Sebum secretion promoter

Abstract

To provide a sebum secretion promoter that promotes sebum secretion.SOLUTION: A heparin analog has a higher sebum secretion action than that of γ-oryzanol and can be used for a sebum secretion promoter.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a sebum secretion promoter that can promote sebum secretion.

Background Art

[0002] Sebum has the functions of giving flexibility and elasticity to the skin and protecting the skin from ultraviolet rays, bacteria, etc., and plays an important role in maintaining a normal skin state. Sebum is secreted by sebaceous glands, but its secretion amount may decrease due to factors such as age, constitution, season, lifestyle, and drug administration. When the sebum secretion amount decreases, not only the flexibility and elasticity of the skin are impaired, and the skin resistance decreases, but also skin diseases such as sebum deficiency and seborrheic dermatitis may develop. Therefore, it is important to supplement sebum in the skin with reduced sebum secretion amount in order to improve or maintain a normal skin state.

[0003] Conventionally, as a countermeasure against the decrease in sebum secretion amount, 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 components of sebum, is known. However, such a method is only a treatment for the decrease in sebum secretion amount, and its effect is limited, and it has a drawback that it is not a fundamental solution.

[0004] On the other hand, as a countermeasure against the decrease in sebum secretion amount, a method of increasing the sebum secretion amount itself by using a component that can promote sebum secretion is also known. By such a method, it is expected that the skin with reduced sebum secretion amount can be effectively improved in order to activate sebaceous glands.

[0005] Conventionally, various components that promote sebum secretion have been reported. For example, γ-oryzanol is known to have an effect of promoting sebum secretion. In addition, it has been reported that extracts of Paeonia lactiflora, ursolic acid, and maltooligosaccharides have an effect of promoting 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 formulation prescriptions and the further improvement of sebum secretion promoting effects, the development of new formulation technologies for promoting sebum secretion is desired.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a sebum secretion promoter that promotes sebum secretion.

Means for Solving the Problems

[0008] The present inventor has intensively studied to solve the above problems and found that heparin-like substances have a sebum secretion effect superior to that of γ-oryzanol and can be used as sebum secretion promoters. Furthermore, the present inventor has also found that when heparin-like substances are used in combination with diphenhydramine and / or its salts, the sebum secretion effect is synergistically improved. The present invention has been completed by further studies based on these findings.

[0009] That is, the present invention provides the invention in the following aspects. Item 1. A sebum secretion promoter containing a heparin-like substance. Item 2. The sebum secretion promoter according to Item 1, further containing diphenhydramine and / or a salt thereof. Item 3. The sebum secretion promoter according to Item 1 or 2, which is a skin external preparation.

Advantages of the Invention

[0010] According to the sebum secretion promoter of the present invention, since the secretion of sebum can be effectively promoted, it is possible to improve or maintain a normal skin state. For example, it is effective in preventing or treating skin diseases and skin symptoms in which a decrease in the sebum secretion amount is one of the causative factors.

Brief Description of the Drawings

[0011]

Figure 1

Modes for Carrying Out the Invention

[0012] The sebum secretion promoter of the present invention is characterized by containing a heparin-like substance. Hereinafter, the sebum secretion promoter of the present invention will be described in detail.

[0013] Heparin-like substance The heparin-like substance has a sebum secretion promoting action higher than that of γ-oryzanol, and the sebum secretion promoter of the present invention contains the heparin-like substance as an active ingredient. The heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have an anti-inflammatory action, a blood circulation promoting action, and the like.

[0014] The origin of the heparin-like substance used in the present invention is not particularly limited. For example, it may be obtained by polysulfating mucopolysaccharides, or extracted from the tissues of edible animals (e.g., lungs including tracheal cartilage of cows, pigs, etc.). In the sebum secretion promoter of the present invention, a heparin-like substance included in the Japanese Pharmaceutical Excipients Standards is preferably used as the heparin-like substance.

[0015] The content of the heparin-like substance in the sebum secretion promoter of the present invention may be appropriately set according to the dosage form, etc. For example, 0.05 to 1% by weight can be mentioned. From the viewpoint of more effectively promoting sebum secretion, the content of the heparin-like substance is preferably 0.05 to 0.3% by weight, and more preferably 0.1 to 0.3% by weight.

[0016] Diphenhydramine and / or its salt The sebum secretion promoter of the present invention may contain diphenhydramine and / or its salt together with the heparin-like substance. The present inventors have found that diphenhydramine and / or its salt also has an effect of promoting sebum secretion. By using the heparin-like substance in combination with diphenhydramine and / or its salt, the effect of promoting sebum secretion can be synergistically improved.

[0017] Diphenhydramine is a known drug known to have an antihistamine effect.

[0018] The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable. Specifically, acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate can be mentioned. These salts may be used alone or in combination of two or more.

[0019] The sebum secretion promoter of the present invention may be used by selecting one kind from diphenhydramine and its salts, or in combination of two or more kinds.

[0020] Among diphenhydramine and its salts, from the viewpoint of further effectively improving the sebum secretion promoting effect, preferably diphenhydramine and diphenhydramine hydrochloride can be mentioned.

[0021] When diphenhydramine and / or its salt is contained in the sebum secretion promoter of the present invention, its content is not particularly limited, and for example, 0.01 to 5% by weight can be mentioned. From the viewpoint of further effectively improving the sebum secretion promoting effect, as the content of diphenhydramine and / or its salt, preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight can be mentioned.

[0022] When diphenhydramine and / or its salt is contained in the sebum secretion promoter of the present invention, the ratio of diphenhydramine and / or its salt to the heparin-like substance is determined according to the content of each component described above. For example, 1 to 10,000 parts by weight of diphenhydramine and / or its salt per 100 parts by weight of the heparin-like substance can be mentioned. From the viewpoint of further effectively improving the sebum secretion promoting effect, 50 to 350 parts by weight, more preferably 100 to 250 parts by weight of diphenhydramine and / or its salt per 100 parts by weight of the heparin-like substance can be mentioned.

[0023] 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 a heparin-like substance and γ-oryzanol in combination, it becomes possible to exhibit an extremely excellent sebum secretion promoting effect. In particular, when a heparin-like substance, diphenhydramine and / or its salt, and γ-oryzanol are combined, the sebum secretion promoting effect can be dramatically improved by the synergistic action of these components.

[0024] γ-Oryzanol is an ester of ferulic acid and triterpene alcohol, or an ester of ferulic acid and sterol.

[0025] In the sebum secretion promoter 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 they may be used in combination. Preferred examples of γ-oryzanol used in the present invention include those containing cycloartenyl ferulate (C 40 H 58 O4), 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.

[0026] The CAS registration number of γ-oryzanol is represented by "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]), etc.

[0027] Regarding γ-oryzanol used in the present invention, its raw materials, production methods, purification methods, etc. are not particularly limited, and examples include those isolated and purified from rice bran, etc.

[0028] When γ-oryzanol is contained in the sebum secretion promoter of the present invention, its content is not particularly limited, and for example, 0.05% by weight or more can be mentioned. From the viewpoint of further improving 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.

[0029] When γ-oryzanol is contained in the sebum secretion promoter of the present invention, the ratio of γ-oryzanol to the heparin-like substance is determined according to the content of each component described above. For example, 5 to 4,000 parts by weight of γ-oryzanol per 100 parts by weight of the heparin-like substance can be mentioned. From the viewpoint of further improving the sebum secretion promoting effect more effectively, 100 to 600 parts by weight, more preferably 250 to 400 parts by weight of γ-oryzanol per 100 parts by weight of the heparin-like substance can be mentioned.

[0030] Surfactant In addition, the sebum secretion promoter of the present invention may contain a surfactant in order to obtain a desired dosage form. In particular, when γ-oryzanol is contained, it is preferable that a surfactant is contained in order to solubilize or emulsify γ-oryzanol into a desired dosage 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 preferably mentioned.

[0031] As the surfactant, specifically, 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, POE(10 - 50 mol) polyoxypropylene(2 - 30 mol) cetyl ether; their phosphates and phosphoric acid salts (such as sodium POE cetyl ether phosphate); POE(20 - 60 mol) sorbitan monooleate, POE(10 - 60 mol) sorbitan monoisostearate, 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 dilinoleate, polyoxyethylene hydrogenated castor oil(5 - 100), polysorbate(20 - 85), glycerin fatty acid esters (such as glycerin monostearate), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol, etc. These surfactants may be used alone or in combination of two or more kinds.

[0032] When a surfactant is contained in the sebum secretion promoter of the present invention, its content may be appropriately set according to the dosage form and the like. For example, 0.1 to 30% by weight can be mentioned. More specifically, when the sebum secretion promoter of the present invention is a cream preparation, the content of the surfactant is 0.1 to 15% by weight, preferably 0.5 to 10% by weight. Further, when the sebum secretion promoter of the present invention is a liquid preparation, the content of the surfactant is 0.1 to 30% by weight, preferably 0.5 to 15% by weight.

[0033] Oily base The sebum secretion promoter of the present invention may contain an oily base as necessary for the preparation into a desired dosage form and the like. The oily base is not particularly limited as long as it is pharmaceutically acceptable. For example, vegetable oil, animal oil, mineral oil, fatty acid alkyl ester, fatty acid, higher alcohol, silicone oil and the like can be mentioned.

[0034] As the oily base, specifically, vegetable oils such as 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, perilla oil, clove oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, wood wax, etc.; animal oils such as lard, fish oil, squalane, beeswax, etc.; mineral oils such as paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbons (such as plastibase), petrolatum, etc.; esters of fatty acids having 4 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms such as diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, ethyl oleate, etc.; fatty acids having 4 to 30 carbon atoms such as lauric acid, myristic acid, palmitic acid, sebacic acid, oleic acid, linoleic acid, etc.; monohydric higher alcohols having 6 to 34 carbon atoms such as myristyl alcohol, cetanol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.; silicone oils such as methylpolysiloxane, crosslinked methylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, phenyl-modified silicone, etc. These oily bases may be used alone or in combination of two or more.

[0035] When the sebum secretion promoter of the present invention contains an oily base, the content thereof may be appropriately set according to the preparation form, etc., and for example, 0.05 to 60% by weight can be mentioned. More specifically, when the sebum secretion promoter of the present invention is a cream preparation, the content of the oily base is 0.1 to 60% by weight, preferably 1 to 40% by weight. Also, when the sebum secretion promoter of the present invention is a liquid preparation, the content of the oily base is 0.05 to 30% by weight, preferably 0.1 to 15% by weight.

[0036] Water The sebum secretion promoter of the present invention may contain water as necessary for preparation into a desired dosage form or the like.

[0037] When water is contained in the sebum secretion promoter of the present invention, the content thereof may be appropriately set according to the dosage form. For example, it may be 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.

[0038] Other components

[0039] In addition to the aforementioned components, the sebum secretion promoter of the present invention may contain, as necessary, pharmacological components other than the aforementioned components. Examples of such pharmacological components include antihistamines (such as chlorpheniramine maleate), local anesthetics (procaine, tetracaine, bupivacaine, mepivacaine, chloroprocaine, propanocaine, meprilocaine or their salts, orthocaine, oxysezaine, oxy polyethoxydodecane, rosin extract, percamide pase, tesitin desitin, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting components (nonyl vanillylamide, benzyl nicotinate, capsaicin, pepper extract, etc.), cooling agents (menthol, camphor, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.). These pharmacological components may be used alone or in combination of two or more. When these pharmacological components are contained, the content thereof may be appropriately set according to the type of pharmacological component used, the expected effect, etc.

[0040] Furthermore, in order to obtain the desired dosage form, the sebum secretion promoter of the present invention may contain, if necessary, a base material and additives other than the aforementioned components. 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 (methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, etc.), fragrances (citral, 1,8-cineole, citronellal, farnesol, etc.), coloring agents (tar dyes (Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cocoa pigment, chlorophyll, aluminum oxide, etc.), thickeners (polyvinyl pyrrolidone, sodium alginate, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, 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, solubilizing aids, solubilizers, preservatives, and other additives. These additives may be used alone or in combination of two or more. The content of these additives can be appropriately set according to the dosage form and the like.

[0041] Form of preparation The sebum secretion promoter of the present invention is desirably used as a topical skin preparation. When the sebum secretion promoter of the present invention is used as a topical skin preparation, its shape is not particularly limited as long as it can be applied transdermally. For example, liquid, solid, semi-solid (gel-like, ointment-like, paste-like), etc. can be mentioned.

[0042] Also, when the sebum secretion promoter of the present invention is used as a topical skin preparation, its dosage form is not particularly limited as long as it can be applied transdermally. For example, topical skin pharmaceuticals, quasi-drugs for external use on the skin, cosmetics, skin cleansers, etc. can be mentioned. Specific examples of the dosage form when the sebum secretion promoter of the present invention is made into a topical skin preparation include topical skin pharmaceuticals such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, etc.; quasi-drugs for external use on the skin such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, etc.; cosmetics such as creams, lotions, gels, emulsions, liquids, ointments, packs, etc.; skin cleansers such as body shampoos, hair shampoos, rinses, etc. Among these dosage forms, topical skin pharmaceuticals are preferred, and creams, lotions, gels, emulsions, and packs are more preferred.

[0043] Use and dosage The sebum secretion promoter of the present invention can improve or maintain a normal skin condition by promoting sebum secretion. Therefore, the sebum secretion promoter of the present invention can be used for normalizing the skin with reduced sebum secretion, suppressing the decrease in sebum secretion amount in normal skin, etc.

[0044] In addition, the sebum secretion promoter of the present invention is also effective for preventing or treating diseases and symptoms in which a decrease in sebum secretion amount is one of the factors. Specific examples of diseases and symptoms in which a decrease in sebum secretion amount is one of the factors include sebum deficiency, seborrheic dermatitis, seborrheic eczema, etc.

[0045] Regarding the dosage of the sebum secretion promoter of the present invention, it may be appropriately set according to the dosage form, formulation form, degree of symptoms to be applied, etc. For example, when the sebum secretion promoter of the present invention is used as a topical skin preparation, as an example of its dosage, per application, for 1 cm of skin 2 per, the amount of the heparin-like substance is about 0.1 to 3 mg, and the frequency is about 1 to several times a day.

Example

[0046] Examples are shown below to more specifically explain the present invention, but the present invention is not limited thereto.

[0047] Test example A cream preparation (oil-in-water type emulsion composition) having the composition shown in Table 1 was prepared. The specific production method of the cream preparation is as follows. Each component shown in (I) in Table 1 was mixed in a predetermined amount, heated to 80°C, and uniformly stirred to prepare an oil-phase composition. Separately, each component shown in (II) in Table 1 was mixed in a predetermined amount, heated to 80°C, and uniformly stirred to prepare an aqueous-phase composition. The obtained oil-phase composition and aqueous-phase composition were mixed in a heated state at 80°C, subjected to an emulsification treatment, and then cooled to obtain a cream preparation.

[0048] The sebum secretion promoting effect of the obtained cream preparation was evaluated. The specific test method is as follows. The cream preparation was applied to the inner side of the auricle of a golden hamster (8 weeks old, female) once a day, and on the 15th day, an auricle skin piece on the inner side of the central part of the auricle was collected with a medical punch. After removing the outer skin and cartilage from the auricle skin piece, it was immersed in a 2N aqueous sodium bromide solution 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 with a system biological microscope (manufactured by Olympus). The area of the sebaceous glands was measured, and the relative value of the sebum secretion amount was calculated according to the following calculation formula.

[0049]

Number

[0050] In this test, three golden hamsters in each group were used, and one dermal sheet was prepared from each hamster. In one dermal sheet, the areas of 15 randomly selected sebaceous glands were measured. In this way, a total of 45 sebaceous glands (N = 45) were measured for each group, and the average value was substituted into the above calculation formula as the area of the sebaceous glands in each group.

[0051] Note that in this test method, the sebum secretion amount is evaluated by measuring the size of the sebaceous glands. Generally, sebaceous glands are holocrine glands, and cells accumulating lipids autolyze to become sebum and are discharged onto the skin surface. Therefore, there is a direct relationship between the area of the sebaceous glands and the sebaceous gland function, and it is generally known that the sebum secretion amount and the area of the 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). Therefore, the results obtained by this test method can correctly reflect the sebum secretion amount.

[0052] The image when the dermal sheet was stained with Sudan III and observed under a microscope is shown in Fig. 1, and the results of obtaining the relative values of the sebum secretion amount are shown in Table 1. As a result, it was confirmed that the heparin-like substance alone has a higher sebum secretion promoting effect than γ-oryzanol, which is known to have a sebum secretion promoting effect (Example 1). In addition, when the heparin-like substance was used in combination with diphenhydramine or γ-oryzanol, the sebum secretion promoting effect was significantly improved (Examples 2 to 4). In particular, when the heparin-like substance was used in combination with diphenhydramine, a synergistic improvement in the sebum secretion promoting effect was observed (Examples 2 and 4), and when the heparin-like substance, diphenhydramine and γ-oryzanol were used in combination, the sebum secretion promoting effect was significantly improved (Example 4).

[0053]

Table 1

[0054] Prescription example A cream preparation shown in Table 2, a lotion preparation shown in Table 3, a gel preparation shown in Table 4, and an emulsion preparation shown in Table 5 were prepared. All of these preparations are expected to have an effect of promoting sebum secretion, similar to the case of the above test example, and are effective for use in promoting sebum secretion.

[0055] [Table 2]

[0056] [Table 3]

[0057] [Table 4]

[0058] [Table 5]

Claims

**Claim 1** An emulsified composition containing a heparin analogue and diphenhydramine, which is a sebum secretion promoter (excluding those applied to itching symptoms). **Claim 2** The sebum secretion promoter according to claim 1, which is a topical skin preparation.

Images