KR20160145470A - Soluble microneedle patch for delivery of hydroquinone - Google Patents

Abstract

The present invention relates to a hydroquinone skin administration system which stably impregnates hydroquinone, effectively deliveries the hydroquinone into skin, and reduces side effects of skin irritation caused by the hydroquinone and, more specifically, to a hydroquinone skin administration system comprising hydroquinone, as an active ingredient, in a microneedle. More preferably, the present invention comprises the hydroquinone in a soluble microneedle of skin. In addition, the present invention provides a skin administration method of the hydroquinone using the microneedle. The microneedle according to the present invention are very effective for skin whitening.

Description

Soluble microneedle patch for delivery of hydroquinone for hydroquinone delivery [

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

Benzene-1,4-diol strongly inhibits the activity of tyrosinase involved in the formation of melanin, which is a major factor of skin color. However, hydroquinone is molecularly unstable and easily destabilized by physical or chemical factors such as light, oxygen, pH, and becomes brown, and its activity is easily lowered. Because of this unstable property, hydroquinone was applied only to gel or ointment so far, and hydroquinone stability in gel or ointment was not good even when applied. Storage containers for storing hydroquinone were also used only in sealed containers that block light and air in consideration of light and other environmental factors.

In addition, hydroquinone is mainly applied to skin for the purpose of suppressing the activity of tyrosinase and exerting a skin whitening effect. When hydroquinone is applied to skin for a long period of time, side effects such as skin rash, itching, Is often reported, and there is a problem that it may cause serious side effects such as an abnormal growth of the skin layer and an increase of keratinization.

Korean Patent Publication No. 10-2003-0082765 (published on October 23, 2003) Korean Registered Patent No. 10-0793615 (2008. 1. 10. Announcement) International Patent Application Publication No. WO 02/064193 (published Aug. 22, 2002)

Accordingly, a problem to be solved by the present invention is to provide a product, in particular, a cosmetic product, which can secure the stability of hydroquinone and efficiently deliver hydroquinone into the skin while reducing skin side effects.

In order to solve the above-described problems, the present invention provides a system for transferring hydroquinone, wherein hydroquinone as an active ingredient is contained in a microneedle (microneedle) and a microneedle having such microneedles, and more preferably, The material forming the needles is decomposed and / or dissolved in the skin to provide microneedles releasing hydroquinone contained therein by dissolving or collapsing the microneedles upon application of the microneedles to the skin. That is, preferably, the present invention is a cosmetic product for skin whitening comprising hydroquinone as an active ingredient, wherein the cosmetic comprises a skin-soluble microneedle in which hydroquinone is contained in a microneedle Cosmetics.

When the microneedle encapsulated with hydroquinone as an active ingredient is applied to the skin, the hydroquinone component is permeated into the skin by the microneedles, and the microneedle is dissolved by the moisture in the skin to transfer the hydroquinone component into the skin. Whereby the hydroquinone component can be effectively delivered into the skin.

The present inventors have studied various administration systems, and it is not easy for any system to simultaneously solve the above-mentioned problems of hydroquinone. The present inventors have succeeded in various efforts to ensure stability of hydroquinone by including hydroquinone component in soluble microneedle in the skin, and it is possible to reduce the skin irritation and achieve the desired skin whitening effect efficiently To complete the present invention. In particular, in the initial stage of the research, it was expected that the skin irritation would be greater due to the physical stimulation. However, when the hydroquinone was incorporated into a conventional composition for external application for skin, Which was surprisingly superior to the skin irritation that occurred.

Further, the present inventors have found that hydroquinone is useful for applying a micro needle system in the course of manufacturing a conventional microneedle patch and maintaining stability even in a soluble microneedle during storage, thereby completing the present invention.

The length of the microneedles according to the present invention is not limited to a specific size. However, for the purpose of skin administration for the whitening effect of hydroquinone, the upper and lower lengths of the microneedles are preferably 0.05 to 2.5 mm, more preferably 0.1 to 2.0 mm.

In order to achieve the desired effect of the present invention, the material forming the microneedles is biodegraded or dissolved in the skin, and when the microneedles are applied to the skin, the microneedles are dissolved or collapsed to form hydroquinone (microneedles) Is preferably released into the skin.

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

Such microneedles can be produced, for example, by using materials described in Korean Patent Publication No. 10-0793615, International Patent Application Publication No. WO 02/064193, Korean Patent Laid-Open Publication No. 10-2011-0065361, .

More specifically, for the skin administration of hydroquinone according to the present invention, it is preferable that the microneedle is made of a substance that dissolves in the skin rather than a biodegradable polymer. Examples of such a microneedle include hyaluronic acid, sodium carboxymethyl Sodium carboxymethyl cellulose, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, saccharide or a mixture thereof may be used. The sugar may be xylose, sucrose, maltose, lactose, trehalose or a mixture thereof.

Among these microneedle forming materials, it is necessary to comprehensively consider the skin permeation intensity of the microneedles and the dissolution rate in the skin, and in particular, the stability of hydroquinone in the process of microneedle formation, compatibility with hydroquinone, and the like Taken together, it is preferable to use a mixture of hyaluronic acid, sodium carboxymethylcellulose and a sugar as the material for forming the microneedles, and in this mixture, the sugar is more preferably trehalose.

In the present invention, the hydroquinone may be contained in an amount of 0.1 to 5% by weight, preferably 0.2 to 4% by weight, based on the weight of the preparation liquid for preparing a microneedle, 0.3 to 3% by weight. If it is contained in an amount less than 0.1% by weight, it may not exhibit an effective effect, and if it is contained in an amount exceeding 5% by weight, the physical properties and durability of the fine needle may be affected.

Preferably, the microneedles according to the present invention may further include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, an antioxidant, etc. in addition to the hydroquinone and microneedle structure-forming materials.

Examples of the plasticizer include polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin, Or may be used in combination.

As the antioxidant, sodium metabisulfite, dibutylhydroxytoluene, tocopherol, dibutylhydroxyanisole, ascorbyl palmitate, etc. may be used alone or in combination, but the present invention is not limited thereto. The microneedles of the present invention can further improve the stability of hydroquinone when these antioxidants are added together with hydroquinone.

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

The present invention also provides a method for improving skin whitening, which comprises applying micro-needles containing hydroquinone as an active ingredient to the skin according to the present invention. For example, as a method of applying or using such a microneedle, a microneedle device such as a roller having a microneedle according to the present invention is used to form a predetermined number or more holes in the skin, May remain in the skin.

The present invention provides skin whitening products, particularly skin whitening cosmetics, containing hydroquinone as an active ingredient, which is improved in terms of stability, skin irritation and whitening effect. The present invention relates to a process for the production of hydroquinone which is permeated into the skin by the microneedles by applying hydroquinone to the skin by impregnating the microneedles with biodegradability or intracutaneous solubility, more preferably into the skin, and the microneedles dissolve The active ingredient can be efficiently delivered to the desired site.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate exemplary embodiments of the invention and, together with the description of the invention, It should not be construed as limited.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing one example of various methods for manufacturing microneedle according to the present invention. FIG. The dissolvable microneedles can be prepared by a solution casting method. The solution in which the microneedle forming material is dissolved is cast in a mold, the microneedle is filled with the solution by vacuum and / or centrifugation Followed by drying. As the material forming the micro needle (micro needle) structure, various materials well known to those skilled in the art can be used, and general biocompatible synthetic polymers, natural water-soluble polymers and the like can be used.
2 shows a Franz diffusion cell for evaluating hydroquinone release behavior of a micro needle according to the present invention.
FIG. 3 is a graph showing hydroquinone release evaluation results from microneedles, which were evaluated using a Franz diffusion cell equipped with pig skin.
FIG. 4 shows the results of the comparison of the effects of the hydroquinone-containing cream used as the comparative example with the hydroquinone-containing micro-needle patch according to the present invention, and the result of the measurement of the melanin index using the colorimeter.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can 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 invention are provided to more fully describe the present invention to those skilled in the art.

Example 1: Preparation of a soluble microneedle containing hydroquinone

According to the following Table 1, hydroquinone-impregnated microneedle patches were prepared using methods well known to those of ordinary skill in the art. In the present specification, the contents of the compositions are expressed as weight% unless otherwise specified.

(Unit: wt%) 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 prepared microneedle manufacturing solution was cast in a silicon microneedle mold and centrifuged at 3000 rpm for 10 minutes to fill the micro mold with the solution.

After filling the solution, it was dried in a drying oven (70 ° C) for 3 hours, and the micro-needles produced using the adhesive film were separated from the silicon mold.

Comparative Example 1: Manufacture of hydroquinone-containing cream

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

Were prepared by the compositions and contents shown in Table 2. [ First, raw materials 1 to 5 and raw materials 6 to 13 were heated and dissolved at 75 to 80 캜, stirred at 5500 rpm for 2 minutes, and cooled to room temperature to prepare a cream of Comparative Example 1.

Ingredients (Unit: wt%) Comparative Example 1 One Cetearyl alcohol 2.5 2 Polyglyceryl-3 methyl glucoside 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: Confirmation of stability over time

Example 1 and Comparative Example 1 were stored at a constant temperature of 0 ° C, room temperature, 40 ° C, and 50 ° C for 4 weeks to confirm the stability of sample precipitation, discoloration and the like. The results are shown in Fig.

division 30 days Room temperature 40 degrees 50 degrees 0 degrees Example 1 stability stability stability stability Comparative Example 1 Non-discolored Discoloration Discoloration Non-discolored

As can be seen from the results of Table 3, it can be seen that Example 1 showed good stability at both low temperature and high temperature, unlike Comparative Example 1.

Experimental Example 2: Effect of improving skin irritation

Example 1 and Comparative Example 1 were applied to the inside of the arms for 2 weeks each day. In the case of the fine needle, it was attached for 1 hour every day, and cream was applied to confirm the degree of skin irritation. At this time, the test number of each sample was 20 (N = 20). The results are shown in Table 4 below.

Classification (n = 20) After 1 day Two days later After 4 days After 6 days After 8 days After 10 days After 12 days After 14 days 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 more, skin irritation is judged. In the case of functional cosmetics, skin irritation is 0.05 ~ 0.1.

As shown in Table 4, the skin irritation of Example 1 was significantly lower than that of Comparative Example 1. The reason why the skin irritation of Example 1 is smaller than that of Comparative Example 1 is that it is because the cream is applied for a long time in the actual use, but the contact time of the skin is short because the microneedles are removed after a short time (1 hour) .

Experimental Example 3: Drug release behavior

Using Franz diffusion cell, the content of hydroquinone in porcine skin tissue and the acceptor solution with time was measured by liquid chromatography (Liquid Chromatography). Hydroquinone cream was applied to pig skin or hydroquinone-impregnated micro needle (mite needle) was attached to compare the skin permeation amount of hydroquinone over time.

That is, the content of hydroquinone in porcine skin tissue and acceptor solution with time was measured using Franz diffusion cell using liquid chromatography. The micro needle was immersed in the pig skin and allowed to dissolve (attachment time: 2 hours, temperature: 32 ° C). The micro needle was removed by attaching the micro needle to the pig skin with hydroquinone. The pig skin with hydroquinone absorbed by the micro needle was inserted into the franz diffusion cell and the behavior of hydroquinone released from the pig skin to the receptor solution over time was confirmed. The results are shown in Fig.

As shown in FIG. 3, the amount of the hydroquinone-containing cream penetrated through the skin was less than about 1 μg, but the amount of hydroquinone impregnated in the fine needle was directly transmitted to the skin by the needle, 20 μg, which is about 20 times higher than the cream formulation.

Experimental Example 4: Measurement of melanin index using color difference meter

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

　
　 The 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 FIG. 4, the melanin index of the test group using Example 1 was lower than that of the test group using Comparative Example 1 as a result of Melanin Index analysis at each time point. That is, the improvement effect was about twice as much as that of the Example 1 in comparison with the Comparative Example 1, showing that the hydroquinone effectively penetrates into the skin by the microneedles to exert the skin whitening effect more highly.

Claims (6)

A product for skin whitening comprising hydroquinone as an active ingredient,
Characterized in that the product comprises a skin-soluble microneedle in which the hydroquinone is contained within the microneedles. The article of claim 1, wherein the article is a cosmetic article. The method of claim 1, wherein the microneedle is selected from the group consisting of hyaluronic acid, sodium carboxymethyl cellulose, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone (polyvinyl pyrrolidone), and a sugar. [4] The product of claim 3, wherein the microneedle is manufactured using a mixture of hyaluronic acid, sodium carboxymethylcellulose and a saccharide as a microneedle forming material. 5. The article of claim 4, wherein the sugar is trehalose. A method for improving skin whitening, comprising applying micro-needles containing hydroquinone as an active ingredient to the skin in a microneedle.

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