KR20160128896A - Soluble Microneedle patch for Oxyresveratrol delivery - Google Patents

Abstract

The present invention relates to a dermal injection system of oxyresveratrol, which exhibits an excellent effect by stably immerse oxyresveratrol, and effectively delivering the immersed oxyresveratrol into the skin. The dermal injection system includes a microneedle containing oxyresveratrol. According to the present invention, provided is a dermal injection method of oxyresveratrol, which applies the microneedle.

Description

Soluble Microneedle patch for Oxyresveratrol delivery containing Oxy Resveratrol}

The present invention relates to a microneedle and a method for producing the microneedle.

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.

Therefore, skin irritation occurs when the microneedles are applied to the skin, and erythema or the like occurs on the skin when the degree is too high.

On the other hand, Oxyresveratrol greatly inhibits the activity of tyrosinase in melanoma cells, giving excellent whitening effect, but has a problem that transdermal absorption is hardly observed. Methods for encapsulation and formulation of lipid-based (liposome, ethosome, etc.), derivatization of efficacious components, and various enhancers have been studied to promote transdermal absorption, but they have been effectively solved by problems such as skin irritation and transdermal absorption I can not do that.

Therefore, there is an urgent need to develop a system capable of improving the skin permeability of oxyreservatrix and exerting an excellent skin whitening effect while alleviating skin irritation caused by the application of the microneedles to the skin.

Korean Patent Publication No. 10-2013-0058926

SUMMARY OF THE INVENTION The object of the present invention is to provide a system for effectively delivering oximes resveratrol to a skin by stably impregnating a resorcinol with a soluble fine needle, a method for producing such a system, and a method for administering oximes resveratrol to skin using such a system It is to provide a method.

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

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

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

In addition, the present invention provides a cosmetic skin administration method of oxyreservatrol which stably impregnates oxirebazel hydrochloride and effectively delivers oximes resveratrol into the skin, characterized by applying the microneedles.

In order to solve the above-mentioned problems, the present invention provides a dissolvable microneedle comprising oxyresveratrol, more preferably, the material forming the microneedle is dissolved in the skin, and when the skin of the microneedle is applied, Is dissociated or collapsed, resulting in the release of oxyreservatrix into the skin.

The inventors of the present invention confirmed that oxirebazel hydrochloride can be effectively delivered into the skin by impregnating oxyservatrol in a soluble microneedle at the end of a long period of research and that the problem of skin irritation due to the application of microneedles can be remarkably improved, . More specifically, oxiresveratrol is impregnated in a soluble micro-needle, and oxiresveratrol acts directly on the inside of the skin to exert an excellent skin whitening effect. As oximes resveratrol is impregnated into the micro-needle, the skin caused by the application of the micro- And thus the present invention has been completed.

As used herein, the term "skin irritation mitigation" refers to prevention, mitigation, and treatment of inflammatory irritation such as itching, tingling, burning, and erythema caused by skin irritants, .

In the present invention, the molecular formula of oxyresveratrol is C ₁₄ H ₁₂ O ₄ and the molar mass is 244.24 g / mol. If the compound represented by the structural formula (1) is oxyreservatase, which is isolated from a sample containing oxyreservatol, Artificial < / RTI > synthetic resveratrol, artificially synthesized oxyreservatrol, and commercially available oxyreservatolone.

[Chemical Formula 1]

The inventors of the present invention have studied various administration systems and have found that none of the systems can solve various problems of oxyreservatrix at the same time. In particular, it has been difficult to solve skin irritation problems that must be caused by the application of conventional micro- The inventors of the present invention have surprisingly invented that it is possible to remarkably alleviate the skin irritation caused by the application of the microneedles to the skin by impregnating the dissolvable microneedles with the oxirevacrol after the various efforts and to deliver the oxirezavelat effectively into the skin to exert an excellent skin whitening effect.

As used herein, the term "impregnation" may refer to a form in which oxirebazepam may be contained in a microneedle, preferably i) contains oxyreservatol with a solubilizing material that forms a microneedle, or ii) A hole may be made in the microneedles to contain oxirebazelet in the hole. In the case of preparing microneedles in the form of i) or ii), oxiresveratrol can effectively penetrate into the skin, and particularly when producing microneedles in the form of i), the problem of low solubility and transdermal permeability of ox reseratrol It can be solved at its source.

Therefore, it is most preferable that the substance forming the microneedle is dissolved in the living body so that the oxireservatol contained in the microneedle is effectively released into the skin, and the oxyreservatrix contained in the microneedle is used for skin irritation caused by microneedles in the skin It has the effect of alleviating.

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

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 micro-needle and the dissolution rate in the skin in general, it is preferable to use hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (Trehalose) is preferable, and it is more preferable to mix glycerin.

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.

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

In the present invention, the oxyreservatrix may be contained in an amount of 0.001 to 5% by weight, preferably 0.01 to 3% by weight, more preferably 0.1 to 1% by weight, based on the total weight of the microneedles. If it is contained in an amount of less than 0.001% by weight, it may not exhibit an effective effect. If it is contained in an amount exceeding 5% by weight, the physical properties and durability of the fine needle may be deteriorated.

In the present invention, the oxyreservatrix can be stably impregnated with the oxyreservatrix so as not to be discolored or removed during the production of the microneedle. Conventionally, in the cream formulations to be applied to the skin, various methods such as cyclodextrin and liposome have been tried to stabilize the formulation in anhydrous form in order to contain sensitive oxyreservatrol. However, in the case of the present invention, impregnation into micro- I solved the problem originally.

When the microneedles according to the present invention are applied to the skin, the skin permeation amount can be remarkably improved as compared with the conventional skin administration systems.

In addition, the microneedles according to the present invention can be used for skin whitening purposes.

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

In the present invention, the patch may be a sheet having one or more micro-needles impregnated with the oxireservatrol of the present invention and having a surface on which the micro-needles are attached to the skin. The size of the sheet is not limited to a specific size, but can be appropriately adjusted depending on the amount or attachment site of oxyreservatol 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.

In addition, oxireservatrol can be added to the surface of the patch that can be adhered to the skin, so that the oxiresveratrol can be penetrated into the hole formed by the microneedles. In order to achieve an excellent skin irritation mitigation effect, It is desirable to impregnate.

The present invention also relates to a method for preparing a microcapsule comprising the steps of: S1) filling a mold with a substance forming a microneedle including an oxygen resveratrol and an intracutaneously soluble substance; And S2) heating and drying the mold, and then separating the mold. The present invention also provides a method of manufacturing a microneedle comprising the same.

The method may be prepared by impregnating a microneedle with ox resveratrol, and the impregnation may include, but is not limited to, i) containing oxyreservatol with a solubility in skin forming a microneedle, ii) A hole in the needle to contain oxygen resveratrol in the hole, and the like.

In the present invention, in order to impregnate oxygen resveratrol into a microneedle, a material for forming microneedle and oxygen resveratrol are mixed together in a mold for microneedle formation, and then the mold is heated, dried, Needles can be made.

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 ox resveratrol, which effectively delivers oxir reseratrol to the skin, wherein the microneedle according to the present invention is applied.

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 preparing an administration system of oxyservatrol which can exert an excellent effect through effective skin transfer of oxyreservatol. The present invention also provides a skin administration method of oxireservatrol which is characterized in that such microneedles are applied.

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 is a view showing a Franz diffusion cell for evaluating drug release behavior of a microneedle according to the present invention. FIG.
FIG. 3 is a graph showing the permeation amount of oxyreservatable skin in Example 1 and Comparative Example 1. FIG.
FIG. 4 is a photograph showing skin irritation when Example 1 and Comparative Example 1 according to the present invention were applied to skin (Oxyresveratrol Cream: Comparative Example 1, Oxyresveratrol microneedle: Example 1)

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 (see FIG. 1), casting solution into a mold, filling the micro mold with 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-needle containing oxyreservatrix (Example 1) >

ingredient Example 1
(Unit: wt%) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 HCO-40 0.2 Oxyresveratrol 0.3 water To 100

Hyaluronic acid (Hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose) and trehalose were dissolved in purified water and glycerin, HCO-40 (Hydrogenated castor oil) and Oxyresveratrol were added, Resveratrol solution was prepared. The prepared 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 Cream containing Oxy Resveratrol (Comparative Example 1) >

Raw material name Comparative Example 1
(Unit: wt%) One Cetearyl alcohol 1.5 2 C14-22 Alcohol / C12-20 alkyl glucoside
(Mixture C14-22 alcohol: C12-20 alkyl glucoside = 80:20 weight ratio) 1.5 3 Polyglyceryl-3 methyl glucoside distearate 1.5 4 Glyceryl stearate & PEG-100 stearate
(Mixture 50:50 weight ratio) 2 5 Hydrogenated polydecene 5 6 Cyclohexasiloxane 3 7 Purified water To 100 8 glycerin 5 9 1,2-hexanediol 2 10 Carbomer Suitable amount 11 Xanthan gum 0.2 12 Tromethamine Suitable amount 13 Oxy Resveratrol One 14 Dipropylene glycol 5

In order to compare the active ingredient impregnated with the microneedle and the active ingredient applied to the oil-in-water cream, a cream containing oxyreservatrix was prepared.

The raw materials 1 to 6 and the raw materials 7 to 12 were heated and dissolved at 75 ° C to 80 ° C as shown in Table 2, and the mixture was stirred at 5500 rpm by a homomixer and cooled. After the raw materials 13 and 14 were added at 55 ° C, the mixture was homogenized at 5500 rpm for 2 minutes Followed by cooling to room temperature (Comparative Example 1).

< Experimental Example  1>

Drug release behavior

The present inventors measured the content of oxyreservatrix of 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 (time: 2 hours, temperature: 32 ° C) to penetrate the pig skin and dissolve, and then the microneedles and cream were removed.

Porcine skin absorbed with oxyreservatrix by Example 1 and Comparative Example 1 was placed in a franz diffusion cell (FIG. 2), and skin permeation amount of oxyreservatolone was compared with time.

As a result, as shown in FIG. 3, the amount of the permeation through the skin was about 15 μg, which was insignificant in Comparative Example 1, but the oxygen resveratrol impregnated in the microneedles was directly penetrated to the skin by the needles, Or more than 6 times of cream.

< Experimental Example  2>

Skin irritation test

The present inventors observed the degree of skin irritation (N = 20) by applying the cream of Example 1 and Comparative Example 1 to the inside of the arm for 2 hours each day and the microneedles for 1 hour, respectively.

The results are shown in Table 3 and FIG. In the case of Example 1, the skin irritation was insignificant at the level of general functional cosmetics (skin irritation index: about 0.1), and skin irritation was lower than that of Comparative Example 1. As can be seen from FIG. 4, It was found that the color of the surface changed to red compared to Example 1. [

The reason why the skin irritation of Example 1 is smaller than that of Comparative Example 1 is that it is because the cream is applied for a long time in actual use, but 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 The skin irritation index 0.08 0.08 0.08 0.08 0.08 0.09 0.10 0.12 The skin irritation index of Comparative Example 1 0.08 0.08 0.08 0.09 0.10 0.15 0.2 0.3

* 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>

Test for whitening effect on human skin

The inventors of the present invention were able to stabilize a healthy male and female twenty-five subjects sufficiently for 10 minutes, then attach fine needles for one hour on a daily basis to Example 1 in a square area of 7 x ² cm x 7 cm ² around the clown of a subject, The changes of L *, a * and b * values were measured using a Chromameter CR-400 (Minolta, Japan).

CIE L * a * b * In the color space, the L * value represents brightness. If L * = 0, it is black. If L * = 100, it represents white.

The results are shown in Table 4 below. [Table 4] &lt; EMI ID = 16.1 &gt; &lt; tb &gt; &lt; TABLE &gt;

The number of subjects who have improved skin brightness 19 people Improved 19 Mean L * Value Change 4.6

As shown in Table 4, it was found that effective facial whitening was achieved using the product according to the present invention (Example 1).

Claims (10)

Soluble microneedles containing Oxyresveratrol. The method according to claim 1,
Wherein the material forming the microneedle is dissolved in the skin. 3. The method of claim 2,
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. The method of claim 3,
Wherein the microneedles further comprise a plasticizer in addition to the material forming the microneedles. The method according to claim 1,
Wherein the oxyreservatrix is contained in an amount of 0.001 to 5 wt% based on the total weight of the microneedles. The method according to claim 1,
Wherein the microneedles improve the skin permeation amount of oxyreservatrix. The method according to claim 1,
Wherein the microneedles are for skin whitening. A microneedle patch comprising a microneedle according to any one of claims 1 to 7. S1) filling a mold with a material forming a microneedle comprising an oxygen resveratrol and an intracutaneously soluble substance; And
S2) heating the mold, drying and then separating the mold. A method for the cosmetic skin administration of oxyreservatrol which delivers oxygen resveratrol into the skin, characterized by applying a microneedle according to any one of claims 1 to 7.

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