JP7313111B2 - Sebum secretion stimulator and composition for external use - Google Patents

Description

TECHNICAL FIELD The present invention relates to a sebum secretion stimulant capable of promoting sebum secretion. The present invention also relates to a composition for external use having an excellent sebum secretion promoting effect.

Sebum has the effect of imparting flexibility, elasticity, moisturizing properties, etc. to the skin and protecting the skin from ultraviolet rays, bacteria, etc., and plays an important role in maintaining a normal skin condition. Sebum is secreted by the sebaceous glands, but the amount of secretion may decrease due to factors such as age, constitution, season, lifestyle, and drug administration. Decreased sebum secretion reduces skin flexibility, elasticity, moisture retention, skin resistance, etc., and is a factor in the deterioration of skin barrier function. It is also a factor in skin symptoms and diseases such as sebum deficiency, sebum deficiency eczema, xerosis, atopic dermatitis, dry skin, cracks, and chapped skin.

Conventionally, as a countermeasure against a decrease in sebum secretion, a method of supplying oil to the skin using an external composition containing oils such as triglycerides, wax esters, squalene, and free fatty acids, which are constituents of sebum, is known. However, such a method is only a remedy for a decrease in sebum secretion, has a limited effect, and has the drawback of not being a fundamental solution.

On the other hand, as a countermeasure against the decrease in sebum secretion, there is also known a method of increasing the sebum secretion itself by using a component capable of promoting sebum secretion. Since such a method activates the sebaceous glands, it is expected to effectively improve skin with decreased sebum secretion.

Conventionally, various reports have been made on ingredients that promote the secretion of sebum. For example, γ-oryzanol is known to promote sebum secretion. In addition, it has been reported that the extract, bryonolic acid, and malto-oligosaccharide have sebum secretion-promoting action and can be used as a sebum secretion-promoting agent (see Patent Documents 1 to 3). However, in order to respond to the diversification of pharmaceutical formulations, further improvement of sebum secretion-promoting action, and the like, development of new formulation techniques for promoting sebum secretion is desired.

JP-A-9-176030 JP-A-7-109214 JP-A-5-294837

An object of the present invention is to provide a sebum secretion stimulator that promotes sebum secretion.

The present inventors conducted intensive studies to solve the above problems, and found that by using at least one selected from the group consisting of heparin analogues, diphenhydramine, and salts of diphenhydramine together with γ-oryzanol, a remarkably excellent sebum secretion effect can be exhibited. In particular, it was found that the combined use of γ-oryzanol, a heparinoid, and diphenhydramine and/or a salt thereof synergistically improves sebum secretion. The present invention has been completed through further studies based on such findings.

That is, the present invention provides inventions in the following aspects.
Item 1. A sebum secretion stimulant containing (A) γ-oryzanol and (B) at least one selected from the group consisting of a heparinoid, diphenhydramine, and a salt of diphenhydramine.
Section 2. Item 2. The sebum secretion stimulant according to Item 1, which contains at least a heparinoid as the component (B).
Item 3. Item 3. The sebum secretion stimulant according to Item 1 or 2, wherein the component (B) is a combination of a heparinoid and diphenhydramine and/or a salt thereof.
Section 4. Item 4. The sebum secretion stimulator according to any one of Items 1 to 3, which is an external preparation for skin.
Item 5. A composition for external use comprising (A) γ-oryzanol, (B-1) a heparinoid, and (B-2) diphenhydramine and/or a salt thereof.

According to the sebum secretion stimulator of the present invention, the secretion of sebum can be remarkably promoted, so that it is possible to improve or maintain a normal skin condition.

After each cream was applied inside the auricle of a golden hamster for a predetermined period, a dermal sheet was prepared from the applied part, and the sebaceous gland was stained with Sudan III and observed under a microscope.

1. Sebum Secretion Promoting Agent The sebum secretion promoting agent of the present invention is characterized by containing γ-oryzanol (hereinafter sometimes referred to as component (A)) and at least one selected from the group consisting of heparinoids, diphenhydramine, and salts of diphenhydramine (hereinafter sometimes referred to as component (B)). The sebum secretion stimulator of the present invention is described in detail below.

(A) γ-oryzanol The sebum secretion stimulator of the present invention contains γ-oryzanol. γ-Oryzanol is a known component known to have a sebum secretion-promoting effect. In the sebum secretion stimulating agent of the present invention, by using the component (B) described later together with γ-oryzanol, it is possible to exhibit remarkably superior sebum secretion action compared to the case where γ-oryzanol is used alone.

γ-oryzanol is an ester of ferulic acid and triterpene alcohol or an ester of ferulic acid and sterol.

In the sebum secretion stimulating agent of the present invention, as γ-oryzanol, either an ester of ferulic acid and triterpene alcohol or an ester of ferulic acid and sterol may be used alone or in combination. Preferred examples of γ-oryzanol used in the present invention include those containing cycloartenyl ferulate (C ₄₀ H ₅₈ O ₄ ), more preferably 95% by weight or more of cycloartenyl ferulate, and particularly preferably 98% by weight or more of cycloartenyl ferulate.

The CAS registry number for γ-oryzanol is represented by "11042-64-1". The γ-oryzanols used in the present invention may include oryzanol A (CAS registry number [21238-33-5]), oryzanol C (CAS registry number [469-36-3]), and the like.

The γ-oryzanol used in the present invention is not particularly limited in its raw material, production method, purification method, etc. Examples thereof include those isolated and purified from rice bran or the like.

The content of (A) in the sebum secretion stimulating agent of the present invention may be appropriately set according to the formulation form and the like, and is, for example, 0.05% by weight or more. From the viewpoint of exhibiting the sebum secretion promoting effect more effectively, the content of γ-oryzanol is preferably 0.05 to 2% by weight, more preferably 0.1 to 1% by weight, and particularly preferably 0.5 to 1% by weight.

(B) Heparinoid, diphenhydramine and/or diphenhydramine salt The sebum secretion stimulator of the present invention contains γ-oryzanol, a heparinoid (hereinafter sometimes referred to as component (B-1)), diphenhydramine and/or a diphenhydramine salt (hereinafter sometimes referred to as component (B-2)). Heparin-like substances, diphenhydramine, and salts of diphenhydramine have not been known to have a sebum secretion-promoting action, but when used in combination with γ-oryzanol, it is possible to exert a remarkably excellent sebum secretion action.

Heparin-like substances are polysulfated mucopolysaccharides such as chondroitin polysulfate, and are known drugs known to have moisturizing, anti-inflammatory, and blood circulation promoting effects. The origin of the heparin-like substance used in the present invention is not particularly limited, but examples thereof include those obtained by polysulfating mucopolysaccharides and those extracted from tissues of edible animals (e.g., lungs containing tracheal cartilage of bovine, porcine, etc.). In the sebum secretion stimulating agent of the present invention, a heparin analogue listed in the Japanese Pharmaceutical Standards outside the Pharmacopoeia is preferably used as the heparin analogue.

Diphenhydramine is a known drug known to have antihistamine properties.

The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. These salts may be used singly or in combination of two or more.

In the sebum secretion stimulating agent of the present invention, as the component (B), one of heparinoids, diphenhydramine, and salts of diphenhydramine may be used alone, or two or more thereof may be used in combination.

Among these components (B), from the viewpoint of further improving the sebum secretion-promoting action, it is preferable that at least a heparin analogue is contained, and it is more preferable that the component contains a heparin analogue and diphenhydramine and/or a salt thereof.

The content of (B) in the sebum secretion stimulating agent of the present invention may be appropriately set according to the type of component (B) used, the formulation form, and the like.

For example, in the case of component (B-1), the content of component (B-1) in the sebum secretion stimulant of the present invention is 0.05 to 1% by weight. From the viewpoint of more effectively promoting sebum secretion, the content of component (B-1) is preferably 0.05 to 0.3% by weight, more preferably 0.1 to 0.3% by weight.

Further, for example, in the case of component (B-2), the content of component (B-2) in the sebum secretion stimulant of the present invention is 0.01 to 5% by weight. From the viewpoint of promoting sebum secretion more effectively, the content of component (B-2) is preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight.

In the sebum secretion stimulating agent of the present invention, the ratio of component (B) to component (A) is determined according to the content of each component described above. ) is 5 to 6000 parts by weight, preferably 20 to 100 parts by weight, more preferably 40 to 60 parts by weight.

Surfactant In addition, the sebum secretion stimulating agent of the present invention preferably contains a surfactant for solubilizing or emulsifying γ-oryzanol into a desired formulation form. The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and any of nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants may be used, but nonionic surfactants are preferred.

Specific examples of surfactants include POE (10 to 50 mol) phytosterol ether, POE (10 to 50 mol) dihydrocholesterol ether, POE (10 to 50 mol) 2-octyldodecyl ether, POE (10 to 50 mol) decyltetradecyl ether, POE (10 to 50 mol) oleyl ether, POE (2 to 50 mol) cetyl ether, POE (5 to 50 mol) behenyl ether, POE. (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) polyoxyethylene alkyl ether such as cetyl ether, their phosphoric acid/phosphate (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) glycerol Seryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol)/polyoxypropylene-modified silicone, POE/alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-10) 0), polysorbates (20 to 85), glycerin fatty acid esters (glyceryl monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol, and the like. These surfactants may be used singly or in combination of two or more.

When the sebum secretion stimulating agent of the present invention contains a surfactant, the content thereof may be appropriately set according to the formulation form and the like, and is, for example, 0.1 to 30 wt%. More specifically, when the sebum secretion stimulator of the present invention is a cream, the surfactant content is 0.1 to 15% by weight, preferably 0.5 to 10% by weight. In addition, when the sebum secretion stimulating agent of the present invention is a liquid formulation, the surfactant content is 0.1 to 30% by weight, preferably 0.5 to 15% by weight.

Oily Base The sebum secretion stimulator of the present invention may contain an oily base, if necessary, for preparation into a desired formulation. Oily bases are not particularly limited as long as they are pharmaceutically acceptable, and examples include vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, higher alcohols, and silicone oils.

Specific examples of oily bases include olive oil, wheat germ oil, rice bran oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, castor oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, hydrogenated oil, avocado oil, fennel oil, clove oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, and wood. Vegetable oils such as wax; Animal oils such as lard, fish oil, squalane, and beeswax; Mineral oils such as paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbons (plastibase, etc.), petrolatum; Fatty acids with 4 to 30 carbon atoms such as cinic acid, palmitic acid, sebacic acid, oleic acid and linoleic acid; Monohydric alcohols with 6 to 34 carbon atoms such as myristyl alcohol, cetanol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol and lanolin alcohol; silicone oil and the like. These oily bases may be used singly or in combination of two or more.

When the sebum secretion stimulating agent of the present invention contains an oily base, the content thereof may be appropriately set according to the form of the formulation, and is, for example, 0.05 to 60% by weight. More specifically, when the sebum secretion stimulator of the present invention is a cream, the content of the oily base is 0.1 to 60% by weight, preferably 1 to 40% by weight. Further, when the sebum secretion stimulating agent of the present invention is a liquid formulation, the content of the oily base is 0.05 to 30% by weight, preferably 0.1 to 15% by weight.

Water The sebum secretion stimulator of the present invention may contain water, if necessary, for preparation into a desired formulation form.

When water is contained in the sebum secretion stimulating agent of the present invention, the content thereof may be appropriately set according to the form of the formulation.

Other ingredients

The sebum secretion stimulating agent of the present invention may contain pharmacological ingredients other than the ingredients mentioned above, if necessary, in addition to the ingredients mentioned above. Such pharmacological ingredients include, for example, antihistamines (chlorpheniramine maleate, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine, or salts thereof, orthocaine, oxethazaine, oxypolyentoxydecane, Rohto extract, perchaminpase, tecitdecitin, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation-promoting ingredients (nonylic acid vanillylamide, benzyl nicotinate, capsaicin, hot pepper extract, etc.), cooling agents (menthol, camphor, etc.), mucopolysaccharides (chondroitin sulfate sodium, glucosamine, etc.), and the like. These pharmacological ingredients may be used singly or in combination of two or more. When these pharmacological ingredients are contained, the content thereof may be appropriately set according to the type of the pharmacological ingredient to be used, the expected effect, and the like.

Furthermore, the sebum secretion stimulating agent of the present invention may contain base materials and additives other than the above-described components, if necessary, in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. Examples include polyhydric alcohols (ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, polypropylene glycol, glycerin, etc.), lower alcohols (ethanol, isopropanol, etc.), cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, Sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cioneal, citronellal, farnesol, etc.), coloring agents (tar pigments (brown No. 201, blue No. 201, yellow No. 4, yellow No. 403, etc.), cacao pigments, chlorophyll, aluminum oxide, etc.), thickeners (polyvinylpyrrolidone, sodium alginate, ethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (dl-pyrrolidone sodium carboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate) , sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives and other additives. These additives may be used singly or in combination of two or more. The content of these additives can be appropriately set according to the dosage form and the like.

FORMULATION FORM The sebum secretion stimulator of the present invention is desirably used as an external skin preparation. When the sebum secretion-enhancing agent of the present invention is used as a skin preparation for external use, its shape is not particularly limited as long as it can be applied transdermally.

In addition, when the sebum secretion stimulator of the present invention is used as a skin external preparation, the formulation form is not particularly limited as long as it can be applied transdermally. When the sebum secretion promoting agent of the present invention is used as a skin external preparation, specifically, skin external pharmaceuticals such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs; cosmetic agents such as agents and packs; skin cleansers such as body shampoos, hair shampoos and rinses; Among these formulation forms, pharmaceuticals for external use on the skin are preferred, and creams, lotions, gels, milky lotions and packs are more preferred.

Use/dosage The sebum secretion-promoting agent of the present invention can improve or maintain skin flexibility, elasticity, barrier function and the like in a normal state by promoting sebum secretion. Therefore, the sebum secretion stimulator of the present invention can be used for normalizing skin with decreased sebum secretion, suppressing a decrease in sebum secretion in normal skin, and the like.

The sebum secretion-promoting agent of the present invention is also effective in preventing or treating diseases and symptoms in which decreased sebum secretion is one of the factors. Diseases and symptoms in which a decrease in sebum secretion is one of the factors include, specifically, sebum deficiency, sebum deficiency dermatitis, sebum deficiency eczema, xerosis, atopic dermatitis, progressive keratoderma palmar, keratoderma of the foot, infantile dry eczema, lichen pilaris, xerosis, pruritus, ichthyosis, shark skin, keratosis of elbows, knees, heels and ankles, dry skin, Rough fingers, cracked hands and feet, dry skin in children, etc.

The dose of the sebum secretion stimulating agent of the present invention may be appropriately set according to the dosage form, formulation form, severity of symptoms to be applied, and the like. For example, when the sebum secretion-promoting agent of the present invention is used as an external skin preparation, an example of the dosage is such that γ-oryzanol is about 0.05 to 20 mg per 1 cm ² of skin, and the frequency is about once to several times a day.

2. Composition for external use The present invention further provides a composition for external use containing γ-oryzanol, a heparinoid, and diphenhydramine and/or a salt thereof. Due to the synergistic action of these ingredients, the sebum secretion-promoting action of the composition for external use of the present invention is dramatically improved.

The types and contents of γ-oryzanol, heparinoids, diphenhydramine and/or salts thereof used in the composition for external use of the present invention are as described in the section "1. Sebum secretion stimulator".

In the composition for external use of the present invention, the types and contents of other ingredients that can be blended, and the formulation form are also as described in the section "1. Sebum secretion stimulator".

In addition, the application of the composition for external use of the present invention is not particularly limited, and it may be used for any purpose as long as the effect can be recognized by transdermal application of the composition for external use of the present invention. As described above, the composition for external use of the present invention has remarkably improved sebum secretion-promoting action, and thus can be suitably used for sebum secretion-promoting purposes. Specific embodiments of sebum secretion-promoting applications are as described in the section "1. Sebum secretion-promoting agent" above.

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

A cream (oil-in-water emulsion composition) having the composition shown in Test Example Table 1 was prepared. A specific method for producing the cream is as follows. A predetermined amount of each component shown in (I) in Table 1 was mixed, heated to 80° C., and uniformly stirred to prepare an oil phase composition. Separately, a predetermined amount of each component shown in (II) in Table 1 was mixed, heated to 80° C., and uniformly stirred to prepare an aqueous phase composition. The composition for oil phase and the composition for water phase thus obtained were mixed while being heated to 80° C., emulsified, and then cooled to obtain a cream.

The sebum secretion-promoting action of the resulting cream was evaluated. A specific test method is as follows. The cream was applied to the inner side of the auricle of golden hamsters (8 weeks old, female) once a day, and on the 15th day, auricle skin pieces from the inner side of the central part of the auricle were collected with a medical punch. After removing the outer skin and cartilage from the auricular skin piece, the piece was immersed in a 2N sodium bromide aqueous solution to peel off the epidermis to prepare a dermis sheet. The sebaceous glands of the obtained dermal sheet were stained with Sudan III and observed with a system biological microscope (manufactured by Olympus). The area of the sebaceous gland was measured, and the relative value of sebum secretion was calculated according to the following formula.

In this test, three golden hamsters were used in each group, one dermal sheet was prepared from each animal, and the areas of 15 randomly selected sebaceous glands were measured on one dermal sheet. In this way, a total of 45 (N=45) sebaceous gland areas were measured per group, and the average value was substituted into the above calculation formula as the sebaceous gland area of each group.

In this test method, the amount of sebum secreted is evaluated by measuring the size of the sebaceous gland. In general, sebaceous glands are holocrine glands, and cells that accumulate lipids self-destruct to become sebum, which is excreted to the skin surface. Therefore, it is generally known that there is a direct relationship between the area of sebaceous glands and the function of sebaceous glands, and that the amount of sebum secreted and the area of sebaceous glands are in a substantially proportional relationship (Mie Kobayashi, Local Action of Ferulic Acid Ester Mixture on Sebaceous Glands - Biochemical and Histological Studies -, Skin, Vol. 21, No. 1, published by the Japanese Dermatological Association, February 1979).

FIG. 1 shows an image of the dermal sheet stained with Sudan III and observed under a microscope, and Table 1 shows the results of relative sebum secretion amounts. As a result, γ-oryzanol, a heparin analogue, and diphenhydramine alone were found to have a sebum secretion-promoting action (Reference Examples 1 to 3), but when γ-oryzanol and a heparin analogue were combined, the sebum secretion-promoting action was synergistically improved (Examples 1 and 2). In particular, when a heparinoid, diphenhydramine, and γ-oryzanol were used in combination, the sebum secretion-promoting action was remarkably improved (Example 2).

Formulation Examples Creams shown in Table 2, lotions shown in Table 3, gels shown in Table 4, and emulsions shown in Table 5 were prepared. All of these preparations are expected to have the effect of promoting the secretion of sebum, as in the case of the above test examples, and are effective for promoting sebum secretion.

Claims (2)

A composition for external use, which contains (A) γ-oryzanol, (B-1) a heparin analogue, and (B-2) diphenhydramine , is used as a sebum secretagogue, and is an emulsified composition (excluding cases containing panthenol, an ester of panthenol, a salt of pantothenic acid, and/or pantothenyl ethyl ether, cases containing urea and glycyrrhetinic acid, and cases applied to itching symptoms ). The external composition according to claim 1, which is a skin external preparation.