KR20170032808A

KR20170032808A - Soluble microneedle patch containing menthol or menthol derivative

Info

Publication number: KR20170032808A
Application number: KR1020150167681A
Authority: KR
Inventors: 이현종; 김태윤; 장윤희; 김기영; 심우선; 강내규
Original assignee: 주식회사 엘지생활건강
Priority date: 2015-09-15
Filing date: 2015-11-27
Publication date: 2017-03-23

Abstract

The present invention relates to a system for administering menthol, menthol derivatives or mixtures thereof into the skin showing excellent effects by stably immersing menthol, menthol derivatives or mixtures thereof and effectively transferring the same into the skin and, more specifically, to a microneedle including menthol, menthol derivatives or mixtures thereof, and to a method for administering menthol, menthol derivatives or mixtures thereof into the skin by applying the microneedle.

Description

Soluble microneedle patch containing menthol or menthol derivative containing menthol or menthol derivative < RTI ID = 0.0 >

The present invention relates to a microneedle and a microneedle patch.

In general, microneedle is used for the delivery of active substances such as drugs, vaccines and the like in vivo, detection of biosolids, and biopsy. The delivery of the pharmacologically or cosmetically active ingredient using micro needles 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 micro needle include a method of forming a predetermined number of holes or more on the skin by using a micro needle device such as a roller with a micro needle and applying a drug thereto, And the active ingredient is administered simultaneously with the perforation of the skin by coating the active ingredient).

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.

On the other hand, synaptic vesicles containing neurotransmitters at the time of neurotransmitter release must be fused with a presynaptic membrane to form a passage between the two interfaces. At this time, the protein that provides the fundamental force of membrane fusion is three protein complexes called SNARE (Soluble N-ethylmaleimide-sensitive factor attachment protein receptor). Membrane fusion between synaptic vesicles and synaptic membrane opens the neurotransmitter exit pathway, which involves the t-SNARE complex attached to the target membrane and v-SNARE attached to the vesicle. t-SNARE is a complex of two proteins called Syntaxin 1a and SNAP-25. These SNARE proteins are twisted like twine. Upon membrane fusion, rearrangement of the lipid bilayer, which is well known in the art, occurs. Since the biomembranes strongly push each other out, these membranes are not fused spontaneously but are given strong force from the outside to overcome the repulsive force between the membranes. At this time, the SNARE protein produces a strong force enough to overcome the repulsive force between the membranes.

In other words, the formation of the SNARE complex is a source of power overcoming the interlaminar repulsive force and a key phenomenon of exocytosis including the release of neurotransmitters. On the other hand, there is a neuromuscular junction in the upper layer of the muscle to control muscle relaxation and contraction, and the nerve terminal is loaded with synaptic vesicles. Botulinum neurotoxin (BoNT) is a protease that cleaves the SNARE protein, a key protein involved in neurotransmitter release. Botox cleaves the SNARE protein and blocks neurotransmission, resulting in paralysis of the muscle cells that have infiltrated Botox. While Botox blocks the transmission of nerves by irreversibly cleaving the SNARE protein, the so-called "Botox Bottle" is a sort of "competitive inhibitor" that interferes with neurotransmission by inhibiting the formation of the SNARE complex. Argyrenelin, a major component of currently available Botox products, has an uncertain effect and is disadvantageous in price due to the nature of synthetic peptides and is not consumer friendly.

Therefore, it is urgent to develop a new component for improving the wrinkle of the skin which is safe to the living body and the risk of side effects is low, and to develop a new system for applying it.

Korean Patent Publication No. 10-2014-0137103

A problem to be solved by the present invention is a system for stably impregnating menthol, a menthol derivative or a mixture thereof with a soluble fine needle to effectively deliver menthol, menthol derivatives or a mixture thereof into the skin, a method for producing such a system, To provide a cosmetic method of administering menthol, a menthol derivative or a mixture thereof to the skin.

Accordingly, the present invention provides a soluble micro-needle for improving skin wrinkles comprising menthol, a menthol derivative or a mixture thereof.

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

The present invention also provides a method for producing a microneedle comprising menthol, a menthol derivative or a mixture thereof.

The present invention also provides a cosmetic skin administration method of menthol, menthol derivative or a mixture thereof, which delivers the menthol, menthol derivative or a mixture thereof to the skin, characterized by applying the microneedle.

In order to solve the above problems, the present invention provides a soluble micro-needle for improving skin wrinkles comprising menthol, a menthol derivative or a mixture thereof, and more preferably, the material forming the microneedle is dissolved in the skin, Application of the skin causes the fine needle to dissolve or collapse so that the menthol, menthol derivative or mixture thereof is released into the skin.

After a long period of research, the inventors of the present invention have confirmed that menthol, menthol derivatives or a mixture thereof inhibits the formation of SNARE complexes and inhibits the release of neurotransmitters from nerve cells, thereby exerting an effect of improving skin wrinkles. This shows a similar effect to Botox which has been used for the treatment of skin wrinkles in the past, and it has been used for a long time in the human body and can greatly improve the wrinkles of the skin without side effects.

In addition, it has been confirmed that the problem of skin irritation due to the application of microneedles can be remarkably improved as well as the fact that menthol, menthol derivative or a mixture thereof is impregnated into soluble fine needles, and menthol, menthol derivatives or a mixture thereof can be effectively delivered into the skin Thereby completing the present invention. More specifically, menthol, a menthol derivative or a mixture thereof is impregnated in a dissolvable microneedle so that menthol, a menthol derivative or a mixture thereof is directly applied to the inside of the skin to exert an effect of improving skin wrinkles, and menthol, menthol derivatives, The present inventors have found that the present invention has the effect of remarkably alleviating the skin irritation caused by scratches and the like caused by the application of the conventional microneedle as the needle is impregnated with the needle.

As used herein, the term "skin wrinkles" may mean, but is not limited to, scarring of the skin.

As used herein, the term "skin wrinkle" means, but is not limited to, inhibiting or inhibiting wrinkle formation on the skin, or alleviating already formed wrinkles.

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, "menthol" is an alcohol belonging to monoterpene consisting of one ring as shown by the structural formula of the following formula (1), and is usually obtained by extracting from leaves or stems of peppermint. Menthol of formula is C ₁₀ H ₂₀ O, molecular weight is 156.27. Menthol that can be used in the present invention includes menthol separated from menthol-containing plants, artificially synthesized menthol, and commercially available menthol.

[Chemical Formula 1]

The term " menthol derivative "in the present invention includes a compound in which a part of the menthol is substituted by another atom or atomic group, a cosmetically acceptable salt, a solvate, an hydrate or an isomer, preferably a stereoisomer, of menthol Is a comprehensive term.

Preferred menthol derivatives that can be used in the present invention include (+) - menthol, (+) - isomenthol, (+) - neomenthol, (+) - neoisomenthol, (-) - neomenthol, (-) - neoisomerol, menthyl lactate, camphor, pulegol, isopulegol, cineole, 3-1-menthoxypropane-1,2-diol, N-alkyl-p-menthane-3 -carboxamide, 3-1-menthoxy-2-methylpropane-1,2-diol, p-menthan-3,8-diol (p -menthane-3,8-diol, 2-1-menthoxyethane-1-ol, 3-1-menthoxypropane- -1-ol, 4-1-menthyl 3-hydroxybutanate), menthol (menthol-3-hydroxybutanate) glycerin ketal, N-methyl-2,2-isopropylmethyl-3-methylbutanamide, (+) - neoisomersol, (-) - menthol, (-) - isomenthol, (-) - neomenthol, -) - neoisomenthol or a mixture of two or more thereof.

Particularly, the present inventors have confirmed that the menthol inhibitory effect and the muscle contraction inhibitory effect of the menthol are remarkably inhibited and that the microneedles according to the present invention can be used for improving the skin wrinkles.

Therefore, menthol may be most preferably used.

The inventors of the present invention have studied various administration systems. In particular, it has been difficult to solve skin irritation problems caused by the application of conventional microneedles. However, the inventors of the present invention have found that when menthol, menthol derivatives, Impregnation has remarkably alleviated the skin irritation caused by the application of the fine needle to the skin and effectively transmits the menthol, menthol derivative or a mixture thereof to the skin, thereby exhibiting an excellent skin wrinkle-improving effect.

As used herein, the term "impregnation" may refer to a form in which menthol, a menthol derivative or a mixture thereof may be contained in the microneedles, preferably i) a micelle- Derivative, or mixture thereof (including a form in which menthol, menthol derivative, or mixture thereof is dispersed between the substances forming the microneedles), or ii) a hole in the microneedle to form menthol, menthol derivative or a mixture thereof &Lt; / RTI > In the case of preparing microneedles in the form of i) and ii) above, it is preferred that menthol, menthol derivatives or mixtures thereof can penetrate effectively into the skin, in particular microneedles in the form of i).

Therefore, it is most preferable that the material forming the microneedles is dissolved in the living body so that the menthol, menthol derivative or a mixture thereof contained in the microneedle is effectively released into the skin, and the menthol, menthol derivative or mixture thereof contained in the microneedle And has the effect of alleviating the skin irritation caused by the microneedles in the skin.

In addition, the microneedles according to the present invention can inhibit the formation of the SNARE complex. Preferably, the microneedles are capable of inhibiting the formation of nerve SNARE complexes that are involved in neurotransmission. The neural SNARE complexes may include syntaxin 1a, SNAP25 and VAMP and preferably include the soluble SNARE motifs SynH3, SNAP25, and the VSP protein, the soluble SNARE motif of VAMP, .

In addition, the microneedles according to the present invention can inhibit the release of neurotransmitters from neurons. Preferably the release of neurotransmitters present in the synaptic vesicles of the nerve cells. As a result, muscle contraction is less likely to occur and the effect of improving skin wrinkles can be exhibited. In the present invention, it was confirmed that the effect of wrinkle improvement was substantially improved in concrete experiments on the wrinkle reducing effect.

In a preferred embodiment of the present invention, the material forming the microneedle is dissolved in the skin, and when the microneedle is applied to the skin, the microneedles are dissolved or collapsed, whereby the menthol, menthol derivative, It can effectively penetrate the inside.

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.

Although the length of the microneedles according to the present invention is not limited to a specific size, the upper and lower lengths of the microneedles for the purpose of the present invention, which targets skin cells through the stratum corneum, may preferably be 10 to 2000 mu m, To 50 [mu] m.

In the present invention, the menthol, the menthol derivative or a mixture thereof may be contained in an amount of 0.00001 to 10% by weight, preferably 0.00005 to 5% by weight, more preferably 0.00005 to 3% by weight, based on the total weight of the microneedles . If it is contained in an amount less than 0.00001% by weight, it may not exhibit an effective effect. If it is contained in an amount exceeding 10% by weight, the physical properties and durability of the micro needle may be affected and adverse effects due to excessive use may be caused.

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.

The present invention also provides a microneedle patch comprising the microneedle, that is, a microneedle patch for administration (or delivery) of the menthol, menthol derivative or mixture thereof to which the microneedle is attached.

In the present invention, the patch may be a sheet prepared by attaching one or more micro-needles impregnated with the menthol, menthol derivative, or a mixture thereof according to the present invention and attaching the micro-needle attached surface to the skin. have. The size of the sheet is not limited to a specific size and can be appropriately adjusted depending on the amount of the menthol or the menthol derivative or mixture thereof to be absorbed into the skin or the attachment site thereof. 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, menthol, menthol derivatives, or a mixture thereof may be contained in the surface of the patch that can be adhered to the skin, so that the menthol, the menthol derivative, or a mixture thereof can penetrate into the hole formed by the fine needle. It is preferred that the menthol, menthol derivative or mixture thereof is impregnated with a microneedle.

The present invention also relates to a method for preparing a microcapsule comprising the steps of: S1) filling a mold with a substance which forms a microneedle comprising menthol, a menthol derivative or a mixture thereof and an intracutaneous solubility material; And S2) warming the mold, drying and then separating the mold, and a method for producing the microneedle comprising the menthol, the menthol derivative or a mixture thereof.

The method may be carried out by impregnating a microneedle with menthol, a menthol derivative or a mixture thereof, and the impregnation is preferably, but not exclusively, i) a step of mixing i) a menthol with a solubility in the skin forming the microneedle, Or a mixture thereof, or ii) a hole in the fine needle to contain menthol, menthol derivatives or a mixture thereof in the hole, and the like.

In the present invention, in order to impregnate the menthol, the menthol derivative or the mixture thereof into the microneedles, a material for forming the microneedles and a menthol, a menthol derivative or a mixture thereof are mixed and filled in a mold for microneedle formation, The mold can be heated, dried and then separated to produce 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 provides a cosmetic skin administration method of menthol, menthol derivative or a mixture thereof, which effectively transfers the menthol, menthol derivative or a mixture thereof to the skin, characterized by applying the microneedles 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 preparing a system for the administration of menthol, menthol derivatives, or mixtures thereof, which can exert excellent effects through effective skin delivery of menthol, menthol derivatives or mixtures thereof. The present invention also provides a skin administration method of menthol, menthol derivatives or a mixture thereof, 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 the permeation amount of menthol skin in Example 1 and Comparative Example 1. Fig.
4 is a graph showing the effect of improving the wrinkles of the micro-needle according to the present invention.
FIG. 5 is a graph showing the skin irritation mitigation effect of the microneedles according to the present invention.
6 is a photograph showing the inhibitory effect of menthol on SNARE complex formation. (Menthol 1: menthol 1 ppm, menthol 10: menthol 10 ppm, menthol 100: menthol 100 ppm)
FIG. 7 is a graph showing that menthol inhibits the release of neurotransmitter from neurons and thus inhibits muscle contraction. (Menthol 1: menthol 1 ppm, menthol 10: menthol 10 ppm, menthol 100: menthol 100 ppm)

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.

&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.

&Lt; Preparation of soluble fine needle including menthol (Example 1) >

ingredient Example 1
(Unit: wt%) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 HCO-40 0.2 menthol 0.15 water To 100

Hyaluronic acid (HA), sodium carboxymethyl cellulose (Na-CMC) and trehalose were dissolved in purified water and glycerin, PEG-40 hydrogenated castor oil (HCO-40) and menthol were added A microneedle 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).

&Lt; Preparation of Oil-in-Water Cream Containing Menthol (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)
(MONTANOV L, SEPPIC) 1.5 Glyceryl stearate, phage-100 stearate
(Mixture 50:50 weight ratio)
(Arlacel 170, CRODA) 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 DPG 5 1,2-hexanediol 2 menthol 0.5 Purified water To 100

In order to compare the effect of the active ingredient applied to the active ingredient impregnated in the microneedle with that of the underwater emulsifier type cream, a cream containing menthol was prepared according to the composition of Table 2 (Comparative Example 1).

<Experimental Example 1>

Drug release behavior

The present inventors measured the menthol content 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 to penetrate into pig skin and dissolve, followed by removal of fine needle and cream.

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

As a result, as shown in FIG. 3, the amount of the permeation through the skin of Comparative Example 1 was insignificant at about 5 μg, but the menthol impregnated with the fine needle was directly penetrated to the skin by the needle and its permeation amount was about 13 μg or more The skin permeability was higher than that of cream by about 2 times.

<Experimental Example 2>

Wrinkle improvement effect

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

As a result, as shown in Fig. 4, the improvement effect was more than three times better than that of Comparative Example 1, and it was confirmed that the menthol effectively penetrated into the skin by the microneedles and the wrinkle-reducing effect was high .

<Experimental Example 3>

Stimulation effect

The present inventors confirmed that menthol-impregnated microneedles and general microneedles were applied to the eye wrinkles and evaluated the user's sensory level to 1 to 5 after 30 minutes of application (N = 20).

As a result, as shown in FIG. 5, the improvement effect of the menthol was more than three times better than that of the micro-needle impregnated with menthol, and it was confirmed that the menthol effectively penetrated into the skin by the microneedles and the wrinkle-improving effect was high.

<Experimental Example 4>

Confirmation of inhibition of SNARE complex formation

The present inventors performed SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) analysis to confirm inhibition of SNARE complex formation of menthol. More specifically, it was confirmed that the complex formed when the SNARE proteins SNAP5, SynH3, and Vps proteins were mixed at a molar concentration of 1: 1: 1 was inhibited by menthol at a concentration of 1-100 ppm.

First, each protein was placed in a 1 ml tube, and then menthol was added thereto, followed by reaction at room temperature for 30 minutes. After that, electrophoresis was performed on 12% SDS-PAGE to confirm formation of SNARE complex.

As a result, as shown in Fig. 6, it was confirmed that menthol effectively inhibited the SNARE complex in a concentration-dependent manner. As a result, it was confirmed that the SNARE complex was hardly formed at a concentration of 100 ppm, and it was confirmed that SNARE complex formation inhibitory ability was active even at a concentration of 1 ppm.

<Experimental Example 5>

Menthol Confirmation of muscle contraction inhibitory effect

The present inventors cultured C2C12 cells in DMEM medium containing 10% fetal bovine serum and 1% antibiotic on a plate in order to confirm the effect of suppressing muscle contraction of menthol. The neuroblasts were then co-cultured further in the same plate.

Thereafter, C2C12 cells were shrunk for 30 seconds at the start of cell shrinkage of C2C12 cells. After the medium was completely removed, the cells were washed three times with PBS. Then, medium containing no calf serum and menthol were added to the cells for 2 hours . Thereafter, the number of contractions of C2C12 cells was measured again for 30 seconds to confirm the degree of suppression of muscle contraction.

As a result, as shown in FIG. 7, it was confirmed that menthol suppresses the release of neurotransmitter from neurons and reduces the number of contractions of C2C12 cells. It was confirmed that no contraction occurred at the concentration of 10 ppm and 100 ppm, and it was confirmed that the inhibition effect was very high even at the concentration of 1 ppm.

Claims

A dissolvable microneedle for improving skin wrinkles comprising menthol, menthol derivatives or a mixture 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 menthol, menthol derivative or mixture thereof is contained in an amount of 0.00001 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 of menthol, menthol derivatives or mixtures thereof.

The method according to claim 1,
The menthol derivative may be selected from the group consisting of (+) - menthol, (+) - isomenthol, (+) - neomenthol, (+) - neoisomenthol, Menthyl lactate, camphor, pulegol, isopulegol, cineole, 3-l-menthoxypropane-1, 3-1-menthoxypropane-1,2-diol, N-alkyl-p-menthane-3-carboxamide, 3-1- Menthoxy-2-methylpropane-1,2-diol, p-menthane-3,8-diol 2-1-menthoxyethane-1-ol, 3-1-menthoxypropane-1-ol, 4- (4-1-menthyl 3-hydroxybutanate), menthol glycerin ketal, N-methyl-3-hydroxybutanate, N-methyl-2,2-isopropylmethyl-3-methylbutanamide or a mixture of two or more thereof As a fine needle.

A microneedle patch comprising a microneedle according to any one of claims 1 to 7.

S1) menthol, menthol derivatives or mixtures thereof; Filling a mold with a material forming a microneedle including a skin-soluble material; And
S2) heating the mold, drying and then separating the menthol, menthol derivative or a mixture thereof.

A method for the cosmetic skin administration of menthol, menthol derivative or mixture thereof, which delivers a menthol, menthol derivative or a mixture thereof to the skin, characterized by applying the microneedle according to any one of claims 1 to 7.