JP2001240548A - Inhibitor of plasminogen activator and combination skin external preparations - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inhibitor of plasminogenactivator that improves the chapped skin by inorganic compound, and to provide the combination external preparations for skin and the improvement method of the chapped skin by using them. SOLUTION: The inhibitor of plasminogenactivator is characterized by adsorbing plasminogenactivator and also by containing one kind or two kinds or more of the zinc oxides that inhibit the activity, and the combination external preparations for skin and the improvement method of the chapped skin by using them are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a plasminogen activator inhibitor, an external preparation for skin containing the same, and a method for improving skin roughness using the same, particularly to an improvement of an inorganic active ingredient.

[0002]

2. Description of the Related Art Various therapeutic agents, external preparations for the skin, cosmetics, and the like have been conventionally known as having an effect of improving and preventing skin diseases, rough skin, acne, and the like. Active ingredients in these conventional drugs and cosmetics include anti-inflammatory agents and extracts of animals and plants which are considered to have anti-inflammatory effects, or amino acids, polysaccharides, lipids and natural polymers having a high moisturizing and water-retaining effect include skin It has been used because of its excellent ability to prevent inflammation of the (affected part) and loss of water in the stratum corneum.

[0003] On the other hand, in the case of pathological dermatitis such as atopic dermatitis or severe acne skin, various components may cause irritability or irritation, and particularly cautious use of active ingredients is required. Selection is required.

[0004] In addition, molecular drugs such as organic polymers which have been conventionally studied as active ingredients for the purpose of improving rough skin, include:
The active ingredient is a solid substance that does not penetrate into the skin, such as powder, while it has permeability to the skin and may have other effects on the skin in some cases because it is absorbed percutaneously into the skin. If it can be used to improve skin roughness, safety can be further improved. However, such a technique is not conventionally known.

[0005]

However, the improvement / prevention effect has not always been sufficient in any case. In addition, since these active ingredients are skin to be treated, particularly pathological dermatitis such as atopic dermatitis is accompanied by inflammation and a decrease in barrier function, it has an excellent effect and has no irritation. The development of a safer drug is expected.

The present invention has been made in view of the above-mentioned problems of the prior art, and an object of the present invention is to provide a plasminogen activator inhibitor exhibiting an effect of improving skin roughness and a skin external preparation containing the same.

[0007]

Means for Solving the Problems In order to achieve the above object, the present inventors have made intensive studies and found that specific zinc oxide has a plasminogen activator inhibitory action,
In addition, they have found that this has an excellent effect of improving rough skin, and have completed the present invention. Furthermore, they have found that a highly safe powder can be used as an active ingredient having a skin roughness improving effect, and have completed the present invention. That is, the plasminogen activator inhibitor according to the present invention adsorbs plasminogen activator,
Further, it is characterized in that it contains one or more kinds of zinc oxides that inhibit its activity.

[0008] Further, in the inhibitor according to the present invention, the adsorption rate of plasminogen activator is 60% or more;
The inhibition rate is preferably at least 60%. The adsorption rate and inhibition rate of the plasminogen activator are measured by the following methods. Measurement of plasminogen activator adsorption effect After mixing a 0.1% test sample and a single-chain urokinase-type plasminogen activator (1 µg / mL) in a buffer for a certain period of time, remove the test sample. The remaining single-chain urokinase-type plasminogen activator in the buffer
Evaluation was performed by quantification by ELISA.

Measurement of inhibitory action on plasminogen activator activity [0009] The activity of a 0.1% test sample and a buffer containing a double-chain urokinase-type plasminogen activator (100 U / mL) was evaluated based on the activity of decomposing a synthetic substrate. . In addition, in the inhibitor according to the present invention, it is particularly preferable that zinc oxide has a plasminogen activator adsorption rate and an inhibition rate of 70% or more. In the inhibitor according to the present invention, the zinc oxide is preferably zinc oxide whose surface is coated with 0.1 to 70% by weight of silica gel.

[0010] The skin external preparation for improving skin roughness according to the present invention is characterized in that it contains a powder that adsorbs plasminogen activator and inhibits its activity. Further, the skin external preparation for improving rough skin according to the present invention is characterized in that it contains one or more of the above-mentioned plasminogen activator inhibitors. Further, the skin external preparation for improving pathological dermatitis according to the present invention is characterized in that it contains one or more plasminogen activator inhibitors comprising the silica gel-coated zinc oxide.

[0011] Further, the method for suppressing plasminogen activation according to the present invention is characterized in that plasminogen activator is adsorbed on powder and its activity is inhibited. The method for improving skin roughness according to the present invention is characterized in that a powder that adsorbs plasminogen activator and inhibits its activity is applied to the skin.

The skin external preparation for improving skin roughness according to the present invention is characterized by containing zinc oxide.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The plasminogen activator inhibitor and the external preparation for skin containing the same according to the present invention have been made in the following manner. That is, changes in the activities of proteases, particularly fibrinolytic enzymes (plasminogen activating enzymes), such as plasmin and plasminogen activator, are deeply involved in the formation of disease images of various skin diseases accompanied by rough skin and abnormal keratinization in recent years. Is being revealed.

For example, a change in the distribution of plasmin is observed in the epidermal cell layer that has been experimentally roughened, and it has been reported that an antiplasmin agent is effective for improving and preventing rough skin (Kenji kitamura: J. Soc). .Cosmet.Chem.Jpn; 29
(2), 1995). High fibrinolytic activity is also found in the epidermis in atopic dermatitis (T. Lotti: Departme
ntof Dermatology; 28 (7), 1989). Furthermore, in psoriasis, which is a representative of inflammatory dyskeratosis, the presence of strong plasminogen activator activity at the parakeratotic site of the affected epidermis (Haustein: Arch. Klin. Exp. Dermatol; 234,19
69) and reports that plasminogen activator was extracted from psoriasis scales using a high-concentration salt solution (Fraki, H
opsu-Havu: Arch. Dermatol. Res; 256, 1976).

[0015] Plasminogen activator is a protease that works specifically on plasminogen, a precursor of plasmin, and converts it into active plasmin. In view of the above-mentioned situation, the present inventors have focused on the development of a new medicinal agent, and have noticed that plasminogen activator, which activates plasminogen, is present in the rough stratum corneum such as psoriasis scales. In other words, substances that adsorb and inactivate plasminogen activator on the skin surface without percutaneous absorption are highly safe, and various skin diseases, such as rough skin, accompanied by changes in the activity of plasminogen activating enzymes Therefore, the effect was examined for various inorganic powder substances. As a result, specific zinc oxide, particularly zinc oxide coated on the surface with 0.1 to 70% by weight of silica gel, has an excellent plasminogen activator adsorption / inhibiting action,
Furthermore, they found that a skin external preparation containing this had an excellent skin improving effect, and completed the present invention.

Hereinafter, embodiments of the present invention will be described in more detail. In the present invention, as the zinc oxide that adsorbs the plasminogen activator and inhibits its activity, zinc oxide whose surface is coated with 0.1 to 70% by weight of silica gel is particularly preferably used. In this specification, silica gel includes anhydrous silica gel.

Zinc oxide has been used for a long time mainly as an external agent such as cosmetics, as an ultraviolet scattering agent or a white pigment. However, the effect of preventing ultraviolet rays is not always sufficient, and there is a problem that the stability of the formulated preparation system is impaired due to its catalytic activity.
Therefore, with the aim of improving the stability and usability in pharmaceutical systems while improving the ultraviolet protection effect and transparency, or maintaining the function as an ultraviolet scattering agent, zinc oxide with finer particles (JP-B 60-33766, A number of composites with other inorganic or organic compounds and the like have been developed (JP-A-1-190625, JP-A-3-183620, JP-A-7-27791).
4, JP-A-10-87434, JP-A-10-87467, JP-A-10-874
68).

On the other hand, zinc oxide is also listed in the Japanese Pharmacopoeia, and is known to have a pharmacological effect by binding to skin proteins to form a film, and to have astringent, anti-inflammatory and protective effects. Based on these pharmacological actions, zinc oxide is a zinc white ointment (a mixture of zinc oxide, lanolin and white ointment)
And powders mixed with talc, starch, talc, and the like have been used for skin diseases, diaper rash, and the like since ancient times.
Furthermore, zinc oxide and other anti-inflammatory and antibacterial agents (JP-B-4-63046, JP-B6-76330, JP-A-2-23361, JP
6-157277, JP-A-8-217616, JP-A-57-62220, antioxidant (JP-A-7-304665), protease inhibitor (JP-A-3-169822), etc., or make a complex It is known to apply to the skin.

However, there have been few reports and descriptions on the characteristics (restrictions on particle size, production method, etc.) of zinc oxide suitable for use for pharmacological effects.
Japanese Patent Application Laid-Open No. Hei 6-239728 only mentions that ultrafine zinc oxide has a greater drug effect such as astringent action than conventional zinc oxide, but no specific example is described therein.

Similarly, it is already known that zinc oxide adsorbs proteins, but as far as the present inventor knows, there is no report that examined the adsorption effect of a plurality of zinc oxides in detail, and plasminogen was not considered. There is no report showing that the activator is adsorbed on zinc oxide and its activity is inhibited. As a reference, trypsin, which is classified into the same serine protease as plasminogen activator, was also examined. Although trypsin was adsorbed on zinc oxide, almost no activity was lost.
That is, zinc oxide does not necessarily non-specifically inhibit enzyme activity.

The external preparation for skin of the present invention contains zinc oxide which adsorbs plasminogen activator and inhibits its activity, particularly preferably zinc oxide coated with silica gel, as an active ingredient. In general, zinc oxide is produced by igniting a zinc plate in a suitable furnace or by igniting zinc hydroxide or zinc nitrate to obtain zinc oxide, or zinc sulfate or zinc chloride and sodium carbonate solution. Is added to precipitate basic zinc carbonate, which is washed, dried, and then ignited to obtain zinc oxide. Comparing the zinc oxides obtained by both the production methods, those produced by the dry method tend to be superior.

Further, depending on the particle diameter or specific surface area, ordinary zinc oxide is converted to fine particle zinc oxide (specific surface area is 10 m ² / g
<), And ultrafine zinc oxide (particle diameter: 0.1 μm>).

The effect of zinc oxide according to the present invention is superior to that of ordinary zinc oxide in that the average particle diameter is 0.2 μm or less, that is, zinc oxide classified as fine particles or ultrafine particles. However, it is known that when zinc oxide is fired in a reducing atmosphere such as H ₂ or CO, a zinc oxide which emits fluorescence is obtained (Japanese Patent Laid-Open No. 5-117127). Plasminogen activator adsorption and
Almost no activity-inhibiting and skin-improving effects are observed.

The reason why the above zinc oxide is more excellent in the plasminogen activator adsorption / inhibiting action is unknown at present. In addition, inorganic or organic compounds other than zinc oxide, such as carbonates and sulfates (JP-A-10-87468), magnesium aluminate metasilicate, mainly for the purpose of improving the ultraviolet ray preventing effect, safety, stability and usability. (JP-A-1-308819), silica gel, alumina (JP-A-3-183620, JP-A-10-87467), fluorine-modified silicone (JP-A-7-277914), polyester, nylon,
Coating zinc oxide with cellulose etc. (patent No. 2628058),
Alternatively, composite powders coated with zinc oxide have been developed.

In the present invention, in particular, the plasminogen activator adsorption / inhibition effect of zinc oxide used as a carrier is further improved by coating with silica gel, and it is effective for sensitive skin having pathological dermatitis and the like. Silica gel-coated zinc oxide is preferably used because it also reduces irritation. In addition, a method for producing zinc oxide used as a carrier,
The particle size and the like are not particularly limited, but the use of zinc oxide having an average particle size of 0.2 μm or less, which does not have the above-mentioned fluorescence, has a better plasminogen activator adsorption / inhibition effect and skin improving effect. Is preferred.

The proportion of silica gel coated on the surface of zinc oxide is 0.1 to 70% by weight, particularly 5 to 40% by weight.
Is preferred. If it is less than 0.1%, no effect of the silica gel is observed, and if it exceeds 70%, the effect is undesirably reduced.

There are known several silica gel-coated zinc oxides having different production methods and different coating structures (Japanese Patent Laid-Open No.
-183620, Japanese Patent Application No. 9-529975, JP-A-10-87434, JP-A-10-87434
11-193354), the silica gel coated with zinc oxide used in the present invention may have any manufacturing method or coating structure as long as the weight ratio of silica gel to zinc oxide is within the above range.

Further, when blending the zinc oxide of the present invention with an external preparation for skin, it may be blended after hydrophobization by silicone treatment or the like, if necessary. By combining one or more of the above zinc oxides, a plasminogen activator is adsorbed, and has excellent activity inhibiting action, and furthermore, an extremely safe skin external preparation excellent in skin improving action. Can be provided. There are two types of plasminogen activators, called urokinase and tissue-type plasminogen activator, the former being found in healthy epidermis and the latter being found mainly in diseased epidermis.

The zinc oxide according to the present invention has an adsorbing / inhibiting action on both of these plasminogen activators. When applying an external preparation containing zinc oxide at a high concentration, irritable symptoms and irritation that may be rarely seen in patients such as atopic dermatitis that is sensitive to irritation and severe acne skin And the like are hardly found in the silica gel-coated zinc oxide, and the silica gel-coated zinc oxide according to the present invention is particularly useful as a skin external preparation for improving pathological dermatitis.

The amount of zinc oxide that adsorbs and inhibits plasminogen activator in the external preparation for skin of the present invention is 0.005 to 50.0% by weight, preferably 0.1 to 20.0% by weight of the total amount. It is. If the amount is less than 0.005% by weight, the effects of the present invention cannot be sufficiently exerted.
If it exceeds 0%, it is not preferable because preparation is difficult. The above-mentioned skin external preparation containing zinc oxide which adsorbs and inhibits plasminogen activator, as long as the effects of the present invention are not impaired, components usually used in skin external preparations such as cosmetics and pharmaceuticals, for example, moisturizing Agents, antioxidants, oily components, ultraviolet absorbers, emulsifiers, surfactants, thickeners, alcohols, powder components, coloring materials, aqueous components, water, various skin nutrients, etc., as necessary. be able to.

Further, sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, malic acid, caffeine, tannin, verapamil, tranexamic acid and derivatives thereof Various herbal extracts such as licorice, karin, and Ichiyakuso, drugs such as tocopherol acetate, glycyrrhizic acid, glycyrrhizic acid and derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, kojic acid and the like. Whitening agents, amino acids such as arginine and lysine and derivatives thereof, and sugars such as fructose, mannose, erythritol, trehalose, and xylitol can also be appropriately blended.

The external preparation for skin of the present invention includes, for example, ointments, creams, emulsions, lotions, packs, foundations,
It can be applied in any form as long as it is conventionally used for external preparations for skin, such as lipstick, bath agent, oil removing paper, paper towel, etc., and the dosage form is not particularly limited.

[0033]

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. In addition, all compounding amounts are weight%. Prior to the examples, a description will be given of a test method and a result of a plasminogen activator adsorption action, a plasminogen activator activity inhibitory action, and a skin improvement action of zinc oxide used in the present invention.

1. Plasminogen activator adsorption / inhibition test (in vitro) (1) Preparation of sample talc, mica, kaolin, zeolite, sericite,
Sodium magnesium metasilicate (neusilin), hydroxyapatite, aluminum oxide, silica gel, titanium oxide, the above 10 kinds of inorganic powders other than zinc oxide, and 8 kinds (~) of zinc oxides with different production methods and particle diameters were used as samples. And 0.1% suspension water were prepared to evaluate the adsorption action on urokinase and the activity inhibition action.

(2) Measurement of plasminogen activator adsorbing action Tris-HCl buffer (pH 7.4) was added to 20 μL of sample suspension water to make a total volume of 180 μL, and 20 μL of 10 μg / mL precursor urokinase was added thereto. And left at room temperature for 5 minutes. Thereafter, the sample powder was filtered, and the filtrate was collected. Furthermore, a certain amount of Tris-HCl
The powder was sufficiently washed with a buffer, the filtrate and the washing solution were combined, and this was used as an unadsorbed urokinase solution. TintElize
Using uPA (biopool), the urokinase concentration in the unadsorbed urokinase solution was determined by ELISA, and the amount of urokinase adsorbed on the sample powder was calculated from the value. Table 1 shows the results
Shown in

(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 1000 U / mL of active urokinase was added thereto.
After adding 20 μL, the mixture was left in a thermostat at 37 ° C. After 15 minutes, a specific synthetic substrate of urokinase, S2444 (CHROMOGENI
X) was added, and the mixture was further left at 37 ° C. for 15 minutes. afterwards
After stopping the reaction by adding 20 μL of a 12% aqueous solution of trichloroacetic acid, the sample powder was filtered, and the urokinase activity in the evaluation system was determined by measuring the absorbance of the filtrate at 405 nm. Was calculated. Table 1 shows the results.

2. Skin roughness prevention effect test (in vivo) (1) Sample preparation As in the in vitro test, talc, mica, kaolin, zeolite, sericite, neucillin, hydroxyapatite, aluminum oxide, silica gel, titanium oxide, A total of 18 samples of 8 kinds of zinc oxides were used as samples, and 3% suspension water was prepared for each sample to evaluate the effect of preventing the rough skin caused by the active agent.

(2) Determination of Skin Roughness Prevention Effect Absorbent cotton (2 × 2 cm) soaked with a 5% SDS aqueous solution was applied to two places on the inner side of the forearm of 54 male panels, and fixed for 15 minutes to wash off the active agent. The sample suspension water allocated to each panel and 0.5 mL of water as a control were applied thereto (n = 3). This operation was repeated for 7 days. On the 8th day, the test site was thoroughly washed and left for 60 minutes, and then the degree of rough skin caused by SDS was observed, and a score was given based on the following criteria. Further, the evaluation score difference between the control site and the sample application site was obtained for each panel, and this was summed up for each sample, and the effect of each sample was determined based on the following criteria for preventing skin roughness. The results are shown in Table 1 together with the in vitro results.

<Criterion of rough skin score> Score 4: Clear erythema and / or desquamation is observed. Score 3: Moderate erythema and / or slight desquamation is observed. Score 2: Slight erythema and / or cracks in the stratum corneum are observed. Rating 1: The stratum corneum surface appears whitish or powdery. Rating 0: No symptoms.

<Criteria for Preventing Roughness of Skin Roughness> ＝= Effective effect: score difference of 6 or more ○ = Slightly effective: score difference of 4 or 5 △ = Preventive tendency: score difference of 2 or 3 × = ineffective: score difference of 1 Less than.

[0041]

[Table 1]Sample (Characteristics) Adsorption rate% Inhibition rate% Prevention effect  Talc 68.1 3.9 × Mica 60.3 11.5 × Kaolin 70.1 0 × Zeolite 28.0 0 × Sericite 68.5 0 × Neusilin 84.2 0 × Hydroxyapatite 0 0 × Aluminum oxide 11.0 0 × Silica gel 70.1 0 × Titanium oxide 39.1 0 × Zinc oxide (average particle size (0.5 μm, dry) 47.9 54.1 △ (average particle diameter 0.4 μm, wet) 38.5 56.0 △ (average particle diameter 0.04 μm, wet) 30.1 56.4 △(Calcined in H ₂ = phosphor) 15.6 52.2 ×  Invention product Zinc oxide (average particle diameter 0.02 μm, wet type) 69.7 63.6 ○ Silica-coated zinc oxide (coated with 30% by weight of silica) 76.9 72.1 ◎ Silica-coated zinc oxide (coated with 30% by weight of silica) 70.0 68.6 ○Silica-coated zinc oxide (coated with 30% by weight of silica) 84.5 77.8 ◎ 

As is clear from Table 1, most of the evaluated inorganic powders had a plasminogen activator (urokinase) adsorption effect, but only zinc oxide had an activity inhibitory effect. On the other hand, zinc oxide has a relatively high activity inhibitory effect, but there is also an extremely low adsorption effect such as fluorescent zinc oxide,
When viewed only with zinc oxide, the effect on skin roughness is almost proportional to the plasminogen activator adsorption action. From this fact, it is important for the effect on the skin to have both the action of inhibiting the adsorption of plasminogen activator and the activity of the plasminogen activator. It is understood that those having both of 70% or more have a remarkable effect. Then, it was recognized that the same zinc oxide coating with silica improved the plasminogen activator adsorption effect, the inhibitory effect, and the skin roughness prevention effect.

The following Table 2 shows the results of comparison between the zinc oxide, silica-coated zinc oxide, and a mixture of zinc oxide and silica gel.

[Table 2]Sample (Characteristics) Adsorption rate% Inhibition rate% Prevention effect  Zinc oxide (average particle size 0.02μm, wet type) 69.7 63.6 ○ Zinc oxide / silica gel mixture (weight ratio 7: 3) 82.1 68.8 ○ Silica coated Zinc oxide (coated with 10% by weight silica) 79.0 69.0 ○ Silicon treated silica coated Zinc oxide (10) (3% by weight silicon treatment) NDND ○Silica-coated zinc oxide (coated with 30% by weight of silica) 84.5 77.8 ◎ 

As is clear from Table 2 above, in the case of only mixing zinc oxide and silica gel, although the adsorption rate was improved, no significant improvement was observed in the inhibition rate. On the other hand, it is understood that the silica gel-coated zinc oxide has a remarkable improvement in the inhibition rate and has an extremely high effect of preventing rough skin.

When the silica gel coating amount was 10% (), the effect was slightly inferior to the case of 30% by weight (), but a sufficient effect was confirmed. In addition, as the silica gel coating effect, not only the enhancement effect of the skin roughness improvement effect, but also the irritation reduction effect on the sensitive skin having pathological dermatitis described later is recognized. ~ 70% by weight, especially 5%
Appears significantly at で 40% by weight.

On the other hand, when the silica-coated zinc oxide having a remarkable effect was subjected to a silicon treatment of 3% to impart water repellency ((10)), the sample was not dispersed in the evaluation system due to its hydrophobicity. Adsorption rate and inhibition rate could not be measured (ND)
However, although it was inferior to untreated silica-coated zinc oxide as a result of actual use, a sufficient effect of preventing rough skin was observed.

3. Skin improvement effect actual use test (1) Efficacy test for atopic dermatitis As a sample, a table containing a silica coating of dry zinc oxide with an average particle diameter of 0.04 μm (20% silica coating of Saine Chemical's FINEX-25) 3, a lotion containing a dry zinc oxide having an average particle size of 0.5 μm (Zinc Oxide, manufactured by Sakai Chemical Co., Ltd.) instead of silica-coated zinc oxide as a comparative example (Comparative Product 1), The improvement effect on atopic dermatitis was evaluated using a lotion containing no zinc oxide (Comparative product 2).

That is, 40 patients with atopic dermatitis diagnosed as mild or moderate were divided into two groups of 20 patients each. The group contains the lotion of the product of the present invention and the comparative product 2, and the other group contains the lotion of the comparative product 1 and the comparative product 2.
Assigned randomly to each test site twice daily in the morning and evening, 4
It was applied continuously for weeks. 4 weeks later, flushing, drying (desquamation),
The pruritus was observed and interviewed, and scored according to the following criteria. Further, the score difference between the comparative product 2 and the present invention product or the comparative product 2 and the comparative product 1 was obtained, and the improvement effect was determined based on the following criteria. Table 4 shows the results.

<Criterion> Score 4: Advanced Score 3: Moderate Score 2: Mild Score 1: Minor Score 0: No symptom

<Criteria for judging improvement effect> Significant improvement: score difference 3 or more Improvement: score difference 2 Slight improvement: score difference 1 Invariant: score difference 0 Deterioration: score difference -1 or less

[0051]

[Table 3]Sample (% by weight) Inventive product Comparative product 1 Comparative product 2  Zinc oxide (FINEX-25 coated with silica) 5.0--Zinc oxide (Zinc oxide, Japanese Pharmacopoeia)-5.0-Polyethylene glycol 400 12.0 12.0 12.0 Glycerin 7.0 7.0 7.0 Polyoxyethylene (60 mol) hydrogenated castor oil 1.0 1.0 1.0 Ethyl alcohol 40.0 40.0 40.0 Purified water Residue Residue ResidueFragrance appropriate amount appropriate amount appropriate amount

[0052]

[Table 4] Significant improvementOr the number of improved cases The number of slightly improved cases The number of invariable cases The number of deteriorated cases  Flushing Invented product 5 11 40 Comparative product 1 2 8 9 1 Dry Invented product 8 9 3 0 Comparative product 1 3 6 9 2 Pruritus Invented product 2 8 10 0Comparative product 1 1 7 12 0

As is evident from Table 4, the lotion of the present invention has a more improved effect on atopic dermatitis than the comparative lotion containing zinc oxide, which is generally used in medicine. Was observed. In addition, in general zinc oxide (Comparative Example 1), some cases of worsening of symptoms were observed, and in some cases, the stimulating effect of zinc oxide on pathological dermatitis was observed. In particular, the excellent suitability of silica gel-coated zinc oxide as an external preparation for improving pathological dermatitis was shown.

(2) Effectiveness test on acne skin As a sample, silica coating of wet zinc oxide having an average particle diameter of 0.03 μm (HARCROS ACTIVOX 20% by weight silica coating)
A foundation of the present invention as shown in Table 5 comprising:
Average particle size instead of silica coated zinc oxide for comparison
The improvement effect on acne skin was evaluated using a foundation (comparative product 3) containing 0.04 μm wet zinc oxide (AZO-BS manufactured by Seido Chemical Co., Ltd.).

That is, a panel of 40 women aged 16 to 24 years suffering from acne was divided into two groups of 20 women, and the face was used as a test site.
The group was given the foundation of the product of the present invention, and the other group was given the foundation of Comparative Product 3 for 4 weeks. Four weeks later, the panel itself evaluated the condition of the acne before the test, and reported as “A” if the condition improved, and “B” if the condition remained unchanged or worsened, based on the following criteria. The improvement effect was judged. Table 5 shows the results.

<Criteria for Improvement Effect Evaluation> ＝= High improvement effect: 15 or more out of 20 evaluated as “A” ○ = Effective improvement: 10 to 14 out of 20 evaluated as “A” △ = Improved There is a tendency: 5 to 9 out of 20 evaluate as {A} × = invalid: <A> out of 20 has less than 5 evaluations

[0057]

[Table 5]Sample (% by weight) Inventive product Comparative product 3  Zinc oxide (silica-coated ACTIVOX) 15.0-Zinc oxide (AZO-BS)-15.0 Sericite 48.0 48.0 Talc 20.0 20.0 Titanium dioxide 6.5 6.5 6.5 Iron oxide 3.5 3.5 Squalane 6.0 6.0Sorbitan sesquiolate 1.0 1.0 Improvement effect ◎ △   As can be seen from Table 5, the foundation of the present invention has a comparative
Compared to the foundation of the comparative product, more for acne skin
An excellent improvement effect was observed.

[0058]Example 1 Cream  (Formulation)% by weight 1) Monoglyceride stearate 2.0 2) Stearyl alcohol 4.0 3) Beeswax 3.0 4) Lanolin 5.0 5) Ethyl paraben 0.3 6) P.O. O. E (20 mol) sorbitan monooleate 2.0 7) Squalane 20.08) Zinc oxide (FINEX-25 coated with silica) 5.0 9) Fragrance 0.2 10) 1,3-butylene glycol 5.0 11) Glycerin 5.0 12) Purified water residue (Preparation method) 1) to 7) and 9) are heated and kept at 75 ° C.
(Oil phase). After dissolving 10) and 11) in 12), add 8) and
Disperse and heat to 75 ° C. (aqueous phase). Add water phase to oil phase
And emulsify uniformly with a homomixer.
Cool to 0 ° C.

[0059]Example 2 Powdered external preparation  (Formulation)% by weight 1) Talc 49.95 2) Zinc oxide (FINEX-50 coated with silica) 50.0 3) Fragrance 0.05 (Preparation method) 1) and 2) should not be sufficiently stirred and mixed with a blender.
Spray 3) uniformly.

[0060]Example 3 Baby powder  (Prescription)% by weight 1) Talc 77.0 2) Calcium carbonate 17.0 3) Starch 0.5 4) Zinc oxide (FINEX-75 coated with silica) 5.0 5) Disinfectant 0.3 6) Preservative 0 .2 (Production method) 1) to 6) are mixed well with a blender.

[0061]Example 4 Lipstick  (Formulation)% by weight 1) Hydrocarbon wax 3.0 2) Candelilla wax 1.0 3) Glyceryl isostate 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 (ACTIVOX coated with silica) 3.0 9) Titanium dioxide 4.0 10) Fragrance 0.002 (Production method) 1) to 4) are heated and melted at 85 ° C. And this 5)
Add 9), stir and mix, then 10) stir and mix and place in a container
Fill and cool.

[0062]Example 5 Emulsion foundation  (Formulation)% by weight 1) Stearic acid 0.4 2) Isostearic acid 0.3 3) Cetyl 2-ethylhexanoate 4.0 4) Liquid paraffin 11.05) O. E (10) Stearyl ether 2.0 6) Talc 15.0 7) Red iron oxide 0.01 8) Yellow iron oxide 0.001 9) Black iron oxide 0.05 10) Cetyl alcohol 0.3 11) Preservative 0.07 12) Zinc oxide (FINEX-25 coated with silicon-treated silica) 5.0 13) Triethanolamine 0.4 14) Propylene glycol 5.0 15) Fragrance 0.01 16) Purified water residue (Production method) 1) After melting 11) by heating to 85 ° C, 12)
Add and disperse uniformly. 13) 14) 16) to 85 ℃
The mixture obtained by heating and mixing is gradually added and emulsified. During emulsification
After stirring for 10 minutes while maintaining the temperature, stir and cool to 45 ° C.
And Add 15) to this and continue stirring and cooling to 35 ° C.
Fill container.

[0063]Example 6 Pack  (Formulation)% by weight 1) Polyvinyl alcohol 15.0 2) Polyethylene glycol 3.0 3) Propylene glycol 7.0 4) Ethanol 10.0 5) Zinc oxide (Silica coated exact same) 10.0 6) Methyl paraben 0. 05 7) Fragrance 0.1 8) Purified water Residue (Production method) 2) 3) 6) is added to 8) and dissolved. Then
After adding 1) and dissolving by heating, 5) is dispersed. 4)
Add 7) and dissolve with stirring.

[0064]Example 7 Stick Foundation  (Prescription)% by weight 1) Titanium dioxide 13.0 2) Kaolin 12.0 3) Zinc oxide (ACTIVOX coated with silica) 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 sesquiolate 1.0 10) Microcrystalline wax 4.0 11) Carbanalow 1.3 12) Fragrance 0. 2 (Production method) 7) to 9) were mixed at 80 ° C, and 1) to
6) Add, mix with a disc, and TK mill.
You. Furthermore, heat-dissolved 10) and 11) are added and mixed.
Degas after joining. 12) After gently mixing, mix at 80 ° C.
Fill vessel and cool.

[0065]Example 8 Solid powder foundation  (Prescription) 1) Sericite 22.0 2) Synthetic mica 15.0 3) Residual talc 4) Silica anhydride-coated zinc oxide 7.0 (Silica anhydride 20% by weight average particle size 0.03 μm) 5) Bengala 0 .8 6) Yellow iron oxide 2.0 7) Black iron oxide 0.1 8) Zinc white 2.0 9) Silicone elastic powder 2.0 10) Spherical polyethylene 4.0 11) Dimethyl polysiloxane 3.0 12) Liquid paraffin 5.0 13) Vaseline 5.0 14) Sorbitan sesquiisostearate 1.0 15) Paraben appropriate amount 16) Antioxidant appropriate amount 17) Perfume appropriate amount (Production method) 1) to 17) are mixed well with a blender. .

[0066]Example 9 W / O type emulsified makeup base  (Formulation) 1) Cyclomethicone 30.0 2) Dimethicone 2.0 3) Silicone resin 1.0 4) Antioxidant appropriate amount 5) Octylmethoxycinnamate 3.0 6) 4-tertbutyl-4'-methoxybenzoyl Methane 1.0 7) Isostearic acid 1.0 8) Silicone-treated alumina 8.0 9) Cation-modified bentonite 2.0 10) Silicic anhydride-composited zinc oxide 5.0 (Siliconic anhydride 30% by weight average zinc oxide particles) Diameter 0.1μm) 11) Talc 5.0 12) Spherical PMMA resin powder 5.0 13) Ion-exchanged water Remaining 14) Glycerin 4.0 15) Polyethylene glycol 1.0 16) Preservative proper amount 17) Stabilizer proper amount 18) Appropriate amount of fragrance (Production method) 1) ~ 9), 12), 16) ~ 18) heated to 85 ℃
Dissolve, add 10), 11) and disperse (oil phase). 13)
Add 14) and 15) and disperse uniformly (aqueous phase). In the aqueous phase
The oil phase was added, and the mixture was stirred at 85 ° C. for 100 minutes.
Thereafter, the mixture is stirred and cooled to 45 ° C.

[0067]Example 10 W / O emulsification foundation  1) Silicone-treated synthetic mica 15.0 2) Silicone-treated sericite 7.0 3) Silicone-treated titanium oxide 12.0 4) Silicone-treated Bengala 1.2 5) Silicone-treated yellow iron oxide 2.3 6) Silicone-treated black Iron oxide 0.6 7) Silica anhydride-coated fine particle zinc oxide 12.0 (silica anhydride 10% by weight, zinc oxide average particle diameter 0.02 μm) 8) Spherical PMMA powder 4.0 9) Cyclomethicone residue 10) Dimethyl Polysiloxane 4.0 11) Squalane 3.0 12) Polyether-modified silicone 2.0 13) Sorbitan sesquiisostearate 1.0 14) Dispersing aid Suitable amount 15) Dipropylene glycol 2.0 16) Ion exchange water 20 0.0 17) Paraben appropriate amount 18) Antioxidant appropriate amount 19) Flavor appropriate amount (Preparation method) 1) to 14) are heated and dissolved at 85 ° C (oil phase).
Add 15) to 16) and disperse uniformly (aqueous phase). In the aqueous phase
The oil phase was added, and the mixture was stirred at 85 ° C. for 100 minutes.
Thereafter, 17) to 19) are added, and the mixture is stirred and cooled to 45 ° C.

[0068]Example 11 White powder  1) Residual talc 2) Synthetic mica 22.0 3) Silica anhydride coated fine particle zinc oxide 13.0 (Silica anhydride 20% by weight, particle diameter about 0.03 μm) 4) Spherical silicone powder 4.0 5) Squalane 3 6) Proper amount of paraben 7) Proper amount of fragrance (Preparation method) 1) to 6) should not be sufficiently stirred and mixed with a blender.
Spray 7) uniformly.

[0069]Example 12 O / W emulsion foundation  1) Sericite 17.0 2) Mica 20.0 3) Silica anhydride coated zinc oxide 8.0 (silica anhydride 10% by weight, zinc oxide average particle size 0.03 μm) 4) Bengala 0.3 5) Yellow Iron oxide 1.2 6) Black iron oxide 0.6 7) Spherical polyethylene powder 6.0 8) Squalane 10.0 9) Olive oil 10.0 10) Stearic acid 2.0 11) Glyceryl monostearate 2.0 12 ) POE (40) sorbitan monostearate 2.0 13) glycerin 5.0 14) triethanolamine 0.8 15) pH adjuster qs 16) preservative qs 17) ion exchange water balance (production method) 1) ~ 12 ) Is heated and dissolved at 85 ° C. (oil phase).
Add 13) to 15) to 17) and uniformly disperse (aqueous phase). water
Add oil phase to the phase, hold at 85 ° C for 100 minutes and stir
After that, 16) was added, and the mixture was stirred and cooled to 45 ° C.

[0070]Example 13 O / W type emulsified makeup base  1) ion-exchanged water balance 2) glycerin 20.0 3) 1,2-pentanediol 3.0 4) 1,3-butylene glycol 1.0 5) liquid paraffin 7.5 6) isostearic acid 0.5 7) Ascorbic acid (whitening agent) 0.2 8) Chamomile extract (whitening agent) 0.1 9) Saxifraga extract (whitening agent) 0.3 10) Di-2-ethylhexyl phthalate 0.3 11) Spherical silica 4.0 12 ) Silicic anhydride-composited zinc oxide 5.0 (40% by weight of silicic anhydride, average particle diameter of zinc oxide 0.03 μm) 13) Talc 5.0 14) Suitable amount of stabilizer 15) Suitable amount of fragrance (Production method) 5) ~ 14) is heated and dissolved at 85 ° C. (oil phase).
2) to 4) are added to 1) and uniformly dispersed (aqueous phase). water
Add oil phase to the phase, hold at 85 ° C for 100 minutes and stir
After that, 15) is added, and the mixture is stirred and cooled to 45 ° C.

[0071]Example 14 Oily Eye Shadow  1) Dimethicone 10.0 2) Ester oil 10.0 3) Liquid paraffin balance 4) Squalane 10.0 5) Sorbitan sesquiisostearate 1.0 6) Polyethylene wax 8.0 7) Selecin wax 3.0 8) Mica 7.0 9) Spherical cellulose powder (about 6 μm) 5.0 10) Titanium mica titanium 8.0 11) Silicic anhydride composite zinc oxide 7.0 (Siliconic anhydride 35% by weight, average zinc oxide particle diameter 0) .01 μm) 12) Kaolin 10.0 13) Suitable amount of antioxidant 14) Suitable amount of fragrance (Preparation method) 1) to 7) are heated and dissolved at 85 ° C, and 8)
~ 12) is added and stirred and mixed, and then 13) and 14) are stirred and mixed.
Fill container and cool.

[0072]Example 15 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. 7) ester oil balance 8) titanium oxide 4.5 9) Red No. 201 0.5 10) Red No. 202 1.1 11) Red No. 223 0.3 12) Spherical polyethylene powder (about 5 μm) 3.0 13) Bengala-coated interference mica titanium 12.0 14) Silica anhydride-coated zinc oxide 5.0 (20% by weight of silicic anhydride, zinc oxide average particle diameter 0.03 μm) 15) Boron nitride powder (average particle diameter 15 μm) 5.0 16) Antioxidant appropriate amount 17) Appropriate amount of fragrance (Preparation method) 1) to 7) are dissolved by heating at 85 ° C, and
~ 15) and mix with stirring, then mix with 16) and 17),
Fill container and cool.

[0073]Example 16 Dual-Use Powder Foundation  1) Silicone-treated sericite 13.0 2) Silicone-treated mica Remaining 3) Silicone-treated talc 15.0 4) Silica anhydride-coated zinc oxide 5.0 (20% weight of silicic anhydride, average particle size 0.03 μm) 5) Aluminum stearate-treated fine particle titanium oxide 6.0 6) Silicone-treated titanium oxide 9.0 7) Silicone-treated red iron oxide 1.2 8) Silicone-treated yellow iron oxide 2.5 9) Silicone-treated black iron oxide 0.910 ) Barium sulfate powder 7.0 11) Polyurethane powder 1.0 12) Silicone elastic powder 5.0 13) Polyethylene powder 2.0 14) Titanium mica 4.0 15) Paraben proper amount 16) Dimethyl polysiloxane 3.0 17) Methylphenylpolysiloxane 2.0 18) Vaseline 2.0 19) Octyl methoxycinnamate 3.0 20) Sorbitan sesquis Stearate 1.0 21) Polyether silicone 1.0 22) Antioxidant suitable amount 23) Perfume suitable amount (Preparation method) 1) to 22) were heated and mixed at a 85 ° C., 23)
Spray evenly.

[0074]Example 17 Dual-Use Powder Foundation  1) Fluorine-modified silicone-treated sericite 22.0 2) Fluorine-modified silicone-treated mica Remaining amount 3) Fluorine-modified silicone-treated kaolin 10.0 4) Silica anhydride-coated zinc oxide 7.0 (10% by weight of silicic anhydride, average) 5) Silicon-treated fine particle titanium oxide 8.0 6) Fluorine-modified silicone-treated titanium oxide 9.0 7) Fluorine-modified silicone-treated Bengala 1.2 8) Fluorine-modified silicone-treated yellow iron oxide 2.59 ) Fluorine-modified silicone-treated black iron oxide 0.9 10) Spherical silicone powder 8.0 11) Lauroyl lysine coated titanium oxide 4.0 12) Paraben suitable amount 13) Dimethyl polysiloxane 4.0 14) Polyethylene glycol 2.0 15) Fluoropolyether 2.0 16) Octyl methoxycinnamate 2.0 17) Sorbitan sesqui Sosuteareto 1.0 18) Antioxidant suitable amount 19) Perfume suitable amount (the production method) 1) to 18) after heat-mixed at a 85 ° C. 19)
Spray evenly.

[0075]Example 18 Cleaning Wiping Agent  1) Ion-exchanged water 91.945 2) Salt (listed in the Japanese Pharmacopoeia) 0.35 3) Dipropylene glycol 2.0 4) Sodium hexametaphosphate 0.005 5) Silicic anhydride-coated zinc oxide 5.0 6) Bentonite 0.5 7) Methyl paraben 0.1 8) POE (20) octyl dodecyl ether 0.1 (Preparation method) 2) to 8) are dissolved and stirred in 1) with good stirring.
Dust and impregnate it into the nonwoven.

[0076]Example 19  1) Colorant 25 2) Silicic anhydride-coated zinc oxide 3 3) Sodium carboxymethylcellulose 0.2 4) Sodium dehydroacetate 0.1 5) Sodium metaphosphate 0.2 6) Polyoxyethylene sorbitan monooleate 0.2 (20E.O.) 7) Fragrance 0.1 8) Suitable amount of ordinary water 100% by weight Total (production method) 8) 1) to 7) mixed with a coating liquid on paper
After processing, it is dried.

Each of the skin external preparations of Examples 1 to 19 has a plasminogen activator adsorption / inhibition effect, and has contact dermatitis, psoriasis, atopic dermatitis, and rough skin experienced by healthy persons. Alternatively, it shows an excellent improvement / prevention effect on acne.

[0078]

As described above, according to the present invention,
Since specific zinc oxide is used as the plasminogen activator inhibitor, it can exhibit high safety and excellent inhibitory effect. In addition, in the present invention, particularly by using silica gel-coated zinc oxide as a plasminogen activator inhibitor, it does not exhibit hypersensitivity to pathological dermatitis such as atopic dermatitis, and has a high preventive / ameliorating effect. Can be demonstrated.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 7/032 A61K 7/032 7/035 7/035 7/48 7/48 47/04 47/04 A61P 17/00 A61P 17/00 43/00 111 43/00 111 G01N 33/15 G01N 33/15 Z 33/573 33/573 A (72) Inventor Katsumoto Ogawa 2-2-1 Hayabuchi, Tsuzuki-ku, Yokohama, Kanagawa Prefecture No. Shiseido Research Center (Shin-Yokohama) (72) Inventor Daisuke Aso 2-2-1 Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa Prefecture Shiseido Research Center (Shin-Yokohama)

Claims (10)

[Claims] 1. A plasminogen activator inhibitor comprising one or more zinc oxides that adsorb plasminogen activator and inhibit its activity. 2. The plasminogen activator inhibitor according to claim 1, wherein the plasminogen activator has an adsorption rate of 60% or more and an inhibition rate of 60% or more. The adsorption rate and inhibition rate of the plasminogen activator are measured by the following methods. Measurement of plasminogen activator adsorption effect After mixing a 0.1% test sample and a single-chain urokinase-type plasminogen activator (1 µg / mL) in a buffer for a certain period of time, remove the test sample. The remaining single-chain urokinase-type plasminogen activator in the buffer
Evaluation was performed by quantification by ELISA. Measurement of inhibitory action on plasminogen activator activity The evaluation was made based on the synthetic substrate degradation activity of a buffer containing 0.1% of a test sample and a double-chain urokinase-type plasminogen activator (100 U / mL). 3. The inhibitor according to claim 2, wherein the plasminogen activator adsorption rate and the inhibition rate are 70%.
A plasminogen activator inhibitor, which is zinc oxide as described above. 4. The inhibitor according to claim 1, wherein the zinc oxide is zinc oxide whose surface is coated with 0.1 to 70% by weight of silica gel. Activator inhibitor. 5. An external preparation for improving rough skin, which comprises a powder that adsorbs plasminogen activator and inhibits its activity. 6. An external preparation for improving rough skin, comprising one or more of the plasminogen activator inhibitors according to claim 1. Description: 7. An external preparation for the treatment of pathological dermatitis, which comprises one or more of the plasminogen activator inhibitors according to claim 4. Description: 8. A method for suppressing plasminogen activation, comprising adsorbing plasminogen activator to a powder and inhibiting its activity. 9. A method for improving skin roughness, which comprises applying to the skin a powder that adsorbs plasminogen activator and inhibits its activity. 10. An external preparation for improving skin roughness, which comprises zinc oxide.