JP6959596B2 - Topical skin agents and skin barrier function improvers - Google Patents

Description

The present invention relates to an external preparation for skin and an agent for improving skin barrier function.

Decreased skin barrier function increases the risk of inflammation due to decreased keratin water content and increased permeability of irritants such as dust and germs, as well as disturbed keratin morphology and keratin turnover, and wrinkles and stains due to accumulation of microinflammation. It is known that it can cause cosmetic problems such as dullness and roughness. Therefore, the development of an external preparation for skin for strengthening the barrier function is required.

Supplementation of oil-soluble components such as ceramide and cholesterol is said to be effective in strengthening the barrier function. However, skin with reduced barrier function and active water transpiration and skin that is hydrophilic in a high humidity environment have poor affinity for oil-soluble components, so the barrier function is sufficiently strengthened by oil-soluble components. Hard to get. In addition, NMF (Natural Moisturizing Factor), which is involved in keratin flexibility and supports the keratin skeleton in corneocytes, is important for maintaining keratin morphology, which is important for normalizing the barrier function. It is necessary to apply an aqueous component to the skin in order to supply it to the skin. However, the effect of supplying the water-based component tends to be transient, and the low humidity environment after the high humidity environment may cause a deterioration of the barrier function.

In addition, thickened skin has a seemingly high barrier function and less water evaporation, but lacks flexibility and may cause skin troubles such as keratin cracking, dusting, and xerosis.

Therefore, in order to keep the skin normal, it is important to properly supply both the oil-soluble component and the water-soluble component. As a means for this, various emulsified preparations have been developed, and a typical example thereof is a preparation in which an oil-soluble component and a water-soluble component are dispersed with each other by a surface-active action.

On the other hand, it is known that emulsification based on a surface-active action has low stability and has concerns such as oil-water separation. For this reason, an emulsified preparation based on so-called three-phase emulsification has also been developed in which closed vesicles formed by an amphipathic substance that spontaneously forms closed vesicles or particles of a polycondensation polymer having a hydroxyl group intervene at the oil-water interface. (See, for example, Patent Document 1).

Japanese Unexamined Patent Publication No. 2014-141479

However, conventional surfactant-based formulations have room for improvement in terms of reduced barrier function due to many surfactants themselves and low skin affinity. Further, although the emulsified preparation disclosed in Patent Document 1 is excellent in emulsification stability, there is room for improvement in terms of skin affinity.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an external preparation for skin and an agent for improving skin barrier function, which have excellent skin affinity and can suppress deterioration of barrier function.

The present inventors have found that reducing the average particle size of the internal phase of an O / W emulsion containing closed endoplasmic reticulum improves skin affinity, and have completed the present invention. Specifically, the present invention provides the following.

(1) The internal phase is the oil phase, the external phase is the aqueous phase, and
It is an O / W emulsion type containing closed endoplasmic reticulum formed by an amphipathic substance that spontaneously forms closed endoplasmic reticulum.
An external preparation for skin having an average particle size of less than 1000 nm in the internal phase.

(2) The internal phase is the oil phase, the external phase is the aqueous phase, and
It is an O / W emulsion type containing closed endoplasmic reticulum formed by an amphipathic substance that spontaneously forms closed endoplasmic reticulum.
A skin barrier function improving agent having an average particle size of less than 1000 nm in the internal phase.

According to the present invention, when the average particle size of the internal phase of the O / W emulsion containing the closed endoplasmic reticulum is less than 1000 nm, the skin affinity can be improved and the deterioration of the barrier function can be suppressed.

It is a graph which shows the fusion to the intercellular lipid liposome (SCLL) when the external preparation for skin which concerns on Example and the comparative example of this invention is applied. It is a graph which shows the fusion to SCLL when the external preparation for skin which concerns on Example of this invention is applied. It is a graph which shows the fusion to SCLL when the external preparation for skin which concerns on Example of this invention is applied. It is a graph which shows the amount of sodium fluorescein in the epidermis (granular layer-basal layer)-dermis when the external preparation for skin which concerns on Example and comparative example of this invention is applied. It is a graph which shows the fusion to SCLL when the external preparation for skin which concerns on Example of this invention is applied. It is a graph which shows the fusion to SCLL when the external preparation for skin which concerns on Example of this invention is applied. It is a graph which shows the amount of dipotassium glycyrrhizinate in the epidermis (the stratum corneum to the basal layer) to the dermis when the external preparation for skin which concerns on Example and the comparative example of this invention is applied. It is a graph which shows the amount of sodium fluorescein in the epidermis (granular layer-basal layer)-dermis when the external preparation for skin which concerns on Example and comparative example of this invention is applied.

Hereinafter, embodiments of the present invention will be described, but the present invention is not limited thereto.

In the present invention, the inner phase is an oil phase, the outer phase is an aqueous phase, and an O / W emulsion containing closed vesicles formed by an amphipathic substance that spontaneously forms closed vesicles (hereinafter, three phases). It is a type (also referred to as an emulsified emulsion), and is an external preparation for skin in which the average particle size of the internal phase is less than 1000 nm.

Closed endoplasmic reticulum is a particle whose surface is hydrophilic, and maintains an emulsified state by interposing at the interface between the aqueous phase and the oil phase by van der Waals force. This emulsification mechanism is known as a three-phase emulsification mechanism by closed vesicles, and the emulsification mechanism by a surfactant, that is, by directing the hydrophilic part and the hydrophobic part toward the aqueous phase and the oil phase, respectively, to reduce the oil-water interface tension. It is completely different from the emulsification mechanism that maintains the emulsified state (see, for example, Japanese Patent No. 3855203).

As described above, the average particle size of the internal phase in the present invention is less than 1000 nm. In conventional formulations based on surfactant action, if an attempt is made to reduce the internal phase, the required amount of surfactant increases, which tends to reduce the barrier function. On the other hand, the present inventor has found that as the internal phase of the three-phase emulsified emulsion becomes smaller, the skin affinity is improved while the deterioration of the barrier function is suppressed. The reason why the deterioration of the barrier function is suppressed is that, in the present invention, the amphipathic substance forms a closed endoplasmic reticulum rather than a single molecule form exhibiting a surface-active action. On the other hand, the closed endoplasmic reticulum has a small effect on the skin surface unlike the surfactant, and is expected to be inferior to the skin of oil and water. Therefore, the three-phase emulsified emulsion of the present invention has skin compatibility. Goodness is an unexpected effect. In addition, the three-phase emulsified emulsion of the present invention also has an advantage that the active ingredient has excellent skin permeability. On the other hand, in the three-phase emulsified emulsion constituting the conventional external preparation for skin, including the above-mentioned Patent Document 1, the average particle size of the internal phase is 1 μm (1000 nm) or more.

From the viewpoint of improving skin affinity, the average particle size of the internal phase in the present invention is preferably 970 nm or less, more preferably 750 nm or less, 500 nm or less, 450 nm or less, 420 nm or less, 400 nm or less, 375 nm or less, 350 nm or less. It is 325 nm or less. The lower limit of the average particle size of the internal phase in the present invention is not particularly limited as long as the three-phase emulsified emulsion is formed, and specifically, it may be 10 nm or more, 50 nm or more, 100 nm or more, 150 nm or more, 200 nm or more. .. The average particle size of the internal phase is measured by a measuring device "Zetasizer Nano S" (manufactured by Malvern Instruments) based on a dynamic light scattering method. The average particle size of the internal phase can be adjusted by the stirring conditions at the time of preparing the emulsion, and for example, the average particle size of the present invention can be realized by a high-pressure homogenizer.

The oil phase may contain oil that is liquid at room temperature and is used as a base for external preparations for the skin. Such oils are not particularly limited, but are ester oils such as octyldodecyl myristate, ethylhexyl palmitate and isononyl isononanoate, hydrocarbons such as squalane and mineral oil, higher alcohols such as isostearyl alcohol, olive oil and jojoba oil. It may be one kind or two or more kinds such as natural oils such as shea butter. Among them, octyldodecyl myristate and squalane are particularly preferable because they have excellent skin compatibility. However, since silicone oil has a chemical structure that does not have a carbon skeleton, it does not easily blend into the skin. Therefore, the external preparation for skin of the present invention is contained in an amount of less than 1% by mass, preferably substantially, with respect to the external preparation for skin. It is preferable not to.

The content of the oil phase is not particularly limited, and may be appropriately selected in the range of 0.1 to 94% by mass with respect to the external preparation for skin. However, in conventional emulsions based on surfactant action, if the oil phase content is large, a large amount of oil and a mixture of surfactant molecules will be adsorbed on the skin surface and remain after application of the external preparation for skin. While the electrical conductivity is reduced and the keratin water content cannot be expected to increase early, if the oil phase content is small, the keratin water content is expected to increase early after application, but it is difficult to maintain it. On the other hand, in the present invention, even if the oil phase content is large, the closed vesicles are less likely to be adsorbed on the skin surface, so that an early increase in the keratin water content is expected, while the oil phase content is increased. Since the effect of increasing the water content of the keratin is high, the content of the oil phase required to obtain the desired effect can be reduced. From this viewpoint, the lower limit of the oil phase content in the present invention is preferably 5% by mass or more, more preferably 10% by mass or more, 20% by mass or more, and 25% by mass or more with respect to the external preparation for skin. The upper limit may be 90% by mass or less, 75% by mass or less, 50% by mass or less, 40% by mass or less, and 35% by mass or less.

The amphipathic substance that spontaneously forms closed vesicles is not particularly limited, but a phospholipid, a phospholipid derivative, a polyglycerin fatty acid ester, or the like, in which a hydrophobic group and a hydrophilic group are ester-bonded, is adopted. You may. In addition, lysine Na dilauroyl glutamate is also preferable because it has excellent irritation-relieving properties.

As the phospholipid, among the configurations represented by the following general formula 3, DLPC (1,2-Dialamitoyl-sn-glycero-3-phospho-rac-1-choline) having a carbon chain length of 12 and carbon chain length 14 have a carbon chain length of 14. DMPC (1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-1-choline), DPPC with a carbon chain length of 16 (1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-1-choline) Can be adopted.

General formula 3

Further, among the configurations represented by the following general formula 4, the Na salt or NH4 salt of DLPG (1,2-Dialauroyl-sn-glycero-3-phospho-rac-1-glycerol) having a carbon chain length of 12 and a carbon chain Na salt or NH4 salt of DMPG (1,2-Dimyristoyll-sn-glycero-3-phospho-rac-1-glycero) with a length of 14 and DPPG (1,2-Dipalmitoyl-sn-glycero-3) with a carbon chain length of 16 -Phospho-rac-1-glycero) Na salt or NH4 salt may be adopted.

General formula 4

Further, as the phospholipid, lecithin such as egg yolk lecithin or soybean lecithin or a hydrogenated product thereof may be adopted.

The polyglycerin fatty acid ester is an ester of polyglycerin and a linear fatty acid or a branched fatty acid, and specifically, polyglyceryl monopalmitate, polyglyceryl dipalmitate, polyglyceryl tripalmitate, polyglyceryl monostearate, polyglyceryl distearate, Examples thereof include polyglyceryl triisostearate, polyglyceryl monoisostearate, polyglyceryl diisostearate, and polyglyceryl triisostearate.

Further, as the amphoteric substance, a derivative of polyoxyethylene hydrogenated castor oil represented by the following general formula 1, or a dialkylammonium derivative, a trialkylammonium derivative, a tetraalkylammonium derivative, or a dialkenylammonium represented by the general formula 2 Derivatives, trialkenylammonium derivatives, or halogen salt derivatives of tetraalkenylammonium derivatives may be employed.

General formula 1

In the formula, E, which is the average number of moles of ethylene oxide added, is 3 to 100. When E becomes excessive, the type of good solvent that dissolves the amphipathic substance is limited, so that the degree of freedom in producing hydrophilic nanoparticles is narrowed. The upper limit of E is preferably 50, more preferably 40, and the lower limit of E is preferably 5.

General formula 2

In the formula, R1 and R2 are independently alkyl groups or alkenyl groups having 8 to 22 carbon atoms, R3 and R4 are independently hydrogen or alkyl groups having 1 to 4 carbon atoms, and X is F, Cl, Br, I or CH3COO.

The closed endoplasmic reticulum has an average particle size of about 8 nm to 800 nm before emulsion formation, but has an average particle size of about 8 nm to 500 nm in the O / W emulsion structure. The amount of closed endoplasmic reticulum may be appropriately set according to the amount of the oil phase, and is not particularly limited, but may be 0.0001 to 5% by mass with respect to the external preparation for skin. It may be 1 to 2.5% by mass and 0.5 to 2% by mass.

The external preparation for skin in the present invention includes cosmetics such as beauty essences, quasi-drugs, and pharmaceuticals for the treatment of skin diseases. The oil phase and the aqueous phase in the present invention may contain any components that can be used depending on the use of the external preparation for skin. As described above, since the three-phase emulsion of the present invention is also excellent in skin permeability of the ingredients, applications in which it is desired to allow the active ingredient to penetrate into the skin (for example, quasi-drugs) are preferable.

The skin permeation (penetration) improving effect is due to the excellent skin affinity of the emulsion (more specifically, the transferability of the emulsion component to the intercellular lipids of the stratum corneum), and thus has a wide range of oil-soluble or water-soluble effects. It is possible to improve skin permeability with respect to the ingredients. From this point of view, the above-mentioned active ingredient is not particularly limited, but is oil-soluble active ingredient such as glycyrrhetinic acid, retinol, tocopherol, ascorbic acid derivative, and water-soluble such as glycyrrhizinate, riboflavin, ascorbic acid, and allantin. Active ingredients are mentioned, and water-soluble active ingredients are preferable.

The above emulsion comprises a step of dispersing a layered body of a bilayer film of an amphipathic substance in water to form an emulsifier dispersion liquid containing closed vesicles formed by the amphipathic substance, and an emulsifier dispersion liquid and an oil agent. Is produced by a method having a step of forming an O / W emulsion by mixing the above. In the step of forming this O / W emulsion, by performing stirring under severe conditions (for example, high-pressure homogenization), a three-phase emulsified emulsion having an internal phase having a small particle size of the present invention can be easily produced. The water-soluble active ingredient may be added after the formation of the O / W emulsion, or may be added during the formation process of the O / W emulsion, while the oil-soluble active ingredient may be added to the oil agent before the formation of the O / W emulsion. It is preferable to add it.

Further, by sufficiently forming closed endoplasmic reticulum, it becomes easy to obtain oil droplets having a small average particle size. Examples of such a method include adding the above amphipathic substance to a dispersion medium (that is, water) and stirring, dissolving the amphipathic substance in a good solvent, and then mixing the solution with water. (See, for example, Japanese Patent Application Laid-Open No. 2006-241424).

The present invention is an O / W emulsion type in which the inner phase is an oil phase, the outer phase is an aqueous phase, and the closed vesicles are formed by an amphipathic substance that spontaneously forms closed vesicles. It also includes skin barrier function improving agents having an average phase particle size of less than 1000 nm. Unlike the surfactant, the skin barrier function improving agent of the present invention does not easily destroy the intercellular lipids in the stratum corneum, so that the barrier function can be improved. In addition, the skin barrier function improving agent itself can be fused with the intercellular lipids in the stratum corneum to efficiently permeate the active ingredient applied to the skin.

The active ingredient may be applied at the same time as or before or after the application of the skin barrier function improving agent. Therefore, the present invention may include an external skin kit containing a skin barrier function improving agent and a water-soluble or oil-soluble active ingredient separately in the form of two or more agents.

<Examples 1 to 5, Comparative Example 2>
A dispersion of closed endoplasmic reticulum was prepared from a solution of decaglyceryl distearate. The active ingredient, the base, and the liquid oil were added thereto, and the mixture was stirred by appropriately adjusting the rotation speed using a high-pressure homogenizer in Example and a homomixer in Comparative Example 2, and the formulation and internal phase average particles shown in Table 1 were used. An external preparation for skin was prepared for the diameter.

(Comparative Example 1)
In Comparative Example 1, an external preparation for skin was prepared in the same procedure as in Example except that a solution of decaglyceryl distearate was used.

(Average particle size)
The average particle size of the internal phase was calculated from the particle size distribution measured using a measuring device "Zetasizer Nano S" (manufactured by Malvern Instruments) based on the dynamic light scattering method.

(Zeta potential)
Using the zeta potential / particle size measurement system ELS-Z (manufactured by Otsuka Electronics Co., Ltd.), an electric field is applied to the sample to perform electrophoresis, and the moving speed of the particles is measured by the laser Doppler speed measurement method. It was applied to determine the zeta potential.

(Preparation of intercellular lipid liposome (SCLL))
The intercellular lipid liposome (SCLL) is a liposome designed based on the composition of the intercellular lipid in the stratum corneum, and has been conventionally used as a pseudo-intercellular lipid whose skin affinity can be evaluated by its fusion to the liposome (SCLL). See Kuntsche J., et al., Int. J. Pharma., 354, 180-195 (2008)). 40% by mass of ceramide, 25% by mass of cholesterol, 25% by mass of palmitic acid, 10% by mass of cholesterol sulfate, and NBD-PE as a fluorescent substance (N- (7-nitro-2,1,3-benzoxadiazol-4-yl)) -Phosphatidylethanolamine) and Rho-PE (N- (lissamine rhodamine B sulfonyl) -phosphatidylethanolamine) were placed in eggplant-shaped flasks and the solvent was removed with an evaporator. Then, it was hydrated with PBS (phosphate buffer), frozen and thawed, and then the size of the liposome was adjusted with an extruder (passed through a filter having a pore size of 100 nm) to obtain SCLL.

(Affinity evaluation)
The above SCLL and each external preparation for skin were appropriately mixed, and the fusion rate of this mixture was measured over time using the fluorescence intensity as an index (measured for 30 minutes. The temperature of the mixture was maintained at 32 ° C.). .. The measurement results are shown in FIGS. 1 to 3. Then, based on the measurement results of FIGS. 1 to 3, the fusion property with SCLL was evaluated on a scale of 1 (low) to 5 (high). The evaluation results are shown in Table 1. The numerical value of "n" shown in the figure indicates the number of measured samples, and the numerical value described in the figure and the table indicates the average value of all the measured samples (hereinafter, the same applies). ..
〔Evaluation criteria〕
5: The fusion rate increases linearly. Fusion rate after 30 minutes: High 4: Fusion rate increases linearly. Fusion rate after 30 minutes: High to medium 3: Fusion rate gradually increases. Fusion rate after 30 minutes: Medium 2: Fusion rate gradually increases. Fusion rate after 30 minutes: Medium to slightly low 1: Fusion rate hardly changes.
0: The fusion rate reaches 100% within a few minutes (meaning that SCLL has collapsed).

The abbreviations in Table 1 mean the components below.
2S10G: Decaglyceryl distearate MOD: Octyldodecyl myristate GlySte: Stearyl glycyrrhetinate Gly2K: Dipotassium glycyrrhizinate BG: 1,3-butylene glycol

As shown in Table 1, unlike the skin external preparations of Examples 1 to 5 and Comparative Example 2 containing closed endoplasmic reticulum, the skin external preparation of Comparative Example 1 containing a surfactant destroyed SCLL. It was suggested that the skin barrier was lowered. Among the external preparations for skin of Examples 1 to 5 and Comparative Example 2, the external preparations for skin of Examples 1 to 5 were excellent in SCLL fusion, that is, skin affinity. Since Example 1 and Comparative Example 2 are common in composition and differ only in the average particle size of the internal phase, the excellent skin affinity in each of the Examples shown in Table 1 and FIG. 1 is internal. It was suggested that it was obtained when the average particle size of the phase was less than 1000 nm. Further, as shown in Table 1 and FIG. 2, since the excellent fusion of the examples was obtained regardless of the zeta potential of the oil agent, the improvement of skin affinity and the suppression of the decrease in barrier function achieved by the present invention were achieved. It was suggested that the effect did not depend on the oil agent. Therefore, the external preparation for skin of the present invention is considered to be useful as a skin affinity improver or a skin barrier function improver.

(Evaluation of hydrophilicity)
One drop of the external preparation for skin of Example 1 and Comparative Example 2 was dropped on the inside of the forearm of the subject with a dropper, and then the drop was applied to the skin and water was dropped on the site after 3 minutes. Table 2 shows the results of evaluating the affinity of the dropped water on a scale of 1 (water repellency) to 5 (hydrophilicity).

As shown in FIG. 1, in Comparative Example 2 in which the average particle size of the internal phase is 1000 nm, the emulsion disintegrates due to friction during application to the skin, and the oil agent forms an oil film to cover the skin (immediately after acclimation), and further familiarize. An oil film remained even after 3 minutes, resulting in water repellency. On the other hand, in Example 1, which is consistent with Comparative Example 2 in terms of composition and differs in that the average particle size of the internal phase is less than 1000 nm, it exhibits skin affinity 3 minutes after acclimation, and the oil film is not visible, and the oil film is not visible. , The affinity for water droplets was high. In Example 1, it is presumed that the keratinous state was adjusted by the affinity of both the aqueous component and the oily component.

(Keratin water content)
After washing the test part (inside of the forearm) of the subject, acclimatize to a constant temperature and humidity environment (25 ° C, 50%) for 30 minutes, and measure the keratin water content before applying the drug using SKICON-200EX (manufactured by IBS). bottom. Then, after applying the external preparation for skin of Example 1 or Comparative Example 2 and leaving it for 3 minutes, the keratin water content was measured using SKICON-200EX (manufactured by IBS). Then, the applied external preparation for skin was rinsed with water to remove it, and after wiping off the water and leaving it for 27 minutes, the amount of keratin water was measured using SKICON-200EX (manufactured by IBS). The measurement was performed 5 times per test site, and the average value was calculated. Table 2 shows the relative values of the keratin water content 3 minutes after application and 27 minutes after running water with respect to the keratin water content before application.

The amount of water in the keratin 3 minutes after application is an index of the water-soluble component's familiarity with the skin. As shown in Table 2, in Example 1, which is different from Comparative Example 2 in which the average particle size of the internal phase is 1000 nm, the composition is the same and the average particle size of the internal phase is less than 1000 nm. After minutes, the water content of the stratum corneum was high, and it was confirmed that the moisturizing property of the stratum corneum was increased. From this, it was suggested that the skin external preparation of Example 1 was superior to the skin external preparation of Comparative Example 2 in that the water-soluble component was more compatible with the skin. Therefore, the external preparation for skin of the present invention is considered to be useful as an agent for improving the compatibility of water-soluble components with the skin, an agent for increasing the amount of keratin water, or a moisturizer.
On the other hand, the amount of keratinous water 27 minutes after washing with running water is an index of the oil-soluble component's familiarity with the skin. This is because, after 27 minutes of washing with running water, the water-soluble component is removed or evaporated by washing, so that the moisturizing effect of the oil-soluble component familiar to the skin is reflected in the keratin water content. As shown in Table 2, the keratin water content of Example 1 was higher than that of Comparative Example 2. Generally, about 30 minutes after washing the external preparation with running water, when the water adhering to the skin during washing evaporates, the water originally present on the skin surface also evaporates, so that the skin surface becomes overdried. It is said that the water content of the keratin is lower than that before the application of the external preparation. However, in Example 1 and Comparative Example 2, even after 27 minutes of running water washing, the keratin moisture content was higher than that before application, and in particular, Example 1 had 1.3 times the keratin moisture content before application. Was maintained. This was even higher than 1.1 times that of Comparative Example 2. From this, it was suggested that the skin external preparation of Example 1 was superior to the skin external preparation of Comparative Example 1 in terms of the compatibility of the oil-soluble component with the skin. Therefore, the external preparation for skin of the present invention is considered to be useful as an oil-soluble component for improving skin compatibility and as a moisturizer. Further, since both the water-soluble component and the oil-soluble component can be appropriately supplied, the effect of keeping the skin normal can be expected, and it is considered to be useful as a skin quality improving agent or a skin barrier function improving agent.

(Skin permeability)
Samples were prepared by adding sodium fluorescein to the external preparations for skin of Example 1 and Comparative Example 2 to a final concentration of 0.5 mM and stirring for 10 minutes. The skin of a hairless mouse (epidermis (granular layer-basal layer) -dermis) is set in a vertical diffusion cell, a sample is added to the donor side, and the amount of sodium fluorescein in the epidermis-dermis 8 hours later is measured by spectrophotometric intensity. It was calculated based on the fluorescence intensity of sodium fluorescein measured by a meter (λex = 495 nm, λem = 520 nm). The result is shown in FIG.

As shown in FIG. 4, as compared with Comparative Example 2 in which the average particle size of the internal phase is 1000 nm, in Example 1, the epidermis is different in that the average particle size of the internal phase is less than 1000 nm. It was found that the amount of sodium fluorescein in the dermis is high and the skin permeability can be improved. Therefore, the external preparation for skin of the present invention is useful as a skin permeability improver for an active ingredient (particularly, a water-soluble active ingredient) or a composition for transdermal delivery of an active ingredient (particularly, a water-soluble active ingredient). The possibility was suggested.

<Examples 6 to 18, Comparative Example 6>
An external preparation for skin was prepared in the same procedure as in Example 1 except that the formulation and the average particle size of the internal phase were changed as shown in Tables 3-5.

(Comparative Example 3)
An external preparation for skin was prepared in the same procedure as in Example 12, except that squalane was not included.

(Comparative Examples 4 and 5)
An external preparation for skin was prepared in the same procedure as in Examples 14 and 17, except that a solution of polysorbate and sorbitan stearate was used.

For the prepared external preparation for skin, the average particle size of the internal phase was measured according to the above conditions.

(Affinity evaluation)
The results of measuring the affinity of the external preparations for skin of Examples 6 to 11 with SCLL according to the above conditions are shown in FIGS. 5 and 6. As shown in FIGS. 5 and 6, it was suggested that as the content of the oil agent increased, the SCLL fusion property, that is, the skin affinity, improved, and the presence or absence of this tendency did not depend on the oil agent.

(Skin permeability)
Samples were prepared by adding dipotassium glycyrrhizinate to the skin external preparations of Examples 12 to 17 and Comparative Examples 3 to 5 to a final concentration of 3% and stirring the mixture. The skin of a hairless mouse (epidermis (granular layer-basal layer) -dermis) is set in a vertical diffusion cell, a sample is added to the donor side, and 24 hours later, dipotassium glycyrrhizinate in the epidermis-dermis is extracted with methanol. And quantified by high performance liquid chromatography (HPLC). The result is shown in FIG. For HPLC, "Waters 2695 Separations Model" and "Waters 2487 Dual λ Absorbance Detector" were used, "CAPCELL PAK C18" was used as the column, and CH3CN: CH3COOH = 55: 45 (v / v) was used as the mobile phase. The flow rate was 0.6 mL / min and the temperature was 40 ° C.
As shown in FIG. 7, when emulsified by the three-phase emulsification technique, the amount of dipotassium glycyrrhizinate in the epidermis to the dermis was larger than that when emulsified by the surfactant. In addition, as the content of the oil agent increased, the amount of dipotassium glycyrrhizinate in the epidermis to the dermis increased, and the skin permeability could be improved, suggesting that the presence or absence of this tendency does not depend on the oil agent.

For the external skin preparations of Example 18 and Comparative Example 6, the skin (stratum corneum to dermis) of a pig (Yukatan micro pig) was set in a vertical diffusion cell, and 8 hours after adding the sample to the donor side. After extracting sodium fluorosane from the epidermis to the dermis with methanol, the amount of sodium fluorosane was calculated by intensifying the fluorescence intensity at a measurement excitation wavelength of 495 nm / fluorescence wavelength of 520 nm.
As shown in FIG. 8, as compared with Comparative Example 6 in which the average particle size of the internal phase is 1000 nm, in Example 18, the epidermis is similar in that the average particle size of the internal phase is less than 1000 nm. The amount of sodium fluorescein in the dermis was high.

Claims (11)

The inner phase is the oil phase, the outer phase is the aqueous phase,
Containing closed endoplasmic reticulum formed by amphipathic substances that spontaneously form closed endoplasmic reticulum
The closed endoplasmic reticulum is an O / W emulsion type in which the closed endoplasmic reticulum is interposed at the interface between the oil phase and the aqueous phase.
The content of the oil phase is 3% by mass or more and 30% by mass or less.
The average particle size of the internal phase is less than 1000 nm.
The oil phase, octyldodecyl myristate, ethylhexyl palmitate, isononyl isononanoate, squalane, Lee triisostearate allyl alcohol, the skin external preparation containing one or more selected from the group consisting of jojoba oil and shea oil. The inner phase is the oil phase, the outer phase is the aqueous phase,
Containing closed endoplasmic reticulum formed by amphipathic substances that spontaneously form closed endoplasmic reticulum
The closed endoplasmic reticulum is an O / W emulsion type in which the closed endoplasmic reticulum is interposed at the interface between the oil phase and the aqueous phase.
The content of the oil phase is 3% by mass or more and 30% by mass or less.
The average particle size of the internal phase is less than 1000 nm.
The aqueous phase is a skin external preparation containing at least one selected from the group consisting of glycyrrhizate, riboflavins, ascorbic acid salt and allantoin. The skin external preparation according to claim 1 or 2, wherein the average particle size of the internal phase is 150 nm or more and less than 1000 nm. The skin external preparation according to any one of claims 1 to 3, wherein the content of the oil phase is 3% by mass or more and 10% by mass or less. The external preparation for skin according to any one of claims 1 to 4, wherein the average particle size of the closed endoplasmic reticulum is 8 nm to 500 nm. The inner phase is the oil phase, the outer phase is the aqueous phase,
Containing closed endoplasmic reticulum formed by amphipathic substances that spontaneously form closed endoplasmic reticulum
The closed endoplasmic reticulum is an O / W emulsion type in which the closed endoplasmic reticulum is interposed at the interface between the oil phase and the aqueous phase.
The content of the oil phase is 3% by mass or more and 30% by mass or less.
The average particle size of the internal phase is less than 1000 nm.
The oil phase, octyldodecyl myristate, ethylhexyl palmitate, isononyl isononanoate, squalane, Lee triisostearate allyl alcohol, the skin barrier function-improving agent containing one or more selected from the group consisting of jojoba oil and shea oil. The inner phase is the oil phase, the outer phase is the aqueous phase,
Containing closed endoplasmic reticulum formed by amphipathic substances that spontaneously form closed endoplasmic reticulum
The closed endoplasmic reticulum is an O / W emulsion type in which the closed endoplasmic reticulum is interposed at the interface between the oil phase and the aqueous phase.
The content of the oil phase is 3% by mass or more and 30% by mass or less.
The average particle size of the internal phase is less than 1000 nm.
The aqueous phase is a skin barrier function improving agent containing at least one selected from the group consisting of glycyrrhizate, riboflavins, ascorbic acid salt and allantoin. The skin external preparation according to claim 6 or 7, wherein the average particle size of the internal phase is 150 nm or more and less than 1000 nm. The skin external preparation according to any one of claims 6 to 8, wherein the content of the oil phase is 3% by mass or more and 10% by mass or less. The skin barrier function improving agent according to any one of claims 6 to 9, wherein the average particle size of the closed endoplasmic reticulum is 8 nm to 500 nm. An external skin kit containing the skin barrier function improving agent according to any one of claims 6 to 10 and a water-soluble or oil-soluble active ingredient separately in the form of two or more agents.

Images