KR102494542B1 - Soluble microneedle patch containing anti-itching drug in atopic dermatitis - Google Patents

Abstract

The present invention relates to a system for skin administration of a therapeutic agent for pruritus, which can exhibit excellent effects by stably impregnating a therapeutic agent for itch, in particular, a therapeutic agent for itch caused by atopic dermatitis, and effectively delivering it into the skin. as a technical feature.

Description

Soluble microneedle patch containing anti-itching drug in atopic dermatitis}

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.

Meanwhile, atopic dermatitis is a chronic and recurrent inflammatory skin disease that starts in infancy or childhood and is accompanied by pruritus (itching), dry skin, and characteristic eczema. In infancy, it starts as eczema on the spread side of the face and limbs, but as it grows, it appears in the form of eczema on the bent part of the arm and behind the knee, and in many cases, it tends to improve naturally as it grows. . In the case of adults, lichenification, in which the skin in the fold area becomes thicker, occurs, and eczema on the face is more common than in childhood. Atopic dermatitis is an increasing trend worldwide, and there is also a report that the prevalence is 20% of the population.

As a treatment for itching caused by atopic dermatitis, drugs such as Doxepin are used on the skin. In the case of such drugs, they are almost insoluble in water, so their inclusion in general cosmetics and ointment formulations is limited, and skin penetration is not easy. Due to this, there is a problem that it is difficult to see the effect by absorbing poorly soluble active ingredients.

Therefore, in the application of anti-pruritic agents, especially anti-pruritic agents caused by atopic dermatitis, there is a need for a new method that can be used to overcome the limitations of effective substance delivery due to the skin barrier and improve skin permeation 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 a therapeutic agent for itching and effectively delivering the anti-itch agent into the skin, and a method for manufacturing such a system.

Accordingly, the present invention provides soluble microneedles containing an anti-itch 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 a therapeutic agent for itching.

In order to solve the above problems, the present invention provides soluble microneedles containing an anti-pruritic agent, 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. The collapse causes the anti-itching agent to be released into the skin.

After a long period of research, the present inventors have found that the anti-itch treatment can be effectively delivered into the skin by impregnating the anti-itch 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 generally, the anti-itch treatment is water The present invention was completed by fundamentally solving the problem that it does not dissolve well in general cosmetics and / or ointment formulations, and it is limited by contact with the applied ointment or cream.

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

In addition, in the present invention, the "itch" is also referred to as pruritus, and includes all itching caused by a specific disease or specific cause, and the specific disease includes atopic dermatitis, contact dermatitis, nummular eczema, hives, scabies, insect bites, skin Dryness, mycosis fungoides, diabetes, chronic renal failure, biliary obstructive disease, and anemia may be present. In particular, in the present invention, the itching may be itching caused by atopic dermatitis.

Antipruritic agents that can be used in the present invention include, for example, doxepin, amitriptyline, naloxone, menthol, calamine, capsaicin, pheniramine maleate maleate), cyproheptadine hydrochloride, hydroxyzine hydrochloride, cetirizine, loratadine, ebastine, and fexofenadine.

In particular, in the present invention, doxepin can be used preferably among the anti-pruritic agents by confirming a remarkable effect using doxepin.

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

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

Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the anti-pruritic agent 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 anti-itching agent contained in the microneedles effectively penetrates into the skin, , Since the microneedles contain a soluble polymer, it is possible to release a small amount of anti-itching agent within the skin to sustain the effect for a long time, thereby reducing the number of applications and maximizing the effect of the anti-itching agent. In particular, the microneedles may include a sustained-release polymer in order to release a small amount of the anti-pruritic agent 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 anti-itch agent may be included in 0.001 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, based on the total weight of the microneedles. When included in less than 0.001% by weight, effective effects may not be exerted, and when included in more than 10% 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) an anti-pruritic agent 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-itching agent 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-itching agent 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-itching agent so that the anti-itching agent can penetrate the hole formed by the microneedles, and the anti-itching 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 material for forming microneedles including a therapeutic agent for itching and a material soluble in the skin; And S2) provides a method for producing microneedles containing an anti-itch treatment comprising the step of warming and drying the mold and separating it.

The method may be prepared by impregnating the anti-itching agent into microneedles, and the impregnation is not limited thereto, but preferably i) contains the anti-itching agent 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 anti-itch agent in the hole.

In the present invention, in order to impregnate the anti-itching agent into the microneedles, the material forming the structure of the microneedles and the anti-itching agent are mixed together, filled in a mold for forming the microneedles, and then the mold is heated, dried, and separated to finely 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-itch therapeutic agent capable of exhibiting excellent effects through effective skin delivery of the anti-itch therapeutic agent.

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 anti-itch treatment (Doxepin) 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.

<Manufacture of soluble microneedles containing Doxepin (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 Doxepin 0.3 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 Doxepin solution (Doxepin 10%, dipropylene glycol 90%) was added to prepare a microneedle solution in which Doxepin was dispersed. The prepared Doxepin dispersion solution was cast in a silicone 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).

<Manufacture of cream containing Doxepin (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 Doxepin 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 Doxepin was prepared with the composition shown in Table 2 above (Comparative Example 1).

<Experimental Example 1>

drug release behavior

The present inventors measured the doxepin content of porcine skin tissues and acceptor solutions 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 Doxepin was absorbed in Example 1 and Comparative Example 1 was put into a franz diffusion cell (FIG. 2), and the skin permeation amount of Doxepin over time was compared.

As a result, as shown in FIG. 3, Comparative Example 1 had an insignificant amount of about 1.56 μg permeated through the skin, but Doxepin impregnated into the microneedles was directly penetrated into the skin by the needle. The permeation amount was about 16 μg or more, which was about 10 times higher than that of cream.

Claims (10)

A water-soluble microneedle containing a material forming the microneedle and doxepin as a therapeutic agent for itching,
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 delete According to claim 1,
The anti-itch treatment 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 amount of skin permeation of the anti-itch treatment. According to claim 1,
The itching is a water-soluble microneedle, characterized in that itching caused by atopic dermatitis. A microneedle patch comprising the water-soluble microneedle according to any one of claims 1 and 6 to 8. A method for manufacturing a water-soluble microneedle according to claim 1,
S1) filling a mold with a mixture of doxepin as an anti-itch agent and a material for forming the microneedles; 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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