Azelaic acid derivatives and azelaic acid-containing topical skin preparations containing them.

Abstract

To provide an azelaic acid derivative capable of inhibiting stimulation of skin by a skin external preparation applied thereto.SOLUTION: The azelaic acid derivative is represented by AO-C(=O)-R-C(=O)-OA (formula 1) or BO-C(=O)-R-C(=O)-OA (formula 2). The skin external preparation contains active agents, oil-based agents and water-based agents, where the azelaic acid derivative is contained as an oil-based agent. In the formulas 1 and 2, R is a C7 linear hydrocarbon group, A is represented by the general formula CnH2n+1, CnH2n+1O or CnH2n+1O2 comprising a hydrocarbon group, and B is hydrogen or the general formula CnH2n+1, CnH2n+1O or CnH2n+1O2 comprising a hydrocarbon group.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates, for example, to azelaic acid derivatives contained in topical skin preparations and azelaic acid-containing topical skin preparations containing the same. [Background technology]

[0002] Traditionally, topical skin preparations containing azelaic acid have been used. Azelaic acid has a whitening effect that suppresses melanin production and an anti-acne effect that suppresses the occurrence of acne, and is considered suitable for use in topical skin preparations. In addition, there is a method of containing azelaic acid as a derivative in order to efficiently incorporate it into topical skin preparations.

[0003] For example, it has been disclosed that azelaic acid derivative, potassium azeloyldiglycine, may be contained in at least one form of a cream, lotion, serum, gel, and moisturizer (see Patent Document 1).

[0004] However, when azeroyl diglycinate potassium is included in topical skin preparations, it has the property of breaking down the emulsification caused by the emulsifier contained in the preparation. In other words, when azeroyl diglycinate potassium is used as an azelaic acid derivative, recrystallization occurs over time, causing azelaic acid to precipitate in the topical skin preparation, which can cause strong irritation to the skin to which it is applied. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Special Publication No. 2018-501298 [Overview of the project] [Problems that the invention aims to solve]

[0006] The present invention provides an azelaic acid derivative capable of suppressing the irritation to the skin to which a topical skin preparation containing the same is applied, and aims to improve user satisfaction.

Means for Solving the Problems

[0007] The present invention is characterized by being an azelaic acid derivative represented by (Formula 1) or (Formula 2).

Chemical Formula

Chemical Formula

Effects of the Invention

[0008] According to the present invention, an azelaic acid derivative capable of suppressing the irritation to the skin to which a topical skin preparation containing the same is applied can be provided, and user satisfaction can be improved.

Modes for Carrying Out the Invention

[0009] Hereinafter, one embodiment of the present invention will be shown. Regarding the azelaic acid-containing topical skin preparation of the present embodiment, first, the azelaic acid derivative will be described, and then the topical skin preparation containing this azelaic acid derivative will be described.

[0010] <Azelaic Acid Derivative> The azelaic acid derivative of the present invention is represented by the general formula of (Formula 1) or (Formula 2). [ka] [ka] (In formulas 1 and 2, R is a straight-chain hydrocarbon group having 7 carbon atoms, and A is a general formula C containing a hydrocarbon group) n H 2n+1 , C n H 2n+1 O or C n H 2n+1 Represented by O2, B is a hydrogen or hydrocarbon group in the general formula C n H 2n+1 , C n H 2n+1 O or C n H 2n+1 (Represented by O2.)

[0011] In equations (1) and (2), R is a straight-chain hydrocarbon group with 7 carbon atoms. Therefore, R is a C7H group. 14 It is represented as follows.

[0012] In formulas (1) and (2), A is a general formula C containing a hydrocarbon group. n H 2n+1 , C n H 2n+1 O or C n H 2n+1 It is represented as O2. n is an integer of 1 or more. Preferably, n is 3 (represented by the general formulas C3H7, C3H7O, or C3H7O2). Furthermore, A contains one O as a hydroxyl group (general formula C n H 2n+1 It is preferable that A be represented by O. Furthermore, it is more preferable that A be a 2-propanol group.

[0013] In formula (2), B is a general formula C containing hydrogen or a hydrocarbon group. n H 2n+1 , C n H 2n+1 O or C n H 2n+1It is represented as O2. n is an integer greater than or equal to 1, and is either a different integer from n in A, or the same integer but with a different structure in B than in A. Furthermore, B preferably contains a hydroxyl group and a hydrocarbon group.

[0014] The most preferred form of the azelaic acid derivative of the present invention is azelaic acid di-1,2-propanediol having two general formula A (2-propanol groups) where n is 3.

[0015] The azelaic acid derivatives of the present invention are synthesized by mixing azelaic acid with an alcohol, diol, or triol having a predetermined hydrocarbon group corresponding to the number of n, and heating the mixture. For example, azelaic acid di-1,2-propanediol is synthesized (created) by mixing azelaic acid with 1,2-propylene glycol and heating the mixture.

[0016] <Topical skin preparations> The azelaic acid derivative of the present invention can be suitably used as an ingredient in topical skin preparations. The term "topical skin preparation" as used herein includes pharmaceuticals and quasi-drugs. There are no particular restrictions on the form of the topical skin preparation; it can take any form, such as liquid, paste, gel, solid, powder, foam, jelly, or cream. Specific examples of such topical skin preparations include lotions (nanoemulsions), creams, emulsions, serums, shampoos, hair rinses, hair conditioners, hair mousses, hair gels, hair waxes, foundations, eyeliners, eyebrow pencils, mascaras, eyeshadows, blushes, lipsticks, face powders, powders, packs, masks, perfumes, colognes, facial cleansers, cleansing foams, cleansing oils, cleansing gels, cleansing milks, toothpastes, soaps, aerosols, bath products, hair tonics, sunscreens, and the like.

[0017] The topical skin preparation containing the azelaic acid derivative of the present invention contains an oily agent, an aqueous agent, and an activator. The content of the oily agent can be 0.01% by mass or more, preferably 0.05% by mass or more, and more preferably 0.1% by mass or more, based on 100% by mass of the total. Furthermore, the content of the oily agent can be 50% by mass or less, preferably 40% by mass or less, and more preferably 30% by mass or less, based on 100% by mass of the total.

[0018] Furthermore, the preferred content of the oily agent is determined by the type of topical skin preparation. For example, when used as a lotion, the oily agent content is preferably 0.1% by mass or more, based on 100% by mass of the total. Also, for example, when used as an emulsion, the oily agent content is preferably 5% by mass or more, based on 100% by mass of the total. Furthermore, for example, when used as a cream, the oily agent content is preferably 20% by mass or more, based on 100% by mass of the total.

[0019] Unlike conventional water-soluble azelaic acid derivatives such as potassium azeroyldiglycine, the azelaic acid derivative of the present invention is dissolved in an oily agent and is treated as an oily agent in topical skin preparations.

[0020] Furthermore, the azelaic acid derivative content can be 10% by mass or more, preferably 30% by mass or more, and more preferably 50% by mass or more, based on the oily agent content of 100% by mass. Moreover, the azelaic acid derivative content can be 100% by mass or less, based on the oily agent content of 100% by mass. Note that the azelaic acid derivative content relative to the oily agent varies depending on the type and form of the topical skin preparation in which it is contained. For example, if the topical skin preparation is a lotion, it is necessary to keep the content relative to the total oily agent low, so it is preferable to contain only azelaic acid derivative as the oily agent, i.e., 100% by mass of azelaic acid derivative out of 100% by mass of the oily agent. In the case of emulsions and creams, it is preferable to contain 90% by mass or less of azelaic acid derivative out of 100% by mass of the oily agent, and more preferably 80% by mass or less. If the topical skin preparation is an emulsion, it is preferable that the azelaic acid derivative content be 5% by mass or more. When the topical skin preparation is a cream, the azelaic acid derivative content is preferably 10% by mass or more. When the topical skin preparation is a lotion, the azelaic acid derivative content can be about 1% by mass.

[0021] The oily agents included may be components commonly used in topical skin preparations. For example, these may include components used as emulsifying stabilizers, texture enhancers, emollients, antioxidants, and preservatives; one or more of these may be selected and included. The aqueous agents included may also be components commonly used in topical skin preparations. For example, these may include components used as bases, humectants, preservatives, thickeners, stabilizers, and chelating agents; one or more of these may be selected and included. Furthermore, the active agents included may also be components commonly used in topical skin preparations. For example, these may include components used as emulsifiers.

[0022] As an emulsifier, any ingredient commonly used in topical skin preparations can be used, but it is preferable to use one or more of the following: polyglyceryl-10 oleate, polyglyceryl-2 oleate, lecithin, polyglyceryl-10 myristate, sorbeth-30 tetraoleate, glyceryl stearate (SE), sorbitan stearate, glycol stearate, cetearyl alcohol / cetearyl glucoside, PEG-40 hydrogenated castor oil, or beheneth-20.

[0023] As emulsifying stabilizers, ingredients commonly used in topical skin preparations can be used, but it is preferable to use one or more of behenyl alcohol, cetearyl alcohol, stearyl alcohol, and stearic acid.

[0024] As a moisturizer, it can be any ingredient commonly used in topical skin preparations, but it is preferable to use one or more of the following: butylene glycol (BG), glycerin, propylene glycol (PG), dipropylene glycol (DPG), hexanediol, pentylene glycol, and betaine.

[0025] As a preservative, it can be an ingredient commonly used in topical skin preparations, but it is preferable to use one or more of phenoxyethanol and parabens (methylparaben, propylparaben).

[0026] As a thickening agent, any ingredient commonly used in topical skin preparations can be used, but xanthan gum, carbomer, or sclerotium gum is preferred.

[0027] As texture enhancers, they can be ingredients commonly used in topical skin preparations.

[0028] As an emollient, it can be any ingredient commonly used in topical skin preparations, but it is preferable to use one or more of the following: dimethicone, dicholesteryl lauroyl glutamate, dibehenyl lauroyl glutamate, dioctyldodecyl lauroyl glutamate, squalane, cetyl ethylhexanoate, triethylhexanoin, hydrogenated polybutene, or petrolatum.

[0029] As antioxidants, ingredients commonly used in topical skin preparations can be used, but tocopherol is preferred.

[0030] As a chelating agent, any ingredient commonly used in topical skin preparations can be used, but it is preferable to use EDTA-2Na (sodium edetate).

[0031] As a stabilizer, it can be an ingredient commonly used in cosmetics.

[0032] The base material can be an ingredient commonly used in cosmetics.

[0033] Furthermore, the topical skin preparation containing the azelaic acid derivative of the present invention may further contain one or more active ingredients. Examples of active ingredients include anti-wrinkle ingredients, moisturizing ingredients, irritation-relieving ingredients, blood flow-promoting ingredients, whitening ingredients, anti-acne ingredients, anti-inflammatory ingredients, antibacterial ingredients, skin roughness-preventing ingredients, UV-blocking ingredients, and cooling ingredients.

[0034] As anti-wrinkle ingredients, any ingredients commonly used in topical skin preparations can be used, but it is preferable to use one or more of the following: retinyl palmitate, trisodium ascorbyl palmitate phosphate, and vitamin A oil.

[0035] As moisturizing ingredients, those commonly used in topical skin preparations can be used, but it is preferable to use one or more from D-pantothenyl alcohol and urea.

[0036] As irritation-reducing ingredients, any ingredient commonly used in topical skin preparations can be used, but D-pantothenyl alcohol is preferred.

[0037] As blood flow promoting ingredients, any ingredients commonly used in topical skin preparations can be used, but it is preferable to use one or more from DL-α-tocopherol acetate and tocopherol nicotinate.

[0038] As for the whitening ingredients, any ingredients commonly used in topical skin preparations can be used, but it is preferable to use one or more of the following: tetra-2-hexyldecanoate ascorbyl, magnesium L-ascorbyl phosphate, trisodium ascorbyl palmitate phosphate, and L-ascorbic acid 2-glucoside.

[0039] The anti-acne ingredients can be those commonly used in topical skin preparations, but it is preferable to use one or more of the following: tetra-2-hexyldecanoate ascorbyl, photosensitizer 201, and salicylic acid.

[0040] The anti-inflammatory component can be any ingredient commonly used in topical skin preparations, but it is preferable to use one or more of allantoin, dipotassium glycyrrhizate, or stearyl glycyrrhetinate.

[0041] The antibacterial component can be any component commonly used in topical skin preparations, but it is preferable to use one or more of isopropylmethylphenol, salicylic acid, and benzalkonium chloride.

[0042] As for the skin-soothing ingredients, any ingredients commonly used in topical skin preparations can be used, but it is preferable to use one or more from estradiol and pyridoxine hydrochloride.

[0043] The UV-blocking component can be any component commonly used in topical skin preparations, but it is preferable to use one or more from zinc oxide and titanium dioxide.

[0044] The cooling ingredients can be those commonly used in topical skin preparations, but it is preferable to use one or more from menthol and ethanol.

[0045] Furthermore, the azelaic acid derivative of the present invention contained in the topical skin preparation is lipophilic. Therefore, the azelaic acid derivative of the present invention contained in the topical skin preparation is included as an oily agent, and if other oily agents are also included, it will be dissolved in the oily agent.

[0046] Furthermore, azelaic acid derivatives containing a 2-propanol group exhibit a higher whitening effect compared to azelaic acid derivatives that do not contain a 2-propanol group.

[0047] With the above configuration, it is possible to provide an azelaic acid derivative that can suppress irritation to the skin to which the contained topical skin preparation has been applied. The azelaic acid derivative of the present invention has the general formula C at its terminus. n H 2n+1 , C n H 2n+1 O or C n H 2n+1 It has a structure containing a hydrocarbon group represented by O2. This configuration makes the azelaic acid derivative lipophilic. That is, it has a terminal part of the general formula C n H 2n+1 , C n H 2n+1 O or C n H 2n+1 Compared to azelaic acid and azelaic acid derivatives that do not have a structure containing a hydrocarbon group represented by O2, this derivative exhibits better solubility in oily agents. Furthermore, because of its good solubility in oily agents, azelaic acid does not crystallize and precipitate over time. In particular, when used as a topical skin preparation, precipitated azelaic acid does not cause strong irritation to the skin to which it is applied. This prevents skin problems such as redness and itching even when the amount of azelaic acid derivative is increased, thereby improving user satisfaction. In other words, it can be used more suitably as an ingredient in topical skin preparations.

[0048] Furthermore, the azelaic acid derivative of the present invention has the general formula C at its terminus. n H 2n+1 It has a structure containing a hydroxyl group represented by O and a hydrocarbon. This configuration allows for better solubility in oily agents compared to azelaic acid derivatives that do not have this configuration.

[0049] Furthermore, the azelaic acid derivative of the present invention has a structure containing a hydroxyl group and a hydrocarbon group represented by the general formula C3H7O at its terminal end. This configuration allows it to exhibit a higher whitening effect when used as a topical skin preparation compared to azelaic acid derivatives that do not have this configuration. In addition, this configuration makes the azelaic acid derivative more lipophilic. As a result, a larger amount of azelaic acid can be included in the topical skin preparation, allowing it to exhibit a high melanin-inhibiting effect (whitening effect) and an anti-acne effect.

[0050] Furthermore, the azelaic acid derivative of the present invention is azelaic acid di-1,2-propanediol having two 2-propanol groups at its terminus. This configuration allows the azelaic acid derivative to have even higher lipophilicity. Moreover, compared to azelaic acid and azelaic acid derivatives that do not have two 2-propanol groups at their terminus, it can further reduce irritation to the human skin when contained in topical skin preparations, making it more suitable for use as an ingredient in topical skin preparations. In addition, topical skin preparations containing azelaic acid di-1,2-propanediol can exhibit a higher whitening effect compared to azelaic acid and azelaic acid derivatives that do not have two 2-propanol groups at their terminus, thereby improving user satisfaction. Furthermore, even when contained in large quantities in topical skin preparations, it is less likely to cause stickiness and can result in a refreshing topical skin preparation, further improving user satisfaction.

[0051] Furthermore, the topical skin preparation containing the azelaic acid derivative of the present invention contains an oily agent, an aqueous agent, and an activator. Unlike conventional azelaic acid and azelaic acid derivatives present in powder form in topical skin preparations, the azelaic acid derivative is either included in the topical skin preparation as an oily agent or dissolved in the oily agent. This configuration prevents the azelaic acid from disrupting the emulsion and makes it less likely to recrystallize and precipitate over time. In other words, precipitated and unevenly distributed azelaic acid does not irritate the skin to which the topical skin preparation is applied, making it less likely to cause reactions such as rashes and improving user satisfaction. In addition, it improves the handling performance during the manufacturing of the topical skin preparation.

[0052] The topical skin preparation containing the azelaic acid derivative of the present invention may contain 10% by mass or more of the azelaic acid derivative, preferably 20% by mass or more, more preferably 30% by mass or more, even more preferably 40% by mass or more, and preferably 50% by mass or more, based on 100% by mass of the oily agent. Furthermore, the topical skin preparation containing the azelaic acid derivative of the present invention may contain 100% by mass or less of the azelaic acid derivative, based on 100% by mass of the oily agent. When the azelaic acid derivative is considered to be 100% by mass, it refers to the case where the azelaic acid derivative itself functions as an oily agent in the topical skin preparation, and no other oily agent is present. This configuration allows for a higher melanin-inhibiting effect (whitening effect) and can improve user satisfaction.

[0053] <Example 1> A lotion was prepared by blending the multiple ingredients shown in Table 1 in the proportions shown in Table 1, and this was designated as Example 1. The prepared lotion contains 2% by mass of azelaic acid di-1,2-propanediol, which is an azelaic acid derivative of the present invention, and contains only azelaic acid di-1,2-propanediol as an oily agent. That is, when the total amount of oily agents is considered to be 100% by mass, the amount of azelaic acid di-1,2-propanediol contained in the oily agents is 100% by mass.

[0054] [Table 1]

[0055] The created lotion did not cause symptoms of severe irritation such as itching when applied to the skin (topical use), and exhibited high melanin-inhibiting effects (whitening effect) and anti-acne effects.

[0056] <Example 2> A lotion was prepared by combining the multiple components shown in Table 2 in the proportions shown in Table 2, and this was designated as Example 2. The prepared emulsion contains 5% by mass of azelaic acid di-1,2-propanediol, which is an azelaic acid derivative of the present invention, and contains a total of 8.14% by mass of azelaic acid di-1,2-propanediol, behenyl alcohol, lauroyl glutamate di(cholesteryl / behenyl / octyldodecyl), squalane, dimethicone, tocopherol, and propylparaben as oily agents. In other words, when the total amount of oily agents is taken as 100% by mass, the amount of azelaic acid di-1,2-propanediol contained in the oily agents is approximately 61.4% by mass.

[0057] [Table 2]

[0058] The created lotion did not cause symptoms of strong irritation such as itching when applied to the skin, and exhibited high melanin-inhibiting (whitening) and anti-acne effects.

[0059] <Example 3> A facial cream was prepared by combining the multiple ingredients shown in Table 3 in the proportions shown in Table 3, and this was designated as Example 3. The prepared facial cream contains 20% by mass of azelaic acid di-1,2-propanediol, an azelaic acid derivative of the present invention, and a total of 25.8% by mass of azelaic acid di-1,2-propanediol, behenyl alcohol, cetearyl alcohol, cetyl palmitate, dimethicone, tocopheryl acetate, and propylparaben as oily agents. In other words, when the total amount of oily agents is considered as 100% by mass, the amount of azelaic acid di-1,2-propanediol contained in the oily agents is approximately 77.5% by mass.

[0060] [Table 3]

[0061] The facial cream we created did not cause symptoms such as itching or other strong irritation when applied to the skin, and exhibited high melanin-inhibiting (whitening) and anti-acne effects.

[0062] <Example 4> A facial cream was prepared by combining the multiple ingredients shown in Table 4 in the proportions shown in Table 4, and this was designated as Example 4. The facial cream prepared contains 20% by mass of azelaic acid di-1,2-propanediol, an azelaic acid derivative of the present invention, and a total of 34.35% by mass of azelaic acid di-1,2-propanediol, stearyl alcohol, stearyl acid, triethylhexanoin, hydrogenated polybutene, petrolatum, dimethicone, and propylparaben as oily agents. That is, when the total amount of oily agents is taken as 100% by mass, the amount of azelaic acid di-1,2-propanediol contained in the oily agents is approximately 58.2% by mass.

[0063] [Table 4]

[0064] Furthermore, in a study of 148 people with acne, when the facial cream from Example 4 was applied to the acne-affected areas twice daily (morning and evening) for three months, 116 people reported significant improvement, and 32 people reported slight improvement. Zero people reported no effect. Moreover, although the study period was three months, the improvement in acne became apparent after approximately two weeks. This indicates that the facial cream from Example 3 possesses a high anti-acne effect. Furthermore, in a study of 27 people with blemishes, when the facial cream from Example 3 was applied to the blemished areas twice daily, morning and evening, for three months, 10 people reported significant improvement after the prescribed application period, and 17 people reported slight improvement. Additionally, no one reported any effect. This indicates that the facial cream from Example 3 has a high whitening effect.

[0065] This invention is not limited to the configuration of the above-described embodiment, and many other embodiments can be obtained. [Industrial applicability]

[0066] This invention can be used in the manufacture and sale of cosmetics containing azelaic acid derivatives.

Claims

1. A topical skin preparation containing an oily agent, an aqueous agent, and an activator, The oily agent contains at least a portion of azelaic acid di-1,2-propanediol, and the azelaic acid di-1,2-propanediol is represented by (Formula 1). A topical skin preparation containing azelaic acid. 【Chemistry 1】 (In formula 1, R is represented by the general formula C7H14, and A is a 2-propanol group.)

2. The content of the azelaic acid di-1,2-propanediol is 10 to 100% by mass of the total oily agent. A topical skin preparation containing azelaic acid according to claim 1.

3. The azelaic acid di-1,2-propanediol is contained in the oily agent in a dissolved state without precipitation of crystals. A topical skin preparation containing azelaic acid according to claim 2.

4. The content of the azelaic acid di-1,2-propanediol is 50 to 100% by mass of the total oily agent. A topical skin preparation containing azelaic acid according to claim 1, 2, or 3.

5. At least a portion of the aqueous agent is contained as a humectant, The aforementioned humectant contains butylene glycol (BG). A topical skin preparation containing azelaic acid according to claim 4.

6. At least a portion of the oily agent is contained as an emollient, The aforementioned emollient contains cetyl ethylhexanoate. A topical skin preparation containing azelaic acid according to claim 5.

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