JP7678657B2 - Sebum secretion promoter - Google Patents

Description

The present invention relates to a sebum secretion promoter that can promote sebum secretion.

Sebum provides flexibility, elasticity, and moisture retention to the skin, and protects it from ultraviolet rays and bacteria, and plays an important role in maintaining a normal skin condition. Sebum is secreted by the sebaceous glands, but the amount of sebum secreted can decrease depending on factors such as age, constitution, season, lifestyle, and drug administration. A decrease in sebum secretion reduces the flexibility, elasticity, moisture retention, and resistance of the skin, and is a factor in the decrease of the skin barrier function, and is also a factor in skin symptoms and diseases such as asteatosis, asteatotic eczema, xerosis, atopic dermatitis, dry skin, cracks, and chapped skin.

Conventionally, as a countermeasure against the decrease in sebum secretion, a method of replenishing oil to the skin using an external composition containing oils such as triglycerides, wax esters, squalene, and free fatty acids, which are components of sebum, has been known. However, such a method has the drawback that it is only a symptomatic treatment for the decrease in sebum secretion, and its effectiveness is limited, and it does not provide a fundamental solution.

On the other hand, as a countermeasure to the decrease in sebum secretion, a method is also known in which ingredients that can promote sebum secretion are used to increase the amount of sebum secreted itself. This method is expected to effectively improve skin with a decrease in sebum secretion, as it activates the sebaceous glands.

Various ingredients that promote sebum secretion have been reported in the past. For example, gamma-oryzanol is known to promote sebum secretion. It has also been reported that angelica tree extract, bryonolic acid, and maltooligosaccharide promote sebum secretion and can be used as sebum secretion promoters (see Patent Documents 1 to 3). However, in order to respond to the diversification of pharmaceutical formulations and further improvements in the sebum secretion promotion effect, the development of new formulation technologies that promote sebum secretion is desired.

Japanese Patent Application Publication No. 9-176030 Japanese Unexamined Patent Publication No. 7-109214 Japanese Patent Application Publication No. 5-294837

The present invention aims to provide a sebum secretion promoter that promotes sebum secretion.

The inventors conducted extensive research to solve the above problems and found that diphenhydramine and/or its salts have a sebum secretion effect superior to that of γ-oryzanol and can be used as a sebum secretion promoter. The present invention was completed through further research based on this knowledge.

That is, the present invention provides the following aspects.
Item 1. A sebum secretion promoter comprising diphenhydramine and/or a salt thereof.
Item 2. The sebum secretion promoter according to Item 1, which is an external preparation for skin.

The sebum secretion promoter of the present invention can effectively promote sebum secretion, making it possible to improve or maintain a normal skin condition, and is effective in preventing or treating, for example, skin diseases or skin symptoms caused in part by a decrease in the amount of sebum secretion.

After each cream was applied to the inside of the ear of a golden hamster for a specified period of time, a dermal sheet was prepared from the applied area, and the sebaceous glands were stained with Sudan III and observed under a microscope.

The sebum secretion promoter of the present invention is characterized by containing diphenhydramine and/or a salt thereof. The sebum secretion promoter of the present invention is described in detail below.

Diphenhydramine and/or its salts Diphenhydramine and/or its salts have a higher sebum secretion promoting effect than γ-oryzanol, and the sebum secretion promoter of the present invention contains diphenhydramine and/or its salts as an active ingredient.

Diphenhydramine is a known drug known to have antihistamine properties.

There are no particular limitations on the salts of diphenhydramine as long as they are pharma- ceutically acceptable, but specific examples include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyl disulfonate, tannate, lauryl sulfate, and sulfate. These salts may be used alone or in combination of two or more.

The sebum secretion promoter of the present invention may be one selected from diphenhydramine and its salts, or two or more may be used in combination.

Among diphenhydramine and its salts, diphenhydramine and diphenhydramine hydrochloride are preferred from the viewpoint of more effectively enhancing the sebum secretion promoting effect.

The content of diphenhydramine and/or its salt in the sebum secretion promoter of the present invention may be appropriately set depending on the formulation, etc., and may be, for example, 0.01 to 5% by weight. From the viewpoint of more effectively improving the sebum secretion promoting effect, the content of diphenhydramine and/or its salt is preferably 0.1 to 3% by weight, and more preferably 0.1 to 2% by weight.

Heparinoids The sebum secretion promoter of the present invention may contain a heparinoid together with diphenhydramine and/or its salt. The inventors have found that heparinoids also have a sebum secretion promoting effect. By using diphenhydramine and/or its salt in combination with a heparinoid, the sebum secretion promoting effect can be synergistically improved.

Heparinoids are polysulfated mucopolysaccharides such as chondroitin polysulfate, and are known drugs that are known to have moisturizing, anti-inflammatory, and blood circulation promoting effects.

The origin of the heparinoid used in the present invention is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides and those extracted from the tissues of edible animals (e.g., lungs containing tracheal cartilage of cattle, pigs, etc.). In the sebum secretion promoter of the present invention, a heparinoid listed in the Japanese Pharmacopoeia Extra Pharmaceutical Standards is preferably used as the heparinoid.

When a heparinoid is contained in the sebum secretion promoter of the present invention, the content is not particularly limited, but may be, for example, 0.05 to 1% by weight. From the viewpoint of promoting sebum secretion more effectively, the content of the heparinoid is preferably 0.05 to 0.3% by weight, and more preferably 0.1 to 0.3% by weight.

When a heparinoid is contained in the sebum secretion promoter of the present invention, the ratio of the heparinoid to diphenhydramine and/or its salt is determined according to the content of each of the above-mentioned components, but may be, for example, 1 to 10,000 parts by weight of the heparinoid per 100 parts by weight of diphenhydramine and/or its salt. From the viewpoint of more effectively improving the sebum secretion promoting effect, the heparinoid is preferably 10 to 300 parts by weight, more preferably 40 to 80 parts by weight, per 100 parts by weight of diphenhydramine and/or its salt.

γ-oryzanol The sebum secretion promoter of the present invention may further contain γ-oryzanol. γ-oryzanol is known to have a sebum secretion promoting effect, and by using diphenhydramine and/or a salt thereof in combination with γ-oryzanol, it is possible to exert a significantly superior sebum secretion promoting effect. In particular, when diphenhydramine and/or a salt thereof is combined with a heparinoid and γ-oryzanol, the sebum secretion promoting effect can be dramatically improved by the synergistic effect of these components.

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

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

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

The raw materials, production method, purification method, etc. of the γ-oryzanol used in the present invention are not particularly limited, and examples include those that are isolated and purified by the γ-oryzanol itself from rice bran, etc.

When γ-oryzanol is contained in the sebum secretion promoter of the present invention, its content is not particularly limited, but may be, for example, 0.05% by weight or more. From the viewpoint of more effectively improving the sebum secretion promoting effect, 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.

When γ-oryzanol is contained in the sebum secretion promoter of the present invention, the ratio of γ-oryzanol to diphenhydramine and/or a salt thereof is determined according to the content of each of the above-mentioned components, and may be, for example, 1 to 20,000 parts by weight of γ-oryzanol per 100 parts by weight of diphenhydramine and/or a salt thereof. From the viewpoint of more effectively improving the sebum secretion promoting effect, the ratio of γ-oryzanol is preferably 50 to 400 parts by weight, more preferably 150 to 250 parts by weight, per 100 parts by weight of diphenhydramine and/or a salt thereof.

Surfactant The sebum secretion promoter of the present invention may contain a surfactant in order to obtain a desired formulation. In particular, when γ-oryzanol is contained, it is preferable that a surfactant is contained in order to solubilize or emulsify γ-oryzanol to obtain a desired formulation. The surfactant is not particularly limited as long as it is pharma- ceutically acceptable, and any of nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants may be used, with nonionic surfactants being preferred.

Specific examples of surfactants include polyoxyethylene alkyl ethers such as POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, and POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether; phosphoric acid and phosphate salts thereof (e.g., sodium POE cetyl ether phosphate); POE (20-60 mol) sorbitan monooleate; and POE (10-60 mol) sorbitan mono Examples of surfactants include isostearate, POE (10-80 mol) glyceryl 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 (5-100), polysorbate (20-85), glycerin fatty acid ester (glycerin monostearate, etc.), hydrogenated soybean phospholipid, and hydrogenated lanolin alcohol. These surfactants may be used alone or in combination of two or more.

When the sebum secretion promoter of the present invention contains a surfactant, the content of the surfactant may be appropriately set depending on the formulation, etc., and may be, for example, 0.1 to 30% by weight. More specifically, when the sebum secretion promoter of the present invention is a cream, the content of the surfactant may be 0.1 to 15% by weight, preferably 0.5 to 10% by weight. When the sebum secretion promoter of the present invention is a liquid, the content of the surfactant may be 0.1 to 30% by weight, preferably 0.5 to 15% by weight.

The sebum secretion promoter of the present invention may contain an oily base as necessary for preparation into a desired formulation, etc. The oily base is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, higher alcohols, silicone oils, etc.

Specific examples of oily bases include vegetable oils such as olive oil, wheat germ oil, rice oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, castor oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, hardened oil, avocado oil, fennel oil, clove oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, and wood wax; animal oils such as lard, fish oil, squalane, and beeswax; mineral oils such as paraffin, hydrogenated polyisobutene, liquid paraffin, gelling hydrocarbons (Plastibase, etc.), and petrolatum; diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, and ethyl oleate. esters of fatty acids having 4 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms; fatty acids having 4 to 30 carbon atoms such as lauric acid, myristic acid, palmitic acid, sebacic acid, oleic acid, and linoleic acid; monohydric higher alcohols having 6 to 34 carbon atoms such as myristyl alcohol, cetanol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, and lanolin alcohol; silicone oils such as ethyl polysiloxane, crosslinked methyl polysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, and phenyl-modified silicone. These oily bases may be used alone or in combination of two or more.

When the sebum secretion promoter of the present invention contains an oily base, the content of the oily base may be appropriately set depending on the formulation, etc., and may be, for example, 0.05 to 60% by weight. More specifically, when the sebum secretion promoter of the present invention is a cream, the content of the oily base may be 0.1 to 60% by weight, preferably 1 to 40% by weight. When the sebum secretion promoter of the present invention is a liquid, the content of the oily base may be 0.05 to 30% by weight, preferably 0.1 to 15% by weight.

Water The sebum secretion promoter of the present invention may contain water as necessary for preparing a desired formulation.

When the sebum secretion promoter of the present invention contains water, the content of water may be appropriately set depending on the formulation, but may be, for example, 30% by weight or more, preferably 40 to 99.5% by weight, more preferably 50 to 99% by weight, and particularly preferably 60 to 95% by weight.

Other Ingredients

In addition to the components described above, the sebum secretion promoter of the present invention may contain pharmacological ingredients other than those described above, if necessary. Examples of such pharmacological ingredients include antihistamines (chlorpheniramine maleate, etc.), local anesthetics (procaine, tetracaine, bupivacaine, mepipacaine, chloroprocaine, proparacaine, meprylcaine or salts thereof, orthocaine, oxethazaine, oxypolyethyleneoxydecane, Scopolia extract, percaminpase, tesitdesitin, 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, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), cooling agents (menthol, camphor, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.), etc. These pharmacological ingredients may be used alone or in combination of two or more. When these pharmacological ingredients are included, their content can be set appropriately depending on the type of pharmacological ingredient used, the desired effect, etc.

Furthermore, the sebum secretion promoter of the present invention may contain base materials or additives other than the aforementioned components as necessary to obtain the desired formulation. Such bases and additives are not particularly limited as long as they are pharma- ceutically acceptable, and examples thereof 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.), freshening agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-thioneol, citronellal, farnesol, etc.), coloring agents (tar dyes (Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cacao dyes, chlorophyll, aluminum oxide, etc.), thickening agents (polyvinylpyrrolidone, sodium alginate, ethylcellulose, etc.), and the like. Examples of additives include: cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, 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 (sodium dl-pyrrolidone 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, ultraviolet absorbers, chelating agents, adhesives, buffers, dissolution aids, solubilizers, preservatives, etc. These additives may be used alone or in combination of two or more. The content of these additives can be appropriately set depending on the formulation, etc.

Formulation The sebum secretion promoter of the present invention is preferably used as a skin external preparation. When the sebum secretion promoter of the present invention is used as a skin external preparation, its form is not particularly limited as long as it can be applied transdermally, and examples thereof include liquid, solid, and semi-solid forms (gel, ointment, paste, etc.).

When the sebum secretion promoter of the present invention is used as a skin topical preparation, the formulation form is not particularly limited as long as it can be applied transdermally, and examples of the formulation include skin topical medicines, skin topical quasi-drugs, cosmetics, skin cleansing agents, etc. Specific formulation forms when the sebum secretion promoter of the present invention is used as a skin topical preparation include skin topical medicines such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, etc.; skin topical quasi-drugs such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, etc.; cosmetics such as creams, lotions, gels, emulsions, liquids, ointments, packs, etc.; skin cleansing agents such as body shampoos, hair shampoos, and rinses, etc. Among these formulation forms, preferred are skin topical medicines, and more preferred are creams, lotions, gels, emulsions, and packs.

Use and Dosage The sebum secretion promoter of the present invention can improve or maintain the softness, elasticity, barrier function, etc. of the skin to normal conditions by promoting sebum secretion. Therefore, the sebum secretion promoter of the present invention can be used for normalizing skin with reduced sebum secretion, suppressing a reduction in the amount of sebum secretion in normal skin, etc.

The sebum secretion promoter of the present invention is also effective in preventing or treating diseases or symptoms caused in part by a decrease in the amount of sebum secreted. Specific examples of diseases or symptoms caused in part by a decrease in the amount of sebum secreted include asteatosis, asteatotic dermatitis, asteatotic eczema, xerosis, atopic dermatitis, keratoderma tylodes palmaris progressiva, keratoderma plantaris, pediatric dry eczema, lichen pilaris, xerosis, pruritus, ichthyosis, keratosis of the elbows, knees, heels, and ankles, dry skin, rough hands and fingers, cracked and chapped hands and feet, and pediatric dry skin.

The dose of the sebum secretion promoter of the present invention may be appropriately determined depending on the dosage form, preparation form, the severity of symptoms to which it is applied, etc. For example, when the sebum secretion promoter of the present invention is used as an external preparation for skin, an example of the dose is an amount of about 0.01 to 50 mg of diphenhydramine and/or a salt thereof per 1 ^cm2 of skin per application, and the frequency is about 1 to several times a day.

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

Test Example A cream (oil-in-water emulsion composition) having the composition shown in Table 1 was prepared. The 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 stirred uniformly 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 stirred uniformly to prepare an aqueous phase composition. The obtained oil phase composition and aqueous phase composition were mixed while heated to 80°C, emulsified, and then cooled to obtain a cream.

The sebum secretion-promoting effect of the obtained cream was evaluated. The specific test method is as follows. The cream was applied once a day to the inside of the ear of a golden hamster (8 weeks old, female), and on the 15th day, a piece of ear skin from the inside of the center of the ear was taken with a medical punch. After removing the outer skin and cartilage from the ear skin piece, it was immersed in a 2N aqueous solution of sodium bromide to peel off the epidermis and create a dermal sheet. The sebaceous glands of the obtained dermal sheet were stained with Sudan III, and the sebaceous glands were observed under a system biological microscope (Olympus). The area of the sebaceous glands was measured, and the relative value of the amount of sebum secretion was calculated according to the following calculation formula.

In this test, three golden hamsters were used for each group, one dermal sheet was prepared from each hamster, and the area of 15 randomly selected sebaceous glands was measured on each dermal sheet. In this way, the area of a total of 45 sebaceous glands (N=45) per group was measured, and the average value was substituted into the above calculation formula as the area of the sebaceous glands for 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 have accumulated lipids self-destruct to become sebum, which is then excreted on the skin surface. For this reason, it is generally known that there is a direct relationship between the area of the sebaceous gland and sebaceous gland function, and that the amount of sebum secreted is approximately proportional to the area of the sebaceous gland (Kobayashi Mie, 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). Therefore, the results obtained by this test method accurately reflect the amount of sebum secreted.

Figure 1 shows the image of the dermis sheet stained with Sudan III and observed under a microscope, and Table 1 shows the relative values of sebum secretion. As a result, it was confirmed that diphenhydramine alone has a higher sebum secretion promoting effect than γ-oryzanol, which is known to have a sebum secretion promoting effect (Example 1). Furthermore, when diphenhydramine was used in combination with a heparinoid, the sebum secretion promoting effect was further improved (Examples 2 and 3), and in particular, when diphenhydramine, a heparinoid, and γ-oryzanol were used in combination, the sebum secretion promoting effect was significantly improved (Example 3).

Formulation Examples A cream shown in Table 2, a lotion shown in Table 3, a gel shown in Table 4, and an emulsion shown in Table 5 were prepared. As in the case of the test examples, all of these preparations are expected to have the effect of promoting sebum secretion, and are effective for promoting sebum secretion.

Claims (2)

A sebum secretion promoter which is an emulsion composition containing diphenhydramine (excluding those which also contain γ-oryzanol, those which also contain urea and lidocaine, and those which also contain a heparinoid ). The sebum secretion promoter according to claim 1 , which is an external skin preparation.