JP2001114701A - External preparation for skin - Google Patents

Abstract

(57) [Problem] To provide a skin external preparation which can remarkably improve the transdermal absorbability of a medicinal ingredient. A skin external preparation comprising creatinine or creatine and a transdermal absorption enhancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for skin which has significantly improved percutaneous absorption of a medicinal ingredient.

[0002]

2. Description of the Related Art In recent years, with the development of dermatology, various effects have been imparted to skin external preparations, and their functions have been enhanced.
For example, various active ingredients such as a whitening ingredient and a wrinkle improving ingredient have been found and commercialized.

As the whitening components, those containing arbutin (JP-A-60-56912), those containing koji (Japanese Patent Publication No. 61-60801), those containing ellagic acid of the present applicant ( Patent 1839986
No.) is known. It is known that wrinkle improving ingredients include vitamin A (kligma
n, LH et al, Connect Tissue Res 12: 139-150, 1984).

[0004] However, if it is attempted to sufficiently mix the above-mentioned various components so that their effects can be exhibited, some components may cause irritation or degrade the stability of the preparation, and the odor of the components may be deteriorated. Since there may be problems such as impairing the palatability of the preparation, the amounts of these compounds are limited.

[0005] In order to solve these problems, a search and development of a transdermal absorption enhancer have been conducted. However, the percutaneous absorption enhancer itself may be irritating, and a sufficient effect can be obtained. Is not reached. Therefore, biodegradable compounds (unsaturated cyclic urea, N, N-dimethylamino acid alkyl ester, lactic acid ester), natural product-derived compounds (monoterpenes and their derivatives, vitamin E)
Etc.), high molecular compounds (cationic surfactant polymers,
A study on the safety of percutaneous absorption enhancers composed of polydimethylsiloxane having a cationic group at one end) on the skin [Takao Aoyagi, Fragrance Journal, 24 (4), 3
4 (1996)], Stabilization and release control of liposomes as DDS (Drug Delivery System) technology [Kumiko Makino, Fragrance Journal, 24 (4), 85 (1996)], synthesis of derivatives of medicinal ingredients, and prodrugs Research (So
lan KB (ed), Prodrugs, Topical and Ocular Drug Del
ivery, Marcel Dekker Inc., NewYork (1992)], etc., but some of them have been effective, but they are not applicable to all drugs (medicinal ingredients). There is a problem in that the versatility is poor.

[0006] On the other hand, creatine is also called methylglycosamine, which is produced in vivo by the methylation of guanidinoacetic acid generated from glycine and arginine by S-adenosylmethionine, and is mostly phosphagen. It exists as phosphocreatine and regenerates adenosine triphosphate (ATP) upon muscle contraction under anaerobic conditions. In addition, creatinine, also called methylglycocyanidin, is a physiological metabolite of creatine (creatine is dehydrated and cyclized), is contained in normal urine and muscle, and is used as an index in clinical tests. It is a substance that plays an important role in muscle contraction through the creatine cycle in vivo (Biochemical Encyclopedia, published November 22, 1990 by Tokyo Chemical Dojin). In addition, creatinine is found in the skin in NMF (Natural
Moistirizing Factor (natural moisturizing factor) is known to be involved in moisturizing the skin as one of the components (Takeo Mitsui, edited by New Cosmetics, Nanzan-do, January 12, 1993). Utilizing its structural features, it is also used as an amino acid type deodorant (JP-A-6-240579 by the present applicant). However, there are few examples in which creatine or creatinine has been used as a cosmetic or an external preparation, such as pyrrolidone carboxylic acid, amino acids, and sodium hyaluronate, which are other NMF components.

[0007] Japanese Patent Publication No. Hei 8-506081 discloses that creatinine is added as a low-temperature protective agent for a preparation obtained by drying a submicron emulsion. It is not an ordinary emulsion or solubilized substance, and has a completely different technical idea from the present invention.

[0008]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned problems in the prior art, and has been made in order to solve the problem. The purpose is to provide.

[0009]

Means for Solving the Problems The present inventors have conducted intensive studies on creatine or creatinine in order to solve the above-mentioned conventional problems and the like. By incorporating it into a product, the inventor newly found that it has a function of significantly improving the percutaneous absorbability of various medicinal ingredients as compared with the case of using a transdermal absorbent alone, and completed the present invention. . That is, the skin external preparation of the present invention is characterized by containing creatinine or creatine and a transdermal absorption enhancer.

[0010]

Embodiments of the present invention will be described below in detail. The external preparation for skin of the present invention is characterized by containing creatinine or creatine and a transdermal absorption enhancer.

The creatinine or creatine used in the present invention is incorporated into a composition for external application to the skin together with a percutaneous absorption enhancer, whereby the creatinine or creatine can be used as compared with the case of using the percutaneous absorption enhancer alone.
The transdermal absorbability of various medicinal ingredients can be significantly improved. As creatinine or creatine used in the present invention, for example, creatinine or creatine powder, which is commercially available as a liquid, is used. The amount of creatinine or creatine is 0.01 to 10% by weight, preferably 0.05 to 5% by weight, based on the total amount of the external preparation for skin. If the amount of creatinine or creatine is less than 0.01%, the effect of the present invention is insufficient, and if it exceeds 10% by weight, the stability in a skin external preparation tends to be impaired, which is not preferable.

The percutaneous absorption enhancers used in the present invention include:
Usually, it is not particularly limited as long as it is incorporated in a skin external preparation (medicine, quasi-drug, cosmetic).
Specific examples of transdermal absorption enhancers that can be used include:
Ester oils with high affinity for skin, such as isopropyl palmitate, isopropyl myristate, diisopropyl adipate, dioctyl succinate, and octyl dodecyl lactate Fatty acids or esters thereof, for example, oleic acid, ethyl oleate, decyl oleate, oleyl oleate, octyl dodecyl oleate, propylene glycol oleate, etc., substances having a protein denaturing action on keratin proteins, such as urea and the like Derivatives, glycolic acid and its salts, lactic acid and its salts, salicylic acid, and other substances that change the distribution ratio of active ingredients to the skin, for example, alcohols (ethanol, isopropanol), polyhydric alcohols (propylene glycol, dipropy Glycol,
Polymeric transdermal absorption enhancers that improve the retention of components on the skin, such as 1,3-butylene glycol and polyethylene glycol), for example, cyclodextrin, polyethylene glycol / polydimethylsiloxane copolymer, and the like. In addition, these transdermal absorption enhancers can be used alone or in combination of two or more.

Preferred transdermal absorption enhancers are isopropyl palmitate, oleic acid and its derivatives, urea and its derivatives, glycolic acid and its derivatives, salicylic acid and its derivatives, ethanol, propylene glycol, dipropylene glycol, 1,3- Butylene glycol, polyethylene glycol, more preferably isopropyl palmitate, ethyl oleate, urea, glycolic acid, ammonium glycolate, salicylic acid, methyl salicylate, ethanol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, Polyethylene glycol is preferred.

The amount of the percutaneous absorption enhancer varies depending on the kind of the percutaneous absorption enhancer and the type of the preparation, but is 0.0 based on the total amount of the external preparation for skin.
It is 1 to 15% by weight, preferably 0.1 to 10% by weight. When the amount of the transdermal absorption enhancer is less than 0.01% by weight, the effect of the present invention is not exhibited, and when the amount exceeds 15% by weight, there is no difference in the effect of the present invention. May hinder the stability of skin external preparations.

The external preparation for skin of the present invention may further contain a pharmaceutically active ingredient. The medicinal component is not particularly limited as long as it is usually compounded in a skin external preparation (medicine, quasi-drug, cosmetic). For example, normal skin such as whitening component, anti-aging component to prevent and improve wrinkles and sagging, blood circulation promoting component, component to improve dullness and darkness, sebum control component, anti-acne component, anti-inflammatory component, rough skin improving component, etc. Pharmaceutical ingredients having an effect related to an external preparation are exemplified. In addition, a water-soluble medicinal component and a sparingly soluble medicinal component, which are generally considered to have low absorbability, can also achieve a high transdermal absorption effect in the present invention. Specific examples of medicinal ingredients that can be used include ellagic acid,
Dipotassium glycyrrhizinate, oxidized coenzyme A
(Oxidized CoA), hydroxycitronellal, stearyl glycyrrhetinate, oil-soluble licorice extract, vitamin E
And its derivatives, vitamin C and its derivatives, allantoin, etc., and these can be used alone or in combination of two or more. The compounding amount of these medicinal ingredients differs depending on the medicinal ingredients to be selected and used and also according to the use of the external preparation for skin, and is not specified unconditionally. .0
It is about 1 to 10% by weight. In the present invention,
A skin external preparation prepared by mixing the medicinal ingredient with creatinine or creatine and a percutaneous absorption enhancer, or a preparation containing a medicinal ingredient separately was prepared, and the preparation was mixed with creatinine or creatine and a percutaneous absorption enhancer. It may be used after or before use of the external preparation for skin, and in any of these cases, the transdermal absorbability of the medicinal ingredient can be significantly improved (these points are described in Examples described later). Etc.).

In addition to the above-mentioned components, the skin external preparation of the present invention usually contains optional ingredients used in skin external preparations, such as surfactants, oils, alcohols, humectants, and thickeners. , Preservatives, antioxidants, chelating agents, pH adjusters, fragrances, dyes, UV absorbers / scatterers, water (purified water,
Ion-exchanged water) and the like can be appropriately added. The optional components are not limited to the above-mentioned various components.

The creatinine used in the present invention is usually in equilibrium with creatine on the acidic side and creatinine on the alkaline side depending on the pH environment, but the effect of improving percutaneous absorbability does not change on either side. It is. Accordingly, the pH of the external preparation for skin of the present invention is not particularly limited, but is preferably pH 3 to 9, which is suitable as an external preparation for skin.

The dosage form of the external preparation for skin of the present invention is not particularly limited as long as it is in the form of a general external preparation for skin. The external preparation for skin of the present invention can be emulsified according to a usual method, and various creams, emulsions, lotions,
It can be suitably used for serums, packs, patches, ointments and the like.

In the external preparation for skin constituted as described above, by incorporating creatinine or creatine and a transdermal absorption enhancer, the transdermal absorbability of a medicinal component can be remarkably improved. Conventionally, in order to further improve the percutaneous absorption of a medicinal ingredient, for example, when increasing the amount of a percutaneous absorption enhancer, a problem such as skin irritation has occurred. The percutaneous absorption of the medicinal component can be remarkably improved without increasing the amount, and the skin irritation is reduced because the amount of the percutaneous absorption promoter is not increased.

[0020]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. The compositions of the skin external preparations in Examples and Comparative Examples are indicated by “% by weight”, and the total amount is 100% by weight.

[Examples 1 to 6 and Comparative Examples 1 to 8] To the common compositions shown in Table 1 below, the components shown in Table 2 or below (creatinine, transdermal absorption enhancer, medicinal ingredients, etc.) were added, respectively. A gel to be used as a skin external preparation was prepared by a conventional method.
Pharmaceutical components of the obtained skin external preparation (ellagic acid, oxidized Co
The transdermal absorbability of A) was evaluated by the following method. The results are shown in Tables 1 and 2 below.

(1) Method for evaluating the percutaneous absorption of ellagic acid The skin of the back of six guinea pigs (Std. Hartley, male) was cut out and sandwiched between a donor and a receptor of a cell for a percutaneous absorption test. Fixed. Next, after filling the receptor side with sterile physiological saline, the cell was placed in a water bath and incubated at 32 ° C. with stirring. Subsequently, 50 mg of the sample was added onto the skin on the donor side. In addition, ellagic acid is
A mixture in which radioactive isotopes labeled with 14C were uniformly mixed at 10% was used. After incubation for 24 hours, 1 ml of the receptor solution was sampled, 3 ml of Picoflow (manufactured by Packard Japan) was added, and the radioactivity was measured using a liquid scintillation counter to determine the amount of ellagic acid permeating the skin. It was measured.
Then, after thoroughly washing the unabsorbed portion of the drug, the diameter 1c
A certain area of skin is collected with a m-punch, cut into glass vials for liquid scintillation measurement with scissors so as to be easily dissolved, 2 ml of Solen-350 (manufactured by Packard Japan) is added, and the mixture is heated to 60 ° C. and dissolved. did.
After 8 days, 20 ml of Hyonic Flow (manufactured by Packard Japan) was added, and ellagic acid in the skin was measured with a liquid scintillation counter. Then, the amount permeating the skin and the amount in the skin were totaled to evaluate the transdermal absorbability of ellagic acid in the various compositions. The results are shown as relative values with the percutaneous absorption amount of only the percutaneous absorption enhancer taken as 1, and the larger the numerical value of the percutaneous absorption amount, the better the percutaneous absorption of the active ingredient.

(2) Evaluation method of percutaneous absorbability of oxidized CoA Using oxidized CoA labeled with 14C, evaluation was carried out in the same manner as in the above-mentioned method of evaluating ellagic acid (1).

[0024]

[Table 1]

[0025]

[Table 2]

As is clear from the results shown in Tables 1 and 2 above, Examples 1 to 6 according to the present invention are compared with Comparative Examples 1 to 8 which are out of the scope of the present invention, and the active ingredients (ellagic acid, ellagic acid,
It was found that oxidized CoA) was extremely excellent in percutaneous absorption.

[Examples 7 to 12 and Comparative Examples 9 to 16] To the common compositions shown in Table 3 below, the components shown in Table 4 or below (creatinine, transdermal absorption enhancer, medicinal ingredients, etc.) were added, respectively. A cream to be used as a skin external preparation was prepared by a conventional method. The percutaneous absorbability of the medicinal components (ellagic acid, oxidized CoA) of the obtained skin external preparation was evaluated by the method of Example 1 described above. The results are shown in Tables 3 and 4 below.

[0028]

[Table 3]

[0029]

[Table 4]

As is clear from the results of Tables 3 and 4, Examples 7 to 12 according to the present invention are compared with Comparative Examples 9 to 16 which are out of the scope of the present invention, in which the medicinal ingredients (ellagic acid, oxidized acid) are used. Type CoA) was found to be extremely excellent in percutaneous absorption.

[Examples 13 to 21 and Comparative Examples 17 to 2]
4) i) (Examples 13 to 17 and Comparative Examples 17 to 20, in the case of pre-use) An embodiment containing creatinine and a transdermal absorption enhancer without containing a medicinal ingredient prepared with the composition shown in Table 5 below. Example 13
Comparative Examples 4, 8, 12, 16 after applying the lotion
The gel or cream containing the pharmaceutically active ingredient (ellagic acid, oxidized CoA) was applied, and the transdermal absorbability of the pharmaceutically active ingredient was evaluated by the method of Example 1 described above. The results are shown in Table 5 below.
And Table 6. ii) (Examples 18 to 21 and Comparative Examples 21 to 24, in the case of later use) After applying the gel or cream containing the active ingredients (ellagic acid, oxidized CoA) of Comparative Examples 4, 8, 12, and 16 Then, a lotion as in Example 13 containing creatinine having no medicinal component and a percutaneous absorption enhancer having the composition shown in Table 5 below was applied to apply medicinal components (ellagic acid, oxidized Co).
The transdermal absorbability of A) was evaluated by the method of Example 1 above.
The results are shown in Tables 5 and 6 below.

[0032]

[Table 5]

[0033]

[Table 6]

As is clear from the results of Tables 5 and 6, when the lotion containing no medicinal ingredient of Example 13 was applied, and then a gel or cream containing the medicinal ingredient was applied, and the medicinal ingredient was used. Is excellent in transdermal absorbability of medicinal ingredients (ellagic acid, oxidized CoA) in both cases of applying a gel or cream containing the medicinal ingredient and applying a lotion containing no medicinal ingredient of Example 13 It turned out that. In addition, when the results of Tables 1 to 4 and the results of Tables 5 and 6 above are combined, a skin external preparation (gel or cream of Examples 1 to 12) in which a medicinal ingredient is blended with creatinine and a transdermal absorption enhancer is used. Or a preparation containing a medicinal ingredient without containing creatinine and a transdermal absorption enhancer (gels or creams of Comparative Examples 4, 8, 12, and 16) and preparing the preparation with creatinine or creatine. The transdermal absorbability of a medicinal ingredient can be remarkably improved either after use or before use of a skin external preparation (skin lotion of Example 13) mixed with a skin absorption enhancer. found.

Examples 22 to 37 Based on the results of Examples 1 to 21 and Comparative Examples 1 to 24, the following emulsions containing creatinine, which is extremely excellent in percutaneous absorption of the active ingredient, are shown in Tables 7 and 8 below. And was prepared by a conventional method. In Examples 22 to 29 of the composition shown in Table 7 below and Examples 30 to 37 of the composition shown in Table 8 below, a composition excluding the medicinal component was prepared, and the composition was treated with the medicinal component. May be used before or after use of a preparation containing the compound. In addition, it was confirmed that the same effects as those of the present invention can be obtained in any of the sheet products in which each of the emulsions of Examples 22 to 29 and Examples 30 to 37 was impregnated into the following three types of nonwoven fabrics. 100% rayon non-woven fabric sheet [Production method: spunlace, basis weight 70 g / m ² , impregnating liquid by weight ratio: sheet = 7:
1). Rayon / polyester = 50/50 nonwoven fabric sheet (manufacturing method: spunlace, basis weight 100 g / m ² , impregnating liquid: sheet = 10: 1 by weight ratio). 100% cotton nonwoven sheet (production method: spunlace, basis weight 80 g / m ² , impregnating liquid: sheet = 8: 1 by weight ratio)

[0036]

[Table 7]

[0037]

[Table 8]

[Examples 38 to 45] From the results of the above Examples 1 to 21 and Comparative Examples 1 to 24, creams containing creatinine which is extremely excellent in percutaneous absorption of medicinal ingredients are shown in Tables 9 and 10 below. And was prepared by a conventional method. In Examples 38 to 45 of the composition shown in Tables 9 and 10 below, a composition excluding the medicinal ingredient was prepared, and the composition was used before or after use of the preparation containing the medicinal ingredient. Is also good.

[0039]

[Table 9]

[0040]

[Table 10]

[Examples 46 and 47] Based on the results of Examples 1 to 21 and Comparative Examples 1 to 24, cosmetic liquids containing creatinine, which is extremely excellent in percutaneous absorption of medicinal ingredients, were prepared as shown in Table 11 and Table 11 below. The composition was prepared by a conventional method using 12 compositions. In Examples 46 and 47 of the composition shown in Tables 11 and 12 below, a composition excluding the medicinal component was prepared, and the composition was used before or after use of the preparation containing the medicinal component. Is also good. Further, it was confirmed that the same effects as those of the present invention can be obtained in any of the sheet products obtained by impregnating the above three types of nonwoven fabrics with each of the cosmetic liquids of Examples 46 and 47.

[0042]

[Table 11]

[0043]

[Table 12]

Examples 48 to 52 From the results of the above Examples 1 to 21 and Comparative Examples 1 to 24, a lotion containing creatinine, which is extremely excellent in percutaneous absorption of a medicinal ingredient, was formulated as shown in Table 13 below. The composition was prepared by a conventional method. In addition,
In Examples 48 to 52 of the composition shown in Table 13 below, a composition excluding a medicinal ingredient is prepared, and the composition may be used before or after use of a preparation containing the medicinal ingredient. . Further, it was confirmed that the same effects as those of the present invention can be obtained in any of the sheet products obtained by impregnating the three types of nonwoven fabrics with the lotions of Examples 48 to 52.

[0045]

[Table 13]

[0046]

According to the present invention, there is provided an external preparation for skin which can remarkably improve the transdermal absorbability of a medicinal component.

Continuing on the front page F-term (reference) 4C076 AA09 AA12 AA16 AA72 BB31 CC18 DD51N DD60N FF34 4C083 AA112 AA122 AB432 AC022 AC072 AC102 AC122 AC212 AC302 AC352 AC422 AC432 AC442 AC482 AC542 AC581 AC582 AC682 AC842 AC851 AC852 AD912AD472AD CC04 CC05 CC07 DD12 DD23 DD27 DD31 EE03 EE12 EE14 EE16

Claims (1)

[Claims] 1. An external preparation for skin comprising creatinine or creatine and a transdermal absorption enhancer.