KR102517754B1 - Soluble microneedle patch for tranexamic acid delivery - Google Patents

Abstract

The present invention relates to a system for administering tranexamic acid to the skin, which can exhibit excellent effects by stably impregnating tranexamic acid and effectively delivering it into the skin, and is characterized in that it is a microneedle containing tranexamic acid.

Description

Soluble microneedle patch for tranexamic acid delivery}

The present invention relates to microneedles and methods of making microneedles.

In general, microneedles are used for delivery of active substances such as drugs and vaccines in vivo, detection of analytes in the body, and biopsy. The purpose of delivery of pharmaceutically or cosmetically active ingredients using microneedles is to deliver active substances through the skin rather than through a biological circulatory system such as blood vessels or lymphatic vessels.

As a method of using these microneedles, a microneedle device such as a roller to which microneedles are attached is used to form a certain number of holes in the skin and then reapplying drugs, active ingredients on the surface of the microneedles Forms in which the active ingredient is administered simultaneously with skin puncture by coating (active ingredient) are generally used.

In general, unlike color cosmetics that act on the surface of the skin in cosmetic preparations and show their effects, the effects of hair growth, hair growth, hair loss prevention, wrinkle improvement, whitening, skin moisturizing, hair removal, and skin nutrition are more effective than skin surface action. It acts inside the skin, such as the dermis and dermis, to show its effect.

On the other hand, tranexamic acid is a kind of amino acid and is generally used as a hemostatic agent when taken or as a blood coagulant, anti-allergic or anti-inflammatory agent when applied, and its whitening function has been known since 1979. It has been actively used for the treatment of melasma, which becomes darker in color, and it is known that tranexamic acid regulates melanocyte stimulating substances to control the production of melanin as a treatment mechanism for melasma.

On the other hand, when tranexamic acid is used as an external skin preparation, various problems have been pointed out in terms of feeling of use, skin irritation, storage stability, and skin permeation. For example, Korean Patent Registration No. 10-1087602 discloses that when a low-viscosity liquid composition formulated with tranexamic acids is applied to the skin, a sticky or stiff feeling occurs, and in particular, tranexamic acids are 0.5% by weight in the formulation. According to Korean Patent Registration No. 10-1159574, the crystallinity of tranexamic acid is very high, so crystals may be precipitated during evaporation and drying over time in external skin preparations containing tranexamic acid. However, Japanese Patent Laid-open Publication No. 2010-229100 points out that when tranexamic acid is applied to the skin, the skin permeability is very low.

Composition for external use using transdermal absorption enhancers (sorbitol, isopropyl myristate, concentrated glycerin, propylene glycol monolaurate, polysorbate, butylene glycol, glyceryl monorate, etc.) to improve skin permeation of tranexamic acid (disclosed) No. 10-2014-0120827), a liquid composition for external application for skin containing carboxymethyl cellulose and having a viscosity of 500 mPa s or less to improve the feeling of use of tranexamic acid (Korean Patent No. 10-1406830) and preventing precipitation of tranexamic acid crystals There are compositions for external application for skin using higher alcohols and anionic surfactants such as stearoyl methyl taurate (Korean Patent No. 10-1159574), but there is a limit to simultaneously satisfying skin safety, skin permeation and precipitation prevention. .

Republic of Korea Patent Publication No. 10-2014-0120827

Therefore, the problem to be solved by the present invention is to provide a system for stably impregnating soluble microneedles with tranexamic acid to effectively deliver tranexamic acid into the skin and a method for manufacturing such a system.

Accordingly, the present invention provides soluble microneedles comprising tranexamic acid.

In addition, the present invention provides a microneedle patch including the microneedles.

In addition, the present invention provides a method for preparing microneedles containing tranexamic acid.

In order to solve the above problems, the present invention provides soluble microneedles containing tranexamic acid, and more preferably, the substance forming the microneedles is dissolved in the skin, so that when the microneedles are applied to the skin As the microneedles dissolve or collapse, tranexamic acid is released into the skin.

After a long period of research, the present inventors impregnated soluble microneedles with tranexamic acid and found that tranexamic acid can be effectively delivered into the skin, as well as the fact that tranexamic acid can occur when used as an external skin agent (eg, cream formulation). i) unpleasant feeling of stickiness or stiffness (in particular, it can be remarkably increased when containing more than 0.5% by weight), ii) crystallization problem due to high crystallinity of tranexamic acid in terms of storage stability, and iii) ) It was confirmed that the problem of skin safety caused by skin irritation could be fundamentally solved, and the present invention was completed. That is, it was confirmed that the effect of tranexamic acid can be maximized by impregnating the soluble microneedles with tranexamic acid to overcome problems of feeling of use, storage stability, and skin safety of tranexamic acid.

More specifically, in the case of conventional cream formulations containing tranexamic acid, which are applied to the skin, various alternatives have been proposed and used because tranexamic acid has problems with unpleasant feeling of use, storage stability, and skin safety. However, in the case of the alternative solution, it was not possible to solve the unpleasant feeling of stickiness or stiffness of tranexamic acid, and especially when it was contained in an amount of 0.5% by weight or more, the level became severe, so it was difficult to add tranexamic acid at a desired concentration. In addition, there are cases in which various components are added to formulate to solve the problem of crystal precipitation (eg, Korean Patent Registration No. 10-1406830), but other substances (compounds, etc.) are added as solved in the present invention. However, a means to solve the feeling of use, storage stability and skin safety at the same time has not been presented.

The microneedles according to the present invention do not fundamentally cause the above problems even if they contain a certain amount (0.5% by weight) or more of tranexamic acid, so they can be used conveniently and an excellent effect can be obtained by applying a sufficient amount of tranexamic acid to the skin. There are technical features.

In addition, although there is a problem that skin penetration is not easy, it is impregnated with microneedles to fundamentally penetrate tranexamic acid into the skin. Conventionally, when tranexamic acid is included in an external skin preparation and used, it is difficult for tranexamic acid to pass through the skin barrier, making it difficult to achieve an excellent skin whitening effect. It was difficult to achieve an excellent skin whitening effect compared to the administered dose because it was difficult to directly administer to the basal layer, which is the optimal location for use for skin care.

Therefore, the microneedles can improve the skin permeation amount of tranexamic acid, and through this, an excellent skin whitening effect can be achieved.

In the present invention, the tranexamic acid is a compound having a molecular formula of C ₈ H ₁₅ NO ₂ represented by the following Chemical Formula 1 and a molar mass of 157.21 g/mol, and may be a kind of lysine amino acid derivative. Any compound represented by the structural formula of Formula 1 below may include tranexamic acid isolated from samples containing tranexamic acid, artificially synthesized tranexamic acid, and commercially distributed tranexamic acid.

[Formula 1]

The present inventors have studied various administration systems, and none of the systems are easy to solve the various problems of the tranexamic acid at the same time. After many efforts, the present inventors have come up with a surprising invention that fundamentally solves the problems of feeling of use, storage stability, and skin safety of tranexamic acid by impregnating microneedles with tranexamic acid, and can effectively deliver it into the skin. In addition, the present inventors confirmed that tranexamic acid maintains stability in the soluble microneedles during storage as well as during the normal manufacturing process of microneedles, confirming that tranexamic acid is useful for application to the microneedle system.

As used herein, the term "impregnation" may refer to a form in which tranexamic acid may be contained in microneedles, preferably i) containing tranexamic acid together with soluble substances forming microneedles, or ii) A hole may be made in the microneedle to contain tranexamic acid in the hole. When the microneedles are prepared in the form of i) and ii), tranexamic acid can effectively penetrate into the skin, and in particular, when the microneedles are prepared in the form of i), the feeling of use, storage stability and Skin safety problems can be fundamentally solved.

Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the tranexamic acid contained in the microneedles is effectively released into the skin.

In a preferred embodiment of the present invention, the material forming the microneedles is dissolved in the skin and the microneedles are dissolved or collapsed when the microneedles are applied to the skin, so that the tranexamic acid contained in the microneedles effectively penetrates into the skin In addition, since the microneedles contain a soluble polymer, a small amount of tranexamic acid can be released in the skin and the effect can be maintained for a long time.

Therefore, in the case of using tranexamic acid in the conventional cream form applied to the skin, it was not possible to fundamentally solve the problem of feeling of use, precipitation, and skin safety, so it was applied for a short time and then washed off. However, using the microneedle according to the present invention It has the advantage of being able to maintain a long-term effect with a single application by controlling the release rate within the skin.

In the present invention, the microneedles may preferably be soluble in the skin, and to form soluble microneedles, for example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) , water-soluble polymers such as vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used. In particular, considering the skin penetration strength of the microneedle and the dissolution rate in the skin comprehensively, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (preferably is preferably a mixture of trehalose), and more preferably a mixture of glycerin.

Preferably, the microneedles of the present invention may additionally include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like in addition to the above components forming the microneedles.

As the 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.

The total length of the microneedles according to the present invention may be 0.05 mm to 2.5 mm based on the triangular cross section of the microneedles cut from the center so that tranexamic acid can directly act on the basal layer to exert an effective whitening effect, preferably It may be 0.1 mm to 2 mm, more preferably 0.2 mm to 1.5 mm. If the thickness is less than 0.05 mm, tranexamic acid may not reach the basal layer and the whitening effect may not be effectively exhibited, and if the thickness exceeds 2.5 mm, it may damage the depth of the dermal layer, which is undesirable.

In the present invention, the tranexamic acid may be included in 0.001 to 5% by weight, preferably 0.005 to 3% by weight, and more preferably 0.01 to 1% by weight, based on the total weight of the preparation solution for preparing microneedles. can When included in less than 0.001% by weight, an effective effect may not be exerted, and when included in more than 5% by weight, physical properties and durability of microneedles may be affected, which is undesirable.

In the present invention, the tranexamic acid may be included in an amount of 0.001 to 30% by weight, preferably 0.002 to 25% by weight, and more preferably 0.003 to 18% by weight, based on the total weight of the microneedles. When included in less than 0.001% by weight, an effective effect may not be exerted, and when included in more than 30% by weight, physical properties and durability of microneedles may be affected, which is undesirable.

In particular, in the case of conventional external skin formulations such as creams containing tranexamic acid, there was a problem that an unpleasant feeling of use could not be solved when 0.5% by weight or more was included, but this problem can be fundamentally solved by applying the microneedles according to the present invention. .

In addition, the microneedles according to the present invention can be used for skin whitening.

In addition, the present invention provides a microneedle patch including the microneedles, that is, a microneedle patch for administering (or delivering) tranexamic acid to which the microneedles are attached.

In the present invention, the patch may refer to a sheet to which one or more microneedles impregnated with tranexamic acid of the present invention are attached and the surface to which the microneedles are attached can be attached to the skin. The size of the sheet is not limited to a specific size, and may be appropriately adjusted according to the amount of tranexamic acid to be absorbed into the skin or the attachment site. In addition, one or more, preferably a plurality of microneedles may be attached to the surface of the sheet attachable to the skin.

In addition, tranexamic acid can be contained in the surface of the patch that can be attached to the skin so that tranexamic acid can penetrate into the hole formed by the microneedles, and to solve the storage stability and skin safety problems of tranexamic acid. For this purpose, it is preferable to impregnate the microneedles with tranexamic acid.

In addition, the present invention comprises the steps of S1) filling and mixing a material for forming microneedles including tranexamic acid and a material soluble in the skin in a mold; and S2) warming and drying the mold and then separating the microneedles containing tranexamic acid.

The method can be prepared by impregnating tranexamic acid into microneedles, and the impregnation is preferably, but not limited to, i) containing tranexamic acid together with a soluble substance in the skin that forms microneedles, or ii ) making a hole in the microneedle and containing tranexamic acid in the hole;

In the present invention, in order to impregnate tranexamic acid into microneedles, the material forming the structure of microneedles and tranexamic acid are filled and mixed in a mold for forming microneedles, then the mold is heated, dried, and then separated Thus, microneedles can be prepared.

In the present invention, the soluble substance in the skin is, for example, hyaluronic acid (Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (Poly vinyl alcohol), and water-soluble polymers such as polyvinylpyrrolidone (Poly vinyl pyrrolidone); sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used.

In addition, the present invention provides a method for cosmetically administering tranexamic acid to the skin, wherein the microneedle according to the present invention is applied to effectively deliver tranexamic acid into the skin.

In the present specification, the term "application" includes both attaching the microneedles according to the present invention to the skin or attaching the microneedle patch according to the present invention to the skin.

The microneedle according to the present invention can fundamentally solve the problems of feeling of use, storage stability and skin safety of tranexamic acid through effective skin delivery of tranexamic acid.

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 according to the present invention.
Figure 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedles according to the present invention.
3 is a graph showing the tranexamic acid content of porcine skin tissue and acceptor solution over time using liquid chromatography.

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.

<Preparation of soluble microneedles>

Soluble microneedles are prepared by a solution casting method, and the solution is cast into a mold, filled with a liquid in a micromold by vacuum or centrifugal separation, and then dried.

As the material forming the microneedle structure, general synthetic and natural water-soluble polymers were used.

<Preparation of soluble microneedles containing tranexamic acid>

Ingredients (Unit: % by weight) Example 1 oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 tranexamic acid 0.5 water To 100

A solution was prepared after dissolving Oligo-HA (hyaluronic acid, Na-CMC (sodium carboxymethyl cellulose), Trehalose, Glycerin, and tranexamic acid in purified water).

After casting the prepared solution in a silicon microneedle mold, centrifugation was performed at 3000 rpm for 10 minutes to fill the micromold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedles were separated from the silicon mold using an adhesive film.

<Preparation of tranexamic acid-containing cream>

Raw material name (unit: % by weight) Comparative Example 1 One Cetearyl Alcohol 2.5 2 Polyglyceryl-3 methylglucose distearate 2.0 3 Glyceryl Stearate One 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 0.2 12 tranexamic acid 0.05 13 tromethamine Appropriate amount

It was prepared to compare the effects of tranexamic acid impregnated with microneedles and tranexamic acid applied to oil-in-water cream.

As shown in Table 2, raw materials 1 to 5 and raw materials 6 to 12 were heated and dissolved at 75 ° C to 80 ° C, stirred at 5500 rpm with a homomixer, cooled, and then added with raw material 13 at a temperature of 65 ° C and then stirred at 5500 rpm with a homomixer. After mixing, it was cooled to room temperature and prepared.

<Experimental Example 1>

Check stability over time

The inventors of Example 1 and Comparative Example 1 were stored at constant temperature conditions of 0°C, room temperature, 40°C, and 50°C for 4 weeks to confirm stability such as precipitation and discoloration of the samples.

division 30 days room temperature 40℃ 50℃ 0℃ Example 1 stability stability stability stability Comparative Example 1 stability discoloration, peculiar smell discoloration, peculiar smell precipitation

As a result, as can be seen from the results of Table 3, in the case of Example 1, compared to Comparative Example 1, both low and high temperatures showed good results.

<Experimental Example 2>

Skin irritation improvement effect

The inventors of Example 1 and Comparative Example 1 each attached microneedles to the inside of the arm for 1 hour every day for 2 weeks, and applied the cream to confirm the degree of skin irritation (N=20).

As a result, as shown in Table 4 below, Example 1 and Comparative Example 1 were both acceptable levels, but Example 1 showed less skin irritation than Comparative Example 1, while the cream was applied for a long time in actual use, while the microscopic It was determined that this was because the needle was removed after a short time (1 hour) of use and the contact time with the skin was short.

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 0.04 0.00 0.08 0.08 0.08 0.10 0.10 0.08 Comparative Example 1 0.04 0.08 0.16 0.20 0.18 0.20 0.18 0.20

- 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 the level of 0.05 to 0.1.

<Drug Release Behavior>

Using a Franz diffusion cell, tranexamic acid content of porcine skin tissue and acceptor solution over time was measured using liquid chromatography. After applying Comparative Example 1 to pig skin or attaching the microneedles of Example 1 (attachment time: 2 hours, temperature: 32 ° C.) to penetrate and melt the microneedles into the pig skin, the microneedles were removed. Porcine skin, in which tranexamic acid was absorbed by a microneedle, was placed in a franz diffusion cell, and the skin permeation amount of tranexamic acid over time was compared.

In Comparative Example 1, the amount permeated through the skin was about 12ug, which was insignificant, but the tranexamic acid impregnated into the microneedles was directly penetrated into the skin by the needles, and the permeation amount was 150ug or more, about 100 times higher than that of cream. The skin permeation amount was shown.

Claims (9)

A soluble microneedle containing a substance forming microneedles and tranexamic acid,
The material forming the microneedles is hyaluronic acid or a salt thereof; carboxymethyl cellulose or a salt thereof; trehalose; and glycerin,
The soluble microneedles wherein the tranexamic acid is stably impregnated in the soluble microneedles without being precipitated as crystals. According to claim 1,
Microneedles, characterized in that the material forming the microneedles is dissolved in the skin. delete delete According to claim 1,
The microneedles, characterized in that the tranexamic acid is contained in 0.001 to 30% by weight relative to the total weight of the microneedles. According to claim 1,
The microneedles are microneedles, characterized in that to improve the skin permeation amount of tranexamic acid. According to claim 1,
The microneedles are characterized in that the microneedles for skin whitening. A microneedle patch comprising the microneedles according to any one of claims 1, 2, and 5 to 7. S1) filling and mixing tranexamic acid and a material forming microneedles in a mold; and
S2) A method for preparing a microneedle containing tranexamic acid according to claim 1, comprising the step of heating and drying the mold and separating it.

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