CN115531230A

CN115531230A - Surface modified retinoid-loaded porous silica

Info

Publication number: CN115531230A
Application number: CN202210710367.7A
Authority: CN
Inventors: 权纯轼; 赵桓一; 宋荣淑
Original assignee: LG Household and Health Care Ltd
Current assignee: LG H&H Co Ltd
Priority date: 2021-06-29
Filing date: 2022-06-22
Publication date: 2022-12-30
Also published as: TW202317065A; WO2023277479A1; KR20230001874A

Abstract

The present invention relates to a surface-modified retinoid-supported porous silica, and more particularly, to a surface-modified retinoid-supported porous silica that can be used as an active ingredient of a functional cosmetic with improved stability and safety by increasing the loading efficiency of the retinoid by supporting the retinoid in a polyethoxylated form on the porous silica and then performing surface treatment with a silane-based compound, thereby improving the sustained-release efficiency.

Description

Surface-modified retinoid-supported porous silica

Technical Field

The present invention relates to low-irritation, surface-modified, retinoid-supported porous silicas with improved stability and safety.

Background

Vitamin a or its derivatives are currently known as representative substances for improving aged skin, and products containing them are being sold in large quantities. Vitamin a or its derivatives are known to increase fibroblast proliferation and collagen synthesis in the skin, and are widely used as an effective ingredient of wrinkle-functional cosmetics. However, vitamin a is fat-soluble, has a disadvantage of being unstable due to light, oxygen, heat, lipid peroxide, and thus a stabilization technique is necessary, and in product development, containers that block light and oxygen are also used to ensure stability. In addition, an excess of vitamin a or a derivative thereof is a substance that can increase skin sensitivity by sunlight. When consumers use cosmetics including vitamin a or its derivatives, the skin may be exposed to various forms of reddening, erythema, stinging, itching, etc. on the skin.

In order to improve the stability and safety of such vitamin a and its derivatives, an effort to improve the stability/safety by using various drug delivery systems of liposomes and the like has been made in korean registered patent (10-1314100) and the like. However, with such a drug delivery vehicle, not only the loading efficiency of the active ingredient is significantly low, but also a phenomenon in which the form of the drug delivery vehicle is temporarily collapsed or partially collapsed occurs in the preparation process of other auxiliary ingredients and dosage forms within the cosmetic dosage form. Therefore, the stability-improving effect of the retinoid is not so large, and the safety-improving effect by the sustained-release type release is still insufficient.

Disclosure of Invention

Technical subject

It is an object of the present invention to provide a low-irritation retinoid-supported porous silica having improved stability/safety and a method for preparing the same.

It is another object of the present invention to provide a cosmetic composition comprising the above low irritation retinoid-loaded porous silica.

Solution scheme

In order to achieve the above object, the present invention provides a retinoid-supported porous silica which is supported with a polyethyleneoxy retinoid and is surface-modified with a silane-based compound.

The present invention also provides a method for preparing a surface-modified retinoid-supported porous silica, comprising:

a step of mixing a polyethoxylated retinoid solution and porous silica to support the polyethoxylated retinoid in the porous silica; and

a step of reacting the porous silica loaded with the polyethoxylated retinoid with a silane-based compound to modify the surface of the porous silica.

The present invention also provides a cosmetic composition comprising the above surface-modified retinoid-supported porous silica.

ADVANTAGEOUS EFFECTS OF INVENTION

The present invention can improve the efficiency of loading retinoid in a polyethoxylated form on porous silica and then surface-treating the same with a silane compound to improve the efficiency of sustained release, thereby being useful as an active ingredient of a functional cosmetic with improved stability and safety.

Drawings

Fig. 1 shows a process for preparing the surface-modified retinoid-supported porous silica of the present invention.

Fig. 2 shows the results of the retinoid release behavior experiment of the surface-modified retinol-like loaded porous silica of the present invention in O/W (Oil in Water) dosage form using franz diffusion cell (franz diffusion cell), which is the results of the formulation in vitro skin absorption experiment.

Fig. 3 and 4 show the results of retinoid release behavior experiments in O/W dosage forms using the surface-modified retinoids-loaded porous silica of the present invention in franz diffusion cells (franz diffusion cells), as a result of skin uptake over the time of application of the dosage forms.

Fig. 5 is an in vivo consumer evaluation test result for the surface-modified retinoid-loaded porous silica of the present invention.

Fig. 6 is a diagram showing a powder obtained after charging a silane compound into porous silica (example 3) supporting a polyethoxylated retinoid, uniformly dispersing the same in a henschel mixer, and then reacting the same for 4 hours under a heat treatment temperature condition.

Detailed Description

The structure of the present invention will be specifically described below.

The present invention relates to a retinoid-supported porous silica which is supported with a polyethoxylated retinoid and surface-modified with a silane-based compound.

The present invention is characterized in that, for a vitamin a derivative, i.e., retinoid, 1) in order to improve the stability of the retinoid, porous silica having advantages that it is not easily decomposed/denatured by other ingredients within a cosmetic formulation, and the stability can be improved by reducing the light/oxygen exposure of the retinoid, and a high content of the retinoid can be loaded as compared to other drug delivery vehicles is used as a carrier, and 2) in order to improve the safety of the retinoid, the retinoid is dissolved in a sustained release type by surface-treating the surface of the porous silica with a silane compound.

According to one embodiment of the invention, the surface-modified retinoid-loaded porous silica of the invention and the retinoid not loaded on porous silica in O/W dosage forms were compared using a franz diffusion cell (franz diffusion cell) for the release behavior of the retinoid, and for the purpose of comparing the safety of the retinoid, the irritation index was confirmed by the HET-CAM test and consumer evaluation of the surface-modified retinoid-loaded porous silica powder. As a result, the application form of the surface-modified retinoid-loaded porous silica powder at 25 ℃ and 40 ℃ was stable even in 16 weeks, and the elution amount of retinoid decreased depending on the concentration of the silane compound, and the retinoid was slowly eluted, confirming the possibility of application as a sustained release preparation.

As the polyethoxylated retinoid, polyethoxylated retinoids (polyethoxylated retinoamides) can be used.

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

The silane compound may be triethoxyoctylsilane (triethoxycaprylsilane), aminopropyltriethoxysilane (Aminopropyl triethoxy silane), glycidyloxypropyltrimethoxysilane (Glycidoxypropyl triethoxy silane), isobutyltriethoxysilane (isobutoxytriethoxysilane), perfluorooctylethyltriethoxysilane (perfluorooxysilane), perfluorooctyltriethoxysilane (perfluorooxysilane), stearyltriethoxysilane (stearyltriethoxysilane), methyltriethoxysilane (Methyltriethoxysilane), PEG-8 methylethertriethoxysilane (PEG-8 triethoxyethylsilane), vinylethoxysilane (vinylethoxysilane), etc., alone or in combination.

The invention also relates to a preparation method of the surface modified retinoid-loaded porous silica, which comprises the following steps:

The surface-modified retinoid-supported porous silica of the present invention is characterized in that the retinoid having a hydrophilic portion is supported on the porous silica by PEGylation (PEGylation), and then surface-coated with a hydrophobic silane-based compound by heat treatment.

The method for preparing the surface-modified retinoid-supported porous silica of the present invention is specifically illustrated in the following steps.

The 1 st step is a step of supporting a polyethoxylated retinoid on porous silica.

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

The above-mentioned polyethoxylated retinoids can be blended 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 content of the remaining retinoid, which is not supported in the porous silica, increases, and thus the economy may be reduced.

The solvent may be methanol or ethanol. The content of the above solvent may be appropriately adjusted at the level of those skilled in the art according to the content of the retinoid, and thus is not particularly limited.

When the above retinoid solution is prepared, a hydrocarbon oil, ester oil, natural oil, silicone oil, antioxidant, light stabilizer, anti-inflammatory agent, discoloration inhibitor, ultraviolet blocker, dye, pigment, etc. may be further added as necessary.

Next, the polyethoxylated retinoid solution is slowly poured into the porous silica, and uniformly mixed for 10 minutes or more at normal temperature by a mixer, for example, a henschel mixer.

The above porous silica may have a diameter size of 1 to 50 μm. The oil absorption of the above porous silica can be at a level of 0.3 to 3cc/g of the raw material. The above porous silica may be mixed in an amount of 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-supported porous silica. When exceeding the above range, the porous silica powder can be prepared in a coagulated form without forming a uniform powder form. It can have an effect on stability when dispersed in other cosmetic formulations.

The 2 nd step is a step of modifying the surface of the porous silica supporting a polyethoxylated retinol by using a silane compound as a surface treatment (modifying) agent.

The silane-based compound was put into the porous silica loaded with the polyethoxylated retinoid prepared in the step 1, and uniformly mixed with a henschel mixer for about 10 minutes. Next, for surface treatment, heat treatment of reaction at 40 to 120 ℃ for 30 minutes to 5 hours, more specifically, reaction at 80 to 100 ℃ for 1 hour to 4 hours is performed, followed by cooling, to prepare a surface-modified retinoid-supported porous silica. When the heat treatment exceeds the above range, the surface treatment may not be normally performed at a low temperature, and discoloration of the retinoid and stability of other substances may be affected at a high temperature.

The amount to be mixed of the above silane-based 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 exceeding the above range, the amount of elution of the retinoid decreases, the effect of the retinoid decreases, or when being excessively increased, it may not be trapped inside the porous silica but exist on the silica surface.

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

The retinoid increases fibroblast proliferation and collagen synthesis in the skin, and thus the cosmetic composition of the present invention can be used for wrinkle-functional cosmetics.

In addition, the surface-modified retinoid-loaded porous silicas of the invention can be used in O/W dosage forms 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 exceeding the above range, the retinoid effect is not significant or may have an influence on stability and safety due to excessive use.

The cosmetic composition of the present invention can be prepared in the form of a general emulsifier-type or solubilized cosmetic. For example, there may be a formulation of a makeup lotion such as a smoothing lotion or a nourishing lotion, an emulsion such as a face lotion (facial lotion), a body lotion (body lotion), a cream such as a nourishing cream, a moisturizing cream, an eye cream, an essence, a makeup ointment, a spray, a gel, a mask, a sunscreen cream, a makeup base, a foundation of a liquid type, a solid type or a spray type, a powder, a makeup remover such as a cleansing cream (cleansing cream), a cleansing lotion (cleansing lotion), a cleansing foam, a soap, a body wash, or the like.

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 agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers, metal ion-blocking and chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles, or any other ingredients commonly used in cosmetics as auxiliary ingredients used in the preparation of general cosmetic compositions.

According to one embodiment of the present invention, the surface-modified retinoid-supported porous silica of the present invention may be used in powder form for O/W dosage forms, and the O/W dosage forms may be prepared by completely dissolving the oil-phase and water-phase components at 75 ℃ according to the composition of table 2 below, followed by primary emulsification using a homomixer, and secondary emulsification is performed by adding the surface-modified retinoid-supported porous silica powder of the present invention at 45 ℃.

Detailed description of the preferred embodiments

Hereinafter, the present invention is described in more detail by 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> preparation and application of surface-modified retinoid-loaded porous silica powder

The retinoids used to prepare the surface modified retinoid loaded porous silica use polyethoxylated retinoids. 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 charged in porous silica using a henschel mixer and uniformly mixed for 10 minutes. The porous silica used has a diameter of 1 to 50 μm, and the oil absorption of the porous silica is 0.3 to 3 cc/g. Triethoxyoctylsilane (triethoxycaprylsilane) was put into the once-prepared powder and uniformly mixed for 10 minutes using a henschel mixer. For surface treatment, the reaction was carried out at about 100 ℃ for 4 hours to carry out the surface treatment reaction, followed by cooling, to finally obtain a surface-modified retinoid-supported porous silica powder.

The prepared retinoid-loaded porous silica powder was applied to actual O/W dosage forms, and the compositions are shown in table 2. The preparation method is prepared by completely dissolving the oil phase and the aqueous phase at 75 ℃ and then performing primary emulsification using a homomixer, and the retinoid porous silica powder are subjected to secondary emulsification after being charged at 45 ℃.

[ Table 1]

Retinoid porous silica powder composition and surface treatment agent composition (% by weight)

The retinoid used in the present invention was Medimin A (average molecular weight 831) available from LSchem, SUNSIL-130 available from SUNJIN BEAUTY SCIENCE was used as porous silica, AES material available from shinetsu corporation was used as surface treatment agent, and Retinol 50C available from BASF was used as Retinol.

[ Table 2]

Retinoid porous silica powder application O/W dosage form composition (% by weight)

Composition of	Comparative example 4	Comparative example 5	Example 4
				Cetostearyl alcohol	2.25	2.25	2.25
Glycerol stearate	0.5	0.5	0.5
				Stearic acid	0.5	0.5	0.5
Macadamia nut seed oil	10	10	10
				PEG-40 stearate	1	1	1
Sorbitan stearate	1	1	1
				Polydimethylsiloxane	5	5	5
Purified water	Balance of	Balance of	Balance of
				Glycerol	25	25	25
1, 2-hexanediol	2	2	2
				Xanthan gum	0.1	0.1	0.1
Polyacrylate crosslinked Polymer-6	0.1	0.1	0.1
				Glycyrrhizic acid dipotassium salt	0.2	0.2	0.2
Comparative example 2 (No surface treatment)	-	5	-
				Example 3 (with surface treatment)	-	-	5
Retinoids	0.5	-	-

< Experimental example 1> comparative experiment for discoloration of retinol/retinoid

The powder obtained by charging a silane compound into porous silica loaded with polyethoxylated retinoid (example 3), uniformly dispersing the same in a henschel mixer, and then reacting the same at a heat treatment temperature for 4 hours is shown in fig. 6. As shown in comparative example 3, with retinol, discoloration occurred upon heat treatment, whereas with example 3, a pale yellow powder was obtained at a heat treatment temperature of 100 ℃. In contrast, when heat treatment is performed at a high temperature of 130 ℃ or higher, an orange powder is obtained.

< Experimental example 2> retinoid stability-improving effect

To confirm the stability of the retinoid, the titer over time (titer) analysis was performed on pure retinoid (comparative example 4), retinoid-loaded porous silica powder application formulation (comparative example 5), surface-modified retinoid-loaded porous silica powder application formulation (example 4).

As shown in table 3, it was confirmed that the stability was improved in the order of comparative example 4 < comparative example 5= example 4.

[ Table 3]

Comparison of retinoid stability

< experimental example 3> test of dissolution behavior of retinoid as sustained-release drug delivery body for improving safety (test of dissolution behavior of retinoid under solvent condition)

In order to observe the release behavior of retinoid, first dissolution test was performed on comparative example 2 and examples 1 to 3 using a solvent commonly used in cosmetics. 1, 3-butanediol (1, 3-butylene glycol) was used as a solvent, and after 5% of the powder of comparative example 2 and examples 1 to 3 was dispersed in the solvent, the powder was dissolved in a shaking incubator (shaking incubator) for one week. After one week, only the supernatant of the solvent was analyzed, and the amount of elution was calculated.

As shown in table 4, it was confirmed that all of the retinoid was eluted in comparative example 2 in which no surface treatment was performed, and that the retinoid was slowly eluted in examples 1 to 3 in which the surface treatment was performed using the sustained-release drug delivery device. In addition, the amount of elution of retinoids decreased depending on the concentration (2 to 7%) of triethoxyoctylsilane, and it was confirmed that the surface-modified retinoids porous silica powder has a possibility of application as sustained-release preparations.

[ Table 4]

Retinoid solvent elution amount (%) test

	Amount of elution (%)
		Comparative example 2	100％
Example 1	92％
		Example 2	49％
Example 3	38％

(retinoid Release behavior in O/W dosage forms)

In order to confirm the dissolution behavior of the retinoid in an actual cosmetic formulation and skin permeation, the formulation of comparative example 4 and the formulation of example 4 using the lowest dissolution amount were compared by a franz diffusion cell (Franze diffusion cell) experiment. Skin permeation device a device shown in the following figures was used, and the skin permeation device was constituted of a donor chamber (donor chamber) and a receptor chamber (receptor chamber) with skin interposed therebetween and then fixed (refer to fig. 2). Each cell (cell) used in the same experiment had a length of 2.54cm ² The same surface area of. The prepared skin was fixed to the skin permeation mechanism so that stratum corneum (stratum corneum) was positioned upward. The amount of the aqueous solution in the receptor chamber was 2.4mL, and stirring was performed at 300rpm so as not to affect the diffusion of the test substance. The concentration of the retinoid in this test was set to 196.85. Mu.g/cm ² And used. The amount of dosage form applied to maintain the maximum absorption rate in the skin was 39.370. Mu.l/cm ² So as to maintain a certain skin absorption state and be uniformly applied on the skin. After application of the test substance, the skin was collected at the time point of 6 hours/24 hours at which the experiment was ended, and the skin absorption rate was determined.

As shown in tables 5 and 6 and fig. 3 and 4, when comparing skin absorption at 6 hours, the content of the retinoid eluted with the sustained-release drug delivery body was less in example 4 compared to comparative example 4, but the same amount as that of the retinoid not supported on porous silica was confirmed as a result of comparing skin absorption at 24 hours. Thus, it could be confirmed that example 4 slowly dissolves the retinoid as a sustained release formulation, but is absorbed at a level similar to that of the retinoid not supported on porous silica, and may exhibit the same efficacy/effect.

[ Table 5]

Retinoid release behavior in O/W dosage forms using Franz diffusion cells (results of in vitro skin absorption test of dosage forms)

	Comparative example 4	Example 4
			Residual amount of skin (μ g/cm) ² )	58.886	56.739
Skin penetration amount (μ g/cm) ² )	2.349	2.314
			Skin absorption (. Mu.g/cm) ² )	61.235	59.053
Skin absorption rate (%)	31.107	29.999

[ Table 6]

Retinoid release behavior in O/W dosage forms using Franz diffusion cells (skin uptake by time of dosage application)

< Experimental example 4> safety improving effect of retinoid-loaded porous silica powder (in vitro HET-CAM test)

The safety-improving effect was investigated by evaluating the possibility of irritation of the eye mucosa by fertilized egg (fertile eg). The species and strain of fertilized eggs used were white leghorn (white leghorn, white egg). To examine the sensitivity of fertilized eggs, preliminary experiments were performed using Texapon (Texapon) as a standard substance, and the degree of bleeding and hemolysis were determined and compared with the experimental group. Criteria for stimulation were classified into weak stimulation (stimulation), moderate stimulation (stimulation), and strong stimulation (stimulation) and evaluated. To confirm the safety of the surface-modified retinoid-loaded porous silica powder, the HET-CAM test was performed on the samples of comparative example 1 and example 3.

As shown in table 7, it was confirmed that the irritation index of the example 3 sample in which the porous silica was supported and the surface was modified was lower than that of the comparative example 1.

[ Table 7]

HET-CAM test stimulation index comparison

Experimental group	Stimulation index
		Comparative example 1	8 (moderate irritation)
Example 3	4 (weak irritant, bright irritating)

(evaluation test for in vivo Consumer)

In order to investigate the safety improvement effect of the surface-modified retinoid porous silica powder, consumer irritation evaluation tests were performed using the samples of comparative example 5 and example 4. For evaluation, 25 female consumers were used once in the evening, and after one week of use, final stimulation evaluation was performed. The scale of the stimulus score is 5 points, and a higher score means a stronger stimulus intensity.

As shown in fig. 5, both comparative example 5 and example 4 were under 2 points, showing weak stimulation.

[ Industrial Applicability ]

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

Claims

1. A retinoid-supported porous silica which is supported with a polyethoxylated retinoid and surface-modified with a silane-based compound.

2. The retinoid-loaded porous silica according to claim 1, wherein the polyethoxylated retinoid comprises polyethoxylated retinoamide (polyethoxylated retinamide).

3. The retinoid-loaded porous silica according to claim 1, wherein the porous silica has a diameter size of 1 to 50 μm.

4. The retinoid-supported porous silica according to claim 1, wherein the silane-based compound is one or more selected from the group consisting of triethoxyoctylsilane (triethoxycaprylsilane), aminopropyltriethoxysilane (aminoprophyl triethyisilane), glycidyloxypropyltrimethoxysilane (glycidyloxypropyltrimethoxysilane), isobutyltriethoxysilane (isobutoxytriethoxysilane), perfluorooctylethyltriethoxysilane (perfluorooctyltriethoxysilane), perfluorooctyltriethoxysilane (perfluorooctyltriethoxysilane), PEG-8 methylethertriethoxysilane (PEG-8 ethyl triethanol Triethoxysilane), and vinylethoxysilane (vinylisilane).

5. The retinoid-supported porous silica according to claim 1, wherein the retinoid-supported porous silica is prepared by mixing a polyethoxylated retinoid solution and porous silica to support polyethoxylated retinoid within the porous silica, and reacting the polyethoxylated retinoid-supported porous silica with a silane-based compound to modify the surface of the porous silica.

6. A method for preparing a surface-modified retinoid-supported porous silica, comprising:

7. The method for preparing a surface-modified retinoid-supported porous silica according to claim 6, wherein the polyethoxylated retinoid comprises polyethoxylated retinoamide (polyethoxylated retinamide).

8. The method for preparing surface-modified retinoid-supported porous silica according to claim 6, wherein the polyethoxylated retinoid solution is prepared by dissolving polyethoxylated retinoid in a solvent under light blocking conditions.

9. The method for preparing surface-modified retinoid-supported porous silica according to claim 8, wherein the solvent is methanol or ethanol.

10. The method for preparing a surface-modified retinoid-supported 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, anti-discoloring agents, uv blockers, dyes, and pigments.

11. The method for preparing surface-modified retinoid-supported porous silica according to claim 6, wherein the porous silica has a diameter size of 1 to 50 μm.

12. The method for producing the surface-modified retinoid-supported porous silica according to claim 6, wherein the reaction of the polyethoxylated retinoid-supported porous silica and the silane-based compound is carried out at 40 to 120 ℃ for 30 minutes to 5 hours.

13. The method for preparing surface-modified retinoid-supported porous silica according to claim 6, wherein the silane-based compound is one or more selected from the group consisting of triethoxyoctylsilane (triethoxycaprylsilane), aminopropyltriethoxysilane (aminopropyltriethoxysilane), glycidyloxypropyltrimethoxysilane (Glycidoxypropyl trimethyoxysilane), isobutyltriethoxysilane (isobutyltriethyltriethoxysilane), perfluorooctylethyltriethoxysilane (perfluoroethylene Triethoxysilane), perfluorooctyltriethoxysilane (Perfluorooctyl triethoxy silane), PEG-8-methylethertriethoxysilane (PEG-8 Methyl Ether ethyl Ether) and vinyloxyethyl (vinyl ethyl Ether).

14. The method for producing the surface-modified retinoid-supported porous silica according to claim 6, wherein the silane compound is mixed in an amount of 0.5 to 20 wt% relative to 100 wt% of the surface-modified retinoid-supported porous silica.

15. A cosmetic composition comprising the surface-modified retinoid-supported porous silica of claim 1.