TW202317065A - Surface modified retinoid immersion porous silica - Google Patents

Abstract

The present invention relates to a surface-modified retinoid-impregnated porous silica. More specifically, the present invention is characterized in that porous silica is impregnated with a polyethoxylated retinoid and then surface-treated with a silane-based compound to increase the impregnation efficiency of the retinoid and improve sustained release efficiency, and thus can be used as an active ingredient in functional cosmetics having improved stability and safety.

Description

Surface-modified retinoid-loaded porous silica

The present invention relates to low irritation surface modified retinoid loaded porous silica with improved stability and safety.

Vitamin A or its derivatives are currently known representative substances for improving aging skin, and products containing them are being sold in large quantities. It is reported that vitamin A or its derivatives increase the proliferation of fibroblasts and collagen synthesis in the skin, and are widely used as active ingredients in functional cosmetics for wrinkles. However, vitamin A is fat-soluble and has the disadvantage of being unstable due to light, oxygen, heat, and lipid peroxides. Therefore, stabilization technology is necessary, and during product development, containers that block light and oxygen should also be used. Containers ensure stability. In addition, excessive vitamin A or its derivatives are substances that can increase skin sensitivity to sunlight. When consumers use cosmetics containing vitamin A or its derivatives, it will appear on the skin in various forms such as skin redness, erythema, tingling, itching, and the like.

In order to improve the stability and safety of such vitamin A and its derivatives, efforts have been made to improve stability/safety by utilizing various drug delivery systems such as liposomes in Korean Registered Patent (10-1314100) and the like. However, for this kind of drug delivery carrier, not only the loading efficiency of the active ingredient is significantly low, but also the form of the drug delivery carrier may temporarily collapse or partially collapse during the preparation process of other auxiliary ingredients in the cosmetic dosage form and the dosage form. Therefore, the effect of improving the stability of retinoids is not large, and the effect of improving safety by sustained-release type release is still insufficient.

[Technical Issues]

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

Another object of the present invention is to provide a cosmetic composition comprising the above-mentioned low-irritation retinoid-loaded porous silica. [solution]

In order to achieve the above object, the present invention provides a retinoid-loaded porous silica, which is loaded with polyethoxylated retinoid and surface-modified by silane compounds.

The present invention also provides a preparation method of surface-modified retinoid-loaded porous silica, comprising: a step of mixing the polyethoxylated retinoid solution and the porous silica to load the polyethoxylated retinoid in the porous silica; and A step of modifying the surface of the porous silica by reacting the polyethoxylated retinoid-loaded porous silica with a silane compound.

The present invention also provides a cosmetic composition comprising the above-mentioned surface-modified retinoid-loaded porous silica. [Effect of the invention]

The present invention can improve the loading efficiency of retinoids by loading polyethoxylated retinoids on porous silicon dioxide and then surface-treating them with silane compounds, and improve the sustained-release release efficiency, so as to be used as Active ingredients for functional cosmetics with improved stability and safety.

Hereinafter, the structure of this invention is demonstrated concretely.

The invention relates to a retinoid-loaded porous silicon dioxide, which is loaded with polyethoxylated retinoid and surface-modified by silane compounds.

The present invention is characterized in that, for vitamin A derivatives, ie, retinoids, 1) in order to improve the stability of retinoids, it is difficult to decompose/denature due to other ingredients in the cosmetic formulation, and it can be reduced by reducing the retinoids. Light/oxygen exposure of retinoids to improve stability, and porous silica as a carrier that can load high content of retinoids compared to other drug delivery vehicles, and 2) in order to improve retinoids Alcohol safety, by surface-treating the surface of porous silica with silane compounds to dissolve retinoids in a sustained release type.

According to a specific example of the present invention, for the release behavior of retinoids, the surface-modified retinoid-loaded porous dioxide of the present invention in O/W dosage forms was compared using a Franz diffusion cell. Silicon and retinoids not loaded on porous silica, and to compare the safety of retinoids by HET-CAM testing and consumer evaluation of surface-modified retinoid-loaded porous silica powders Stimulus index confirmed. As a result, the application dosage form of the surface-modified retinoid-loaded porous silica powder was stable even for 16 weeks at 25°C and 40°C, and the amount of retinoid eluted was reduced depending on the concentration of the silane compound , to slowly dissolve the retinoid, thereby confirming the possibility of application as a sustained-release preparation.

As the above-mentioned polyethoxylated retinoid, polyethoxylated retinamide (polyethoxylated retinamide) can be used.

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

The above-mentioned silane compounds can be independently used triethoxycaprylylsilane (Triethoxycaprylylsilane), aminopropyl triethoxysilane (Aminopropyl Triethoxysilane), glycidyl etheroxypropyl trimethoxysilane (Glycidoxypropyl Trimethoxysilane), isobutyl Isobutyltriethoxysilane, Perfluorooctylethyl Triethoxysilane, Perfluorooctyl Triethoxysilane, Stearyl Triethoxysilane ), Methyltriethoxysilane, PEG-8 Methyl Ether Triethoxysilane, Vinylethoxysilane, etc., or two or more .

The present invention also relates to a preparation method of surface-modified retinoid-loaded porous silica, comprising: a step of mixing the polyethoxylated retinoid solution and the porous silica to load the polyethoxylated retinoid in the porous silica; and A step of modifying the surface of the porous silica by reacting the polyethoxylated retinoid-loaded porous silica with a silane compound.

The surface-modified retinoid-supported porous silica of the present invention is characterized in that a retinoid having a hydrophilic portion is supported on the porous silica by PEGylation, and then the hydrophobicity is reduced by heat treatment. prepared by surface coating of silane compounds.

The preparation method of the surface-modified retinoid-loaded porous silica of the present invention is described in detail as follows.

The first step is a step of loading polyethoxylated retinoid on porous silica.

For this, first, polyethoxylated retinoid was uniformly dissolved in a solvent under light-blocking conditions to prepare a retinoid solution.

The above polyethoxylated retinoid may be mixed in an amount of 0.5 to 20% by weight, more specifically 5 to 15% by weight, relative to 100% by weight of the surface-modified retinoid-supported porous silica. When the above range is exceeded, the residual retinoid content that is not supported in the porous silica increases, and thus the economical efficiency may decrease.

Methanol or ethanol can be used as the above-mentioned solvent. The content of the above-mentioned solvent can be appropriately adjusted according to the content of the retinoid at the level of those skilled in the art, and thus is not particularly limited.

When preparing the above retinoid solution, hydrocarbon oils, ester oils, natural oils, silicone oils, antioxidants, light stabilizers, anti-inflammatory agents, anti-tarnish agents, UV blockers, dyes, pigments can be further added as needed wait.

Next, the polyethoxylated retinoid solution is slowly poured into the porous silica, and uniformly mixed at room temperature for more than 10 minutes using a mixer such as a Henschel mixer.

The aforementioned porous silica may have a diameter size of 1 to 50 μm. The oil absorption of the above-mentioned porous silica can use a raw material at the level of 0.3 to 3 cc/g. With respect to 100% by weight of the surface-modified retinoid-loaded porous silica, the mixing amount of the above-mentioned porous silica may be 50 to 99% by weight, preferably 60 to 99% by weight, more preferably 65 to 94% by weight. When the above range is exceeded, the porous silica powder may be prepared in an agglomerated form without forming a uniform powder form. It can have an impact on stability when dispersed in other cosmetic formulations.

The second step is a step of modifying the surface of the porous silica loaded with polyethoxylated retinoid using a silane compound as a surface treatment (modification) agent.

Put the silane compound into the polyethoxylated retinoid-loaded porous silica prepared in the first step, and mix uniformly for about 10 minutes with a Henschel mixer. Next, for surface treatment, heat treatment of reacting at 40 to 120° C. for 30 minutes to 5 hours, more specifically, reacting at 80 to 100° C. for 1 hour to 4 hours, followed by cooling to prepare a surface-modified retinoid Alcohol-loaded porous silica. When the heat treatment exceeds the above range, the surface treatment may not be performed normally at low temperature, and the discoloration of retinoid and the stability of other substances may be affected at high temperature.

The compounding amount of the above-mentioned silane compound may be 0.5 to 20% by weight, more specifically 1 to 15% by weight, relative to 100% by weight of the surface-modified retinoid-supported porous silica. When the above range is exceeded, the eluted amount of retinoid decreases and the effect of retinoid decreases, or when it is very excessive, it may not be trapped inside porous silica and may exist on the surface of silica.

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

Retinoids increase the proliferation of fibroblasts and collagen synthesis in the skin, so the cosmetic composition of the present invention can be used for functional cosmetics for wrinkles.

In addition, the surface-modified retinoid-loaded porous silica of the present invention can be used in O/W dosage form in powder form. The content of the surface-modified retinoid-supported porous silica of the present invention may be 0.01 to 5% by weight, more specifically 0.05 to 4% by weight, relative to 100% by weight of the cosmetic composition. When the above range is exceeded, the effect of the retinoid is not significant, or the stability and safety may be affected due to excessive use.

The cosmetic composition of the present invention can be prepared as a general emulsified formulation or a solubilized formulation. For example, there may be lotions such as skin toner or nourishing lotion, lotions such as facial lotion and body lotion, creams such as nourishing cream, moisturizing cream, eye cream, essence, cosmetic ointment, Spray, gel, mask, sunscreen, primer, liquid, solid or spray foundation, powder, such as cleansing cream, cleansing lotion, cleansing oil and other makeup removers, such as cleansing foam, soap, body wash and other detergents.

In addition, the cosmetic composition of the present invention may contain adjuvants commonly used in the field of cosmetics, such as fatty substances, organic solvents, solubilizers, concentrating and gelling agents, emollients, antioxidants, suspending agents, stabilizers, Foaming agent, fragrance, surfactant, water, ionic or nonionic emulsifier, filler, metal ion blocker and chelating agent, preservative, vitamin, blocking agent, wetting agent, Essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or any other ingredients commonly used in cosmetics are used as auxiliary ingredients in the preparation of general cosmetic compositions.

According to a specific example of the present invention, the surface-modified retinoid-loaded porous silica of the present invention can be used in O/W dosage form in powder form, and the O/W dosage form can be formulated according to the following Table 2 at 75 Dissolve the oil phase and water phase components completely at ℃, and then use a homomixer to perform primary emulsification, and add the surface-modified retinoid-loaded porous silica powder of the present invention at 45 °C for secondary emulsification. preparation.

Implementation

Hereinafter, the present invention will be described in more detail through examples according to the present invention, but the scope of the present invention is not limited to the examples given below.

<Example 1> to <Example 4> Surface-modified retinoid-loaded porous silica powder preparation and application dosage form

The retinoid used to prepare the surface-modified retinoid-loaded porous silica used polyethoxylated retinamide. As shown in the composition of Table 1, the retinoid and ethanol were uniformly dissolved under light-blocking conditions, and then the prepared retinoid solution was slowly poured into the porous silica using a Henschel mixer and mixed uniformly 10 minutes. The size of the porous silica uses a diameter of 1 to 50 μm, and the oil absorption of the porous silica uses a material at the level of 0.3 to 3 cc/g. Put triethoxycaprylylsilane (triethoxycaprylylsilane) into the powder made at one time and mix uniformly for 10 minutes with a Henschel mixer. For surface treatment, react at about 100° C. for 4 hours to implement the surface treatment reaction, and then cool to finally obtain surface-modified retinoid-loaded porous silica powder.

The prepared retinoid-loaded porous silica powder was applied to the actual O/W dosage form, and the composition is shown in Table 2. The preparation method is prepared by completely dissolving the oil phase and the water phase at 75 ° C, and then using a homomixer to perform primary emulsification, and after putting the retinoid and retinoid porous silica powder at 45 ° C, carry out secondary emulsification. secondary emulsification.

[Table 1] Retinoid Porous Silica Powder Composition and Surface Treatment Agent Composition (% by weight) composition Comparative example 1 Comparative example 2 Comparative example 3 Example 1 Example 2 Example 3 Retinoids (polyethoxylated retinamides) 10 10 - 10 10 10 Retinol - - 10 - - - porous silica - 70 70 70 70 70 Surface treatment agent (triethoxyoctylsilane) - - 7 2 5 7 ethanol margin margin margin margin margin margin

The retinoid used in the present invention is Medimin A (average molecular weight 831) manufactured by LSchem Co., Ltd., the porous silica is sunsil-130 manufactured by SUNJIN BEAUTY SCIENCE, and the surface treatment agent is AES raw material of Shinetsu Corporation. As the alcohol, Retinol 50C from BASF was used.

[Table 2] Retinoid porous silica powder application O/W dosage form composition (weight %) composition Comparative example 4 Comparative Example 5 Example 4 cetearyl alcohol 2.25 2.25 2.25 Glyceryl Stearate 0.5 0.5 0.5 stearic acid 0.5 0.5 0.5 Macadamia Seed Oil 10 10 10 PEG-40 stearate 1 1 1 Sorbitan Stearate 1 1 1 Polydimethylsiloxane 5 5 5 pure water margin margin margin glycerin 25 25 25 1,2-Hexanediol 2 2 2 xanthan gum 0.1 0.1 0.1 Polyacrylate Crosspolymer-6 0.1 0.1 0.1 Dipotassium glycyrrhizinate 0.2 0.2 0.2 Comparative example 2 (no surface treatment) - 5 - Embodiment 3 (surface treatment is arranged) - - 5 Retinoids 0.5 - -

＜Experimental example 1＞ Retinol/retinoid discoloration comparative experiment

The silane compound is put into the porous silica loaded with polyethoxylated retinoid (Example 3), uniformly dispersed by Henschel mixer, and then reacted under heat treatment temperature for 4 hours to obtain The powders are shown in Table 3. As shown in Comparative Example 3, in the case of retinol, discoloration occurred upon heat treatment, whereas in Example 3, a pale yellow powder was obtained when the heat treatment temperature was 100°C. On the contrary, an orange powder is obtained when heat treatment is performed at high temperature above 130 °C.

[table 3]

＜Experimental example 2＞ Retinoid stability improvement effect

In order to confirm the stability of retinoid, pure retinoid (comparative example 4), retinoid-loaded porous silica powder application formulation (comparative example 5), surface-modified retinoid-loaded porous The silica powder application dosage form (Example 4) was subjected to titer analysis over time.

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

[Table 4] Retinoid Stability Comparison Comparative example 4 Comparative Example 5 Example 4 4 weeks 25°C 100 100 100 40°C 100 100 100 16 weeks 25°C 82.69 100 100 40°C 71.15 100 100

<Experimental Example 3> Dissolution behavior test of retinoid as a sustained-release drug delivery body for improving safety (dissolution behavior test of retinoid according to solvent conditions)

In order to observe the release behavior of retinoids, the first dissolution test was carried out for Comparative Example 2 and Examples 1 to 3 using solvents commonly used in cosmetics. 1,3-butanediol (1,3-butylene glycol) was used as the solvent, and after the powders of Comparative Example 2 and Examples 1 to 3 were dispersed in the solvent by 5%, they were placed in a shaking incubator (shaking incubator) within one week. ) for one week. After one week, only the supernatant of the solvent was analyzed and the amount dissolved was calculated.

As shown in Table 5, it can be confirmed that in Comparative Example 2 without surface treatment, all the retinoids were eluted, and in Examples 1 to 3 with surface treatment, it was confirmed that the retinoids were slowly eluted with the sustained-release drug delivery body. In addition, the amount of elution of retinoid decreased depending on the concentration of triethoxyoctylsilane (2~7%), thus confirming that the surface-modified retinoid porous silica powder has the function of sustained release. Possibility of application of formulations.

[Table 5] Retinoid Solvent Dissolution (%) Test Dissolution (%) Comparative example 2 100% Example 1 92% Example 2 49% Example 3 38% (Retinoid Release Behavior Experiment in O/W Dosage Form)

In order to confirm the retinoid dissolution behavior and skin penetration in the actual cosmetic dosage form, the dosage form of Comparative Example 4 was compared with Example 4 with the lowest dissolution amount of Example 3 by using a Franz diffusion cell experiment. dosage form. The skin penetration device uses the device shown in the figure below. The skin penetration device is composed of a donor chamber and a receptor chamber, and the skin is placed between them and then fixed (see Figure 2). Each cell used in the same experiment had the same surface area of 2.54 cm ² . The prepared skin is secured to the skin penetration device with the stratum corneum positioned upwards. The volume of aqueous solution in the receptor chamber is 2.4 mL, and it is stirred at 300 rpm so as not to affect the diffusion of the test substance. The concentration of retinoid in this test was set at 196.85 μg/cm ² and used. In order to maintain the maximum absorption rate in the skin, the amount of the dosage form applied is 39.370 μl/cm ² to maintain a certain state of skin absorption, and evenly spread on the skin. After the test substance was applied, the skin was collected at the time point of 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, compared with Comparative Example 4 in Example 4, the content of the retinoid eluted with the sustained-release drug delivery body is less, However, as a result of comparing the amount of skin absorption in 24 hours, it was confirmed that the same amount was absorbed as retinoids not supported on porous silica. Therefore, it was confirmed that Example 4 elutes retinoid slowly as a sustained-release preparation, but is absorbed at a level similar to that of retinoid not supported on porous silica, and can exhibit the same efficacy/effect.

[Table 6] Retinoid release behavior test in O/W dosage form using Franz diffusion cell (results of dosage form in vitro skin absorption test) Comparative example 4 Example 4 Skin residue (μg/cm ² ) 58.886 56.739 Skin penetration (μg/cm ² ) 2.349 2.314 Skin absorption (μg/cm ² ) 61.235 59.053 Skin absorption rate (%) 31.107 29.999

[Table 7] Retinoid release behavior test in O/W dosage form using Franz diffusion cell (skin absorption amount according to dosage form application time) Comparative example 4 Example 4 Skin absorption (μg/cm ² ) 6 hours 10.003 6.222 24h 61.235 59.053 Skin absorption rate (%) (24 hours) 31.107 29.999

<Experimental Example 4> Safety improvement effect of retinoid-loaded porous silica powder (in vitro HET-CAM test)

The safety improvement effect was studied by evaluating the possibility of ocular mucous membrane irritation of fertilized eggs. The species and strain of fertilized eggs used were white leghorn (white egg). In order to check the sensitivity of fertilized eggs, a preliminary experiment was carried out using Texapon as a standard substance to determine the degree of bleeding and hemolysis, and compared with the experimental group. The criteria for judging irritation are divided into slightly irritating, moderately irritating, irritating, and severely irritating and evaluated. In order to confirm the safety of the surface-modified retinoid-loaded porous silica powder, HET-CAM tests were carried out on the samples of Comparative Example 1 and Example 3.

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.

[Table 8] HET-CAM Test Stimulation Index Comparison Experimental group stimulus index Comparative example 1 8 (moderately irritating) Example 3 4 (weakly irritating, slightly irritating)

(In Vivo Consumer Tasting Test)

In order to study the safety improvement effect of the surface-modified retinoid porous silica powder, a consumer irritation test was carried out using the samples of Comparative Example 5 and Example 4. For evaluation, take 25 female consumers as objects, use it once in the evening, and conduct final stimulation evaluation after using it for a week. Stimulus evaluation scale is a 5-point scale, the higher the score, the stronger the intensity of the stimulus.

As shown in FIG. 5 , both of Comparative Example 5 and Example 4 were 2 points or less, showing weak stimulation.

[Industrial Utilization Possibility]

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

[ Fig. 1 ] shows the production process of the surface-modified retinoid-supported porous silica of the present invention. [Fig. 2] Showing the surface-modified retinoid-loaded porous silica of the present invention in an O/W (Oil in Water type) dosage form using a Franze diffusion cell The results of the retinoid release behavior test are the results of the in vitro skin absorption test of the dosage form. [ FIG. 3 ] and [ FIG. 4 ] show the retinoid release of the surface-modified retinoid-loaded porous silica of the present invention in an O/W dosage form using a Franze diffusion cell The results of behavioral experiments are the results of skin absorption according to the application time of dosage forms. [ Fig. 5 ] is the in vivo consumer evaluation test result of the surface-modified retinoid-loaded porous silica of the present invention.

Claims (15)

A retinoid-loaded porous silica loaded with polyethoxylated retinoid and surface-modified by silane compounds. The retinoid-loaded porous silica according to claim 1, wherein the polyethoxylated retinoid comprises polyethoxylated retinamide. The retinoid-loaded porous silica according to claim 1, wherein the porous silica has a diameter of 1 to 50 μm. The retinoid-loaded porous silica as described in claim 1, wherein the silane compound is selected from triethoxycaprylylsilane, aminopropyl triethoxysilane, Glycidoxypropyl Trimethoxysilane, Isobutyltriethoxysilane, Perfluorooctylethyl Triethoxysilane, Perfluorooctyltriethoxysilane Perfluorooctyl Triethoxysilane, Stearyl Triethoxysilane, Methyltriethoxysilane, PEG-8 Methyl Ether Triethoxysilane ) and Vinylethoxysilane (Vinylethoxysilane) in the group consisting of more than one. The retinoid-loaded porous silica as described in claim 1, wherein the retinoid-loaded porous silica is mixed with polyethoxylated retinoid solution and porous silica to convert polyethoxylated Prepared by loading polyethoxylated retinoids in porous silica and reacting porous silica loaded with polyethoxylated retinoids with silane compounds to modify the surface of porous silica . A method for preparing surface-modified retinoid-loaded porous silica, comprising: a step of mixing the polyethoxylated retinoid solution and porous silica to load the polyethoxylated retinoid within the porous silica; and A step of modifying the surface of the porous silica by reacting the porous silica loaded with the polyethoxylated retinoid and a silane compound. The method for preparing surface-modified retinoid-loaded porous silica as described in Claim 6, wherein the polyethoxylated retinoid comprises polyethoxylated retinamide (polyethoxylated retinamide) . The method for preparing surface-modified retinoid-loaded porous silica as described in Claim 6, wherein the polyethoxylated retinoid solution is prepared by adding polyethoxylated Prepared by dissolving retinoids in a solvent. The method for preparing surface-modified retinoid-loaded porous silica as claimed in item 8, wherein the solvent is methanol or ethanol. The method for preparing surface-modified retinoid-loaded porous silica as described in claim 6, wherein the polyethoxylated retinoid solution also contains a compound selected from hydrocarbon oil, ester oil, natural oil , silicone oil, antioxidant, light stabilizer, anti-inflammatory agent, anti-tarnish agent, UV blocker, dye and pigment group consisting of more than one. The method for preparing surface-modified retinoid-loaded porous silica according to claim 6, wherein the porous silica has a diameter of 1 to 50 μm. The method for preparing surface-modified retinoid-loaded porous silica as described in claim 6, wherein the porous silica loaded with the polyethoxylated retinoid and the silane compound are The reaction is carried out at 40 to 120°C for 30 minutes to 5 hours. The preparation method of surface-modified retinoid-loaded porous silica as described in claim 6, wherein the silane compound is selected from triethoxycaprylylsilane (Triethoxycaprylylsilane), aminopropyltriethoxy Aminopropyl Triethoxysilane, Glycidoxypropyl Trimethoxysilane, Isobutyltriethoxysilane, Perfluorooctylethyl Triethoxysilane , Perfluorooctyl Triethoxysilane (Perfluorooctyl Triethoxysilane), Stearyl Triethoxysilane (Stearyl Triethoxysilane), Methyltriethoxysilane (Methyltriethoxysilane), PEG-8 methyl ether triethoxysilane (PEG-8 Methyl Ether Triethoxysilane) and Vinylethoxysilane (Vinyltriethoxysilane) group consisting of more than one. The method for preparing surface-modified retinoid-loaded porous silica as described in Claim 6, wherein, relative to 100% by weight of the surface-modified retinoid-loaded porous silica, the amount of silane compound The blending amount is 0.5 to 20% by weight. A cosmetic composition comprising the surface-modified retinoid-loaded porous silica as described in Claim 1.

Images