KR20180021282A - Multilamellar vesicle containing retinol and method for preparing thereof - Google Patents

Abstract

The present invention relates to a multilamellar vesicle containing retinol. More specifically, the present invention relates to a multilamellar vesicle containing retinol, composed of: (1) retinol-containing nanoemulsion consisting of retinol, hydrogenated lecithin, phytosteryl macadamiate, middle chain triglyceride, and water; (2) double layered hydroxide; (3) phosphatidylcholine; (4) hexanediol; (5) glycerin; (6) middle chain triglyceride; and (7) water. The present invention further relates to a production method thereof. In addition, the present invention relates to a cosmetic composition containing the multilamellar vesicle containing retinol.

Description

TECHNICAL FIELD [0001] The present invention relates to retinol-containing multi-lamellar vesicles,

The present invention relates to retinol-containing multilamellar vesicles, and more particularly to a retinol-containing multi-lamellar vesicle comprising retinol-containing nanoemulsion comprising retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water; 2) layered double hydroxides; 3) phosphatidylcholine; 4) hexanediol; 5) glycerin; 6) heavy chain triglyceride; And 7) water. ≪ / RTI >

The present invention also relates to a cosmetic composition comprising said retinol-containing multi-lamellar vesicles.

The present invention also relates to a process for preparing a nanoemulsion comprising i) mixing retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water to prepare a nanoemulsion; ii) combining the retinol-containing nanoemulsion prepared in the step (i) with a layered double hydroxide to adsorb the retinol-containing nanoemulsion between the layers of the layered double hydroxide to prepare a composite of the retinol-containing nanoemulsion and the layered double hydroxide; iii) a retinol-containing multilamellar vesicle comprising the step of mixing the retinol-containing nanoemulsion and the layered double hydroxide complex prepared in the step (ii) with phosphatidylcholine, hexanediol, glycerin, heavy chain triglyceride and water to prepare multi- And to a method for producing vesicles.

Due to the development of functional materials, a variety of functionalization methods have been extensively studied to give higher stability to cosmetic raw materials. In particular, it is well known that light, heat and oxygen in the air seriously reduce the biological activity of functional raw materials. Therefore, new functionalization techniques are needed to stabilize various cosmetic raw materials.

Vitamin A is a vitamin that participates in visual function and acts as a growth factor. Vitamin A acts in the form of a light-absorbing molecule retinal, a metabolite in the retina of the eye, which is absolutely necessary for lightening (the ability to see objects in dark environments) and tonality. Vitamin A also acts as an important growth factor, like hormones, in epithelial cells, in the form of retinoic acid, an irreversibly oxidized form of retinol. Vitamin A in animal foods is mostly present in the form of an ester, such as retinyl palmitate, which is converted into retinol, a kind of alcohol, in the small intestine after ingestion. The body stores vitamin A in the form of retinol, and whenever necessary. It is converted into retinal, which is an aldehyde in the visual system.

Retinol (vitamin A ₁ ) is an animal form of vitamin A that can be converted to other forms of vitamin A, and the retinyl ester derivative of alcohol acts as a form of vitamin storage in animals. Retinol is produced from the hydrolysis of retinyl esters and retinal reduction in the body.

Retinol is also known to play an important role in maintaining the original function of the epidermal cells, sometimes transformed into retinoic acid, the active form. It promotes the cell differentiation by expressing the RNA of the cell nucleus existing in skin cells, promotes the biosynthesis of collagen, which is a light protein existing as a fibrous solid between the cells of the animal, and elastic fiber, and reduces the wrinkles , And it is known to have an effect of increasing skin elasticity. Focusing on this efficacy, retinol began to develop early as a cosmetic product that prevents wrinkles and skin aging. Since the late 1990s, several cosmetic companies have competitively launched retinol-containing cosmetics. However, retinol is unstable in heat, light, and moisture, and skin absorption is not smooth, so efforts to improve it are needed.

As an example for stabilizing retinol, Korean Patent Laid-Open Publication No. 10-2011-0138527 discloses a cosmetic composition containing porous polymer beads and nanoemulsion stabilized retinol.

Korean Patent Publication No. 10-2011-0138527

Accordingly, it is a technical object of the present invention to provide a retinol-containing delivery system capable of efficiently transferring retinol into the skin in a stable state.

Another object of the present invention is to provide a cosmetic composition comprising the retinol-containing delivery system.

In addition, another object of the present invention is to provide a production method for effectively producing the retinol-containing delivery system.

In order to solve the above problems, the present invention provides retinol-containing multilamellar vesicles comprising the following components:

1) retinol-containing nanoemulsion comprising retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water; 2) layered double hydroxide; 3) phosphatidylcholine; 4) hexanediol; 5) glycerin; 6) heavy chain triglyceride; And 7) water.

The present invention also provides a cosmetic composition comprising the retinol-containing multilamellar vesicles.

The present invention also relates to a process for preparing a nanoemulsion comprising i) mixing retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water to prepare a nanoemulsion;

ii) combining the retinol-containing nanoemulsion prepared in the step (i) with a layered double hydroxide to adsorb the retinol-containing nanoemulsion between the layers of the layered double hydroxide to prepare a composite of the retinol-containing nanoemulsion and the layered double hydroxide;

iii) a retinol-containing multilamellar vesicle comprising the step of mixing the retinol-containing nanoemulsion and the layered double hydroxide complex prepared in the step (ii) with phosphatidylcholine, hexanediol, glycerin, heavy chain triglyceride and water to prepare multi- A method for producing a vesicle is provided.

Hereinafter, the present invention will be described in detail.

According to one aspect of the present invention there is provided retinol-containing multilamellar vesicles comprising:

1) a retinol-containing nanoemulsion comprising retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water;

2) layered double hydroxides;

3) phosphatidylcholine;

4) hexanediol;

5) glycerin;

6) heavy chain triglyceride; And

7) Water.

In the present invention, retinol is primarily stabilized by nanoemulsification using hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water.

The retinol-containing nanoemulsion of the present invention preferably contains 5 to 40% by weight, more preferably 10 to 30% by weight of retinol. If retinol is contained in an amount of less than 5% by weight, retinol may not exhibit its efficacy sufficiently. If it is contained in an amount of more than 40% by weight, there may be a problem in formation of nanoemulsion.

The retinol-containing nanoemulsion of the present invention preferably contains 1 to 10 wt%, more preferably 2 to 8 wt%, of hydrogenated lecithin as an emulsifier. Lecithin refers to a mixture of various phospholipids and the composition of the phospholipid may vary depending on its origin. Hydrogenated lecithin can be obtained by adding hydrogen to lecithin. Hydrogenated lecithin may be present in less than 1% by weight, but in excess of 10% by weight, there may be a problem with the formation of the nanoemulsion.

The retinol-containing nanoemulsion of the present invention preferably contains 1 to 10% by weight, more preferably 2 to 8% by weight of phytosteryl macadamiate as a secondary emulsifier. Phytostearyl methadamate is a combination of phytosterol and macadamia nut oil. In the present invention, it is difficult to completely form a bilayer membrane of liposome when hydrolyzed lecithin alone is used to form a nanoemulsion. Therefore, it can be used as a secondary emulsifier, . When phytosteryl methadamate is contained in an amount of less than 1% by weight but more than 10% by weight, there may be a problem in formation of the nano emulsion.

The retinol-containing nanoemulsion of the present invention preferably contains 2 to 20% by weight, more preferably 5 to 15% by weight, of medium-chain triglyceride (MCT). The heavy chain triglyceride is a 6-12 carbon fatty acid ester of glycerol, similar to the skin structure, which helps penetrate the skin. When the heavy chain triglyceride is contained in an amount of less than 2% by weight, the effect according to the heavy chain triglyceride may be insufficient. If the heavy chain triglyceride is contained in an amount exceeding 20% by weight, there may be a problem in formation of the nano emulsion.

The retinol-containing nanoemulsion of the present invention preferably contains 40 to 80% by weight, more preferably 50 to 70% by weight of water.

In the present invention, the retinol-containing nanoemulsion is mixed with a layered double hydroxide (LDH) to form a complex to secondarily stabilize retinol.

LDH is an inorganic compound in the layer structure, the composition is expressed by the _{^{[M 2+ 1-x M 3+}} x (OH) 2] x + (A n-) x / n · mH 2 O Structure. In the above formula, M ²⁺ and M ³⁺ are metal cations and occupy the octahedral site of brucite, A ^n- represents anions located between layers, and M ²⁺ = Ca ²⁺ , Mg ^{2 + , Mn 2 +, Fe 2 +} , or the like Co ^{2 +,} Zn ^{2 +,} and the like ^{M 3+ = Al 3 +, Fe} 3 +, Ti 3 +, a n- is _{^{Cl -, Br -, NO 3}} -, CO ₃ ^2- , SO ₄ ^2- , and the like, and 0.2? X? 0.33 and m is generally 0.5 to 4 in the fixed composition state.

The anions located between the layers of the LDH structure can be easily replaced, so that biomolecules such as collagen tripeptides and solid nanoparticles containing Ag, Au, Pt, etc., as well as biomolecules having negative charges such as DNA to DNA, Intercalation can be performed. An example of the basic lamellar structure of LDH and possible metal cations and anions is shown in Fig.

In the present invention, retinol is tertiarily stabilized by preparing a composite obtained by mixing the retinol-containing nanoemulsion and a layered double hydroxide with multi-lamellar vesicles using forsteridylcholine, hexanediol, glycerin, heavy chain triglyceride and water .

The multi-lamellar vesicles of the present invention preferably contain 10 to 40% by weight, more preferably 20 to 30% by weight, respectively, of the retinol-containing nanoemulsion and the layered double hydroxide.

The multi-lamellar vesicles of the present invention preferably contain 5 to 30% by weight, more preferably 10 to 20% by weight, of phosphatidylcholine. Phosphatidylcholine is the most representative phospholipid, a major component of lipid biomaterials and a member of the lecithin group. In the present invention, the phosphatidylcholine forms a membrane of multilamellar vesicles. When the content of phosphatidylcholine is less than 5% by weight, there may be a problem in formation of multi-lamellar vesicles. When the content of the phosphatidylcholine is more than 30% by weight, the effect of retinol may be inadequate There may be a problem.

The multicamera vesicles of the present invention preferably comprise 0.5 to 5% by weight, more preferably 1 to 3% by weight, of 1,2-hexanediol. In the present invention, hexanediol can impart moisturizing and preservative effects to multicamera vesicles. When hexanediol is contained in an amount of less than 0.5% by weight, the moisturizing or preservative effect may be insufficient. If the hexanediol is contained in an amount exceeding 5% by weight, there may be a problem in formation of multi-lamellar vesicles.

The multicamera vesicles of the present invention preferably comprise 5 to 20% by weight, more preferably 7 to 15% by weight of glycerin. In the present invention, glycerin imparts stability to multi-lamella vesicles. If glycerin is contained in an amount of less than 5% by weight, formation of multi-lamellar vesicles may become unstable, and if it exceeds 20% by weight, formation of multi-lamellar vesicles may be problematic.

The multi-lamella vesicles of the present invention preferably comprise from 5 to 20% by weight, more preferably from 7 to 15% by weight, of the heavy chain triglyceride. Medium chain triglycerides play a role in helping the skin penetrate the multicamera vesicles. When the heavy chain triglyceride is contained in an amount of less than 5% by weight, the effect according to the heavy chain triglyceride may be insufficient. If the heavy chain triglyceride is contained in an amount exceeding 20% by weight, there may be a problem in formation of the multilamellar vesicle.

The multi-lamellar vesicles of the present invention preferably comprise 5 to 30% by weight, more preferably 8 to 20% by weight of water.

According to another aspect of the present invention, there is provided a cosmetic composition comprising the retinol-containing multilamellar vesicles.

In the present invention, the cosmetic composition may be formulated into, for example, a skin, a lotion, a cream, an essence or the like, but is not limited thereto. The cosmetic composition preferably contains 1 to 40% by weight of the retinol-containing multilamellar vesicle according to the present invention. In the present invention, when the cosmetic composition contains less than 1% by weight of retinol-containing multilamellar vesicles, the effect of retinol may be poor, and even if it exceeds 40% by weight, the effect of retinol is increased in proportion to its addition It is difficult to expect more than this and is not economically desirable.

According to another aspect of the present invention,

i) mixing retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water to prepare a nanoemulsion;

ii) combining the retinol-containing nanoemulsion prepared in the step (i) with a layered double hydroxide to adsorb the retinol-containing nanoemulsion between the layers of the layered double hydroxide to prepare a composite of the retinol-containing nanoemulsion and the layered double hydroxide;

iii) a retinol-containing multilamellar vesicle comprising the step of mixing the retinol-containing nanoemulsion and the layered double hydroxide complex prepared in the step (ii) with phosphatidylcholine, hexanediol, glycerin, heavy chain triglyceride and water to prepare multi- A method of making a vesicle is provided.

In step (i) of the above method, preferably 5 to 40% by weight of retinol, 1 to 10% by weight of hydrogenconted lecithin, 1 to 10% by weight of phytosteryl macadamate, 2 to 20% More preferably from 10 to 30% by weight of retinol, from 2 to 8% by weight of hydrogenated lecithin, from 2 to 8% by weight of phytosteryl methadamate, from 5 to 10% To 15% by weight of heavy chain triglyceride and 50 to 70% by weight of water to prepare a nano emulsion.

In step (ii) of the above production method, preferably 30 to 70 wt% of retinol-containing nanoemulsion and 30 to 70 wt% of layered double hydroxide, more preferably 40 to 60 wt% of retinol-containing nanoemulsion, and 40 To 60 wt% of the layered double hydroxide is mixed to adsorb the retinol-containing nanoemulsion between the layers of the layered double hydroxide to prepare a composite of the layered double hydroxide and the retinol-containing nanoemulsion.

In step (iii) of the above production method, preferably 20 to 80% by weight of a composite of a retinol-containing nanoemulsion and a layered double hydroxide, 5 to 30% by weight of phosphatidylcholine, 0.5 to 5% by weight of hexanediol, Compositions of layered double hydroxides with glycerin, 5 to 20% by weight of heavy chain triglycerides and 5 to 30% by weight of water, more preferably 40 to 60% by weight of retinol-containing nanoemulsion, 10 to 20% Phosphatidylcholine, 1 to 3% by weight of hexanediol, 7 to 15% by weight of glycerin, 7 to 15% by weight of heavy chain triglycerides and 8 to 20% by weight of water are mixed to prepare a multilamellar vesicle.

By stabilizing retinol three times, the present invention can efficiently deliver retinol into the skin in a highly stable form, thereby increasing the bioavailability and exhibiting excellent efficacy in reducing wrinkles and increasing skin elasticity even with a small amount of retinol.

1 is a schematic view showing the layered structure and composition of a layered double hydroxide.
Fig. 2 shows the result of measuring the particle diameter size of the retinol-containing nanoemulsion using Photal ELS-Z.
Fig. 3 shows the results of measurement of the particle diameter size of retinol-containing multilamellar vesicles using Photal ELS-Z.
4 is an enlarged photograph of retinol-containing nanoemulsion using a freezing electron microscope.
5 is an enlarged photograph of a composite of a retinol-containing nanoemulsion and a layered double hydroxide using a freezing electron microscope.
6 is an enlarged photograph of a retinol-containing multilamellar vesicle using a freezing electron microscope.
7 is a graph showing the results of analyzing the stability of retinol against light and temperature by HPLC.

Hereinafter, the present invention will be described more specifically by way of examples. However, the following examples are given to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

Preparation Example: Preparation of ZnAl-carbonate layered double hydroxide (c-LDH)

The ZnAl-LDH containing carbonate was synthesized as follows by coprecipitation. To the mixed solution of 0.2 M Zn (NO ₃ ) ₂ and 0.1 M Al (NO ₃ ) ₃ , ₁ M Na ₂ CO ₃ solution was gradually added until the final pH was about 7.0. The mixed solution was stored in an oven at about 70 ° C for one day, filtered, washed with distilled water and ethanol, and then dried using a vacuum pump. The possible structure of the synthesized c-LDH is as follows: [Zn ₄ Al ₂ (OH) ₁₂ ] CO ₃ .xH ₂ O.

Example 1-1: Preparation of retinol-containing nanoemulsion

The components were introduced into the container in the following composition of Table 1 and dissolved at a temperature of 50 DEG C and then mixed for 5 minutes using a homomixer and then passed through the high pressure homogenizer for 5 consecutive times at 1,000 bar, , And defoamed to obtain a retinol-containing nanoemulsion.

Example 1-2: Preparation of a composite of a retinol-containing nanoemulsion and a layered double hydroxide (LDH)

Two components were put into a beaker with the composition shown in the following Table 2, and then mixed with a disper at 3,000 rpm for 10-20 minutes to obtain a retinol-containing nanoemulsion-LDH complex.

Example 1-3: Preparation of retinol-containing multilamellar vesicles

The components were introduced into a container at the temperature shown in Table 3 below and dissolved at a temperature of 80 캜. After mixing for 10 minutes using a homomixer, the mixture was passed through 1,000 times continuously for 5 consecutive times in a high pressure homogenizer, Containing multi-lamella vesicles.

Example  2: Retinol content Multi-lamella  Vesicles Skin  Produce

A skin containing retinol was prepared with the composition shown in Table 4 below.

Example  3: Retinol content Multi-lamella  Production of lotion using parcels

A lotion containing retinol was prepared with the composition shown in the following Table 5.

Example  4: Retinol content Multi-lamella  Manufacture of cream using vesicles

Two types of cream containing retinol were prepared according to the composition shown in Table 6 below.

Example  5: retinol content Multi-lamella  Manufacture of essences using vesicles

Essences containing retinol were prepared according to the compositions shown in Table 7 below.

Experimental Example 1: Measurement of particle distribution

Particle distributions of the retinol-containing nanoemulsion prepared in Example 1-1 and the retinol-containing multi-lamellar vesicles prepared in Example 1-3 were measured using Photal ELS-Z and are shown in FIGS. 2 and 3, respectively. The results showed that the average particle sizes of retinol-containing nanoemulsion and retinol-containing multilamellar vesicles were 89.1 nm and 370.4 nm, respectively.

Experimental Example 2: Freezing electron microscope photographing

The retinol-containing nanoemulsion, retinol-containing nanoemulsion-LDH complexes and retinol-containing multilamellar vesicles prepared in Examples 1-1, 1-2 and 1-3 were photographed. Since the particle size was too small to measure with a general optical microscope, it was photographed using a freezing electron microscope (JEM 1010, JEOL, Japan) (Figs. 4 to 6). From FIG. 6, it can be seen that multi-lamella vesicles are well formed.

Experimental Example 3: Effect of stimulation of transdermal absorption of retinol-containing multilamellar vesicles

8 weeks of female guinea pig strain (strain IAF / HA-hrBR) was used. The skin of the abdomen of guinea pig was cut and tested in a Franz-type diffusion cell (Lab fine instruments, Korea). 50 mM phosphate buffer (pH 7.4, 0.1 M NaCl) was added to a receptor container (5 ml) of a Franz-type diffusion cell, and diffusion cells were mixed and dispersed at 32 ° C and 600 rpm. And 50 mu l of the emulsion of the comparative example were placed in a donor container. Absorbed and diffused according to the predetermined time, and the skin on which the absorption diffusion occurred was made to be 0.64 cm ² . After the absorption and diffusion of the active ingredient is completed, the emulsions remaining on the skin can not be absorbed by the dried kimwipes or 10 ml of ethanol, and the active ingredient is absorbed and diffused by using a tip-type homogenizer After changing the skin, the amount of retinol absorbed into the skin was extracted with 4 ml of dichloromethane. After that, the extract was filtered with a 0.45 μm nylon membrane filtration membrane, and the content was measured by HPLC method under the following conditions. The results are shown in Table 8.

As can be seen from the above Table 8, it was found that the multi-lamella vesicle of the present invention can deliver retinol into the skin very efficiently.

Experimental Example 4: Measurement of stability of retinol-containing multilamellar vesicles

In order to examine the stabilizing effect of retinol in the multi-lamellar vesicles of the present invention, the stability of the cream A and B against light and temperature was analyzed by HPLC (Fig. 7). As a result, the multi-lamella vesicle of the present invention effectively stabilized retinol .

Claims (11)

Retinol-containing multicamera vesicles containing the following ingredients:
1) retinol-containing nanoemulsion comprising retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water;
2) layered double hydroxide;
3) phosphatidylcholine;
4) hexanediol;
5) glycerin;
6) heavy chain triglyceride; And
7) Water. The retinol-containing nanoemulsion according to claim 1, wherein the retinol-containing nanoemulsion comprises 5 to 40% by weight of retinol, 1 to 10% by weight of hydrogenated lecithin, 1 to 10% by weight of phytosteryl methadamate, 2 to 20% A heavy chain triglyceride and 40 to 80 wt% water. 3. The composition of claim 2, wherein the retinol-containing nanoemulsion comprises from 10 to 30% by weight of retinol, from 2 to 8% by weight of hydrogenated lecithin, from 2 to 8% by weight of phytosteryl methadamate, from 5 to 15% A heavy chain triglyceride and 50 to 70 wt% water. The composition of claim 1, further comprising 10 to 40% by weight of a retinol-containing nanoemulsion, 10 to 40% by weight of a layered double hydroxide, 5 to 30% by weight of phosphatidylcholine, 0.5 to 5% by weight of hexanediol, 5 to 20% Glycerin, from 5 to 20% by weight of heavy chain triglycerides and from 5 to 30% by weight of water. 5. The composition of claim 4, further comprising 20 to 30% by weight of a retinol-containing nanoemulsion, 20 to 30% by weight of a layered double hydroxide, 10 to 20% by weight of phosphatidylcholine, 1 to 3% by weight of hexanediol, 7 to 15% Glycerin, 7 to 15% by weight of heavy chain triglycerides and 8 to 20% by weight of water. A cosmetic composition comprising the retinol-containing multilamellar vesicle of any one of claims 1 to 5. The cosmetic composition according to claim 6, which comprises 1 to 40% by weight of retinol-containing multilamellar vesicles. i) mixing retinol, hydrogenated lecithin, phytosteryl methadamate, heavy chain triglyceride and water to prepare a nanoemulsion;
ii) combining the retinol-containing nanoemulsion prepared in the step (i) with a layered double hydroxide to adsorb the retinol-containing nanoemulsion between the layers of the layered double hydroxide to prepare a composite of the retinol-containing nanoemulsion and the layered double hydroxide;
iii) a retinol-containing multilamellar vesicle comprising the step of mixing the retinol-containing nanoemulsion and the layered double hydroxide complex prepared in the step (ii) with phosphatidylcholine, hexanediol, glycerin, heavy chain triglyceride and water to prepare multi- Method of manufacturing vesicles. The method according to claim 8, wherein in step (i), 5 to 40 wt% of retinol, 1 to 10 wt% of hydrogenated lecithin, 1 to 10 wt% of phytosteryl methadamate, 2 to 20 wt% A heavy chain triglyceride and 40 to 80% by weight of water. 9. The method according to claim 8, wherein in step (ii), 30 to 70% by weight of the retinol-containing nanoemulsion and 30 to 70% by weight of the layered double hydroxide are mixed. The method according to claim 8, wherein, in step (iii), the composite of the retinol-containing nanoemulsion and the layered double hydroxide, 20 to 80 wt% of phosphatidylcholine, 0.5 to 5 wt% of hexanediol, 5 to 20 wt% By weight of glycerin, 5 to 20% by weight of heavy chain triglycerides and 5 to 30% by weight of water.

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