JP2003012558A - Hardenable preparation for external use for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide hardenable preparation for external use for the skin having high safety and exhibiting high efficacy to the skin. SOLUTION: This hardenable preparation for external use for the skin is obtained by compounding a hardenable base with powder sucking or adsorbing a specific enzyme and a 2nd kind of powder having inhibitory or activating effect for the enzyme.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to a solidifying external preparation for skin,
In particular, it relates to a powder having functionality for living bodies.

2. Description of the Related Art Conventionally, various therapeutic agents, external preparations for skin, cosmetics and the like have been known as those having an improving / preventing effect on skin diseases, rough skin, acne and the like. Active ingredients in these conventional drugs and cosmetics include anti-inflammatory agents and extracts of plants and animals that are said to have anti-inflammatory effects, or amino acids and polysaccharides with high moisturizing and water retaining effects, lipids, natural polymers, etc. It has been used because of its excellent ability to prevent inflammation in (affected area) and loss of water in the stratum corneum. on the other hand,
For example, in the case of atopic dermatitis or pathological dermatitis such as severe acne skin, it goes without saying that it is not pathological, but so-called sensitive skin that shows a hypersensitive reaction to environmental changes is also a problem. These skins may have hypersensitivity symptoms and irritation to various ingredients, and thus it is necessary to select the active ingredients with particular caution. In addition, molecular drugs such as organic polymers, which have been conventionally studied as active ingredients for the purpose of improving skin roughness, are presumed to penetrate the skin and are percutaneously absorbed even inside the skin. May have an impact. On the other hand, if a solid substance such as powder that does not penetrate into the skin can be used as an active ingredient for improving rough skin, the safety can be further enhanced.

However, the improvement / preventive effects have not always been sufficient in any of the conventional methods. In addition, the skin to be treated by these active ingredients, especially pathological dermatitis such as atopic dermatitis or sensitive skin, is often accompanied by inflammation and deterioration of the barrier function, and therefore, an excellent effect is obtained. It is expected that a safer drug efficacy agent having no irritation will be developed. The present invention has been made in view of the above-mentioned problems of the prior art, and an object thereof is to provide a solidifying skin external preparation containing a powder that exhibits an effect of improving rough skin without assuming percutaneous absorption.

Means for Solving the Problems In order to achieve the above-mentioned object, the inventors of the present invention have conducted extensive studies and found that a specific enzyme on the skin has a close relationship with skin roughness and the like. It has been found that there is a substance that adsorbs or inhibits these enzymes on the skin, and has completed the present invention. That is, the solidifying skin external preparation according to the present invention is characterized in that an adsorbent powder for inhaling or adsorbing a specific enzyme and an action powder having the inhibitory or activating property of the enzyme are blended. Further, in the solidifying external preparation for skin, it is preferable that the adsorbed powder is a powder having a negative ζ potential at pH 7.5. In the solidifying skin external preparation, the adsorbed powder has a ζ potential of −2 at pH 7.5.
It is preferable that the powder is 0 mV or less. In the solidifying external preparation for skin, the specific enzyme is a plasminogen activator, and the acting powder is a powder capable of releasing a metal compound or a metal ion having a plasminogen activator inhibitory effect. It is suitable. Further, in the solidifying external preparation for skin, the adsorbing powder and the working powder, or the adsorbing powder, the working powder and the base powder are premixed before mixing with the solidifying base to act with the adsorbing powder. It is preferable that the powder is obtained by arranging the powder directly or through a base powder at a close site and then mixing it with a solidifying base. In the solidifying skin external preparation, it is preferable that the acting powder is a metal or a metal compound capable of releasing zinc ions, and the adsorbing powder is silica, talc, or mica. In the solidifying external preparation for skin, it is preferable that the inhibition rate of the plasminogen activator is 40% or more. The inhibition rate of plasminogen activator is measured by the following method. Measurement of plasminogen activator activity inhibitory effect 0.1% test sample and a buffer containing double-chain urokinase type plasminogen activator (30 U / mL),
It was evaluated by the synthetic substrate degrading activity. Further, the solidifying external preparation for skin is preferably for improving rough skin. The solidifying external preparation for skin is preferably for sensitive skin.

DETAILED DESCRIPTION OF THE INVENTION Solidifying external preparation for skin according to the present invention.
Is based on the following circumstances. sand
That is, in recent years, various skin diseases accompanied by rough skin and abnormal keratinization.
Imaging involves proteases, especially plasmin and plasma.
Fibrinolytic enzymes such as Nogen Activator (Plasmid
Changes in the activity of the noogen activation system enzyme are deeply involved
It is becoming clear. For example, experimentally rough skin
Changes in the distribution of plasmin were observed in the epidermal cell layer
Therefore, antiplasmin agents are effective in improving and preventing rough skin.
Have been reported (Kenji kitamura: J.Soc.Cosme
t. Chem. Jpn; 29 (2), 1995). Also, for atopic dermatitis
High fibrinolytic activity was observed in the epidermis (T.Lo
tti: Department of Dermatology; 28 (7), 1989). Furthermore
In psoriasis, which is a representative of inflammatory hyperkeratosis,
Plasminogen activate, which is strong in the keratinized area of the affected epidermis
The existence of a motor activity (Haustein: Arch.Klin.Exp.D
ermatol; 234,1969) or a highly concentrated salt solution from psoriatic scales.
You used to extract plasminogen activator
Report (Fraki, Hopsu-Havu: Arch.Dermatol.Res; 256,197
6) has been done. Plasminogen activator
Specifically for plasminogen, the precursor of plasmin
Protears that work and convert it to active plasmin
It's Ze. In view of the current situation as described above, the present inventors
Pay attention to the behavior of various enzymes on the skin when developing a new drug
did. For example, plasmin is not percutaneously absorbed on the skin surface.
The substances that adsorb and inactivate the gene activator
It is highly safe and does not change the activity of plasminogen activating enzyme.
Improvement / preventive effect against various skin diseases and rough skin
A wide variety of inorganic powder substances are expected,
The effect was investigated for. As a result, certain inorganic powders
Inhibitory effect on plasminogen activator,
Alternatively, it was found that an adsorption action was recognized.Adsorbed powder In the solidifying external preparation for skin according to the present invention, the adsorbed powder is
It is determined in relation to the enzyme to be adsorbed, but preferably
It is evaluated by the correlation with the ζ potential of the target enzyme. Where ζ electric
The position is preferably used to evaluate the surface charge state of the object,
The ability to electrically adsorb the element can be evaluated.
If the target enzyme is a plasminogen activator,
A suitable substance that constitutes the powder is pH 7.5 and has a negative ζ potential.
Value, preferably -10 mV or less,
It is preferably −20 mV or less. Specifically, Siri
Mosquito, talc, mica and the like. Note that ζ potential measurement
Is performed as follows. Tris HC with pH 7.5
18 hours after dispersing and sonicating the sample in 1 buffer solution
The supernatant liquid left to stand was used for the measurement. ζ potential is Otsuka Electronics Co., Ltd.
Using the electrophoretic light scattering altimeter LEZA-600 manufactured by Shikisha Co., Ltd.
I measured it. The measurement was performed 3 times, and the result is shown as the average value.
did. Ζ potential of main substances and plasminogen activator
Table 1 shows the relationship with the adsorption rate of tar (UK).

[Table 1]Sample ζ potential (mV) UK adsorption rate Alumina +17.3 Talc-26.5 68 Silica-27.985 Mica-36.1 70Zinc oxide-11.830 As is clear from Table 1, there is not necessarily a proportional relationship.
However, the ζ potential well expresses the UK adsorption rate.Working powder In the solidifying external preparation for skin according to the present invention, the action powder is also
It is determined in relation to the enzyme that acts on it. The target enzyme is
In case of plasminogen activator, 4th group, 9th group,
Elements of groups 10, 11 and 12 can be mentioned, solidifying skin
Zinc as a particularly preferred element when used in an external preparation,
Cobalt, nickel, copper, silver, zirconium, titanium,
Examples include gold and platinum. Next, the main substance plasmin
Shows the rate of gene activator (UK) inhibition.

[Table 2]Sample UK inhibition rate Zinc oxide 118 Zinc oxide 220 Alumina-18Titanium oxide-12 As is clear from Table 2 above, zinc oxide has excellent inhibition.
Although it has an effect, it does not work in alumina, titanium oxide, etc.
Qualitatively no inhibitory effect is observed. From this, each substance
Has been found to have a high degree of specificity in its action on enzymes.
It The metal compounds include oxides, hydroxides, and glass.
Acid salts, chlorides, hydrates, carbonates, bicarbonates, sulfates,
Oxalates, persulfates and mineralization containing them in the molecule
Inorganic compounds such as compounds containing compounds (complexes), glyceroli
Phosphates, acetates, hydroxides, and α-hydroxy acids
(Citrate, tartrate, lactate, malate)
Is fruit acid salt, amino acid salt (aspartate,
Ginate, glycolate, fumarate) or fat
Acid salts (palmitate, oleate, caseinate,
Organic acid salts such as behenyl acid salt). these
Of these, zinc oxide particularly suitable in the present invention is mainly used as a cosmetic.
As an external agent such as an ultraviolet scattering agent or a white pigment.
It has been used for a long time. However, its UV protection
The effect is not always sufficient, and it has catalytic activity.
Therefore, there is a problem that the stability of the formulated formulation system is impaired.
I had a problem. Therefore, the effect of UV protection and transparency
Or while maintaining the function as an ultraviolet scattering agent,
In order to improve stability and usability in the formulation system, more particles
Fine zinc oxide (Japanese Patent Publication No. 60-33766, Japanese Patent Publication No. 5-7764)
4) and complex with other inorganic or organic compounds
Many have been developed (JP-A-1-190625, JP-A-3-1836)
20, JP-A-7-277914, JP-A-10-87434, JP-A-10-87
467, JP-A-10-87468). On the other hand, zinc oxide is the Japanese Pharmacopoeia
It is also listed in the
It forms a film by combining with the humor and has astringent, anti-inflammatory and protective effects.
Known to have. Based on these pharmacological actions
Zinc oxide is zinc white ointment (zinc oxide, lanolin and white
Mix with ointment mixture), talc, starch, talc, etc.
For a long time as a powder formulation for skin diseases and diaper rash
I have been told. In addition, it enhances the medicinal effect and adds acid to other substances.
Zinc oxide and other anti-inflammatory agents for the purpose of adding the beneficial effects of zinc oxide
And antibacterial agents (Japanese Patent Publication No. 4-63046, Japanese Patent Publication No. 6-76330)
-23361, JP-A-6-157277, JP-A-8-217616, JP-A-5
7-62220), antioxidant (JP-A-7-304665), Protea
Enzyme inhibitors (JP-A-3-169822), etc.
Or there are known examples of creating a complex and applying it to the skin
There is. However, it has been used so far for the purpose of pharmacological effect.
Features of zinc oxide suitable for
There is almost no report or description regarding
In 6-239728, ultrafine zinc oxide is conventional zinc oxide.
Description that drug effects such as astringent action are greater than
However, no specific example is given there.
Similarly, it is already known that zinc oxide adsorbs proteins.
However, to the best knowledge of the inventor,
There is no report that examined the adsorption effect on zinc oxide in detail,
Also, plasminogen activator is adsorbed on zinc oxide.
And there is no report showing that the activity is inhibited.
For reference, the same as the plasminogen activator.
Trypsin classified as a serine protease
In addition, trypsin is adsorbed on zinc oxide
However, the activity was hardly lost. Ie oxidation
Zinc does not necessarily non-specifically inhibit enzyme activity
Absent. By the way, zinc oxide is H_Two, CO-like reducing atmosphere
When fired with air, zinc oxide that emits fluorescence can be obtained.
Although known (JP-A-5-117127), these fluorescent acids
Zinc oxide was manufactured by either method.
However, plasminogen activator adsorption / activity inhibition
Almost no effect or skin improving effect is observed.Coexistence effect The solidifying external preparation for skin of the present invention is a plasminogen activator.
Adsorbs beta-like enzymes on the skin and inhibits its activity
In order to prevent this, adsorption powder such as silica and inhibition of zinc oxide etc.
For) powder. Regarding the coexistence effect, the present inventors
Has no inhibitory effect and has no adsorption effect with zinc ion
When aluminum oxide coexists (Fig. 1), zinc oxide
When coexisting on and silica having adsorption effect (Fig.
2) was compared and examined. As a result, as shown in each figure
Plasminogen activator depending on zinc ion concentration
(UK) Inhibition rate is improved
0.1 to 50p, which is a realistic zinc ion concentration
When aluminum oxide coexists in the pm region,
If the inhibition effect is not improved,
A significant improvement in the inhibitory effect was observed when coexisting
It From the above, plasminogen activator
For effective inhibition of, simply compounding the inhibitor is not enough,
It is understood that the adsorbent powder formulation is extremely effective.
Particularly in the present invention, zinc oxide plastic used as an inhibitor powder is used.
The action of inhibiting minogen activator is due to the presence of silica etc.
It is further improved in the presence of
It is believed that Furthermore, each powder is applied to the external skin of the present invention.
Silicone treatment if necessary
You may mix after making it hydrophobic. The above action
Mix one or more kinds of powder and adsorbent powder respectively
By doing so, the skin of plasminogen activator etc.
Adsorbs enzymes on the skin and has an excellent activity-inhibiting effect.
An extremely safe solidifying external preparation for skin with excellent improving action
Can be provided. Plasminogen Activator
Urokinase and tissue-type plasminogen activator
There are two types called beta, the former is healthy epidermis.
The latter is mainly found in the pathological epidermis.
ing. The solidifying external preparation for skin according to the present invention is
Adsorption / inhibition of plasminogen activator
Typified by those having a need. External solidifying skin of the present invention
The amount of adsorbing powder and working powder in the agent is
0.005 to 50.0% by weight, preferably 0.1 to 2
It is 0.0% by weight. Book with less than 0.005% by weight
The effect of the invention is not sufficiently exerted and exceeds 50.0%.
If this is the case, formulation is difficult, which is not preferable.Base powder The acting powder or the adsorbing powder is the acting substance or the adsorbed substance, respectively.
Even if the quality is supported, coated, included, adsorbed or mixed with other base powder
Good. The base powder includes the following.
It Inorganic base powder Kaolinite, Decite, Nakrite, Haloid Rhino
Kaolins, patriotic, antigorite, chrysotile, etc.
Ilophyllite, Montmorillonite, Nontronite,
Smoke such as saponite, hectorite, bentonite
Tight, sericite, muscovite, lithia mica, synthetic mica, etc.
Illite, Hyderite, Aluminum Silicate Mug
Silicates such as nesium, tricalcium phosphate, hydro
Calcium compounds such as xiapatite, talc, ja
Magnesium silicates such as monlite, silica, al
Single component powder such as mina, other zeolites, silicon
Powder, glass powder, glass beads, titanium oxide
Iron-containing silica, zinc oxide-containing silica, iron oxide-containing silica
F, silica containing cerium oxide, PMMA containing titanium oxide
(Methyl polymethacrylate), zinc oxide inclusion PMM
A, hard capsules such as PMMA containing cerium oxide,
Tanmica, titanium oxide-barium sulfate, titanium oxide-
Tantalum, bismuth oxychloride, bismuth oxychloride-
Examples include pearl pigments such as mica. Organic base powder Nylon powder, polyethylene powder, Teflon
^TMPowder, polypropylene powder, silk powder
ー, vinyl acetate powder, polymethacrylic acid ester
Powder, polyacrylonitrile powder, polystyrene
Powder, cellulose powder and the like. Inorganic pigment base powder Titanium oxide, zinc oxide, zirconium oxide, cerium oxide
White oxides of iron and their complex oxides, iron oxides, hydrated oxides
Iron, chromium oxide, chromium hydroxide, ultramarine blue, navy blue, red oxide
Ruto and the like. Organic pigment base powder Red 201, Red 202, Red 204, Red 20
5, Red 220, Red 226, Red 228, Red
Color 405, Orange 203, Orange 204, Orange 205
Pigment No., Yellow No. 401, Blue No. 404, etc., Red
Color 3, Red 104, Red 106, Red 227,
Red 230, Red 401, Red 505, Orange 20
No. 5, Yellow No. 4, Yellow No. 5, Yellow No. 202, Yellow No. 203
No. 3, Green No. 3, and Blue No. 1 Zirconium and Barium
Alternatively, an aluminum lake or the like may be used.Solidifying base In the present invention, a wax is blended as a solidifying base.
It is possible to As the wax used in the present invention
For ceresin wax, carnauba wax, polyethylene
Wax, paraffin wax, candelilla wax, ma
Iclocrystallin wax, behenic acid, behenyla
Such as rucor, mokuro, beeswax, and cetanol
Can be mentioned. Used as a solidifying base in the present invention
Examples of the thickener include gum arabic, carrageenan,
Karaya gum, tragacanth gum, cabbage gum, quill
Ness seed (quince), casein, dextrin, ze
Latin, sodium pectate, sodium alginate
Membrane, methyl cellulose, ethyl cellulose, carboxy
Methyl cellulose, hydroxyethyl cellulose, hydr
Roxypropyl cellulose, polyvinyl alcohol,
Livinylmethyl ether, polyvinylpyrrolidone, poly
Sodium acrylate, carboxyvinyl polymer,
Luquil modified carboxyvinyl polymer, Locust bee
Gum, guar gum, tamarind gum, dialkyl dime
Chilly ammonium sulfate cellulose, xanthan gum, ke
Aluminum magnesium iodide, bentonite, hect
Examples include lights. One of these thickeners
Alternatively, two or more kinds can be arbitrarily selected and used.
In addition, similarly, the water repellency that is suitably used as a solidifying base
Examples of polymers include silicone resin, silicone rubber,
Fluorine modified silicone resin, alkyl modified silicone resin, etc.
Among them, silicone resin is particularly preferable. In particular,
Average formula (1) RnSiO (4-n) / 2 (1) (R is a hydrocarbon group having 1 to 6 carbon atoms or a phenyl group
The value of n is 1.0 to 1.8. )
There is a silicone resin. This silicone resin is R3Si
O1 / 2 unit, R2SiO unit, RSiO2 / 3 unit and
And SiO2 units, consisting of an appropriate combination,
It has an average molecular weight of 1,500 to 20,000.
And are preferred.Other ingredients The solidifying external preparation for skin according to the present invention has the effects of the present invention.
As long as it is not damaged, it is usually for external use on the skin of cosmetics and pharmaceuticals.
Ingredients used in agents such as moisturizers, antioxidants, oils
Active ingredients, UV absorbers, emulsifiers, surfactants, thickeners,
Alcohols, powder components, coloring materials, aqueous components, water, various skins
Skin nutrients and the like can be appropriately blended as necessary.
In addition, disodium edetate, trisodium edetate
System, sodium citrate, sodium polyphosphate, meta
Sequestration of sodium phosphate, gluconic acid, malic acid, etc.
Agent, caffeine, tannin, verapamil, tranexam
Acids and their derivatives, licorice, quince, pomegranate, etc.
Various crude drug extracts, tocopherol acetate, glycyl resin
Acid, glycyrrhizic acid and its derivatives or salts thereof, etc.
Drugs, vitamin C, magnesium ascorbyl phosphate
, Ascorbic acid glucoside, arbutin, kojic acid
Whitening agents such as, amino acids such as arginine, lysine and the like
Derivative, fructose, mannose, erythritol,
Add saccharides such as trehalose and xylitol as appropriate.
You can The solidifying external preparation for skin of the present invention is, for example,
Stick foundation, lipstick, pack, sheet
Conventional solidifying skin (such as kneaded into non-woven fabric)
Apply in any form as long as it is used as an external preparation
The dosage form is not particularly limited. Solidifying leather according to the present invention
For external use, it is difficult to use conventional cosmetics, especially for sensitive skin.
It has an excellent effect when applied to existing skin. Sensitive skin is below
Is defined as "Usually, external medicines and cosmetics
Goods, plants, UV rays, metals, etc.
Reacts specifically with substances and is prone to skin problems
skin. Barrier function is reduced and allergenic substances (flower
Constitution for powder, fragrances, etc. and stimulants (alcohol, etc.)
Sensitive skin "and" sleep deprivation, overwork, menstruation, seasonal changes
The natural resistance of the skin due to the appearance of eyes and mental stress
Or, when the physiological function of the skin is weakened, a stimulant
Against the skin that is prone to temporary skin problems.
You may feel uneasy about using the cosmetics that you usually use.
Worried skin. " In this way, the factors that make the skin condition sensitive are skin barriers.
Decreased rear function, decreased skin irritation threshold, dry skin, contact
Tactile dermatitis-causing substances, physicochemical irritation, stress, body
Tones, seasonal changes, ultraviolet rays, physiology, etc. Furthermore
In addition, erroneous skin care may make the skin sensitive and
It is also possible that you will be sensitive to your own beliefs
It

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the technical scope of the present invention is not limited to these examples. The blending amounts are all weight%. First, a specific test method and its result concerning the plasminogen activator adsorption action, the plasminogen activator activity inhibition action, and the skin improvement action used in the evaluation of this example will be described. 1. Plasminogen activator adsorption / inhibition test (in vitro) (1) Sample preparation Talc, mica, silica, kaolin, zeolite, sericite, sodium magnesium metasilicate (neucillin), hydroxyapatite, aluminum oxide, silica gel, oxidation Inorganic powders other than zinc oxide of titanium, and coexistence examples of zinc oxide and other powders were used as samples, and 0.1% suspensions of water were prepared to evaluate the adsorption action and activity inhibition action on urokinase. (2) Measurement of plasminogen activator adsorption action Tris-HCl buffer (pH7.4) was added to 20 μL of sample suspension water to make a total volume of 180 μL, and 10 μg / mL of precursor urokinase 20 μL was added at room temperature. Leave for 5 minutes. Then, the sample powder was filtered and the filtrate was collected. A certain amount of Tris-HCl
The powder was thoroughly washed with buffer, and the filtrate and the washing solution were combined to obtain an unadsorbed urokinase solution. TintElize
Using uPA (biopool), the urokinase concentration in the unadsorbed urokinase solution was determined by the ELISA method, and the amount of urokinase adsorbed on the sample powder was calculated from the value. (3) Measurement of plasminogen activator activity inhibitory activity Tris-HCl buffer (pH 7.4) was added to 20 μL of sample suspension water to make a total volume of 180 μL, and 300 U / mL of active urokinase 2 was added.
0 μL was added and left at room temperature. After 30 minutes, S2444 (CHROMOGENIX), a specific synthetic substrate for urokinase,
0 μL was added, and the mixture was further left in a 37 ° C. incubator for 30 minutes. Then, add 20 μL of 12% trichloroacetic acid aqueous solution to stop the reaction, filter the sample powder, measure the absorbance at 405 nm of the filtrate to determine the urokinase activity in the evaluation system, and further inhibit the urokinase activity by the sample. The rate was calculated. 2. Skin roughness prevention effect test (in vivo) (1) Sample preparation Similar to the in vitro test, talc, mica, silica, kaolin, zeolite, sericite, noicillin, hydroxyapatite, aluminum oxide, silica gel, titanium oxide, and A sample of coexistence of zinc oxide and other powders,
Each 3% suspension water was prepared and evaluated for the effect of preventing the rough skin caused by the active agent. (2) Judgment of the effect of preventing rough skin A panel of 54 men was applied with absorbent cotton (2 x 2 cm) soaked in a 5% SDS aqueous solution to the two inner parts of the forearm for 15 minutes, the active agent was washed off, and the panel was placed there. The sample suspension water allocated for each and 0.5 mL of water were applied as a control (n = 3). This operation was repeated for 7 days, and on the 8th day, the test site was thoroughly washed, allowed to stand for 60 minutes, and then the degree of skin roughness caused by SDS was observed, and a rating was given based on the following criteria. Further, the difference in score between the control site and the sample application site was calculated for each panel, and the differences were totaled for each sample, and the effect of each sample was determined based on the following criteria for preventing rough skin. The results are shown in Table 3 together with the in vitro results. <Roughness rating criteria> Rating 4: Clear erythema and / or desquamation are observed. Rating 3: Moderate erythema and / or slight scaling are observed. Rating 2: slight erythema and / or cracks in the stratum corneum. Score 1: The surface of the stratum corneum is whitish or appears to be dusty. Score 0: No symptoms. <Evaluation Criteria for Preventing Skin Roughness> ⊚ = Clearly effective: Score difference of 6 or more ○ = Slightly effective: Score difference of 4 or 5 Δ = Prevention tendency: Score difference of 2 or 3 × = Invalid: Score difference of 1 or less.

[Table 3]Sample (Characteristic) Adsorption rate% Inhibition rate% Prevention effect Talc 68 15 × Mica 60 10 × Silica 82 5 × Kaolin 60 0 × Zeolite 280 × Serisite 68 0 × Neusilin (sodium magnesium metasilicate) 80 0 × Hydroxyapatite 0 0 × Aluminum oxide 110 × Silica gel 70 0 × Titanium oxide 39 0 × Zinc oxide 47 29 △ Zinc oxide + hydroxyapatite (1: 1) 23 20 △Zinc oxide + zeolite (1: 1) 33 22 △ Invention product Zinc oxide + talc (1: 1) 55 55 ○ Zinc oxide + mica (1: 1) 51 50 ○Zinc oxide + silica (1: 1) 65 42 ○ As is clear from Table 3, most of the evaluated inorganic powders have a large amount.
At least plasminogen activator (urokina
It has an adsorption function. On the other hand, zinc oxide is relatively
It has a high activity-inhibiting effect, but coexistence with other powders
In terms of fruit, the effect on skin roughness is
Plasminogen activator
Be improved. Therefore, the effectiveness on skin is
Lasminogen activator adsorption powder and activity inhibitor powder
Both effects of the body are important, but the topic of solidifying external skin preparations
In actual evaluation, only the inhibition rate is sufficient. And the inhibition rate is high
If the standard is 30% or more, it has a high effect of preventing rough skin.
However, it is understood that especially 40% or more has a remarkable effect.
Be done. Table 4 shows the mixture of zinc oxide and talc.
The result of the discussion is shown. That is, use the following basic prescription
Change the compounding method of zinc oxide, talc, and study the effect.
It was

[Table 4]Sample of the present invention (Prescription)% by weight   1) Titanium dioxide 13.0   2) Talc 12.0   3) Zinc oxide 13.7   4) Red iron oxide 1.0   5) Yellow iron oxide 0.7   6) Black iron oxide 0.1   7) Squalane 37.0   8) Cetyl 2-ethylhexanoate 16.0   9) Sorbitan sesquioleate 1.0   10) Microcrystalline wax 4.0   11) Carnavar 1.312) Fragrance 0.2 (Production method) 7) to 9) are mixed at 80 ° C., and 1) to
6) is added, mixed with a disbar and then TK milled
It Furthermore, heat-dissolved 10) and 11) are added and mixed.
Degas after combination. 12) Mix gently and mix at 80 ° C.
Fill vessel and cool. All based on the above basic prescription
When powders of the above are mixed with a blender at the same time, zinc oxide and
When premixed with talc, zinc oxide and titanium dioxide
Of each solidifying external skin preparation when premixed with
Then, the skin roughening preventive effect was evaluated in the same manner as described above. The result
The results are shown in Table 5 below.

[Table 5]Preparation method Prevention effect No premix △ Premixed zinc oxide and talc ○Premix zinc oxide and titanium dioxide △ As is clear from Table 5 above, zinc oxide that is an inhibitor powder
When talc, which is an adsorbed powder, is premixed,
A remarkable prevention effect is obtained. Meanwhile, do the premix
If not, or with titanium dioxide, which has a low adsorption effect
When zinc oxide is premixed, the prevention effect decreases
Tend to do. This is the case in the case of solidifying external skin preparations.
There is no qualitatively solvent, and only the powder comes in direct contact with the skin.
Therefore, the adsorbing powder and the inhibiting powder are not physically close to each other.
It is considered that the synergistic effect of both cannot be exerted. This
On the other hand, when adsorbed powder and inhibitor powder are premixed
The other powder adheres to the surface of either powder.
Both powders are physically located very close to each other.
It is presumed that the collaborative action of persons is likely to occur. Na
The solidifying external preparation for skin according to the present invention simply improves the rough skin.
Not only the enhancement of good effects but also the pathological dermatitis described below
A stimulating effect on rubbing sensitive skin is also recognized.
On the other hand, each powder is treated with 3% silicone to make it water repellent.
When the property is given, the sample is hydrophobic and is not analyzed by the evaluation system.
It was not dispersed and the adsorption rate and inhibition rate could not be measured (ND).
However, in actual use, the combination of untreated zinc oxide and talc
Although the effect is inferior to that of Kaze, it does not prevent the rough skin
Was observed. Furthermore, the present inventors have found that the dispersion of zinc oxide powder
The relationship between the inhibitory effect (secondary particle size) and the inhibitory effect
It was The result is shown in FIG. In the figure, the same origin of oxidation
Change the dispersion and crushing method for zinc (crush by hand,
Emide crushing, mechanical dispersion, ultrasonic dispersion, etc.) Various secondary
Zinc oxide having a particle size was obtained. As is clear from the figure,
The smaller the average secondary particle size, the higher the inhibitory effect.
The particle surface area has a close influence on the inhibition rate.
To be understood. 3. Skin improvement effect Actual use test (1) Efficacy test for atopic dermatitis As a sample, the solidifying skin external preparation shown in Table 6 was used.
The improving effect on topy dermatitis was evaluated. That is, light
Patients with atopic dermatitis who are diagnosed as sick or moderate
For each name, the test interval is 4 weeks and there are 2 groups.
The site where the same level of skin rash is observed symmetrically is the test site
As a first group, for the solidifying skin of the product of the present invention and the comparative product 2
Agent for the other group, which is the solidifying skin of Comparative Product 1 and Comparative Product 2
Randomly allocate the drug to the left and right of each test site in the morning
It was applied twice a day for 4 weeks. After 4 weeks, flush and dry
(Scalping), Itching and observation and interview
The rating was given according to the standard. Comparative product 2 and the present invention
Product, or the difference in rating between comparative product 2 and comparative product 1
The improvement effect was judged based on the criterion. The results are shown in Table 7.
Shown in. <Grading criteria> Rating 4: Altitude Rating 3: Moderate Rating 2: Mild Rating 1: Minor Score 0: No symptoms <Criteria for improvement effect> Significant improvement: Score difference of 3 or more Improvement: Score difference 2 Slight improvement: Score difference 1 Invariant: Score difference 0 Deterioration: Score difference -1 or less

[Table 6]Sample (% by weight) Inventive product Comparative product 1 Comparative product 2   1) Titanium dioxide 13.0 13.0 13.0   2) Talc 12.0-25.7   3) Zinc oxide 13.7 25.7-   4) Red iron oxide 1.0 1.0 1.0   5) Yellow iron oxide 0.7 0.7 0.7 0.7   6) Black iron oxide 0.1 0.1 0.1   7) Squalane 37.0 37.0 37.0   8) Cetyl 2-ethylhexanoate 16.0 16.0 16.0   9) Sorbitan sesquioleate 1.0 1.0 1.0   10) Microcrystalline wax 4.0 4.0 4.0   11) Carnavar 1.3 1.3 1.3 1.312) Fragrance 0.2 0.2 0.2 (Production method) 7) to 9) are mixed at 80 ° C., and 1) to
6) (For the product of the present invention, premix talc and zinc oxide.
Kus) is added, mixed with a disbar, and then TK milled.
It Furthermore, heat-dissolved 10) and 11) are added and mixed.
Degas after combination. 12) Mix gently and mix at 80 ° C.
Fill vessel and cool.

[Table 7]                       Remarkably improvedOr the number of improved cases The number of improved cases The number of invariant cases The number of deteriorated cases Hot flush Product of the present invention 2 3 3 0         Comparative product 1 1 2 4 1 Dried product of the present invention 2 2 4 0         Comparative product 1 1 2 4 1 Pruritus product of the present invention 1 2 5 0Comparative product 1 0 4 4 0 As is clear from Table 7, the solidifying skin external preparation of the present invention
Contains other zinc oxide commonly used in medicine
Compared to the solidifying skin external preparation of
A better improvement effect on the flame was observed. Also general
With zinc oxide (Comparative Example 1), some cases of worsening of symptoms were observed.
And the stimulating effect of zinc oxide on pathological dermatitis was found.
In some cases, deterioration of symptoms was not observed with the product of the present invention.
, Especially for solidifying skin external preparations for improving pathological dermatitis
Excellent suitability for (2) Effectiveness test for acne skin As a sample, the solidifying external preparation for skin shown in Table 6 (the present invention
Product) was used to evaluate the effect of improving acne skin.
That is, 10 female panels aged 16 to 24 who suffer from acne
Were divided into 2 groups with a test interval of 4 weeks, and the face was
As one group, the solidifying external preparation for skin of the present invention, the other group
For comparison, the solidifying external preparation for skin of Comparative Product 3 was continuously used for 4 weeks. Four
Panel itself evaluates the condition of acne after a week and before the test
If the symptom is improved, {A}, the symptom remains unchanged or
If it gets worse, declare it as {B} and based on the following criteria
The improvement effect was judged. The results are shown in Table 8. <Criteria for improvement effect>   ◎ = High improvement effect: 8 or more out of 10 are evaluated as {A}   ○ = Improvement effect: 5 to 7 people out of 10 evaluated as {A}   △: There is a tendency for improvement: 3 to 4 people out of 10 evaluated as {A}   × = Invalid: {A} evaluation less than 3 out of 10

[Table 8]Invention product Comparative product 1 Improvement effect ◎ △ As can be seen from Table 8, the foundation of the present invention has a
Compared to the foundation of the comparison product, it is better for acne skin
An excellent improvement effect was recognized.Example 1 Lipstick (Prescription)% by weight   1) Hydrocarbon wax 3.0   2) Candelilla wax 1.0   3) Glyceryl isostearate 40.0   4) Liquid paraffin 46.448   5) Red No. 202 0.5   6) Red No. 204 2.0   7) Red No. 223 0.05   8) Zinc oxide 3.0   9) Mica 4.0   10) Fragrance 0.002 (Production method) 1) to 4) are heated and dissolved at 85 ° C., and 5)
~ 9) (premix with zinc oxide and mica)
After stirring and mixing, 10) is mixed by stirring, filled in a container and cooled.
To do.Example 2 Stick foundation (Prescription)% by weight   1) Titanium dioxide 13.0   2) Mica 12.0   3) Zinc oxide 13.7   4) Red iron oxide 1.0   5) Yellow iron oxide 0.7   6) Black iron oxide 0.1   7) Squalane 37.0   8) Cetyl 2-ethylhexanoate 16.0   9) Sorbitan sesquioleate 1.0   10) Microcrystalline wax 4.0   11) Carnavar 1.3   12) Fragrance 0.2 (Production method) 7) to 9) are mixed at 80 ° C., and 1) to
6) (premix with mica and zinc oxide)
Mix with a Disbar and then TK mill. More this
Add 10) and 11) heated and dissolved in, and mix and degas.
After gently mixing 12), fill the container at 80 ° C and cool.
To reject.Example 3 Lipstick   1) Polyethylene wax 10.0   2) Ceresin wax 3.0   3) Lanolin 20.0   4) Polybutene 20.0   5) Octyl methoxycinnamate 5.0   6) Dimethicone 12.0   7) Ester oil balance   8) Titanium oxide 4.5   9) Red No. 201 0.5   10) Red No. 202 1.1   11) Red 223 0.3   12) Spherical silica powder (about 5 μm) 3.0   13) Red iron oxide coated interference mica titanium 12.0   14) Zinc oxide 5.0   15) Boron nitride powder (average particle size 15 μm) 5.0   16) Antioxidant amount   17) Perfume (Production method) 1) to 7) are heated and dissolved at 85 ° C., and 8)
~ 15) (Spherical silica powder and zinc oxide premixed
) Is added and mixed with stirring, and then 16) and 17) are mixed with stirring and mixed.
Fill the vessel and cool.Example 4 Peeling type pack cosmetic (1) Polyvinyl alcohol 10 (2) 1,3-butanediol 5 (3) Purified water 56 (4) Talc 10 (5) Zinc oxide 15 (6) Polyoxyethylene-modified methylpolysiloxane 4 (7) Suitable amount of fragrance Premix the manufacturing methods (4) and (5). And
(2), (4), and (5) are mixed and stirred in (3), and 70-
After heating to 80 ° C., (1) is added and dissolved. (6),
(7) was added and mixed to obtain a pasty pack cosmetic.
The solidifying skin external preparations of Examples 1 to 4 were all
Has the activity of adsorbing and inhibiting the Nogen activator, and is accessible
Other than dermatitis, psoriasis, atopic dermatitis, experienced by healthy people
Excellent improvement / preventive effect against rough skin or acne
Show the result.

As described above, according to the present invention,
By using a solidifying external preparation for skin having a specific enzyme-adsorbing powder and an acting powder, it is possible to exhibit high safety and an excellent anti-skin effect.

[Brief description of drawings]

FIG. 1 is an explanatory diagram showing a relationship between a zinc ion concentration and the presence of aluminum oxide.

FIG. 2 is an explanatory diagram showing the relationship between zinc ion concentration and the presence of silica.

FIG. 3 is an explanatory diagram of a relationship between a dispersed state of zinc oxide powder and an inhibition rate.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 9/06 A61K 9/06 33/24 33/24 33/30 33/30 47/04 47/04 A61P 17/04 A61P 17/04 17/06 17/06 17/10 17/10 17/16 17/16 43/00 111 43/00 111 (72) Inventor Katsuki Ogawa 2-2 Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa No. 1 Shiseido Research Center (Shin-Yokohama) (72) Inventor Satoshi Tomomasa 2-2-1 Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa Shiseido Research Center (Shin-Yokohama) (72) Invention Eriko Kawai 2-2-1 Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa Shiseido Research Center (Shin-Yokohama) (72) Inventor Toshinori Yoshikawa 2-2-1 Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa Shiseido Lisa F-term in Chi Center (Shin-Yokohama) (reference) 4C076 AA08 BB31 CC18 CC20 DD08 DD29 DD34 DD45 EE55 FF16 FF17 4C083 AB052 AB152 AB171 AB172 AB211 AB212 AB232 AB242 AB431 AB432 AC012 AC022 AC122 AC352 AC422 AC442 AC792 AC812 AC842 AD022 AD112 AD112 AD112 AD112 AD112 AD112 AD112 AD112 AD112 AD112 AD112 AD112 BB21 BB51 CC03 CC07 CC12 CC13 DD11 DD12 DD21 DD23 DD39 EE06 EE07 EE10 EE13 EE14 4C084 AA17 MA28 MA63 NA06 NA14 ZA892 ZB11 ZC20 4C086 AA01 AA02 HA01 HA03 HA06 HA10 HA18 MA05 MA28 MA63 NA07 NA14 ZA89 Z11

Claims (9)

[Claims] 1. A solidifying external preparation for skin, comprising an adsorbent powder for inhaling or adsorbing a specific enzyme, and an active powder having an inhibitory or activating property of the enzyme in a solidifying base. . 2. The external preparation for skin according to claim 1, wherein the adsorbed powder is a powder having a negative ζ potential at pH 7.5. 3. The solidified external preparation for skin according to claim 2, wherein the adsorbed powder is a powder having a ζ potential of −20 mV or less at pH 7.5. 4. The external skin preparation according to any one of claims 1 to 3, wherein the specific enzyme is a plasminogen activator and the action powder is a metal compound or a metal having a plasminogen activator inhibitory action. A solidifying external preparation for skin, which is a powder capable of releasing ions. 5. The external skin preparation according to any one of claims 1 to 4, wherein the adsorbing powder and the working powder, or the adsorbing powder, the working powder and the base powder are mixed with a solidifying base. A solidifying skin characterized by being premixed before, adsorbed powder and working powder being placed directly or through a base powder at a close location, and then being mixed with a solidifying base. Topical agent. 6. The external skin preparation according to any one of claims 1 to 5, wherein the acting powder is a metal or a metal compound capable of releasing zinc ions, and the adsorbing powder is silica, talc,
A solidifying external skin preparation characterized by being mica. 7. The external preparation for skin according to claim 1, wherein the plasminogen activator inhibition rate is 40% or more. The inhibition rate of plasminogen activator is measured by the following method. Measurement of plasminogen activator activity inhibitory effect 0.1% test sample and a buffer containing double-chain urokinase type plasminogen activator (30 U / mL),
It was evaluated by the synthetic substrate degrading activity. 8. A solidifying external preparation for skin, wherein the external preparation for skin according to claim 1 is for improving rough skin. 9. A solidifying external preparation for skin, wherein the external preparation for skin according to claim 1 is for sensitive skin.