JP4804728B2 - DFA-containing transdermal absorption enhancer - Google Patents

Description

  The present invention relates to a transdermal absorption enhancer containing difructose anhydride and a whitening cosmetic containing difructose anhydride and a vitamin C derivative.

  Promoting the percutaneous absorption of the active ingredient of the external preparation for skin is important for enhancing the effect of the active ingredient. To date, a number of transdermal absorption enhancers have been disclosed. For example, a polysiloxane-based transdermal absorption accelerator (Patent Document 1: JP-A-5-139997), an aliphatic alcohol or a fatty acid ester of an aliphatic alcohol, or a fatty acid ester of isopropyl alcohol (Patent Document 2: JP-A-6-247846). No.), carboxylic acid amide (Patent Document 3: JP-A-62-215537), polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene glycol (Patent Document 4: JP-A-7-316046), Glycerol or polyglycerol fatty acid ester (Patent Document 5: JP-A-61-85328), phosphatidylglycerol (Patent Document 6: JP-A-8-3068), amine oxide (Patent Document 7: JP-A-1) 224329), guanidine derivatives Is α-monoglyceryl ether or urea (Patent Document 8: JP-A-9-157129), serine or alanine (Patent Document 9: JP-A-11-224212), sucrose fatty acid ester (Patent Document 10: JP-A-2003-157504). 2003-238446) and the like. Thus, the percutaneous absorption enhancer suitable for various preparations continues to be demanded.

  With respect to difructose anhydride, which is an indigestible disaccharide of the present invention, difructose anhydride III (hereinafter sometimes referred to as DFAIII) increases the permeability of tight junctions present in the mucosal epithelial cell gap of the intestinal tract. It is known to enhance the absorption of Ca (Non-patent Document 1: Hitomi Kashio et al., Indigestible sugar promotes intestinal calcium absorption through an intercellular pathway, digestion and absorption, 2001, Vol. 24. , Pp. 56-60) (Patent Document 11: JP-A-11-43438). However, it has not been known that DFAIII has a transdermal absorption promoting effect. Further, as a whitening agent of the present invention, vitamin C derivatives can be mentioned. Ascorbic acid 2-glucoside and ascorbyl magnesium phosphate, which are vitamin C derivatives, are percutaneously absorbed, hydrolyzed into ascorbic acid and excreted in urine. (Non-Patent Document 2: Y. Kumano et al., J. of Nutritional Science and Vitaminology, 1998, 44, pp. 345-359). It has also been reported that percutaneous absorption is increased by acylating ascorbic acid 2-glucoside (Non-patent Document 3: I. Yamamoto et al., J. of Medical Chemistry, 2002, 45, pp. .462-468). However, a technique for promoting transdermal absorption of vitamin C derivatives has not been well established.

Japanese Patent Laid-Open No. 5-139997 Japanese Patent Laid-Open No. 6-247846 JP-A-62-215537 Japanese Patent Laid-Open No. 7-316046 JP-A-61-85328 JP-A-8-3068 JP-A-1-224329 Japanese Patent Laid-Open No. 9-157129 Japanese Patent Laid-Open No. 11-222412 JP 2003-238446 A Japanese Patent Laid-Open No. 11-43438 Jin Hagio et al., Indigestible Sugar Promotes Intestinal Calcium Absorption Through Intercellular Pathways, Digestion and Absorption, 2001, 24, pp. 56-60 Y. Kumano et al., J. of Nutritional Science and Vitaminology, 1998, 44, pp. 345-359 I. Yamamoto et al., J. of Medical Chemistry, 2002, 45, pp. 462-468

  An object of the present invention is to provide a novel transdermal absorption enhancer and to provide a whitening cosmetic that promotes transdermal absorption of a vitamin C derivative with the transdermal absorption enhancer.

The main configuration of the present invention is as follows.
1 . A percutaneous absorption enhancer of the whitening agent comprising as an active ingredient difructose anhydride, percutaneous absorption enhancer, wherein the whitening agent is ascorbic acid 2-glucoside.
2 . A whitening cosmetic composition containing difructose anhydride and whitening agents, whitening cosmetic, wherein the whitening agent is ascorbic acid 2-glucoside.

  DFA was found as a novel transdermal absorption enhancer. By using in combination with vitamin C derivatives, an effective whitening cosmetic was realized.

Details of the present invention will be described below.
The present invention finds the use of DFA to promote the absorption of drugs into the skin.
The difructose anhydride (DFA) as used in the present invention is a cyclic disaccharide in which the reducing ends of two fructose are bonded to a hydroxyl group other than one reducing end. Conventionally, it has been known to exist in caramel and the like, but industrially, inulin is produced by an inulin-degrading enzyme such as Artrinbacter sp. H65-7 strain (EC 2.4.1.93). Or levan can be fermented with levanfructotransferase (EC 2.4.1.10) produced by Arthrobacter nicotinovorans GS-9. There are five types of derivatives due to the difference in the binding mode of bimolecular fructose, which are referred to as DFAI, DFAII, DFAIII, DFAIV, and DFAV, respectively. The DFA as used in the present invention refers to all of them. In the present invention, DFAIII (di-D-fructofuranose-1,2 ′) which is excellent in industrial production efficiency, stability after purification, etc. : 2,3'dianhydride) and DFAIV (di-D-fructofuranose-2,6 ': 6,2'dianhydride) are preferably used.
Although the compounding quantity of the difructose anhydride of this invention is not necessarily restrict | limited, 0.001-30 mass% is preferable with respect to the skin external preparation whole quantity.

  Examples of the whitening agent of the present invention include vitamin C derivatives, arbutin, kojic acid, ellagic acid, glutathione, and a plant extract having a whitening effect. Examples of vitamin C derivatives include ascorbyl 2-glucoside, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbate, ascorbyl tetraisopalmitate, ascorbyl dipalmitate, ascorbyl stearate, ascorbyl palmitate and the like. Examples of the plant extract having a whitening effect include Sakuhakuhi, Babopi, Yukinoshita, and licorice.

  Examples of the agent to be absorbed from the skin used in combination with DFA include a skin external preparation, a skin external preparation, a quasi-drug, and a skin cosmetic. Examples of the external preparation for skin include anti-inflammatory external preparations, anti-acne external preparations, and bactericidal external preparations. Examples of quasi-drugs for external skin use include quasi-drugs for whitening, quasi-drugs for improving rough skin, and quasi-drugs for acne. Examples of the skin cosmetic of the present invention include lotions, emulsions, skin creams, hand creams, body milks, sunscreen agents, liquid foundations and the like.

  The cosmetics of the present invention include fats and oils such as vegetable oils, higher fatty acids, higher alcohols, anionic surfactants, cationic surfactants, amphoteric surfactants, non-active substances, depending on the use, purpose of use, dosage form, etc. Ionic surfactants, preservatives, saccharides, sequestering agents, powder components, UV absorbers, UV blockers, humectants such as hyaluronic acid, fragrances, pH adjusters, and the like can be included. Vitamins, skin activators, blood circulation promoters, resident bacteria control agents, active oxygen scavengers, anti-inflammatory agents, whitening agents, bactericides, and other medicinal and physiologically active components can also be included.

  Examples of the fats and oils include camellia oil, evening primrose oil, macadamia nut oil, olive oil, rapeseed oil, corn oil, sesame oil, jojoba oil, germ oil, wheat germ oil, glycerin trioctanoate, cocoa butter, coconut oil, Solid fats such as hydrogenated coconut oil, palm oil, palm kernel oil, mole owl kernel oil, hydrogenated oil, hydrogenated castor oil, wax such as beeswax, candelilla wax, cotton wax, nuta wax, lanolin, lanolin acetate, liquid lanolin, sugarcane wax And liquid paraffin, squalene, squalane, microcrystalline wax and the like.

  Examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA).

  Examples of the higher alcohol include linear alcohols such as lauryl alcohol, stearyl alcohol, cetyl alcohol, and cetostearyl alcohol, and branched chain alcohols such as monostearyl glycerin ether, lanolin alcohol, cholesterol, phytosterol, and octyldodecanol.

  Examples of the anionic surfactant include fatty acid salts such as sodium laurate, higher alkyl sulfates such as sodium lauryl sulfate, alkyl ether sulfates such as POE lauryl sulfate triethanolamine, N-acyl sarcosine acid, sulfosuccinate N-acyl amino acid salts and the like.

Examples of the cationic surfactant include alkyltrimethylammonium salts such as stearyltrimethylammonium chloride, benzalkonium chloride, and benzethonium chloride.
Examples of amphoteric surfactants include betaine surfactants such as alkyl betaines and amide betaines.
Examples of nonionic surfactants include sorbitan fatty acid esters such as sorbitan monooleate, and hardened castor oil derivatives.

Examples of preservatives include methyl paraben and ethyl paraben.
Examples of the sequestering agent include edetate such as disodium ethylenediaminetetraacetate, edetic acid, and sodium edetate.

  In order to suppress stickiness and color, powder components include, for example, talc, kaolin, mica, silica, zeolite, polyethylene powder, polystyrene powder, cellulose powder, inorganic white pigment, inorganic red pigment, titanium oxide coated Mention may be made of pearl pigments such as mica, titanium oxide coated talc and colored titanium oxide coated mica, and tar dyes such as red 201 and red 202.

Examples of the ultraviolet absorber include paraaminobenzoic acid, phenyl salicylate, isopropyl paramethoxycinnamate, octyl paramethoxycinnamate, 2,4-dihydroxybenzophenone, and the like.
Examples of the ultraviolet blocking agent include titanium oxide, talc, carmine, bentonite, kaolin, and zinc oxide.

  Examples of the humectant include xylitol, maltitol, maltose, sorbitol, glucose, fructose, sucrose, lactose, sodium chondroitin sulfate, sodium hyaluronate, sodium lactate, pyrrolidone carboxylic acid, cyclodextrin and the like.

  Medicinal ingredients include, for example, vitamin A oils such as vitamin A oil and retinol, vitamin B2 such as riboflavin, B6 such as pyridoxine hydrochloride, pantothenic acids such as calcium pantothenate, vitamin D such as vitamin D2 and cholecalciferol And vitamins such as vitamin E such as α-tocopherol, tocopherol acetate, and DL-α-tocopherol nicotinate.

  In addition, skin activators such as royal jelly and beech tree extract, capsaicin, gingerone, cantalis tincture, ictamol, caffeine, tannic acid, γ-oryzanol and other blood circulation promoters, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, azulene, etc. Anti-inflammatory agents, amino acids such as arginine, serine, leucine and tryptophan, maltose sucrose condensate of resident bacteria control agent, lysozyme chloride and the like.

  In addition, chamomile extract, parsley extract, wine yeast extract, grapefruit extract, honeysuckle extract, rice extract, grape extract, hop extract, rice bran extract, loquat extract, buckwheat extract, yakuinin extract, assembly extract, merilot extract, birch extract, peonies extract, savonso Extract, loofah extract, red pepper extract, lemon extract, gentian extract, perilla extract, aloe extract, rosemary extract, sage extract, thyme extract, tea extract, seaweed extract, cucumber extract, clove extract, maronier extract, hamamelis extract, mulberry extract, etc. Various extracts can be blended.

(Skin permeability test)
Test sample A test sample having the composition shown in Table 1 was prepared.

*) AA-2G: Ascorbic acid 2-glucoside **) PBS (−): KCl: 0.2 g / L, KH ₂ PO ₄ : 0.2 g / L, NaCl: 8.0 g / L, Na ₂ HPO ₄ : 1.15 g / L, Dithioreitol: 0.5 g / L,
Kanamycin: 0.5 g / L phosphate buffer

The test was performed using a Franz diffusion cell under the following conditions.
Ascorbic acid that fills 100 μL of samples 1 to 3 in the upper part of the Franz diffusion cell, fills the receptor solution in the lower part with the permeable membrane sandwiched in a 32 ° C. water bath, and diffuses the permeable membrane in each sample The amount of 2-glucoside diffused was determined.
Yucatan minipig skin was heated at 60 ° C. for 1 minute to peel the epidermis and dermis, and the epidermis was used as a permeable membrane. The effective area of the transmission part was 0.95 cm ² . As the receptor, 4 mL of phosphate buffered saline having a pH of 7.4 was used. That is, KCl: 0.2 g / L, KH ₂ PO ₄ : 0.2 g / L, NaCl: 8.0 g / L, Na ₂ HPO ₄ : 1.15 g / L, Dithioreitol: 0.5 g / L, Kanamycin: 0.5 g / L phosphate buffer. While immersed in a water bath, the Franz diffusion cell was stirred with a stirrer.
After the test started, the receptor phase was collected over time, and ascorbic acid 2-glucoside was measured by HPLC.
The HPLC measurement conditions were analytical instrument: HPLC (manufactured by Shimadzu Corporation), column: TSK-GEL ODS-80Ts 4.6 mmφ × 150 mm, column temperature: 40 ° C., detector: UV 240 nm, flow rate: 0.7 mL / min, sample Injection volume: 10 μL, mobile phase: 0.1 M phosphate-sodium dihydrogen phosphate buffer (pH 2.0).
The results are shown in FIG.

  Number of tests n: DFA III 0.0% n = 8, DFA III 3.3% n = 7, DFA III 16.8% n = 10

  As shown in FIG. 1, the amount of ascorbic acid 2-glucoside permeated through the skin is larger in DFAIII 3.3 mass% sample 2 and DFAIII 16.8 mass% sample 3 than in DFAIII 0.0 mass% sample 1. . The amount of ascorbic acid 2-glucoside permeated through the skin of Samples 2 and 3 9 hours after the start of the test is about 5 times that of Sample 1. Moreover, after 20 hours, it has become 3 times or more. Therefore, it can be seen that DFA III promotes percutaneous absorption of ascorbic acid 2-glucoside. On the other hand, the amount of skin permeation between sample 2 and sample 3 is not so different. By adding 3.3% by mass of DFA III, a sufficient transdermal absorption promoting effect can be expected.

Formulation Example 1
A whitening lotion was produced according to the following formulation.
Ingredient name Compounding amount (% by mass)
(1) Glycerin 9.5
(2) 1,3-butylene glycol 4.5
(3) DFAIII 1.5
(4) Ascorbic acid 2-glucoside 2.0
(5) Carboxyvinyl polymer 0.02
(6) Dipotassium glycyrrhizinate 0.1
(7) Sodium hyaluronate 0.1
(8) Citric acid 0.05
(9) Sodium citrate 0.1
(10) Sodium hydroxide 0.26
(11) Button pi extract 0.5
(12) Residue of ion-exchanged water [Production method] At room temperature, the components (1) to (11) were added to the component (12), dissolved by stirring, and dissolved uniformly to obtain a whitening lotion.
[Usage feeling] Highly moist, non-sticky, uncomfortable after familiarization, and no irritation to skin. This lotion has a high whitening effect.

Formulation example 2
A whitening emulsion was prepared according to the following formulation.
Ingredient name Compounding amount (% by mass)
(1) Squalane 6.0
(2) Jojoba oil 3.0
(3) POE (20) cetyl ether 0.5
(4) POE (50) hydrogenated castor oil 1.0
(5) Stearic acid 2.0
(6) Behenyl alcohol 3.0
(7) Ethyl paraoxybenzoate 0.15
(8) Propyl paraoxybenzoate 0.1
(9) 1,3-butylene glycol 7.0
(10) Concentrated glycerin 2.5
(11) DFA III 3.0
(12) Magnesium ascorbyl phosphate 3.0
(13) Xanthan gum 0.2
(14) Yukinoshita extract 0.2
(15) Sodium hydroxide 0.3
(16) Purified water residue
[Production Method] Oil phase components (1) to (8) and aqueous phase components (9) to (16) are heated to 78 to 85 ° C. and completely dissolved. The oil phase component is added to the water phase component and emulsified with an emulsifier. The obtained emulsion was cooled to obtain a whitening emulsion.
[Usage feeling] Highly moist, non-sticky, uncomfortable after familiarization, and no irritation to skin.

Formulation Example 3
A whitening emulsion was prepared according to the following formulation.
Ingredient name Compounding amount (% by mass)
(1) Squalane 5.0
(2) Jojoba oil 3.0
(3) POE (20) cetyl ether 0.5
(4) POE (50) hydrogenated castor oil 1.0
(5) Stearic acid 2.0
(6) Behenyl alcohol 3.0
(7) Sclerotium gum 0.4
(8) 1,2-pentanediol 1.0
(9) 1,3-butylene glycol 7.0
(10) Concentrated glycerin 1.0
(11) DFA III 3.0
(12) Ascorbic acid 2-glucoside 2.0
(13) Xanthan gum 0.05
(13) Tissou extract 0.2
(14) Yukinoshita extract 0.2
(15) Potassium hydroxide 0.4
(16) Purified water residue
[Production Method] Water phase components (7) and (16) are mixed and dissolved by stirring in an emulsifier at 60 ° C. Next, the aqueous phase components (8) to (15) are mixed and dissolved. The oil phase components (1) to (8) are heated at about 80 ° C. and completely dissolved. The oil phase component is added to the water phase component and emulsified with an emulsifier. The obtained emulsion was cooled to obtain a whitening emulsion.
[Usage feeling] Highly moist, non-sticky, uncomfortable after familiarization, and no irritation to skin.

Formulation Example 4
A whitening cream was produced according to the following formulation.
Ingredient name Compounding amount (% by mass)
(1) Purified water Residue (2) Dipropylene glycol 10.0
(3) Xanthan gum 0.3
(4) Aluminum silicate / magnesium 0.2
(5) Glycerin 3.0
(6) Betaine 3.0
(7) DFAIII 3.0
(8) Ascorbic acid 2-glucoside 2.0
(9) Dipotassium glycyrrhizinate 0.1
(10) Jojoba oil 8.5
(11) Squalane 10.0
(12) Dimethylpolysiloxane (50cs) 2.0
(13) New oil type glyceryl monostearate 3.0
(14) Sorbitan monostearate 1.5
(15) Polyoxyethylene monostearate 1.0
Sorbitan (20E.O.)
(16) Parsley extract 0.1
(17) Grape seed extract 0.1
(18) Potassium hydroxide 0.4
[Production Method] Water phase components (1) to (9) and oil phase components (10) to (15) are dissolved by heating, the oil phase component is mixed with the water phase component, and emulsified with an emulsifier. After cooling, components (16) to (18) were mixed to obtain a whitening cream.
[Usage feeling] Highly moist, non-sticky, uncomfortable after familiarization, and no irritation to skin.

A graph showing the influence of DFAIII on AA2G permeation.

Claims (2)

A percutaneous absorption enhancer of the whitening agent comprising as an active ingredient difructose anhydride, percutaneous absorption enhancer, wherein the whitening agent is ascorbic acid 2-glucoside. A whitening cosmetic containing difructose anhydride and a whitening agent,
A whitening cosmetic, wherein the whitening agent is ascorbic acid 2-glucoside.