JP3160415B2 - Wrinkle improver and keratosis improver - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a wrinkle improving agent and a keratinizing agent, and more particularly, to a wrinkle improving agent excellent in preventing and improving wrinkles and a keratinizing agent excellent in antidandruff effect and sunburn improving effect. About.

[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 and a decrease in subcutaneous adipose tissue, 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, these methods are generally intended to replenish moisture on the epidermis, especially the surface of the stratum corneum, or to supplement a part of moisturizing components.
Its efficacy and effects were temporary and permanent skin 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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The present invention also provides a wrinkle improver or a keratosis improver comprising the amine derivative represented by the formula (1) or an acid addition salt or quaternized product thereof.

Further, the present invention provides the following general formula (1 ')

[0013]

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The present invention also provides an external preparation for skin containing less than 1% by weight of the amine derivative represented by the formula (1) or an acid addition salt or quaternized product thereof.

A part of the amine derivative (1) used in the present invention has been conventionally used as an intermediate for producing an amide derivative which is an N-acyl derivative thereof (JP-A-63-227514) and a surfactant (specially, JP-A-63-284295), brain function improving agents, antiallergic agents (JP-A-63-179850), transdermal absorption enhancers (JP-A-1-268648) and the like. However, it has never been known that these compounds are effective in improving wrinkles and keratinization.

In the general formula (1), the hydrocarbon group represented by R ¹ may be saturated or unsaturated, and specific examples thereof include methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, dodecyl, Tetradecyl, hexadecyl, eicosyl, methyl-branched isopalmityl, 7-hexadecenyl, 4,8,12-trimethyltridecyl, 4
-Methyl-3-pentenyl, cyclohexyl, phenyl and the like.

In the general formula (1), specific examples of the hydrocarbon group represented by R ² include methyl, ethyl, butyl, pentyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, Groups such as 5-hydroxypentyl.

In the general formula (1), specific examples of the hydrocarbon group represented by R ³ include methyl, ethyl, butyl, hexyl, phenyl, benzyl, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl , 1, 2,
3-trihydroxypropyl, 1,2,3,4-tetrahydroxybutyl, 1,2,3,4,5-pentahydroxypentyl, methoxymethyl, dodecyloxymethyl,
Groups such as tetradecyloxymethyl and methyl-branched isostearyloxymethyl.

In the general formula (1), specific examples of the hydrocarbon group represented by R ⁴ include methyl, ethyl, butyl, hexyl, phenyl, benzyl, hydroxyethyl, 2,3-
Dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl,
And groups such as 2,3,4,5,6-pentahydroxyhexyl.

In the general formula (1), specific examples of R ⁵ include:

[0021]

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And the like. In the general formula (1), X
And the phosphoric acid residue represented by Y may form a salt with a metal or an amine.

Amine derivative (1) used in the present invention
Can be prepared by various known methods, for example, the following reaction formulas I, II or II
I can be manufactured.

[0024]

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(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above). That is, by adding an amine (3-A) to the epoxide (2), A) [Compound of general formula (1) where X = OH and Y = H] can be produced.

[0026]

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(Where X is H or OH, R ¹ , R ² , R
³ , R ⁴ and R ⁵ are as defined above. )

[0028]

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That is, the amide (4) is reduced with LiAlH ₄ or the like to obtain (1-B) [X in the general formula (1).
H or OH, a compound of Y = H, R ³ = H], and the compound (5) is reacted with an amine (3-A) to obtain (1-C) [X = H in the general formula (1). Or a compound of OH, Y = H].

X is -O (O) P (OH) ₂ or Y is-(O) P (OH)
_In the case of ₂ , the amine derivative (1-D) is obtained by converting the amine derivatives (1-A) to (1-C) obtained by the methods I to III into H ₃ P
It can be produced by phosphorylation with a phosphorylating agent such as O ₄ , P ₂ O ₅ and POCl ₃ .

The amine derivative (1) thus obtained may be further subjected to an inorganic acid salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like, or succinic acid, fumaric acid, hexadecanoic acid, octadecanoic acid by a conventional method, if necessary. , Lactic acid, glycolic acid,
Organic hydrochloric acid such as citric acid, tartaric acid and benzoic acid can also be used. Further, it can be converted to a quaternary compound by reacting with a lower alkyl halide.

The amine derivative (1) or an acid addition salt or quaternary compound thereof has the effect of suppressing the generation of wrinkles and eliminating wrinkles, and thus can be used as a wrinkle improver. The wrinkle improving agent of the present invention can be administered by internal use, external use, or any other method. In addition to the amine derivative (1) or an acid addition salt or quaternized product thereof as an active ingredient, a commonly used anti-wrinkle agent can be used. Inflammatory agents, vitamins, and the like can be appropriately added as necessary.

On the other hand, the amine derivative (1) or an acid addition salt or quaternary compound thereof has an action 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. The keratinizing agent of the present invention can be administered by internal administration, external use, or any other method, similarly to the wrinkle improving agent, and as the active ingredient, the amine derivative (1) or an acid addition salt or quaternary compound thereof In addition to the above, commonly used anti-inflammatory agents, vitamins and the like can be appropriately compounded as needed.

The amine derivative (1) of the present invention or an acid addition salt 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 external preparation for medicated skin and the external preparation for skin for cosmetics 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, for example,
An analgesic antiphlogistic, an analgesic, a germicidal antiseptic, 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, 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 styling It can be used as an agent, a hair restorer and 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 its acid addition salt or quaternized compound in the external preparation for skin is 0.0001 to less than 1% by weight of the total composition in the case of the external preparation for emulsion. (Hereinafter, referred to as “%”), and especially 0.
0001-0.1% is preferable. In the case of an oily skin external preparation based on a liquid hydrocarbon such as squalane, it is 0.0001 to 10% of the total composition amount, and particularly preferably 0.0001 to 0.1%.

[0039]

The wrinkle improver of the present invention has a remarkable effect of suppressing the generation of wrinkles and eliminating wrinkles. On the other hand, the keratinizing agent of the present invention has a remarkable inhibitory effect on parakeratosis due to the influence of ultraviolet rays and various other factors, epidermal hyperplasia, abnormal lipid metabolism, etc. It restores and further contributes to maintaining homeostasis, and has particularly excellent antidandruff effect and skin tanning improvement effect.

[0040]

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 Production of 1- (2-hydroxyethylamino) -2-octadecanol (1a)

[0042]

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In a 300 ml flask equipped with a stirrer and a dropping funnel, 45.8 g (0.75 mol) of ethanolamine was added.
), 9 g of ethanol and stirring at 80 ° C.
13.4 g (50 mmol) of 1,2-epoxyoctadecane
Was added dropwise over 2 hours. Water was added to the reaction mixture, the resulting white crystals were filtered, washed with water, and then recrystallized from methanol to give 12.3 g of the title compound (1a).
(Yield: 74.6%).

Colorless solid Melting point: 84.5-86.0 ° C. IR (KBr, cm ⁻¹ ): 3400, 2920, 285
2,1472,1126,1076. ¹ H-NMR (CDCl ₃ , δ): 0.82-0.96
(M, 3H), 1.14 to 1.51 (m, 31H),
2.42-2.88 (m, 7H), 3.69 (t, J =
4.8 Hz, 2H).

Production Example 2 Production of 1- [N- (2-hydroxyethyl) -N-methylamino) -2-octadecanol (1b)

[0046]

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In a 100 ml flask equipped with a stirrer,
26.85 g of 2-epoxyoctadecane (0.1 mol
), 7.51 g of N-methylethanolamine (0.1 m
ol) and 50 ml of ethanol and stirred at 80 ° C. for 18 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 23.0 g (yield 67%) of the title compound (1b).

Colorless solid Melting point: 39.0-40.6 ° C IR (NaCl, cm ^-1 ): 3392, 2920, 285
2,1660,1466,1300,1080,104
2,874. ¹ H-NMR (CDCl ₃ , δ): 0.82-0.96
(M, 3H), 1.12 to 1.55 (m, 30H),
2.33 (s, 3H), 2.34-2.77 (m, 6
H), 3.55-3.84 (m, 3H).

Production Example 3 2- (2-hydroxyethylamino) -3,7,11,
Production of 15-tetramethyl-1,3-hexadecanediol (1c)

[0050]

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In a 100 ml two-necked flask equipped with a stirrer and a dropping funnel, 8.79 g (0.1%) of ethanolamine was added.
4mol) and 20.0 g of ethanol, and the mixture was heated and stirred at 80 ° C. under a nitrogen atmosphere.
3.01 g (9.6 mmol) of 7,11,15-tetramethyl-1,3-hexadecanediol (phytyl oxide)
l) was added dropwise over 1 hour. After further heating and stirring for 2 hours, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography, and 3.02 g of the title compound was obtained.
(84% yield).

Yellow solid Melting point: 49.1-50.2 ° C IR (KBr, cm ^-1 ): 3388, 3276, 292
0, 2852, 1464, 1380, 1058, 103
4. ¹ H-NMR (CDCl ₃ , δ): 0.80-0.95
(M, 15H), 0.98-1.68 (m, 21H),
2.44 (t, J = 4.3 Hz, 1H), 2.72-
3.08 (m, 6H), 3.58-3.66 (m, 4
H).

Production Example 4 Production of 3- (2-hydroxyethylamino) -4-tetradecyloxy-2-methyl-2-butanol (1d)

[0054]

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In a 100 ml two-necked flask equipped with a stirrer and a dropping funnel, 15.3 g of ethanolamine (16.
7 mmol), 5.0 g of ethanol and 8 g under nitrogen atmosphere.
While heating and stirring at 0 ° C., 1-tetradecyloxy-3-
5.00 g of methyl-2-butene oxide (16.7 mmol
The ethanol solution of l) was added dropwise over 3 hours. One more
After heating and stirring for 6 hours, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain 3.47 g (yield 58%) of the title compound (1d).

Light yellow oil IR (NaCl, cm ^-1 ): 3384, 2924, 285
2,1462,1374,1114,1060. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.4 Hz, 3H), 1.06-1.72 (m, 30
H), 2.55 (dd, J = 4.1 Hz, 6.4 Hz,
1H), 2.63-3.05 (m, 5H), 3.30-
3.80 (m, 6H).

Production Example 5 In Production Example 4, 1-tetradecyloxy-3-methyl-
The reaction was carried out using 1-tetradecyloxy-2-butene oxide instead of 2-butene oxide to obtain the following amine derivative (1e).

[0058]

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Light yellow solid Melting point: 54.4-55.4 ° C IR (KBr, cm ^-1 ): 3280, 2920, 285
2,1468,1374,1116,1060. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.4 Hz, 3H), 1.08-1.68 (m, 27
H), 2.41 (brs, 3H), 2.65 (ddd,
J = 6.2 Hz, 4.1 Hz, 4.1 Hz, 1H),
2.83 (t, J = 2.3 Hz, 2H), 3.30 −
3.78 (m, 6H), 3.90 (dq, J = 3.9H)
z, 6.2 Hz, 1H).

Production Example 6 Production of 2- (9-octadecenylamino) -1-ethanol (1f)

[0061]

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In a 100 ml eggplant flask equipped with a stirrer, put L
1.40 g (37.2 mmol) of iAlH ₄ and 30 ml of tetrahydrofuran were charged, and a solution of 1.67 g (5.12 mmol) of N- (9-octadecenoyl) ethanolamine in tetrahydrofuran was stirred in a N ₂ atmosphere at room temperature. In minutes. After heating to 60 ° C. and stirring for 16 hours, the mixture was cooled to room temperature, and 14 g of a 5% KOH aqueous solution.
Was added. The precipitated salt was separated by filtration and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.96 g (yield 65%) of the title compound.

Yellow oil IR (NaCl, cm ^-1 ): 3328, 2920, 285
2,1458,1376,1118,1060. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.6 Hz, 3H), 1.15-1.65 (m, 24
H), 1.88-2.15 (m, 4H), 2.35 (b
rs, 2H), 2.61 (t, J = 7.3 Hz, 2
H), 2.76 (t, J = 5.3 Hz, 2H), 3.6
4 (t, J = 5.3 Hz, 2H), 5.22-5.48
(M, 2H).

Production Examples 7 and 8 In Production Example 6, the same reaction was carried out using N-octadecanoylethanolamine and N-methyl branched isostearylethanolamine in place of N- (9-octadecenoyl) ethanolamine. The following amine derivatives (1g) and (1i) were synthesized.

[0065]

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(1 g) Colorless solid Melting point: 57.3-58.2 ° C. IR (KBr, cm ⁻¹ ): 3370, 2914, 284
8, 1467, 1035. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.7 Hz, 3H), 1.04-1.75 (m, 32
H), 2.42 (brs, 2H), 2.61 (t, J =
7.3 Hz, 2H), 2.77 (t, J = 5.1 Hz,
2H), 3.65 (t, J = 5.1 Hz, 2H).

(1h) Colorless oil IR (NaCl, cm ^-1 ): 3196, 2924, 285
6, 1460, 1376, 1122, 1062. ¹ H-NMR (CDCl ₃ , δ): 0.77-1.00
(M, 6H), 1.14-1.78 (m, 29H),
2.24-2.56 (m, 2H), 2.62 (t, J =
7.3 Hz, 2H), 2.77 (t, J = 5.1 Hz,
2H). 3.65 (t, J = 5.1 Hz, 2H).

Production Example 9 2- [N- (2-hydroxyoctadecyl) -N-phosphate
-Methylamino] ethyl monosodium salt [(1h) monosodium salt]

[0069]

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In a 200 ml flask equipped with a stirrer, 5.10 g (14.8 g) of the amine derivative (1b) obtained in Production Example 2.
mmol), 50 ml of tetrahydrofuran, 85% phosphoric acid 1.
95 g (16.9 mmol) was charged and stirred at room temperature for 20 minutes. Next, 3.54 g (30.7 mmol) of P ₂ O ₅ was added,
The mixture was stirred at 65 ° C. for 7 hours, allowed to cool, added with 0.56 g of water, and stirred for 30 minutes. Next, 2.38 g of NaOH and 3 g of water were added thereto, stirred for 30 minutes, and concentrated under reduced pressure. The obtained residue was extracted with ethanol using a Soxhlet extractor, the solvent was distilled off, and the residue was purified by column chromatography to give 0.75 g of the title compound (yield 11).
%).

Colorless solid IR (KBr, cm ^-1 ): 3296, 2920, 285
2,1470,1148,1074,938. ¹ H-NMR (CD ₃ OD, δ): 0.78-0.98
(M, 3H), 1.04-1.87 (m, 30H),
2.82-3.68 (m, 7H), 3.75-4.32
(M, 3H).

Example 1 A treatment for wrinkles generated in a hairless mouse by UVB irradiation
Action of Min Derivative: (1) Hairless mouse (HR / ICR, 9 weeks at the start of experiment)
Age), using 6 Toshiba health line lamps 20SE
VB light was irradiated three times a week. Energy amount is TOKYO
OPTICAL UV-Radiometer
It measured using UVR-305 / 365D. One illumination
The irradiation amount should be 1MED or less, 0.28mM / cm ^TwoEnergy
The amount was 65 mJ. Irradiation period is 20 weeks, hairless
After confirming that wrinkles are formed on the back of the mouse,
Amine derivative of 0.025% concentration divided into groups of 8 animals
80 μl of the ethanol solution of (1a) to (1h) was added weekly.
The application was continued five times for six weeks. Etano as control
In the same manner as the sample. End of application
After completion, the degree of wrinkles is visually checked according to the following criteria (wrinkle finger
Number). Table 1 shows the results.

(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.

Further, in order to analyze the details of wrinkles, skin replicas of each mouse were collected from three locations with a size of 1 cm ² in diameter 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. The results are shown in Table 1.

[0075]

[Table 1]

As is evident from the results shown in Table 1, the wrinkles generated on the back of the hairless mouse can be eliminated by applying the amine derivatives (1a) to (1h).

Example 2 Inhibitory effect of amine derivative 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 measurement) Keratinocytes cultured in a proliferating 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 had been added was added to replace the medium. Thereafter, the amine derivatives (1a) to (1h) obtained in the above Production Examples were added. Further, 0.2 μCi / ml [ ³ H] thymidine was added over time, followed by incubation for 4 hours. Thereafter, the supernatant was removed by suction, and PBS was removed.
After washing three times with (−), 500 μl of 2N NaOH was added. After incubation at 37 ° C. for 10 minutes, the same amount of 2N HCl was added for neutralization, and 4 ml of ice-cooled 10% trichloroacetic acid was added, followed by standing 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, the glass filter was air-dried, and its radioactivity was measured with a liquid scintillation counter to calculate the incorporation of thymidine into the cells. Table 2 shows the results.

[0079]

[Table 2]

From Table 2, it can be seen that the incorporation of thymidine is significantly reduced by the addition of the above amine derivative.
It was revealed that DNA synthesis of human keratinocytes was inhibited. Observation of the human keratinocytes treated under the same conditions on day 4 revealed 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.

[0082]

(Composition) (% by weight) (1) Amine derivative (1a) 0.01 (2) Cholesterol 0.5 (3) Cholesterol isostearate 1.0 (4) Polyether-modified silicone 1.5 ( 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 heated to 80 ° C. to dissolve, and (8) to (11) were added thereto and mixed uniformly to prepare a W / O cream.

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

[0085]

(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 (1e) 0.001 (7) Cholesterol 1.5 (8) Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8 5.0 (10) Methyl polysiloxane 5.0 (11) Glycerin 5.0 (12) Purified water balance

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

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

[0088]

(Composition) (% by weight) (1) Amine derivative (1d) 0.05 (2) Silicon-coated zinc oxide 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 to 80 ° C. to dissolve them, and (8) to (10) were added and uniformly mixed to prepare a moisturizing sunscreen cream.

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

[0091]

(Composition) (% by weight) (1) Amine derivative (1 h) Monosodium salt 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (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.

[0094]

(Composition) (% by weight) (1) Amine derivative (1f) 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 and dissolved at 80 ° C., 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, epidermal hyperplasia and abnormal lipid metabolism, and recovering normal function and maintaining homeostasis. It was excellent.

Continued on the front page (72) Inventor Kazuhiko Higuchi 4594 Hanawa, Kaimachi-cho, Haga-gun, Tochigi Pref. (72) Inventor Yoshinori Takema 2606-6, Akabane, Kaiga-cho, Haga-gun, Tochigi (72) Inventor Tsutomu Fujimura Kaito-cho, Haga-gun, Tochigi 4594 Hanawa-shi (72) Inventor Genji Imokawa 1022-89 Himurocho, Utsunomiya-shi, Tochigi Prefecture (56) References JP-A-1-268648 (JP, A) Patent 2699132 (JP, B2) Patent 2934441 (JP, B2) ( 58) Field surveyed (Int. Cl. ⁷ , DB name) A61K ^7/ 00-7/50 CA (STN) WPI (DIALOG) EPAT (QUESTEL)

Claims (3)

(57) [Claims] [Claim 1] The following general formula (1) A wrinkle improver comprising an amine derivative represented by the formula: or an acid addition salt or quaternary compound thereof. 2. A keratinizing agent comprising the amine derivative (1) according to claim 1, or an acid addition salt or quaternary compound thereof. 3. The following general formula (1 ′): An external preparation for skin containing less than 1% by weight of an amine derivative represented by the formula or an acid addition salt or quaternary compound thereof