JP3215534B2 - External preparation for skin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for skin which is excellent in the effect of preventing and improving wrinkles, and an external preparation for skin which enables maintenance of the normal function of the skin and which has an excellent antidandruff effect and an improvement effect after sunburn. .

[0002]

2. Description of the Related Art In recent years,
Maintaining healthy and beautiful skin is a major concern for men and women of all ages. However, the skin is delicately affected by temperature, humidity, ultraviolet rays, cosmetics, aging, illness, stress, eating habits, etc. Therefore, various functions of the skin (to prevent loss of moisture etc. from the living body, Various functions such as the function of maintaining the body, the function of protecting the body from physical and chemical stimuli from the outside world and various bacteria, the function of maintaining the elasticity of the skin and determining the surface morphology, etc.), the aging of the skin, etc. Trouble occurs.

[0003] Of these, wrinkles, one of the problems of the dermis, occur due to aging of the skin due to aging or sunlight. In other words, the cells that make up the dermal fibrous tissue become smaller and smaller with increasing sun exposure and age.
In particular, collagen fibers are greatly lost, and the skin ages due to degeneration of the dermis, decrease in subcutaneous adipose tissue, etc., which mainly causes wrinkles, relaxation and loss of elasticity. Hitherto, various compositions and methods have been proposed for suppressing or treating wrinkles due to such an aging effect (Japanese Patent Application Laid-Open No. Sho 6).
JP-A-2-185005, JP-A-62-502546, JP-A-2-72157, JP-A-2-288
822, etc.).

[0004] However, none of them has a satisfactory effect of improving wrinkles.

On the other hand, vulnerable skin troubles such as dry, greasy skin and dandruff in the epidermis are caused by changes in the external environment (seasonal changes, ultraviolet rays, etc.) and fluctuations in physiological functions (associated with aging and diseases).
Such abnormalities occur in the skin tissue due to factors inside and outside the body acting on the living body, such as skin hypertrophy and parakeratosis induced by these factors. The main attempts to prevent and improve such skin troubles are to apply a synthetic or natural moisturizing component to prevent the skin from drying and increase the moisturizing ability of the skin, and to apply a blood circulation enhancer to improve blood circulation. Has been done.

However, these methods have various problems in terms of the effects of preventing and improving various skin troubles, their persistence, and the stability and safety of drugs. That is, since these methods generally replenish moisture on the epidermis, particularly on the surface of the stratum corneum, or supplement a part of moisturizing components, the effects and effects thereof are temporary and permanent. The improvement could not be expected.

[0007] Therefore, it is excellent in the action of suppressing and eliminating wrinkles. On the other hand, the skin has parakeratosis, thickened epidermis,
There has been a demand for the development of a substance having a remarkable inhibitory action on lipid metabolism abnormality and the like.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies in view of such circumstances, and as a result, have found that the specific amine derivative described below has a remarkable effect on the improvement of wrinkles and keratinization. Was completed.

That is, the present invention provides the following general formula (1)

[0010]

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(Wherein, R ¹ represents a linear saturated hydrocarbon group which may have a hydroxyl group having 7 to 24 carbon atoms, and R ² and R ³ are the same or different and each represents a hydrogen atom or a carbon atom. Number 1
10 represents a hydrocarbon group optionally having 1 or 2 or more hydroxyl groups; R ⁴ represents a hydrocarbon group optionally having 1 or 2 or more hydroxyl groups having 2 to 6 carbon atoms; Is 2
An external preparation for skin containing an amine derivative represented by the following formula (indicating an integer of 6) or an acid addition salt or quaternary compound thereof (however,
Hair styling agent). The present invention also provides a wrinkle improver and a keratosis improver comprising the amine derivative represented by the general formula (1) or an acid addition salt or quaternary compound thereof.

[0012] Among the amine derivatives (1) used in the present invention, some are known compounds, and their use for surfactants and the like is conventionally known (see "Oil Chemistry", Vol. 27, p. 793).
Published by Japan Petrochemical Association (1978). However, the effects of these compounds on wrinkle improvement and keratinization improvement were not known at all.

The hetero atom contained in R ¹ of the amine derivative represented by the general formula (1) includes an oxygen atom, a sulfur atom, a nitrogen atom, a silicon atom and the like, and an oxygen atom is particularly preferable. In the general formula (1), R ¹ is a saturated or unsaturated hydrocarbon group, and specific examples thereof include methyl, ethyl, propyl, pentyl, heptyl, nonyl,
Undecyl, tridecyl, pentadecyl, heptadecyl, hentriacontyl, methyl-branched isoheptadecyl, hepta-3-yl, heptadec-8-yl, 8-heptadecenyl, 8,11-heptadecadienyl, 9-decenyl, cyclohexyl, phenyl, 8 -Hydroxyoctyl, 11-hydroxyundecyl, 14-hydroxytetradecyl, 15-hydroxypentadecyl, 11
-Hydroxyheptadecyl, 8,9-dihydroxyheptadecyl, 11-hydroxy-8-heptadecenyl, 1
1-methoxyheptadecyl, 9- (2-ethylhexyl) -nonyl, 10-carboxydecyl, 10-butoxycarbonyldecyl, 10- (2-ethylhexanoylamino) decyl, 10- (butyldimethylsilyl) decyl, 8, And groups such as 9-isopropylidenedioxyheptadecyl.

In the general formula (1), specific examples of R ² and R ³ include a hydrogen atom and methyl, ethyl, butyl, hexyl,
Phenyl, benzyl, hydroxyethyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl, 2,
Groups such as 3,4,5,6-pentahydroxyhexyl are exemplified.

In the general formula (1), specific examples of R ⁴ include

[0016]

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[0017] In the general formula (1), n is particularly preferably 2 or 3.

Amine derivative (1) used in the present invention
Is particularly preferably (1 ′) wherein R ¹ is a linear or branched hydrocarbon group containing an oxygen atom having 7 to 24 carbon atoms.

Amine derivative (1) used in the present invention
Is synthesized by various known methods. For example, it is synthesized by reacting an ester (2) with an amine (3) in the presence of a base catalyst as represented by the following reaction formula.

[0020]

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(Wherein R ⁵ represents a lower alkyl group;
R ¹ , R ² , R ³ and R ⁴ are as defined above. )

The amine derivative (1) thus obtained is
In addition, if necessary, hydrochloric acid, sulfuric acid, nitric acid, inorganic acid salts such as phosphoric acid or succinic acid, fumaric acid, hexadecanoic acid, octadecanoic acid, lactic acid, glycolic acid, citric acid, according to a conventional method, if necessary.
Organic salts such as tartaric acid and benzoic acid can be used.

Further, by reacting with a lower alkyl halide, a quaternary compound can be obtained.

The amine derivative (1) or (1 ')
Or, the acid addition salt or quaternary compound thereof suppresses the generation of wrinkles, and has an action of eliminating wrinkles,
It can be used as a wrinkle improver. As a wrinkle improving agent, it is usually used externally, but it can also be administered internally, and as an active ingredient, it is usually used in addition to the above-mentioned amine derivative (1) or (1 ') or an acid addition salt or quaternary compound thereof. The anti-inflammatory agent, vitamins, and the like to be used can be appropriately added as necessary.

On the other hand, the above-mentioned amine derivative (1) or (1 ′) or an acid addition salt or quaternary compound thereof has an effect of suppressing epidermal cell DNA synthesis, promoting differentiation induction, and suppressing epidermal hyperplasia. That is, it has an effect of normalizing abnormal keratinization of epidermal cells of the skin, and can be used as a keratinizing agent. As the keratinization improver, like the wrinkle improver,
It is used externally, but can also be administered internally, and as an active ingredient, in addition to the amine derivative (1) or (1 ′) or an acid addition salt or quaternary compound thereof, commonly used anti-inflammatory agents, vitamins And the like can be appropriately compounded as needed.

The amine derivative (1) or (1 ') of the present invention or an acid adduct or quaternary compound thereof is blended in a skin external preparation. As the external preparation for skin, various forms of use such as external preparation for medicinal skin, external preparation for skin for cosmetics, and cosmetics can be used.

Examples of the medicated skin external preparation and the cosmetic skin external preparation include various ointments containing a pharmaceutically active ingredient.

The ointment may be any of those based on an oily base and those based on an oil / water or water / oil type emulsion base. The oily base is not particularly limited and includes, for example, vegetable oil, animal oil, synthetic oil, fatty acid, and natural or synthetic glyceride.
The medicinal component is not particularly limited, and for example, an analgesic / inflammatory agent, an analgesic, a disinfectant, an astringent, an emollient, a hormonal agent, a vitamin, and the like can be used as needed. .

When used as cosmetics, oils, humectants, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners, pigments, and the like commonly used as cosmetic ingredients are used. Flavors and the like can be arbitrarily combined and blended. As cosmetics, there are various uses and forms, for example, water / oil or oil / water type emulsified cosmetics, creams, emulsions, lotions, oily cosmetics, lipsticks, foundations, skin cleansers, hair tonics, hair restorers , Can be used as a hair restorer. The external preparation for skin of the present invention can be prepared into the above various forms by a conventional method.

The amount of the amine derivative (1) or (1 ') or an acid addition salt or quaternary compound thereof to be added to the external preparation for skin is not particularly limited. 0.0001 to 5% by weight of the total composition
(Hereinafter, referred to as “%”), particularly 0.0001 to
0.1% is preferred. In the case of oily skin external preparations based on liquid hydrocarbons such as squalane, the amount is 0.0001 to 10% of the total composition, respectively, and particularly 0.001 to 10%.
01-0.1% is preferable.

[0031]

EFFECT OF THE INVENTION The external preparation for skin of the present invention has an excellent effect of remarkably suppressing the generation of wrinkles and eliminating wrinkles. On the other hand, the skin external preparation of the present invention has a remarkable inhibitory effect on parakeratosis, epidermal hyperplasia, abnormal lipid metabolism, etc. due to the influence of ultraviolet rays and various other factors, and restores the normal function of the skin. It also contributes to the maintenance of homeostasis and has a particularly excellent antidandruff effect and an effect of improving skin after sunburn.

[0032]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Production Example 1 N- [2- (2-hydroxyethylamino) ethyl]-
Production of 12-hydroxyoctadecanamide (1'a)

[0034]

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30 ml of 2 equipped with a stirrer and a dropping funnel
In a flask with aminoethylaminoethanol 2.08
g (20 mmol) and 0.054 g of sodium methoxide
(1 mmol), a solution of 3.29 g (10 mmol) of ethyl 12-hydroxystearate in 10 ml of THF was added dropwise thereto over 2 hours while heating and stirring at 80 ° C. under a N ₂ atmosphere. Stir for 13 hours.
After completion of the reaction, the reaction mixture was poured into 500 ml of water, and the resulting precipitate was purified by silica gel flash column chromatography to give the title compound (1'a) 2.85.
g was obtained (yield 74%).

Colorless powder Melting point: 101.9-102.4 ° C IR (KBr, cm ^-1 ): 3292, 2920, 2852, 1642, 1552, 1470,
_{^{1068. 1 H-NMR (CDCl 3}} , δ): 0.90 (t, J = 6.6Hz, 3H), 1.18-1.71
(m, 30H), 2.19 (t, J = 7.8Hz, 2H), 2.70-2.77 (m, 4H), 3.29-
3.68 (m, 5H).

Preparation Example 2 The same reaction as in Preparation Example 1 was carried out except that methyl 12-hydroxydodecanoate was used instead of ethyl 12-hydroxystearate, to obtain the following amine derivative (1'b).

[0038]

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Light yellow solid Melting point: 73.4-74.0 ° C IR (KBr, cm ^-1 ): 3284, 2924, 2848, 1628, 1554, 1468,
^{1388, 1040, 956. 1 H-} NMR (CDCl 3, δ): 0.82-1.74 (m, 18H), 2.18 (t, J = 7.4H
(z, 2H), 2.75-2.82 (m, 4H), 3.29-3.69 (m, 6H).

Example 1 Effect of amine derivative on wrinkles formed in hairless mice by UVB irradiation: Hairless mice (HR / ICR, 9 weeks old at the start of the experiment) were treated with a Toshiba Health Line lamp 20SE for 6 weeks.
This was used to irradiate UVB light three times a week. The amount of energy is UV-radiom manufactured by TOKYO OPTICAL.
The measurement was carried out using an ETER UVR-305 / 365D. One irradiation dose is 1 MED or less, 0.28 mM / cm
The energy amount of ² was 65 mJ. The irradiation period was 20 weeks, and after confirming that wrinkles were formed on the back of the hairless mouse, the hairless mice were divided into groups of 8 animals and each of the amine derivatives having a 0.025% concentration (1'a) and (1'b) Of ethanol solution was continued to be applied 80 μl 5 times a week for 6 weeks.
As a control, 80 μl of ethanol alone was applied similarly to the sample. After the completion of the application, the degree of wrinkles was visually evaluated according to the following criteria (wrinkle index). Table 1 shows the results
Shown in

(Wrinkle Index Evaluation Criteria) 1: Wrinkles completely disappear. 2: I do not know whether there are wrinkles or not. 3: There are some wrinkles. 4: There are very wrinkles.

[0042]

[Table 1]

As is clear from the results shown in Table 1, the wrinkles generated on the back of the hairless mouse could be eliminated by applying each of the amine derivatives (1'a) and (1'b).

Further, in order to analyze details of wrinkles, replicas of the skin were collected from three places with a size of 1 cm ² in diameter for each mouse using a hydrophilic exaflex hydrophilic vinyl silicone impression material. The replica was placed in a horizontal state and irradiated with light from a direction of 30 degrees, and the ratio of shadow formed by wrinkling was determined as an area ratio using an image analyzer. Table 2 shows the results.

[0045]

[Table 2]

As is clear from the results in Table 2, the wrinkles formed on the back of the hairless mouse can be eliminated by applying the amine derivatives (1'a) and (1'b).

Example 2 Inhibitory effect of amine derivatives on DNA synthesis of keratinocytes (1) Method

A) Culture of human epidermal keratinocytes Human normal keratinocytes (trade name: Epipack) sold by Kurabo Industries, Ltd. were used. The cells were maintained and passaged using a medium for human normal keratinocytes (trade name: K-GM) sold by the company. b) Measurement of DNA synthesis (thymidine incorporation) Keratinocytes cultured in a growing state in a 24-well plate were used. First, the medium in each well was removed by suction, and 450 μl of K-GM to which no pituitary extract was added was added to replace the medium. Thereafter, the amine derivatives (1′a) and (1′b) obtained in the above Production Examples were added. further,
Over time, 0.2 μCi / ml [ ³ H] thymidine was added and 4
Incubated for hours. Thereafter, the supernatant is removed by suction,
After washing three times with PBS (−), 500 μl of 2N NaO
H was added. After incubating at 37 ° C for 10 minutes,
The same amount of 2N HCl was added for neutralization, 4 ml of ice-cooled 10% trichloroacetic acid was added, and the mixture was allowed to stand for 30 minutes. After collecting the precipitate with a glass filter, the precipitate was washed three times with 3 ml of ice-cooled 10% trichloroacetic acid. After washing the filter once with 3 ml of ice-cold ethanol, air-dry the glass filter,
Thymidine incorporation into cells was calculated by measuring its radioactivity with a liquid scintillation counter.

[0049]

[Table 3]

From Table 3, it can be seen that the incorporation of thymidine is significantly reduced by the addition of the amine derivative,
It was revealed that DNA synthesis of human keratinocytes was inhibited. In addition, observation of human epidermal keratinocytes treated under the same conditions on day 4 showed that most of the cells became insoluble membranes (cornified envelopes) and were keratinized. From this, it became clear that the present amine derivative has an activity of promoting keratinization of the epidermis.

Example 3 A W / O cream having the following composition was obtained by the following production method.

[0052]

(Composition) (% by weight) (1) Amine derivative (1'a) 0.08 (2) Cholesterol 0.5 (3) Cholesterol isostearate 1.0 (4) Polyether-modified silicone 5 (5) Cyclic silicone 20.0 (6) Methyl phenyl polysiloxane 2.0 (7) Methyl polysiloxane 2.0 (8) Magnesium sulfate 0.5 (9) 55% ethanol 5.0 (10) Carboxymethyl Chitin (Ichimaru Falcos, Chitin Liquid HV) 0.5 (11) Purified water balance

(Manufacturing method) (1) to (7) were dissolved by heating to 80 ° C., and (8) to (11) were added and uniformly mixed to prepare a W / O cream.

Example 4 An O / W cream having the following composition was obtained by the following production method.

[0055]

(Table 5) (Composition) (% by weight) (1) Polyoxyethylene (10) hydrogenated castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Stearoyl methyl taurine sodium 0.5 (4) Set Stearyl alcohol 2.0 (5) Stearic acid 1.8 (6) Amine derivative (1'b) 0.001 (7) Cholesterol 1.5 (8) Cholesteryl isostearate 1.0 (9) Neopentyl dicaprate Glycol 8.0 (10) Methyl polysiloxane 5.0 (11) Glycerin 5.0 (12) Purified water Balance

(Manufacturing method) (1) to (10) were heated to 80 ° C. and dissolved, and (11) to (12) were added thereto and mixed uniformly to prepare an O / W cream.

Example 5 A sunscreen cream having the following composition was obtained by the following production method.

[0058]

(Composition) (% by weight) (1) Amine derivative (1'b) 0.05 (2) Zinc oxide coated with silicon 7.0 (3) 2-Ethylhexyl p-methoxycinnamate 3.0 (4) ) Cholesteryl isostearate 1.0 (5) Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7) Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerin 5.0 (10) Purified water balance

(Production method) (1) to (7) were heated and dissolved at 80 ° C., and (8) to (10) were added thereto and mixed uniformly to prepare a moisturizing sunscreen cream.

Example 6 A pack having the following composition was obtained by the following production method.

[0061]

(Composition) (% by weight) (1) amine derivative (1′b) hydrochloride 0.05 (2) polyvinyl alcohol 15.0 (3) sodium carboxymethylcellulose 5.0 (4) propylene glycol 0 (5) Ethanol 8.0 (6) Purified water balance (7) Fragrance 0.5 (8) Preservative, oxidizing agent

(Production method) (1) to (8) were heated to 70 ° C. to dissolve and then cooled to produce a pack.

Example 7 An ointment having the following composition was obtained by the following production method.

[0064]

(Composition) (% by weight) (1) Amine derivative (1′b) 0.075 (2) White petrolatum balance (3) Cholesteryl isostearate 3.0 (4) Liquid paraffin 10.0 (5) ) Glyceryl ether 1.0 (6) Glycerin 10.0

(Production method) (1) to (6) were heated to 80 ° C. to dissolve and then cooled to prepare an ointment.

The skin external preparations of the present invention prepared in Examples 3 to 7 are excellent in the effects of suppressing and eliminating wrinkles, suppressing parakeratosis of the skin, hyperplasia of the epidermis, abnormalities in lipid metabolism, and restoring normal function and homeostasis. It was excellent for maintenance.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/16 A61K 31/16 A61P 17/00 A61P 17/00 (72) Inventor Kazuhiko Higuchi 4594 Hanawa, Kaimachi-shi, Haga-gun, Tochigi ( 72) Inventor Yoshinori Takema 2606-6, Akabane, Kaiga-cho, Haga-gun, Tochigi (72) Inventor Hiroyuki Osu 2606-6, Akabane, Kai-machi, Haga-gun, Tochigi 89 (56) References JP-A-3-128309 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K ^7/ 00-7/50 A61K 31/16 CA (STN)

Claims (3)

(57) [Claims] [Claim 1] The following general formula (1) (In the formula, R ¹ represents a linear saturated hydrocarbon group which may have a hydroxyl group having 7 to 24 carbon atoms, and R ² and R ³ are the same or different and each represent a hydrogen atom or a carbon atom having 1 to 24 carbon atoms. 10 represents a hydrocarbon group optionally having 1 or 2 or more hydroxyl groups; R ⁴ represents a hydrocarbon group optionally having 1 or 2 or more hydroxyl groups having 2 to 6 carbon atoms; Is an integer of 2 to 6), or an external preparation for skin containing an amine derivative or an acid addition salt or quaternized product thereof (however, excluding a hair styling agent). 2. A wrinkle improver comprising the amine derivative according to claim 1 or an acid addition salt or quaternary compound thereof. 3. A keratinizing agent comprising the amine derivative according to claim 1 or an acid addition salt or quaternary compound thereof.