KR102594170B1 - Soluble microneedle patch for delivery of hydroquinone - Google Patents

Abstract

The present invention relates to a skin administration system for hydroquinone that can stably impregnate hydroquinone and effectively deliver it into the skin, as well as reduce the skin irritation side effects of hydroquinone. It is a technical feature. More preferably, hydroquinone is included in the soluble microneedles in the skin. The present invention also provides a method for dermal administration of hydroquinone characterized by using such microneedles. Microneedles according to the present invention are very effective in skin whitening.

Description

Soluble microneedle patch for delivery of hydroquinone}

The present invention relates to a system for effectively delivering hydroquinone, an active ingredient, to the skin, and particularly to a system for effectively delivering hydroquinone to the skin while improving the problems of chemical instability and skin irritation of hydroquinone.

Hydroquinone (Benzene-1,4-diol) strongly inhibits the activity of tyrosinase, which is involved in the formation of melanin, a major factor in skin color. However, hydroquinone is molecularly unstable and is easily destabilized by physical or chemical factors such as light, oxygen, pH, etc., turns brown, and its activity is easily reduced. Due to these unstable characteristics, hydroquinone has so far been applied only in gels or ointments, and even when applied, the stability of hydroquinone in gels or ointments is not good. In addition, there was a trend to use only airtight containers that block light and air in consideration of light and other environmental factors for storage containers for storing hydroquinone.

In addition, hydroquinone is mainly applied to the skin for the purpose of exerting a skin whitening effect by inhibiting the activity of tyrosinase. When hydroquinone is applied to the skin for a long period of time, side effects such as skin rash, itching, and folliculitis due to dermatitis can occur. This is often reported, and there is a problem that it may cause serious side effects such as abnormal proliferation of the skin layer and increased keratinization.

Republic of Korea Patent Publication No. 10-2003-0082765 (published on October 23, 2003) Republic of Korea Patent Publication No. 10-0793615 (announced on January 10, 2008) International Patent Application Publication WO 02/064193 (published on August 22, 2002)

Therefore, the problem to be solved by the present invention is to provide products, especially cosmetics, that can efficiently deliver hydroquinone into the skin while ensuring the stability of hydroquinone and reducing skin side effects.

In order to solve the above problems, the present invention provides a microneedle containing hydroquinone as an active ingredient inside a microneedle (microneedle) and a hydroquinone delivery system having such microneedles, and more preferably, the microneedle. The material forming the needle decomposes and/or dissolves within the skin, providing a microneedle that releases the hydroquinone contained therein by dissolving or disintegrating the microneedle when the microneedle is applied to the skin. That is, preferably, the present invention contains hydroquinone as an active ingredient, and in the cosmetic for skin whitening, the cosmetic is characterized by comprising microneedle soluble in the skin containing hydroquinone inside the microneedle. We provide cosmetics that

When a microneedle containing hydroquinone as an active ingredient is applied to the skin, the hydroquinone component penetrates into the skin by the microneedle, and the hydroquinone component is delivered into the skin as the microneedle is dissolved by moisture in the skin. Through this, the hydroquinone component can be effectively delivered into the skin.

The present inventors studied various administration systems, and it was difficult for any system to simultaneously solve the various problems of hydroquinone mentioned above. After many efforts, the present inventors secured the stability of hydroquinone by including hydroquinone in soluble microneedle in the skin, and were able to efficiently achieve the desired skin whitening effect while reducing skin irritation. was confirmed and the present invention was completed. In particular, in the case of microneedles at the beginning of the study, it was expected that skin irritation would be greater due to their physical stimulation, but when hydroquinone was included in a typical skin-applied topical composition and applied directly to the skin, the irritation that occurred was due to the physical stimulation of the microneedles. It showed surprising results that exceeded the skin irritation that occurred.

In addition, the present inventors completed the present invention by confirming that hydroquinone maintains stability during the manufacturing process of a conventional microneedle patch and also within soluble microneedles during storage, making it useful for applying a microneedle system.

The length of the microneedle according to the present invention is not limited to a specific size. However, for the purpose of the present invention, which aims to administer hydroquinone to the skin for the whitening effect, the vertical length of the microneedle is preferably 0.05 to 2.5 mm, and more preferably 0.1 to 2.0 mm.

In order to achieve the desired effect of the present invention, the material forming the microneedles biodegrades or dissolves within the skin, and when the microneedles are applied to the skin, the microneedles dissolve or collapse, thereby dissolving the hydroquinone contained within the microneedles (microneedles). This is preferably released into the skin.

Preferably, hydroquinone, the active ingredient according to the present invention, is contained in a dispersed form inside the microneedles. When impregnated in dispersed form, hydroquinone exists between biodegradable or skin-soluble substances that form microneedles.

These microneedles are manufactured using materials and manufacturing methods described, for example, in Korean Patent Publication No. 10-0793615, International Patent Application Publication WO 02/064193, and Korean Patent Publication No. 10-2011-0065361. It can be.

More specifically, for the dermal administration of hydroquinone according to the present invention, the microneedles are preferably made of materials that dissolve in the skin rather than biodegradable polymers, and such components include hyaluronic acid and sodium carboxymethyl. Cellulose (sodium carboxymethyl cellulose), vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, saccharide, or mixtures thereof may be used. The sugar may be xylose, sucrose, maltose, lactose, trehalose, or a mixture thereof.

Among these microneedle-forming materials, the skin penetration strength of the microneedles and the dissolution rate in the skin are comprehensively considered, and in particular, the stability of hydroquinone during the microneedle manufacturing process and compatibility with hydroquinone are considered. Considering comprehensively, the material for forming the microneedles is preferably a mixture of hyaluronic acid, sodium carboxymethylcellulose, and sugar, and in this mixture, the sugar is even more preferably trehalose.

In the present invention, the hydroquinone may be included in an amount of 0.1 to 5% by weight, preferably 0.2 to 4% by weight, based on the weight of the preparation solution for manufacturing microneedles, relative to the total weight of the preparation solution. It may contain 0.3 to 3% by weight. If it is included in less than 0.1% by weight, it may not have an effective effect, and if it is included in more than 5% by weight, it may affect the physical properties and durability of the microneedle, which is undesirable.

Preferably, the microneedles according to the present invention may further contain plasticizers, surfactants, preservatives, anti-inflammatory agents, antioxidants, etc. in addition to the hydroquinone and microneedle structure-forming materials mentioned above.

The plasticizer includes, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin. It can be used alone or in combination.

The antioxidants include sodium metabisulfite, dibutylhydroxytoluene, tocopherol, dibutylhydroxyanisole, ascorbyl palmitate, etc., which may be used alone or in combination, but are not limited thereto. When the microneedle of the present invention further contains such antioxidants along with hydroquinone, the stability of hydroquinone can be further improved.

The present invention provides not only the hydroquinone-containing microneedles themselves, but also a microneedle patch with a plurality of such microneedles attached. The size of the patch is not limited to a specific size and can be appropriately adjusted depending on the amount of hydroquinone to be absorbed into the skin or the attachment site.

The present invention also provides a method for improving skin whitening, characterized by applying microneedles containing hydroquinone as an active ingredient to the skin according to the present invention. For example, a method of applying or using such microneedles involves forming a certain number of holes in the skin by using a microneedle device, such as a roller with microneedles attached according to the present invention, and forming soluble microneedles. This can be used as a method to allow it to remain on the skin.

The present invention provides a skin whitening product containing hydroquinone as an active ingredient, particularly a skin whitening cosmetic, which is improved in terms of stability, skin irritation, and whitening effect. The present invention is applied to the skin by impregnating hydroquinone with biodegradable or soluble in the skin, more preferably soluble in the skin microneedles, so that the hydroquinone penetrates into the skin by the microneedles, and the microneedles are dissolved in the skin by moisture in the skin. This allows the active ingredients to be efficiently delivered to the target area.

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention along with the contents of the above-described invention. Therefore, the present invention is limited to the matters described in such drawings. It should not be interpreted in a limited way.
1 is a diagram showing an example of several methods for manufacturing a microneedle according to the present invention. Dissolvable microneedles can be manufactured by a solution casting method, by casting a solution in which the microneedle-forming material is dissolved into a mold and filling the micromold with the solution by vacuum and/or centrifugation. It can be manufactured by drying. As materials forming the microneedle structure, various materials well known to those skilled in the art may be used, and general biocompatible synthetic polymers, natural water-soluble polymers, etc. may be used.
Figure 2 shows a Franz diffusion cell for evaluating the hydroquinone release behavior of the microneedle according to the present invention.
Figure 3 is a graph showing the results of hydroquinone release evaluation from microneedles, evaluated using a Franz diffusion cell equipped with pig skin.
Figure 4 shows the results of comparing and evaluating the effects of the hydroquinone-containing cream used as a comparative example and the hydroquinone-containing microneedle patch according to the present invention, and shows the results of melanin index measurement using a colorimeter.

Hereinafter, to aid understanding of the present invention, it will be described in detail through examples. However, the embodiments according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1: Preparation of soluble microneedles containing hydroquinone

According to Table 1 below, a microneedle patch impregnated with hydroquinone was prepared using a method well known to those skilled in the art. In this specification, the content of the compositions is expressed in weight percent unless otherwise specified.

(Unit: weight%) Example 1 oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 Dipropylene glycol 5 Sodium metabisulfite 0.03 hydroquinone 1.5 water To 100

More specifically, a soluble microneedle patch impregnated with hydroquinone was prepared as follows. First, a solution was prepared by dissolving Oligo-HA (hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose), trehalose, glycerin, dipropylene glycol, sodium metabisulfite, and hydroquinone in purified water. The resulting microneedle manufacturing solution was casted into a silicon microneedle mold, centrifuged at 3000 rpm for 10 minutes, and the solution was filled into the micromold.

After filling the solution, it was dried in a drying oven (70°C) for 3 hours, and the manufactured microneedles were separated from the silicone mold using an adhesive film.

Comparative Example 1: Preparation of hydroquinone-containing cream

The following Comparative Example 1 was prepared to compare the effect of hydroquinone impregnated in microneedles with that of hydroquinone impregnated in a conventional oil-in-water cream.

It was prepared with the composition and content listed in Table 2. First, raw materials 1 to 5 and raw materials 6 to 13 were heated and dissolved at 75 to 80°C, stirred for 2 minutes at 5500 rpm in a homomixer, and then cooled to room temperature to prepare the cream of Comparative Example 1.

Raw material name (unit: weight %) Comparative Example 1 One Cetearyl alcohol 2.5 2 Polyglyceryl-3methylglucose distearate 2.0 3 Glyceryl Stearate 1.0 4 Hydrogenated polydecene 5 5 Cyclohexasiloxane 3 6 Purified water To 100 7 glycerin 5 8 1,2-hexanediol 2 9 carbomer 0.2 10 xanthan gum 0.3 11 Dipropylene glycol 5 12 hydroquinone 4 13 Sodium metabisulfite 0.03

Experimental Example 1: Checking stability over time

Example 1 and Comparative Example 1 were stored for 4 weeks at constant temperature conditions of 0°C, room temperature, 40°C, and 50°C to check the stability of the samples, such as precipitation and discoloration. The results are shown in Figure 3.

division 30 days room temperature 40 degrees 50 degrees 0 degrees Example 1 stability stability stability stability Comparative Example 1 No discoloration Discoloration, unusual odor Discoloration, unusual odor No discoloration

As can be seen from the results in Table 3, it was confirmed that Example 1, unlike Comparative Example 1, exhibited good stability at both low and high temperatures.

Experimental Example 2: Skin irritation improvement effect

Example 1 and Comparative Example 1 were each applied to the inside of the arm every day for two weeks. In the case of microneedles, they were attached for one hour every day, and cream was applied to check the degree of skin irritation. At this time, the number of tests for each sample was 20 (N=20). The results are shown in Table 4 below.

Classification (n=20) 1 day later 2 days later 4 days later 6 days later 8 days later 10 days later 12 days later 14 days later Example 1 0.04 0.00 0.08 0.08 0.08 0.10 0.10 0.08 Comparative Example 1 0.04 0.10 0.16 0.30 0.28 0.26 0.24 0.26

* If the skin irritation index is 0.2 or higher, it is judged that there is skin irritation. Usually, for functional cosmetics, skin irritation is at the level of 0.05 to 0.1.

As shown in Table 4, skin irritation in Example 1 was significantly lower than in Comparative Example 1. The reason that Example 1 showed less skin irritation than Comparative Example 1 was believed to be because in actual use, the cream is applied for a long time, while the microneedles are removed after being used for a short period of time (1 hour), so the time in contact with the skin is short. .

Experimental Example 3: Drug release behavior

Using a Franz diffusion cell, the hydroquinone content of pig skin tissue and receptor solution over time was measured using liquid chromatography. Hydroquinone cream was applied to pig skin or a microneedle (microneedle) impregnated with hydroquinone was attached to compare the amount of hydroquinone permeated through the skin over time.

That is, using a Franz diffusion cell, the hydroquinone content of pig skin tissue and receptor solution over time was measured using liquid chromatography. A microneedle containing hydroquinone was attached to the pig skin, the microneedle was allowed to penetrate and melt into the pig skin (attachment time: 2 hours, temperature: 32°C), and then the microneedle was removed. Pig skin in which hydroquinone had been absorbed by a microneedle was placed in a Franz diffusion cell to confirm the release of hydroquinone from pig skin into the receptor solution over time. The results are shown in Figure 3.

As shown in Figure 3, the amount of cream containing hydroquinone permeated through the skin was insignificant, about 1 μg or less, but the hydroquinone impregnated with microneedles directly permeated into the skin through the needle, and the permeation amount was about 1 μg. At 20μg, the skin penetration amount was about 20 times higher than that of the cream formulation.

Experimental Example 4: Melanin index measurement using a colorimeter

Example 1 and Comparative Example 1 were treated daily for 6 weeks on the area around the eyes. During the treatment process, the melanin index was measured using a colorimeter (MPA-580), and the degree of improvement in skin color was evaluated through this. The results of evaluating the melanin index at each time point are shown in Table 5 and Figure 4 below. At this time, the number of testers was 20 (N=20).

　
　 Melanin index (N=20) 0 weeks 1 week 2 weeks 4 weeks 6 weeks Comparative Example 1 215.63 203.98 198.99 194.57 185.53 Example 1 211.04 196.21 191.96 182.22 170.45

As shown in Table 5 and Figure 4, as a result of melanin index analysis at each time point, the melanin index of the test group using Example 1 decreased compared to the test group using Comparative Example 1. That is, compared to Comparative Example 1, Example 1 showed an improvement effect that was about twice as good, which shows that hydroquinone effectively penetrates into the skin through microneedles, thereby exerting a higher skin whitening effect.

Claims (6)

In products containing hydroquinone as an active ingredient and for skin whitening,
The product is characterized in that it contains (i) a substance forming microneedles and (ii) soluble microneedles in the skin containing hydroquinone,
Here, the material forming the microneedles is hyaluronic acid or a salt thereof; Carboxymethyl cellulose or a salt thereof; sugar; glycerin; and antioxidants,
A product characterized in that (ii) hydroquinone is mixed with (i) a substance forming microneedles and is impregnated inside the soluble microneedles. The product according to claim 1, wherein the product is a cosmetic. delete delete The product according to claim 1, wherein the sugar is trehalose. A method for improving skin whitening, comprising applying microneedles containing (i) a soluble microneedle-forming substance and (ii) hydroquinone to the skin,
The material forming the microneedles is hyaluronic acid or a salt thereof; Carboxymethyl cellulose or a salt thereof; sugar; glycerin; and antioxidants,
A method for improving skin whitening, wherein (ii) hydroquinone is mixed with (i) a substance forming microneedles and impregnated inside the soluble microneedles.