Skin permeation promoter and skin permeation promotion method

Abstract

The present disclosure relates to a skin penetration enhancer and a skin penetration enhancing method for infiltrating a physiologically active substance, the skin penetration enhancer containing alpha-glucosyl naringin.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480043901.0 (22) Application Date 2024.07.05 (30) Priority Data 2023-123149 2023.07.28 JP (85) PCT International Application Entering National Phase Date 2025.12.29 (86) PCT International Application Application Data PCT / JP2024 / 024376 2024.07.05 (87) PCT International Application Publication Data WO2025 / 028157 JA 2025.02.06 (71) Applicant: Toyo Gintoki Co., Ltd. Address: Tokyo, Japan (72) Inventors: Yuichi Totsuka, Kazuki Monda, Hiromasa Uchiyama, Akira Nakanishi, M. Tandia (74) Patent Agency: Shanghai Patent & Trademark Agency Co., Ltd. 31100 Patent Attorneys: Jiaxin Zhang, Qing Dong (51) Int.Cl. A61K 31 / 7048 (2006.01) A61K 31 / 196 (2006.01) A61K 31 / 352 (2006.01) A61P 29 / 00 (2006.01) A61P 43 / 00 (2006.01) (54) Invention Title: Skin Penetration Enhancer and Skin Penetration Enhancement Method (57) Abstract: This disclosure relates to a skin penetration enhancer containing α-glucosyl naringin for the penetration of physiologically active substances and a skin penetration enhancement method. Claims 1 page, Description 10 pages, Drawings 3 pages, CN 121419779 A 2026.01.27 CN 1 21 41 97 79 A 1. A skin penetration enhancer for facilitating the penetration of a physiologically active substance, comprising α-glucosyl naringin. 2. The skin penetration enhancer of claim 1, wherein the α-glucosyl naringin comprises α-monoglucosyl naringin. 3. The skin penetration enhancer of claim 2, wherein, in 100% by mass of the skin penetration enhancer, the content of α-monoglucosyl naringin is 65% by mass or more. 4. The skin penetration enhancer of claim 1, wherein the physiologically active substance is at least one selected from acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids. 5. The skin penetration enhancer of claim 4, wherein the acidic nonsteroidal anti-inflammatory drugs (NSAIDs) are aromatic compounds having two or more benzene rings. 6. The skin penetration enhancer of claim 1, wherein the physiologically active substance is at least one selected from mefenamic acid or its salt, flavonoids, and hesperidin. 7. A method for enhancing skin penetration of the physiologically active substance, comprising the step of topically administering α-glucosyl naringin and the physiologically active substance to the skin.Claims 1 / 1 Page 2 CN 121419779 A Skin Penetration Enhancer and Skin Penetration Enhancement Method Technical Field

[0001] This disclosure relates to skin penetration enhancers and skin penetration enhancement methods. Background Art

[0002] The skin is a highly regarded site for drug administration (physiologically active substances) that can be expected to have both local and systemic effects, due to its ability to avoid the first-pass effect of the liver, its simple administration method, and its ease of interruption. In order for the administered drug to exhibit its efficacy, it needs to penetrate the skin, and therefore various attempts have been made to enable drug penetration.

[0003] As for the skin penetration pathway of drugs, there are transstratum corneum pathways that penetrate through the intercellular spaces and inside the corneocytes of the stratum corneum, and trans-accessory pathways that penetrate through accessory organs such as pores and sweat pores, but the main penetration pathway is the transstratum corneum pathway. The stratum corneum is a dense membrane with high overall lipid solubility, which acts as a barrier to protect the body from external influences, so most drugs can hardly penetrate the skin. In particular, the skin permeability of drugs with large molecular weight and water-soluble drugs is significantly lower (Non-Patent Literature 1).

[0004] Fatty alcohols and fatty acids, as well as their esters, monoterpenes, essential oils, etc., are known as drug penetration enhancers. However, they improve the skin permeability of drugs by acting on the lipids of the stratum corneum and weakening its barrier function (Non-Patent Document 1), and therefore often pose safety concerns. In addition, depending on the drug, skin permeability is often insufficient even when using penetration enhancers.

[0005] It has been reported that if flavonoid compounds such as quercetin, apigenin, or myricetin are used as drug penetration enhancers with low skin irritation, the skin permeability of drugs such as loxoprofen sodium, certain peptides, aspirin, imiquimod, and adrenaline can be enhanced (Patent Document 1).

[0006] It has been reported that α-glucosyl naringin, as a type of glycosylated flavonoid compound, can improve the solubility of certain water-poorly soluble substances in water better than before, thereby also improving absorption in vivo and achieving the desired efficacy with a smaller dosage (Patent Document 2). However, in Patent Document 2, the absorption of water-insoluble substances in vivo was only predicted, and no information was given about how α-glucosyl naringin would affect the skin penetration of the drug.

[0007] Prior Art Documents

[0008] Patent Documents

[0009] Patent Document 1: Japanese Patent Application Publication No. 2015-163606

[0010] Patent Document 2: Japanese Patent Application Publication No. 2017-48127

[0011] Non-Patent Documents

[0012] Non-Patent Document 1: "Transdermal Delivery of Poorly Absorbable 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

[0013] Technical Problem to be Solved by the Invention

[0014] Quercetin, apigenin, or myricetin, etc., the flavonoid compounds described in Patent Document 1 are poorly soluble in water, and therefore difficult to formulate into aqueous preparations, etc. Specification 1 / 10 pages 3 CN 121419779 A

[0015] In view of the above facts, the present disclosure provides a skin penetration enhancer that allows physiologically active substances to penetrate, is easy to formulate into aqueous preparations, etc., and has low skin irritation, and a method for promoting skin penetration of physiologically active substances.

[0016] Technical solution adopted to solve the technical problem

[0017] The inventors have conducted in-depth research to solve the above-mentioned technical problem. As a result, it was found that the above-mentioned technical problem can be solved by having the following structure, thereby completing the present invention.

[0018] The present invention relates to, for example, the following [1] to [7].

[0019] [1] A skin penetration enhancer for allowing physiologically active substances to penetrate, wherein it contains α-glucosyl naringin.

[0020] [2] [1] The skin penetration enhancer, wherein the α-glucosyl naringin comprises α-monoglucosyl naringin.

[0021] [3][2] The skin penetration enhancer, wherein, in 100% by mass of the skin penetration enhancer, the content of α-monoglucosyl naringin is 65% by mass or more.

[0022] [4][1] to [3] The skin penetration enhancer, wherein, the physiologically active substance is at least one selected from acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids.

[0023] [5][4] The skin penetration enhancer, wherein, the acidic nonsteroidal anti-inflammatory drugs (NSAIDs) are aromatic compounds having two or more benzene rings.

[0024] [6][1] to [4] The skin penetration enhancer, wherein, the physiologically active substance is at least one selected from mefenamic acid or its salt, flavonoids and hesperidin.

[0025] [7] The skin penetration enhancer method of the physiologically active substance, comprising the step of administering α-glucosyl naringin and the physiologically active substance topically to the skin.

[0026] Effects of the Invention

[0027] According to this disclosure, a skin penetration enhancer that allows physiologically active substances to penetrate, is easily formulated into aqueous preparations, and has low skin irritation, and a method for enhancing the skin penetration of physiologically active substances can be provided. Brief Description of the Drawings

[0028] FIG1 is a graph showing the time-dependent changes in the skin penetration of flavonoids when α-glucosyl naringin, α-glucosyl rutin, α-glucosyl hesperidin, or naringin are added.

[0029] FIG2 is a graph showing the time-dependent changes in the skin penetration of flavonoids when α-glucosyl naringin is added.

[0030] FIG3 is a graph showing the time-dependent changes in the skin penetration of hesperidin when α-glucosyl naringin is added.

[0031] FIG4 is a graph showing the time-dependent changes in the skin penetration of mefenamic acid when α-glucosyl naringin is added. Detailed Description of the Invention

[0032] The present invention will now be described in detail.

[0033] Unless otherwise specified, the reference to "A-B" in numerical ranges refers to A and below B. Furthermore, % refers to mass %.

[0034] <α-glucosyl naringin>

[0035] α-glucosyl naringin (also known as α-glucosyl naringin) is a general term for compounds obtained by adding one or more molecules of glucose to the hydroxyl group of naringin. Naringin is a type of flavonoid compound with a structure formed by the β-bonding of a hydroxyl group at the 7-position of a neohesperidin (L-rhamnoside, specification 2 / 10 page 4 CN 121419779 A glycosyl-(α1→2)-D-glucose) backbone to naringenin (5,7,4'-trihydroxyflavanone). α-Glucosyl naringin has the following structure: one or more α-glucose molecules are linked to at least one of the hydroxyl groups at the 3-position (3'' position) of the glucose residue in the neohesperidin residue and the hydroxyl group at the 4-position (4' position) of the phenyl group in the naringenin skeleton. The α-glucosyl naringin of the present invention can be composed of a single compound having this structure or a mixture of two or more.

[0036] α-Glucosyl naringin can be represented by the following formula (1). In formula (1), m of R1 and n of R2 represent the number of α-glucose residues bonded to the hydroxyl group at the 3'' position and the hydroxyl group at the 4' position, respectively, and they independently represent integers greater than 0 and usually less than 25. In order for formula (1) to represent "α-glucosyl naringin", it is necessary to satisfy m + n ≥ 1, that is, at least one molecule of α-glucose must be linked to naringin (when m = n = 0, that is, when R1 and R2 are both -H, formula (1) represents "naringin").

[0037] [Chemical Formula 1]

[0038] α-glucosyl naringin is a compound that is included as a main component in a raw material called "enzyme-treated naringin" (sometimes also called "glycan-transferred naringin").Among α-glucosyl naringin, those with only one glucose molecule bonded are called "α-monoglucosyl naringin", and those with two or more glucose molecule bonded are called "α-polyglucosyl naringin".

[0039] Enzymatically treated naringin is a product (referred to in this specification as "first enzyme-treated naringin") obtained, for example, by reacting a glycosyltransferase (e.g., cyclodextrin glucosyltransferase) with a mixture of naringin and a sugar donor (e.g., dextrin). It is an aggregate of various compounds obtained by adding one or more glucose molecules to the hydroxyl groups of naringin. Therefore, enzyme-treated naringin usually includes a mixture of compounds with different numbers of glucose molecules bonded to hesperidin, such as a mixture of α-monoglucosyl naringin and α-polyglucosyl naringin. In addition to α-glucosyl naringin, it may also contain unreacted naringin and 7-glucosyl naringenin and other naringin derivatives other than α-glucosyl naringin (also known as other naringin derivatives).

[0040] The basic manufacturing method of the first enzyme-treated naringin can be referred to, for example, Japanese Patent Application Publication No. 4-13691. As needed, the first enzyme-treated naringin can be purified by using, for example, a porous synthetic adsorbent material and a suitable eluent to remove sugar donors and other impurities and further reduce the content of naringin, thereby obtaining the first enzyme-treated naringin with improved purity (α-glucosyl naringin purified product).

[0041] As α-glucosyl naringin, preferably α-glucosyl naringin obtained by linking one molecule of α-glucose to the hydroxyl group at the 3'' position of naringin and / or linking one molecule of α-glucose to the hydroxyl group at the 4' position of naringin, i.e., at least one α-glucosyl naringin selected from 3''-α-monoglucosyl naringin (in formula (1), m=1, n=0), 4'-α-monoglucosyl naringin (also m=0, n=1), and 3''-4'-α-diplucosyl naringin (also m=1, n=1), with 3''-α-monoglucosyl naringin being more preferred. This is believed to be 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 of α-monoglucosyl naringin is greater, which is advantageous in promoting skin penetration.

[0042] α-Glucosyl naringin preferably includes α-monoglucosyl naringin.

[0043] Enzyme-treated naringin containing a large amount of the above three types of α-monoglucosyl / diglucosyl 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 glucosyl amylase activity, thereby cleaving the sugar chain of more than two molecules of α-glucose obtained by the above-mentioned glycosyltransferase transferring to the hydroxyl group at the 3'' position and / or the hydroxyl group at the 4' position of naringin through α-1,4 bonds, leaving only the equivalent of one molecule of α-glucose residue in the root.Furthermore, by treating naringin with an enzyme having α-glucosidase activity, the α-glucose residue equivalent to one molecule directly bonded to the hydroxyl group at the 4' position is cleaved, leaving 3''-α-monoglucosylnaringin residue, thus obtaining enzyme-treated naringin (referred to as "third enzyme-treated naringin" in this specification) that contains almost no or no 4'-α-monoglucose naringin and 3''-4'-α-diglucosylnaringin. The basic manufacturing methods of the second and third enzyme-treated naringin can be found, for example, in Japanese Patent Application Publication No. 2002-199896.

[0044] Furthermore, by acting α-L-rhamnosidase on the third enzyme-treated naringin, the rhamnose contained in the rutin unit of naringin is cleaved, generating 7-glucosylnaringenin, thus obtaining enzyme-treated naringin containing 7-glucosylnaringenin and α-monoglucosylnaringin (referred to as "fourth enzyme-treated naringin" in this specification).

[0045] Furthermore, since transglucosidase is an enzyme that possesses both glucosylamylase and α-glucosidase activities, if transglucosidase is acted upon by the first enzyme to treat naringin, a third enzyme-treated naringin rich in 3''-α-monoglucosidase can be obtained through a one-stage treatment as described above, without the need for a two-stage treatment. Additionally, if necessary, an enzyme with β-glucosidase activity can be acted upon by the third enzyme to treat naringin (which can act simultaneously with transglucosidase on the first enzyme-treated naringin), performing a treatment that cleaves the neohesperidose residues (glycan chains not modified by glycosyltransferase) of the unreacted naringin dissolved in the aqueous solution from the naringin aglycone. The naringenin produced by such treatment has lower solubility than naringin and easily precipitates and can be removed from the aqueous solution, thus enabling the recovery of 3''-α-monoglucosylnaringin from the aqueous solution with higher purity.

[0046] In this invention, considering the effects of the invention, it is preferable to use a composition containing α-glucosyl naringin, i.e., enzyme-treated naringin. Any combination of first enzyme-treated naringin, second enzyme-treated naringin, third enzyme-treated naringin, and fourth enzyme-treated naringin can be used, with fourth enzyme-treated naringin being preferred.

[0047] Considering the effects of the invention, enzyme-treated naringin is preferably a mixture containing α-glucosyl naringin and at least one selected from naringin and 7-glucosyl naringenin.

[0048] The presence of various α-glucosyl naringin, naringin, and other components contained in enzyme-treated naringin can be confirmed by HPLC chromatography, and the content of each component or the purity of a desired specific component can be calculated by the peak area of ​​the chromatography. Specification 4 / 10 pages 6 CN 121419779 A

[0049] The method for manufacturing α-glucosyl naringin is not particularly limited, and known methods can be used. It is preferred to manufacture it by enzyme treatment of the above-mentioned naringin because the yield is good and the manufacturing is easy.There are no particular restrictions on the methods for obtaining and preparing naringin. Compounds that are commonly manufactured and sold as reagents or purified products can be used, or compounds extracted from raw materials such as the peel of citrus fruits (such as summer oranges and grapefruits) can be used.

[0050] <Physiologically Active Substances>

[0051] The above-mentioned physiologically active substances are any substances known to have physiological activity, and there are no particular limitations.

[0052] Examples of the above-mentioned physiologically active substances include, for example, anti-inflammatory drugs, antibacterial agents, hormones, antihistamines, anti-allergic drugs, blood flow improvers, vasodilators, cardiotonics, antiarrhythmic agents, antianginal agents, antihypertensive agents, insulin preparations, metal ion blockers, vitamins, skin softeners, moisturizers, whitening agents, antiwrinkle agents, astringents, ultraviolet absorbers, hair growth agents, hair growth promoters, antiperspirants, deodorants, etc.

[0053] As the above-mentioned physiologically active substance, a water-insoluble substance is preferred because it readily exhibits the skin penetration-promoting effect of α-glucosylnaringin, and a water-insoluble substance having two or more benzene rings is more preferred.

[0054] As an anti-inflammatory drug, more specifically, steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs (NSAIDs) can be cited, with non-steroidal anti-inflammatory drugs being preferred, and acidic non-steroidal anti-inflammatory drugs (NSAIDs) being more preferred.

[0055] Examples of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) include: salicylates such as aspirin, ethylsalicylate, diflunisal (diflunisalic acid), and methyl salicylate; propionic acids such as ibuprofen, naproxen, fenprofen, ketoprofen, dextroketoprofen, flurbiprofen, oxapazine, and loxoprofen; acetic acids such as indomethacin, tometidine, sulindac, etodoxacin, ketoroxylic acid, and diclofenac; acetic acids such as piroxicam, meloxicam, tenoxicam, lornoxicam, or isoxicam; fenanoic acid such as mefenamic acid, meclofenamic acid, flufenamic acid, and tofenamic acid; and their salts.

[0056] The above-mentioned salts are pharmaceutically acceptable salts, and examples include inorganic salts containing metals such as sodium, potassium, magnesium, calcium, aluminum, and lithium, or organic salts, phosphates, and ammonium salts of methylamine, ethylamine, ethanolamine, lysine, etc.

[0057] Among acidic nonsteroidal anti-inflammatory drugs (NSAIDs), aromatic compounds having two or more benzene rings are preferred because they readily exhibit the skin penetration-enhancing effect of α-glucosyl naringin. Examples of aromatic compounds having two or more benzene rings include diflunisal (diflunilic acid), naproxen, fenprofen, ketoprofen, dextroketoprofen, flurbiprofen, oxaprazin, indomethacin, sulindac, diclofenac, piroxicam, mefenamic acid, meclofenamic acid, flufenamic acid, and tofenamic acid, with mefenamic acid, meclofenamic acid, flufenamic acid, and tofenamic acid being preferred.

[0058] More specifically, examples of blood flow improvers include flavonoids, tocopherol or its derivatives, heparin analogs, dl-camphor, ginkgo biloba extract, ginger rhizome extract, capsicum fruit extract, ginger extract, cilostazol, ticlopidine hydrochloride, alprostadil, limaprost, beraprost sodium, sargrelate hydrochloride, argatroban, naproxen, isocortin hydrochloride, batroxobin, dihydroergotamine mesylate, tolazoline hydrochloride, decanedin, and Siwu decoction extract. Among these, flavonoids are preferred because they readily exhibit the skin penetration-enhancing effect of α-glucosylnaringin.

[0059] Examples of flavonoids include: flavonoids such as apigenin, luteolin, hesperidin, diosmin, norihesperidin, and flavonols; isoflavones such as daidzein, daidzein, and genistein; flavonols such as kaempferol, myricetin, quercetin, and rutin; flavanones such as sennaol, hesperidin, hesperidin, sennaol, and naringenin; flavanols such as catechin, epicatechin, and epigallocatechin; dihydroflavonols such as dihydroquercetin; and anthocyanins such as anthocyanins, anthocyanins, delphinidin, dimethyl cyanidin, anthocyanins, and peony anthocyanins.

[0060] Among them, flavonols, flavones, and flavanones are preferred because they readily exhibit the skin penetration promoting effect of α-glucosyl naringin; more preferably, rutin, quercetin, hesperidin, flavones, and hesperidin; and even more preferably, flavones and hesperidin.

[0061] The above-mentioned physiologically active substances are preferably selected from at least one of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids, as they readily exhibit the skin penetration promoting effect of α-glucosyl naringin.

[0062] The above-mentioned physiologically active substances are preferably selected from at least one of mefenamic acid or its salt, flavones, and hesperidin, as they readily exhibit the skin penetration promoting effect of α-glucosyl naringin.

[0063] <Skin Penetration Promoter>

[0064] As one aspect of the present invention, the skin penetration promoter contains α-glucosyl naringin, which promotes the skin penetration of the physiologically active substances.

[0065] There is no particular limitation on the method for evaluating the effect of promoting skin penetration, and known methods can be used. For example, if the skin penetration of the physiologically active substance with the test substance added is higher than that without the test substance added, it can be evaluated as having an effect of promoting skin penetration of the test substance.

[0066] The skin penetration of the physiologically active substance can be evaluated at a single point in time or at multiple different points in time, i.e., evaluated over time. There is no particular limitation on the time point for evaluating the skin penetration of the physiologically active substance, but it is preferably after 4 hours from the start of the test, more preferably after 6 hours from the start of the test, further preferably after 8 hours from the start of the test, and particularly preferably after 12 hours from the start of the test.

[0067] The skin permeability of the physiologically active substance can be determined by known methods, preferably by using a Franz diffusion cell. The permeation membrane for the Franz diffusion cell is known, and artificial skin permeability testing membranes such as those derived from human, guinea pig, or mouse skin, three-dimensional cultured skin, Permea Pad Barrier, or Strat-M membrane can be used.

[0068] As for the degree of skin permeability enhancement, if the skin permeability of the physiologically active substance without α-glucosyl naringin (when the physiologically active substance is used alone) is set to 100%, the skin permeability of the physiologically active substance using α-glucosyl naringin is not particularly limited as long as it is greater than 100%, 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.

[0069] The amount of α-glucosyl naringin contained in the skin penetration enhancer is not particularly limited. For example, examples of lower limits for the amount of α-glucosyl naringin contained in the skin penetration enhancer of the present invention include 30% by mass, 40% by mass, 45% by mass, 50% by mass, 60% by mass, 70% by mass, and 80% by mass. Furthermore, examples of upper limits for the amount of α-glucosyl naringin contained in the skin penetration enhancer of the present invention include 100% by mass, 99% by mass, 98% by mass, 95% by mass, 90% by mass, and 85% by mass. The range of the amount of α-glucosyl naringin contained in the skin penetration enhancer of the present invention can be arbitrarily set as a range combining any of the above lower and upper limits, for example, a range of 30–100% by mass, 60–100% by mass, or 60–90% by mass. In 100% by mass of the skin penetration enhancer, the content of α-glucosyl naringin is preferably 65% ​​by mass or more, more preferably 70% by mass or more, and the content of α-monoglucosyl naringin in 100% by mass of the skin penetration enhancer is further preferably 65% ​​by mass or more, particularly preferably 70% by mass or more.

[0070] The skin penetration enhancer only needs to contain α-glucosyl naringin, and can be composed solely of α-glucosyl naringin. As long as it does not impair the skin penetration promoting effect of α-glucosyl naringin, it can also further contain any known components such as excipients, stabilizers, humectants, and emulsifiers. In addition, the skin penetration enhancer can also be a composition containing α-glucosyl naringin, i.e., enzyme-treated naringin.

[0071] The mechanism by which α-glucosyl naringin promotes the skin penetration of physiologically active substances is not clear, but the inventors speculate as follows.

[0072] Skin is formed of lipids, so it is generally believed that water-soluble drugs have significantly lower permeability to the skin, while the higher the lipid solubility, the easier it is to be distributed into the skin and the faster the skin penetration rate.That is, common technical knowledge holds that if a poorly soluble substance is made soluble, thus increasing its water solubility, then its skin permeability will decrease.

[0073] However, the inventors believe that both solubility and subsequent release contribute significantly to the skin permeability of poorly soluble substances. That is, to promote the skin permeability of poorly soluble substances, firstly, it is necessary to make the substance soluble, thus increasing its water solubility; secondly, it is necessary to ensure that the soluble substance is fully released into the skin.

[0074] It has been reported that α-glucosyl naringin can improve the solubility of certain poorly soluble substances in water better than before (Patent Document 2). Since α-glucosyl naringin can make poorly soluble substances soluble, thus increasing their water solubility, it can be predicted, based on common technical knowledge, that the skin permeability of poorly soluble substances will decrease when α-glucosyl naringin is added. However, as shown in the examples of this specification, α-glucosyl naringin significantly promotes the skin penetration of poorly soluble substances compared to naringin, which has no solubility effect.

[0075] Furthermore, it has been reported that not only α-glucosyl naringin, but also α-glucosyl hesperidin and α-glucosyl rutin, which are also glycosylated flavonoid compounds, can improve the solubility of poorly soluble substances in water better than before (Patent Document 2). However, as shown in the examples of this specification, only α-glucosyl naringin significantly promotes the skin penetration of physiologically active substances, while the skin penetration promoting effects of α-glucosyl hesperidin and α-glucosyl rutin are weak.

[0076] Based on these facts, it can be considered that α-glucosyl naringin has a higher effect on improving the release of soluble poorly soluble substances than α-glucosyl hesperidin and α-glucosyl rutin, and the excellent skin penetration promoting effect of α-glucosyl naringin mainly comes from this effect.

[0077] The use of the skin penetration enhancer is not particularly limited. The skin penetration enhancer of the present invention has an excellent effect of promoting the skin penetration of physiologically active substances. Therefore, for example, for the purpose of promoting the skin penetration of physiologically active substances in the body, it can be administered to the body once or multiple times.

[0078] The skin penetration enhancer administered to the body promotes the skin penetration of physiologically active substances, thus, for example, helping the physiologically active substances to exert their activity locally or systemically.

[0079] <Administration of the skin penetration enhancer to the body>

[0080] When the skin penetration enhancer is administered to the body, the route of administration is usually external application to the skin.

[0081] The method of administration of the skin penetration enhancer is not particularly limited. It is sufficient to administer the skin penetration enhancer and the physiologically active substance whose penetration is to be promoted in combination. Usually, the skin penetration enhancer and the physiologically active substance whose penetration is to be promoted are administered simultaneously.

[0082] Skin penetration enhancers can be administered directly to the body, but are preferably administered in the form of a formulation which combines an effective amount of the skin penetration enhancer with a physiologically active substance for which penetration is to be enhanced.

[0083] The content of the skin penetration enhancer in the above formulation can be appropriately selected according to the type or concentration of the physiologically active substance for which penetration is to be enhanced. From the viewpoint of skin penetration enhancement effect, the above formulation preferably contains 0.01 to 5% by mass, more preferably 0.025 to 2% by mass, and even more preferably 0.05 to 1% by mass of α-glucosyl naringin in 100% by mass of the formulation.

[0084] The concentration of the physiologically active substance in the above formulation can be appropriately selected according to the type of physiologically active substance, the site of its activity (local or systemic), and the degree of activity to be exerted. When the physiologically active substance is flavonoid, hesperidin, or mefenamic acid, the concentration of the physiologically active substance in the formulation is preferably 0.01 to 5 mg / mL, more preferably 0.1 to 1 mg / mL.

[0085] The ratio of α-glucosyl naringin to the physiologically active substance in the above-mentioned preparation can be appropriately selected according to the type of physiologically active substance, the site of its activity (local or systemic), and the desired degree of activity. The mass ratio of α-glucosyl naringin to the physiologically active substance in the above-mentioned preparation is preferably 150:1 to 1:1, more preferably 40:1 to 2:1. When the physiologically active substance is flavonoid, hesperidin, or mefenamic acid, the mass ratio of α-glucosyl naringin to the physiologically active substance in the above-mentioned preparation is preferably 100:1 to 2:1, more preferably 40:1 to 4:1.

[0086] The above-mentioned preparation can be any preparation that can be applied to the skin, and can be any of the following: pharmaceuticals, quasi-pharmaceuticals, and cosmetics.

[0087] The properties and dosage form of the above-mentioned preparations are not particularly limited, and may be, for example, solid, semi-solid, liquid, emulsion, ointment, gel, mousse, spray, or a two-component formulation using a mixture thereof, liniment, mud, plaster, patch (e.g., film, strip), etc.

[0088] In the above-mentioned preparations, ingredients commonly used in cosmetics and as pharmaceutical topical agents or cleansers may be appropriately incorporated as needed, without impairing the effects of the present invention, such as oils, waxes, hydrocarbon oils, ester oils, higher alcohols, silicone oils, ultraviolet absorbers, ultraviolet scattering agents, moisturizers, surfactants, water-soluble polymers, thickeners, powders, skin protectants, whitening agents, wrinkle improvers, anti-aging agents, plant extracts, preservatives, anti-inflammatory agents, pH adjusters, metal ion occlusive agents, antioxidants, stabilizers, fragrances, pigments, etc. These ingredients may be used alone or in combination of two or more.

[0089] The above-mentioned formulations can be manufactured by adding skin penetration enhancers and physiologically active substances according to the methods commonly used in these formulations. Skin penetration enhancers and physiologically active substances can be added at the beginning, middle, or end of the manufacturing process of the formulation, and the addition method can be selected from appropriate methods such as mixing, compounding, dissolving, impregnation, dispersing, spraying, and coating, depending on the form of the formulation.

[0090] α-glucosyl naringin, the active ingredient of the skin penetration enhancer, has good water solubility. Therefore, the skin penetration enhancer of the present invention has high water solubility and can be uniformly dissolved or dispersed evenly when added to water or formulations with a high water content, making it easy to mix with aqueous formulations. Therefore, the range of formulations into which the skin penetration enhancer of the present invention can be mixed is very wide.

[0091] α-glucosyl naringin, the active ingredient of the skin penetration enhancer, has low skin irritation, is widely used, and has good safety. Therefore, the skin penetration enhancer of the present invention has low skin irritation and high safety.

[0092] <Skin Penetration Enhancement Method>

[0093] One aspect of the present invention is a skin penetration enhancement method for the said physiologically active substance, comprising the step of administering α-glucosyl naringin and the physiologically active substance topically to the skin.

[0094] The method of administering α-glucosyl naringin and the physiologically active substance topically to the skin is not particularly limited, as described in the section <Administration of Skin Penetration Enhancer to the Body>.

[0095] One aspect of the present invention is the application of α-glucosyl naringin for enhancing the skin penetration of the physiologically active substance.

[0096] One aspect of the present invention is the application of α-glucosyl naringin in the preparation of a skin penetration enhancer for enabling the penetration of the physiologically active substance.

[0097] Examples

[0098] Hereinafter, examples are shown to further illustrate the present invention in detail, but the present invention is not limited thereto.

[0099] <Skin permeability test using Franz diffusion cell 1>

[0100] (Method)

[0101] As material 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.

[0102] α-Glucosyl naringin (Naringin-G): Enzyme-treated naringin (manufactured by Toyo Seikan Co., Ltd., containing 75% by mass of α-monoglucosyl naringin and trace amounts of naringin and 7-glucosyl naringenin in 100% by mass of enzyme-treated naringin) Instruction manual 8 / 10 pages 10 CN 121419779 A

[0103] Naringin: Naringin reagent (manufactured by Tokyo Chemical Industry Co., Ltd., containing 96% by mass of naringin in 100% by mass of naringin reagent)

[0104] α-Glucosyl hesperidin (Hsp-G): Enzyme-treated hesperidin (manufactured by Toyo Seikan Co., Ltd., containing 80% by mass of α-monoglucosyl hesperidin in 100% by mass of enzyme-treated hesperidin)

[0105] α-Glucosylrutin (Rutin-G): Enzyme-treated rutin (manufactured by Toyo Ginko Co., Ltd., containing 75% by mass α-monoglucosylrutin in 100% by mass of enzyme-treated rutin)

[0106] As a physiologically active substance, flavonoids (manufactured by Tokyo Chemical Industry Co., Ltd., NO. HO721) were used.

[0107] Any substance from substance group A and the physiologically active substance were added to 10 mL of distilled water, mixed, and prepared into a solution (or suspension) as a test solution. The amount of substance from substance group A added was such that the concentration in the test solution reached 10 mg / mL. The amount of physiologically active substance added was such that the concentration in the test solution reached 250 μg / mL. As a control, a test solution without the addition of substance group A (flavonoids only) was also prepared.

[0108] The receiver section of the Franz vertical diffusion cell was filled with phosphate buffer (pH 7.4) containing 0.5% sodium taurocholate as a permeation membrane, using a Strat-M membrane (Merck) for percutaneous diffusion testing. After adding 400 μL of the above test solution to the feeder side, the receiver fluid sample was collected over time. The amount of physiologically active substances in the collected receiver fluid sample was quantified by high performance liquid chromatography. The experiment was conducted under N=1 conditions.

[0109] (Results)

[0110] The results are shown in Figure 1.

[0111] When the water-insoluble flavonoid compound naringin was added, the skin permeability of flavonoids hardly changed. However, when the water-soluble glycosylated flavonoid compounds α-glucosylhesperidin or α-glucosylrutin were added, although the skin permeability of flavonoids increased, the increase was small.

[0112] On the other hand, when α-glucosyl naringin was added, the skin penetration of flavonoids increased significantly. That is, it is known that α-glucosyl naringin promotes the skin penetration of physiologically active substances.

[0113] <Skin permeability test 2 using Franz diffusion cell>

[0114] (Method)

[0115] As the substance in substance group A, the same α-glucosyl naringin (Naringin-G) as in skin permeability test 1 was used.

[0116] Flavonoids (manufactured by Tokyo Chemical Industry Co., Ltd., NO. H0721, Example 2), hesperidin (manufactured by SIGMA-ALDRICH, NO. F2003, Example 3), and mefenamic acid (manufactured by Tokyo Chemical Industry Co., Ltd., NO. M1782, Example 4) were used as physiologically active substances.

[0117] α-glucosyl naringin and any one of the physiologically active substances were added to 10 mL of distilled water, mixed, and prepared into a solution (or suspension) as the test solution. The amount of α-glucosyl naringin added was such that the concentration in the test solution reached 0.5 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, 10 mg / mL, or 20 mg / mL (relative to mefenamic acid, 10 mg / mL or 25 mg / mL, and relative to hesperidin, 1 mg / mL or 20 mg / mL). The amount of physiologically active substance added was such that the concentration in the test solution reached 250 μg / mL. As a control, a test solution of the substance group A without the addition of substance A (flavonoids only, hesperidin only, mefenamic acid only) was also prepared.

[0118] The skin permeability test was performed in the same manner as the skin permeability test 1 using a Franz diffusion cell. The experiment was conducted under the condition of N=3, and the average value was calculated.

[0119] (Results)

[0120] The results when flavonoids were used as the physiologically active substance (Example 2) are shown in Figure 2, the results when hesperidin was used as the physiologically active substance (Example 3) are shown in Figure 3, and the results when mefenamic acid was used as the physiologically active substance (Example 4) are shown in Figure 4.

[0121] As can be seen from Figures 2, 3, and 4, the skin permeability of flavonoids, hesperidin, and mefenamic acid increased by adding α-glucosyl naringin. Furthermore, the skin penetration-enhancing effect of α-glucosyl naringin exhibits a concentration-dependent effect within a certain concentration range. (See: Instruction manual, page 10 / 10, CN 121419779 A, ​​Figure 1; Figure 2; Instruction manual figure 1 / 3, page 13, CN 121419779 A, ​​Figure 3; Instruction manual figure 2 / 3, page 14, CN 121419779 A, ​​Figure 4; Instruction manual figure 3 / 3, page 15, CN 121419779 A.)

Claims

1. A skin penetration enhancer for facilitating the penetration of physiologically active substances, containing α-glucosyl naringin.

2. The skin penetration enhancer as described in claim 1, wherein, The α-glucosyl naringin comprises α-monoglucosyl naringin.

3. The skin penetration enhancer as described in claim 2, wherein, In the 100% by mass of skin penetration enhancer, the content of α-monoglucosyl naringin is above 65% by mass.

4. The skin penetration enhancer as described in claim 1, wherein, The physiologically active substance is selected from at least one of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) and flavonoids.

5. The skin penetration enhancer as described in claim 4, wherein, The acidic nonsteroidal anti-inflammatory drugs (NSAIDs) are aromatic compounds having two or more benzene rings.

6. The skin penetration enhancer as described in claim 1, wherein, The physiologically active substance is selected from at least one of mefenamic acid or its salt, flavonoids and hesperidin.

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

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