KR102494064B1 - Soluble microneedle patch for anti inflammatory effect - Google Patents

Abstract

The present invention relates to a skin administration system for an anti-inflammatory substance capable of exhibiting excellent effects by stably impregnating the anti-inflammatory substance and effectively delivering it into the skin, and is characterized in that it is a microneedle containing an anti-inflammatory substance.

Description

Soluble microneedle patch for anti inflammatory effect {Soluble microneedle patch for anti inflammatory effect}

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, inflammation (inflammation) is a kind of biological tissue defense response to injury, this defense reaction goes through three stages of tissue injury, reaction, and recovery. Involved tissue is terminal vascular phase, and in a typical example, such as a series of changes in blood and connective tissue, removing the cause acts to restore damaged tissue.

In the human body, inflammation occurs for many reasons, and anti-inflammatory substances are taken or applied to treat it. As one of these anti-inflammatory substances, triterpene species such as β-sitosterol are also used as oral or transdermal preparations, through systemic action when used as oral preparations, and burns when used as transdermal preparations. Or, it is used locally in the treatment of inflammation, such as wounds.

However, when used as an ointment or cream, it is not easy to adjust the application amount and may be lost while wiping on clothes or other objects.

Therefore, there is a need for a new method for overcoming the limitations of effective substance delivery due to the skin barrier and improving 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 an anti-inflammatory substance into soluble microneedles and effectively delivering the anti-inflammatory substance into the skin and a method for manufacturing such a system.

Accordingly, the present invention provides soluble microneedles comprising an anti-inflammatory substance.

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

In addition, the present invention provides a method for preparing microneedles containing an anti-inflammatory substance.

In order to solve the above problems, the present invention provides soluble microneedles containing anti-inflammatory substances, 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. Disintegration releases anti-inflammatory substances into the skin.

After a long period of research, the present inventors have impregnated anti-inflammatory substances into soluble microneedles to effectively deliver the anti-inflammatory substances into the skin to have an excellent anti-inflammatory effect. There is a problem that the amount is small and the appearance is not good, and a certain amount is lost while being applied to clothes or other objects after application, but it was confirmed that the problem was fundamentally solved and the present invention was completed.

As used herein, the term "anti-inflammatory substance" is a term that collectively refers to all substances having an anti-inflammatory effect, and is not limited to any substance as long as it has an anti-inflammatory effect, and may preferably be a triterpene compound.

The triterpene compound is not limited thereto, but, for example, the anti-inflammatory substance is beta-sitosterol (β-sitosterol), 18-a-glycyrrhetinic acid, 18-β-glycyrrhetinic acid, 2-a- 3-a-dihydrooxyurs-12-3n-28-ionic acid, 3-a-hydroxyursolic acid, 3-oxo-ursolic acid, betulin, betulinic acid, celastrol, eburic acid, preedelin, glycyrrhizin , gypsogenin, oleanolic acid, oleanolic acid-3-acetate, pachymic acid, pinicolic acid, sorporadiol, soyasapogenol A, soyasapogenol B, trypterin, tryptophenolide, tumulosic acid, ursolic acid, ursol acid-3-acetate, uvaol or a mixture of two or more thereof.

In particular, in the present invention, a remarkable effect was confirmed using soluble microneedles containing β-sitosterol. Therefore, most preferably, it may be beta-sitosterol.

The present inventors have studied various administration systems, and none of the systems is similar to the method of impregnating soluble microneedles with the anti-inflammatory substance. After many efforts, the present inventors made a surprising invention that confirmed a remarkable effect without side effects by impregnating anti-inflammatory substances into microneedles.

As used herein, the term "impregnation" may refer to a form in which an anti-inflammatory substance can be contained in microneedles, and preferably i) contains an anti-inflammatory substance together with a soluble substance forming microneedles (microneedle structure Including a form in which the anti-inflammatory substance is dispersed within), or ii) by making a hole in the microneedle, the anti-inflammatory substance may be contained in the hole. When preparing the microneedles in the form of i) and ii), the anti-inflammatory material can effectively penetrate into the skin, and it is preferable to manufacture the microneedles in the form of i).

Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the anti-inflammatory substance 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 so that the anti-inflammatory substances contained in the microneedles can effectively penetrate into the skin by dissolving or collapsing the microneedles when the microneedles are applied to the skin. can

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 anti-inflammatory material may be included in an amount of 0.001 to 3% by weight, preferably 0.01 to 2% by weight, based on the weight of the preparation solution for preparing microneedles, based on the total weight of the preparation solution. 0.1 to 1% by weight may be included. When included in less than 0.001% by weight, an effective effect may not be exerted, and when included in more than 3% by weight, physical properties and durability of microneedles may be affected, which is undesirable.

In the present invention, the anti-inflammatory material may be included in 0.01 to 30% by weight, preferably 0.1 to 20% by weight, and more preferably 1 to 10% by weight, based on the total weight of the microneedles. When included in less than 0.01% by weight, effective effects 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.

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 administering (or delivering) anti-inflammatory substances 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 anti-inflammatory substance 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 anti-inflammatory substance 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 an anti-inflammatory substance so that the anti-inflammatory substance can penetrate into the hole formed by the microneedles, and the anti-inflammatory substance is impregnated into the microneedles to achieve an excellent skin administration effect. It is desirable to do

In addition, when the patch according to the present invention is used, the portion to which the patch is attached can be sealed from the outside, thereby preventing external contact and secondary infection of the affected area. In particular, since inflammation is vulnerable to external contact, when using the patch according to the present invention, exposure of the inflammation site to the outside can be fundamentally blocked.

In addition, the present invention comprises the steps of: S1) filling and mixing a material for forming microneedles including an anti-inflammatory material and a material soluble in the skin in a mold; And S2) providing a method for producing microneedles containing an anti-inflammatory material comprising the step of heating and drying the mold and separating it.

The method can be prepared by impregnating an anti-inflammatory substance into microneedles, and the impregnation is not limited thereto, but preferably i) contains an anti-inflammatory substance together with a soluble substance in the skin forming microneedles, or ii) microneedles piercing a needle and containing an anti-inflammatory substance in the puncture; and the like.

In the present invention, in order to impregnate the anti-inflammatory substance into the microneedles, the substance forming the structure of the microneedles and the anti-inflammatory substance are filled and mixed in a mold for forming the microneedles, and then the mold is heated, dried, and separated to obtain fine 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.

When applying the microneedles according to the present invention, it is easy to apply only the desired amount of the anti-inflammatory substance, which is difficult to control the amount of application, and the efficiency is excellent because the skin penetration amount is significantly higher than that of other formulations.

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.
Figure 3 is a graph showing the beta-sitosterol skin permeation amount 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 soluble microneedles containing beta-sitosterol (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 Beta-sitosterol One 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 beta-sitosterol ( β-sitosterol) was added to prepare a microneedle solution. 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 beta-sitosterol-containing cream (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 Beta-sitosterol 0.5 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 β-sitosterol was prepared with the composition shown in Table 2 above (Comparative Example 1).

<Experimental Example 1>

drug release behavior

The present inventors measured the β-sitosterol content of porcine skin tissues and acceptor solutions over time using a Franz diffusion cell using liquid chromatography. Example 1 was attached to pig skin and Comparative Example 1 was applied to compare the skin permeation amount of beta-sitosterol over time for 8 hours.

As a result, as shown in FIG. 3, Comparative Example 1 had an insignificant amount of about 0.14 μg permeated through the skin, but beta-sitosterol impregnated into the microneedles was directly penetrated into the skin by the needle, and the amount of permeation was At about 1.3 μg or more, it showed about 9 times higher skin permeation than cream.

Claims (9)

A water-soluble microneedle containing β-sitosterol as a microneedle-forming substance and an anti-inflammatory substance,
The β-sitosterol is impregnated into the water-soluble microneedles,
The material forming the microneedle may be hyaluronic acid or a salt thereof; carboxymethyl cellulose or a salt thereof; trehalose; and glycerin,
Water-soluble microneedle, characterized in that when the microneedle is applied to the skin, the material forming the microneedle is dissolved by moisture in the skin. delete delete delete According to claim 1,
The anti-inflammatory material is a water-soluble microneedle, characterized in that contained 0.01 to 30% 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 the anti-inflammatory material. delete A microneedle patch comprising the water-soluble microneedle according to any one of claims 1, 5 and 6. A method for manufacturing a water-soluble microneedle according to claim 1,
S1) filling and mixing the anti-inflammatory material and the material forming the microneedle in a 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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