KR102399484B1 - Soluble microneedle patch for delivery of antipsoriatic drug - Google Patents

Abstract

The present invention relates to a system for administering anthraline to the skin that can exhibit excellent effects by stably impregnating the anthralin and effectively delivering it into the skin.

Description

Soluble microneedle patch for delivery of antipsoriatic drug

The present invention relates to microneedles and a method for manufacturing 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. Delivery of a pharmaceutically or cosmetically active ingredient using a microneedle aims to deliver an active substance through the skin rather than the biological circulation system such as blood vessels or lymphatic vessels.

As a method of using such a microneedle, a microneedle device such as a roller to which the microneedle is attached is used to form more than a certain number of holes in the skin, then a drug is applied over the surface of the microneedle, and the active ingredient is applied to the surface of the microneedle. A form in which the active ingredient is administered at the same time as the skin is punctured by coating (active ingredient) is generally used.

Psoriasis is a chronic inflammatory skin disease in which red papules or plate-like rashes of various sizes and covered with silvery-white scales repeatedly occur on the skin of the body. It is characterized by inflammation and occurs with a frequency of 1-2% of the population. The location of the disease occurs in various areas such as elbows, knees, buttocks, scalp, and the skin of the palms, nails, and toenails.

There are several methods used to treat psoriasis. In other words, there are topical treatment with medicine, phototherapy with light, and systemic treatment with medicine, and treatment is carried out in consideration of the patient's age, access to treatment, and mental condition.

Currently, anthralin, which is used as a treatment for psoriasis, is used as a compound for topical treatment of psoriasis. However, when used in a way that is applied to the general skin surface, it can irritate the skin and cause discoloration. In particular, since it can cause coloration on clothes and bedding, it is inconvenient in daily life, such as avoiding contact with clothes and bedding after applying anthralin.

In addition, the solubility of anthralin is low, which limits its inclusion in general cosmetics and ointment formulations, and although skin penetration is not easy, there is currently no technology capable of solving this problem.

Republic of Korea Patent Publication No. 10-2008-0047312

The problem to be solved by the present invention is to provide a system for effectively delivering anthralin into the skin by stably impregnating a poorly soluble component, particularly anthralin, into a soluble microneedle, and a method for manufacturing such a system.

Accordingly, the present invention provides a soluble microneedle comprising anthralin.

In addition, the present invention provides a method for producing a microneedle containing anthralin.

In order to solve the above problems, the present invention provides a soluble microneedle containing anthralin, and more preferably, the material forming the microneedle is dissolved in the skin and microneedles are applied to the skin. Dissolving or disintegration of the needle causes the release of anthralin into the skin.

After a long period of research, the present inventors have confirmed that by impregnating anthralin in soluble microneedles, anthralin can be effectively delivered into the skin as well as the problem of skin irritation and coloring of anthralin can be fundamentally solved, and the present invention was completed. More specifically, by impregnating anthralin in the soluble microneedles, it was confirmed that the effects of anthralin were more effective while overcoming the problems of low skin permeability, skin irritation and coloration of anthralin.

More specifically, in the case of a cream formulation that is conventionally applied to the skin containing anthralin, anthralin has problems with skin irritation and coloration, so low concentration of anthralin is used, high concentration short-term contact therapy to shorten the application time, etc. It was proposed and used as a countermeasure. However, in the case of the above alternatives, when anthralin is used at a low concentration, it may not be effective for psoriasis, and in the case of short-term contact with a high concentration (10-20%), a lasting effect cannot be expected, and any countermeasures can solve the problem of coloration. Couldn't come up with a way to solve it. However, when the microneedle of the present invention is impregnated with anthralin, the conventional problem can be fundamentally solved. In particular, it is possible to fundamentally solve the problem of coloring by directly penetrating into the skin without adding other compounds.

In addition, although there is a problem that skin penetration is not easy, the microneedle is impregnated so that anthralin can fundamentally penetrate into the skin.

As used herein, the term "alleviating skin irritation" means preventing, alleviating, and treating irritation such as itching, stinging, and burning on the skin caused by skin irritants and inflammatory irritant reactions such as erythema and edema means to do

In the present invention, the anthralin is a compound of the molecular formula C ₁₄ H ₁₀ O ₃ and a molecular weight of 266 represented by the following formula (1), also called dithranol (dithranol). If it is a compound represented by the structural formula of Formula 1 below, it may include anthralin isolated from an anthralin-containing sample, artificially synthesized anthralin, and commercially available anthralin.

[Formula 1]

The present inventors have studied various administration systems, and none of them are easy to solve the various problems of anthralin at the same time. The present inventors have made a surprising invention that can fundamentally solve the problems of skin permeability, skin irritation, and coloration of anthralin by impregnating the microneedle with anthralin after several efforts, and can effectively deliver it into the skin.

As used herein, the term "impregnated" may refer to a form in which anthralin can be contained in microneedles, preferably i) containing anthralin together with a soluble substance forming the microneedles, or ii ) may be punctured with a microneedle to contain anthralin in the hole. When the microneedles are manufactured in the form of i) and ii), anthralin, a poorly soluble substance, can effectively penetrate into the skin. , it can fundamentally solve skin irritation and pigmentation problems.

Therefore, it is most preferable that the substance forming the microneedles is dissolved in the living body and the anthralin 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 when the microneedles are applied to the skin, the microneedles are dissolved or collapsed, thereby effectively penetrating the anthralin contained in the microneedles into the skin. , The microneedle contains a soluble polymer, so that anthralin can be released little by little in the skin, so that the effect can be sustained for a long time. In particular, in order to continuously release anthralin from the skin, the microneedle may contain a sustained-release polymer. The sustained-release polymer is not limited thereto, but for example, poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyether ester , polycaprolactone, polyesteramide, poly (butyric acid), poly (valeric acid), polyurethane, and may be a biodegradable polymer such as copolymers thereof. In particular, during 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 copolymer material.

Therefore, when anthralin is used as a method of applying a conventional cream to the skin, skin irritation and coloring problems cannot be fundamentally solved, so it is applied for a short time and then washed off. It has the advantage of being able to maintain the effect for a long time with one application by controlling the release rate.

In the present invention, the microneedles may be preferably soluble in the skin, and in order to form a soluble microneedle, for example, hyaluronic acid, sodium-carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) Water-soluble polymers such as , vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used. In particular, when the skin penetration strength of the microneedles and the dissolution rate in the skin are comprehensively considered, hyaluronic acid, sodium-carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose), and saccharides (preferably A mixture of trehalose) is preferable, and it is more preferable that it is also mixed with glycerine (Glycerine).

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

As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerine are alone. may be used as or in combination.

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

In the present invention, the anthralin may be included in an amount of 0.001 to 5% by weight, preferably 0.01 to 3% by weight, and more preferably 0.1 to 1% by weight, based on the total weight of the microneedles. When included in an amount of less than 0.001% by weight, an effective effect may not be exhibited, and when included in an amount of more than 5% by weight, it is undesirable because it may affect the physical properties and durability of the microneedles.

When the microneedle according to the present invention is applied to the skin, anthralin, which has problems such as skin permeability, skin irritation and coloration, can be significantly improved compared to other conventional skin administration systems, and skin irritation This is significantly alleviated and no coloring problem occurs.

In addition, the microneedle according to the present invention can be used for the treatment of psoriasis.

In addition, the present invention provides a microneedle patch for administering (or delivering) anthralin to which the microneedles are attached.

In the present invention, the patch may refer to a sheet to which one or more anthralin-impregnated microneedles of the present invention are attached, and a 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 anthralin to be absorbed into the skin or an attachment site. In addition, one or more, preferably, a plurality of microneedles may be attached to the surface of the sheet that can be attached to the skin.

In addition, by containing anthralin on the side that can be attached to the skin of the patch, anthralin can penetrate into the hole formed by the microneedles. Lin is preferably impregnated with the microneedles.

In addition, the present invention comprises the steps of: S1) mixing anthralin and a material forming a microneedle containing a soluble substance in the skin by filling a mold; and S2) heating and drying the mold, and then separating the microneedles.

The method may be prepared by impregnating the microneedles with anthralin, wherein the impregnation is preferably, but not limited to, i) containing anthralin together with a soluble substance in the skin forming the microneedles, or ii ) by making a hole in the microneedle to contain anthralin in the hole.

In the present invention, in order to impregnate the microneedles with anthralin, the material forming the microneedle structure and anthralin are filled and mixed together in a mold for forming microneedles, then the mold is heated, dried, and separated Thus, microneedles can be manufactured.

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), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (Poly vinyl alcohol), and water-soluble polymers such as polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used.

The present invention can fundamentally solve the problems of skin permeability, skin irritation and coloration of anthralin through effective skin delivery of anthralin.

The following drawings attached to the present specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the above-described content of the present invention, so the present invention is limited to the matters described in those drawings It should not be construed as limiting.
1 is a view showing an example of several methods for manufacturing a microneedle according to the present invention.
Figure 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedle according to the present invention.
3 is a graph showing the amount of anthralin skin permeation of Example 1 and Comparative Example 1. FIG.

Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<Production of soluble microneedles>

The soluble microneedles are manufactured by the solution casting method, by casting the solution to a mold, filling the micro-mold with a liquid by vacuum or centrifugation, and then drying it.

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

<Preparation of soluble microneedles containing anthralin (Example 1)>

Raw material name (content wt(%)) Example 1 oligo-HA 6.0 Na-CMC 6.0 Trehalose 10.0 Glycerin 4.0 dipropylene glycol 2.7 PEG-40 Hydrogenated Castor Oil 1.0 anthralin 0.3 Purified water To 100

After dissolving Oligo-HA ^TM (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and trehalose in purified water, glycerin, PEG-40 hydrogenated castor oil (HCO-40 ^TM ) and anthral A solution in which anthralin was dispersed was prepared by adding a lean solution (anthralin 10% by weight, dipropylene glycol 90% by weight). The prepared solution was cast on a silicone microneedle mold, and then 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 microneedles were separated from the silicone mold using an adhesive film (Example 1).

<Anthralin-containing oil-in-water cream preparation (Comparative Example 1)>

Raw material name (content wt(%)) Comparative Example 1 One C14-22 alcohol, C12-20 alkyl glucoside 1.5 2 Glyceryl Stearate, PEG-100 Stearate 1.2 3 Glyceryl Stearate 0.9 4 cetearyl alcohol 1.5 5 Polyglyceryl-3-methylglucose distearate 1.5 6 Hydrogenated Polydecene 4.5 7 Cyclohexasiloxane 3.5 8 Carbomer 0.2 9 tromethamine 0.2 10 glycerin 3.0 11 dipropylene glycol 5.0 12 1,2-Hexanediol 2.0 13 anthralin 1.0 14 Purified water To 100

In order to compare the active ingredient impregnated in the microneedle with the active ingredient applied to the oil-in-water cream, an anthralin-containing cream was prepared with the composition of Table 2 above.

< Experimental example 1>

drug release behavior

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

Pig skin into which anthralin was absorbed according to Example 1 and Comparative Example 1 was put into a franz diffusion cell (FIG. 2), and the amount of anthralin permeation through the skin was compared with time.

As a result, as shown in FIG. 3 , in Comparative Example 1, the amount permeated through the skin was insignificant, about 1 μg, but the anthralin impregnated in the microneedles directly penetrated into the skin by the needle and the permeation amount was about At 17 μg or more, it showed a higher skin permeation amount than the cream by about 15 times or more.

Claims (9)

A soluble microneedle in the skin comprising (i) anthralin as an active ingredient and (ii) a substance forming a microneedle,
The microneedle, characterized in that the material forming the microneedle is dissolved in the skin. delete According to claim 1,
The material forming the microneedle is hyaluronic acid, sodium-carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (Poly vinyl alcohol), poly A microneedle, characterized in that it is a vinyl pyrrolidone (Poly vinyl pyrrolidone), a saccharide, or a mixture of two or more thereof. 4. The method of claim 3,
The microneedle, characterized in that it further comprises a plasticizer (plasticizer). According to claim 1,
The microneedle, characterized in that the anthralin is contained in 0.001 to 5% by weight based on the total weight of the microneedle. According to claim 1,
The microneedle is a microneedle, characterized in that it improves the skin permeation amount of anthralin. According to claim 1,
The microneedle is a microneedle, characterized in that it is for the treatment of psoriasis. A microneedle patch comprising the microneedle according to any one of claims 1 and 3 to 7. S1) mixing anthralin as an active ingredient and a material forming a microneedle containing a soluble substance in the skin by filling a mold; and
S2) A method for producing a microneedle soluble in the skin containing anthralin, comprising the step of separating after heating and drying the mold.

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