JP7585564B2 - Cosmetics containing ceramide-containing niosomes - Google Patents

Description

The present invention relates to a cosmetic preparation containing ceramide-containing niosomes.

Ceramide is a compound in which sphingosine and fatty acids form an amide bond, and is found in large amounts in cell membranes. Ceramide is the main component of the lamellar structure formed by intercellular lipids in the stratum corneum of the skin, and plays an important role in the skin's barrier function. For this reason, it is often incorporated into cosmetics to improve the skin's barrier function. However, because ceramide is highly crystalline, it has been difficult to stably incorporate it into cosmetics as is. It has been particularly difficult to incorporate it into cosmetics that contain little oil, such as lotions.

In order to stably incorporate ceramide into a lotion, it is necessary to complex the ceramide with micelles or vesicles, i.e., vesicular structures formed by surfactants and phospholipids. However, when ceramide is stably complexed as a component of a micelle or vesicle structure, this structure is maintained even when applied to the skin, and therefore the ceramide cannot be supplied to the inside of the stratum corneum of the skin, and the expected beneficial functions of ceramide may be lost.

Among vesicles, an endoplasmic reticulum structure consisting of a bilayer membrane similar to liposomes formed by nonionic surfactants has been attracting attention in recent years. This endoplasmic reticulum is called a "niosome." Niosomes are closed endoplasmic reticulum (vesicles) with a bilayer membrane mainly composed of nonionic surfactants, and like liposomes composed of phospholipids, they are used in drug delivery systems (DDS), cosmetics, etc.
Patent Documents 1 and 2 describe niosomes containing ceramide as a component of the bilayer membrane in the form of a complex, and cosmetics containing the niosomes.

Patent Document 3 discloses a copolymer and a liposome complex that are temperature and pH responsive.

JP 2007-246538 A Special Publication No. 2010-513221 JP 2015-209494 A

The objective of the present invention is to provide a skin topical composition containing niosomes that have the function of disintegrating under specific temperature and pH conditions to release ceramide, and niosomes.

The present invention comprises the following configuration.
1. A composition for external use on the skin comprising niosomes containing the following (A) to (E):
(A) a copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol (B) a ceramide (C) a nonionic surfactant (D) a polyhydric alcohol (E) water 2. The composition for external use on the skin according to 1, wherein the average molecular weight of (A) a copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol is 1,000 to 1,000,000.
3. The composition for external application to the skin according to 1 or 2, wherein the nonionic surfactant (C) contains both polyoxyethylene hydrogenated castor oil and sorbitan fatty acid.
4. The composition for external use on the skin according to 3, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil having an average degree of polymerization of polyoxyethylene chains of 60 to 100, and the sorbitan fatty acid is one or more selected from sorbitan sesquiisostearate, sorbitan sesquioleate, and sorbitan oleate.
5. The composition for external application to skin according to any one of 1 to 4, wherein the polyhydric alcohol (D) is either dipropylene glycol or pentylene glycol, or both.
6. The composition for external application to the skin according to any one of 1 to 5, wherein the composition for external application to the skin is in the form of a lotion.
7. Niosomes comprising a copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol and ceramides complexed in a bilayer membrane.
8. The niosome according to 7, wherein the copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol is a random copolymer.
9. The niosome according to 7 or 8, wherein the methoxydiethylene glycol (MDEGMA) portion and the lauroxytetraethylene glycol (LTEGMA) portion of the copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol are 50 to 70% and 2 to 10%, respectively, when the total carboxyl groups of polymethacrylic acid are taken as 100%.

The niosome contained in the skin external composition of the present invention behaves as a stable bilayer vesicle under normal conditions.Therefore, in the external composition containing it, ceramide is stably held in the bilayer of niosome, and ceramide crystals do not precipitate.However, when the stable niosome is broken down under the temperature and pH conditions of skin, the ceramide that constitutes this niosome is released.
When the ceramide released from the niosomes disintegrated by the temperature and pH of the skin is released in the stratum corneum of the skin, it is incorporated into the lamellar structure of the stratum corneum and promotes the formation of the lamellar structure, thereby further strengthening the barrier function of the skin. Therefore, the composition containing the niosomes of the present invention makes it possible to achieve the strengthening of the skin barrier function by ceramide, which was difficult to achieve with conventional techniques.
The niosome of the present invention contains a copolymer having a structure in which a part of the carboxyl group of ceramides and polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol. This niosome disintegrates at the temperature and pH of the skin.

FIG. 2 is a schematic diagram showing a synthesis reaction process of a copolymer. FIG. 1 is a schematic diagram showing the structure of a niosome of the present invention and a schematic diagram showing the collapse principle of a niosome. 1 is a graph showing the results of particle size measurement of particles contained in a composition performed in Test Example 3. This is a microscopic observation image of stable niosomes in Test Example 3. An enlarged image of the circled portion in the figure is shown overlapping the rectangular frame. FIG. 1 is a microscopic observation image of collapsed niosomes in Test Example 4. 1 is a graph showing the results of a test of ceramide release temperature from niosomes of the compositions of Example 1 and Comparative Example 1 at pH 5, performed in Test Example 5. 1 is a graph showing the test results of a human stratum corneum lamella formation test in Test Example 6. 1 is a graph showing the results of a moisturizing test carried out in Test Example 7.

The topical skin composition of the present invention is a composition containing a niosome containing (A) a copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol, (B) ceramides, (C) a nonionic surfactant, (D) a polyhydric alcohol, and (E) water.
Each component will be explained below.
(A) A copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol In this specification, (A) a copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol is simply referred to as a "copolymer".
The copolymer has a structure in which the carboxyl groups of polymethacrylic acid are esterified with methoxydiethylene glycol (MDEGMA) and lauroxytetraethylene glycol (LTEGMA).

The copolymer has the repeating structure shown in Chemical Formula 1 below.
Note that l, m, and n are the numbers of bonds in each residue (chemical formula 1).

The copolymer can be prepared by synthesis using known methods. For example, based on the method disclosed in Patent Document 3, a copolymer having a desired average molecular weight and esterification rate can be easily synthesized. This copolymer has the property of adopting a hydrophilic random coil structure under conditions of near-neutral pH and room temperature, and adopting a hydrophobic globule structure under conditions of acidic pH of near pH 5 and 32°C on the skin surface.

The esterification ratios of methoxydiethylene glycol and lauroxytetraethylene glycol in the copolymer are preferably such that, when the total amount of carboxyl groups contained in the original polymethacrylic acid is taken as 100%, the binding rates of methoxydiethylene glycol (MDEGMA) and lauroxytetraethylene glycol (LTEGMA) per copolymer are 50 to 70% and 2 to 10%, respectively, and more preferably 55 to 60% and 2 to 5%, respectively.
In the present invention, the (A) copolymer is contained in the niosome-containing composition of the present invention in an amount of 0.01 to 10.0% by mass, preferably 0.1 to 5.0% by mass, and particularly preferably 0.3 to 1% by mass, based on the total amount.
Furthermore, the composition containing the niosome of the present invention contains the copolymer (A) in an amount of preferably 0.1 to 10.0 parts by mass, more preferably 0.5 to 5.0 parts by mass, per part by mass of the ceramides (B).
The number average molecular weight of the copolymer is not particularly limited, but is preferably from 1,000 to 1,000,000, more preferably from 15,000 to 40,000, and particularly preferably from 20,000 to 30,000.

(B) Ceramides The ceramides used in the present invention include ceramide, ceramide derivatives, and ceramide analogues.
Ceramide is an amide derivative that accounts for approximately 50% of the intercellular lipids present in human skin (stratum corneum). Examples of ceramide include N-acylsphingosine (ceramide), N-acyldihydrosphingosine (dihydroceramide), and N-acylphytosphingosine (phytoceramide). The chemical name of the aforementioned sphingosine is (2S,3R,4E)-2-amino-4-octadecene-1,3-diol, the chemical name of dihydrosphingosine is (2S,3R)-2-aminooctadecane-1,3-diol, and the chemical name of phytosphingosine is (2S,3S,4R)-2-amino-1,3,4-octadecanetriol.
The ceramides contained in the composition containing the niosome of the present invention are preferably those generally used in cosmetics among external skin preparations, and more preferably those called poorly soluble ceramides. Examples of such ceramides include ceramides 1 to 6. The ceramides can be used alone or in combination of two or more. Ceramide 2 or ceramide 3 is particularly preferred.
The chemical name of ceramide 2 is (2S,3R)-2-octadecanoylaminooctadecane-1,3-diol, and a commercially available product (Ceramide TIC-001, manufactured by Takasago International Corporation) can be used. The chemical name of ceramide 3 used in the present invention is 2-octadecanoylamino-1,3,4-octadecanetriol, and a commercially available product (DS-Ceramide Y3S, manufactured by DOOSAN Corporation) can be used.
The ceramides in the present invention are preferably contained in an amount of 0.01 to 5.0% by mass, more preferably 0.05 to 1.0% by mass, and particularly preferably 0.1 to 0.5% by mass, based on the total amount of the composition containing the niosome of the present invention.

(C) Nonionic Surfactant As the nonionic surfactant used in the composition of the present invention, any surfactant that is usually used in cosmetics or external preparations can be used. Specifically, polyoxyethylene alkyl ethers (laureth-4, laureth-7, laureth-9, laureth-21, laureth-23, ceteth-10, ceteth-20, steareth-2, steareth-20, steareth-21, ceteareth-25, beheneth-20, beheneth-30, oleth-2, oleth-10), polyoxyethylene steryl ethers (PEG-5 phytosterol, PEG-10 phytosterol, PEG-30 phytosterol), polyoxyethylene fatty acid esters (PEG-25 stearate, PEG-40 stearate, PEG-45 stearate, PEG-55 stearate, PEG-75 stearate, PEG-100 stearate, PEG-150 stearate, PEG-150 distearate), polyoxyethylene Polyethylene polyhydric alcohol fatty acid ester (PEG-7 glyceryl coconut oil fatty acid, PEG-8 glyceryl isostearate, PEG-20 glyceryl isostearate, PEG-60 glyceryl isostearate, PEG-20 glyceryl triisostearate, sorbeth-30 tetraoleate, sorbeth-40 tetraoleate, sorbeth-60 tetraoleate), polyoxyethylene hydrogenated castor oil (PEG-10 hydrogenated castor oil, PEG-20 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-100 hydrogenated castor oil), polyoxyethylene sorbitan fatty acid ester (polysorbate 20, polysorbate 60, polysorbate 80), glycol fatty acid ester (PG stearate, glycerin fatty acid ester, Glyceryl stearate, glyceryl stearate (SE), glyceryl isostearate, glyceryl oleate, glyceryl behenate), fatty acid sorbitan esters (sorbitan laurate, sorbitan palmitate, sorbitan stearate, sorbitan isostearate, sorbitan oleate, sorbitan sesquistearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan olivate, sorbitan coconutate), sucrose fatty acid esters (sucrose laurate, sucrose palmitate, sucrose stearate, sucrose coconutate), polyglycerin fatty acid esters (polyglyceryl-2 laurate, polyglyceryl stearate Examples of the isostearate include polyglyceryl-2, polyglyceryl-2 oleate, polyglyceryl-2 isostearate, polyglyceryl-4 isostearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 stearate, polyglyceryl-10 oleate, polyglyceryl-10 isostearate, polyglyceryl-2 diisostearate, polyglyceryl-3 diisostearate, polyglyceryl-10 diisostearate, polyglyceryl-6 polyricinoleate, fatty acid alkanolamides (cocamide DEA, cocamide MEA, lauramide DEA), alkyl glycosides (caprylyl/capryl) glucoside, decyl glucoside, lauryl glucoside, cetearyl glucoside, coconut oil alkyl glucoside).
In the present invention, a combined use of polyoxyethylene hydrogenated castor oil and fatty acid sorbitan is preferred.

Polyoxyethylene hydrogenated castor oil The polyoxyethylene hydrogenated castor oil used in the present invention preferably has an average degree of polymerization of polyoxyethylene chains of 60 to 100, more preferably 80 to 100, and particularly preferably 100.
If the average degree of polymerization of the polyoxyethylene chain is less than 60, the stability over time may be insufficient.
The polyoxyethylene hydrogenated castor oils can be used alone or in combination of two kinds, as required.
As the polyoxyethylene hydrogenated castor oil, commercially available products (POE (100) hydrogenated castor oil (NIKKOL HCO-100) manufactured by Nippon Surfactant Industry Co., Ltd., POE (100) hydrogenated castor oil (EMALEX HC-100) manufactured by Nippon Emulsion Co., Ltd., POE (80) hydrogenated castor oil (NIKKOL HCO-80) manufactured by Nippon Surfactant Industry Co., Ltd., etc.) can be preferably used.

Fatty acid sorbitan The fatty acid sorbitan in the present invention is also called sorbitan fatty acid ester. As the sorbitan fatty acid ester, a fatty acid having 8 to 22 carbon atoms can be used in which sorbitol is ester-bonded. Suitable for the present invention is sorbitan sesquiisostearate, sorbitan sesquioleate, or sorbitan oleate, preferably sorbitan sesquiisostearate or sorbitan sesquioleate, more preferably sorbitan sesquioleate. Examples of commercially available sorbitan sesquiisostearate include NIKKOL SI-15RV (Nikko Chemicals Co., Ltd.) and Cosmol 182V (The Nisshin Oillio Group, Ltd.), and examples of commercially available sorbitan sesquioleate include Rheodol AO-15V (Kao Corporation) and Cosmol 82 (The Nisshin Oillio Group, Ltd.). Examples of commercially available sorbitan oleate include Rheodol AO-10V (Kao Corporation).
The above-mentioned fatty acid sorbitan may be used alone or in combination of two kinds, if necessary.

When the composition of the present invention contains polyoxyethylene hydrogenated castor oil and fatty acid sorbitan as the nonionic surfactant of component (C), the ratio of polyoxyethylene hydrogenated castor oil to fatty acid sorbitan is 2 parts by mass or less per part by mass of fatty acid sorbitan, more preferably 0.5 parts by mass or less, particularly preferably 0.3 parts by mass or less of polyoxyethylene hydrogenated castor oil per part by mass of fatty acid sorbitan.
In addition, the composition containing the niosome of the present invention contains a nonionic surfactant as component (C) in an amount of preferably 0.5 to 20.0 parts by mass, more preferably 1 to 10.0 parts by mass, and particularly preferably 2.0 to 6.0 parts by mass of (C) relative to 1 part by mass of the ceramides (B).

(D) Polyhydric alcohol The composition containing niosomes of the present invention contains (D) polyhydric alcohol. As the polyhydric alcohol, it is preferable to contain dipropylene glycol or pentylene glycol, or both. When dipropylene glycol is contained, the content of polyhydric alcohol is 20 parts by mass or more per part by mass of ceramides. When pentylene glycol is contained, it is preferable to contain 15 parts by mass or more per part by mass of ceramides. When both polyhydric alcohols are contained, the content ratio of dipropylene glycol to pentylene glycol is obtained, and the content of ceramides is confirmed to meet the standard based on this. When the content of dipropylene glycol or pentylene glycol is less than the above amount relative to ceramide, crystallization of ceramide may occur.

(E) Water The composition containing the niosome of the present invention contains water as an essential component. Water is an important component in forming niosomes. When the composition containing the niosome of the present invention is 100% by mass, the remaining amount of the total amount of the above components and the optional components of (F) is the water content.
The content of water in the composition containing niosomes is preferably 50% by mass or more, more preferably 70% by mass or more, and particularly preferably 80% by mass or more. The content of water contained in the composition containing niosomes of the present invention can be adjusted by the content of optional component (F).

(F) Optional components The composition containing the niosome of the present invention can contain various components contained in skin external preparations and cosmetics, as long as the effects of the present invention are not impaired.The composition containing the niosome of the present invention can contain optional components, as long as the effects of the present invention are not impaired, that are generally used in cosmetics, such as organic powders, water-soluble polymers, salts, pH adjusters, preservatives, sequestering agents, medicinal ingredients, fragrances, etc.In addition, cosmetic ingredients such as ascorbic acid derivatives and plant extracts can be added.

As organic powders, polymer beads such as polymethylmethacrylate resin (PMMA), silicone resin powders such as polysilicone 1 crosspolymer, polyurethane powders, etc. can be blended.

Examples of water-soluble polymers include gum arabic, gum tragacanth, galactan, guar gum, carrageenan, pectin, agar, quince seed, dextran, pullulan, carboxymethyl starch, collagen, casein, gelatin, methylcellulose, methylhydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, sodium alginate, and carboxyvinyl polymer.

Examples of salts include sodium chloride and magnesium sulfate.

Examples of pH adjusters include citric acid, sodium citrate, phosphoric acid, sodium phosphate, etc.

Examples of preservatives include methylparaben, ethylparaben, etc.

Examples of sequestering agents include disodium ethylenediaminetetraacetate, edetic acid, and edetate salts such as sodium edetate.

Examples of medicinal ingredients include vitamins such as vitamin A oil, vitamin A such as retinol, vitamin B6 such as riboflavin, vitamin B6 such as pyridoxine hydrochloride, vitamin C such as L-ascorbic acid, L-ascorbic acid phosphate, L-ascorbic acid monopalmitate, L-ascorbic acid dipalmitate, and L-ascorbic acid-2-glucoside, pantothenic acids such as calcium pantothenate, vitamin D such as vitamin D6 and cholecalciferol, and vitamin E such as α-tocopherol, tocopherol acetate, and DL-α-tocopherol nicotinate. Examples of useful ingredients include water-soluble organic solvents such as ethanol, chelating agents, whitening agents, emollients, moisturizing agents, antioxidants, coloring agents, preservatives, fragrances (including essential oils), various oily ingredients, and various aqueous ingredients.

To prepare a composition containing niosomes of the present invention, for example, dissolve the copolymer of component (A) in water (E) and adjust the pH to 10 with a pH adjuster such as potassium hydroxide, then heat and heat to about 85°C, and add dropwise the components (B), (C), and (D) that have been uniformly heated and dissolved at about 85°C while stirring, and cool to 30°C using an ice bath, and then adjust the pH to 6.5 using citric acid as a pH adjuster. Note that the heating temperature when mixing each component should not be lower than 80°C. In addition, the heating temperature is preferably lower than 90°C in order to prevent oxidation and denaturation.
Thus, by heating and stirring, it is possible to obtain a composition containing the niosomes of the present invention in which niosomes containing ceramides in the niosome structure are dispersed. This composition is extremely stable at room temperature or low temperature without separation of the contained niosomes or niosome components or change in viscosity of the composition.
The specific form of the composition containing the niosome of the present invention is suitably a liquid formulation such as a lotion, milky lotion, or cream.

The niosomes produced in the above process are vesicles made of a double membrane of a nonionic surfactant, and a copolymer (copolymer) having a structure in which a part of the carboxyl group of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol. This copolymer protrudes from the surface of the niosome as a hydrophilic random coil under conditions of room temperature and pH 6.5 (a cross-sectional view of the niosome of the present invention is shown in the schematic diagram of Figure 2). When the niosomes come into contact with the skin, as shown in the lower part of Figure 2, the hydrophilic coil becomes a hydrophobic spherical polymer (hereinafter referred to as "globule") due to the temperature and pH of the skin. As a result, the niosomes collapse due to hydrophobic interactions (see the lower part of Figure 2), and the ceramide that constitutes the niosomes is released, and this ceramide is directly dispersed in the stratum corneum of the skin.

In other words, when the niosomes contained in the composition of the present invention are applied to the skin or used externally, the three-dimensional structure of the copolymer changes from hydrophilic random coil to hydrophobic globule depending on the temperature and pH of the skin, and the niosomes gradually collapse, releasing ceramides. The released ceramides disperse in the stratum corneum of the skin and strengthen the lamellar structure of the stratum corneum.

A more specific explanation of the principle by which the bilayer membrane of niosomes is destroyed is as follows.
In the aqueous dispersion of the niosome complex, under conditions where the copolymer can maintain its hydrophilicity, the copolymer is stably present in water in a state supported by the niosome. When the copolymer becomes hydrophobic with a change in temperature and/or pH of this aqueous dispersion, the copolymer aggregates in water to form hydrophobic globules. In the niosome complex, since the copolymer is supported by the niosome, this conformational change of the copolymer occurs near the surface of the bilayer membrane of the niosome. The globules, which are aggregates of the hydrophobic copolymer, penetrate into the lipophilic portion of the nonionic surfactant bilayer membrane, and the bilayer membrane is destroyed.

The niosome of the present invention has a double membrane vesicle structure formed by complexing at least (A) a copolymer, (B) a ceramide, and (C) a nonionic surfactant, and contains (D) a polyhydric alcohol and (E) water within the vesicle.
In the niosome containing the copolymer and ceramides complexed in a double membrane of a nonionic surfactant, the content ratio of the (A) copolymer, the (B) ceramides, and the (C) nonionic surfactant is preferably 0.01 to 3, more preferably 0.04 to 2, particularly preferably 0.1 to 1, and the (C) nonionic surfactant is preferably 0.5 to 10, more preferably 1 to 6, particularly preferably 2 to 4, when the mass of the (A) copolymer is taken as 1.

The nonionic surfactant (C) contained in the niosome may be any nonionic surfactant used in cosmetics, but it is preferable to use polyoxyethylene hydrogenated castor oil and fatty acid sorbitan in combination. The polyoxyethylene hydrogenated castor oil is preferably one having an average degree of polymerization of polyoxyethylene chains of 60 to 100, and the fatty acid sorbitan is preferably one or more selected from sorbitan sesquiisostearate, sorbitan sesquioleate, and sorbitan oleate. When polyoxyethylene hydrogenated castor oil and fatty acid sorbitan are blended, the content ratio of fatty acid sorbitan is preferably 0.4 to 16, more preferably 1 to 8, and particularly preferably 2 to 6, when polyoxyethylene hydrogenated castor oil is taken as 1.

Examples of ceramides contained in niosomes include ceramides 1 to 6. Ceramides can be used alone or in combination of two or more. Among them, ceramide 2 or ceramide 3 is particularly preferred.

The present invention will be described in more detail below with reference to Test Examples and Examples.
Test Example 1: Synthesis of copolymer
1. Synthesis of the copolymer The copolymer was synthesized by the method described in Patent Document 3. A schematic diagram of the reaction process is shown in FIG. 1. That is, 64.1 g of methoxydiethylene glycol methacrylate (MD), 21.6 g of methacrylate (MAA), 14.4 g of lauroxytetraethylene glycol methacrylate (LT), and 1.94 g of dipropyl peroxydicarbonate were dropped into distilled isopropanol (100 g) under a nitrogen atmosphere and allowed to stand at 60° C. for 2 hours. The solution was heated to 80° C. under a nitrogen atmosphere and reacted for 1 hour. The copolymer was recovered by freeze-drying. The yield of the copolymer was 99.8 g (97.8%).
The number average molecular weight (Mn), weight average molecular weight (Mw) and polydispersity index (Mw/Mn) of the resulting copolymers were determined by GPC using THF as the mobile phase. The composition of the polymers was determined by proton NMR.

2. Copolymer Properties The copolymer is synthesized by radical copolymerization of MD, MAA, and LT, and therefore has a carboxyl group, an oligoethylene glycol group, and a hydrophobic group. The composition and molecular weight of these functional groups were evaluated by NMR and GPC, respectively, and the results are shown in Table 1 below.
As a result, the functional group ratio of MD, MAA and LT in the copolymer could be roughly controlled by the amount of monomer added. The number average molecular weight of the obtained copolymer was about 22,000. The polydispersity of the copolymer was 2.7, which is relatively high, because it was radical polymerization. The molecular weight of the copolymer can be controlled by adjusting the reaction time.

The functional group ratio of the obtained copolymer could be roughly controlled by the amount of monomer added. The number average molecular weight of the obtained copolymer was about 22,000. The polydispersity of the copolymer was 2.7, which is relatively high, because it was a radical polymerization.
This copolymer was used in the following tests.

Test Example 2: Preparation of compositions of Example 1 and Comparative Example 1
A composition containing the niosome of the present invention (Example 1) was prepared using the copolymer prepared in Test Example 1, and a composition containing the niosome without the copolymer (Comparative Example 1) was prepared. The compositions of each are shown in Table 2 below.
The composition is prepared by conventional methods.

The compositions of Example 1 and Comparative Example 1 were adjusted to have two different pH values, pH 5 and pH 6.5, respectively.
The particle sizes of Example 1 and Comparative Example 1 adjusted to pH 6.5 were measured by dynamic light scattering, and all compositions showed a monomodal particle size distribution. From this result, it was revealed that the compositions containing sorbitan sesquioleate and polyoxyethylene hydrogenated castor oil spontaneously formed niosomes with stable curvature, regardless of the presence or absence of copolymer. In addition, all of the obtained compositions were stable solutions.

<Test Example 3: Stability test over time>
1. Test method The stability over time of Example 1 and Comparative Example 1 adjusted to pH 6.5 was evaluated by storing them for one month in thermostatic chambers set at 5, 25, 40, and 50° C. After the predetermined time had passed, the average particle size of various niosomes formed was measured by dynamic light scattering, and the change in particle size was used as an index of stability.

2. Results The particle size measurement results are shown in FIG.
Both Example 1 and Comparative Example 1, which were adjusted to pH 6.5, showed a single-peak particle size distribution measurement result in all temperature ranges, and it was found that they had temperature stability. The pH 6.5, which is the preparation condition of the test sample, is assumed to be a weakly acidic lotion. In other words, in the case of a cosmetic composition with a pH of 6.5, it was confirmed that the niosomes containing sorbitan sesquioleate and polyoxyethylene hydrogenated castor oil as nonionic surfactants were stable.

<Test Example 4: pH condition and temperature stability test of skin surface>
1. Test method A solution of the composition of Example 1 adjusted to pH 5.0, which is the pH condition of the human skin surface, and a solution having the composition of Comparative Example 1 adjusted to pH 5.0 were stored in thermostatic chambers set at 5, 25, and 40° C. for 8 hours. After storage, particle size measurement by dynamic light scattering and microscopic observation were performed. The responsiveness to pH and temperature was evaluated from the change in particle size and appearance under microscopic observation.
For comparison, the composition of Example 1 and the composition of Comparative Example 1 were each adjusted only to pH 6.5 and stored at 25° C. for 8 hours.
The composition of Example 1 stored at pH 6.5 and 40° C. for 8 hours was also observed under a microscope.

2. Results The particle size measurement results are shown in FIG.
Moreover, images obtained by microscopic observation are shown in FIG. 4 and FIG.
The average particle size of the comparative composition did not change regardless of pH and temperature. This result shows that the niosomes contained in the comparative composition, i.e., the niosomes not containing copolymer, did not respond to changes in conditions even when placed under conditions of pH 5.0, which is the pH of the skin, and at a temperature of 40°C.
On the other hand, the composition of Example 1 showed a slight increase in particle size when the temperature was increased to 25° C. at pH 5.0, and a significant increase in particle size when the temperature was increased to 40° C. That is, it is considered that the niosomes of Example 1 are destabilized at the temperature and pH of the skin surface, causing a structural change.

The images in FIGS. 4 and 5 reveal the following.
At a pH of 6.5, the niosomes contained in the composition of Example 1 maintain a uniform spherical shape (FIG. 4). Even when enlarged, uniform spherical vesicles are observed (see the enlarged image in FIG. 4).
On the other hand, under the condition of pH 5.0, the niosome particles expanded and the release of ceramide crystals was confirmed (Figure 5).

The above test results show that the niosomes contained in the composition of the present invention are extremely stable at pH 6.5, but when placed at the pH of the skin surface, the niosomes collapse and release ceramide. This is because the niosomes contained in the composition of Example 1 contain a copolymer.

<Test Example 5: Ceramide Release Measurement Test>
1. Test method The compositions containing niosomes of Example 1 and Comparative Example 1 were stored under the conditions of pH 5.0 and constant temperature storage conditions of 5°C, 25°C, and 40°C, and after 8 hours, each composition was filtered through a membrane filter with a pore size of 0.45 μm to remove the released and crystallized ceramide. The ceramide concentration in the filtrate was measured using HPLC. The ceramide was measured by a conventional method using a liquid chromatography column (CAPCELLPAK MGIII: manufactured by Osaka Soda Co., Ltd.).

2. Results The results of the test for measuring the amount of ceramide released from niosomes (the results of measuring the amount of ceramide in the filtrate) are shown in Figure 6. As shown in Figure 6, the amount of ceramide in the filtrate of the composition is clearly reduced. This indicates that the amount of ceramide in the niosomal state is reduced. In other words, the niosomes of Example 1 release ceramide in a temperature-dependent manner under the condition of pH 5.0. When the temperature rises to 25°C, the amount of release increases, and the effect is maximized at 40°C.
From these test results, it became clear that the composition of Example 1 released ceramide in a temperature-dependent manner under the pH conditions of the skin.

<Test Example 6: Evaluation of the effect on stratum corneum lamella formation by continuous use test on humans>
1. Test Method The composition of Example 1 and the composition of Comparative Example 1 were applied twice a day to the inside of the right forearm (composition of Example 1) and the inside of the left forearm (composition of Comparative Example 1) for one week to three subjects, and the evaluation was performed.
In evaluating the effect, the stratum corneum lamellae were quantified before and after continuous use to confirm the effect.
The stratum corneum lamellae were quantified by tape stripping samples taken from the stratum corneum before and after the start of continuous use, and image analysis was performed using a microscope. The area of the lamellae relative to the area of the stratum corneum cells was calculated as the lamellar ratio. The change (increase) in this lamellar area represents the lamellar formation effect.

2. Results The measurement results of the lamellar ratio are shown in FIG.
The measurement results are the average value and standard deviation of the lamellar ratios of three subjects. As shown in Fig. 7, the lamellar ratio increased significantly in Example 1. On the other hand, in Comparative Example 1, the lamellar formation was hardly promoted even though the ceramide content was as high as in the Examples.

<Test Example 7: Evaluation of moisturizing effect by continuous use test on humans>
1. Test Method As in Test Example 5, the composition of Example 1 and the composition of Comparative Example 1 were applied to the inside of the right forearm (composition of Example 1) and the inside of the left forearm (composition of Comparative Example 1) of three subjects, and evaluation was performed.
The skin moisturizing effect was evaluated by measuring the conductance of the applied area 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after application using a moisture meter, and the increase in conductance compared to before application was taken as the skin moisturizing effect.

2. Results The increase in conductance (μS) from the conductance value before use was plotted against the measurement time on the X-axis in a graph shown in Figure 8. The measurement results are the average value and standard deviation of the conductance change for three subjects.
Up to 30 minutes after application, no significant difference was observed between the compositions of Example 1 and Comparative Example 1, but after 1 hour, the composition of Comparative Example 1 showed a large decrease in conductance value over time. On the other hand, when the composition containing the niosome of the present invention was applied, the decrease in conductance was gradual. In other words, Example 1 of the present invention was able to maintain moisturizing properties for a long time.

<Examples 2 to 7>
Examples 2 to 7 were prepared in the same manner as Example 1 and tested (stability and responsiveness to pH and temperature).
The test results were equivalent to those of Example 1. The compositions and results are shown in Table 3 below. In the columns for stability and responsiveness to pH and temperature, the symbol "◯" indicates that the results are equivalent to those of Example 1.

Claims (6)

A composition for external use on the skin comprising niosomes comprising the following (A) to ( F ):
(A) is a copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol, and has an average molecular weight of 1,000 to 1,000,000 , and the content is 0.1 to 10.0 parts by mass per part by mass of (B).
(B) a ceramide containing ceramide 2 or 3; (C) a nonionic surfactant containing polyoxyethylene hydrogenated castor oil and fatty acid sorbitan, and containing fatty acid sorbitan in a mass ratio of 0.4 to 16 when the polyoxyethylene hydrogenated castor oil is taken as 1 , and the content is 0.5 to 20.0 parts by mass per 1 part by mass of (B).
(D) dipropylene glycol and/or pentylene glycol,
In the case where dipropylene glycol is contained without pentylene glycol, dipropylene glycol is contained in an amount of 20 parts by mass or more per 1 part by mass of (B);
In the case where pentylene glycol is contained without dipropylene glycol, 15 parts by mass or more of pentylene glycol per 1 part by mass of (B) is used.
(E) Water
(F) pH adjuster The composition for external use on the skin according to claim 1, wherein the polyoxyethylene hydrogenated castor oil is a polyoxyethylene hydrogenated castor oil having an average degree of polymerization of the polyoxyethylene chain of 60 to 100, and the fatty acid sorbitan is one or more selected from sorbitan sesquiisostearate, sorbitan sesquioleate, and sorbitan oleate. 3. The composition for external application to the skin according to claim 1 or 2 , which is in the form of a skin lotion. A niosome formed by combining a copolymer having a structure in which some of the carboxyl groups of polymethacrylic acid are esterified with methoxydiethylene glycol and lauroxytetraethylene glycol with ceramides in a bilayer membrane. The niosome according to claim 4 , wherein the copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol is a random copolymer. The niosome according to claim 5, wherein the methoxydiethylene glycol (MDEGMA) portion and the lauroxytetraethylene glycol (LTEGMA) portion of the copolymer having a structure in which a portion of the carboxyl groups of polymethacrylic acid is esterified with methoxydiethylene glycol and lauroxytetraethylene glycol are 50 to 70% and 2 to 10%, respectively, when the entire carboxyl groups of polymethacrylic acid are taken as 100 %.