KR20120041294A - Hexagonal structured skin external composition comprising polyglyceryl fatty acid ester - Google Patents

Abstract

PURPOSE: A composition for external use on the skin stabilized by a hexagonal structure is provided to recover skin barrier functions such as skin protection and moisturization. CONSTITUTION: A composition for external use on the skin having a hexagonal structure contains ceramide analogue; cholesterol or derivative thereof and fatty acid; polyglyceryl fatty acid ester; a higher fatty alcohol of cetyl alcohol, stearyl alcohol, or cetostearyl alcohol; general oils; or polyvalent alcohol. The ceramide analogue includes MEA(myristoyl/palmitoyl oxostearamide/arachamide), dihydroxyisopropyl palmoylpalmamide, or a mixture thereof.

Description

Hexagonal structured skin external composition comprising polyglyceryl fatty acid ester

The present invention relates to an external preparation for skin, comprising keratocellular intercellular lipid components of pseudoceramide, cholesterol or derivatives thereof and fatty acids and stabilized with hexagonal structure, which is one of the layered structures of intercellular keratinocyte lipids. It relates to a skin external preparation stabilized with a hexagonal structure prepared by mixing a polyglyceryl fatty acid ester having an HLB value of 8 to 12 as an emulsifier to a lipid component between keratinocytes.

The stratum corneum is largely divided into sections consisting of keratinocytes and skin keratocytes. The Brick and Mortar Model, which compares these structures with brick and cement, is established as a model of the stratum corneum. In general, the main functions of the stratum corneum are roughly divided into the protection function from the external environment and the moisturizing function to keep moisture on the skin. The most important role in the protection and moisturizing function of the stratum corneum, that is, the skin barrier function, is the lamellar structure formed by lipid components of keratinocytes (Elias PM, Lipid and the epidermal permeability barrier, Arch dermatol Res 1981; 27; : 95-117). In addition, the lipid components between keratinocytes are composed of ceramide, cholesterol or derivatives thereof, fatty acids, etc. Among them, ceramide is known as a very important component, accounting for about 50% of all lipid components. However, since ceramide is a component present in trace amounts in an animal's brain or the like in nature, a method using synthetic ceramide having a similar molecular structure has been used.

In general, the abnormality of the skin barrier function is closely related to the abnormality of the lipid structure between the keratinocytes, and various skin diseases occur when the skin barrier function is weakened by any factor. In particular, in the case of atopic dermatitis, damage to the skin barrier caused by a decrease in the ceramide content of the stratum corneum is understood as a major factor (Ogawa H and Yoshiike T, A speculative view of atopic dermatitis: barrier dysfunction in pathogenesis. J Dermatol Sci 1993; 5 : 197-204). The supply of lipid components between keratinocytes such as ceramide to the skin is known to be effective for normalizing the stratum corneum of the skin.

In the 1960s, X-ray diffraction (XRD) was first introduced for the analysis of the stratification of lipids between keratinocytes in the skin.In the 1970s, freeze fracture electron microscopy was performed. It has been shown that lipids between keratinocytes have a lamellae structure among keratinocytes (Breathnach AS, Goodman T, Stolinski C, Gross M. freeze fracture replication of stratum corneum of human cells.H Anat 1973; 114: 65-81). Lamellar structure between the keratinocytes through the wide angle XRD (WXRD) study, the lamellar structure of lipids between the keratinocytes according to the arrangement of the head group and the side-packing method of the alkyl group. It has been reported to exist as an orthorhombic crystallin phase, a hexagonal gel phase, and a liquid lamellar structure.

WXRD analysis of the stratum corneum showed typical orthorhombic peak patterns (0.375 nm and 0.416 nm) and liquid lamellar peak pattern (0.46 nm) at 25 ° C, and 0.375 nm peak (45 ° C) at 45 ° C. And peaks of 0.46 nm (liquid lamellae) disappear and only one peak of 0.412 nm is shown to be transferred to a homogeneous phase in the hexagonal gel state (White SH, Mirejovski D, and King GJ, Structure of lamellar lipid domains and corneocyte envelopes of murine stratum corneum: An X-ray diffraction study, Biochemistry 1988; 27: 3725-3732). As XRD experiments at room temperature, orthorombic structures, hexagoanl gels, and liquid lamellars were mixed, it was recognized that the lamellar structures of the stratum corneum were actually mixed. According to the results of (Noren) et al., The stratum corneum lipid is hexagonal gel monostructure, and it is known that the stratum corneum is mixed by phase transition during the preparation of the sample for XRD imaging. The hexagonal structure is known to be more robust than the liquid lamellar structure to suppress the loss of moisture in the stratum corneum and to protect the stratum corneum more robustly to help normalize the stratum corneum.

On the other hand, the lamellar structure which is currently used industrially, as a liposome form similar to the biomembrane structure, has been studied as a membrane model system and a delivery medium of physiological substances (R. Sundler, D. papahadjpovlos, Biochim Biophys Acta, 1981; 648-743). ), It is widely used in pharmaceuticals, cosmetics, and food. These lamellar liposomes are largely divided into multi-layered liposomes (MLV: Uni Lamella Vesicle) (ULV: Uni Lamella Vesicle), MLV is 400-3500nm in size, LUV is 100-1000nm in size. Among these, MLV has a lamellar structure, which is a lipid structure between keratinocytes, and is known to have affinity with skin (Korean Patent Publication No. 2003-0007990). Such liposomes have the advantage of being able to deliver bioactive components more effectively into the skin when they are made of nano-sized liposomes, and contain both lipophilic and water-soluble bioactive components, while limiting the amount of liposomes contained in liposomes. It has the disadvantage of low formulation stability and low stability of lipophilic bioactive components.

In addition, there are attempts to develop external preparations for skin in multiple lamellar emulsions as new formulations. It is mainly made of a multi-lamellae emulsion using a nonionic surfactant-cetostearyl alcohol system, but when the lamellar structure has a relatively high fluidity structure such as a liquid lamellar, it causes a swelling phenomenon in the emulsion system. To increase the viscosity and hardness of, there is a disadvantage that the unstable multiple lamellar structure is easily lost. Of course, such a multi-lamellar emulsion may be useful because it has a superior formulation stability than a formulation for a conventional external preparation, but whether it is useful for phase stability and skin function in connection with the hexagonal gel structure of the skin's lamellar structure. Is not yet known.

The present inventors have studied the formation of a multi-layer lamellae emulsion having a hexagonal structure, which is a structure of lipid components between skin keratinocytes, by searching for various emulsifiers and changing the composition ratio. When hydrates are prepared by mixing sorbitan stearate and / or sucrose cocoate as emulsifiers with cholesterol, derivatives and fatty acids thereof, they form hexagonal gel structures, which are in the form of actual keratinocyte lipids. Has been filed a patent (10-2006-0051896). The present invention is to develop a skin external preparation for which a hexagonal gel structure is formed by using an emulsifier different from the preceding invention.

Therefore, the first object of the present invention is formulated in the same hexagonal gel structure as the skin structure of keratinocytes, applicable to various skin types and applied to the skin damaged by various diseases, excellent skin protection effect and moisturizing function recovery effect To provide a topical skin composition for exhibiting.

A second object of the present invention is to provide a topical skin composition having excellent formulation stability in addition to the first object described above.

According to the present invention for achieving the above object, a pseudoceramide, cholesterol or derivatives thereof and fatty acids as lipid components between the keratinocytes; Polyglyceryl fatty acid esters having an HLB value of 8 to 12 as an emulsifier; At least one higher fatty alcohol selected from the group consisting of cetyl alcohol, stearyl alcohol and cetostearyl alcohol; A hexagonal structure external skin composition containing general oils and polyhydric alcohols is provided. As the pseudoceramide, myristoyl / palmitoyl oxostearamide / arachamide MEA, dihydroxyisopropyl palmoylpalmamide, or a mixture thereof may be used. The emulsifiers include polyglyceryl-6 stearate (HLB 12), polyglyceryl-6 distearate (HLB 8), polyglyceryl-10 triisostearate (Polyglyceryl) At least one selected from the group consisting of -10 triisostearate, HLB 8) and polyglyceryl-10 distearate (HLB 10) can be used.

The pseudoceramide in the lipid component is included in the ratio of 0.1% to 2.0% based on the total weight of the emulsion, the emulsifier is preferably included in the ratio of 1.5% to 2.5% of the total amount of the emulsion.

Since the external composition for skin according to the present invention has a single hexagonal gel structure identical to the lipid structure between the keratinocytes, the external composition of the present invention not only shows an excellent effect of restoring the damaged skin barrier function in various skin diseases, but also a multilayer lamellar. It shows good formulation stability as an emulsion.

The emulsion of the present invention containing pseudoceramide as a constituent of intercellular keratinocytes, cholesterol or its derivatives and fatty acids, and containing a polyglyceryl fatty acid ester having an HLB value of 8 to 12 as an emulsifier has a distinct single hexagonal gel structure. It has the advantage of restoring skin barrier function such as skin protection and moisturizing function, formulation stability is also very good, and skin irritation is not.

1 is a polarization micrograph showing the formation of a multi-layer lamellar structure of the emulsion according to the Examples and Comparative Examples of the present invention.
2a to 2f are graphs showing hexagonal gel structure formation of an emulsion according to Examples and Comparative Examples of the present invention.
Figure 3a is a change in the water content in the stratum corneum when the external application for skin according to the present invention Examples and Comparative Examples, Figure 3b is a transdermal when the external application for skin according to the Examples and Comparative Examples of the present invention applied to the skin A graph showing the amount of water loss recovery.

Hereinafter, the present invention will be described in more detail.

According to one embodiment of the present invention, the pseudoceramide is Myristoyl / palmitoyl oxostearamide / arachamide MEA, Dihydroxyisopropyl Palmoylpalmamide Or mixtures thereof.

In the present invention, the pseudoceramide used may be used as long as it forms a hexagonal gel structure in the emulsion in a form having a structure similar to that of natural ceramide in the skin, and thus is not limited to the pseudoceramide.

The cholesterol or derivatives thereof include cholesterol, cholesterol sulfate, phytosterol, and may include various other derivatives having a chemical structure similar to cholesterol. Preferred in the present invention are phytosterols and cholesterol, and phytosterols may be more preferable in terms of expression of the hexagonal gel structure.

In addition, the fatty acids include palmitic acid, cetic acid, stearic acid, arachidonic acid and the like which can be used as external preparations for skin. Here, there is no particular limitation on the compounding ratio of the above pseudoceramide, cholesterol or derivatives thereof, and fatty acids. The emulsifier used in the present invention is a polyglyceryl fatty acid ester having an HLB value of 8 to 12, preferably a polyglyceryl fatty acid ester having an HLB value of 9 to 11. If the HLB (Hydrophile-Lipophile Balance) value is out of the above range, no hexagonal structure is formed.

The pseudoceramide in the lipid component is included in the ratio of 0.1% to 2.0% based on the total weight of the emulsion, the emulsifier is preferably included in the ratio of 1.5% to 2.5% of the total amount of the emulsion.

In the external preparation composition for skin, higher fatty alcohols contribute not only to the stability of the formulation but also to the formation of a multilayer lamellar structure of the emulsion, and preferably, cetostearyl alcohol can be used.

The external composition for skin having a hexagonal gel structure according to an embodiment of the present invention is a polyglyceryl having 0.05 to 10% by weight of pseudoceramide, cholesterol or its derivatives and fatty acids as a lipid component of skin keratinocytes, and an HLB value of 8 to 12. 0.05-25 weight% of fatty acid ester, 0.05-20 weight% of at least 1 sort (s) of higher fatty alcohol selected from the group which consists of cetyl alcohol, stearyl alcohol, and cetostearyl alcohol. In the present invention, the lipid component between the keratinocytes, the emulsifier and higher fatty alcohol is not limited, but the ratio of 1.0: 0.8-3.0: 0.01-2.0, preferably 1.0: 1.0-2.0: 0.1-2.0 Can be mixed in proportions.

Meanwhile, the composition for external application for skin according to the present invention includes natural oils and other synthetic oils including vegetable oils, animal oils and mineral oils in order to enhance various usefulness to the skin and effectively form and stabilize the multilayer lamella emulsion in addition to the above components. Preferred oils in the invention are vegetable natural oils. In the present invention, the oil content may be included in the range of 0.5 to 1.8 by weight relative to the combined amount of the skin keratinocyte lipid component, the emulsifier and higher fatty alcohol. In addition, the composition for external application for skin according to the present invention may include polyhydric alcohols such as glycerin and butylene glycol, various extract mixtures, thickeners, preservatives, antioxidants, other additives, purified water, and the like.

The preparation method for the external preparation for skin stabilized with hexagonal gel structure according to the present invention is as follows.

Firstly, the keratinocyte intercellular lipid component including pseudoceramide, cholesterol or derivatives thereof, and fatty acids; a polyglyceryl fatty acid ester emulsifier having an HLB value of 8 to 12; cetyl alcohol, stearyl alcohol, and cetostearyl alcohol. At least one higher fatty alcohol selected from the group consisting of: homogeneously mixed with heating and dissolving at 70 to 100 ° C, preferably 85 to 95 ° C, and then adding oils and polyhydric alcohols thereto, followed by heating It is prepared by emulsifying the phase transition while adding purified purified water or by adding the mixed oil phase to the heated purified water. After the addition of other additives such as thickener and cooled to room temperature to complete the manufacture. The raw material mixed in the oil phase in the additive can be added by adding in the process of adding oils and polyhydric alcohol during the above process.

Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, which are intended to illustrate the present invention but are not intended to limit the present invention.

EXAMPLE

Examples 1-4 and Comparative Examples 1-2

External skin stabilized with hexagonal gel structure according to the present invention using lipid components, emulsifiers, higher fatty alcohols, general oils, polyhydric alcohols, thickeners, and purified water as components and composition ratios as shown in Table 1 below. Was prepared.

First, the keratinocyte intercellular lipid component composed of pseudoceramide, cholesterol or derivatives thereof and fatty acid, polyglyceryl fatty acid ester emulsifier with HLB value of 8-12, cetyl alcohol, stearyl alcohol or cetostearyl alcohol, etc. The higher fatty alcohols were weighed and then dissolved by heating at 85-95 ° C., then oils and polyhydric alcohols were added and mixed homogeneously. After emulsification by vigorous stirring, cooled to 50 ° C or less, and then added to a pre-hydrated thickener was mixed homogeneously to complete the preparation. Pseudo-ceramides include Myristoyl / palmitoyl oxostearamide / arachamide MEA (trade name: PC-9S), Dihydroxyisopropyl Palmoylpalmamide (trade name). The mixture which mixed: PC-5) by the same weight ratio was used. As the thickener, carboxyvinyl polymer was used.

Raw material name Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Pseudoceramide (PC-9S / PC-5) 2.0 2.0 2.0 2.0 2.0 2.0 cholesterol 0.2 0.2 0.2 0.2 0.2 0.2 Stearic acid 0.5 0.5 0.5 0.5 0.5 0.5 Polyglyceryl-6 Stearate 2.5 Polyglyceryl-6 Distearate 2.5 Polyglyceryl-10
Triisostearate 2.5 Polyglyceryl-10
Distearate 2.5 Polyglyceryl-3
Diisostearate 2.5 Polyglyceryl-2
Triisostearate 2.5 Cetostearyl alcohol 1.5 1.5 1.5 1.5 1.5 1.5 Med Foam Seed Oil 2.5 2.5 2.5 2.5 2.5 2.5 Grape Seed Oil 2.5 2.5 2.5 2.5 2.5 2.5 Thickener 0.2 0.2 0.2 0.2 0.2 0.2 Purified water Balance Balance Balance Balance Balance Balance

In Examples 1 to 4, polyglyceryl-6 stearate (HLB 12), polyglyceryl-6 distearate (HLB 8), and polyglyceryl-10 as emulsifiers, respectively Polyglyceryl-10 triisostearate (HLB 8) and Polyglyceryl-10 distearate (HLB 10) were used. In Comparative Examples 1 and 2, polyglyceryl-3 diiso is used as an emulsifier. An emulsion was prepared using stearate (Polyglyceryl-3 diisostearate, HLB 5), polyglyceryl-2 triisostearate (HLB 3).

Experimental Example 1: Confirmation of Liquid Crystal Structure Using Polarizing Microscope

In order to confirm whether the emulsions prepared in Examples 1 to 4 formed lamellar liquid crystals, a characteristic cross shape (Maltese Cross) appearing in the liquid crystal emulsion was observed and shown in FIG. 1. A polarizing microscope (Optiphto-2, manufactured by Nikon) was used to observe the cross shape.

An appropriate amount of the prepared emulsion was placed on a slide glass, and the cover glass was lightly pressed to observe 500 times. As shown in FIG. 1, in Examples 1 to 4 using polyglyceryl fatty acid ester having an HLB value of 8 to 12 as an emulsifier, a unique cross-shaped shape (Maltese Cross) was formed under a polarizing microscope to give a good emulsion of lamellae. It was confirmed that a structure was formed, but when an emulsifier having an HLB value of 5 or less was used, it was found that a lamellar liquid crystal structure could not be formed.

Experimental Example 2: Confirmation of hexagonal structure formation of lamellar liquid crystalline emulsion

In Examples 1 to 4 in Experimental Example 1 was confirmed to form an effective lamellae liquid emulsion. Whether the lamellar liquid crystalline emulsion exhibited the most stable hexagonal form was confirmed by using wide-angle X-ray diffraction (WXRD).

The emulsions prepared in Examples 1 to 4 and Comparative Examples 1 and 2 were placed in a capillary (Mark- Rohrchem aus Glas no 10, length 80 mm, auβen 0.7 mm, Article no. 4007807, Hilgenberg, Germany) The temperature was controlled by D8 discover XRD for high temperature WXRD. Cu-Kα wavelength was installed at 40kV and 40mA. Collimators were fixed at 0.3 mm and measured at 150 seconds per step. The wavelength from the sample was measured by transmitting through a 30 cm helium gas tube. The results are shown in Figures 2a to 2f. 2A to 2D show Examples 1 to 4, and FIGS. 2E and 2F show Comparative Example 1 and Comparative Example 2, respectively.

As can be seen in the figures, all samples of Examples 1-4 showed a typical single hexagonal gel peak around about d = 4.12. However, Comparative Examples 1 and 2 did not appear in the liquid crystal gap did not appear to form a liquid crystal. From this, in the case of using a polyglyceryl fatty acid ester emulsifier having an HLB value of 8 to 12, it was confirmed that a hexagonal structure was formed to stabilize the emulsion.

Experimental Example 3: Stability Test of Formulation

The stability of the formulations for lamellar structure emulsions according to the invention was tested in the following manner.

The emulsions of Examples 1 to 4 and Comparative Examples 1 and 2 were stored in an opaque glass container in a constant temperature bath at 45 ° C. for 12 weeks, and then opaque in a completely shaded refrigerator kept at 4 ° C. The separation degree and the discoloration degree of the sample stored in the vitreous container for 12 weeks and the sample stored for 12 weeks in a circulation chamber circulating at 37 ° C. at 5 ° C. were measured. The results of the product separation and discoloration classified into the following six grades are shown in Table 2 below.

Product separation and discoloration evaluation criteria:

0: no change

1: very little separation (discoloration)

2: a little separation (discoloration)

3: Separate slightly badly (discoloration)

4: severely separated (discolored)

5: extremely severe separation (discoloration)

Separation and discoloration Temperature Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 45 ° C 0 0 0 0 2 3 4 ℃ 0 0 0 0 One One cycle 0 0 0 0 2 3

From the results of Table 2, the emulsions of Examples 1 to 4 of the present invention using polyglyceryl fatty acid ester having an HLB value of 8 to 12 as an emulsifier were stable at 45 ° C, 4 ° C, and circulation conditions. However, Comparative Examples 1 and 2 exhibited a separation phenomenon at 4 ° C., 45 ° C., and circulation conditions.

Experimental Example 4: Skin Stimulation Test

In order to examine the skin irritation properties of the multilayered emulsion of the present invention, a certain amount (about 2.0 g) of emulsions of Examples 1 to 4 and Comparative Examples 1 and 2 was applied to the upper arm of a healthy adult male and female using a patch test finn chamber. After patching for 48 hours, the Finn Chamber was removed and the skin condition change was visually read after 30 minutes to 1 hour, and this was determined first, and after 48 hours, it was determined second.

sample

Number of test subjects

Judgment result Stimulus

none Uncertainty Slightly irritating Irritation Severe irritation Primary Secondary Primary Secondary Primary Secondary Primary Secondary Primary Secondary Example 1 30 30 30 0 0 0 0 0 0 0 0 0.00 Example 2 30 30 30 0 0 0 0 0 0 0 0 0.00 Example 3 30 30 30 0 0 0 0 0 0 0 0 0.00 Example 4 30 30 30 0 0 0 0 0 0 0 0 0.00 Comparative Example 1 30 30 30 0 0 0 0 0 0 0 0 0.00 Comparative Example 2 30 30 30 0 0 0 0 0 0 0 0 0.00

As shown in Table 3, Examples 1 to 4 and Comparative Examples 1 and 2 of the present invention were confirmed to have no irritation to the skin.

Experimental Example 5: Skin Function Improvement Effect

To measure the skin hydration and transepidermal water loss (TEWL) in the three areas of the upper arm of both arms for 10 normal women aged 20 to 30 years, each corneometer (CM825, Courage & Khazaka) , Germany) and Tewameter (TM300, Courage & Khazaka, Germany) to measure the moisture content and transdermal moisture loss in the stratum corneum. Then, in order to induce acute skin barrier damage, repeat tape-stripping using D-Squame tape (Cu-Derm Corporation, USA) in the same area, so that the transdermal moisture loss is 35-40 g / hr / m ² . It was. After the acute skin barrier injury, immediately apply each of Examples 1 to 4 and Comparative Examples 1 and 2 once each to the skin of the damaged area, and then apply it once daily for 5 days to evaluate the change in the function of the skin over time. It was. Changes in water content and transdermal moisture loss in the stratum corneum were measured after 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 120 hours, respectively. Calculated using the same formula. Statistical significance was performed using the ANOVA test and was determined to be significant when p <0.05 or less. As a result of the measurement, in Examples 1 to 4, there was no statistically significant difference in recovering moisture content and transdermal moisture loss in the stratum corneum, and no statistically significant difference was observed in Comparative Examples 1 and 2. However, in Examples 1 to 4 and Comparative Examples 1 and 2, the statistically significant difference between the groups was determined to be 0.05 or less as p value.

 Change of Skin hydration = Skin hydration at measured time-Skin hydration before barrier disruption

% Recovery of TEWL = [1- (TEWL at measured time-TEWL before barrier disruption) / (TEWL at immediate after barrier disruption-TEWL before barrier disruption)] X 100

The results are shown in Figures 3a and 3b.

As can be seen from the figures, Examples 1 to 4 showed a high moisture retention and a high transdermal moisture recovery rate.

Claims (5)

Pseudoceramides, cholesterol or derivatives thereof and fatty acids as lipid components of keratinocytes; Polyglyceryl fatty acid esters having an HLB value of 8 to 12 as an emulsifier; At least one higher fatty alcohol selected from the group consisting of cetyl alcohol, stearyl alcohol and cetostearyl alcohol; A skin external preparation composition of hexagonal structure containing general oils and polyhydric alcohols. The method of claim 1, wherein the pseudoceramide is Myristoyl / palmitoyl oxostearamide / arachamide MEA, Dihydroxyisopropyl Palmoyl palmmamide or mixtures thereof A composition for external preparation of the skin of hexagonal structure, which is characterized in that. The method of claim 1, wherein the emulsifier is Polyglyceryl-6 stearate (HLB 12), Polyglyceryl-6 distearate (HLB 8), Polyglyceryl-10 tri Hexagonal external skin composition, characterized in that at least one selected from the group consisting of isostearate (Polyglyceryl-10 triisostearate (HLB 8) and polyglyceryl-10 distearate (HLB 10)) . The composition for external application of hexagonal structure according to claim 1, wherein the pseudoceramide is contained in a ratio of 0.1% to 2.0% based on the total weight of the emulsion. According to claim 1, wherein the emulsifier is a hexagonal structure of the external composition for skin, characterized in that it is contained in a ratio of 1.5% to 2.5% by weight of the total emulsion.

Images