KR20170000747A - Soluble microneedle patch for improvement of trouble and skin regeneration - Google Patents

Abstract

The present invention relates to a skin dose system of an onion extract, allantoin, sodium heparin, or a mixture of two or more thereof. The soluble microneedle patch safely impregnates the onion extract, allantoin, sodium heparin, or a mixture of two or more thereof, and effectively delivers substances into the skin. The present invention features a microneedle including the onion extract, allantoin, sodium heparin, or a mixture of two or more thereof. The present invention also provides a skin dose method of the onion extract, allantoin, sodium heparin, or a mixture of two or more thereof, which uses the microneedle. The soluble microneedle patch plays a role for the treatment of troubles and the improvement of skin regeneration.

Description

(Soluble microneedle patch for improvement and skin regeneration)

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.

Recently, various substances for improving skin troubles and regenerating skin have been developed, and various cosmetics containing such substances have been developed and released.

Allium Cepa Ext., Allantoin, and Sodium Heparin, which are mainly used as active ingredients for scar treatment and scar remedy, can improve skin troubles in addition to scar treatment and scar treatment (Korean Patent Laid- -0063162, Korean Patent Laid-Open No. 10-2015-0066810) and wrinkle improvement (wrinkle-improving effect of facial mask pack containing onion skin extract, KSBB Journal 28 (6) 387-393 1225-7117 KCI, Korean Patent Laid-Open Publication No. 10-2012-0129600, Korean Patent Laid-Open No. 10-2008-0038066, etc.), it is known that it is effective for the onion extract, but the problem of recrystallization of allantoin, There is a problem in that there is a limit to

Korean Patent No. 10-0844831 discloses a method of using the above substances as an external preparation for skin through alkali emulsification and the like. However, there is no way to solve the specific problem of the onion extract when used as an external preparation for skin, Alkaline emulsifiers and the like have been used to solve the problem of recrystallization of allantoin which is a poorly soluble substance. However, there are problems such as skin redness, wrinkle and drying when the skin is weakly basic, and the defenses against external bacteria Suggesting a possibility.

Accordingly, the present inventors completed the present invention by stably impregnating the soluble micro-needle with the above materials in order to fundamentally solve such a problem.

Korean Patent No. 10-0844831

The problem to be solved by the present invention is to stably impregnate a soluble micro-needle with an onion extract (Allium Cepa Ext.), Allantoin, Sodium Heparin or a mixture of two or more thereof to prepare onion extract, allantoin, heparin Sodium or a mixture of two or more thereof into the skin, a method for producing such a system, and a cosmetic method for administering the onion extract, allantoin, heparin sodium or a mixture of two or more thereof to the skin using such a system .

Accordingly, the present invention provides a soluble microneedle comprising Allium Cepa Ext., Allantoin, Sodium Heparin or a mixture of two or more thereof.

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

The present invention also relates to a method for the production of a micro-needle comprising an onion extract, allantoin, heparin sodium or a mixture of two or more thereof, comprising the step of producing a microneedle containing an onion extract, allantoin, heparin sodium or a mixture of two or more thereof and a soluble substance A method for manufacturing a needle is provided.

The present invention also relates to an onion extract, an allantoin, heparin sodium or a mixture of two or more thereof, which is characterized by using the microneedle, and onion extract, allantoin, heparin sodium or a mixture of two or more thereof, ≪ / RTI >

In order to solve the above problems, the present invention provides a soluble micro-needle comprising an onion extract (Allium Cepa Ext.), Allantoin, sodium heparin or a mixture of two or more thereof, The material forming the microneedle is dissolved in the skin, and upon application of the microneedle to the skin, the microneedles are dissolved or collapsed to release the onion extract, allantoin, heparin sodium or a mixture of two or more thereof into the skin.

After a long period of research, the present inventors have found that the onion extract, allantoin, and heparin sodium can be impregnated into the soluble micro-needle to thereby effectively transmit the onion extract, allantoin, heparin sodium or a mixture of two or more thereof into the skin, And that the problem of recrystallization of allantoin, which is a poorly soluble substance, can be solved fundamentally, confirming the present invention and completing the present invention. More specifically, the onion extract, allantoin, heparin sodium, or a mixture of two or more thereof are impregnated in the soluble micro-needle to solve the problem of the odor of the onion extract, that is, the odor of the tortoise, and the low solubility and recrystallization Overcoming the problem, it was confirmed that the effect of the active ingredient is more effective by alleviating the skin irritation by acting directly inside the skin.

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, .

The present inventors have studied various administration systems, and any system has not been able to simultaneously solve various problems of onion extract and allantoin. After various efforts, the inventors of the present invention have succeeded in solving the specific problem of the onion extract by impregnating the microneedle with onion extract, allantoin, heparin sodium or a mixture of two or more thereof, and have developed a remarkable invention capable of effectively transferring the poorly soluble allantoin into the skin Respectively.

In addition, the problems associated with the inclusion of a synthetic polymer by excluding synthetic polymers such as carbomer, which were inevitably added in order to incorporate these materials, can be solved.

In the present invention, the onion extract can be prepared using conventional solvents known in the art, that is, under ordinary temperature and pressure conditions, using conventional solvents. Examples of the extraction solvent which can be used in the production of the onion extract of the present invention include water, purified water, lower alcohol of C ₁ to C ₃ carbon atoms, extraction with acetone, ethyl acetate, butyl acetate and 1,3-butylene glycol Solvents may be used alone or in combination. The onion extract may preferably be a mixed solvent extract of purified water and ethanol.

The suitable amount of the extraction solvent may be 1 to 15 times, preferably 5 to 12 times, the weight of the onion, but is not limited thereto. As the extraction method, it is possible to use heat extraction, cold extraction, reflux cooling extraction, ultrasonic extraction, etc., and it can be extracted once or repeatedly and used many times. The extraction temperature is not particularly limited as long as the temperature is such that the effective activity of the useful component of the onion extract is not removed.

The portion of the onion which can be used in the present invention is not limited to any part such as onion skin, onion root, onion sphere (scaly stem), but preferably onion sphere (scaly stem) can be used.

Also, the allantoin is a compound represented by the structural formula (1), the molecular formula is C ₄ H ₆ N ₄ O ₃ , the molar mass is 158.12 g / mol, and the powder is in the form of a white powder. The compound represented by the structural formula (1) below may include allantoin isolated from a sample containing allantoin, artificially synthesized allantoin, and commercially available allantoin.

[Chemical Formula 1]

As used herein, the term "impregnation" may refer to a form in which the onion extract, allantoin, heparin sodium or a mixture of two or more thereof may be contained in the microneedles, preferably i) the solubility Allantoin, heparin sodium or a mixture of two or more thereof, or ii) a hole in the microneedles to contain an onion extract, allantoin, heparin sodium or a mixture of two or more thereof in combination with the substance. When the microneedles are prepared in the form of i) or ii), the poorly soluble allantoin can effectively penetrate into the skin. In particular, when microneedles are prepared in the form of i), the specific problem of onion extract It can be solved at its source.

Therefore, it is most preferable that the substance forming the microneedles is dissolved in the living body so that the onion extract, allantoin, heparin sodium, or a mixture of two or more thereof contained in the microneedles are effectively released into the skin.

In a preferred embodiment of the present invention, the material forming the microneedles is dissolved in the skin and melted or collapsed when the microneedles are applied to the skin, whereby the onion extract, allantoin, heparin sodium or the like contained in the microneedles Can penetrate effectively 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. In consideration of compatibility of the onion extract, allantoin, heparin sodium or a mixture of two or more thereof, considering hyaluronic acid (Hyaluronic acid) and the like in consideration of the skin permeation intensity of the fine needle and the dissolution rate in the skin comprehensively, sodium carbonate, sodium carboxymethyl cellulose, and saccharide (preferably trehalose) are preferable, and it is more preferable to mix glycerin with 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 microneedle may include 0.5-10% by weight of onion extract, 0.01-2% by weight of allantoin, 0.001-0.5% by weight of sodium heparin or a mixture of two or more thereof, preferably onion From 1 to 7% by weight of extract, from 0.05 to 1.5% by weight of allantoin, from 0.005 to 0.2% by weight of sodium heparin or a mixture of two or more thereof, more preferably from 2 to 6% by weight of onion extract, 0.1 to 1% %, 0.01 to 0.1% by weight of sodium heparin, or a mixture of two or more thereof.

In the present invention, the onion extract, allantoin and heparin sodium may be contained in a weight ratio of 50 - 150: 5 - 15: 1, preferably 75 - 125: 7.5 - 12.5: 1, May be included in a weight ratio of 90 - 110: 9 - 11: 1.

In the present invention, the onion extract, allantoin and heparin sodium can be stably impregnated so that the allantoin is not precipitated and recrystallized in the process of producing the micro-needle.

When the microneedles according to the present invention are applied to the skin, allantoin, which has poor solubility and recrystallization problems, can significantly improve the skin permeation rate as compared with other skin administration systems.

Therefore, the microneedles according to the present invention can improve the skin permeation amount of the onion extract, allantoin, heparin sodium or a mixture of two or more thereof.

In addition, the microneedles according to the present invention can be used for skin trouble improvement, wrinkle improvement, or skin regeneration.

As used herein, the term "skin trouble" includes all diseases that occur in the skin due to environmental factors, immunological reactions, etc., and includes rashes, acne, itching, erythema and the like.

The present invention also provides a microneedle patch comprising the microneedles, that is to say a microneedle patch (for delivery) (or delivery) of an onion extract, allantoin, heparin sodium or a mixture of two or more thereof with the microneedles patch.

In the present invention, the patch comprises at least one micro-needle impregnated with the onion extract, allantoin, heparin sodium or a mixture of two or more thereof according to the present invention, and the micro- Quot; sheet " The size of the sheet is not limited to a specific size and can be appropriately adjusted depending on the amount or attachment site of onion extract, allantoin, heparin sodium or a mixture of two or more thereof 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.

It is also possible to include onion extract, allantoin, heparin sodium or a mixture of two or more thereof on the surface which may be adhered to the skin of the patch so that the onion extract, allantoin, heparin sodium or a mixture of two or more thereof penetrates into the hole formed by the micro- In order to solve the specific problem of the onion extract, it is preferable to impregnate the onion extract with the micro-needle.

The present invention also relates to the production of microneedles comprising an onion extract, allantoin, heparin sodium or a mixture of two or more thereof and an in-skin extract, allantoin, heparin sodium or a mixture of two or more thereof, ≪ / RTI >

The method can be produced by impregnating a microneedle with an onion extract, allantoin, heparin sodium or a mixture of two or more thereof, and the impregnation is preferably carried out with i) a soluble material forming a microneedle Onion extract, allantoin, heparin sodium or a mixture of two or more thereof, or ii) piercing the microneedles to contain onion extract, allantoin, sodium heparin or a mixture of two or more thereof, etc. have.

In the present invention, in order to impregnate an onion extract, allantoin, heparin sodium or a mixture of two or more thereof into a microneedle, microneedle formation together with a substance forming a structure of a microneedle and an onion extract, allantoin, heparin sodium or a mixture of two or more thereof And then the mold is heated, dried, and then separated to prepare a microneedle.

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.

The present invention also relates to an onion extract, allantoin, heparin sodium or a mixture of two or more thereof, which effectively transports a mixture of two or more thereof into the skin, characterized by using microneedles according to the present invention. Thereby providing a cosmetic skin administration method.

When the soluble microneedles according to the present invention are applied to the skin, allantoin, which has a problem of solving onion extracts having specific odors and has a problem of precipitation due to recrystallization, is remarkably improved in skin permeation compared with other skin administration systems .

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 the effect of improving the wrinkles of the microneedles according to the present invention. (Red graph: Example 1, blue graph: Comparative 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.

Material preparation

To prepare onion extracts, the onion was washed with water, and then the three kinds of onion bulbs (scaly stem) were extracted for 8 hours at 95 ° C using purified water of 10 times the weight of onion, firstly filtered with 250 mesh, 15% (v / v) ethanol was added. After that, it was stored at 4 캜 for 3 weeks, and then filtered again to 0.5 탆 to obtain an onion extract.

≪ Preparation of soluble fine needle >

Soluble microneedles were prepared by solution casting method. The solutions were prepared by casting the solution into a mold, filling the solution into a 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-needle containing onion extract, allantoin and heparin sodium (Example 1) >

ingredient Example 1
(Unit: wt%) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 Dipropylene glycol 5 Allantoin 0.5 Onion extract 5 Sodium heparin 0.05 water To 100

Solutions were prepared by dissolving oligo-HA, sodium carboxymethyl cellulose, trehalose, glycerin, dipropylene glycol, onion extract, allantoin and heparin sodium in purified water.

The prepared solution was cast in a silicon microneedle mold and then cetrifugated at 3000 rpm for 10 minutes to fill the micro mold. 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 onion extract, allantoin and heparin sodium-containing cream (Comparative Example 1)>

Raw material name Comparative Example 1
(Unit: wt%) One Cetearyl alcohol 2.5 2 Polyglyceryl-3 methyl glucoside distearate 2.0 3 Glyceryl stearate 2 4 Hydrogenated polydecene 5 5 Cyclohexasiloxane 3 6 Purified water To 100 7 glycerin 5 8 Dipropylene glycol 5 9 1,2-hexanediol 2 10 Allantoin 0.5 11 Sodium heparin 0.05 12 Carbomer Suitable amount 13 Polyacrylate Crosspolymer-6 0.5 14 Xanthan gum 0.3 15 Tromethamine (10%) Suitable amount 16 Onion extract 5

A cream containing onion extract, allantoin and sodium heparin was prepared to compare the active ingredients impregnated with the microneedles and the active ingredients applied to the oil - in - water cream.

The raw materials 1 to 5 and the raw materials 6 to 14 were heated and dissolved at a temperature of 75 to 80 ° C as shown in Table 2, and the mixture was stirred at 5500 rpm for 2 minutes and cooled. After the raw material 15 was further added, the mixture was stirred at 5500 rpm for 4 minutes The mixture was cooled, and the raw material 16 was added at 50 캜. The mixture was stirred at 5500 rpm for 2 minutes and cooled to room temperature.

<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 Weak discoloration, stability Comparative Example 1 discoloration Peculiarity Discoloration Precipitation

As can be seen from the results of Table 3, the results of Example 1 were good at both the low temperature and the 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 Example 1 and Comparative Example 1 to the inside of the arm for 2 weeks each day and the microneedles for 1 hour respectively and applying the cream, and the results are shown in Table 4 = 30).

As a result, in the case of Example 1, 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.

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 Example 1 0.04 0.00 0.08 0.08 0.08 0.10 0.10 0.08 Comparative Example 1 0.04 0.10 0.14 0.30 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 content of allantoin and heparin sodium in pig skin tissue and an acceptor solution with the use of Franz diffusion cell by means of liquid chromatography (Liquid Chromatography) over time. 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, in which allantoin and sodium heparin were absorbed by microneedles, was placed in a franz diffusion cell (Fig. 2) and the skin permeation rates of allantoin and heparin sodium over time were compared.

The results are shown in Table 5 below. In Comparative Example 1, the amount of permeation through the skin was insignificant. However, the allantoin and heparin sodium impregnated with the micro needles were directly penetrated to the skin by the needles, 10 times the permeation amount.

Content in pig skin and acceptor solution (ug / mL) Active ingredient 6 hours 12 hours 18 hours 24 hours Example
One Allantoin 12 15 17 20 Sodium heparin 3 5 6 10 Comparative Example
One Allantoin 0.2 2 2 2.2 Sodium heparin 0.1 0.15 0.15 0.2

<Experimental Example 4>

Survey on the effect of improving skin troubles

The present inventors measured the degree of satisfaction with the improvement effect by applying the microneedles for 1 hour every day for two weeks on various skin troubles (rashes, acne, itching, erythema, etc.) And the results are shown.

As a result, it was confirmed that the effect of Example 1 on various skin troubles was excellent, as shown in Table 6 below.

division Number of Respondents Very good Great Inadequate Very inadequate Example 1 11 16 3 0 Comparative Example 1 2 5 14 9

<Experimental Example 5>

Wrinkle improvement effect

The present inventors examined the degree of wrinkle improvement by using silicone replica and wrinkle image analysis method (N = 20) by treating Comparative Example 1 and Example 1 for 12 weeks on the wrinkles of the eye for 12 weeks.

As a result, as shown in FIG. 3, an excellent improvement effect was shown in Example 1 as compared with Comparative Example 1, and it was judged that the effective ingredient was effectively delivered into the skin by the microneedles.

Claims (11)

A soluble micro-needle comprising Allium Cepa Ext., Allantoin, Sodium Heparin or a mixture of two or more thereof. 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 onion extract is a mixed solvent extract of purified water and ethanol. The method according to claim 1,
Wherein the microneedles comprise 0.5 to 10% by weight of onion extract, 0.01 to 2% by weight of allantoin, 0.001 to 0.5% by weight of sodium heparin, or a mixture of two or more thereof, based on the total weight of the microneedles. The method according to claim 1,
Wherein the microneedles enhance the skin permeability of onion extract, allantoin, heparin sodium or a mixture of two or more thereof. The method according to claim 1,
Wherein the microneedles are used for improving skin troubles or improving wrinkles. A microneedle patch comprising a microneedle according to any one of claims 1 to 8. An onion extract, an allantoin, a heparin sodium or a mixture of two or more thereof, and an intracutatively soluble substance. An onion extract, allantoin, heparin sodium or a mixture of two or more thereof, which is transferred into the skin, allantoin, heparin sodium or a combination thereof, characterized by using the microneedle according to any one of claims 1 to 8 RTI ID = 0.0 &gt; cosmetic &lt; / RTI &gt;

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