JP2003183117A - Transdermal absorption promoting agent and skin care preparation containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a transdermal absorption promoting agent or a transdermal absorption controlling agent which selectively and efficiently permeates only an objective pharmaceutical into a target site in skin and can maintain the effective concentration for a long time, and to provide a skin care preparation which contains the pharmaceutical and the transdermal absorption promoting agent or the transdermal absorption controlling agent. <P>SOLUTION: The promoting agent or the controlling agent consists of a hydrophilic polyglycerin-modified silicone. The skin care preparation contains the same. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a percutaneous absorption enhancer or a percutaneous absorption control agent, and a skin external preparation containing the same. More specifically, a water-soluble active ingredient that is present in the aqueous phase or in the vicinity of the aqueous phase region of the preparation and has low permeability to the skin is efficiently accumulated specifically at the target site in the skin to increase the effective concentration. Accordingly, the present invention relates to a percutaneous absorption enhancer or a percutaneous absorption control agent characterized by promoting skin penetration, and a skin external preparation containing the same.

[0002]

2. Description of the Related Art As a method of administering a medicinal component, oral administration, administration by injection and the like have been widely performed. However, in the case of oral administration, there are drawbacks such that absorption is insufficient and side effects such as gastrointestinal disorders are caused. In addition, administration by injection is fast in absorption, but requires a specialist such as a doctor.

In recent years, in order to improve such side effects and drawbacks, external preparations for percutaneous administration have been developed. Transdermal administration has received attention for the following reasons 1 to 4. 1: A long-term administration at a controlled rate is possible. 2: Administration is certain. 3: Less susceptible to metabolism in the liver. 4: Administration can be discontinued if necessary.

In particular, in the case of external preparations for skin such as cosmetics in which the skin is the active site of the medicinal ingredient, the medicinal ingredient can directly penetrate into the skin and the amount of the medicinal ingredient passing through the skin is not increased as in the conventional case. It is preferred to use a transdermal external preparation that increases the drug concentration at each site of the skin that is the target site of the effective drug.

However, even with such an external preparation, there are many cases in which a sufficient skin permeation effect is not yet obtained, and it cannot be said that this is a satisfactory state. That is, the outermost layer of the skin is called the stratum corneum, which originally has a physiological function as a barrier layer that protects the invasion of foreign substances from outside the body. It is not possible to sufficiently improve the concentration of the drug in the skin simply by blending the medicinal component with.

In order to improve this, a low-molecular percutaneous absorption enhancer such as a surfactant or oil is blended, or
The main method is to increase the occlusion effect on the skin by using a pack or sheet as the dosage form. For example, Japanese Unexamined Patent Publication No. 9-118636 discloses a skin external preparation utilizing the percutaneous absorption accelerating property of glyceryl-modified silicone.

[0007]

However, the use of a percutaneous absorption enhancer composed of a low molecular weight surfactant or an oil component disturbs the interlamellar lipids of the stratum corneum, has a limitation on the preparation, and is a temporary skin substance. It cannot be said to be sufficient because the permeation amount increases but the effective concentration cannot be maintained because the concentration at the intradermal target site is not sustained. In addition, a polymer transdermal absorption enhancer that has a small effect on stratum corneum lipids,
Particularly, a water-insoluble oily polymer percutaneous absorption enhancer is not suitable for promoting percutaneous penetration of a water-soluble drug, because it is difficult to interact with the drug in the aqueous phase. In addition, packs and sheets are restricted in their actions when used.

Therefore, the skin permeation enhancer itself does not irritate the skin, and it is possible to selectively and efficiently and continuously permeate the target drug into a target location in the skin. Development of a base has been desired.

In view of the above-mentioned viewpoints, the present inventors have earnestly studied a method for simply and accurately measuring the amount of skin permeation of a test object, and as a result, the applicant of the present application filed Japanese Patent Application No. 2000-33083.
In No. 6, the amount of the test substance that penetrated into each part of the skin was used as an index of the amount of the test substance that penetrated the skin in vitro or in v
It was found that the skin permeation amount (concentration) of the test substance can be easily and accurately grasped by associating with ivo. Then, using this evaluation method, a component that exerts a medicinal effect in the skin, particularly a water-soluble drug having low permeability to the skin selectively, as a result of extensive studies on a base that enhances permeability into the skin, The inventors have found that an organopolysiloxane having a polyglycerin group in the molecule can solve the above problems, and have completed the present invention.

The present invention promotes percutaneous absorption of a water-soluble polymer capable of selectively and efficiently permeating only a target drug into a target site in the skin and maintaining an effective concentration for a long time. An agent or a percutaneous absorption control agent, and a skin external preparation containing the agent.

[0011]

The present invention is as follows. 1: A percutaneous absorption enhancer or a percutaneous absorption control agent composed of hydrophilic polyglycerin-modified silicone. 2: A percutaneous absorption enhancer or a percutaneous absorption control agent comprising a hydrophilic polyglycerin-modified silicone having a polyglycerin group of triglycerin or more. 3: A skin external preparation containing a drug and the above-mentioned percutaneous absorption enhancer or percutaneous absorption control agent as active ingredients. 4: An aqueous external preparation for skin, which contains a water-soluble drug and the above-mentioned percutaneous absorption enhancer or percutaneous absorption control agent as active ingredients, and further contains 80% or more of the total amount of the aqueous component. 5: logP value of 2.0 representing water / octanol partition coefficient
An external preparation for skin containing the following water-soluble drug, water, and the above-mentioned percutaneous absorption enhancer or percutaneous absorption control agent as active ingredients.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

In the present invention, the hydrophilic polyglycerin-modified silicone is a compound having a polyhydric alcoholic polyglycerin group and polysiloxane in the molecule.
A compound having a polysiloxane segment in the molecule and having at least one or more polyglycerin groups represented by the general formulas (a) to (g) via an alkyl group containing a hetero molecule at the side chain or terminal thereof is preferable. Further, a compound having a polysiloxane segment in the molecule and having at least one or more polyglycerin groups represented by the following general formulas (a) to (g) via an alkyl group containing a hetero molecule at the side chain or terminal thereof. Is preferred. Alternatively, it has a polysiloxane segment in the molecule, and in its side chain or terminal, the following general formula (h)
A compound formed by binding to a polyglycerin segment consisting of the repeating unit shown in is preferable. The polyglycerin group is preferably triglycerin or more. Below (a) ~
The polyglycerol group of (h) is shown.

[Chemical 1] The hydrophilic polyglycerin-modified silicone is preferably an organopolysiloxane having a structure of the following general formula (A).

[Chemical 2] In the formula, R ¹ may be the same or different, and at least one of them is a polyglycerin group represented by the general formulas (a) to (g) via an alkyl group containing a hetero molecule, or a general formula (h The group represented by the polyglycerin which consists of the repeating unit represented by this is shown. Further, in the formula, at least one of R ¹ and R ² is an alkyl group (methyl group, ethyl group, isopropyl group, dodecyl group, octadecyl group, etc.), alkenyl group (vinyl group, allyl group, etc.), cycloalkyl Groups, (cycloalkyl groups, cycloheptyl groups, etc.), aryl groups (phenyl groups, naphthyl groups, etc.), or the hydrogen atoms of these groups are partially halogen atoms, any organic groups or ionic groups (carbonyl groups) , Sulfuric acid group, phosphoric acid group, phosphoric acid amide group, sulfonic acid group, amino group, amide group, ammonium group, amine oxide group, betaine group, etc.), nonionic groups (polyalkylene groups such as polyethylene group, polypropylene group, etc.), A sugar residue, etc.)
It is an unsubstituted or substituted monovalent hydrocarbon group having 1 to 20 carbon atoms, and may have a hetero atom such as an oxygen atom interposed. further,
R ² may be substituted with a sugar residue (including all steric structures) such as an allyl glucoside group represented by the general formula (i), or an aminoalkyl group represented by the general formula (j).
k and l are positive integers of 1 or more and m is 0 or more.

[Chemical 3]

As the above-mentioned organopolysiloxane,
Triglycerin-modified silicone, tetraglycerin-modified silicone, pentaglycerin-modified silicone, hexaglycerin-modified silicone, decaglycerin-modified silicone, triglycerin / sugar-modified silicone, triglycerin / polyoxyalkylene-modified silicone, phosphorylated triglycerin-modified silicone, sodium sulfate Examples include triglycerin-modified silicone. These organopolysiloxanes can be easily produced by adding the desired polyglycerin group to the corresponding hydrogen polysiloxane by a known method. Moreover, a commercial item can be used.

The following are examples of more specific structures of the above organopolysiloxanes.

[Chemical 4]

The above-mentioned organopolysiloxane is composed of a hydrophobic part containing a polysiloxane part and a hydrophilic part containing a polyglycerin group, and contains a hydrophobic part and a hydrophilic part in the molecule. As such a structure, there are the following organopolysiloxanes, but in the present invention, water solubility is essential. An organopolysiloxane having an organosiloxane group or a copolymer of a hydrophilic or hydrophobic hydrocarbon group and an organosiloxane group as a main chain and a hydrophilic group containing a polyglycerin group as a side chain. Organopolysiloxane having a hydrophilic group containing a polyglycerin group as a main chain and an organosiloxane group or a hydrocarbon-based hydrophobic group as a side chain

Since the above-mentioned organopolysiloxane is water-soluble, when the drug absorbed by the skin is water-soluble,
Since the drug and the transdermal absorption enhancer are present in the same aqueous phase,
It directly acts on the active ingredient, and the effect of the present invention is further exerted. The polysiloxane part enhances the affinity of the organopolysiloxane having a polyglycerin group in the molecule for sebum, corneal interstitial lipids, etc., and as a result lowers the surface tension of the base containing the active ingredient, and Has a function of assisting penetration of the active ingredient by increasing the affinity with the stratum corneum. Compared with a hydrocarbon-based substance that does not contain a polysiloxane part, it has a lower distribution of the active ingredient into the base and has the effect of enhancing the penetration into the skin. In addition, the polyglycerin group is not only essential for maintaining water solubility, but also has a high water-retaining ability. It becomes possible to continuously release to, and as a result, it has a high skin penetration effect specifically for the water-soluble active ingredient. Further, a relatively high molecular weight organopolysiloxane having a molecular weight of 1,000 or more is preferable,
Since the transdermal absorption enhancer itself does not penetrate the skin,
It is a penetration-promoting base that does not disturb the stratum corneum lipids, is highly safe, and has a good feeling in use.

Other than the above, the other parts are the properties of the base, the formulation (O / W, W / O, water-based, oil-based, alcohol-based),
The composition of the drug can be changed according to its physical properties and purpose.

In order to more effectively exert the skin permeation promoting effect or the controlling effect of the percutaneous absorption enhancer or the percutaneous absorption control agent of the present invention, the base of the skin external preparation containing the drug is water-based or O / It is preferably W type.

The percutaneous absorption enhancer or percutaneous absorption control agent of the present invention is suitably blended with cosmetics, and can effectively and continuously penetrate the medicinal component (medicine) into the skin. As the medicinal component (medicine), any of water-soluble, oil-soluble, and amphipathic substances can be applied, but water-soluble is particularly preferable. Therefore, the external preparation for skin of the present invention is preferably an aqueous cosmetic composition, and the content of the aqueous component constituting the aqueous phase is preferably 50% (mass percentage) or more, more preferably 70% or more with respect to the total amount. In addition, in the lotion containing the water-soluble drug, the content of the aqueous component constituting the aqueous phase is preferably 80% or more based on the total amount.

Examples of the drug absorbed into the skin by the percutaneous absorption enhancer or the percutaneous absorption control agent of the present invention include whitening agents, moisturizers, anti-inflammatory agents, antibacterial agents, hormone agents, vitamins and various amino acids. And drug components such as derivatives thereof, enzymes, antioxidants and hair restorers.
Specific examples are listed below, but water-soluble drugs are preferable.

Examples of the whitening agent include hydroquinone derivatives such as arbutin and glycosides, kojic acid, L-ascorbic acid (vitamin C) and its derivatives, pantothenic acid derivatives, tranexamic acid and its derivatives, and potassium 4-methoxysalicylate. Examples include salicylic acid derivatives, resorcin derivatives, other phenol derivatives, various extracts such as placenta extracts and plant extracts (eg chamomile extract).

Examples of L-ascorbic acid derivatives include L-ascorbic acid monoalkyl esters such as L-ascorbic acid monostearate, L-ascorbic acid monopalmitate and L-ascorbic acid monooleate, and L-ascorbic acid monophosphate. L-ascorbic acid monoesters such as acid ester and L-ascorbic acid-2-sulfate; L-ascorbic acid dialkyl esters such as L-ascorbic acid distearate, L-ascorbic acid dipalmitate and L-ascorbic acid dioleate; L L-ascorbic acid diesters such as ascorbic acid diphosphate; L-ascorbic acid triesters such as L-ascorbic acid tristearate, L-ascorbic acid tripalmitate and L-ascorbic acid trioleate Esters; L- ascorbic acid triesters such as ascorbic acid triphosphate ester; and L- ascorbic acid glucosides such as L- ascorbic acid 2-glucoside and the like. Examples of L-ascorbic acid and its derivatives include L-ascorbic acid, L-ascorbic acid phosphate, L-ascorbic acid-2-sulfate, and L-ascorbic acid 2-.
Glucoside or salts thereof may be mentioned.

Examples of the pantothenic acid derivative include pantothenyl ethyl ether and pantothenyl alcohol.

As the tranexamic acid derivative, for example,
A dimer of tranexamic acid (eg trans-4-hydrochloride)
(Trans-aminomethylcyclohexanecarbonyl)
Aminomethylcyclohexanecarboxylic acid, etc.), an ester form of tranexamic acid and hydroquinone (for example, trans-4-aminomethylcyclohexanecarboxylic acid 4 ′)
-Hydroxyphenyl ester, etc.), an ester form of tranexamic acid and gentisic acid (eg, 2- (trans-4-aminomethylcyclohexylcarbonyloxy))
-5-hydroxybenzoic acid and salts thereof, amide of tranexamic acid (eg, trans-4-aminomethylcyclohexanecarboxylic acid methylamide and salts thereof, trans-4- (P-methoxybenzoyl) aminomethylcyclohexanecarboxylic acid) And salts thereof, trans-4-guanidinomethylcyclohexanecarboxylic acid and salts thereof, etc.) and the like.

Examples of the anti-inflammatory agent include glycyrrhizin, glycyrrhizinate (for example, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc.) and allantoin.

Examples of the moisturizer include urea and the like.

Examples of the antibacterial agent include resorcin, sulfur, salicylic acid and the like.

Examples of hormone agents include oxytocin, corticotropin, vasopressin, secretin,
Examples include gastrin, calcitonin, hinokitiol, ethinyl estradiol and the like.

Examples of vitamins include vitamin A
And its derivatives (e.g., retinol, vitamin A palmitate, etc.), vitamin B _6, vitamin B ₆ derivatives such as vitamin B ₆ hydrochloride, nicotinic acid, nicotinic acid derivatives such as nicotinic acid amide, vitamin E and its derivatives, beta
-Carotenes and the like.

Examples of various amino acids and their derivatives and enzymes include L-glutamic acid, urocanic acid, trypsin, lysozyme chloride, chymotrypsin, semi-alkaline proteinase, serrapeptase, lipase and hyaluronidase.

Examples of the antioxidant include thiotaurine, glutathione, catechin, albumin, ferritin, metallothionein and the like.

Examples of the hair restorer include β-glycyrrhetinic acid, pantothenyl ethyl ether, minoxidil and the like.

It is also possible to use a cooling agent such as camphor or menthol.

In the present invention, the effect of promoting percutaneous absorption or controlling the water-soluble drug is great. In particular, the logP value representing the water / octanol partition coefficient is
Water-soluble drugs of 2.0 or less are preferred. What is logP value?
ical Reviews vol71 (6), 525 (1971), etc., is a coefficient representing the polarity due to the ease of distribution of the substance to water and octanol. Examples of the water-soluble drug having a logP value of 2.0 or less include hydroquinone glycosides and derivatives, ascorbic acid and its derivatives, tranexamic acid and its derivatives, salicylic acid derivatives, pantothenic acid derivatives and the like. More preferably, it is a water-soluble drug having a logP value of 1.2 or less, and examples thereof include hydroquinone glycosides, ascorbic acid and its derivatives, tranexamic acid and its derivatives, and pantothenic acid derivatives.

The amount of the percutaneous absorption enhancer or percutaneous absorption control agent and the drug to be incorporated into the external preparation for skin is appropriately determined depending on the kind of the drug and the intended absorption rate.
Usually, the percutaneous absorption enhancer or the percutaneous absorption control agent is 0.0001 to 50% (mass percentage) with respect to the total amount of the external preparation for skin, and the drug is 0.000 with respect to the total amount of the external preparation for skin.
It is about 1 to 20% (mass percentage). Since the external preparation for skin of the present invention has excellent transdermal absorbability, the compounding amount of the drug can be reduced. In the present invention, a transdermal absorption enhancer or a transdermal absorption control agent means one having an action of promoting absorption of a drug (medicinal component) acting on the skin or controlling the absorption rate thereof. To do.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, other components usually used in external preparations for skin, for example, powder components, liquid oils and fats, solid oils and fats, waxes, hydrocarbon oils and higher fatty acids. , Higher alcohols, ester oils, silicone oils, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, thickeners, film agents,
UV absorbers, sequestering agents, lower alcohols, polyhydric alcohols, sugars, amino acids, organic amines, polymer emulsions, pH adjusting agents, skin nutrition agents, vitamins, antioxidants, antioxidant aids, fragrances, water, etc. Can be appropriately compounded as necessary, and can be produced by a conventional method depending on the intended dosage form and product form.

[0038]

EXAMPLES Next, the present invention will be described with reference to examples. The invention is not limited to these examples. Unless otherwise specified, the blending amount represents% (mass percentage).

[Examples 1 to 6 and Comparative Examples 1 to 12] Skin permeation of water-soluble and oil-soluble drug components according to the formulations described in each table for the percutaneous absorption enhancer of the present invention and other silicone compounds. The permeability enhancing effect was evaluated. The results are shown in Table 1.
~ 3.

[Percutaneous absorption promotion effect] Evaluation test was conducted in vitro.
It was done in the form of. The skin of a miniature pig was used as a skin model, and the method of Japanese Patent Application No. 2000-330836 was followed as follows.

A simple solution of each drug (arbutin which is a water-soluble drug, ascorbic acid 2-glucoside is an aqueous solution, and retinol which is an oil-soluble drug is an O / W emulsion having cetyl octanoate-liquid paraffin as an oil phase. Both are antiseptics. The above solution containing methylparaben or phenoxyethanol) or polyglycerin-modified silicone is applied to minipig skin, incubated at 37 ° C. for 6 hours, and epidermis (arbutin, ascorbic acid 2-glucoside) or epidermis and dermis (retinol, methylparaben) as a solvent are used. The amount of drug extracted per unit weight by HPLC was quantified by HPLC, and the skin permeation amount was compared in the case of containing and not containing (control) organopolysiloxane having a polyglycerin group in the molecule.

From the results shown in Tables 1 to 3, it was confirmed that the incorporation of the organopolysiloxane having a polyglycerin group in the molecule improves the permeability and retention of various drugs into the skin. Even with organopolysiloxanes containing a glycerin group, the non-water-soluble monoglycerin-modified organopolysiloxane and diglycerin-modified organopolysiloxane did not show the skin-penetrating effect of the medicinal component (Comparative Examples 1, 2, 5, 6, 9). 10). On the other hand, a water-soluble organopolysiloxane containing no polyglycerin group but a polyoxyalkylene group in the molecule (Comparative Examples 3, 4,
5, 6, 11, 12), the skin permeation effect of the medicinal components (arbutin, ascorbic acid 2-glucoside, retinol) was not observed. By incorporating a water-soluble organopolysiloxane having a polyglycerin group, no increase in the amount of permeation into the skin of preservatives (methylparaben, phenoxyethanol), which are unnecessary components in the skin, is not observed in the molecule. Water-soluble organopolysiloxanes with polyglycerin groups have been shown to have permeation control. In addition, compared to oil-soluble retinol, water-soluble arbutin, ascorbic acid 2-
A significant effect is seen on the skin penetration ratio of glucoside.

[0043]

[Table 1]

[Table 2]

[Table 3]

[0044]

[Chemical Formula 5] “Silicone compound used in Examples (hydrophilic polyglycerin-modified silicone)” "Silicone compounds used in comparative examples"

The silicone compounds used in the Examples and Comparative Examples can be produced by subjecting the corresponding methyl hydrogen polysiloxane (Si-H bond portion) to an addition reaction of a desired substituent by a known method. For example, the triglycerin-modified silicone 1 and the triglycerin-modified silicone 2 used in the examples are the corresponding methylhydrogenpolysiloxane and allylated diisopropylidene triglycerin in an IPA solvent containing an ethanol solution of potassium sulfate and a platinum catalyst. The mixture was heated to reflux for reaction, and hydrochloric acid was added to deacetone to produce the target modified silicone.

Formulation examples of cosmetics using polyglycerin-modified silicone as a percutaneous absorption enhancer or a percutaneous absorption control agent are shown below.

[Formulation Example 1] Transparent lotion (composition component) Compounding amount (%) 1,3-butylene glycol 6 glycerin 4 polyoxyethylene / polyoxyalkylene copolymer 5 oleyl alcohol 0.1 POE (20 ) Sorbitan monolaurate 0.5 Polyglycerin modified silicone 0.5 Ethanol 10 Arbutin 24 Potassium methoxysalicylate 1 Iron oxide 0.001 Phenoxyethanol 1 Citric acid 0.05 Sodium citrate 0.6 Perfume Suitable amount Purified water Residual ( Manufacturing method) 1,3-butylene glycol, glycerin, polyglycerin-modified silicone, arbutin, and a buffer are dissolved in purified water to obtain an aqueous phase. On the other hand, oleyl alcohol, a surfactant, a fragrance, a coloring agent, and a preservative are dissolved in ethanol to form an ethanol phase. This ethanol phase is added to the above aqueous phase to solubilize it and obtain a transparent lotion.

[Formulation Example 2] Lotion (composition) Compounding amount (%) Dipropylene glycol 1 Solbit 1 POE (20) Oleyl alcohol ether 1 Polyglycerin modified silicone 0.2 Ascorbic acid 2-glucoside 2 Ethanol 15 Phenoxyethanol 0.3 Citric acid 0.05 Sodium citrate 0.6 Iron oxide 0.001 Perfume Appropriate amount Purified water Residual (manufacturing method) Purified water with dipyropyrene glycol, sorbit, polyglycerin modified silicone, ascorbic acid 2
-Glucoside and buffer are dissolved to form an aqueous phase. Meanwhile, POE (20) oleyl alcohol ether in ethanol,
The fragrance, colorant, and preservative are dissolved to form an ethanol phase. This ethanol phase is added to the above aqueous phase to solubilize it and obtain a lotion.

[Formulation Example 3] Lotion (composition) Blending amount (%) Ethanol 10 Dipropylene glycol 1 Polyglycerin-modified silicone 1 Polyethylene glycol 1000 1 Polyoxyethylene methyl glucoside 1 Glyceryl tri-2-ethylhexanoate 0 1 polyoxyethylene (60) hydrogenated castor oil 0.2 polyglyceryl diisostearate 0.15 sodium N-stearoyl-L-glutamate 0.1 citric acid 0.04 sodium citrate 0.18 potassium hydroxide 0.4 glycyrrhizinate Dipotassium 0.1 Arginine 0.1 L-Ascorbic acid 2-Glucoside 2 Ougon extract 0.1 Yukinoshita extract 0.1 Phenoxyethanol 0.2 Edetate 3 sodium 0.05 Para-methoxycinnamic acid 2-ethylhexyl Sil 1.0 Fragrance Appropriate amount of purified water Residual (manufacturing method) After adding a moisturizer and alkali to purified water, add polyglycerin-modified silicone, ascorbic acid 2-glucoside, dipotassium glycyrrhizinate, and buffer to make an aqueous phase. . On the other hand, an oil-soluble component, a flavor and a preservative are dissolved in ethanol to form an ethanol phase. This ethanol phase is added to the above aqueous phase to solubilize it and obtain a lotion.

[Formulation Example 4] Lotion (composition) Blending amount (%) Ethanol 40 Glycerin 38 Dipropylene glycol 8 Erythritol 0.3 Polyglycerin modified silicone 10 Polyethylene glycol 1000 4 Polyoxyethylene methyl glucoside 8 Isostearic acid 0.5 Sanglyceryl tri-2-ethylhexylate 4 Polyoxyethylene (60) hydrogenated castor oil 0.7 Polyglyceryl diisostearate 2 Lauryl dimethylaminoacetic acid betaine 0.5 Citric acid 0.06 Sodium citrate 0.5 Potassium hydroxide 0.7 dipotassium glycyrrhizinate 0.5 trimethylglycine 3 hypotaurine 0.5 oil-soluble licorice extract 0.5 L-ascorbic acid 2-glucoside 2 L-menthol 1 phenoxyethanol 0.5 Ethylenediamine hydroxyethyl triacetate trisodium 0.1 Edetate trisodium 0.2 Para-methoxycinnamic acid 2-ethylhexyl 7 Fragrance Suitable amount Purified water Residual amount (manufacturing method) After adding a moisturizing agent and alkali to purified water, polyglycerin-modified silicone , Ascorbic acid 2-glucoside, dipotassium glycyrrhizinate, and a buffer are added to form an aqueous phase. On the other hand, an oil-soluble component, a flavor and a preservative are dissolved in ethanol to form an ethanol phase. This ethanol phase is added to the above aqueous phase to solubilize it and obtain a lotion.

[Formulation Example 5] Two-layer type lotion (composition component) Compounding amount (%) Squalane 8 Polyglycerin modified silicone 0.2 Sorbite 1 Glycerin 1 POE sorbitan tetraoleate 0.2 Ethanol 10 Glutathione 0 .2 Hinokitiol 0.1 Phenoxyethanol 0.3 Paraoxybenzoate 0.12 Iron oxide 0.001 Orange oil 0.01 Purified water Residue (production method) Hinokitiol with POE sorbitan tetraoleate, preservative, colorant, ethanol Is added to form an oil phase. The remaining ingredients are mixed to form the aqueous phase. A two-layer lotion is obtained by mixing the oil phase and the water phase.

[Formulation Example 6] Emollient lotion (O / W) (composition) Content (%) Stearic acid 2 Cetyl alcohol 1.5 Vaseline 2 Squalane 3 Arbutin 3 Retinol 0.5 Tranexamic acid 2 Yukinoshita extract 0 0.5 Chamomile extract 0.1 Agar 0.5 Polyglycerin modified silicone 0.5 Sorbitan monooleate 2 Dipropylene glycol 5 Polyoxyethylene / polyoxyalkylene copolymer 2 Polyethylene glycol (PEG1500) 3 L-glutamic acid 0. 3 Triethanolamine 0.05 Citric acid 0.05 Sodium citrate 0.6 Phenoxyethanol 0.3 Paraoxybenzoic acid ester 0.12 Perfume Suitable amount Purified water Residual (production method) After adding moisturizer and alkali to purified water , L-guru Min acid, and the aqueous phase by adding buffer. An oil-soluble component is dissolved in oil, which is mixed with an aqueous phase and emulsified with a homomixer to obtain an O / W type emollient lotion.

[Formulation Example 7] Emollient lotion (O / W) (composition component) Blending amount (%) Vaseline 2 Methylpolysiloxane 2 Polyglycerin-modified silicone 0.5 Ethanol 5 Behenyl alcohol 0.5 Batyl alcohol 0.2 Glycerin 7 1,3-butylene glycol 5 Polyethylene glycol 20000 0.5 Jojoba oil 3 Squalane 2 Cholesteryl hydroxystearate 0.5 Pentaerythritol tetra-2-ethylhexanoate 1 Polyoxyethylene (60) hydrogenated castor oil 1 Potassium hydroxide 0.1 Sodium pyrosulfite 0.02 Sodium metaphosphate 0.05 Stearyl glycyrrhetinate 0.1 Pantothenyl ethyl ether 0.1 Arbutin 7 L-serine 1 Acetate DL-α-tocopherol 0.1 Hia Sodium ronate 0.05 Paraoxybenzoic acid ester 0.1 Sodium edetate 0.05 4-t-butyl-4′-methoxydibenzoylmethane 0.5 Diparamethoxycinnamate mono-2-ethylhexylate glyceryl ester 0.5 Xanthan gum 0.1 Carboxyvinyl polymer 0.2 Purified water Residue (manufacturing method) A moisturizer, a surfactant, a polyglycerin-modified silicone, a drug, and a chelating agent are added to purified water to dissolve the carboxyvinyl polymer. The remaining components are mixed, dissolved, and emulsified at 70 ° C. using a homomixer to obtain an O / W type emollient lotion.

[Formulation Example 8] Lotion (O / W) (composition component) Blending amount (%) Stearyl alcohol 0.5 Vitamin E acetate 1 Tranexamic acid 5 Hardened palm oil 2 Liquid paraffin 3 Polyglycerin-modified silicone 1 Poly Oxyethylene-modified silicone 0.1 Dipropylene glycol 6 Polyethylene glycol (PEG400) 4 Sorbitan sesquioleate 1.6 Carboxyvinyl polymer 1.5 Potassium hydroxide 0.42 Phenoxyethanol 0.3 Edetate 3 sodium 0.1 Perfume suitable Quantity Purified water Residual (manufacturing method) Add humectant, surfactant, chemicals and chelating agent to purified water to dissolve carboxyvinyl polymer. The remaining components are mixed, dissolved, and emulsified at 70 ° C. using a homomixer to obtain an O / W type lotion.

[Formulation Example 9] Emollient Lotion (W / O) (Composition) Amount (%) Microcrystalline wax 1 Beeswax 2 Lanolin 2 Liquid paraffin 10 Squalane 20 Vitamin A palmitate 2 4-Methoxysalicylate 2 Poly Glycerin modified silicone 0.5 propylene glycol 7 sorbitan sesquioleate 4 POE (20) sorbitan monooleate 1 phenoxyethanol 0.3 magnesium ascorbate phosphate 2 glycine 0.5 polyglycerin modified silicone 0.5 citric acid 0. 05 Sodium citrate 0.6 Orange oil 0.01 Purified water Residual (manufacturing method) A water-soluble component is added to purified water and dissolved to form an aqueous phase. Mix oil, oil-soluble component, and surfactant to 70 ℃
And the aqueous phase is gradually added thereto to emulsify with a homomixer to obtain a W / O type emollient lotion.

[Formulation Example 10] Cream (O / W) (composition component) Blending amount (%) Methyl polysiloxane 2 Decamethylcyclopentasiloxane 28 Behenyl alcohol 0.77 Batyl alcohol 1.65 Polyglycerin-modified silicone 5 Glycerin 4 Dipropylene glycol 5 Lavender oil 0.04 Salix beeswax 1.65 Glyceryl tri-2-ethylhexanoate 1 Cetyl 2-ethylhexanoate 1 Citric acid 0.01 Sodium citrate 0.09 Potassium hydroxide 0.42 Dipotassium glycyrrhizinate 0.05 trimethylglycine 0.1 L-ascorbic acid 2-glucoside 2 acetic acid DL-α-tocopherol 0.1 paraoxybenzoic acid ester 0.12 dibutylhydroxytoluene 0.01 edetate trisodium 0.1 refined Water production Residue (production method) Add humectant, surfactant, polyglycerin-modified silicone, chemicals and buffer to dissolved water and dissolve. The remaining components are mixed, dissolved, and emulsified at 70 ° C. using a homomixer to obtain an O / W type cream.

[Formulation Example 10] Emollient cream (W / O) (composition) Amount (%) Squalane 15 Decamethylcyclopentasiloxane 5 Cetyl isooctanoate 8.5 Ascorbic acid dipalmitate 2 Microcrystalline wax 1 Polyglycerin-modified silicone 0.2 Organically modified smectite 1.3 POE glycerol triisostearate 0.2 cyclodextrin 0.2 glycerin 10 phenoxyethanol 0.3 paraoxybenzoate 0.2 perfume proper amount purified water residue (production method) A clay mineral, a surfactant, a preservative, and a fragrance are added to the oil component and uniformly dispersed, and then a drug is added to obtain an oily gel. A humectant and other water-soluble components are added to purified water, dissolved, and then added to the above oil phase, stirred by a homomixer, and mixed with W
/ O type emollient cream is obtained.

[Formulation Example 11] Oil-based gel (composition component) Blending amount (%) Liquid paraffin 6 Polydimethylsiloxane 6 Glycerol tri-2 ethylhexanoate 50 Sorbitol 10 Polyethylene glycol (PEG400) 5 Acylmethyl taurine 5 POE Octyldodecyl alcohol ether 10 Polyglycerin-modified silicone 0.5 Vitamin A palmitate 2 Resorcinol derivative 0.5 Lavender oil 0.001 Purified water Residual (manufacturing method) A moisturizer and acylmethyl taurine are added to purified water to obtain an aqueous phase. The remaining components are mixed and dissolved to form an oil phase, which is added to the above aqueous phase while stirring with a homomixer and emulsified to obtain an oily gel.

[Formulation Example 12] Moisture gel (composition component) Compounding amount (%) Dipropylene glycol 7 Polyethylene glycol (PEG400) 8 Carboxyvinyl polymer 0.4 Methylcellulose 0.2 POE (15) Oleyl alcohol ether 1 Water Potassium oxide 0.1 Polyglycerin-modified silicone 0.5 Ascorbic acid 3 Urea 10 Phenoxyethanol 0.3 Citric acid 0.05 Sodium citrate 0.6 Perfume Appropriate amount Purified water Residue (production method) Add water-soluble polymer to purified water After uniform dissolution, the remaining ingredients are added and uniformly dissolved to obtain a moisture gel.

[Formulation Example 13] Moisture gel (composition component) Compounding amount (%) Polyoxyethylene / methylpolysiloxane copolymer 5 Triglycerin-modified silicone 1 Dipropylene glycol 3 1,3-butylene glycol 10 Polyethylene glycol 1500 1 Polyoxyethylene methyl glucoside 1 Polyethylene glycol diisostearate 5 Dipotassium glycyrrhizinate 0.5 Paraoxybenzoic acid ester 0.2 Edetate-3 sodium 0.01 Hydroxypropylmethylcellulose 0.7 Carboxyvinyl polymer potassium 0.5 Purified water residue After the water-soluble polymer is uniformly dissolved in the remaining (manufacturing method) purified water, the remaining components are added and uniformly dissolved to obtain a moisture gel.

[Formulation Example 15] Emollient cream (W / O) (composition component) Amount (%) Squalane 15 Decamethylcyclopentasiloxane 5 Cetyl isooctanoate 8.5 Ascorbic acid dipalmitate 2 4-Methoxysalicylic acid K 2 Microcrystalline wax 1 Polyglycerin modified silicone 0.2 Organic modified smectite 1.3 POE Glycerol triisostearate 0.2 Glycerin 10 Phenoxyethanol 0.3 Perfume Suitable amount Purified water Residue (production method) Clay minerals, interface to oil An activator, an antiseptic and a fragrance are added and uniformly dispersed, and further the drug is added to obtain an oily gel. A humectant and other water-soluble components are added to purified water, dissolved, and then added to the above oil phase, stirred by a homomixer, and mixed with W
/ O type emollient cream is obtained.

[Formulation Example 16] Emollient lotion (O / W) (composition) Content (%) Stearic acid 2 Cetyl alcohol 1.5 Vaseline 4 Squalane 5 Retinol 0.8 Polyglycerin modified silicone 0.5 Sorbitan Monooleate 2 Dipropylene glycol 5 Polyethylene glycol (1500) 3 L-Glutamic acid Na 0.3 Triethanolamine 0.1 Phenoxyethanol 0.3 Citric acid 0.01 Sodium citrate 0.09 Perfume Suitable amount Purified water Residue (Production method) A moisturizer and an alkali are added to purified water, and then L-glutamic acid and a buffer are added. An oil-soluble component is dissolved in an oil component and emulsified with an aqueous phase using a homomixer to obtain an O / W type emollient lotion.

[Formulation Example 17] Mask (composition component) Blending amount (%) Vaseline 6 Behenyl alcohol 2.5 Glycerin 9 Maltitol solution 2 Polyethylene glycol 1500 12 Polyglycerin modified silicone 0.1 Squalane 11 Potassium behenate 2 Hydroxy Cholesteryl stearate 0.1 N-alkylene (20-30) glycol monoisostearate 3 Cetyl 2-ethylhexanoate 4 Polyoxyethylene (60) hydrogenated castor oil 0.3 Self-emulsifying glycerin monostearate 2 Titanium oxide 1 Metaline Sodium acid 0.1 L-arginine 0.1 Vitamin E acetate 0.1 Carrot extract 0.1 Paraoxybenzoic acid ester 0.3 Bentonite 0.5 Purified water Residual fragrance Suitable amount (manufacturing method) Purified water, titanium oxide, Glyceri , Maltitol aqueous solution, polyethylene glycol 15000, polyglycerin-modified silicones, mixed thoroughly added carrot extract. The remaining water-soluble components are added to this mixed solution and stirred to form an aqueous phase. Vaseline and behenyl alcohol are mixed with squalane, the remaining oil-soluble components are added to this, the mixture is stirred, and further the mixture is emulsified with the aqueous phase with a homomixer to obtain a rinse-type mask.

[Formulation Example 18] Lipstick (composition component) Compounding amount (%) Titanium dioxide 4.5 Red No. 201 0.5 Red No. 202 2 Red No. 223 0.05 Ceresin 4 Candelilla wax 8 Carnauba wax 2 Castor Oil 25 Isostearic acid diglyceride 40 POE (25) Polyoxypropylene (20) 2-Tetradecyl ether 1 Retinol 1 Glycerin 2 Propylene glycol 1 Polyglycerin modified silicone 0.5 Octyl methoxycinnamate 0.01 α-Tocopherol 0.1 Purification Water Residue (manufacturing method) Titanium dioxide, red Nos. 201 and 202 are added to a part of castor oil and treated with a roller. Red No. 223 is dissolved in castor oil. Purified water, glycerin, and propylene glycol are uniformly dissolved at 80 ° C. The other components are mixed, the pigment part and the dye part are added and dispersed uniformly with a homomixer, the aqueous phase is added, the mixture is emulsified with a homomixer, and the mixture is poured into a mold and cooled to obtain a lipstick.

[Formulation Example 19] Hair nourishing agent, anti-hair graying agent (composition) Blending amount (%) Pantothenyl ethyl ether 0.5 β-Glycyrrhetinic acid 0.5 Sembri extract paste 0.5 Nicotinic acid amide 0.5 Vitamin E Acetate 0.5 Salamander Extract 0.1 Ethanol 70 Polyglycerin Modified Silicone 0.5 Isostearyl Alcohol 5 Lauryl Dimethylamine Oxide Sodium Oleate 0.5 Hardened Castor Oil Ethylene Oxide (40 mol adduct) 0.5 Purified Water Each component is added to the remaining (manufacturing method) ethanol to obtain an essence for hair care which has a hair nourishing effect and a gray hair preventing effect and the like.

[0066]

According to the present invention, only a target drug is selectively and efficiently permeated into a target site in the skin,
A percutaneous absorption enhancer or a percutaneous absorption control agent capable of maintaining an effective concentration for a long time can be provided. Furthermore, a drug and a percutaneous absorption enhancer or a percutaneous absorption control agent can be blended in a skin external preparation to provide a skin external preparation with high safety and a good feeling in use. The external preparation for skin of the present invention is excellent in drug efficacy and its sustainability in a system containing a drug component, and is also excellent in safety. Particularly, when a water-based drug that is hard to be absorbed into the skin is mixed, the effect of promoting percutaneous absorption is excellent.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Toru Okamoto             2-2-1 Hayabuchi, Tsuzuki Ward, Yokohama City, Kanagawa Prefecture             Shiseido Research Center (Shin-Yokohama)             Within (72) Inventor Toshio Liangki             2-2-1 Hayabuchi, Tsuzuki Ward, Yokohama City, Kanagawa Prefecture             Shiseido Research Center (Shin-Yokohama)             Within F-term (reference) 4C076 AA09 AA12 BB31 CC50 EE27                       FF34                 4C083 AA082 AA112 AA122 AB032                       AB232 AB282 AB352 AB442                       AC012 AC022 AC082 AC102                       AC112 AC122 AC132 AC172                       AC262 AC302 AC342 AC432                       AC442 AC472 AC532 AC542                       AC582 AC622 AC642 AC662                       AC682 AC712 AC792 AC842                       AD042 AD092 AD112 AD152                       AD161 AD162 AD172 AD252                       AD332 AD352 AD432 AD512                       AD532 AD552 AD622 AD642                       AD662 CC04 CC05 CC13                       CC37 DD01 DD05 DD32 DD33                       DD41                 4C084 AA16 CA62 MA05 MA63 NA11                       ZA89

Claims (5)

[Claims] 1. A percutaneous absorption enhancer or a percutaneous absorption control agent comprising a hydrophilic polyglycerin-modified silicone. 2. A percutaneous absorption enhancer or a percutaneous absorption control agent comprising a hydrophilic polyglycerin-modified silicone having a polyglycerin group of triglycerin or more. 3. A skin external preparation containing a drug and the percutaneous absorption enhancer or the percutaneous absorption control agent according to claim 1 as an active ingredient. 4. A water-soluble drug and the percutaneous absorption enhancer or the percutaneous absorption control agent according to claim 1 or 2 as an active ingredient, and the content of the aqueous component is 80% or more based on the total amount. An aqueous external preparation for skin. 5. A log representing a water / octanol partition coefficient.
A skin external preparation containing a water-soluble drug having a P value of 2.0 or less, water, and the percutaneous absorption enhancer or the percutaneous absorption control agent according to claim 1 or 2 as active ingredients.