KR102525629B1 - Soluble microneedle patch for delivery hydroxyacids - Google Patents

Abstract

The present invention provides a dosage form or system for effective administration and efficacy expression of hydroxy acids. In the present invention, the biodegradable or soluble microneedles in the skin are stably impregnated with hydroxy acids and are effectively delivered into the skin, thereby exhibiting excellent effects. The microneedle according to the present invention is particularly effective in improving skin wrinkles.

Description

Soluble microneedle patch for delivery hydroxyacids

The present invention relates to specific formulations or systems for the efficient administration of hydroxy acids.

Hydroxy acids include α-hydroxyacids (AHA), β-hydroxyacids (BHA), polyhydroxy acids, and bionic acids. In cosmetics, various types of acid such as glycolic acid, lactic acid, malic acid, citric acid, tartaric acid, salicylic acid, etc. Types of alpha-hydroxy acids (α-hydroxyacids, AHA) and beta-hydroxy acids (β-hydroxyacids, BHA) ingredients are used.

In particular, alpha-hydroxy acid is a representative chemical peeling agent, and is well known to have an excellent keratin exfoliation effect and to increase moisturizing and whitening effects (Japanese Patent Publication No. 94-279258, International Patent Publication No. 9427579 , Japanese Patent Publication No. 96-133946, Japanese Patent Publication No. 94-234260). In addition, alpha-hydroxy acid shows excellent effects on wrinkle improvement by promoting collagen, hyaluronic acid, and fibroblasts (Dermatologic Surgery , Vol 27, 429-433, 2001, Vol 24, 1054-1058, 1998).

Alpha-hydroxy acid causes serious side effects such as oedema, erythema, tingling, itching, and burning along with excellent effects on the skin. Accordingly, attempts to reduce skin side effects have been made by many inventors so far. US Patent No. 5516793 tried to reduce skin irritation by adding vitamin C, that is, ascorbic acid, and European Patent No. 691126 tried to improve this by containing inorganic powder. However, it is difficult to fundamentally solve the problem of skin side effects of alpha hydroxy acid only by simple addition of vitamin C or inorganic powder.

Therefore, the problem to be solved by the present invention is to provide a dosage form or system for efficiently administering a hydroxy acid without side effects.

In order to solve the above problems, the present invention provides a microneedle containing hydroxy acid as an active ingredient, more preferably, the material forming the microneedle is biodegradable or soluble in the skin, and most preferably Since it is soluble in the skin, when the microneedle is applied to the skin, the hydroxy acid contained therein is released as the microneedle dissolves or collapses.

The present inventors have made various attempts to develop products containing hydroxy acids as active ingredients based on the useful functions of hydroxy acids (particularly, ability to improve skin wrinkles). However, it has not been easy for any administration system to simultaneously solve the various problems of the above-mentioned hydroxy acids. First, in the case of applying a conventional skin external composition, the percutaneous penetration amount of hydroxy acid is insignificant because the hydroxy acid penetrates into the skin to improve skin wrinkles. That is, in order for the hydroxy acid to exert its effect, the corresponding component must reach the skin cells, but it is difficult to reach the skin cells through the composition for external application for skin. When the applied amount is increased to increase the amount reaching skin cells, there is a problem in that various side effects appear due to strong skin irritation caused by hydroxy acid. In addition, when a composition containing hydroxy acid is orally administered, hydroxy acid, an active ingredient, must reach skin cells after systemic circulation. The ratio is very small, so it is difficult to achieve a great effect even in cosmetic formulations for oral administration.

Accordingly, the inventors of the present invention, after many efforts, have found that by including hydroxy acid in biodegradable or skin-soluble (in particular, skin-soluble) microneedles, the hydroxy acid can be effectively and quickly delivered directly into the skin, thereby minimizing skin irritation. It was confirmed that it could be done and the present invention was completed.

More specifically, in the present invention, when the hydroxy acid-encapsulated microneedle is applied to the skin, the hydroxy acid component is painlessly penetrated into the skin by the microneedles, and the microneedles are dissolved by moisture in the skin. The hydroxy acid is rapidly delivered directly into the skin. As a result, since an effective amount of hydroxy acid is directly delivered into the skin in a short time, it is possible to exert a rapid effect, and skin irritation can be minimized because there is no need for repeated/long-term administration.

In the present invention, since microneedles must be dissolved or disintegrated in skin application of microneedles, it is preferable that the material forming the microneedles be biodegraded or dissolved in the skin. More preferably, the microneedle according to the present invention is preferably made of a material that dissolves in the skin rather than a biodegradable polymer for the stability of hydroxy acid, and these ingredients include hyaluronic acid, sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, sugar, or a mixture thereof may be used. As the sugar, xylose, sucrose, maltose, lactose, trehalose, or a mixture thereof may be used.

Among these microneedle-forming materials, comprehensively considering the skin penetration strength of the microneedle, the dissolution rate in the skin, and in particular, considering the stability of hydroxy acid and the compatibility of hydroxy acid comprehensively, As the material for forming the microneedle, a mixture of hyaluronic acid, sodium carboxymethyl cellulose, and sugar is preferable, and in this mixture, it is more preferable that the sugar is trehalose.

In the present invention, the hydroxy acid refers to a compound having a hydroxyl group and a carboxy group in the same molecule, and is classified into alpha-hydroxy acid, beta-hydroxy acid, gamma-hydroxy acid, etc. depending on the position between the hydroxy group and the carboxy group. As a distinction, alpha-hydroxy acids are those in which a hydroxyl group and a carboxyl group are bonded to the same carbon atom, and beta-hydroxy acids are those in which a hydroxyl group and a carboxy group are bonded to adjacent carbon atoms. Alpha-hydroxy acids include, for example, glycolic acid, tartaric acid, lactic acid, malic acid, citric acid and the like. Aliphatic hydroxy acids are also referred to as alcoholic acids, and aromatic hydroxy acids include, for example, salicylic acid or gallic acid.

The microneedle according to the present invention most preferably contains glycolic acid as a hydroxy acid, and may be prepared using a mixture of hyaluronic acid, sodium carboxymethyl cellulose, and sugar as a microneedle forming material.

In the present invention, preferably, the hydroxy acid may be included in 0.1 to 10% by weight, more preferably, 1 to 6% by weight, based on the total weight of the preparation solution for preparing microneedles. When included in less than 0.1% by weight, effective effects may not be exhibited, and when included in more than 10% by weight, physical properties and durability of the microneedle may be affected, which is undesirable.

In the present invention, the microneedle may be a matrix type or a reservoir type, and is not limited as long as the object of the present invention can be achieved. That is, the hydroxy acid may be impregnated inside the microneedle in a dispersed form so that the hydroxy acid may exist between the materials forming the microneedle, or the materials forming the microneedle may be in a core-shell form surrounding the hydroxy acid. may exist

The microneedle according to the present invention may further include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like, in addition to the above-mentioned material for forming the structure of the microneedle. As such a plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin are used alone. or may be used in combination. In particular, as a result of various evaluations in terms of stability with hydroxy acid and compatibility with hydroxy acid, glycerin was more preferable.

The microneedle according to the present invention may further include additional components for causing an additive or synergistic effect on the efficacy of hydroxy acid.

In the present invention, the length of the microneedle is not limited to a specific size. However, for the purpose of the present invention to target skin cells by passing through the stratum corneum, the upper and lower length of the microneedle is preferably 0.05 mm to 2.5 mm micrometer, more preferably 0.1 mm to 2 mm micrometer.

The microneedle according to the present invention can be manufactured using various methods known in the art. For example, it may be manufactured using materials and manufacturing methods described in Korean Patent Registration No. 10-0793615, International Patent Application Publication No. WO 02/064193, and Korean Patent Publication No. 10-2011-0065361. More preferably, the microneedles according to the present invention can be manufactured by a solution casting method.

In addition, the present invention provides a microneedle patch system for administration (delivery) of hydroxy acid to which the microneedle is attached.

The present invention also provides a hydroxy acid that can stably encapsulate hydroxy acid, effectively deliver it into the skin, and exhibit excellent effects, including the step of preparing a microneedle containing hydroxy acid using the above-mentioned polymer. A method for manufacturing a containing microneedle is provided.

The present invention also provides a method for administering hydroxy acid to the skin, characterized by using the microneedle according to the present invention, to achieve effective skin delivery of hydroxy acid. The microneedle according to the present invention can be used for various purposes expected through skin delivery of hydroxy acid, for example, to improve skin wrinkles.

The present invention provides a dosage form or system of hydroxy acid that can stably contain hydroxy acid and exhibit excellent effects through effective skin delivery of hydroxy acid without skin irritation. The present invention is applied to the skin by impregnating biodegradable or soluble in the skin, more preferably microneedles that are soluble in the skin, so that the microneedles are biodegradable in the skin or dissolved by moisture in the skin, thereby dissolving active ingredients into the skin. It can be delivered to skin cells without irritation. In addition, the hydroxy acid in the microneedles according to the present invention has the advantage of being easy to store or handle because stability is maintained.

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 together with the contents of the above-described invention, so the present invention is limited to those described in the drawings. It should not be construed as limiting.
1 is a view showing one example of several methods for manufacturing microneedles (microneedles) according to the present invention. Soluble microneedles can be prepared by a solution casting method, by casting a solution in which the microneedle-forming material is dissolved in a mold, filling the mold with the solution by vacuum and/or centrifugation, and then drying. It can be manufactured by As the material forming the microneedle (microneedle) structure, various materials well known to those skilled in the art may be used, and general biocompatible synthetic polymers, natural water-soluble polymers, and biodegradable polymers may be used. there is.
2 shows a Franz diffusion cell designed to evaluate the hydroxy acid release behavior of the microneedle according to the present invention.
Figure 3 is a graph showing the results of evaluating the change over time in the amount of glycolic acid permeated into the skin from glycolic acid and glycolic acid-containing microneedles using a Franz diffusion cell.
Figure 4 shows the results of the human body application test evaluation for wrinkle improvement.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1: Preparation of microneedles containing glycolic acid

As shown in Table 1 below, soluble microneedles containing glycolic acid were prepared. In the present specification, the contents of the compositions are expressed in weight% unless otherwise specified.

More specifically, a soluble microneedle patch impregnated with glycolic acid was prepared as follows. First, oligo-HA (hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose), trehalose, glycerin, and glycolic acid were dissolved in purified water, and then a solution was prepared. After casting the prepared solution in a silicon microneedle mold, centrifugation was performed at 3000 rpm for 10 minutes to fill the micro-mold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedle was separated from the silicon mold using an adhesive film.

Comparative Example 1: Preparation of cream containing glycolic acid

A glycolic acid-containing cream was prepared as shown in Table 2 below. In the present specification, the contents of the compositions are expressed in weight% unless otherwise specified.

More specifically, raw materials 1 to 5 and raw materials 6 to 12 are heated and dissolved at 75 ° C to 80 ° C, stirred for 4 minutes at 5500 rpm in a homomixer, cooled, and then added with raw material 13 at a temperature of 55 ° C for 4 minutes at 5500 rpm in a homomixer. After stirring, the mixture was cooled to room temperature to prepare a cream containing glycolic acid.

Raw material name (Unit: % by weight) Comparative Example 1 One Cetearyl Alcohol 3.0 2 Polyglyceryl-3methylglucose distearate 2.0 3 Glyceryl Stearate 2 4 Hydrogenated polydecene 5 5 Cyclohexasiloxane 3 6 Purified water To 100 7 glycerin 5 8 Dipropylene Glycol 5 9 1,2-hexanediol 2 10 carbomer Appropriate amount 11 xanthan gum 0.4 12 tromethamine Appropriate amount 13 Chlycolic Acid 4

Experimental Example 1: Skin irritation improvement effect

Microneedles of Example 1 and Comparative Example 1 were attached to the inside of the arm for 1 hour every day for 2 weeks, and the cream was applied to confirm the degree of skin irritation (N=50). The reason why Example 1 shows less skin irritation than Comparative Example 1 is that the cream is applied for a long time in actual use, while the microneedle is removed after a short time (1 hour), so it is judged that the time in contact with the skin is short. However, the present invention should not be construed as being limited thereto.

The skin irritation index is shown below.

division 1 day later 2 days later 4 days later 6 days later 8 days later 10 days later after 12 days after 14 days Example 1 0.08 0.08 0.08 0.08 0.08 0.10 0.10 0.10 Comparative Example 1 0.08 0.20 0.22 0.22 0.26 0.30 0.30 0.30

* Criteria

- ; No erythema or unusual symptoms.

+- ; slightly redder than the surroundings

+ ; Significantly redder than the surroundings

++ ; More reddened and swollen than the surroundings

Stimulus = [{(+-) number×1} + {(+) number×2} + {(++) number×3}]/number of test subjects

* If the skin irritation index is 0.2 or more, it is judged that there is skin irritation, and in the case of normal functional cosmetics, skin irritation is at a level of 0.05 to 0.1.

Experimental Example 2. Drug release behavior

Using a Franz diffusion cell, the glycolic acid content of porcine skin tissue and acceptor solution over time was measured using a liquid chromatography technique.

Comparative Example 1 was applied to the pig skin or the microneedle of Example 1 was attached (attachment time: 2 hours, temperature: 32° C.) to penetrate and melt the microneedle into the pig skin, and then the microneedle was removed. Porcine skin in which glycolic acid was absorbed by the microneedle was placed in a franz diffusion cell, and the amount of glycolic acid permeated through the skin over time was compared. As a result, as shown in FIG. 3, Comparative Example 1 had an insignificant amount of about 0.15 ug permeated through the skin, but the glycolic acid impregnated into the microneedle directly penetrated into the skin by the microneedle, The permeation amount was 18ug or more, which was about 10 times higher than that of cream.

Experimental Example 3: Wrinkle improvement effect

Comparative Example 1 and Example 1 were treated daily for 12 weeks on wrinkles around the eyes, and the degree of wrinkle improvement was confirmed through a silicone replica and wrinkle image analysis method (N=20).

As a result, as shown in FIG. 4, Example 1 showed an excellent wrinkle improvement effect compared to Comparative Example 1. It is determined that the glycolic acid was effectively delivered into the skin by the microneedle impregnated with glycolic acid, but the present invention is not limited thereto.

Claims (7)

A material for forming microneedles; And a biodegradable or skin-soluble microneedle containing glycolic acid or a salt thereof as an active ingredient,
The material forming the microneedle includes glycerin,
The soluble microneedle wherein the glycolic acid or salt thereof is stably impregnated in the microneedle. delete delete According to claim 1, wherein the material forming the microneedle is hyaluronic acid (hyaluronic acid), sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol (polyvinyl alcohol), poly A microneedle further comprising any one selected from the group consisting of polyvinyl pyrrolidone and sugar. The microneedle according to claim 1, wherein the material forming the microneedle further comprises a mixture of hyaluronic acid, sodium carboxymethyl cellulose, and sugar. The microneedle according to claim 5, wherein the sugar is trehalose. The microneedle according to claim 1, wherein the microneedle is used to improve skin wrinkles.

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