance is solubilized to increase its water solubility, its skin permeability will decrease. However, the present inventors believe that two factors, solubility and subsequent release, contribute greatly to the skin permeation of poorly water-soluble substances. That is, in order to promote the skin permeation of poorly water-soluble substances, firstly, it is necessary to solubilize the poorly water-soluble substance to increase its water solubility, and secondly, it is necessary that the poorly water-soluble substance after solubilization is sufficiently released into the skin.

[0044] It has been reported that α-glucosylnaringin can improve the solubility of a specific poorly water-soluble substance in water compared to conventional methods (Patent Document 2). Since α-glucosylnaringin solubilizes poorly water-soluble substances to increase their water solubility, it is expected based on common technical knowledge that the skin permeability of poorly water-soluble substances will be reduced when α-glucosylnaringin is added. However, as shown in the examples of this specification, α-glucosylnaringin significantly promoted the skin permeation of poorly water-soluble substances compared to naringin, which has no solubilizing effect.

[0045] It has also been reported that not only α-glucosylnaringin, but also α-glucosylhesperidin and α-glucosylrutin, which are also glucosylated flavonoid compounds, can improve the solubility of poorly water-soluble substances in water compared to conventional methods (Patent Document 2). However, as shown in the examples of this specification, only α-glucosylnaringin significantly promoted the skin permeation of physiologically active substances, and the skin permeation promoting effect of α-glucosylhesperidin or α-glucosylrutin was slight. Based on these facts, it is believed that α-glucosyl naringin has a greater effect of increasing the release of poorly water-soluble substances after solubilization than α-glucosyl hesperidin or α-glucosyl rutin, and that the high skin permeation-promoting effect of α-glucosyl naringin is mainly due to this effect.

[0046] The use of the skin permeation enhancer is not particularly limited, but since the skin permeation enhancer of the present invention has a high effect of promoting skin permeation of a physiologically active substance, it can be administered to a living body once or multiple times for the purpose of promoting skin permeation of a physiologically active substance in a living body, for example. A skin permeation enhancer administered to a living body enhances the skin permeation of a physiologically active substance, thereby contributing, for example, to the physiologically active substance exerting its activity locally or systemically.

[0047] <Administration of skin permeation enhancer to living body> When a skin permeation enhancer is administered to a living body, the route of administration is usually external application to the skin. The method of administration of the skin permeation enhancer is not particularly limited, and the skin permeation enhancer may be administered in combination with the physiologically active substance whose permeation is to be enhanced. Typically, the skin permeation enhancer and the physiologically active substance whose permeation is to be enhanced are administered simultaneously.

[0048] The skin permeation enhancer may be administered to the living body as it is, but is preferably administered as a preparation in which an effective amount of the skin permeation enhancer is combined with a physiologically active substance the permeation of which is to be enhanced. The content of the skin permeation enhancer in the preparation may be appropriately selected depending on the type or concentration of the physiologically active substance to be enhanced in permeation. From the viewpoint of the skin permeation enhancing effect, the preparation contains α-glucosylnaringin in an amount of preferably 0.01 to 5 mass%, more preferably 0.025 to 2 mass%, and even more preferably 0.05 to 1 mass% based on 100 mass% of the preparation.

[0049] The concentration of the physiologically active substance in the preparation may be appropriately selected depending on the type of physiologically active substance, the site where the activity is to be expressed (local or systemic), the level of activity to be expressed, etc. When the physiologically active substance is flavone, hesperetin, or mefenamic acid, the concentration of the physiologically active substance in the preparation is preferably 0.01 to 5 mg / mL, more preferably 0.1 to 1 mg / mL.

[0050] The preparation may be any of a drug, a quasi-drug, and a cosmetic, so long as it is a preparation that can be applied to the skin. The properties and dosage form of the preparation are not limited, and the preparation may be, for example, a solid, semi-solid, liquid, emulsion, cream, gel, mousse, spray, or a two-component formulation in which these are mixed, a liniment, a cataplasm, a plaster, or a patch (e.g., a film or tape).

[0051] The preparation may contain, as necessary, ingredients typically used in skin external preparations such as cosmetics and pharmaceuticals, cleansers, etc., such as fats and oils, waxes, hydrocarbon oils, ester oils, higher alcohols, silicone oils, UV absorbers, UV scattering agents, moisturizers, surfactants, water-soluble polymers, thickeners, powders, skin protective agents, whitening agents, wrinkle improving agents, anti-aging agents, plant extracts, preservatives, anti-inflammatory agents, pH adjusters, sequestering agents, antioxidants, stabilizers, fragrances, dyes, pigments, etc., within the scope of not impairing the effects of the present invention. These ingredients may be used alone or in combination of two or more.

[0052] The preparation can be produced by adding the skin permeation enhancer and the physiologically active substance according to a method generally used for these preparations. The skin permeation enhancer and the physiologically active substance may be added at the beginning, middle or end of the preparation production process, and the method of addition may be appropriately selected from mixing, kneading, dissolving, immersing, scattering, spraying, coating, etc. according to the form of the preparation.

[0053] Since α-glucosylnaringin, which is the active ingredient of the skin permeation enhancer, has good water solubility, the skin permeation enhancer of the present invention is highly water soluble and can be dissolved or dispersed uniformly even when added to water or a preparation with a high water content, and can be easily incorporated into aqueous preparations, etc. Therefore, the skin permeation enhancer of the present invention can be incorporated into a very wide range of preparations.

[0054] α-glucosylnaringin, the active ingredient of the skin permeation enhancer, is low in irritation to the skin, is widely consumed, and has good safety properties, so the skin permeation enhancer of the present invention is low in irritation to the skin and highly safe.

[0055] <Skin permeation promotion method> One aspect of the present invention is a method for enhancing dermal permeation of a physiologically active substance, comprising the step of topically administering α-glucosyl naringin and the physiologically active substance to the skin. The method for topically administering α-glucosylnaringin and a physiologically active substance to the skin is not particularly limited, and is as described in the section <Administration of a skin permeation enhancer to the living body>.

[0056] One aspect of the present invention is the use of α-glucosyl naringin to enhance the skin permeation of a biologically active substance. One aspect of the present invention is the use of α-glucosyl naringin in the manufacture of a skin permeation enhancer for permeating a biologically active substance. EXAMPLES

[0057] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these.

[0058] <Skin permeation test 1 using Franz diffusion cells> (method) As substance group A, the following α-glucosyl naringin (Example 1), naringin (Comparative Example 1), α-glucosyl hesperidin (Comparative Example 2), and α-glucosyl rutin (Comparative Example 3) were used. α-Glucosyl naringin (Naringin-G): Enzyme-treated naringin (manufactured by Toyo Sugar Refining Co., Ltd., containing 75% by mass of α-monoglucosyl naringin) Naringin: Naringin reagent (manufactured by Tokyo Chemical Industry Co., Ltd., contains 96% naringin by mass). α-Glucosyl hesperidin (Hsp-G): Enzyme-treated hesperidin (manufactured by Toyo Sugar Refining Co., Ltd., containing 80% by mass of α-monoglucosyl hesperidin) α-Glucosyl rutin (Rutin-G): Enzyme-treated rutin (manufactured by Toyo Sugar Refining Co., Ltd., containing 75% by mass of α-monoglucosyl rutin) Flavone (Tokyo Chemical Industry Co., Ltd., No. H0721) was used as the physiologically active substance.

[0059] Any of the substances in substance group A and the physiologically active substance were added to 10 mL of distilled water and mixed to prepare a solution (or suspension) to be used as the test solution. The substance in substance group A was added in an amount that would result in a concentration of 10 mg / mL in the test solution. The physiologically active substance was added in an amount that would result in a concentration of 250 μg / mL in the test solution. As a control, a test solution (only flavone) was also prepared to which no substance in substance group A was added.

[0060] The receptor part of the Franz-type vertical diffusion cell was filled with phosphate buffer (pH 7.4) containing 0.5% sodium taurocholate, and a Strat-M membrane for transdermal diffusion tests (Merck) was attached as a permeable membrane. After dropping 400 μL of the above test solution onto the donor side, the receptor solution was sampled over time. The amount of physiologically active substances in the sampled receptor solution was quantified by high performance liquid chromatography. The experiment was performed with N=1.

[0061] (result) The results are shown in Figure 1. Addition of naringin, a poorly water-soluble flavonoid compound, did not change the amount of flavone that penetrated the skin, whereas addition of α-glucosylhesperidin or α-glucosylrutin, a water-soluble glucosylated flavonoid compound, increased the amount of flavone that penetrated the skin, but the increase was small. On the other hand, the addition of α-glucosylnaringin significantly increased the amount of flavone permeated through the skin, indicating that α-glucosylnaringin promotes the skin permeation of physiologically active substances.

[0062] <Skin permeation test using Franz diffusion cells 2> (method) As the substance of substance group A, α-glucosylnaringin (Naringin-G), the same as that used in skin permeability test 1, was used. As physiologically active substances, flavone (Tokyo Chemical Industry Co., Ltd., No. H0721, Example 2), hesperetin (Sigma-Aldrich, No. F2003, Example 3), and mefenamic acid (Tokyo Chemical Industry Co., Ltd., No. M1782, Example 4) were used. α-Glucosyl naringin and any of the physiologically active substances were added to 10 mL of distilled water and mixed to prepare a solution (or suspension) as a test solution. α-Glucosyl naringin was added at a concentration of 0.5 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, 10 mg / mL, or 20 mg / mL (10 mg / mL or 25 mg / mL for mefenamic acid, and 1 mg / mL or 20 mg / mL for hesperetin). The physiologically active substance was added at a concentration of 250 μg / mL in the test solution. As a control, a test solution without the addition of any substance of substance group A (only flavone, only hesperetin, or only mefenamic acid) was also prepared. A skin permeability test was carried out using a Franz-type diffusion cell in the same manner as in Skin Permeability Test 1. The experiment was carried out with N=3, and the average value was calculated.

[0063] (result) The results when flavone was used as the physiologically active substance (Example 2) are shown in FIG. 2, the results when hesperetin was used (Example 3) are shown in FIG. 3, and the results when mefenamic acid was used (Example 4) are shown in FIG. 2, 3, and 4 show that the addition of α-glucosylnaringin increased the skin permeation amounts of flavone, hesperetin, and mefenamic acid. Furthermore, the skin permeation enhancing effect of α-glucosylnaringin was dependent on the concentration of α-glucosylnaringin within a certain concentration range.

Claims

1. A skin permeation enhancer for permeating a physiologically active substance, comprising α-glucosylnaringin.

2. The skin permeation enhancer of claim 1, wherein the α-glucosyl naringin comprises α-monoglucosyl naringin.

3. The skin permeation enhancer according to claim 2, wherein the content of the α-monoglucosyl naringin is 65% by mass or more in 100% by mass of the skin permeation enhancer.

4. The skin permeation enhancer according to claim 1 , wherein the physiologically active substance is at least one selected from the group consisting of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids.

5. The skin permeation enhancer according to claim 4 , wherein the acidic nonsteroidal anti-inflammatory drug (NSAIDs) is an aromatic compound having two or more benzene rings.

6. The skin permeation enhancer according to claim 1 , wherein the physiologically active substance is at least one selected from the group consisting of mefenamic acid or a salt thereof, flavone, and hesperetin.

7. A method for enhancing skin permeation of a physiologically active substance, comprising the step of topically administering α-glucosyl naringin and the physiologically active substance to the skin.

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