JP2010126494A - Scf isolation inhibitor and antipruritic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a formulation effectively suppressing SCF (Stem Cell Factor) isolation from epidermal keratinocytes in behavior of SCF caused by stimulation of drying, UV irradiation and the like, also provide an antipruritic agent and an external composition for skin preventing abnormal growth of mast cells and abnormal degranulation by suppressing the SCF isolation to suppress isolation of chemical mediators such as histamine from the mast cells, thereby preventing itch, chapped skin, sensitive skin and the like, in particular, preferably used for preventing and ameliorating dry skin diseases represented by atopic dermatitis and xeroderma. <P>SOLUTION: An SCF isolation inhibitor comprising Sekihira mineral water, an antipruritic agent and an external agent for skin comprising 10-95 mass% SCF isolation inhibitor and 1-30 mass% humectant and used in a form of mist spray are provided. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an SCF release inhibitor and an antipruritic agent that suppress the release of stem cell factor (SCF: stem cell factor; hereinafter also referred to as “SCF”) from epidermal keratinocytes. The present invention is particularly suitably used for the prevention and improvement of dry skin diseases represented by atopic dermatitis and xeroderma.

  SCF [also known as kit ligand (= KL), mast cell growth factor (= MCGF)] is a protein produced in keratinocytes, fibroblasts, vascular endothelial cells and the like. Examples of the action of SCF include proliferation of undifferentiated hematopoietic stem cells, promotion of germ cell differentiation, promotion of mast cell (= mast cell) growth, and promotion of pigment cell proliferation. It is known that SCF includes a membrane-bound type (SCF-2) and a secreted type (SCF-1) that is released from a membrane cleaved by the action of a proteolytic enzyme. SCF-2 binds to keratinocytes and binds to the SCF receptor of the pigment cells to activate the proliferation of the pigment cells, and SCF-1 is cleaved at the cleavage site and released from the cell membrane to cause pigment cells and It binds to the SCF receptor of mast cells, leading to proliferation activation of pigment cells and activation of mast cell proliferation and degranulation (see Non-Patent Document 1). Such binding to the SCF receptor is promoted by the skin receiving a stimulus such as dryness or ultraviolet rays. Abnormal production or release of SCF also leads to abnormal growth and abnormal degranulation of mast cells, which enhances the release of chemical mediators such as histamine, serotonin, and LTB4 from the mast cells (see Non-Patent Document 2). Cause rough skin and sensitive skin.

  Therefore, in order to prevent and improve pruritus, rough skin, sensitive skin, etc. caused by the release of chemical mediators such as histamine from mast cells, measures to prevent abnormal production of SCF and release of SCF from keratinocytes are available. It is effective.

  Conventionally, as SCF production-suppressing preparations and SCF release-suppressing preparations, for example, SCF production-inhibiting and releasing, such as SCF release-inhibiting agents (patent document 1) containing extracts of jatoba and / or rock cabbage, hop extract, hawthorn extract A skin external preparation for pruritus (Patent Document 2) and the like containing a component that suppresses the skin has been proposed. In addition, a method for screening an active ingredient that exhibits an effect of improving pruritus, rough skin, or sensitive skin by suppressing the production and / or release of SCF has been proposed (Patent Document 3).

  As will be described later, the present invention is an invention using Kanpei mineral spring water, but conventionally, inventions utilizing mineral spring water and hot spring water are disclosed in, for example, Patent Documents 4 to 6 shown below. .

  That is, Patent Document 4 (Japanese Patent No. 2636140) discloses an atopy in which a mineral composition in which a mixture of sodium chloride and seawater silvin is mixed with citrate is added to hot spring water (bicarbonate earth spring, sulfur spring). A hot spring water composition for the treatment of atopic dermatitis is disclosed. This hot spring water composition is used for hot spring bathing therapy, and it is described that it can be treated in a relatively short period of time compared to conventional hot spring bathing therapy. It is described that, after dissolving in 10 times the amount of tap water, the effect of stopping itchiness can be obtained by warming to a suitable temperature in a bath and bathing in this bath.

  Patent Document 5 (Japanese Patent Application Laid-Open No. 2002-326842) discloses that a topical skin preparation containing a specific mineral spring water, hot spring flower, and / or hot spring flower extract has effects such as improvement of rough skin and acne. Are listed.

  Patent Document 6 (Japanese Patent Application Laid-Open No. 2005-40403) describes a cosmetic for sensitive skin mainly composed of Avene hot spring water and a cosmetic treatment method using the cosmetic.

  However, these Patent Documents 4 to 6 do not describe or suggest SCF release inhibition.

JP 2006-241102 A JP 2006-56902 A Japanese Patent No. 3759714 Japanese Patent No. 2636140 JP 2002-326842 A JP 2005-40403 A T. Kunisada et al., J. Exp. Med., Vol.187, No.10, (1998) pp.1565-1573 J. Grabbe et el., Arch Dermatol Res, 287: 78-84, (1994)

  An object of the present invention is to provide a preparation that effectively suppresses the release of SCF from epidermal keratinocytes, among the behavior of SCF caused by stimulation such as drying or ultraviolet irradiation. In addition, the present invention prevents abnormal growth and abnormal degranulation of mast cells by inhibiting SCF release, thereby suppressing the release of chemical mediators such as histamine from the mast cells, thereby causing pruritus, rough skin, sensitive skin, etc. In particular, an object of the present invention is to provide an antipruritic agent suitably used for preventing and ameliorating dry skin diseases represented by atopic dermatitis and dry skin disease, and an external preparation for skin. To do.

  In order to solve the above-mentioned problems, the present invention provides an SCF release inhibitor comprising Sekihira mineral spring water.

  Moreover, this invention provides the antipruritic agent containing the SCF release inhibitor which consists of Sekihira mineral spring water.

  The present invention also provides a skin external preparation characterized by containing 10 to 95% by mass of an SCF release inhibitor composed of Sekihira mineral spring water and 1 to 30% by mass of a humectant, and being used in the form of a mist spray.

  According to the present invention, an SCF release inhibitor capable of effectively suppressing SCF release, an antipruritic agent, and a skin external preparation are provided. The present invention is particularly suitably used for the prevention and improvement of dry skin diseases represented by atopic dermatitis and xeroderma.

  When water containing minerals springs from the ground to the ground surface, this is called a mineral spring, and a hot spring is generally called a hot spring. The Sekihira mineral spring water used in the present invention is a mineral spring water that springs from the foot of Kirishima Island in Makinoen, Kagoshima Prefecture. Kanpei mineral spring water is a hot spring water that springs in the nature of the foot of Kirishima, the first national park in Japan, and since it has traveled deep underground under high heat, many minerals melted by the high heat underground. Is included.

According to Article 2 of the Hot Spring Law, hot springs are warm water, mineral water, water vapor and other gases (excluding natural gas mainly composed of hydrocarbons) that springs out of the ground. Defined as having a substance. In other words, any condition of the temperature and the substance may be satisfied. The temperature may be 25 ° C. or higher when collected from a hot spring source, and the substance may contain any one or more listed in a separate table (omitted) in a predetermined amount (in 1 kilogram). As substances listed in the attached table, the total amount of dissolved substances (excluding gaseous substances) is 1,000 mg or more, free carbonic acid (CO ₂ ) is 250 mg or more, and various ions (Li ⁺ , Sr ⁺⁺ , Ba ^++). Fe ⁺⁺ or Fe ⁺⁺⁺ , Mn ⁺⁺ , H ⁺ , Br ⁻ , I ⁻ , F ⁻ , HASO 4 ⁻ , etc.), meta arsenous acid (HASO ₂ ), total sulfur (S), meta boric acid (HBO ₂ ), metasilicic acid (H ₂ SiO ₃ ) sodium bicarbonate (NaHCO ₃ ), radon (Rn), radium salt (as Ra), etc. (each with a predetermined amount or more) are described.

  Kanpei mineral spring water is mineral water that falls under the category of hot spring water as defined in the Hot Spring Law and meets the standard items of “Regular Water” of the Japanese Pharmacopoeia so that it can be incorporated into quasi drugs. Excellent supply stability and quality stability.

  Sekihira mineral spring water is also sold as “Kanpira mineral spring water” (registered trademark) at the Kanahira mineral spring sales office in Makion-cho, Kagoshima Prefecture.

  In addition, as a comparison of the mineral composition (unit: mg / L) of Sekihira mineral spring water and other mineral spring water, what was compared with Aqua Panna natural mineral water is shown in Table 1 below.

  Compared with Aqua Panna Natural Mineral Water, it is characterized by low hardness and a high content of potassium, magnesium and calcium.

  Sekihira mineral spring water used in the present invention has an excellent SCF release inhibitory action and is used as an SCF release inhibitor. By applying the SCF release inhibitor to the skin or the like, it is useful for the treatment, prevention, improvement, and the like of various symptoms, diseases, and pathologies caused by SCF release. Specific examples of application include prevention and improvement of dry skin diseases, pigmentation such as stains, and the like. Among them, it is suitably used for the prevention and improvement of dry skin diseases. Dry skin diseases are diseases represented by atopic dermatitis, dry skin disease, contact dermatitis, hand (housewife) eczema, dry eczema, etc. And Therefore, it is possible to effectively suppress itching by applying the preparation of the present invention to these skin diseases, and it is also used as an antipruritic agent.

  When the SCF release inhibitor of the present invention is blended in a skin external preparation, the dosage form is not particularly limited, and is a solution system, a solubilization system, an emulsification system, an oil liquid system, a gel system, a powder dispersion system, water, and the like. -Oil two-layer system, water-oil-powder three-layer system, etc. are arbitrary. The topical skin preparation of the present invention refers to those applied to the outer skin (including the scalp) as cosmetics, pharmaceuticals, and quasi-drugs. For example, facial cosmetics such as skin lotions and emulsions, and scalp and hair makeup. It can be used as a fee.

  Among these, from the viewpoints of ease of use, convenience, etc., the skin external preparation of the present invention is preferably in the form of lotion used in the form of spray mist. By using a spray mist, it is possible to quickly relieve itchiness by spraying on the scooping area easily and anytime and anywhere. For example, it can be used easily and easily even from above the stockings. Further, even if it is sprayed directly on the face or a part close to it, it can effectively and quickly reduce itching without causing makeup collapse.

  When the skin external preparation is a skin lotion used in the form of a spray mist, the spray mist may be either an aerosol type or a non-aerosol type. In the aerosol type, a propellant is blended in addition to the lotion (stock solution).

  The skin lotion used in the form of the spray mist contains Sekihira mineral spring water and a humectant.

  The blending amount of Kanpei mineral water is preferably 10 to 95% by mass, more preferably 40 to 92% by mass, and most preferably 70 to 90% by mass. If the Sekihira mineral spring water is less than 10% by mass, it is difficult to obtain the effects of the present invention.

  Examples of the humectant include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, hexylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, carolinic acid, atelocollagen, cholesteryl-12. -Hydroxy stearate, sodium lactate, bile salt, dl-pyrrolidone carboxylate, short chain soluble collagen, diglycerin (EO) PO adduct and the like are exemplified. However, it is not limited to these examples. One or more moisturizers can be used.

  The blending amount of the humectant is preferably 1 to 30% by mass, more preferably 6 to 25% by mass, and most preferably 10 to 20% by mass. If the humectant is less than 1% by mass, the moisturizing effect is insufficient, while if it exceeds 30% by mass, a sticky tendency is observed.

  Spray mist type lotion can be produced by a conventional method. That is, for example, components such as a moisturizing agent are mixed and dissolved in Sekihira mineral spring water or the like as a solvent to prepare a mixed solution (stock solution), which is filled in a spray container. In the aerosol type, the spray container is usually filled together with a propellant. As the propellant, a propellant known in the aerosol field such as liquefied gas such as propane, butane, pentane and dimethyl ether, and compressed gas such as nitrogen and compressed air can be arbitrarily used. The blending amount of these propellants is preferably 4 to 98% by mass for liquefied gas and 0.2 to 1.2% by mass for compressed gas with respect to 100% by mass of lotion (stock solution). These liquefied gas and compressed gas can be used alone or in combination of two or more.

  The above lotion further contains known components such as water (ion exchange water, purified water, etc.), surfactants, pH adjusters, preservatives, fragrances, oil components, bactericides, plant extracts, vitamins, and the like. It can mix | blend suitably in the range which does not impair an effect.

  Examples of the surfactant include an anionic surfactant, a cationic surfactant, an amphoteric surfactant, a lipophilic nonionic surfactant, and a hydrophilic nonionic surfactant. Of these, hydrophilic nonionic surfactants and cationic surfactants are preferably used, but are not limited thereto.

  Examples of the hydrophilic nonionic surfactant include POE sorbitan fatty acid esters such as POE sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan monooleate, and POE-sorbitan tetraoleate; POE-sorbite mono POE sorbite fatty acid esters such as laurate, POE-sorbite monooleate, POE-sorbite pentaoleate, POE-sorbite monostearate; POE-glycerol monostearate, POE-glycerol monoisostearate, POE-glycerol tris POE glycerin fatty acid esters such as isostearate; POE fatty acid ester such as POE monooleate, POE distearate, POE monodiolate, ethylene glycol stearate POE lauryl ether, POE oleyl ether, POE stearyl ether, POE behenyl ether, POE2-octyldodecyl ether, POE cholestanol ether, and other POE alkyl ethers; POE octyl phenyl ether, POE nonyl phenyl ether, POE dinonyl phenyl POE alkylphenyl ethers such as ethers; Pluralonic types such as brulons; POE / POP cetyl ether, POE / POP2-decyltetradecyl ether, POE / POP monobutyl ether, POE / POP hydrogenated lanolin, POE / POP glycerin ether, etc. POE / POP alkyl ethers; Tetronic PTE / Tetra POP ethylenediamine condensates; POE castor oil, POE hard POE castor oil hydrogenated castor oil derivatives such as castor oil, POE hydrogenated castor oil monoisostearate, POE hydrogenated castor oil triisostearate, POE hydrogenated castor oil monopyroglutamic acid monoisostearic acid diester, POE hydrogenated castor oil maleic acid, etc .; POE POE beeswax and lanolin derivatives such as sorbite beeswax; alkanolamides such as coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide, POE propylene glycol fatty acid ester, POE alkylamine, POE fatty acid amide, sucrose fatty acid ester , POE nonylphenyl formaldehyde condensate, alkylethoxydimethylamine oxide, trioleyl phosphate and the like.

  Examples of the cationic surfactant include alkyltrimethylammonium salts such as stearyltrimethylammonium chloride and lauryltrimethylammonium chloride; distearyldimethylammonium dialkyldimethylammonium chloride, and poly (N, N′-dimethyl-3,5-chloride). Methylenepiperidinium), alkylpyridinium salts such as cetylpyridinium chloride, alkyl quaternary ammonium salts, alkyldimethylbenzylammonium salts, alkylisoquinolinium salts, dialkyl morpholinium salts, POE alkylamines, alkylamine salts, Examples include polyamine fatty acid derivatives, amyl alcohol fatty acid derivatives, benzalkonium chloride, and benzethonium chloride.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited thereto. Unless otherwise specified, the blending amount is mass% (actual amount).

Example 1
Measurement of SCF released from keratinocytes by dry stimulation and screening of inhibitory drugs

1. Test sample A product obtained by diluting Sekihira mineral spring water dissolved in distilled water 50 times with serum-free medium after freeze-drying to a concentration 50 times that of the stock solution is referred to as “dry × 1” (see FIG. 1; hereinafter the same). In the same manner, “dry × 10 ⁻¹ ” obtained by diluting Sekihira mineral spring water dissolved in distilled water 50 times with serum-free medium to a concentration 5 times that of the stock solution is 0.5 times the concentration of the stock solution. Sekihei mineral water dissolved in distilled water 50 times diluted with serum-free medium to “dry × 10 ⁻² ”, dissolved in distilled water to a concentration 0.05 times that of the stock solution A culture solution was prepared using “dry × 10 ⁻³ ” obtained by diluting mineral spring water 50-fold with a serum-free medium. A solution obtained by diluting only distilled water 50-fold with a serum-free medium was designated as “dry control”.

2. Test Method Commercially available human epidermal keratinocytes (newborn: Cryo NHEK-Neo, Sanko Junyaku) were cultured using a commercially available serum-free medium (Define Keratinocyte-SFM, Gibco). Cells were plated at 1 × 10 ⁵ cells / mL in a 12-well microplate and cultured at 37 ° C. for about 72 hours until confluent.
The culture solution was replaced with the test sample and incubated at 37 ° C. for 48 hours.
As a drying stimulus, the supernatant was completely removed and then left in a CO ₂ incubator for 1 hour. The medium was then added and the supernatant was collected 2 hours later. The amount of SCF in the supernatant was quantified with a measurement kit (R & D System) by a commercially available ELISA method.
As a control (control, described as “non-stimulation” in FIG. 1) without the drying stimulus, the SCF release amount inhibitory effect of the test sample was evaluated. The results are shown in FIG.

  As is clear from the results of FIG. 1, it was confirmed that the SCF liberation increased by the drying stimulus could be effectively suppressed with the concentration dependency by the addition of Sekihira mineral spring water.

(Example 2)
A use test was conducted using the mineral spring mist of the present invention, and evaluation was performed.

1. Test sample The lotion (stock solution) shown in Table 2 below was filled in an aluminum aerosol can together with a propellant (nitrogen) to form a mineral water mist.

2. Subject Visits a medical institution (hospital dermatology, dermatology clinic), has mild to moderate dry skin disease (atopic dermatitis, xeroderma), and mild to moderate facial Patients over 20 years of age with a dry condition (total 47). Specifically, it is as follows.
Atopic dermatitis patients: 13 (8 mild, 5 moderate)
Xeroderma patients: 34 (24 mild, 10 moderate)

3. Test site On the face, one site was selected where the symptoms of dryness and desquamation were mild to moderate, and no anti-inflammatory skin drug was used during the test, and was designated as the test site.

4). Site of use: Can be used throughout the body.

5). Use period 4 weeks

6). Method of use The test site was used three times a day in the morning, day and night. Especially after bathing. In addition, it was used appropriately when it felt dry or itchy. Use other parts than the test part as appropriate according to the dryness and itchiness. It was an object of evaluation of the stagnation VAS described in 1. At the time of use, it sprayed for 1 to 2 seconds so that it might separate from the use site | part 20cm and draw a circle | round | yen, and it lightly adapted with the palm after that.

7). Evaluation method and evaluation results [Italian VAS]
On the test start date and the test end date (= after 4 weeks), evaluation was performed by VAS (= visual analogue scale), which is widely used as an evaluation scale for itching.
In other words, on each observation day, a paper with a straight line drawn in a 10 cm horizontal line was distributed to the subjects, and the left end of the straight line was regarded as “smudge”, and the right end was regarded as “the highest itch experienced so far”. Enter the average value of the itch you felt in the day before the day (observation date) (= The subject marks one place on the line according to the strength of the itch), and the distance to the site Was evaluated as a measure of itchiness. FIG. 2 shows the VAS result of facial itch and FIG. 3 shows the VAS result of body itch. As apparent from FIGS. 2 to 3, the VAS for itching was significantly reduced for both the face and the body.

[Observation of skin findings (dryness, desquamation)]
At the start of the test and after completion of the test (after 4 weeks), the skin findings (dry / desquamation) of the test site were observed by a doctor, and the degree of the symptom was evaluated according to the following 5 levels. The results are shown in Table 3.
(Evaluation criteria)
0. None (no symptoms)
1. Minor (slight symptom)
2. Mild (slight symptom)
3. Moderate (with obvious symptoms)
4). Severe (significant symptoms)

[Interview of subjective symptoms (itchiness, irritation)]
At the start of the test and after the end of the test (after 4 weeks), doctors were asked about subjective symptoms (pruritus and irritation) at the test site, and the degree of the symptoms was evaluated according to the following five levels. The results are shown in Table 4.
(Evaluation criteria)
0. None (no symptoms)
1. Minor (to the extent that I hardly care)
2. Mild (somewhat anxious)
3. Moderate (somewhat worrisome)
4). Severe (cannot be used because it cannot be used)

  As is apparent from the results of Tables 3 and 4, the use of the skin lotion (moisturizing mist) of the present invention improved dryness, pruritus and irritation.

[Usage feeling]
The subjects asked and answered about the items shown in Table 5 below regarding the feeling of use of the skin lotion (moisturizing mist) of the present invention. The results are shown in Table 5.

  As is clear from the results in Table 5, 80% or more of the subjects answered that they liked freshness, moistness, and lack of tension.

  Hereinafter, formulation examples (spray mist) of the external preparation for skin of the present invention will be shown.

Formulation example 1 (lotion, non-aerosol type mist)
(Mixed component) (mass%)
Kanpei mineral spring water 81.199
Glycerin 5
1,3-butylene glycol 10
PEG-60 hydrogenated castor oil 0.5
Sodium metaphosphate 0.1
Phenoxyethanol 0.1
Cocoyl Arginine Ethyl PCA 0.001
Xylitol 1
Erythritol 1
Artemisia extract 0.5
Ginkgo biloba extract 0.5
Citric acid 0.05
Sodium citrate 0.05

Formulation example 2 (lotion, non-aerosol type mist)
(Mixed component) (mass%)
Sekihira mineral spring water 65.28
Ethanol 5
Glycerin 10
1,3-butylene glycol 5
Dipropylene glycol 10
PPG-13 decyltetradeces-24 0.3
PEG-60 hydrogenated castor oil 0.3
Sodium metaphosphate 0.01
Phenoxyethanol 0.5
Xylitol 3
Sodium hyaluronate 0.01
Izayoi Rose Extract 0.5
Citric acid 0.05
Sodium citrate 0.05

Formulation Example 3 (lotion, aerosol mist)
(Mixed component) (mass%)
(Stock solution)
Sekihira mineral spring water 74.48
Ethanol 5
Glycerin 1
1,3-butylene glycol 5
Dipropylene glycol 10
PPG-13 decyltetradeces-24 0.1
PEG-60 hydrogenated castor oil 0.3
Sodium metaphosphate 0.01
Phenoxyethanol 0.5
Xylitol 3
Sodium hyaluronate 0.01
Izayoi Rose Extract 0.5
Citric acid 0.05
Sodium citrate 0.05
(Propellant)
Nitrogen gas 0.5

Formulation Example 4 (Lotion, non-aerosol mist)
(Mixed component) (mass%)
Sekihira mineral spring water 10
Ion exchange water 86.89
1,3-butylene glycol 5
PEG / PPG-14 / 7 dimethyl ether 5
PEG-60 hydrogenated castor oil 0.5
Polyglyceryl-2 diisostearate-2 0.2
Triethylhexanoin 0.5
Methylparaben 0.3
PEG-20 1
L-Magnesium phosphate ascorbate 0.01
Cuckoo extract 0.5
Citric acid 0.05
Sodium citrate 0.05

In Example 1, it is a graph which shows that the amount of SCF in the normal human cultured epidermal keratinocyte supernatant by dry stimulation was released and suppressed in a concentration-dependent manner by the addition of Sekihira mineral spring water. In Example 2, it is a graph which shows the VAS evaluation result of the facial itch. In Example 2, it is a graph which shows the VAS evaluation result of a body itch.

Claims (3)

  SCF release inhibitor consisting of Sekihira mineral spring water.   An antipruritic agent comprising the SCF release inhibitor according to claim 1.   A skin external preparation characterized by containing 10 to 95% by mass of the SCF release inhibitor according to claim 1 and 1 to 30% by mass of a humectant and being used in the form of a mist spray.

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