Methods for promoting ceramide production

Abstract

To provide ceramide production promoters capable of increasing the ceramide content in the epidermis while maintaining the compositional balance of ceramide in the epidermis.SOLUTION: Provided is a ceramide production promoter characterized by containing a polymer A having a weight average molecular weight of 2,000 to 1,000,000 and having 50 mol% or more of a structural unit represented by the following formula (1) (where, R1 represents a hydrogen atom or a methyl group).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a ceramide production promoter that adjusts the compositional balance of ceramide in the skin epidermis and increases the amount of ceramide. [Background technology]

[0002] The stratum corneum, which is the outermost layer of the skin, is composed of keratinocytes derived from epidermal keratinocytes, and intercellular lipids consisting of ceramide, cholesterol, and fatty acids form a lamellar structure between the keratinocytes to fill the intercellular spaces and suppress water evaporation from the body. It is known that ceramide, the main component of intercellular lipids, decreases with age, and the amount of water evaporation from the skin increases, causing various skin problems such as dryness, uneven texture, reduced flexibility, and dermatitis. Furthermore, it has been reported that in skin diseases such as atopic dermatitis, xerosis, and psoriasis, ceramide metabolism is hindered, resulting in a decrease in ceramide in the stratum corneum. In order to prevent such skin troubles caused by a decrease in ceramide, methods of supplementing ceramide from the outside have been attempted, but the effect of these methods does not last long enough.

[0003] Therefore, various ceramide production promoters that promote ceramide production in epidermal cells have been proposed. For example, it has been disclosed that a ceramide production promoter consisting of glucosylceramide, a ceramide precursor (Patent Document 1), or a specific plant extract (Patent Document 2) increases the content of specific ceramides in the skin. In recent years, it has been suggested that not only the total amount of ceramide, but also the composition balance of the 12 types of ceramide present in human epidermis is important for suppressing skin troubles. For example, it has been reported that the ceramide composition balance of patients with atopic dermatitis is significantly different from that of healthy skin. However, many conventional ceramide production promoters increase the content of specific ceramides, which leads to a problem of the composition balance of ceramides being lost. Therefore, there has been a demand for a ceramide production promoter that can increase the ceramide content while maintaining the composition ratio balance of ceramides. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2012-184166 A [Patent Document 2] JP 2019-156777 A [Non-patent literature]

[0005] [Non-Patent Document 1] Ishikawa J, Narita H, Kondo N, Hotta M, Takagi Y, Masukawa Y, et al. J Invest Dermatol 130:2511,2010 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a ceramide production promoter capable of increasing the ceramide content in the epidermis while maintaining and adjusting the compositional balance of ceramides in the epidermis. [Means for solving the problem]

[0007] The inventors have conducted extensive research into homopolymers of monomers having a phosphorylcholine group or copolymers of monomers having a phosphorylcholine group with other monomers, which are safe polymers that are neither irritating nor toxic to the skin, and have discovered that these have excellent properties as ceramide production promoters without any adverse effects on the skin, thereby completing the present invention. That is, according to the present invention, there is provided a ceramide production promoter characterized by containing polymer A having a weight-average molecular weight of 2,000 to 1,000,000 and containing 50 mol % or more of constitutional units represented by the following formula (1). [ka] (In the formula, R 1represents a hydrogen atom or a methyl group. Effect of the Invention

[0008] The ceramide production promoter of the present invention can increase the ceramide content in the epidermis while maintaining and adjusting the compositional balance of ceramide in the epidermis, thereby improving not only the barrier function and moisturizing function of the skin but also the skin condition of patients with skin diseases such as atopic dermatitis, xerosis, and psoriasis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention will now be described in further detail. The ceramide production promoter of the present invention contains a polymer A having a constitutional unit represented by the above formula (1). The polymer A is a base component having ceramide production promoting ability. In formula (1), R 1 represents a hydrogen atom or a methyl group. The structural unit represented by formula (1) is a structural unit derived from polymerization of 2-((meth)acryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, which is a monomer represented by the following formula (1'). As the monomer, 2-(methacryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate (hereinafter abbreviated as MPC) is preferable.

[0010] [ka] (R in the formula 1 represents a hydrogen atom or a methyl group.

[0011] Polymer A contained in the ceramide production promoter of the present invention contains 50 mol % or more of the constitutional unit represented by formula (1). If the constitutional unit represented by formula (1) is less than 50 mol %, the ceramide production promoting effect decreases. The constitutional unit represented by formula (1) in polymer A is preferably 60 mol % or more, more preferably 70 mol % or more. The polymer A may consist of only one type of polymer, or may consist of two or more types of polymers in combination.

[0012] The polymer A may contain a constitutional unit other than the constitutional unit represented by formula (1). As the constitutional unit other than the constitutional unit represented by formula (1), a constitutional unit represented by the following formula (2) is preferable. [ka] (R in the formula 2 R represents a hydrogen atom or a methyl group. 3 represents an alkyl group having 1 to 22 carbon atoms, which may be linear or branched.

[0013] When polymer A contains a structural unit represented by formula (2), the structural unit represented by formula (2) in polymer A is preferably 5 mol % or more, more preferably 10 mol % or more, and less than 50 mol %, preferably 40 mol % or less, and even more preferably 30 mol % or less.

[0014] The constitutional unit represented by the above formula (2) is a constitutional unit derived from polymerization of a monomer represented by the following formula (2'). [ka] (R in the formula 2 R represents a hydrogen atom or a methyl group. 3 represents an alkyl group having 1 to 22 carbon atoms, which may be linear or branched.

[0015] Examples of the monomer represented by formula (2') include linear or branched alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, tetradecyl (meth)acrylate, hexadecyl (meth)acrylate, octadecyl (meth)acrylate, and docosanyl (meth)acrylate, with butyl methacrylate being preferred. As the monomer represented by formula (2'), one or more of these may be used in combination.

[0016] The polymer A contained in the ceramide production promoter of the present invention can be obtained by radical polymerization of a monomer composition containing the monomer represented by the above formula (1') and the monomer represented by the formula (2') which is blended as necessary. The monomer composition may contain, in addition to the above monomer, other polymerizable monomers that can be copolymerized.

[0017] The weight-average molecular weight of the polymer A contained in the ceramide production promoter of the present invention varies depending on the polymerization temperature, the amount of polymerization initiator used, the use of a polymerization degree regulator, etc. during production, but is 2,000 to 1,000,000, preferably in the range of 5,000 to 1,000,000. More preferably, it is in the range of 10,000 to 600,000. It is difficult to control the molecular weight of the polymer so that the weight-average molecular weight is less than 2000, and if the weight-average molecular weight exceeds 1,000,000, the viscosity becomes high and it becomes difficult to handle. The weight-average molecular weight of the polymer A can be determined in terms of polyethylene glycol using gel permeation chromatography (GPC), and details are as described in the Examples.

[0018] When the radical polymerization is carried out, a polymerization initiator can be added to the monomer composition to carry out the polymerization. The polymerization initiator is not particularly limited as long as it is a normal radical polymerization initiator, and examples thereof include 2,2'-azobisisobutyronitrile, benzoyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butylperoxypivalate, t-butylperoxydiisobutyrate, t-butylperoxyneodecanoate, succinyl peroxide, potassium persulfate, ammonium persulfate, and other persulfates. These polymerization initiators can be used alone or as a mixture. In addition, a redox-based radical promoter may be used in combination with the polymerization initiator. The amount of the polymerization initiator used is preferably 0.01 to 10 parts by weight, and particularly preferably 0.1 to 5 parts by weight, based on 100 parts by weight of the total monomers.

[0019] The polymerization conditions for the polymerization are preferably 30 to 80° C., particularly preferably 40 to 70° C., and 10 minutes to 72 hours. In this case, a solvent may be used to facilitate the polymerization reaction, and examples of the solvent include water, methanol, ethanol, propanol, dimethylformamide, and mixtures thereof.

[0020] When the ceramide production promoter of the present invention is incorporated into pharmaceuticals, quasi-drugs, cosmetics and the like, it is preferably incorporated at 0.02 to 10 mass %, more preferably 0.05 to 2 mass %, and even more preferably 0.1 to 1 mass %.

[0021] The content of polymer A having a constitutional unit represented by formula (1) in the ceramide production promoter of the present invention is preferably 50 to 100 mass %, and more preferably 80 to 100 mass %.

[0022] The ceramide production promoter of the present invention can contain other components in addition to the polymer A having a structural unit represented by formula (1). The other components are not particularly limited, and any components generally contained in pharmaceuticals, quasi-drugs, cosmetics, etc. can be contained. Examples of such components include polyhydric alcohols, oils, waxes, acids, alkalis, surfactants, powders, pigments, dyes, preservatives, antioxidants, ultraviolet absorbers, chelating agents, water-soluble polymers, alcohols, solvents, and fragrances. In particular, when preparing the ceramide production promoter of the present invention as a base for a cosmetic serum, ointment, or cream, for example, fatty oils, lanolin, petrolatum, paraffin, glycols, higher fatty acids, alkalis, surfactants, higher alcohols, etc. can be blended, and stabilizers, preservatives, emulsifiers, suspending agents, etc. can also be added as necessary. EXAMPLES

[0023] The present invention will be described below with reference to examples, but the present invention is not limited to these.

[0024] (Synthesis Example 1: Synthesis of MPC homopolymer 1) 20 g (68 mmol) of MPC (2-methacryloyloxyethyl phosphorylcholine) monomer and 0.6 g (2.6 mmol) of succinyl peroxide were dissolved in 80 g of ion-exchanged water, and nitrogen was bubbled for 1 hour. The temperature was then raised to 60°C and polymerization was carried out for 5 hours to obtain a polymer crude aqueous solution containing 19.5% by weight of a ceramide production promoter consisting of MPC homopolymer 1. After the reaction was completed, the obtained polymer crude aqueous solution was contacted with a dialysis membrane (manufactured by Spectrapore) with a molecular weight cutoff of 6000 to 8000, and 15 L of ion-exchanged water was used as the dialysis solution, and the dialysis solution was replaced twice every 24 hours, for a total of 72 hours. The resulting aqueous polymer solution was subjected to gel permeation chromatography (GPC) under the conditions shown below, and the weight average molecular weight of MPC homopolymer 1 was found to be 180,000. The content of MPC homopolymer 1 in the resulting aqueous polymer solution was 15.2% by weight. This aqueous polymer solution was adjusted to a predetermined concentration with ion-exchanged water, and the tests shown in the examples described below were carried out. <Molecular weight measurement> 30 mg of the obtained polymer was dissolved in 30 g of 0.05 M aqueous sodium nitrate solution to obtain a sample solution, and the weight average molecular weight was measured by gel permeation chromatography (GPC). Other conditions were as follows. Column: Shodex OHpak SB-802 HQ, SB-806M HQ (Showa Denko K.K.), standard substance: polyethylene glycol, detection: differential refractometer RI-71S, analysis software: JASCO-BORWIN Ver. 1.50 (JASCO K.K.), flow rate: 1 mL / min, column temperature: 40°C

[0025] (Synthesis Examples 2 and 3: Synthesis of MPC-BMA Copolymers 2 and 3) 30g (102mmol) of MPC monomer, 3.6g (26mmol) of butyl methacrylate (hereinafter abbreviated as BMA), and 0.06g (0.35mmol) of t-butyl peroxy neodecanoate were dissolved in 80g of ethanol, placed in a four-neck flask, and nitrogen was blown in for 30 minutes. After that, 0.06g (0.35mmol) of t-butyl peroxy neodecanoate (trade name: Perbutyl-ND, manufactured by NOF Corp.) (hereinafter abbreviated as PB-ND) was added at 50°C and polymerized for 6 hours, and then 6g of NaOH was added to neutralize. The polymerization solution was dropped into 3L of hexane while stirring, and the precipitate was filtered and vacuum dried at room temperature for 48 hours to obtain a ceramide production promoter consisting of MPC-BMA copolymer 2 as a white powder. This MPC-BMA copolymer 2 was adjusted to a predetermined concentration with ion-exchanged water and tested in the examples described below. Polymerization and purification were carried out in the same manner as in Synthesis Example 2, except that the monomer composition ratio was as shown in Table 1, to obtain a ceramide production promoter consisting of MPC-BMA polymer 3. This MPC-BMA copolymer 3 was adjusted to a predetermined concentration with ion-exchanged water and tested in the examples described below. The molecular weight of the resulting polymer was measured according to the above-mentioned molecular weight measurement method, and the results are shown in Table 1.

[0026] [Table 1] Details regarding the abbreviations used in Table 1 are as follows: BMA: butyl methacrylate (manufactured by NOF Corp.) In formula (2'), R 2 = methyl group, R 3 = butyl group

[0027] <Examples 1 to 3 and Comparative Examples 1 to 2> A human 3D cultured epidermis model (LabCyte EPI-MODEL 24) was used as the cell to which the ceramide production promoter of the present invention was added, and the aqueous solution of the polymer obtained in the above synthesis example and an aqueous solution of glucosylceramide (manufactured by Okayasu Co., Ltd.) were applied to the stratum corneum side and cultured for 7 days. After the culture, the skin was collected and sonicated in chloroform:methanol (2:1) to extract lipids. After concentration, ceramides were separated by type using high performance thin layer chromatography, and the amount of ceramide NS (CerNS), ceramide NP (CerNP), ceramide AS (CerAS), ceramide AP (CerAP) and total ceramide was quantified from the band density using an automatic image detection system CemiDoc XRS Imaging Systems (Bio-Rad). The reference example in which no ceramide was added was used as a control, and the content of each ceramide and the ratio of each ceramide to the total ceramide amount in the examples in which a ceramide production promoter was added are shown in Table 2. <Ceramide composition balance evaluation> The ratio of each of the quantified ceramides to the total amount of ceramide was calculated and evaluated according to the following evaluation criteria. ◎: The variation in the ratio of all four ceramides is less than 2% compared to the control ○: The change in the ratio of all four ceramides is 2% or more but less than 5% compared to the control ×: The variation in the ratio of all four ceramides is 5% or more compared to the control

[0028] [Table 2]

[0029] As can be seen from Examples 1 to 3, all of the ceramide production promoters of the present invention were able to increase the ceramide content in the epidermis while maintaining the ceramide composition balance. On the other hand, the comparative examples do not provide sufficient effects. In Comparative Example 1, the molar ratio of the monomer represented by formula (1) in the polymer corresponding to the ceramide production promoter of the present application is less than 50%, so the ceramide production promoting effect is insufficient. In Comparative Example 2, a glucosylceramide different from the ceramide production promoter of the present application is used, so although the product has a production promoting effect on a specific ceramide, the ceramide composition balance is deteriorated. As described above, conventional ceramide production promoters have the potential to disrupt the skin's natural ceramide composition balance, but by using the ceramide production promoter of the present application, it is possible to increase the ceramide content while maintaining the natural ceramide composition balance of healthy skin, and it is also expected to have an effect of improving the skin condition of patients with skin diseases such as atopic dermatitis, xerosis, and psoriasis.

Claims

[Claim 1] A method for promoting ceramide production using polymer A having a weight-average molecular weight of 2,000 to 1,000,000 and containing 50 mol % or more of a constitutional unit represented by the following formula (1): 【Chemistry 1】 (In the formula, R １ represents a hydrogen atom or a methyl group.)

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