KR102486502B1 - Soluble microneedle patch for delivery of anti-acne drug - Google Patents

Abstract

The present invention relates to a system for administering an anti-acne agent to the skin, which can stably impregnate the anti-acne agent and effectively deliver the anti-acne agent into the skin, thereby exhibiting excellent effects, and is characterized in that it is a microneedle containing the anti-acne agent.

Description

Soluble microneedle patch for delivery of anti-acne drug {Soluble microneedle patch for delivery of anti-acne drug}

The present invention relates to microneedles and microneedle patches.

In general, microneedles are used for delivery of active substances such as drugs 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.

On the other hand, acne is an inflammatory skin disease in which clogged pores (open comedones and closed comedones), pimples, deep boils (cysts or nodules) occur on the face, neck, chest, back, and shoulders. Acne usually occurs in the early teens, but symptoms may become severe around the age of 20, and it can also occur in adults in their 30s and 40s. Acne usually clears up in a few years without treatment, but it can leave permanent scars if not treated appropriately. Therefore, it is important to treat it appropriately at an early stage.

In the case of medicines such as adapalene, azelaic acid, and resorcinol, which are acne treatments, their effectiveness in treating skin acne is known through many studies, but they lack skin compatibility (lipid affinity). Therefore, it is not easy to penetrate the skin.

Therefore, in the application of acne treatment, there is a need for a new method that can be used to overcome the limitation of effective substance delivery due to the skin barrier and improve skin penetration efficiency.

Republic of Korea Patent Publication No. 10-2014-0125364

The problem to be solved by the present invention is to provide a system for stably impregnating a soluble microneedle with an anti-acne drug and effectively delivering the anti-acne drug into the skin, and a method for manufacturing such a system.

Accordingly, the present invention provides soluble microneedles containing an acne treatment agent.

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

In addition, the present invention provides a method for manufacturing a microneedle containing an acne treatment.

In order to solve the above problems, the present invention provides soluble microneedles containing an acne treatment, and more preferably, the material forming the microneedles is dissolved in the skin so that the microneedles dissolve or dissolve when the microneedles are applied to the skin. Disruption causes the acne treatment to be released into the skin.

After a long period of research, the present inventors have found that the acne treatment can be effectively delivered into the skin by impregnating the acne treatment into the soluble microneedles, as well as the fact that it is not easy to control the application amount in the case of conventionally used ointment or cream formulations, and in general, acne treatment is Its low permeability limits its inclusion in general cosmetic and/or ointment formulations, and the present invention was completed by fundamentally solving problems such as exacerbation of acne caused by contaminated hands when applying the ointment.

As used herein, the term "acne treatment agent" is a term that includes all substances and/or products used to treat acne, and is not limited to any substance and/or product exhibiting an acne treatment effect. Therefore, it can be used regardless of oral administration, skin application, and the like.

The acne treatment that can be used in the present invention may preferably be a retinoid compound, and the retinoid may be any natural and/or synthetic analog of vitamin A or a retinol-like compound having a biological activity of vitamin A in the skin, and any of these compounds. Includes geometric isomers and stereoisomers. The retinoid is preferably retinol, retinol esters (eg C ₂ -C ₂₂ alkyl esters of retinol including retinyl palmicate, retinyl acetate, retinyl propionate), retinol aldehyde, retinal, beta- carotene and/or retinoic acid (all-trans retinoic acid and/or 13-cis-retinoic acid), more preferably a retinol ester. Among these compounds, adapalene {6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid}, tocopheryl-retinoate [tocopherol ester of retinoic acid (trans- or cis-) and tazarotene (ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate) can be preferably used.

In particular, in the present invention, adapalene can be used to confirm a remarkable effect, and adapalene can be used more preferably among the acne treatments.

The present inventors have studied various administration systems and none of the systems are similar to the method of impregnating the soluble microneedles of the acne treatment. After many efforts, the present inventors made a surprising invention that fundamentally solved the problem of skin permeability of the acne treatment by impregnating the acne treatment into microneedles and confirmed remarkable effects without side effects. In addition, if other microneedles are used in the present invention, even unskilled ordinary people can easily apply acne treatment without side effects in a non-invasive way, and the effect of relieving itching due to the constant pain caused by applying the microneedles and the acne treatment included (dispersed) inside the skin can exert an immediate effect inside the skin to exert an excellent acne treatment and/or alleviating effect.

As used herein, the term "impregnation" may refer to a form in which the anti-acne treatment can be contained in microneedles, and preferably i) contains the anti-acne treatment together with a soluble substance forming microneedles (microneedle structure including a form in which the anti-acne agent is dispersed therein), or ii) making a hole in the microneedle to contain the anti-acne agent in the hole. When the microneedles are prepared in the form of i) and ii), the acne treatment can effectively penetrate into the skin, and in particular, when the microneedles are prepared in the form of i), the problem of low skin permeability of the acne treatment is fundamentally It can be solved and the acne treatment can be impregnated stably in the formulation.

Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the anti-acne treatment contained in the microneedles is effectively released into the skin.

In a preferred embodiment of the present invention, the substance forming the microneedles is dissolved in the skin, and the microneedles dissolve or collapse when the microneedles are applied to the skin, so that the acne treatment contained in the microneedles effectively penetrates into the skin, , Since the microneedles contain a soluble polymer, a small amount of the anti-acne treatment can be released into the skin and the effect can be maintained for a long time, thereby reducing the number of applications and maximizing the effect of the anti-acne treatment. In particular, the microneedles may include a sustained-release polymer in order to release a small amount of the acne treatment within the skin. The sustained-release polymer is, but is not limited to, for example, poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester , polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, and biodegradable polymers such as copolymers thereof. In particular, during their copolymerization, the release behavior can be controlled by changing the decomposition rate of the polymer according to the control of the fraction or molecular weight of the copolymerized material.

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 length of the microneedle according to the present invention is not limited to a specific size.

In the present invention, the acne treatment may be included in 0.001 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.1 to 1% by weight, based on the total weight of the microneedles. If it is included in less than 0.001% by weight, it may not exert an effective effect, and if it is included in more than 10% by weight, it may affect the physical properties and durability of the microneedles, so it is not preferable.

When the microneedle according to the present invention is applied to the skin, the amount of skin penetration can be remarkably improved compared to other conventional skin administration systems.

In addition, the present invention provides a microneedle patch including the microneedles, that is, a microneedle patch for administration (or delivery) of an acne treatment 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 the acne treatment 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 the acne treatment 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, the surface of the patch that can be attached to the skin can also contain the anti-acne agent so that the anti-acne agent can penetrate into the hole formed by the microneedles, and the anti-acne agent is impregnated into the microneedles to achieve an excellent skin administration effect. It is desirable to do

In addition, the present invention comprises the steps of: S1) filling a mold by mixing a substance for forming microneedles including an acne treatment and a substance soluble in the skin; And S2) providing a method for producing microneedles containing an acne treatment comprising the step of warming and drying the mold and separating it.

The method can be prepared by impregnating the acne treatment into microneedles, and the impregnation is not limited thereto, but preferably i) contains the acne treatment together with a soluble substance in the skin forming microneedles, or ii) microneedles. It may include making a hole in a needle and containing an acne treatment in the hole.

In the present invention, in order to impregnate the acne treatment into the microneedles, the substance forming the structure of the microneedles and the acne treatment are mixed together and filled in a mold for forming the microneedles, and then the mold is heated, dried, and separated to obtain microneedles. Needles can be made.

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.

The present invention provides a method for manufacturing an administration system for an anti-acne treatment that can exhibit excellent effects through effective skin delivery of the anti-acne treatment.

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. 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.
Figure 3 is a graph showing the skin permeation amount of the acne treatment (adapalene) of Example 1 and Comparative Example 1.

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 adapalene-containing soluble microneedles (Example 1)>

ingredient Example 1
(Unit: % by weight) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 4 dipropylene glycol 2.7 PEG-40 Hydrogenated Castor Oil One adapalene 0.3 water To 100

After dissolving Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and Trehalose in purified water, glycerin, PEG-40 hydrogenated castor oil (HCO-40) and adapalene solution (adapalene 10%, dipropylene glycol 90%) was added to prepare a microneedle solution in which adapalene was dispersed. The prepared solution was cast in a silicon microneedle mold, and then centrifuged 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 (Example 1).

<Preparation of cream containing adapalene (Comparative Example 1)>

ingredient Comparative Example 1
(Unit: % by weight) C14-22 alcohol, C12-20 alkyl glucoside
(Mixture C14-22 alcohol:C12-20 alkyl glucoside = 80:20 weight ratio) 1.5 Glyceryl Stearate, PEG-100 Stearate
(mixture 50:50 weight ratio) 1.2 Glyceryl Stearate 0.9 Cetearyl Alcohol 1.5 Polyglyceryl-3methylglucose distearate 1.5 Hydrogenated polydecene 4.5 Cyclohexasiloxane 3.5 carbomer 0.2 tromethamine 0.2 glycerin 3 dipropylene glycol 5 1,2-hexanediol 2 adapalene One Purified water To 100

In order to compare the effects of the active ingredient impregnated into the microneedles and the active ingredient applied to the emulsion-in-water cream, a cream containing adapalene was prepared with the composition shown in Table 2 above (Comparative Example 1).

<Experimental Example 1>

drug release behavior

The present inventors measured the adapalene content of porcine skin tissue and acceptor solution over time using a Franz diffusion cell using liquid chromatography. After attaching Example 1 and applying Comparative Example 1 to pig skin to penetrate and melt into pig skin, the microneedles and cream were removed.

Porcine skin, in which adapalene was absorbed in Example 1 and Comparative Example 1, was put into a Franz diffusion cell (FIG. 2), and the skin permeation amount of adapalene over time was compared.

As a result, as shown in FIG. 3, Comparative Example 1 had an insignificant amount of about 1.6 μg permeated through the skin, but the adapalene impregnated into the microneedles was directly penetrated into the skin by the needle, and the permeation amount was about 17 μg. As above, it showed about 10 times higher skin permeation than cream.

Claims (9)

A water-soluble microneedle containing a material forming the microneedle and adapalene,
The material forming the microneedle may include one or more water-soluble polymers selected from hyaluronic acid and salts thereof; and a plasticizer,
The adapalene is impregnated into the microneedle,
When the microneedle is applied to the skin, the material forming the microneedle is dissolved or collapsed by moisture in the skin, so that adapalene is released into the skin. The method of claim 1, wherein the plasticizer is at least one selected from ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin. Water soluble microneedles. The method of claim 1, wherein the material forming the microneedle is hyaluronic acid or a salt thereof; carboxymethyl cellulose or a salt thereof; sugars; And a water-soluble microneedle containing a plasticizer. delete delete According to claim 1,
The adapalene is a water-soluble microneedle, characterized in that contained 0.001 to 10% by weight relative to the total weight of the microneedle. According to claim 1,
The microneedle is a water-soluble microneedle, characterized in that to improve the skin penetration of adapalene. A microneedle patch comprising the water-soluble microneedle according to any one of claims 1 to 3, 6 and 7. A method for manufacturing a water-soluble microneedle according to claim 1,
S1) mixing adapalene and a material for forming the microneedle and filling the mold; and
S2) The method of manufacturing a water-soluble microneedle comprising the step of heating and drying the mold and then separating the mold.

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