KR20170124322A - Soluble microneedle patch for delivery of antiallergic drugs - Google Patents

Abstract

The present invention relates to a specific formulation or a system for efficient injection of allergy treatment agents. According to the present invention, by using the microneedle, the allergy treatment agents contained in the microneedle can penetrate into skin without pain, and can be delivered into skin efficiently, In addition, constant pain generated due to application of the microneedle alleviates symptoms of allergy, while ensuring excellent penetration rate for the allergy treatment agents, thereby bringing remarkable therapeutic effects on allergy.

Description

Soluble microneedle patch for delivery of antiallergic drugs for the treatment of allergic diseases.

The present invention relates to a specific formulation or system for the efficient administration of a therapeutic agent for allergic diseases.

In general, microneedle is used for delivery of an active substance such as a drug in vivo, detection of an analyte in the body, and biopsy. The delivery of the pharmacologically or cosmetically active ingredient using microneedles is intended for the delivery of the active substance through the skin, not the vascular system such as blood vessels or lymphatic vessels.

Examples of the method using the microneedle include a method of forming a predetermined number of holes or more on the skin using a microneedle device such as a roller with a microneedle attached thereto, (Active ingredient) is coated on the skin to allow the active ingredient to be administered simultaneously with the perforation of the skin.

Allergy, on the other hand, is a harmful immune response, and is associated with an unnecessary immune response, or hypersensitivity, to external antigens, such as house dust mites or pollen, that are generally harmless to our bodies. In other words, the human body shows an exaggerated response to the external stimuli, so that it has a harmful effect on the human body. Allergy-related diseases are chronic and recurrent immune-related diseases such as rhinitis, asthma, atopic dermatitis, conjunctivitis, and chronic idiopathic urticaria (urticaria).

Allergic rhinitis is often associated with other allergic diseases such as asthma, atopic dermatitis and conjunctivitis. About 10% of children and 10-15% of puberty are symptomatic. Seasonal allergic rhinitis (seasonal allergic rhinitis) and seasonal allergic rhinitis (seasonal allergic rhinitis) are seen all year round. Chronic idiopathic bilirubin (urticaria) is a common skin disease with increased permeability of blood vessels present in the skin or mucous membranes, temporarily accumulating plasma components in tissues, resulting in reddening of the skin, swelling in white, and severe itching.

Typical treatments for allergic diseases include antihistamines, which are generally used orally. In particular, in the case of urticaria and pruritus (pruritus), the intake of drugs such as chlorpheniramine maleate may cause side effects such as headache, drowsiness and sedation. In addition, antihistamines having poor skin permeability when applied to skin are limited to be included in general cosmetics and ointment formulations, and skin permeation is not easy and the effect is insignificant.

Therefore, in the application of the therapeutic agent for allergic diseases, especially the allergic skin disease caused by hives, it is possible to avoid the side effects due to oral ingestion, to overcome the limit of efficacy transferring due to skin barrier and to improve the skin permeation efficiency There is a need for a method.

Korean Patent Publication No. 10-2014-0125364

A problem to be solved by the present invention is to provide a system for efficient administration of a therapeutic agent for allergic diseases.

In order to solve the above problems, the present invention provides a soluble micro-needle comprising an agent for treating an allergic disease. That is, the microneedles according to the present invention include a therapeutic agent for allergic diseases, and may be soluble micro-needles for treating allergic diseases.

The present inventors have made various attempts to administer therapeutic agents for allergic diseases. First, when an antihistaminic agent is used among the therapeutic agents for allergic diseases, when a conventional composition for oral administration is used, side effects such as headache, drowsiness and sedative effects may occur. Therefore, other methods, in particular transdermal administration, are contemplated for the effective use of antihistamines without side effects, rather than using compositions for oral administration. However, as a conventional composition for external application for skin, there is a problem in that the application of the composition to skin is not easy and the effect is insignificant.

Accordingly, the inventors of the present invention have completed the present invention by confirming that the above-mentioned problem can be solved by introducing microneedle (microneedle) system for skin administration of an allergic disease therapeutic agent.

In particular, the present inventors have experimentally confirmed that the skin permeation amount of antihistaminic agents, particularly diphenhydramine, is significantly improved in the therapeutic agent for allergic diseases as compared with the conventional skin application formulations. That is, the microneedles are characterized by enhancing the skin permeation amount of the therapeutic agent for allergy disease.

As used herein, the term "allergic disease" means a disease caused by an excessive action of a living body immune system when foreign substances such as bacteria or viruses invade from the outside. Such allergic diseases may be caused by environmental changes such as air pollution, changes in eating habits, increase in physical or mental stress, indoor pollution due to changes in the residential environment, or changes in human constitution.

Such allergic diseases include rhinitis, urticaria, asthma, dermatitis, and conjunctivitis. In particular, the urticaria may be caused by physical stimulation (compression, vibration, sunlight, cold temperature, cold food, rapid temperature change, exercise, localized heat exposure, etc.), food (chocolate, shellfish, peanut, tomato, pork, , Drugs (aspirin, vitamins, insulin, anti-inflammatory analgesics, narcotic analgesics, sulfonic antibiotics), food and food additives (yeast, salicylic acid, citric acid, azo dyes and benzoate derivatives) .

The therapeutic agents for allergic diseases that can be used in the present invention include diphenhydramine, chlorpheniramine maleate, dexbrompheniramine maleate, pheniramine maleate, hydroxyzine hydrochloride, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as hydrochloride, diphenylpyraline hydrochloride, acrivastine, cetirizine, levocetirizine, loratadine, desloratadine, ebastine , And fexofenadine, preferably diphenhydramine. [0031] The term " pharmaceutically acceptable carrier "

The length of the microneedles according to the present invention is not limited to a specific size. However, for the purpose of the present invention, the height from the tip of the microneedle is preferably 100 to 1000 mu m, more preferably 150 to 500 mu m.

The micro-needle for achieving the desired effect of the present invention is a soluble micro-needle, and the material forming the micro-needle is biodegraded or dissolved in the skin, so that when the micro-needle is applied to the skin, the micro-needle dissolves or collapses, It is preferable that the antihistamine contained in the drug is released.

The microneedles according to the present invention can be easily applied to allergic diseases without side effects by a non-invasive method even for an unskilled public, and the pain generated by the application of the microneedles can alleviate symptoms of allergic diseases Therapeutic agents for allergic diseases contained in the body (dispersed) can exert an immediate effect in the skin and exert an excellent therapeutic effect on allergic diseases.

The therapeutic agent for allergic disease according to the present invention may be impregnated in a form dispersed in the micro-needle or may be contained in a form coated on the outside of the micro-needle. When impregnated in a dispersed form, a therapeutic agent for allergic diseases is present between biodegradable or skin-soluble substances forming microneedles.

More specifically, in order to administer the therapeutic agent for allergic disease according to the present invention, it is preferable that the micro-needle is made of a substance which dissolves in the skin rather than the biodegradable polymer. Examples of the micro-needle include hyaluronic acid, sodium- One selected from the group consisting of sodium carboxymethyl cellulose (Na-CMC), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, and sugar Or more can be used. The sugar may be xylose, sucrose, maltose, lactose, trehalose or a mixture of two or more thereof.

Considering the skin penetration strength of the micro-needle and the dissolution rate in the skin comprehensively, and considering compatibility with the therapeutic agent for the allergy disease, among the microneedle forming materials, It is preferable that diphenhydramine is used as a therapeutic agent, and the fine needle is preferably prepared using hyaluronic acid, sodium-carboxymethylcellulose and a mixture of sugars. In such a mixture, the sugar is more preferably trehalose.

In the present invention, the therapeutic agent for allergic disease may be included in an amount of 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 micro needle. If it is contained in an amount of less than 0.001% by weight, it may not exhibit an effective effect, and if it is contained in an amount exceeding 10% by weight, the physical properties and durability of the fine needle may be affected.

Preferably, the microneedle of the present invention may further include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent and the like in addition to the above-mentioned materials for forming microneedles.

Examples of the plasticizer include polyols such as ethylene glycol, propylene glycol, dipropylene glycols, butylene glycol, and glycerin. Or may be used in combination. In particular, glycerin is preferable as a result of various evaluations in terms of compatibility with a therapeutic agent for allergy disease.

The present invention also provides a microneedle patch comprising the microneedles. That is, the present invention provides a microneedle patch having a plurality of such microneedles as well as a microneedle itself containing an agent for treating allergies. The size of the patch is not limited to a specific size, but may be appropriately adjusted depending on the amount or the attachment site of the therapeutic agent for allergy to be absorbed into the skin.

More specifically, in the present invention, the patch may refer to a sheet having one or more micro-needles impregnated with an allergic disease therapeutic agent and attached to the skin. The size of the sheet is not limited to a specific size and can be appropriately adjusted depending on the amount or the attachment site of the therapeutic agent for allergy to be absorbed into the skin. In addition, one or more, preferably a plurality of micro-needles may be attached to the surface of the sheet which can be attached to the skin.

The present invention also relates to a method for preparing a microcapsule comprising the steps of: S1) filling a mold with an agent for treating an allergic disease and a micro-needle-forming material containing a skin-solubilizing substance; And S2) warming the mold, drying, and then separating the mold. The present invention also provides a method for producing a micro-needle including an allergic disease agent.

The microneedles according to the present invention can penetrate into the skin without pain and effectively deliver the therapeutic agent for allergy disease contained in the microneedles to the skin, and the pain generated by the application of the microneedles alleviates the symptoms of allergic diseases And has an excellent permeability of the therapeutic agent for allergic diseases, so that it can have a remarkable therapeutic effect on allergic diseases.

FIG. 1 is a view showing one example of various methods for manufacturing a microneedle according to the present invention.
FIG. 2 is a view showing a Franz diffusion cell for evaluating drug release behavior of a microneedle according to the present invention. FIG.
3 is a graph showing the skin permeation amount of the allergic disease agent (diphenhydramine) of Example 1 and Comparative Example 1 according to the present invention.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Preparation of soluble fine needle >

Soluble microneedles are prepared by solution casting method, and they are prepared by casting solution into mold, filling solution into micro mold by vacuum or centrifugation and drying.

Conventional synthetic and natural water-soluble polymers were used for the materials forming the microneedle structure.

Preparation of Dissolving Micro Needles Containing Diphenhydramine (Example 1)

ingredient Example 1
(Unit: wt%) oligo-HA 6 Na-CMC 6 Trehalose 10 glycerin 4 Dipropylene glycol 2.7 PEG-40 Hydrogenated Chain Oil One Diphenhydramine 0.3 water To 100

^{Oligo-HA TM (Hyaluronic acid)} , Na-CMC (Sodium carboxymethyl cellulose) and trehalose (Trehalose) a was dissolved in purified water, glycerin (Glycerin), PEG-40 dihydro jeneyi suited Kester five days (HCO-40 ^TM) and diphenhydramine (Diphenhydramine 10%, dipropylene glycol 90%) was added to prepare diphenhydramine dispersed microneedle solution. The prepared diphenhydramine dispersion solution was cast in a silicon microneedle mold and then centrifuged at 3000 rpm for 10 minutes to fill the micro mold with the solution. After the solution was filled, it was dried in a drying oven (70 ° C) for 3 hours, and the fine needle was separated from the silicone mold using an adhesive film (Example 1).

≪ Preparation of diphenhydramine-containing cream (Comparative Example 1) >

ingredient Comparative Example 1
(Unit: wt%) C14-22 alcohol, C12-20 alkyl glucoside
(Mixture C14-22 alcohol: C12-20 alkyl glucoside = 80:20 weight ratio) 1.5 Glyceryl stearate, phage-100 stearate
(Mixture 50:50 weight ratio) 1.2 Glyceryl stearate 0.9 Cetearyl alcohol 1.5 Polyglyceryl-3 methyl glucoside 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 Diphenhydramine One Purified water To 100

To compare the effect of the effective ingredient applied to the microneedle-impregnated active ingredient and the underwater emulsifier type cream, a cream containing diphenhydramine was prepared according to the composition of Table 2 (Comparative Example 1).

< Experimental Example  1>

Drug release behavior

The present inventors measured the content of diphenhydramine in porcine skin tissue and acceptor solution with Franz diffusion cell using time-lapse chromatography (Liquid Chromatography). Example 1 was applied to pig skin and Comparative Example 1 was applied to penetrate into pig skin and dissolve, followed by removal of fine needle and cream.

Pig skin absorbed with diphenhydramine by Example 1 and Comparative Example 1 was placed in a franz diffusion cell (Fig. 2), and skin permeation amount of diphenhydramine was compared with time.

As a result, as shown in FIG. 3, Comparative Example 1 had a slight amount of about 2.85 μg permeated through the skin, but diphenhydramine impregnated in the fine needle was directly penetrated to the skin by the needle, The skin permeation amount was higher than cream by about 10 times or more at about 29 μg or more.

Claims (8)

Soluble microneedles containing an allergic disease agent. The method according to claim 1,
Wherein the therapeutic agent for allergic disease is diphenhydramine. The method according to claim 1,
The microneedles may be selected from the group consisting of hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinylpyrrolidone (Polyvinyl pyrrolidone), and a saccharide. The micro-needle according to claim 1, The method of claim 3,
Wherein the microneedles further comprise a plasticizer in addition to the material forming the microneedles. The method of claim 3,
&Lt; / RTI &gt; wherein said sugar is trehalose. The method according to claim 1,
Wherein the therapeutic agent for allergic disease is contained in an amount of 0.001 to 10% by weight based on the total weight of the microneedles. The method according to claim 1,
Wherein the microneedles are for the treatment of allergic diseases. A microneedle patch comprising a microneedle according to any one of claims 1 to 7.

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