JP2024525049A - Surface-modified retinoid-loaded porous silica - Google Patents

Abstract

The present invention relates to a surface-modified retinoid-loaded porous silica, and more particularly, the present invention relates to a method for loading a polyethoxylated retinoid onto a porous silica, followed by surface treatment with a silane compound, thereby increasing the loading efficiency of the retinoid, improving the sustained release efficiency, and enabling the product to be used as an active ingredient in functional cosmetics with improved stability and safety.

Description

The present invention relates to a surface-modified retinoid-loaded porous silica that is hypoallergenic and has improved stability and safety.

Vitamin A or its derivatives are representative substances known to date for improving aging skin, and many products containing them are on the market. Vitamin A or its derivatives are known to promote the proliferation of fibroblasts in the skin and collagen synthesis, and are used in a variety of ways as active ingredients in wrinkle-fighting functional cosmetics. However, vitamin A is fat-soluble and has the disadvantage of being unstable due to light, oxygen, heat, and lipid peroxides, so stabilization technology is essential, and stability can be ensured by using containers that block light and oxygen during product development. In addition, excessive amounts of vitamin A or its derivatives are substances that can increase skin sensitivity due to sunlight. When consumers use cosmetics containing vitamin A or its derivatives, various symptoms such as redness, erythema, pain, and itching can appear on the skin.

In order to improve the stability and safety of vitamin A and its derivatives, efforts have been made to improve stability/safety by using various drug delivery systems such as liposomes in Korean patent (10-1314100) and other documents. However, such drug delivery supports not only have a significantly low carrying efficiency of the active ingredient, but also cause a phenomenon in which the form of the drug delivery support temporarily collapses or is partially collapsed during the manufacturing process of the formulation and other auxiliary ingredients in the cosmetic formulation. As a result, the effect of improving the stability of retinoids is not significant, and the effect of improving safety caused by sustained release is still insufficient.

The object of the present invention is to provide a low-irritation retinoid-loaded porous silica with improved stability/safety and a method for producing the same.

Another object of the present invention is to provide a cosmetic composition containing the low-irritation retinoid-loaded porous silica.

To achieve the above object, the present invention provides a retinoid-loaded porous silica that is loaded with a polyethoxylated retinoid and has its surface modified with a silane compound.

The present invention also provides a method for preparing a composition comprising the steps of: mixing a polyethoxylated retinoid solution and a porous silica to load the polyethoxylated retinoid within the porous silica;
and reacting the porous silica carrying a polyethoxylated retinoid with a silane-based compound to modify the surface of the porous silica.

The present invention also provides a cosmetic composition containing the surface-modified retinoid-loaded porous silica.

The present invention involves supporting a polyethoxylated form of retinoid on porous silica, followed by surface treatment with a silane compound, thereby increasing the retinoid supporting efficiency, improving sustained release efficiency, and enabling the product to be used as an active ingredient in functional cosmetics with improved stability and safety.

FIG. 1 is a diagram showing the process for producing the surface-modified retinoid-loaded porous silica of the present invention. FIG. 2 is a diagram showing the experimental results of retinoid release behavior in an O/W (oil in water type) dosage form of the surface-modified retinoid-loaded porous silica of the present invention using a Franz diffusion cell, and is also the experimental results of in vitro skin absorption of the dosage form. FIG. 3 is a diagram showing the experimental results of retinoid release behavior in an O/W formulation of the surface-modified retinoid-loaded porous silica of the present invention using a Franz diffusion cell, and shows the results of the amount of skin absorption according to the application time of the formulation. FIG. 4 is a diagram showing the experimental results of retinoid release behavior in an O/W formulation of the surface-modified retinoid-loaded porous silica of the present invention using a Franz diffusion cell, and shows the results of the amount of skin absorption according to the application time of the formulation. FIG. 5 shows the results of an in vivo consumer evaluation test of the surface-modified retinoid-loaded porous silica of the present invention.

The configuration of the present invention is explained in detail below.

The present invention relates to a retinoid-loaded porous silica that is loaded with a polyethoxylated retinoid and has its surface modified with a silane-based compound.

The present invention is characterized by the use of porous silica as a carrier, which has the advantages of being less susceptible to decomposition/denaturation by other ingredients in a cosmetic formulation, improving stability by reducing exposure of retinoids to light/oxygen, and being able to support a high amount of retinoid compared to other drug delivery supports, in order to 1) improve the stability of retinoid, which is a vitamin A derivative, and by treating the surface of the porous silica with a silane compound to allow the retinoid to be released in a sustained manner, in order to improve the safety of the retinoid.

According to one embodiment of the present invention, the release behavior of retinoid was compared using a Franz diffusion cell between the surface-modified retinoid-loaded porous silica of the present invention and a retinoid not loaded on porous silica in an O/W formulation, and the irritation index was confirmed through a HET-CAM test and consumer evaluation of the surface-modified retinoid-loaded porous silica powder to compare the safety of the retinoid. As a result, the formulation in which the surface-modified retinoid-loaded porous silica powder was applied at 25°C and 40°C was stable even after 16 weeks, and the amount of retinoid eluted decreased depending on the concentration of the silane compound, confirming the possibility of application as a sustained-release formulation by gradually eluting the retinoid.

The polyethoxylated retinoid may be polyethoxylated retinamide.

The porous silica may have a diameter size of 1 to 50 μm.

The silane compounds include triethoxycaprylylsilane, aminopropyl triethoxysilane, glycidoxypropyl trimethoxysilane, isobutyl triethoxysilane, perfluorooctylethyl triethoxysilane, perfluorooctyl triethoxysilane, and stearyl triethoxysilane. Triethoxysilane), methyltriethoxysilane, PEG-8 methyl ether triethoxysilane, vinylethoxysilane, etc. can be used alone or in combination of two or more.

The present invention also provides a method for preparing a composition comprising the steps of: mixing a polyethoxylated retinoid solution and a porous silica to load the polyethoxylated retinoid within the porous silica;
and reacting the porous silica carrying a polyethoxylated retinoid with a silane-based compound to modify the surface of the porous silica.

The surface-modified retinoid-loaded porous silica of the present invention is characterized in that it is produced by loading a retinoid having a hydrophilic portion onto porous silica by PEGylation, and then surface-coating the silica with a hydrophobic silane compound through heat treatment.

The method for producing the surface-modified retinoid-loaded porous silica of the present invention is described in detail below.

The first step is to support the polyethoxylated retinoid onto the porous silica.

To this end, first, a polyethoxylated retinoid is uniformly dissolved in a solvent under light-blocking conditions to prepare a retinoid solution.

The polyethoxylated retinoid can be mixed at 0.5 to 20% by weight, more specifically 5 to 15% by weight, relative to 100% by weight of the surface-modified retinoid-loaded porous silica. Outside this range, the amount of retinoid remaining unloaded in the porous silica increases, which can reduce economic efficiency.

The solvent may be methanol or ethanol. The content of the solvent is not particularly limited and can be adjusted by those skilled in the art depending on the content of the retinoid.

When preparing the retinoid solution, hydrocarbon oils, ester oils, natural oils, silicone oils, antioxidants, light stabilizers, anti-inflammatory agents, discoloration inhibitors, UV blocking agents, dyes, pigments, etc. can be further added as necessary.

Next, gradually add the polyethoxylated retinoid solution to the porous silica and mix evenly at room temperature for at least 10 minutes using a mixer, such as a Henschel mixer.

The porous silica may have a diameter size of 1 to 50 μm. The porous silica may have an oil absorption of 0.3 to 3 cc/g. The porous silica may be mixed at 50 to 99% by weight, preferably 60 to 99% by weight, more preferably 65 to 94% by weight, relative to 100% by weight of the surface-modified retinoid-loaded porous silica. Outside this range, the porous silica powder may not be a uniform powder, but may be produced in clumps. This may affect stability when dispersed in other cosmetic formulations.

The second step is to modify the surface of the porous silica carrying the polyethoxylated retinoid using a silane-based compound as a surface treatment (modification) agent.

A silane compound is added to the polyethoxylated retinoid-loaded porous silica produced in the first step, and the mixture is mixed evenly for about 10 minutes using a Henschel mixer. Next, for surface treatment, heat treatment is carried out at 40-120°C for 30 minutes to 5 hours, or more specifically, at 80-100°C for 1 hour to 4 hours, and then cooled to produce surface-modified retinoid-loaded porous silica. If the heat treatment is outside the above range, low temperatures may not sufficiently advance the surface treatment, and high temperatures may cause discoloration of the retinoid and affect the stability of other substances.

The silane compound can be mixed at 0.5 to 20% by weight, more specifically 1 to 15% by weight, relative to 100% by weight of the surface-modified retinoid-loaded porous silica. Outside this range, the amount of retinoid eluted may decrease, reducing the effect of the retinoid, or in the case of an extremely excessive amount, the retinoid may remain on the surface of the silica rather than being captured inside the porous silica.

The present invention also relates to a cosmetic composition containing the surface-modified retinoid-loaded porous silica.

Since retinoids stimulate the proliferation of dermal fibroblasts and collagen synthesis, the cosmetic composition of the present invention can be used in wrinkle-fighting functional cosmetics.

The surface-modified retinoid-loaded porous silica of the present invention may also be used in the form of a powder in an O/W formulation. The surface-modified retinoid-loaded porous silica of the present invention may be included in an amount of 0.01 to 5% by weight, more specifically 0.05 to 4% by weight, based on 100% by weight of the cosmetic composition. Outside this range, the effect of the retinoid may be insufficient, or excessive use may affect stability and safety.

The cosmetic composition of the present invention can be prepared in the form of a cosmetic product in the general emulsion or solubilization form. For example, it can have the form of a lotion such as a softening lotion or a nutritious lotion, a milky lotion such as a facial lotion or a body lotion, a cream such as a nutritious cream, a moisture cream, or an eye cream, an essence, a cosmetic ointment, a spray, a gel, a pack, a sunscreen, a makeup base, a liquid type, a solid type, or a spray type foundation, a powder, a makeup remover such as a cleansing cream, a cleansing lotion, or a cleansing oil, or a cleansing agent such as a cleansing foam, a soap, or a body wash.

The cosmetic composition of the present invention may also contain auxiliary ingredients commonly used in the field of cosmetology, such as fatty substances, organic solvents, solubilizers, thickening and gelling agents, softeners, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water, ionic or non-ionic emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, blocking agents, moisturizing agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or any other ingredient commonly used in cosmetics, as auxiliary ingredients commonly used in the preparation of cosmetic compositions.

According to one embodiment of the present invention, the surface-modified retinoid-loaded porous silica of the present invention can be used in the form of a powder in an O/W formulation, which can be prepared by completely dissolving the oil phase and water phase components at 75°C according to the composition in Table 2 below, followed by primary emulsification using a homomixer, and then adding the surface-modified retinoid-loaded porous silica powder of the present invention at 45°C for secondary emulsification.

The present invention will be described in more detail below based on examples of the present invention, but the scope of the present invention is not limited to the examples presented below.

<Examples 1> to <Example 4> Preparation of surface-modified retinoid-loaded porous silica powder and application form Polyethoxylated retinamide was used as the retinoid for preparing the surface-modified retinoid-loaded porous silica. As shown in the composition in Table 1, the retinoid and ethanol were uniformly dissolved under light-blocking conditions, and the retinoid solution prepared was gradually added to the porous silica using a Henschel mixer and mixed evenly for 10 minutes. The porous silica used had a diameter of 1 to 50 μm and a porous silica oil absorption of 0.3 to 3 cc/g. Triethoxycaprylylsilane was added to the powder prepared in the first step and mixed evenly for 10 minutes using a Henschel mixer. For the surface treatment, the mixture was reacted at about 100° C. for 4 hours to carry out the surface treatment reaction, and then cooled to obtain the final surface-modified retinoid-loaded porous silica powder.

The retinoid-loaded porous silica powder thus prepared was applied to an actual O/W formulation, and the composition is shown in Table 2. The production method was as follows: the oil phase and the water phase were completely dissolved at 75°C, and then the primary emulsification was carried out using a homomixer. The retinoid and retinoid porous silica powder were added at 45°C, and the secondary emulsification was carried out.

The retinoid used in this invention was Medimin A (average molecular weight 831) manufactured by LS-Chem Co., Ltd., the porous silica was sunsil-130 manufactured by Sendin Beauty Science Co., Ltd., the surface treatment agent was AES raw material manufactured by Shin-Etsu Co., Ltd., and the retinol was Retinol 50C manufactured by BASF Corporation.

Experimental Example 1: Comparative experiment of retinol/retinoid discoloration A silane compound was added to the porous silica carrying polyethoxylated retinoid (Example 3), uniformly dispersed using a Henschel mixer, and reacted for 4 hours under heat treatment temperature conditions to obtain the powder shown below. As in Comparative Example 3, discoloration occurred during heat treatment in the case of retinol, whereas in Example 3, a pale yellow powder was obtained at a heat treatment temperature of 100°C. Meanwhile, when heat treatment was performed at a high temperature of 130°C or higher, an orange powder was obtained.

Experimental Example 2: Effect of improving retinoid stability In order to confirm the stability of retinoid, a time-dependent potency analysis was carried out on a pure retinoid (Comparative Example 4), a formulation containing a retinoid-loaded porous silica powder (Comparative Example 5), and a formulation containing a surface-modified retinoid-loaded porous silica powder (Example 4).

As shown in Table 4, it was confirmed that the stability improved in the following order: Comparative Example 4 < Comparative Example 5 = Example 4.

<Experimental Example 3> Experiment on the dissolution behavior of retinoid as a sustained release drug delivery agent for improving safety (Experiment on the dissolution behavior of retinoid under different solvent conditions)
To investigate the release behavior of retinoid, a primary dissolution experiment was carried out for Comparative Example 2 and Examples 1 to 3 using a solvent that is frequently used in cosmetics. 1,3-butylene glycol was used as the solvent, and the powders of Comparative Example 2 and Examples 1 to 3 were dispersed in the solvent at 5% and then allowed to dissolve for one week in a shaking incubator. After one week, only the supernatant of the solvent was analyzed, and the amount of dissolution was calculated.

As shown in Table 5, in the case of Comparative Example 2 where no surface treatment was performed, all of the retinoid was dissolved, while in the case of Examples 1 to 3 where surface treatment was performed, it was confirmed that the retinoid was gradually dissolved from the sustained-release drug delivery medium. In addition, the amount of retinoid dissolved was reduced depending on the concentration of triethoxycaprylylsilane (2 to 7%), and it was confirmed that the surface-modified retinoid porous silica powder can be used as a sustained-release formulation.

(Retinoid release behavior experiment in O/W formulation)
In order to confirm the retinoid dissolution behavior and skin permeation in the actual cosmetic formulation, the formulation of Comparative Example 4 and the formulation of Example 4, which applied Example 3 with the lowest dissolution amount, were compared through a Franz diffusion cell experiment. The skin permeation device used was as shown in the figure, and the skin permeation device was composed of a donor chamber and a receptor chamber, and the skin was placed between them and then fixed (see FIG. 2). Each cell used in the same test has the same surface area of ^2.54 cm2. The prepared skin is fixed to the skin permeation device with the stratum corneum located at the top. The amount of aqueous solution in the receptor chamber was 2.4 mL, and it was stirred at 300 rpm so as not to affect the diffusion of the test substance. The concentration of retinoid used in this test was set to 196.85 μg/ ^cm2 . The amount of the formulation applied to maintain the maximum absorption rate in the skin was 39.370 μl/ ^cm2 to maintain a constant skin absorption state and to apply evenly on the skin. After application of the test substance, the skin was sampled at the end of the 6-hour/24-hour experiment to determine the skin absorption rate.

As shown in Tables 6 and 7 and Figures 3 and 4, when comparing the 6-hour skin absorption amount, Example 4 had a smaller amount of retinoid dissolved from the sustained-release drug delivery agent than Comparative Example 4, but the comparison of the 24-hour skin absorption amount confirmed that the same amount was absorbed as retinoid not supported in porous silica. Therefore, it was confirmed that Example 4 gradually releases retinoid in the sustained-release formulation, but is absorbed at the same level as retinoid not supported in porous silica, and can exhibit the same efficacy/effect.

<Experimental Example 4> Safety improvement effect of retinoid-loaded porous silica powder (In vitro HET-CAM test)
The safety improvement effect was examined by evaluating the possibility of ocular mucosa irritation of fertilized eggs. The species and lineage of fertilized eggs used were white leghorn (white egg). In order to check the sensitivity of fertilized eggs, a preliminary experiment was conducted using a reference material, Texapon, to grasp the degree of bleeding and hemolysis and compare it with the experimental group. The criteria for irritation judgment were divided into slightly irritating, moderately irritating, irritating, and severely irritating. In order to confirm the safety of the surface-modified retinoid-loaded porous silica powder, the samples of Comparative Example 1 and Example 3 were subjected to HET-CAM tests.

As shown in Table 8, it was confirmed that the irritation index of the porous silica-supported and surface-modified sample of Example 3 was lower than that of Comparative Example 1.

(In vivo consumer evaluation test)
In order to examine the safety improvement effect of the surface-modified retinoid porous silica powder, a consumer irritation evaluation test was conducted using the samples of Comparative Example 5 and Example 4. The evaluation was conducted on 25 female consumers, who used the powder once in the evening for one week, and then a final irritation evaluation was conducted after one week of use. The irritation evaluation was conducted on a 5-point scale, with the higher the score, the stronger the intensity of irritation.

As shown in Figure 5, both Comparative Example 5 and Example 4 were scored below 2 points, indicating that they were less irritating.

The present invention can be applied to the field of functional cosmetics with improved stability and safety.

Claims (15)

Porous silica carrying a polyethoxylated retinoid and surface-modified with a silane compound. The retinoid-loaded porous silica of claim 1, wherein the polyethoxylated retinoid comprises polyethoxylated retinamide. The retinoid-loaded porous silica of claim 1, wherein the porous silica has a diameter size of 1 to 50 μm. Silane compounds include triethoxycaprylylsilane, aminopropyl triethoxysilane, glycidoxypropyl trimethoxysilane, isobutyl triethoxysilane, perfluorooctylethyl triethoxysilane, perfluorooctyl triethoxysilane, and stearyl triethoxysilane. The retinoid-supported porous silica according to claim 1, which is one or more selected from the group consisting of triethoxysilane, methyltriethoxysilane, PEG-8 methyl ether triethoxysilane, and vinyltriethoxysilane. The retinoid-loaded porous silica according to claim 1 is produced by mixing a polyethoxylated retinoid solution with porous silica to load the polyethoxylated retinoid in the porous silica, and then reacting the porous silica loaded with the polyethoxylated retinoid with a silane compound to modify the surface of the porous silica. A method for producing a surface-modified retinoid-loaded porous silica, comprising: mixing a polyethoxylated retinoid solution with porous silica to load the polyethoxylated retinoid in the porous silica; and reacting the porous silica loaded with the polyethoxylated retinoid with a silane compound to modify the surface of the porous silica. The method for producing a surface-modified retinoid-loaded porous silica according to claim 6, wherein the polyethoxylated retinoid includes polyethoxylated retinamide. The method for producing the surface-modified retinoid-loaded porous silica according to claim 6, wherein the polyethoxylated retinoid solution is produced by dissolving the polyethoxylated retinoid in a solvent under light-blocking conditions. The method for producing surface-modified retinoid-loaded porous silica according to claim 8, wherein the solvent is methanol or ethanol. The method for producing a surface-modified retinoid-loaded porous silica according to claim 6, wherein the polyethoxylated retinoid solution further comprises one or more selected from the group consisting of hydrocarbon oils, ester oils, natural oils, silicone oils, antioxidants, light stabilizers, anti-inflammatory agents, discoloration inhibitors, UV blocking agents, dyes and pigments. The method for producing surface-modified retinoid-loaded porous silica according to claim 6, wherein the porous silica has a diameter size of 1 to 50 μm. The method for producing surface-modified retinoid-loaded porous silica according to claim 6, wherein the reaction between the polyethoxylated retinoid-loaded porous silica and the silane-based compound is carried out at 40 to 120°C for 30 minutes to 5 hours. Silane compounds include triethoxycaprylylsilane, aminopropyl triethoxysilane, glycidoxypropyl trimethoxysilane, isobutyl triethoxysilane, perfluorooctylethyl triethoxysilane, perfluorooctyl triethoxysilane, and stearyl triethoxysilane. The method for producing a surface-modified retinoid-loaded porous silica according to claim 6, wherein the silane is one or more selected from the group consisting of methyltriethoxysilane, methyltriethoxysilane, PEG-8 methyl ether triethoxysilane, and vinylethoxysilane. The method for producing surface-modified retinoid-loaded porous silica according to claim 6, wherein the silane-based compound is mixed in an amount of 0.5 to 20% by weight relative to 100% by weight of the surface-modified retinoid-loaded porous silica. A cosmetic composition comprising the surface-modified retinoid-loaded porous silica according to claim 1.