JPH10120558A - Skin preparation for improving sputum for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject skin preparation containing a compound such as capsaicin, sinapine or curcumine and capable of improving the action of sputum. SOLUTION: The skin preparation contains a compound of the formula (R1 and R3 are each a short chain length acyloxy, a short chain length alkyloxy, OH, H; R2 is an acyloxy, OH; R4 is a carbonylalkenyl or alkenylcarbonyl which may have N or an aromatic group) in an amount of 0.001-10wt.% as an active ingredient. The compound of the formula has a beautifully skin-whitening action, actions for treating dermatitis such as atopic dermatitis, eczema, dermatomycosis, verruca, dyspigmentation, psoriasis vulgaris, senile xeroderma, senile keratoma and burn, a hair growth-stimulating action, a perspiration- stimulating action, a digestive juice secretion-stimulating action, a diuretic action, a dejection-stimulating action, etc. These actions are exhibited by the percutaneous administration of the preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for skin such as cosmetics and medicines, which is useful for improving the action of tsukusu.

[0002]

2. Description of the Related Art The concept of qi, blood, and water in Chinese medicine has long been studied because of its uniqueness in understanding its pharmacological action and a rational index for selecting Chinese medicine. Of these, many have been elucidated about the meanings of qi and blood. For example, it is known that blood is a keyword that represents the supply and metabolism mainly of energy such as oxygen and nutrition, and ki is a keyword that represents the status of the homeostasis of life activity and the status of the driving force of life activity. Have been.

[0003] However, only the metabolism and excretion of waste products is known for the function of water (tsu liquor).
Since the recognition was delayed in the logical form of water, the elucidation of its true action (Tsukumi action) was incomplete. Also, little is known about the relationship between the pulp action and the various pharmacological actions recognized in modern medicine, and the role of pulp in modern medicine. The development of cosmetics, medicines, etc. that bring about such problems has been desired.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of such circumstances, and has as its object to clarify the true function of a tsuju and to provide an external preparation for skin used to improve the action of a tsuku. And

[0005]

Means for Solving the Problems In view of such a situation, the present inventors have conducted intensive studies in search of the true function of tsuju. It was found that it stimulates the organs responsible for extracorporeal secretion and promotes the secretion of body water out of the body. Then, as a result of examining substances capable of stimulating such secretory organs and promoting / improving the action of the pulp, the present invention was completed.

[0006] That is, the present invention provides a skin for improving a tsunami containing one or more active ingredients selected from the group consisting of a compound represented by the following general formula (I) and a physiologically acceptable salt thereof. It provides an external preparation.

[0007]

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In the formula (I), R ₁ and R ₃ each independently represent a low-chain alkyl group, a low-chain alkyloxy group, a hydroxyl group or a hydrogen atom; R ₂ represents an acyloxy group or a hydroxyl group; ₄ represents a nitrogen atom or a carbonylalkenyl group or an alkenylcarbonyl group which may have an aromatic group. ]

[0009] The present inventors have found that the tsuyu action promotes the secretion of water from the dermis to the epidermis and causes the epidermis to retain sufficient moisture, resulting in a beautiful skin action, atopic dermatitis, eczema,
Dermatomycosis, warts, pigmentation, psoriasis vulgaris, senile xeroderma, senile keratoma, therapeutic effects on various skin diseases such as burns,
It has been found that the action is related to a hair growth promoting action, a sweat promoting action, a digestive juice secretion promoting action, a diuretic action and a bowel movement promoting action caused by promoting water secretion in the stomach wall, kidney and intestinal tract.

That is, the medicinal classification of Chinese herbal medicines was examined in detail, and compared with modern medicine classifications.
It is said that the effects of the herbs such as shampoo, irrigation, conduction and prosthesis are related to beautiful skin effect, atopic dermatitis treatment, and dermatitis group treatment represented by eczema in the modern pharmaceutical classification. , Dermatomycosis treatment, wart treatment, pigmentation such as hepatitis, psoriasis vulgaris, senile xeroderma, senile keratoma treatment, skin damage treatment due to physical causes It has been found that it is closely related to the action, the hair growth promoting action, the digestive juice secretion promoting action, the sweating promoting action, the diuretic action and the bowel movement promoting action.

Based on this finding, screening was carried out on various substances based on the indicators of skin beautiful action, atopic dermatitis treatment action, hair growth promotion action, eczema treatment action, digestive juice secretion promotion action and sweating promotion action. It has been found that a compound selected from the group consisting of the compound represented by the general formula (I) and a physiologically acceptable salt thereof is excellent in such action. Even more surprisingly, by externally administering a compound selected from the group consisting of the compound represented by the general formula (I) and a physiologically acceptable salt thereof, secretion of digestive juice such as stomach acid is promoted. The present inventors have found that the present invention has such effects as described above, and have completed the present invention.

It is known that the compound represented by the above general formula (I) or a physiologically acceptable salt thereof has a percutaneous absorption promoting action, a liver function improving action and an immune function improving action. However, there was no way to know that there was a true improvement of the tsuyu. Further, the compound represented by the above general formula (I) or a physiologically acceptable salt thereof may be used as a beautifying agent, atopic dermatitis, eczema, dermatomycosis, warts, pigmentation,
It has no action to treat skin diseases such as psoriasis vulgaris, senile xeroderma, senile keratoma, burns, etc., hair growth promoting action, sweat sweat promoting action, digestive juice secretion promoting action, diuretic action, and bowel movement promoting action. Was not known.

[0013]

Embodiments of the present invention will be described below. The skin external preparation for tsumuage improvement of the present invention contains, as an active ingredient, one or more selected from the group consisting of the compound represented by the general formula (I) and a physiologically acceptable salt thereof.

In the formula (I), R ₁ and R ₃ each independently represent a low-chain alkyl group, a low-chain alkyloxy group, a hydroxyl group or a hydrogen atom, and R ₂ represents an acyloxy group or a hydroxyl group. And R ₄ represent a nitrogen atom or a carbonylalkenyl group or an alkenylcarbonyl group which may have an aromatic group. Here, the low chain length is preferably a straight or branched carbon chain having 1 to 4 carbon atoms. Further, the carbonylalkenyl group or the alkenylcarbonyl group preferably has an alkenyl group having 3 to 10 carbon atoms. In the present invention, R ₁ and R ₃ are preferably each independently a hydroxyl group or a methoxy group. Further, R ₂ is preferably a hydroxyl group.

The compound represented by the general formula (I) includes
Examples thereof include capsaicin, sinapine, curcumin, isofelelin, 7-O-ethylisoferrein, respedole C, isosatibanone, neouralenol, and 6-methoxycapsaicin, and any of these can be used. Of these, preferred are capsaicin represented by the following general formula (II), sinapine represented by the following general formula (III), curcumin represented by the following general formula (IV), and acyls of these hydroxyl groups Is a monster.

[0016]

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[0017]

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[0018]

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The acyl group in the acylated product is preferably an acyl group having a low chain length of 1 to 4 carbon atoms, such as an acetyl group. Such an acylated product can be easily obtained, for example, by reacting an acid with an acyl chloride obtained by reacting thionyl chloride or the like with an acid in the presence of an alkali. Further, an acid anhydride may be reacted in the presence of an alkali.
Hereinafter, production examples of the acylated product will be described.

[Preparation Example 1] 1 g of capsaicin was dissolved in 100 ml of pyridine, 100 ml of acetic anhydride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 24 hours, concentrated, purified by silica gel column chromatography, and quantitatively purified with acetylcapsaicin. obtain.

[Production Example 2] 1 g of sinapine was added to pyridine 10
0 ml, and 100 ml of acetic anhydride was added dropwise under ice cooling.
After stirring at room temperature for 24 hours, the mixture is concentrated and purified by silica gel column chromatography to quantitatively obtain acetylsinapine.

[Production Example 3] 1 g of curcumin was added to 1 of pyridine
After dissolving in 100 ml, 100 ml of acetic anhydride was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 24 hours, concentrated, and purified by silica gel column chromatography to quantitatively obtain acetylcurcumin.

The physiologically acceptable salts of the compounds represented by the above general formula (I) include, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and ammonium. Preferred examples thereof include salts, organic amine salts such as triethylamine and triethanolamine, and basic amino acid salts such as lysine and arginine. These counterbases may be used alone or in combination of two or more.

The compound represented by the general formula (I) and / or a physiologically acceptable salt thereof are all commercially available. Examples of the external preparation for skin of the present invention include cosmetics such as basic cosmetics, make-up cosmetics, hair cosmetics, bath preparations and the like, and skin external pharmaceutical compositions such as anti-inflammatory external preparations. Formula (I) in the external preparation for skin of the present invention
The preferred content of the compound represented by or a physiologically acceptable salt thereof is 0.001 to 10
%, More preferably 0.01 to 10% by weight, even more preferably 0.01 to 5% by weight.

The external preparation for skin of the present invention has the above general formula (I)
In addition to the compound represented by the formula (I) or a physiologically acceptable salt thereof, the composition may contain optional components commonly used in cosmetics, skin external pharmaceutical compositions and the like. Such optional components include hydrocarbons such as petrolatum and microcrystalline wax, esters such as jojoba oil and gay wax, triglycerides such as tallow, olive oil, higher alcohols such as cetanol and oleyl alcohol, and stearic acid. , Fatty acids such as oleic acid, glycerin and 1,
Polyhydric alcohols such as 3-butanediol, nonionic surfactants, anionic surfactants, cationic surfactants,
Examples include amphoteric surfactants, thickeners such as ethanol and carbopol, preservatives, ultraviolet absorbers, antioxidants, pigments, and powders. The external preparation for skin of the present invention can be produced by treating these optional components with the compound represented by the above general formula (I) or a physiologically acceptable salt thereof in a conventional manner.

The skin external preparation for improving tidal fluid of the present invention is used for promoting / improving the action of liquor. It is known that the tsuju action is expressed in a living body as a mode of expression, such as a shampooing action, a water-supplying action, a prosthesis action, and a conduction action. As a herbal crude drug having these effects, if it is a shampooing effect, rhubarb, banshayou, rokai, machinin, kengoshi, Kansui, Genka, Zokuzuishi, kyukyu compi, etc. Chorei, Bukuryo, Taksha, Inchinko, Jokuinin, Toukanin, Difushi, Tokhihi, Kinsenso and the like are known, and as herbal crude drugs having a prosthetic effect, Shajin, Eurasia, Tenmondou, Bakumondou,
Ginseng, arctic, antelope, sycamore, renren, jotenishi, sesame, kokuzu, kiban, bekko are known, and as a herbal crude drug having an antidepressant effect, hawthorn, krenkonpi, hishi, kakushitsu, reigan, areca, nankashi, Taisan and the like are known.

Examining the literature and the like about these,
It has been found that pharmacological actions such as beautifying action, hair growth-promoting action, anti-allergic action, anti-inflammatory action, and digestion promoting action overlap. Here, the present inventors pay attention, and consider "water" (Tsu liquid).
Works in modern medicine to treat skin disorders such as skin beautification, atopic dermatitis, eczema, dermatomycosis, warts, pigmentation, psoriasis vulgaris, senile xeroderma, senile keratoma and burns It has been found that the action, the hair growth promoting action, the therapeutic action of pimples, the digestive juice secretion promoting action, the sweat promoting action, the diuretic action, the bowel movement promoting action and the like can be used as indices. In addition, substances having one of these actions often have other actions to a greater or lesser degree. Therefore, if screening is performed using one of these actions as an index, other actions can be estimated.

The topical skin preparation for improving tanning solution of the present invention is represented by a skin beautifying effect, an atopic dermatitis treating effect, a dermatitis group represented by eczema, a dermatomycosis treating effect, a wart treating effect, and hepatitis. Therapeutic action for pigmentation disease, psoriasis vulgaris, senile xeroderma, senile keratoma, skin damage treatment action due to physical causes, hair growth promotion action, digestive juice secretion promotion action, sweat promotion action Has a function to improve at least one selected from the group consisting of a bowel movement promoting action, and a urination promoting (diuretic) action, and by using this,
Exhibits the effects of preventing and improving skin deterioration, treating atopic dermatitis and preventing the onset and worsening, promoting hair growth and preventing hair loss, improving and preventing eczema, promoting bowel movements and promoting urination. Is done.

The preferred dosage of the external preparation for skin of the present invention is
The appropriate amount may be applied once or several times a day to a part or the whole of the affected skin or healthy skin, depending on the kind of the disease and the characteristics of the patient.

In particular, it should be noted that the compound of the present invention represented by the above general formula (I) or a physiologically acceptable salt thereof secretes digestive juices such as gastric acid by transdermal administration. It has the effect of being accelerated and the like, and a substance that can simultaneously expect such an effect by transdermal administration has not been known yet.

[0031]

Embodiments of the present invention will be described below. Incidentally, the numerical values of the prescription in the table are parts by weight.

[0032]

Examples 1 to 5 <Formulation Examples> Skin external preparations (creams) were prepared according to the formulations shown in Table 1 below. That is, each of the component groups (a), (b) and (c) is heated at 80 ° C., (a) is kneaded well, (b) is added thereto, diluted, and (c) Was gradually added and emulsified, followed by stirring and cooling to obtain a skin external preparation.
It is highly safe and has an excellent essence as shown in the following test examples, and is therefore useful as a pharmaceutical composition and as a cosmetic.

[0033]

[Table 1]

[0034]

Examples 6 to 10 <Formulation Examples> A skin external preparation (ointment) was prepared using the components shown in Table 2 below and according to the formulation. That is, each prescription component was weighed into a kneader and kneaded well to obtain an ointment.

[0035]

[Table 2]

[0036]

Examples 11 to 15 <Formulation Example> An external preparation for hair for hair (hair tonic) was prepared using the components shown in Table 3 below and according to the formulation. That is, each formulation component was stirred and solubilized at room temperature to obtain a hair tonic.

[0037]

[Table 3]

[0038]

Examples 16 to 20 <Formulation Examples> Bath ingredients were prepared using the components shown in Table 4 below and according to the formulations. That is, the respective components were kneaded with a kneader to obtain a bath agent.

[0039]

[Table 4]

[0040]

Example 21 <Test Example 1: Effect of improving skin beautifulness> Ten panelists, a group of 23 to 35 year olds suffering from rough skin, applied the skin external preparations (0.02 g) of Examples 1 to 3 twice daily in the morning and evening. Each was applied to the affected area for two months, and the effect of improving skin roughness was evaluated. The evaluation criteria were very improved (gradation 5) to not improved (gradation 0). As a control, a compound represented by the above general formula (I), which is an active ingredient of the present invention, or a physiologically acceptable salt thereof was replaced with water. The results are shown in Table 5 as average scores. This indicates that the external preparation for skin of the present invention has an effect of improving rough skin, that is, has a skin beautiful effect. This shows that the compound of the present invention represented by the above general formula (I) or a physiologically acceptable salt thereof has such an effect.

[0041]

[Table 5]

[0042]

Example 22 <Test Example 2: Hair growth promoting action> The back of 5 mice per group of C3H mice was shaved, and 10 mg of a sample shown in Table 6 below was dissolved or dispersed in 200 µl of physiological saline and applied. The hair growth promoting effect was evaluated by observing the hair growth. The control was vehicle saline only. The evaluation criteria are ++ (score 4): significantly earlier than the control, + (score 2): earlier than the control, ± (score 1): slightly earlier than the control,
-(Score 0): Not earlier than control. The results are shown in Table 6 as average scores. This shows that the compound represented by the above general formula (I) or a physiologically acceptable salt thereof, which is an active ingredient of the external preparation for skin of the present invention, is excellent in hair growth promoting action.

[0043]

[Table 6]

[0044]

Example 23 <Test Example 3: Effect on atopic dermatitis> A group of 10 panelists aged 25 to 48 years old suffering from atopic dermatitis
The external preparation for skin (0.02 g) of the above Examples 1 to 3 was applied to the affected area twice a day and twice a day for 2 months to evaluate the effect of improving atopic dermatitis. The evaluation criteria were very improved (gradation 5) to not improved (gradation 0). As a control, a compound of the present invention represented by the above general formula (I) or a physiologically acceptable salt thereof was replaced with water. The results are shown in Table 7 as average scores. This indicates that the external preparation for skin of the present invention has an effect of improving atopic dermatitis. That is, it is understood that the compound represented by the above general formula (I) of the present invention or a physiologically acceptable salt thereof has such an effect.

[0045]

[Table 7]

[0046]

Example 24 <Test Example 4: Eczema treatment> 18-33 suffering from breakout
A group of 10-year-old panelists applied the skin external preparations of Examples 1 to 3 (0.02 g) twice a day for 2 months to evaluate the eczema improving effect. The evaluation criteria were very improved (gradation 5) to not improved (gradation 0).
As a control, a compound of the present invention represented by the above general formula (I) or a physiologically acceptable salt thereof was replaced with water. The results are shown in Table 8 as average scores. This indicates that the compound represented by the above general formula (I) or a physiologically acceptable salt thereof, which is an active ingredient of the external preparation for skin of the present invention, has an effect of improving eczema.

[0047]

[Table 8]

[0048]

Example 25 <Test Example 5: Gastric secretion promoting action> The secretion of gastric juice was examined using an anesthetized dog. That is, an endoscope with an administration device was introduced into the stomach of a dog anesthetized with a pentobarbitur, and the specimen was used as a sample.
The compound represented by the general formula (I) or a physiologically acceptable salt thereof (10 mg), which is an active ingredient of the external preparation for skin of the present invention shown in (1), is dissolved or dispersed in 200 μl of a 50% aqueous ethanol solution and transdermally applied to the back After administration, the secretion of gastric juice before and after the administration was observed, and the gastric secretion promoting action was evaluated. As a control, only physiological saline was used. Evaluation criteria were as follows: ++ (score 4): gastric secretion increased significantly compared to control, + (score 2): increased gastric secretion compared to control, ± (score 1): slightly increased compared to control ,-(Score 0): the secretion did not increase compared to the control. Table 9 shows the results. This indicates that the compound represented by the above general formula (I) or a physiologically acceptable salt thereof, which is an active ingredient of the present invention, has excellent gastric secretion promoting action.

[0049]

[Table 9]

[0050]

Example 26 <Test Example 6: Effect of promoting bowel movement and urination> ICR mice were bred in metabolic cages. In the administration group, the skin external preparations of Examples 1 to 3 were applied to the shaved back skin as a specimen at a rate of 1 g / day / animal, 0.5 g twice daily in the morning and evening, and transdermally administered for 7 days. . The amount of urine and feces 24 hours after the last dose was monitored. The control group received no specimen. Each group consisted of 10 animals. Table 10 shows the value obtained by dividing the total urine volume of the sample administration group by the total urine volume of the control group and the value obtained by dividing the total feces volume of the sample administration group by the total feces volume of the control group. This shows that the compound represented by the above general formula (I) or a physiologically acceptable salt thereof of the present invention is excellent in the bowel movement promoting action and the urination promoting action (diuretic action).

[0051]

[Table 10]

[0052]

According to the present invention, a beautiful skin effect, a therapeutic effect on atopic dermatitis, a therapeutic effect on a dermatitis group represented by eczema,
Treatment for dermatomycosis, treatment for warts, treatment for pigmentation such as hepatitis, treatment for psoriasis vulgaris, treatment for senile xeroderma, senile keratoma, treatment for skin damage due to physical causes It is possible to provide a skin external preparation capable of improving a tsukusu action selected from the group consisting of a hair growth promoting action, a digestive juice secretion promoting action, a sweating promoting action, a bowel movement promoting action, and a diuretic action.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 233/20 C07C 233/20 // C07C 49/35 49/35 219/10 219/10 (72) Inventor Nobuhiro Ando Kanagawa 27-1 Takashimadai, Kanagawa-ku, Yokohama-shi, Yokohama Research Laboratory, Polar Research Inc. Mitsuo 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pref.

Claims (6)

[Claims] 1. A skin external preparation for improving tsumucus containing one or more active ingredients selected from the group consisting of a compound represented by the following formula (I) and a physiologically acceptable salt thereof. Embedded image [In the formula (I), R ₁ and R ₃ each independently represent a low-chain alkyl group, a low-chain alkyloxy group, a hydroxyl group or a hydrogen atom, R ₂ represents an acyloxy group or a hydroxyl group, and R ₄ represents nitrogen. Represents a carbonylalkenyl group or an alkenylcarbonyl group which may have an atom or an aromatic group. ] 2. The compound represented by the general formula (I)
The capsaicin represented by the following general formula (II), the sinapine represented by the following general formula (III), the curcumin represented by the following general formula (IV), or a low-chain acylated product thereof. The skin external preparation for improving tsukusu according to the above. Embedded image Embedded image Embedded image 3. The composition according to claim 1, which comprises 0.001 to 10% by weight of one or more selected from the group consisting of the compound represented by the general formula (I) and a physiologically acceptable salt thereof. 3. A skin external preparation for improving tsumugi according to 1 or 2. 4. The external preparation for skin according to claim 1, which is a cosmetic. 5. The external preparation for skin according to claim 1, which is a medicament. 6. A beautiful skin effect, an atopic dermatitis treatment effect,
Dermatitis group treatment, dermatomycosis treatment, wart treatment, pigmentation treatment, psoriasis vulgaris, senile xerosis, senile keratoma treatment, skin damage treatment, hair growth The external preparation for skin according to any one of claims 1 to 5, which is used for improving a tsutsuma action selected from the group consisting of a promoting action, a digestive juice secretion promoting action, a sweating promoting action, a bowel movement promoting action, and a diuretic action.