KR20170000745A - Soluble microneedle patch for photosensitizer delivery - Google Patents

Abstract

The present invention relates to a dermal delivery system of a photosensitive material. The dermal delivery system of a photosensitive material stably embeds a photosensitive material, and effectively delivers the photosensitive material into the skin, thereby exhibiting excellent effects. The dermal delivery system is a microneedle comprising a photosensitive material. Also, provided is a dermal delivery system of a photosensitive material, applied with the microneedle.

Description

Soluble microneedle patch for photosensitizer delivery for photoreceptor delivery

The present invention relates to a soluble micro-needle and a method for producing a micro-needle.

In general, microneedle is used for delivery of active substances such as drugs and vaccines in vivo, detection of biological analyte, 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.

Unlike color cosmetics, which generally act on the surface of skin in cosmetic preparations and exhibit their effects, the effects of wool, hair growth, hair loss prevention, wrinkle improvement, whitening, skin moisturizing, hair removal, skin nutrition, etc., It works inside the skin such as transdermal and dermis and shows its effect.

Meanwhile, PDT (Photo Dynamic Therapy) is a method of regenerating and repairing a damaged part by penetrating a skin with a photosensitizer which reacts to a specific light and selectively stimulating the cell using a specific light beam, Blackheads, wrinkles, regrowth, and blackheads. Indole-3-acetic acid is also used as a photosensitizer for anti-cancer use (Korean Patent No. 10-0773475). However, the photosensitizer is hydrophilic or has a large molecular weight, and thus has problems such as not being absorbed into the skin and causing skin irritation due to photosensitivity.

In order to solve this problem, liposomalization of aminolevulinic acid (ALA), one of the photosensitive substances, has been proposed to reduce skin irritation and improve skin absorption ( Journal of Cosmetic and Laser Therapy , 2011: 13: 28-32) (Korean Patent Laid-Open No. 10-2008-0090741) which improves the skin absorption by blending in a natural liquid crystal emulsion base and the like. However, the stability of the base itself is limited with time, A solution to this problem is necessary because it is difficult to solve the above problem.

Korean Patent Publication No. 10-2008-0090741

The present invention is directed to a system for stably impregnating a photosensitizing substance into a dissolvable microneedle and effectively transferring the photosensitizing substance into the skin, a method for producing such a system, and a method for producing the same, Or a pharmaceutically acceptable salt thereof.

Accordingly, the present invention provides a soluble microneedle comprising a photosensitive material.

The present invention also provides a microneedle patch comprising the microneedles.

The present invention also provides a soluble micro-needle comprising microparticles containing a photosensitive substance.

The present invention also provides a method for producing a microneedle comprising a photosensitive material.

In addition, the present invention provides a cosmetic skin administration method of a photosensitizing substance which effectively transfers the photosensitizing substance to the skin, characterized by applying the microneedle.

In order to solve the above problems, the present invention provides a soluble micro-needle comprising a photosensitizer, more preferably, the material forming the micro-needle is dissolved in the skin, The needle dissolves or collapses and the photosensitizer is released into the skin.

The present inventors have confirmed that the stability of the formulation including the photosensitive material can be remarkably improved as well as the fact that the photosensitive material can be effectively delivered into the skin by impregnating the photosensitive material in the soluble fine needle after a long period of research Thereby completing the present invention. More specifically, the present invention overcomes the problem of discoloration and deterioration due to the fact that the photosensitizer is stabilized by impregnating the photosensitizer in the dissolvable microneedles, and the conventional photosensitizer is not absorbed into the skin, Which caused skin irritation.

In addition, the present invention can provide a soluble micro-needle including a microparticle containing a photosensitive material in order to stably impregnate the photosensitive substance in the soluble micro-needle, more preferably, the micro- The material to be formed is dissolved in the skin, and when the skin of the micro-needle is applied, the micro-needle dissolves or collapses, so that the micro-particles contained in the micro-needle rapidly go out into the skin and emit the photosensitive material from the micro-particles.

As used herein, the term "skin irritation mitigation" means prevention, alleviation, and / or prevention of irritation such as itching, tingling and burning appearing on the skin caused by skin irritants and inflammatory irritation such as erythema and edema, Or < / RTI >

In the present invention, the photosensitizer is a term including all substances which react at a specific wavelength used in photo dynamic therapy, such as photosensitizer, photosensitizer, and photosensitizer.

In the present invention, the photosensitizer may be selected from the group consisting of aminolevulinic acid (5-ALA), methylaminolevulinic acid (MAL), porphyrins, indole acetic acid ), Chlorella, xanthin and derivatives thereof, or substances contained in various plants, and reacting at specific wavelengths, and the like. Preferably, it may be 5-aminolevulinic acid (5-ALA), methylaminolevulinic acid (MAL) or indole acetic acid, more preferably indole acetic acid acetic acid, especially indole-3-acetic acid.

The present inventors have studied various administration systems and none of the systems has been able to simultaneously solve various problems of the photosensitive material. The present inventors have remarkably improved the problem of discoloration and detachment due to unstable formulation of the photosensitive material by impregnating the photosensitive material into the micro-needle after various efforts, and made a surprising invention that can effectively transmit the same to the skin without skin irritation.

Conventionally, in order to apply the photosensitizing substance to a site requiring broad-band dynamic therapy, a time period of 1 to 4 hours or more is required after applying the cream containing the substances to the lesion, It is not easily absorbed to the skin and it can not infiltrate the desired lesion in a short time. In particular, when the coating is applied to the outside of the skin due to the nature of the photosensitive material unstable to light, it should be shaded and sealed so as not to be exposed to light at the application site. However, exposure to light for a long time after application is not practically possible considering the application process. The present inventors tried to solve the above problems by infiltrating a photosensitive substance into a site desired to be treated in a short time.

The term "impregnation " as used herein may mean a form in which the photosensitive material may be contained in the microneedles, preferably i) contains a photosensitive material together with a soluble material forming a microneedle, ii ) Microparticles containing a photosensitive material in a microneedle, or iii) a hole in a microneedle to contain a photosensitive material in the hole. When the microneedles are prepared in the form of i) or ii), the photosensitizer can effectively penetrate into the skin, and in particular, when the microneedle is produced in the form of ii), the photosensitizer is applied to the lesion in a short time It is possible to solve the problem of unstable formulation of photosensitizing substance directly and to shorten the time required for photodynamic therapy.

In the case of the microneedle of the i) type, the photosensitive material may be contained in a form dispersed in the microneedle or may be contained in a form coated on the outer side of the microneedle. In the case of being contained in a dispersed form, a photosensitive material is present between the materials forming the microneedles.

Therefore, it is most preferable that the substance forming the microneedles is dissolved in the living body so that the photosensitizing substance contained in the microneedles is effectively released into the skin.

In a preferred embodiment of the present invention, the material forming the microneedle is dissolved in the skin, and when the microneedles are applied to the skin, the microneedles are dissolved or collapsed, so that the photosensitive material contained in the microneedles effectively penetrates into the skin can do.

In the present invention, the microneedles are preferably soluble in the skin. For example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), or the like may be used to form a soluble microneedle. , Water-soluble polymers such as vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinyl pyrrolidone; Sugars such as Xylose, Sucrose, Maltose, Lactose and Trehalose; Or a mixture thereof may be used. Considering the skin penetration strength of the microneedles and the dissolution rate in the skin comprehensively and taking into consideration the stability of the photosensitive material and the compatibility with the photosensitive material in particular, A mixture of hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (preferably trehalose) is preferable as the material for glycerin, and glycerin More preferably mixed.

Preferably, the microneedles of the present invention may further include plasticizers, surfactants, preservatives, anti-inflammatory agents, etc. in addition to the above-mentioned components 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 addition, in the microneedle according to an embodiment of the present invention, the material for forming the microparticles together with the photosensitive material should be capable of stably trapping the photosensitive material in the microneedle manufacturing process.

Examples of the material for forming such microparticles include poly (lactic acid), poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester, Biodegradable polymers such as polycaprolactone, mono-methoxypolyethylene glycol-polycaprolactone (MPEG-PCL), polyester amide, poly (butyric acid), poly (valeric acid), polyurethane, ; And polyesters such as cellulose, polyacrylates, ethylene-vinyl acetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl fluorides, poly (vinylimidazoles), chlorosulphonate polyolefins, , Polyethylene oxide, or a copolymer thereof may be used alone or in combination, but the present invention is not limited thereto.

(Lactic acid), poly (lactide), poly (glycolide), poly (lactide-co), and poly (lactide-co) Poly (lactide), poly (glycolide), and poly (lactide), and more preferably poly (lactide), poly Poly (lactide-co-glycolide) and a mixture of mono-methoxy polyethylene glycol-polycaprolactone (MPEG-PCL).

The microparticles may be of a matrix type or a reservoir type so long as the objects of the present invention can be achieved.

Microparticles that can be used in the present invention can be prepared by a variety of methods well known in the art. For example, microparticles usable in the present invention can be prepared by using a solvent exchange method, a solvent evaporation method, a membrane permeation method, a spray drying method, Can be manufactured. For example, the methods described in the Journal of Controlled Release 70 (2001) 1-20 and International Journal of PharmTech Research, 3 (2011) 1242-1254 may be used. Preferably by the general emulsification and solvent evaporation method.

Preferably, the diameter of the microparticles according to the present invention may be 0.01 to 10 [mu] m. If the microparticle size is more than 10 μm, the strength of the needle is impaired when impregnated with the micro-needle, which makes it difficult to permeate the skin. The diameter of the microparticles according to the present invention can be measured by a laser light scattering (LLS) method, for example, using a Zetasizer 2000 ^™ from Malvern.

Preferably, the microparticles of the present invention may contain 0.01 to 50% by weight, more preferably 0.1 to 30% by weight, of the photosensitive material relative to the total weight of the microparticles. The microneedles of the present invention preferably contain 0.05 to 20% by weight, more preferably 0.1 to 5% by weight, of the microparticles relative to the total weight of the microneedles.

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

In the present invention, the photosensitive material may include 0.0001 to 10% by weight, preferably 0.001 to 8% by weight, more preferably 0.01 to 5% by weight based on the total weight of the micro-needle. If the amount is less than 0.0001% by weight, the effective effect may not be exhibited. If the amount is more than 10% by weight, the possibility of skin irritation may be higher than that of the concentration.

In the present invention, the photosensitive material may be stably impregnated with the photosensitive material so that the photosensitive material is not discolored or removed during the production of the micro-needle. Conventionally, it has been necessary to stabilize a cream formulation including a specific ingredient for containing a photosensitive material sensitive to a light source in a cream formulation. However, in the case of the present invention, this problem is solved by impregnating the micro-needle.

When the microneedles according to the present invention are applied to the skin, the photosensitizing substance having a problem such as discoloration and swelling can be significantly improved in skin permeation compared to other skin administration systems.

The present invention also provides a microneedle patch comprising the microneedles, that is, a microneedle patch for administering (or delivering) a photoreceptor with the microneedles attached thereto.

In the present invention, the patch may refer to a sheet having at least one micro-needle impregnated with the photosensitive material of the present invention and having a surface on which the micro-needle is attached to the skin. The size of the sheet is not limited to a specific size, but may be appropriately adjusted depending on the amount of the photosensitive material to be absorbed on the skin or the attachment site. 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.

In addition, a photosensitive material may be contained in the surface of the patch that can be adhered to the skin, so that the photosensitive material may penetrate into the hole formed by the micro-needle. In order to solve the discoloration and deterioration problem of the photosensitive material, The sensitive material is preferably impregnated with a microneedle.

The present invention also provides a method of preparing a microneedle comprising a photosensitive material comprising a photosensitive material and a skin-soluble material.

The method may be prepared by impregnating a micro-needle with a photosensitive material, and the impregnation may include, but is not limited to, i) containing a photosensitive material together with a soluble material forming a microneedle, ii) The microparticles containing the substance may be contained in the microneedles, or iii) the microneedles may be punctured to contain the photosensitive material in the holes. When a microneedle is prepared in the form of i) or ii), it is possible to effectively penetrate into the skin while solving the problems of discoloration and detachment of the photosensitive material, and in particular, in the case of ii), the photosensitive material is more stable And can be easily controlled in dosage.

In the method of impregnating the photosensitive material with the microneedles, ii) a method of manufacturing microneedles comprising micro-particles containing a photosensitive material, that is, micro-particles, is described.

In the present invention, in order to produce a microneedle comprising a photosensitive material, S1) dissolving a photosensitive material together with a polymer forming microparticles to form microparticles; S2) filling a micro-needle mold with a solubility material forming a micro-needle structure and the microparticles together; And S3) heating the mold, drying and separating the mold.

In the present invention, the material for forming the microparticles may include poly (lactic acid), poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, Such as polyesters, polyesters, ether esters, polycaprolactones, mono-methoxypolyethylene glycol-polycaprolactone (MPEG-PCL), polyester amide, poly (butyric acid) Biodegradable polymers; And polyolefins such as cellulose, polyacrylates, ethylene-vinyl acetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl fluorides, poly (vinylimidazoles), chlorosulphonate polyolefins, , Polyethylene oxide, or a copolymer thereof, may be used alone or in combination.

In the present invention, the in-skin solubility material may include, for example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol vinyl alcohol, and polyvinyl pyrrolidone; Sugars such as Xylose, Sucrose, Maltose, Lactose and Trehalose; Or a mixture thereof may be used.

In addition, the present invention provides a cosmetic skin administration method of a photosensitizing substance that effectively transfers a photosensitizing substance into skin, which is characterized by applying a microneedle according to the present invention.

The term "application" is used herein to include both attaching a microneedle according to the present invention to the skin or attaching a microneedle patch according to the present invention to the skin.

The present invention provides a method for manufacturing a photosensitizing substance administration system capable of exhibiting an excellent effect through effective skin transfer of a photosensitizing substance. The present invention also provides a skin administration method of a photosensitizing substance, characterized by the application of such microneedles.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate exemplary embodiments of the invention and, together with the description of the invention, Should not be construed as limited.
FIG. 1 is a view showing one example of various methods for manufacturing a microneedle according to the present invention.
FIG. 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedles according to the present invention.
3 is a graph showing indole-3-acetic acid skin permeation amounts of Example 1 and Comparative Example 1. FIG.

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 microparticles containing indole-3-acetic acid>

The present inventors manufactured a microparticle containing a photosensitive material by a general emulsification and solvent evaporation method for producing microparticles. The matrix of the particle is a biodegradable polymer (poly lactic acid , poly caprolactone, etc) and cellulose.

At this time, when the particle size exceeds 10 μm, penetration of the skin is difficult because the strength of the needle is weak when the micro needle is impregnated, and preferably 10 μm or less.

In order to prepare microparticles containing indole-3-acetic acid, the present inventors firstly mixed 10 g of poly (lactic acid) (PLA) and 10 g of mono-methoxypolyethylene glycol-polycaprolactone (MPEG-PCL) diblock copolymer Was dissolved in 100 g of methylene chloride, and 3 g of indole-3-acetic acid was mixed to prepare a polymer-indole-3-acetic acid solution.

2.5 g of polyvinyl alcohol (PVA) was dissolved in 500 ml of purified water to prepare a PVA aqueous solution. Thereafter, an oil-in-water emulsion solution was prepared by adding a polymer-indole-3-acetic acid solution while stirring 500 ml of the PVA aqueous solution at 700 rpm. At this time, while stirring at 700 rpm for 24 hours, methylene chloride, which is an organic solvent, evaporated and stable indole-3-acetic acid microparticles were prepared.

The water was evaporated with an organic solvent so that the indole-3-acetic acid content was 3% total, while the remaining methylene chloride was completely removed using a rotary evaporator.

Analysis by liquid chromatography showed that the content of indole-3-acetic acid was 2.95%. The average particle size of microparticles was 450 nm as determined by particle size analyzer.

&Lt; 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 soluble micro-needles containing microparticles containing indole-3-acetic acid (Example 1)

Component (% by weight) Example 1 oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 DPG 10 Microparticles containing indole-3-acetic acid (3%) 3 water To 100

The present inventors have found that, in order to prepare soluble micro-needles containing microparticles containing indole-3-acetic acid, it is possible to use oligo-HA, sodium carboxymethyl cellulose (Na-CMC), trehalose, glycerin, Microparticles (3% of indole-3-acetic acid) containing dipropylene glycol (DPG) and indole-3-acetic acid were added to prepare a solution.

The prepared solution was cast in a silicon microneedle mold and 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 indole-3-acetic acid-containing serum (Comparative Example 1)

Name of raw materials (Unit:% by weight) Comparative Example 1 One Purified water To 100 2 Dipropylene glycol 8 3 1,2-hexanediol 1.5 4 Disodium iodide Suitable amount 5 Carbomer Suitable amount 6 Xanthan gum 0.3 7 glycerin 8 8 PIGGY-60 Hydrogenated Castor Oil 0.5 9 ethanol 5.0 10 Indole-3-acetic acid 0.2 11 Tromethamine (10%) Suitable amount

In order to compare indole-3-acetic acid impregnated with micro-needle and indole-3-acetic acid applied to serum, indole-3-acetic acid acid) was prepared.

The raw materials 1 to 7 and the raw materials 8 to 10 were heated and dissolved at 45 to 50 ° C as shown in Table 2, stirred for 2 minutes at 5500 rpm in a homomixer, and then the raw material 11 was placed in a homomixer and stirred at 5500 rpm for 4 minutes. (Comparative Example 1).

<Experimental Example 1>

Confirmed over time stability

Example 1 and Comparative Example 1 were stored at a constant temperature of 0 ° C, room temperature, 40 ° C, and 50 ° C for 4 weeks to confirm the stability of sample precipitation and discoloration.

division 30 days Room temperature 40 ℃ 50 ℃ 0 ℃ Example 1 stability stability Non-discolored stability Comparative Example 1 discoloration Discoloration Discoloration Non-discolored

As can be seen from the results of Table 3, the results of Example 1 were generally good at low temperature and high temperature as compared with Comparative Example 1. [

<Experimental Example 2>

Skin irritation improvement effect

The present inventors observed the degree of skin irritation by attaching the microneedles for 1 hour to the inside of the arms for 2 weeks and the serum for 2 weeks, respectively, in Example 1 and Comparative Example 1, respectively. (N = 20)

The reason why the skin stimulus of Example 1 is smaller than that of Comparative Example 1 is that the serum is applied for a long time in actual use, while the contact time of the skin is short because the microneedles are removed after a short time (1 hour) .

division After 1 day Two days later After 4 days After 6 days After 8 days After 10 days After 12 days After 14 days Example 1 0.06 0.08 0.06 0.08 0.08 0.10 0.10 0.08 Comparative Example 1 0.06 0.12 0.16 0.26 0.28 0.26 0.24 0.26

* Skin irritation is judged to be irritation when the skin irritation index is 0.2 or more, and skin irritation is usually 0.05 to 0.1 in the case of functional cosmetic.

<Experimental Example 3>

Drug release behavior

The present inventors measured the indole-3-acetic acid content of porcine skin tissue and acceptor solution with time using Liquid Chromatography using Franz diffusion cell. After attaching Example 1 and applying Comparative Example 1 (time: 2 hours, temperature: 32 ° C), it penetrated into the pig skin and dissolved, and the microneedles and serum were removed.

The pig skin, in which indole-3-acetic acid was absorbed by a microneedle, was placed in a franz diffusion cell (FIG. 2), and the concentration of indole-3-acetic acid The skin permeability was compared.

As a result, as shown in FIG. 3, the amount of the indole-3-acetic acid impregnated in the microneedles was directly transmitted through the skin to the skin by the needle, The permeation amount was about 25 μg or more, and the skin permeation amount was about 25 times higher than that of the serum.

Claims (13)

A soluble microneedle comprising a photosensitizer. The method according to claim 1,
The photosensitive material may be selected from the group consisting of aminolevulinic acid (5-ALA), methylaminolevulinic acid (MAL), porphyrins, indole acetic acid, chlorella, xanthin, and derivatives thereof. &lt; RTI ID = 0.0 &gt; 31. &lt; / RTI &gt; The method according to claim 1,
Wherein the material forming the microneedle is dissolved in the skin. The method of claim 3,
The microneedle forming material may be selected from the group consisting of hyaluronic acid, sodium-carboxymethylcellulose, sodium carboxymethyl cellulose (Na-CMC), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol Poly vinyl alcohol, polyvinyl pyrrolidone, saccharides, or a mixture of two or more thereof. 5. The method of claim 4,
Wherein the microneedles further comprise a plasticizer in addition to the material forming the microneedles. The method according to claim 1,
Wherein the photosensitive material is contained in an amount of 0.0001 to 10% by weight based on the total weight of the microneedles. The method according to claim 1,
Wherein the microneedles enhance the skin permeation amount of the photosensitive material. A soluble microneedle comprising microparticles containing a photosensitive material. 9. The method of claim 8,
Wherein the microparticles are selected from the group consisting of poly (lactic acid), poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoesters, polyetherester, polycaprolactone, (Methacrylic acid), methoxypolyethylene glycol-polycaprolactone (MPEG-PCL), polyester amide, poly (butyric acid), poly (valeric acid), polyurethane, cellulose, polyacrylate, ethylene- One selected from the group consisting of acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinylimidazole), chlorosulphonate polyolefins, polyethylene oxide and copolymers thereof Of the microneedle. 9. The method of claim 8,
Wherein the diameter of the microparticles is 0.01 to 10 mu m. A microneedle patch comprising the microneedle according to any one of claims 1 to 10. S1) dissolving the photosensitive material together with the polymer forming microparticles to form microparticles;
S2) filling a micro-needle mold with a solubility material forming a micro-needle structure and the microparticles together; And
S3) heating the mold, drying it, and separating the photosensitive material. 11. A method for the cosmetic skin administration of a photosensitizing substance which transfers a photosensitizing substance into the skin, characterized by applying the micro needle according to any one of claims 1 to 10.

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