JP7221030B2 - Method for producing liquid crystal composition - Google Patents

Description

The present invention relates to a method for producing a liquid crystal composition.

There is a method of applying cosmetics and pharmaceuticals to the skin, and allowing the active ingredients contained in the cosmetics and pharmaceuticals to permeate the skin and take them into the body. Transdermal drug delivery systems (TDDS) have been investigated in order to efficiently penetrate the active ingredient through the skin.

Examples of materials for the TDDS include cubosomes, which are cubic liquid crystal dispersion compositions (see, for example, Patent Documents 1 and 2), hexosomes, which are inverted hexagonal liquid crystal dispersion compositions (see, for example, Patent Document 2), and amphiphilic properties. Examples include vesicles, which are closed vesicles having a bilayer membrane structure formed by substances (see, for example, Patent Document 3). Cosmetics and pharmaceuticals designed to enclose active ingredients such as drugs in these liquid crystal compositions and apply them to the skin to allow the active ingredients to be taken into the body through the skin have been proposed (for example, Patent Documents 1 to 3). reference).
However, the proposed liquid crystal composition has a problem that the active ingredient cannot sufficiently penetrate the skin.

In addition, the proposed liquid crystal composition has a problem of stability over time. For example, the cubosomes often contain glyceryl esters such as glyceryl oleate. However, since the glyceryl ester is decomposed in cosmetics and pharmaceutical preparations having a low pH, odor, coloration, and the like may occur after a long period of time from production.
Furthermore, the vesicles are often formed from phospholipids, and vesicles formed from the phospholipids are called liposomes. However, said liposomes are known to be sensitive to, for example, pH, temperature, electrolytes and the like.
If there is a problem with the stability over time, there will be problems such as the encapsulated drug not being reliably absorbed through the skin. Therefore, there has been a demand for a liquid crystal composition that does not have a problem of stability over time.

Moreover, most cosmetics contain polyhydric alcohols. It is known that when the liquid crystal composition is used as a cosmetic, the structure of the liquid crystal composition changes due to the influence of the polyhydric alcohol, and the liquid crystal composition cannot exist stably for a long period of time. Therefore, there has been a demand for a liquid crystal composition that is stable for a long period of time even when mixed with a polyhydric alcohol.

JP 2012-17318 A JP 2007-45762 A International publication 2012/56956 pamphlet

An object of the present invention is to solve the above-mentioned conventional problems and to achieve the following objects. That is, the present invention provides a liquid crystal composition that is stable for a long period of time even when an active ingredient is included therein and that can improve the skin permeability of the active ingredient, and that the liquid crystal composition can be stably contained for a long period of time. The purpose is to provide cosmetics.

As a result of extensive studies by the present inventors in order to solve the above problems, a monoalkyl glyceryl ether, a dispersant, and water are contained, and with respect to the total mass of the monoalkyl glyceryl ether and the dispersant, The liquid crystal composition that forms a transparent liquid phase when the total mass of water is 10% is stable for a long period of time even when the active ingredient is included, and the liquid crystal is capable of improving the skin penetration of the active ingredient. found to be a composition.

Means for solving the above problems are as follows. Namely
<1> containing a monoalkyl glyceryl ether, a dispersant, and water,
The liquid crystal composition forms a transparent liquid phase when the total mass of the water is 10% with respect to the total mass of the monoalkyl glyceryl ether and the dispersant.
<2> containing a monoalkyl glyceryl ether, a dispersant, and water,
The liquid crystal composition is characterized by having no peak in the range of 3.98 nm±0.5 nm in small-angle X-ray scattering measurement when placed on the surface of the stratum corneum intercellular lipid model.
<3> The liquid crystal composition according to any one of <1> to <2>, wherein the monoalkyl glyceryl ether is isostearyl glyceryl ether.
<4> The above <1> to <3>, wherein the dispersant is at least one of polyethylene glycol hydrogenated castor oil, polyethylene glycol fatty acid ester, polyethylene glycol alkyl ether, and block copolymer of polyoxyethylene polyoxypropylene. A liquid crystal composition according to any one of the above.
<5> The liquid crystal composition according to any one of <1> to <4>, wherein the mass ratio of the monoalkyl glyceryl ether to the dispersant (monoalkyl glyceryl ether/dispersant) is 1 to 5. be.
<6> A method for producing a liquid crystal composition for producing the liquid crystal composition according to any one of <1> to <5>,
mixing the monoalkyl glyceryl ether and a water-soluble solvent to form a liquid crystal;
dispersing the liquid crystal;
A method for producing a liquid crystal composition comprising:
<7> After the step of forming the liquid crystal produces a mixture of the monoalkyl glyceryl ether and the dispersant,
The method for producing a liquid crystal composition according to <6>, wherein the mixture and the water-soluble solvent are mixed.
<8> The above <6> to <7>, wherein the dispersant is at least one of polyethylene glycol hydrogenated castor oil, polyethylene glycol fatty acid ester, polyethylene glycol alkyl ether, and polyoxyethylene polyoxypropylene block copolymer. A method for producing a liquid crystal composition according to any one of the above.
<9> A cosmetic containing the liquid crystal composition according to any one of <1> to <5>.
<10> The cosmetic according to <9>, further comprising a polyhydric alcohol.

ADVANTAGE OF THE INVENTION According to this invention, the above-mentioned problems in the past can be solved, the above-mentioned object can be achieved, the liquid crystal composition is stable for a long period of time even when an active ingredient is included, and the liquid crystal composition can improve the skin permeability of the above-mentioned active ingredient. and a cosmetic that can stably contain the liquid crystal composition for a long period of time.

FIG. 1A shows the results of small-angle X-ray scattering measurement (SAXS) when Example 1, Comparative Example 1, and Comparative Example 3 were arranged in a stratum corneum intercellular lipid model. FIG. 1B shows the results of small-angle X-ray scattering measurement (SAXS) when Example 2, Comparative Example 2, and Comparative Example 3 were arranged in the stratum corneum intercellular lipid model. FIG. 2 shows the results of X-ray scattering measurement (PXRD) when Example 2, Comparative Example 2, and Comparative Example 3, which are one embodiment of the present invention, are arranged in a stratum corneum intercellular lipid model. FIG. 3A is an anisotropic striped reverse hexagonal liquid crystal observed with a polarizing microscope in Example 178. FIG. FIG. 3B is a geometrically patterned reverse hexagonal liquid crystal observed with a polarizing microscope in Example 178. FIG. 3C is an anisotropic cross-shaped lamellar liquid crystal observed with a polarizing microscope in Example 184. FIG. 3D shows striped lamellar liquid crystals observed with a polarizing microscope in Example 184. FIG. FIG. 4 is a diagram showing the amount of active ingredient released in Examples 165 and 166 and Comparative Examples 11 and 12, which are embodiments of the present invention. FIG. 5A is a phase diagram of a liquid crystal composition obtained by mixing the liquid crystal composition of the present invention with 1,3-butylene glycol as a polyhydric alcohol. FIG. 5B is a phase diagram of a liquid crystal composition obtained by mixing the liquid crystal composition of the present invention with dipropylene glycol as a polyhydric alcohol. FIG. 5C is a phase diagram of a liquid crystal composition obtained by mixing the liquid crystal composition of the present invention with 1,2-propanediol as a polyhydric alcohol. FIG. 6 shows the measurement results of the permeation amount of inclusions in Examples 173 and 174 and Comparative Examples 13 and 14, which are one embodiment of the present invention. 7A is the result of SAXS measurement of Example 178. FIG. 7B is the result of SAXS measurement of Example 184. FIG. 7C is the result of SAXS measurement of Example 185. FIG.

(Liquid crystal composition)
The liquid crystal composition of the present invention contains a monoalkyl glyceryl ether, a dispersant, water, and, if necessary, other components.
The liquid crystal composition of the present invention forms a transparent liquid phase when the total mass of the water is 10% with respect to the total mass of the monoalkyl glyceryl ether and the dispersant.
The liquid crystal composition of the present invention does not have a peak in the range of 3.98 nm±0.5 nm in small-angle X-ray scattering measurement when placed on the surface of the stratum corneum intercellular lipid model.

<Monoalkyl glyceryl ether>
The monoalkyl glyceryl ether is one of nonionic surfactants.
In an aqueous solution containing a specific concentration of monoalkyl glyceryl ether, the monoalkyl glyceryl ether forms aggregates such as liquid crystals.

The form of liquid crystal changes depending on the type of monoalkyl glyceryl ether.
Examples of the form of the liquid crystal in the liquid crystal composition include discontinuous cubic liquid crystal, hexagonal liquid crystal, lamellar liquid crystal, reverse hexagonal liquid crystal, and discontinuous reverse cubic liquid crystal. Among these, reverse hexagonal liquid crystals and lamellar liquid crystals are preferable as the form of liquid crystals in the liquid crystal composition.

When the form in the liquid crystal composition present in water is hexagonal liquid crystal, the monoalkyl glyceryl ether is oriented with the hydrophilic portion facing outward and the hydrophobic portion facing inward.
When the form of the liquid crystal composition present in water is a reverse hexagonal liquid crystal, the monoalkyl glyceryl ether is oriented with the hydrophilic portion facing inward and the hydrophobic portion facing outward.
The difference between the hexagonal liquid crystal and the reverse hexagonal liquid crystal is based on the difference in the curvature of the molecular film depending on the type of monoalkyl glyceryl ether.
The reverse hexagonal liquid crystal is preferably dispersed in the liquid crystal composition. A liquid crystal composition containing the inverted hexagonal liquid crystal dispersed therein is also called a hexosome.
When the form in the liquid crystal composition is a lamellar liquid crystal, the monoalkyl glyceryl ether is oriented so that the hydrophilic portion and the hydrophobic portion are aligned in the same direction to form a layer.

The liquid crystal composition forms a transparent liquid phase when the total weight of water is 10% with respect to the total weight of the monoalkyl glyceryl ether and the dispersant. Specifically, when water volatilizes from the liquid crystal composition and the total mass of water is 10% with respect to the total mass of the monoalkyl glyceryl ether and the dispersant, the liquid crystal formed by the monoalkyl glyceryl ether is , undergoes a phase transition to form a transparent liquid phase.
The transparent liquid phase is a state in which the monoalkyl glyceryl ether is infinitely associated. The state in which the monoalkyl glyceryl ether is infinitely associated means a state in which the monoalkyl glyceryl ether holds a large amount of water. The transparent liquid phase presents a colorless and transparent appearance.

When the water contained in the liquid crystal composition evaporates on the skin or the like, the liquid crystal of the monoalkyl glyceryl ether undergoes a phase transition to form a transparent liquid phase. That is, the morphology of the liquid crystal containing a large amount of water in the liquid crystal composition and the morphology of the transparent liquid phase in which water is volatilized, such as on the skin, are different due to the phase transition.
Therefore, when the liquid crystal composition contains an active ingredient, the active ingredient is stably retained for a long period of time in the liquid crystal composition which contains a large amount of water and is in the form of liquid crystal. When applied to the skin surface or the like, the liquid crystal composition undergoes a phase transition due to volatilization of water to form a transparent liquid phase, which acts on the stratum corneum, thereby effectively allowing the active ingredient to permeate the skin. can be done.

In addition, in the transparent liquid phase of the liquid crystal composition of the present invention, when the absorbance is 1.6 or less when measured at a wavelength of 500 nm, it is defined as having "transparency".
For example, the transparency of the transparent liquid phase of the liquid crystal composition can be determined as follows. 3 g of isostearyl glyceryl ether and 4 g of polyoxyethylene hydrogenated castor oil (2) are heated to 70° C. and mixed by hand stirring. Furthermore, 1 g of deionized water heated to 70° C. is added and mixed by hand stirring to obtain sample 1.
Similarly, 5 g of isostearyl glyceryl ether and 2 g of polyoxyethylene hydrogenated castor oil (2) are heated to 70° C. and mixed by hand stirring. Furthermore, 1 g of ion-exchanged water heated to 70° C. is added and mixed by stirring by hand to obtain sample 2.
The samples 1 and 2 are allowed to stand for one month. After that, quartz cells (optical path length: 1 cm) are filled with the samples 1 and 2, respectively. In a spectrophotometer, an incident light _I0 with a wavelength of 500 nm is applied, and the transmitted light I is measured. Also, the absorbance A is calculated using the Lambert-Beer law "A=log(I ₀ /I)".
Wavelength: Absorbance of 1.6 or less when measured at 500 nm is defined as having "transparent" properties.
As the spectrophotometer, for example, apparatus name: UVmini-1240 (manufactured by Shimadzu Corporation) can be used.

The number of carbon atoms in the alkyl group of the monoalkyl glyceryl ether is not particularly limited and can be appropriately selected depending on the intended purpose.
The monoalkyl glyceryl ether may be linear or branched. Also, the structure may consist of only saturated bonds, or may have unsaturated bonds.
Examples of the monoalkyl glyceryl ether having 16 to 18 carbon atoms include monocetyl glyceryl ether (carbon number: 16, linear structure), monostearyl glyceryl ether (carbon number: 18, linear structure), mono Examples include isostearyl glyceryl ether (18 carbon atoms, structure having a branched chain), monooleyl glyceryl ether (18 carbon atoms, structure having a double bond), and the like. Among these, monoisostearyl glyceryl ether is preferred.
In the present invention, monoisostearyl glyceryl ether is also simply referred to as "isostearyl glyceryl ether".

Commercially available products may be used as the monoalkyl glyceryl ether as appropriate.
The commercially available product is not particularly limited and can be appropriately selected depending on the intended purpose. Examples thereof include isostearyl glyceryl ether (trade name: Penetol GE-IS, manufactured by Kao Corporation).

<Dispersant>
In the present invention, the dispersant means one that forms a transparent liquid phase when the total weight of water is 10% with respect to the total weight of the monoalkyl glyceryl ether and the dispersant. The dispersing agent has a function of dispersing the liquid crystal due to the monoalkyl glyceryl ether in the liquid crystal composition.
Also, the dispersant has the ability to change the liquid crystal into a transparent liquid phase by phase transition when the total mass of water with respect to the total mass of the monoalkyl glyceryl ether and the dispersant is 10%.
In addition, when the liquid crystal composition does not contain a dispersant and only the monoalkyl glyceryl ether and water, water volatilizes from the liquid crystal composition on the skin, etc., and the total amount of water with respect to the total mass of the monoalkyl glyceryl ether Even at 10% mass, no phase transition occurs and no clear liquid phase is formed.

The liquid crystal composition of the present invention does not have a peak in the range of 3.98 nm±0.5 nm in small-angle X-ray scattering measurement when placed on the surface of the stratum corneum intercellular lipid model.

In the present invention, the stratum corneum intercellular lipid model is obtained by mixing ceramide:cholesterol:palmitic acid at a ratio of 42:15:43 (mass ratio), Dissolved, dispensed into wells of 96-well plate so that the total lipid amount was 10.5 μg/well, allowed to evaporate the solvent, heated on a hot plate at 120° C. for 30 minutes, and cooled to room temperature. It refers to the composition obtained by
The stratum corneum intercellular lipid model is described by H. Watanabe et al. , Novel preparation of intercellular lipid models of the stratum corneum containing stereoactive ceramide. Chem. Pharm. Bull. 58 (3), 312-317 (2010) can be referred to the stratum corneum intercellular lipid model.

Examples of the method for placing the liquid crystal composition in the stratum corneum intercellular lipid model include the following methods.
The liquid crystal composition of the present invention is added dropwise to a stratum corneum intercellular lipid model prepared in the holes of a 96-well plate so that the liquid crystal composition spreads over the entire surface of the stratum corneum intercellular lipid model. After disposing the liquid crystal composition over the entire surface of the stratum corneum intercellular lipid model, the 96-well plate was allowed to stand at room temperature for 24 hours to remove the solvent contained in the liquid crystal composition, and then small-angle X-ray scattering measurement was performed. conduct.
In addition, "±0.5 nm" of "3.98 nm±0.5 nm" in the present invention takes into consideration the error of the measuring device.

The stratum corneum intercellular lipid model of the present invention has a peak in the range of 3.98 nm±0.5 nm when small-angle X-ray scattering measurement (hereinafter sometimes simply referred to as SAXS or SAXS measurement) is performed.
The peak indicates a partial lamellar structure of the stratum corneum intercellular lipid model.
The absence of a peak in the range of 3.98 nm ± 0.5 nm in the SAXS measurement of the stratum corneum intercellular lipid model suggests that the lamellar structure has disappeared, that is, the stratum corneum intercellular lipid model It can be inferred that the structure of In other words, when the peak disappears, it can be inferred that when the liquid crystal composition was placed on the surface of the stratum corneum intercellular lipid model, the morphology of the liquid crystal changed to form a transparent liquid phase.

Whether or not the liquid crystal composition forms a liquid crystal of monoalkyl glyceryl ether can be determined, for example, by polarizing microscope observation, small angle X-ray scattering (SAXS) measurement, and the like.

When the liquid crystal composition is observed with a polarizing microscope, an anisotropic striped pattern or geometric pattern is observed in the reverse hexagonal liquid crystal due to birefringence. An anisotropic cross-shaped pattern or striped pattern is observed in the lamellar liquid crystal.
FIG. 3A shows the reversed hexagonal liquid crystal with an anisotropic streak pattern, and FIG. 3B shows the reversed hexagonal liquid crystal with the geometrical pattern observed with a polarizing microscope in Example 178 of the present application. FIG. 3C shows the anisotropic cross-shaped lamellar liquid crystal, and FIG. 3D shows the striped lamellar liquid crystal, which were observed with a polarizing microscope in Example 184 of the present application.
The polarizing microscope used for observation is not particularly limited and can be appropriately selected according to the purpose.

In small-angle X-ray scattering (SAXS) measurement, the numerical value of the interplanar spacing (peak length) on the vertical axis can be obtained from 2π/q. Also, the scattering vector (q) can be obtained from 4πsin θ/λ. Therefore, the inter-grid distance can be calculated from the angle (θ) of the horizontal axis.
When measuring the liquid crystal composition by SAXS measurement, if the peak (interplanar spacing) on the lowest angle side is 1, the reverse hexagonal liquid crystal has a ratio of “1:1/√3:1/2” in order from the low angle side. A peak of interplanar spacing appears at .
Further, if the peak (interplanar spacing) on the lowest angle side is 1, the lamellar liquid crystal has an interplanar spacing peak at a ratio of "1:1/2:1/3" in order from the lower angle side.

The dispersant is not particularly limited and can be appropriately selected depending on the purpose, but surfactants other than monoalkyl glyceryl ether are preferred.
Surfactants other than the monoalkyl glyceryl ether are not particularly limited and can be appropriately selected depending on the intended purpose. Examples thereof include nonionic surfactants and polymeric surfactants. These may be used individually by 1 type, and may use 2 or more types together.

Examples of the nonionic surfactants include polyethylene glycol hydrogenated castor oil, fatty acid ester-based nonionic surfactants, alkyl ether-based nonionic surfactants, and polyoxyethylene sorbitol tetraoleate.
Examples of the fatty acid ester-based nonionic surfactant include polyethylene glycol glycerin fatty acid ester, polyethylene glycol sorbitan fatty acid ester, polyethylene glycol sorbit fatty acid ester, and the like.
Examples of the alkyl ether-based nonionic surfactant include polyethylene glycol polypropylene glycol alkyl ether, polyethylene glycol alkyl ether, polyethylene glycol alkyl ether sodium phosphate, and the like.
In addition, "polyethylene glycol" may be described as "polyoxyethylene" or "PEG". Also, "polypropylene glycol" may be abbreviated as "polyoxypropylene" or "PPG".

Examples of the polyethylene glycol hydrogenated castor oil include polyoxyethylene hydrogenated castor oil.
Examples of the polyethylene glycol glycerol fatty acid ester include polyoxyethylene glyceryl isostearate and polyoxyethylene glyceryl monostearate.
Examples of the polyethylene glycol sorbitan fatty acid ester include polyoxyethylene sorbitan isostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, and polyoxyethylene sorbitan trioleate. is mentioned.
Examples of the polyethylene glycol polypropylene glycol alkyl ether include polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene polyoxypropylene decyltetradecyl ether. The numbers in parentheses after polyoxyethylene and polyoxypropylene indicate the number of ethylene oxide and the number of propylene oxide, respectively.
Examples of the polyethylene glycol alkyl ether include polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, and polyoxyethylene cetyl ether.
Examples of the sodium polyethylene glycol alkyl ether phosphate include polyoxyethylene olein ether sodium phosphate.

Examples of the polymer surfactant include copolymers.
Examples of the copolymer include block copolymers of polyoxyethylene polyoxypropylene, (ammonium acryloyldimethyltaurate/VP) copolymer, [(PEG240/decyltetradecel-20/HDI) copolymer, tricedeth-6]. (a copolymer containing a urethane skeleton) and the like. VP is an abbreviation for vinylpyrrolidone.

Among these, polyethylene glycol hydrogenated castor oil and polyethylene glycol alkyl ether are preferable from the viewpoint that the liquid crystal form is stable even when a large amount of dispersant is added to the monoalkyl glyceryl ether.

The content of the dispersant is not particularly limited and can be appropriately selected according to the purpose, but is preferably 0.1% by mass or more and 5% by mass or less with respect to the total amount of the liquid crystal composition.

When at least one of polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, and polyoxyethylene stearyl ether is used as a dispersant, the mass ratio of the monoalkyl glyceryl ether to the dispersant (monoalkyl glyceryl ether /dispersant) is preferably from 0.1 to 5, more preferably from 1 to 2.

As a dispersant, polyoxyethylene sorbitan isostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tetraoleate , polyoxyethylene (20) polyoxypropylene (4) cetyl ether, polyoxyethylene polyoxypropylene decyltetradecyl ether, and polyoxyethylene cetyl ether, the monoalkyl glyceryl ether and the The mass ratio (monoalkyl glyceryl ether/dispersant) to the dispersant is preferably 2 or more and 5 or less.

When using at least one of polyoxyethylene glyceryl isostearate, polyoxyethylene glyceryl monostearate, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, and polyoxyethylene olein ether sodium phosphate as a dispersant, The mass ratio of the monoalkyl glyceryl ether to the dispersant (monoalkyl glyceryl ether/dispersant) is preferably 4 or more and 5 or less.

When a polymeric surfactant is used as a dispersant, the mass ratio of the monoalkyl glyceryl ether to the dispersant (monoalkyl glyceryl ether/dispersant) is preferably 1 or more and 5 or less, and 1.5. 2 or less is more preferable.

<Water>
The water is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include purified water, ion-exchanged water, ultrafiltrated water, reverse osmosis water, pure water such as distilled water, and ultrapure water. . These may be used individually by 1 type, and may use 2 or more types together.

<Other ingredients>
Examples of the other components include active components contained in the liquid crystal.
The active ingredient is not particularly limited and can be appropriately selected depending on the intended purpose. (4-Biphenylacetic acid, felbinac) and the like. These may be used individually by 1 type, and may use 2 or more types together.

(Method for producing liquid crystal composition)
The method for producing the liquid crystal composition of the present invention includes the steps of mixing a monoalkyl glyceryl ether and a water-soluble solvent to form a liquid crystal, dispersing the liquid crystal, and optionally an active ingredient. into the aqueous solvent.

The step of forming the liquid crystal is a step of mixing a monoalkyl glyceryl ether and a water-soluble solvent.
The water-soluble solvent is not particularly limited and can be appropriately selected depending on the intended purpose, but water is preferable because it is easy to use in the cosmetics described later. The water is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include pure water and ion-exchanged water.
The method for mixing the monoalkyl glyceryl ether and the water-soluble solvent is not particularly limited as long as it is a method of stirring with a low shearing force, and can be appropriately selected depending on the purpose. Disper and the like.

The step of forming the liquid crystal is preferably performed by forming a mixture of a monoalkyl glyceryl ether and a dispersant, and then mixing the mixture with the water-soluble solvent. By forming the liquid crystal in this order, the monoalkyl glyceryl ether can be stably dispersed due to the effect of the dispersing ability of the dispersant, resulting in excellent stability over time.
As a specific procedure, first, without applying high energy, a dispersant is added to monoalkyl glyceryl ether to form a mixture, and the desired liquid crystal is added to a heated water-soluble solvent while stirring with a low shear force. is preferably formed. However, since the liquid crystal state at high temperatures is very unstable and easily transitions to another liquid crystal, it is preferable to cool the liquid crystal by adding a water-soluble solvent after forming the mixture.
When the water-soluble solvent and the dispersant are mixed first and then the monoalkyl glyceryl ether is added to form a mixture, the liquid crystal is formed, but the stability over time is insufficient.

The method for producing the mixture of the monoalkyl glyceryl ether and the dispersant is not particularly limited and can be appropriately selected depending on the intended purpose. be done.
The heating temperature is preferably 60° C. or higher and 90° C. or lower, more preferably 65° C. or higher and 75° C. or lower.
As the dispersant, it is preferable to use the one described above.
The method of mixing the mixture and the water-soluble solvent is the same as the method of mixing the monoalkyl glyceryl ether and the water-soluble solvent described above.

The step of dispersing the liquid crystal is not particularly limited and can be appropriately selected according to the purpose.
As a specific procedure, after the step of forming the liquid crystal, it is preferable to stir the obtained liquid crystal with high energy of 8,000 to 10,000 rotations with high shear force to disperse it more finely. Thereby, the dispersion stability of the liquid crystal can be improved.
The aforementioned water-soluble solvent can be used. As the water-soluble solvent, the one used in the step of mixing the monoalkyl glyceryl ether and the water-soluble solvent and the one used in the step of dispersing the liquid crystal may be the same or different.
The stirring device is not particularly limited as long as it is a method of stirring with a high shearing force, and can be appropriately selected according to the purpose.
The preparation temperature is preferably 15° C. or higher and 50° C. or lower, more preferably 20° C. or higher and 30° C. or lower.

(cosmetics)
The cosmetic of the present invention contains a liquid crystal composition, preferably contains a polyhydric alcohol, and further contains other components as necessary.
The liquid crystal composition is the liquid crystal composition of the present invention.

<Polyhydric alcohol>
The polyhydric alcohol is not particularly limited as long as it can be used in ordinary cosmetics, and can be appropriately selected depending on the purpose. Examples include 1,3-butylene glycol, dipropylene glycol, 1 , 2-propanediol and the like. These may be used individually by 1 type, and may use 2 or more types together.

As the polyhydric alcohol, an appropriately synthesized one may be used, or a commercially available product may be used.
Examples of the commercially available products include 1,3-butylene glycol (trade name: 1,3-butylene glycol, manufactured by Daicel Corporation), dipropylene glycol (trade name: DPG-RF, manufactured by ADEKA Corporation), 1, 2-propanediol (trade name: concentrated propylene glycol for cosmetics, manufactured by ADEKA Corporation) and the like.

The content of the polyhydric alcohol is not particularly limited and can be appropriately selected according to the purpose. preferable.

The amount of water contained in the cosmetic is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 50% by mass or more and 90% by mass or less based on the total amount of the cosmetic.
In the case of a cosmetic with a relatively low viscosity, the amount of water is preferably 80% by mass or more and 90% by mass or less with respect to the entire cosmetic. Examples of the cosmetics having a relatively low viscosity include lotions.
In the case of a cosmetic with a slightly high viscosity, the amount of water is preferably 50% by mass or more and 80% by mass or less, more preferably 60% by mass or more and 70% by mass or less, based on the total amount of the cosmetic. Examples of the slightly viscous cosmetics include milky lotions and creams.

Examples of the present invention will be described below, but the present invention is not limited to these examples. In addition, the content of each component in Examples and Comparative Examples is the amount in terms of pure content.

(Example 1)
5% by mass of isostearyl glyceryl ether (trade name: Penetol GE-IS, manufactured by Kao Corporation) as a monoalkyl glyceryl ether, and polyethylene glycol hydrogenated castor oil (2) (trade name: NIKKOL HCO-60, Nikko) as a dispersant Chemicals Co., Ltd.) was mixed and heated to 70°C. The heated solution was mixed with a 70° C. citrate buffer solution (5 mmol/L, pH: 5.9) to produce a liquid crystal composition (liquid crystal dispersion) of Example 1.

<Interaction with stratum corneum intercellular lipid model>
The stratum corneum intercellular lipid model was prepared with ceramide:cholesterol:palmitic acid at a ratio of 42:15:43 (mass ratio) by the following procedure and used.
As ceramides, (2S,3R)-2-(2-hydroxyhexadecanoyl)aminoocdadecane-1,3-diol [(2S,3R)-2-(2-Hydroxyhexadecanoyl)aminooctadecane-1,3-diol ], CER [AS] CERAMIDE TIC-006, manufactured by Takasago International Corporation.
As cholesterol, a reagent (Wako special grade) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. was used.
As palmitic acid, trade name: PALMAC 98-16, manufactured by Acidchem International Sdn Bhd was used.
Ceramide, cholesterol, and palmitic acid were mixed in the above ratio, dissolved in a solvent of chloroform:methanol (2:1, v/v), and added to a 96-well plate so that the total lipid amount was 10.5 µg/well. (trade name: glass microplate for life science research, made of 100% hard glass, manufactured by Nikkei Seisakusho Co., Ltd., diameter: 6 mm, made of glass). After evaporating the solvent at 32°C, the mixture was heated on a hot plate at 120°C for 30 minutes. The warmed 96-well plate was cooled to room temperature again to obtain a 0.5 mm to 2 mm membranous stratum corneum intercellular lipid model containing ceramide, cholesterol, and palmitic acid.
20 μL/well of the liquid crystal composition of Example 1 was added dropwise to the resulting stratum corneum intercellular lipid model, which is the membrane present on the bottom of a 96-well plate, and allowed to stand at room temperature to volatilize water. let me For comparison, instead of the liquid crystal composition of Example 1, a 5% by mass polyethylene glycol hydrogenated castor oil citric acid buffer solution (described as a dispersant, citrate buffer solution is 5 mmol/L, pH: 5.9), citric acid A solution of only an acid buffer (50 mmol/L, pH: 5.9) was added to the stratum corneum intercellular lipid model in the same manner as in Example 1.
Each solution was added, and 24 hours later, the structure of the stratum corneum intercellular lipid model was evaluated by X-ray small-angle scattering measurement (SAXS) and powder X-ray diffraction measurement (PXRD). The SAXS measurement results are shown in FIG. 1A.
As SAXS, a small-angle scattering measurement device (device name: Nano-Viewer, manufactured by Rigaku Corporation) was used, and a detector (device name: Pilatus K-100, manufactured by Rigaku Corporation) was used. The radiation source was CuKα rays, the output was 40 kV-30 mA, the camera length was 680 mm, and the exposure time was 5 minutes.
As the PXRD, a powder X-ray diffraction measurement device (device name: MiniFlex 600 (detector, built-in laser), manufactured by Rigaku Corporation) was used. 2θ side measurement range: 2°-28°, step size: 0.02°, speed: 10°/min, temperature: room temperature, radiation source: CuKα ray (λ = 1.5418 Å), output: measured at 40 kV-15 mA bottom.
The form of the liquid crystal was determined by SAXS measurement at the point where the water content was low. In addition, micelles were judged from their appearance.

(Example 2, Comparative Examples 1 to 3)
In the same manner as in Example 1, Example 2 and Comparative Examples 1 to 3 were prepared, observed, and measured according to the formulations shown in Table 1.
Each solution was added, and 24 hours later, the structure of the stratum corneum intercellular lipid model was evaluated by X-ray small-angle scattering measurement (SAXS) and powder X-ray diffraction measurement (PXRD). The SAXS measurement results of Comparative Examples 1 and 3 are shown in FIG. 1A, and the SAXS measurement results of Example 2, Comparative Example 2 and Comparative Example 3 are shown in FIG. 1B.
FIG. 2 shows the results of X-ray scattering measurement (PXRD) when Example 2, Comparative Example 2, and Comparative Example 3 were arranged in the stratum corneum intercellular lipid model.
The form of the liquid crystal was determined by SAXS measurement at the point where the water content was low. In addition, micelles were judged from their appearance.

なお、表中のＳＡＸＳ測定結果は、以下の意味を示す。
Ｈ：逆ヘキサゴナル液晶
Ｌ：ラメラ液晶
Ｍ：ミセル
Ｄ：透明液体相
Ｔ：白濁液体相
－：会合体なし

The SAXS measurement results in the table have the following meanings.
H: Inverted hexagonal liquid crystal L: Lamellar liquid crystal M: Micelle D: Transparent liquid phase T: Cloudy liquid phase -: No aggregate

The results of SAXS measurements are shown in Tables 2 and 3 below.

When the liquid crystal compositions of Examples 1 and 2 were added, the peak at 3.98 nm that was present in the citrate buffer solution of the dispersant and the citrate buffer solution alone disappeared. This indicates that part of the lamellar structure of the stratum corneum intercellular lipid model has disappeared.
Further, as a result of PXRD measurement, a halo pattern was observed at 2θ=16° to 26° in Example 2, which has a double lattice of cubic and hexagonal crystals observed in the stratum corneum intercellular lipid model. It is considered that part of the stratum corneum intercellular lipid model is amorphized.
These results suggest that the liquid crystal compositions of Examples 1 and 2 changed the structure of the stratum corneum intercellular lipids.

<Definition of transparency>
3 g of isostearyl glyceryl ether and 4 g of polyoxyethylene hydrogenated castor oil (2) were heated to 70° C. and mixed by hand stirring. Furthermore, 1 g of ion-exchanged water heated to 70° C. was added and mixed by hand stirring to obtain sample 1.
Similarly, 5 g of isostearyl glyceryl ether and 2 g of polyoxyethylene hydrogenated castor oil (2) were heated to 70° C. and mixed by hand stirring. Furthermore, 1 g of ion-exchanged water heated to 70° C. was added and mixed by hand stirring to obtain a sample 2.
Samples 1 and 2 were allowed to stand for one month. Then, samples 1 and 2 were filled in quartz cells (optical path length: 1 cm). In a spectrophotometer (apparatus name: UVmini-1240, manufactured by Shimadzu Corporation), incident light I ₀ having wavelengths of 500 nm and 700 nm was irradiated, and transmitted light I was measured. Also, the absorbance A was calculated using the Lambert-Beer law "A=log(I ₀ /I)".
As a result, Sample 1 had an absorbance of 0.055 when measured at a wavelength of 500 nm and an absorbance of 0.042 when measured at a wavelength of 700 nm. Sample 2 had an absorbance of 1.542 when measured at a wavelength of 500 nm and an absorbance of 1.311 when measured at a wavelength of 700 nm.
In Example 1, the transparent liquid phase of the liquid crystal composition of Sample 1 had an absorbance of 1.6 or less when measured at a wavelength of 500 nm, and had sufficient "transparency". In addition, the transparent liquid phase of the liquid crystal composition of sample 2 had an absorbance of 1.6 or less when measured at a wavelength of 500 nm, and had "transparency" properties.

(Examples 3 to 101)
<Study of monoalkyl glyceryl ether and dispersant>
A class of monoalkyl glyceryl ethers and dispersants was investigated which, when included in the liquid crystal composition, forms a clear liquid phase at a total weight of 10% water. A monoalkyl glyceryl ether and a dispersant were mixed at the respective ratios shown in Tables 4 to 10 and heated to 70°C to 80°C. At this time, the transparency of the monoalkyl glyceryl ether and the dispersant was visually observed. This solution was mixed with deionized water heated to 70° C. by hand stirring, and cooled to room temperature.
On the next day, the state was visually observed. In each example, when the total weight of water was 10%, the transparent liquid phase was formed with "○", and the transparent liquid phase and semi-solid state were mixed with "△". (Tables 4 to 10). In addition, the state in the liquid crystal composition was confirmed using a polarizing microscope (apparatus name: CX41, manufactured by OLYMPUS). "H" when reverse hexagonal liquid crystal is formed, "L" when lamellar liquid crystal is formed, "C" when crystal is formed, and "C/L" when lamellar liquid crystal and crystal are mixed ” (Tables 4 to 10).

From the above results, it was clarified that a liquid crystal composition using polyethylene glycol hydrogenated castor oil and polyethylene glycol stearyl ether as a dispersing agent forms a liquid crystal even when blended at a high ratio with respect to isostearyl glyceryl ether. rice field.
Since the above examples form a liquid crystal, a liquid crystal composition similar to that of Example 1 can be obtained by dispersing the liquid crystal.

(Examples 102-125)
<Dispersibility of liquid crystal composition>
Isostearyl glyceryl ether and dispersant were mixed at 70°C in proportions shown in Tables 11 to 13, and added to water that had also been warmed to 70°C. The mixture was stirred at 1,500 rpm for 3 minutes with Disper (trade name: TK HOMODISPER Model 2.5, manufactured by PRIMIX) and cooled to room temperature. Further, the mixture was stirred at 8,000 rpm for 5 minutes with a homomixer (device name: HOMOMIXIER MARK II Model 2.5, manufactured by PRIMIX) to prepare a liquid crystal composition. Confirmation of dispersibility was evaluated by visual observation of appearance.
Appearance observation and evaluation criteria for transparency in the table are as follows.
-Evaluation Criteria for Appearance Observation-
◎: Cloudy liquid ○: Cloudy liquid, but concentration gradient formed after 1 week, causing creaming to aggregate △: Cloudy liquid, but concentration gradient formed the next day after preparation, causing creaming to aggregate △ △: Aggregated -: Due to excess amount, incompatible and undissolved

From the above results, it has been clarified that when the above compound is used as a dispersant, good dispersion is achieved even when the amount of isostearyl glyceryl ether is 5 mass % of the entire liquid crystal composition.

(Example 126, Comparative Examples 4-5)
<Dispersibility of liquid crystal composition>
Isostearyl glyceryl ether as a monoalkyl glyceryl ether and a dispersant (polymeric surfactant) were mixed in proportions shown in Table 14 and heated to 70°C to 80°C. At this time, the transparent compatibility between the isostearyl glyceryl ether and the dispersant was visually observed. After this solution was mixed with ion-exchanged water heated to 70° C. by manual stirring, the mixture was cooled to room temperature, and the next day's state was observed by observing the external appearance.

From the results of Example 126, with respect to the liquid crystal composition containing a monoalkyl glyceryl ether, a dispersant, and water, the total mass of the water relative to the total mass of the monoalkyl glyceryl ether and the dispersant was It was confirmed that a transparent liquid phase was formed at 10%.

(Examples 127-150)
<Stability of Liquid Crystal Composition Dispersed with Polymer Surfactant>
Isostearyl glyceryl ether, polyhydric alcohol and various concentrations of copolymers were mixed at 70°C in proportions shown in Tables 15 and 16, and added to water heated to 70°C. The mixture was stirred at 1,500 rpm for 3 minutes with a disper (apparatus name: TK HOMODISPER Model 2.5, manufactured by PRIMIX) and cooled to room temperature. Further, the mixture was stirred at 8,000 rpm for 5 minutes with a homomixer (device name: HOMOMIXIER MARK II Model 2.5, manufactured by PRIMIX) to prepare liquid crystal composition hexosomes. Stability was evaluated by visually observing the state after one month. The particle size and polydispersity index of the liquid crystal composition hexosomes, which had a stable appearance, were measured by a dynamic light scattering method (device name: ELSZ-2000ZS, manufactured by Otsuka Electronics Co., Ltd.).
The evaluation criteria for observing the appearance after one month in the table are as follows.
-Evaluation criteria-
○: Cloudy liquid △: A concentration gradient was formed after one month, and creaming that aggregated occurred △△: A concentration gradient was formed immediately after preparation, and creaming that aggregated occurred

From the above results, it was clarified that a liquid crystal composition having an average particle size of 100 nm to 350 nm can be produced when any one of polyoxyethylene-polyoxypropylene block copolymers is used as a dispersant. This liquid crystal composition was found to be stable even one month after its production.

(Examples 151-152)
<Stability of Liquid Crystal Composition Dispersed in Polyethylene Glycol Hydrogenated Castor Oil>
Isostearyl glyceryl ether as a monoalkyl glyceryl ether and polyoxyethylene hydrogenated castor oil as a dispersant were mixed at 70°C in proportions shown in Table 17, and added to water heated to 70°C. The mixture was stirred at 1,500 rpm for 3 minutes with a disper (apparatus name: TK HOMODISPER Model 2.5, manufactured by PRIMIX) and cooled to room temperature. Further, the mixture was stirred at 8,000 rpm for 5 minutes using a homomixer (device name: HOMOMIXIER MARK II Model 2.5, manufactured by PRIMIX) to prepare a liquid crystal composition. Stability was evaluated by visually observing the state after 3 months at room temperature (RT), 40°C, and 50°C. The average particle size and polydispersity index of the liquid crystal composition were measured by a dynamic light scattering method (device name: ELSZ-2000ZS, manufactured by Otsuka Electronics Co., Ltd.).
In addition, "◯" in the evaluation results in the table indicates cloudiness.

From the above results, it was clarified that a liquid crystal composition having an average particle size of 100 nm to 200 nm can be produced when polyethylene glycol hydrogenated castor oil is used as a dispersant. This liquid crystal composition was found to be stable even three months after its production. It was also found to be stable even at high temperatures.

(Examples 153-164, Comparative Examples 6-10)
<Stability of Liquid Crystal Composition Encapsulating Active Ingredients>
Liquid crystal compositions encapsulating active ingredients at the ratios shown in Tables 18 and 19 were produced.
Hydrophobic active ingredients tocopherol, retinol palmitate, ascorbyl tetraisopalmitate, stearyl glycyrrhetinate, ubiquinone, and 4-biphenylacetic acid were mixed with glyceryl isostearyl ether and polyoxyethylene hydrogenated castor oil (2) at 70°C, respectively. and added to water also heated to 70°C.
Arbutin and dipotassium glycyrrhizinate, which are hydrophilic active ingredients, are mixed with glyceryl isostearate, polyoxyethylene hydrogenated castor oil (2), and 1,2-propanediol at 70 ° C., and water heated to 70 ° C. was added to
A mixture of a hydrophobic active ingredient with glyceryl ether isostearate and polyoxyethylene hydrogenated castor oil (2) and a mixture of a hydrophilic active ingredient with glyceryl ether isostearate and polyoxyethylene hydrogenated castor oil (2) are, respectively, disper ( Apparatus name: TK HOMODISPER Model 2.5, manufactured by PRIMIX) was stirred at 1,500 rpm for 3 minutes, and cooled to room temperature. Further, the mixture was stirred at 8,000 rpm for 5 minutes with a homomixer (device name: HOMOMIXIER MARK II Model 2.5, manufactured by PRIMIX) to prepare a liquid crystal composition.
Stability was evaluated by visual observation of the state after one month at room temperature (RT) according to the following evaluation criteria. The particle size and polydispersity index of the liquid crystal composition, which was stable in appearance observation, were measured by a dynamic light scattering method (device name: ELSZ-2000ZS, manufactured by Otsuka Electronics Co., Ltd.).
-Evaluation criteria-
○: Cloudy liquid △: A small amount of aggregation was observed ×: Aggregated

From the above results, it has been clarified that the liquid crystal composition of the present invention is stable for a long period of time even when the active ingredient is included.
Moreover, as shown by the results of the comparative examples, it was found that liquid crystals were not formed in liquid crystal compositions that did not contain at least one of monoalkyl glyceryl ether and water.

(Examples 165-166, Comparative Examples 11-12)
<Active ingredient retention rate in formulation>
5 mL of each component in Table 20 was weighed out and enclosed in a semipermeable membrane (Visking tube, diameter 15.9 mm, 25 m roll, manufactured by Nihon Medical Science Co., Ltd.).
250 mL of pH 7.4 phosphate buffer was placed in a beaker, and the temperature of the phosphate buffer was set to 37°C in a constant temperature water bath (trade name: constant temperature water bath HB-1400, Lot 7110659, manufactured by AS ONE Corporation). .
The semipermeable membrane containing the liquid crystal composition of Example or Comparative Example is immersed in a buffer solution and stirred at 500 rpm using a stirrer (trade name: Magnetic Stirrer HS-6AN, Lot Z161314, manufactured by AS ONE Corporation). bottom.
Phosphate buffer solutions were sampled after 1, 2, 3, 4, 6, 24, and 48 hours, and the 4-Biohenylacetic acid concentration was quantified by high performance liquid chromatography (HPLC). The HPLC used was manufactured by Shimadzu Corporation. Details of the apparatus are as follows.
・System controller for high performance liquid chromatogram: CBM-20A
・Liquid delivery unit for high performance liquid chromatogram: LC-20AD
・Autosampler for high performance liquid chromatogram: SIL-20ACHT
・Photodiode array ultraviolet-visible detector for high-performance liquid chromatogram: SPD-20A
・Column oven for high performance liquid chromatogram: CTO-20A
・High performance liquid chromatogram software: LC solution
The mobile phase was water:acetonitrile:phosphoric acid=(500:500:1).
Water is distilled water (for high-performance liquid chromatograph, manufactured by Wako Pure Chemical Industries, Ltd.), and acetonitrile is trade name: acetonitrile (for high-performance liquid chromatograph, manufactured by Wako Pure Chemical Industries, Ltd.), and phosphoric acid. used a product name: phosphoric acid (manufactured by Wako Pure Chemical Industries, Ltd.).
The column temperature was 40° C., the flow rate was 1.6 mL/min, and Inersil (registered trademark) ODS-3 4.6×250 mm manufactured by GL Sciences was used as the column. The wavelength of the photodiode array ultraviolet-visible detector was set at 254 nm and the injected sample volume was 20 μL.
FIG. 4 shows the relationship between the release amount and time.
The form of the liquid crystal was determined by SAXS measurement at the point where the water content was low. In addition, micelles were judged from their appearance.

なお、表中の評価結果は、以下の意味を示す。
Ｈ：逆ヘキサゴナル液晶
Ｌ：ラメラ液晶
Ｍ：ミセル

The evaluation results in the table have the following meanings.
H: Reverse hexagonal liquid crystal L: Lamellar liquid crystal M: Micelle

As a result of measuring the release amount, it can be seen from FIG. 4 that the active ingredient was retained in the liquid crystal composition even after 48 hours from the start of the release test in both liquid crystal compositions having a liquid crystal form of lamellar liquid crystal and reverse hexagonal liquid crystal. It became clear that there is
From this, it was clarified that both the lamellar liquid crystal and the reverse hexagonal liquid crystal by isostearyl glyceryl ether can retain the active ingredient in the liquid crystal composition for a long time.

(Examples 169-172)
<Influence of polyhydric alcohol>
Isostearyl glyceryl ether and polyhydric alcohol were mixed at the ratios shown in Table 21 and the like. Ion-exchanged water was further added to this mixture, and after manual stirring, the mixture was subjected to R.I. T. was left undisturbed. The state of the left still was evaluated by observing the appearance and observing with a polarizing microscope (apparatus name: CX41, manufactured by OLYMPUS).
Polyhydric alcohols include 1,3-butylene glycol (trade name: 1,3-butylene glycol, manufactured by Daicel Corporation), dipropylene glycol (trade name: DPG-RF, manufactured by ADEKA Corporation), and 1,2 - Propanediol (trade name: concentrated propylene glycol for cosmetics, manufactured by ADEKA Corporation) was used.
In addition, when isostearyl glyceryl ether, polyhydric alcohol, and water are mixed at each ratio, the phase diagrams of FIGS. 5A to 5C summarize the states at each ratio.
GE-IS represents isostearyl glyceryl ether in FIGS. 5A to 5C.

なお、表中の偏光顕微鏡観察結果は、以下の意味を示す。
Ｌ：ラメラ液晶
Ｖ：バイコンティニュアスキュービック液晶

The results of observation with a polarizing microscope in the table have the following meanings.
L: Lamellar liquid crystal V: Bicontinuous cubic liquid crystal

These results demonstrate that the liquid crystal composition of the present invention maintains its liquid crystal form even when mixed with a polyhydric alcohol. Since the polyhydric alcohol is a component that is usually contained in cosmetics, the liquid crystal composition of the present invention is stable when contained in cosmetics, and even if an active ingredient is included, the liquid crystal composition remains stable. Since the structure is preserved, its properties are preserved.

(Examples 173-174, Comparative Examples 13-14)
<Skin Penetration Promotion Action of Active Ingredients>
A liquid crystal composition encapsulating an active ingredient was produced in the same manner as in Example 165 at the ratio shown in Table 22. For Comparative Examples 13 and 14, the proportions shown in Table 22 were mixed.
A Franz-type diffusion cell (2 cm ² ) and a hot water circulator (device name: hot water circulator HTC-1000, SERIAL No. 1911003, manufactured by AS ONE Co., Ltd.) were connected, and circulating water at 32° C. was flowed. The receiver side of the Franz diffusion cell was filled with 50 mM phosphate buffer of pH 7.4 and fixed to a stirrer (trade name: magnetic stirrer REMIX RS-6DS, manufactured by AS ONE Corporation).
Lab skin (hairless mouse skin, Hoshino Test Animal Breeding Center) was used as a partition between the receiver side and the donor side of the Franz-type diffusion cell, and 10 μL of each sample was placed on the lab skin surface and tested without sealing.
The stirrer was stirred at 600 rpm and the concentration of felbinac in the receiver after 8 hours was quantified by HPLC. As HPLC, high performance liquid chromatography (G1312Agilent 1100, manufactured by LC System) was used, and the test conditions were the same as in Example 137. HPLC measurement results are shown in FIG.

なお、表中の評価結果は、以下の意味を示す。
Ｈ：逆ヘキサゴナル液晶
Ｌ：ラメラ液晶
Ｍ：ミセル

The evaluation results in the table have the following meanings.
H: Reverse hexagonal liquid crystal L: Lamellar liquid crystal M: Micelle

As shown in FIG. 6 and Table 22, Examples 173 and 174 are superior in skin penetration of the active ingredient compared to Comparative Examples 13 and 14, which do not contain monoalkyl glyceryl ether. Moreover, the results of Examples 173 and 174 show that regardless of the form of the liquid crystal in the liquid crystal composition, the phase transition of the liquid crystal to the transparent liquid phase on the skin surface improves the skin permeability.

(Examples 175-185)
<Percutaneous Absorption Mechanism of Liquid Crystal Composition (Phase Change After Application of Liquid Crystal Composition)>
Isostearyl glyceryl ether as a monoalkyl glyceryl ether and polyoxyethylene hydrogenated castor oil (2) as a dispersant were mixed in the proportions shown in Table 23 in a total amount of 10 g, and heated to 70°C to 80°C. Next, this solution and a citrate buffer solution of pH: 5.9 heated to 70° C. were mixed by hand stirring. Then, it was cooled to room temperature, and the appearance of the next day was observed. Note that, in this example, the liquid crystal composition was prepared without applying energy, so even if the liquid crystal composition has viscosity or is separated, it is included in the preferred embodiments.
In addition, in each example, polarizing microscope observation (apparatus name: CX41, manufactured by OLYMPUS) was performed. The results are shown in Table 23. Of these, the reverse hexagonal liquid crystal with an anisotropic streak pattern observed with a polarizing microscope in Example 178 is shown in FIG. 3A, and the reverse hexagonal liquid crystal with a geometric pattern is shown in FIG. 3B. FIG. 3C shows the anisotropic cross-shaped lamellar liquid crystal, and FIG. 3D shows the striped lamellar liquid crystal, which were observed with a polarizing microscope in Example 184. FIG.
Furthermore, Examples 178, 184, and 185 were subjected to SAXS measurements in the same manner as the SAXS measurements described above. The SAXS results for Example 178 are shown in FIG. 7A, the SAXS results for Example 184 in FIG. 7B, and the SAXS results for Example 185 in FIG. 7C.

なお、表中の評価結果は、以下の意味を示す。
Ｈ：逆ヘキサゴナル液晶
Ｌ：ラメラ液晶
Ｄ：透明液体相
Ｔ：白濁液体相

The evaluation results in the table have the following meanings.
H: reverse hexagonal liquid crystal L: lamellar liquid crystal D: transparent liquid phase T: cloudy liquid phase

From the above results, it can be seen that the morphology of the liquid crystal changes depending on the difference in buffer solution concentration. It can also be seen that the clear liquid phase is independent of the buffer concentration and occurs when the proportion of water is reduced.
Compared to Examples 175-178, Example 179 has less moisture (pH: 5.9 citrate buffer). This is similar to the state in which water evaporates when a liquid crystal composition is applied to the skin or the like. The liquid crystal composition of the present invention forms a transparent liquid phase when applied to the skin or the like, and when the total mass of water is 10% due to removal of water, it ceases to be in a liquid crystal state. This state change (phase change, phase transition) is considered to be the reason why the penetration of the active ingredient contained in the liquid crystal composition into the skin is promoted.

(Examples 186-188)
<Examination of liquid crystal composition preparation method>
Isostearyl glyceryl ether as a monoalkyl glyceryl ether and polyoxyethylene hydrogenated castor oil as a dispersing agent were mixed together to produce a liquid crystal composition.
Isostearyl glyceryl ether and polyoxyethylene hydrogenated castor oil were mixed in the proportions shown in Table 24. The polyoxyethylene hydrogenated castor oil (2) was individually heated to 70°C. The mixture was stirred at 1,500 rpm for 3 minutes with a disper (apparatus name: TK HOMODISPER Model 2.5, manufactured by PRIMIX) and cooled to room temperature. Further, the mixture was stirred at 8,000 rpm for 5 minutes with a homomixer (device name: HOMOMIXIER MARK II Model 2.5, manufactured by PRIMIX) to prepare a liquid crystal composition. The dispersibility was evaluated by visually observing the appearance based on the following evaluation criteria.
-Evaluation criteria-
○: Cloudy liquid △: Occurrence of creaming △△: Aggregation

From the above experimental results, it has been clarified that when the monoalkyl glyceryl ether and the dispersant are mixed without being compatible with each other, a liquid crystal composition is formed but aggregates.

The reagents used in the examples are shown in Tables 25-26 below.

INDUSTRIAL APPLICABILITY The liquid crystal composition of the present invention can change the liquid crystal morphology, remains stable for a long period of time even when encapsulating an active ingredient, and has high skin permeability of the encapsulation. It can be suitably used for cosmetics such as lotions.

Claims (3)

A method for producing a liquid crystal composition containing a reverse hexagonal liquid crystal containing isostearyl glyceryl ether, polyethylene glycol hydrogenated castor oil, water , and an active ingredient ,
forming a mixture of the isostearyl glyceryl ether and the polyethylene glycol hydrogenated castor oil, and then mixing the mixture, the water, and the active ingredient to form an inverted hexagonal liquid crystal;
dispersing the reverse hexagonal liquid crystal;
the water may contain a citrate buffer at a concentration of 5 mM or less;
The active ingredient is any one selected from arbutin, potassium glycyrrhizinate, tocopherol, palmitic acid, stearyl glycyrrhetinate, ubidecarenone, and felbinac,
When the active ingredient is potassium glycyrrhizinate, the content of the potassium glycyrrhizinate is less than 0.3% by mass relative to the total amount of the liquid crystal composition,
The liquid crystal composition forms a transparent liquid phase when the total mass of the water is 10% with respect to the total mass of the isostearyl glyceryl ether and the polyethylene glycol hydrogenated castor oil. manufacturing method . A method for producing a liquid crystal composition containing a reverse hexagonal liquid crystal containing isostearyl glyceryl ether, polyethylene glycol hydrogenated castor oil, water , and an active ingredient ,
forming a mixture of the isostearyl glyceryl ether and the polyethylene glycol hydrogenated castor oil, and then mixing the mixture, the water, and the active ingredient to form an inverted hexagonal liquid crystal;
dispersing the reverse hexagonal liquid crystal;
the water may contain a citrate buffer at a concentration of 5 mM or less;
The active ingredient is any one selected from arbutin, potassium glycyrrhizinate, tocopherol, palmitic acid, stearyl glycyrrhetinate, ubidecarenone, and felbinac,
When the active ingredient is potassium glycyrrhizinate, the content of the potassium glycyrrhizinate is less than 0.3% by mass relative to the total amount of the liquid crystal composition,
The liquid crystal composition, when placed on the surface of the stratum corneum intercellular lipid model, does not have a peak in the range of 3.98 nm ± 0.5 nm in small-angle X-ray scattering measurement . manufacturing method . 3. The method for producing a liquid crystal composition according to claim 1, wherein the mass ratio of the isostearyl glyceryl ether to the polyethylene glycol hydrogenated castor oil (isostearyl glyceryl ether/polyethylene glycol hydrogenated castor oil) is 1 to 5. .

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