TWI722006B - Soluble microneedle comprising agent for controlling of a neurotransmitter - Google Patents

Abstract

The present invention relates to a transdermal drug delivery system, according to which the skin permeability of components that regulate the release of neurotransmitters can be improved. In particular, the invention relates to a microneedle containing components that regulate the release of neurotransmitters.

Description

Soluble microneedles containing components that regulate neurotransmitter release

The present invention relates to a soluble microneedle, in particular to a transdermal drug delivery system capable of delivering substances that control the release of neurotransmitters to the skin.

Due to the ease of use of drug delivery through the skin, it is used in various fields in various forms. This kind of drugs that pass through the skin are mainly used to pass through the skin to the systemic circulation. In addition, there are also drugs such as atopic therapeutics, whitening or wrinkle improvement cosmetics, etc., which are passed to the skin's own organs. Used for purpose. Despite this convenience and functionality, due to the structure of the skin, there are various difficulties in delivering drugs through the skin. Therefore, it is not easy to develop drugs that can pass through the skin. The stratum corneum of the skin is composed of a brick structure and a mortar structure. The brick structure is composed of keratin-rich keratinocytes; the mortar structure is composed of ceramide (Ceramide), fatty acid (fatty acid) or wax (wax) and other lipids fill this structure between keratinocytes. This structure acts as a barrier and has the characteristics of extremely low material permeability. Only low-molecular structural components below 500 Da can be delivered to the skin by diffusion, and only substances with excellent lipid affinity can pass through the skin.

In addition, the release of neurotransmitters occurs through the fusion of synaptic vesicles containing neurotransmitters and located at nerve endings with presynaptic membranes, forming a pathway between the two boundaries. A complex of three proteins consisting of the vesicle protein VAMP (synaptobrevin) and the plasma membrane-binding protein Syntaxin 1a and SNAP-25, namely SNARE proteins, gives synaptic vesicles and presynapses The fusion of the membrane provides the root strength. Among them, the neurotransmitter release pathway is formed by the membrane fusion between the synaptic vesicle and the presynaptic membrane, which is achieved by both the synaptic fusion protein 1a protein and the SNAP-25 protein attached to the target membrane. The result of the action of the complex t-SNARE and v-SNARE attached to vesicles. When the above-mentioned membranes are fused, it will cause the lipid bilayer to rearrange. Since biofilms strongly repel each other, these membranes cannot fuse spontaneously, but need to apply a large force from the outside to overcome the repulsive force between the membranes. According to reports, the substance that provides this force is the SNARE protein. . In summary, the formation of SNARE complex is the core phenomenon of extracellular exocytosis including neurotransmitter release.

The above-mentioned plant polyphenols play a role similar to botulinum by regulating the release of neurotransmitters. Taking advantage of this feature, research is currently underway to apply them to smear-type cosmetics or situations where botulinum cannot actually be used. However, due to Most polyphenols have poor solubility, so the amount that can be contained in cosmetic formulations is limited, so there is a problem that the amount of skin penetration is very low and it is difficult to exert efficacy.

In addition, it is reported that calcium channel blockers inhibit the important factors that promote muscle contraction from entering the muscle vascular fiber cells, that is, by inhibiting calcium from entering the muscle vascular fiber cells, thereby reducing muscle contraction . Facial movement is produced by the contraction of subcutaneous muscles, and different muscles can promote the movement of different parts of the face.

In order for this calcium channel blocker to have the effect of reducing and alleviating muscle contraction, the drug needs to be delivered to the muscle layer. However, it is difficult to absorb the drug to the muscle layer only by applying cosmetics, so its effect is weak.

When a calcium channel blocker is injected into the skin, it is accompanied by pain and surgery is required. Therefore, personal use is limited, and when administered orally, it affects the whole body, so side effects may occur.

As described above, the current situation is that calcium channel blockers are tried to be incorporated into cosmetics and delivered to the skin in order to improve wrinkles and lines, but so far, no consideration has been given to the improvement of the skin permeation effect.

The problem to be solved by the invention

Therefore, the problem to be solved by the present invention is to provide a soluble microneedle with excellent skin penetration.

Specifically, there is provided a soluble microneedle immersed in a soluble microneedle with a component that blocks nerve transmission and has an excellent wrinkle improvement effect. When used on the skin, the microneedle penetrates the skin painlessly, and the microneedle dissolves due to the moisture in the skin. A soluble microneedle that delivers the drug to the skin.

In the present invention, the microneedles are dissolved by moisture in the skin, so that the effective ingredients can be delivered into the skin.

In the present invention, the effective ingredients delivered to the skin block the release of neurotransmitters, thereby relaxing muscles, improving wrinkles and facial lines, and suppressing pain.

The present invention provides a transdermal delivery system. According to the system, the problem of limited use of polyphenols due to poor solubility in ordinary cosmetic compositions can be solved, the solubility of polyphenols can be improved, and the system can be applied to skin.

The way to solve the problem

In order to solve the above-mentioned problems, the present invention provides a microneedle containing a component that regulates the release of neurotransmitters. Preferably, the aforementioned microneedles are soluble microneedles.

The above-mentioned components that regulate the release of neurotransmitters may be: i) polyphenols or derivatives thereof, ii) calcium channel blockers, or iii) mixtures thereof.

According to an embodiment of the present invention, the aforementioned microneedles preferably contain components that regulate the release of neurotransmitters and have a wrinkle improvement effect. The substance forming the above-mentioned microneedles may be a substance that dissolves or biodegrades in the skin, and when the above-mentioned microneedles are used on the skin, the microneedles dissolve or disintegrate and release components that regulate the release of neurotransmitters. Thus, the above-mentioned components that regulate the release of neurotransmitters can be stably delivered to the skin.

According to an embodiment of the present invention, the components contained in the above-mentioned microneedles include polyphenols or derivatives thereof.

The inventors have conducted research on various drug delivery systems. However, in any system, the solubility of polyphenols is low as described above, and the above problems cannot be solved by applying it to ordinary cosmetics and applying them to the skin. Its application is limited. After various efforts, the inventors surprisingly discovered that when polyphenols are contained in soluble microneedles in the skin, the transmission of neurotransmitters can be effectively reduced, and wrinkle improvement effects can be exerted, thus completing the present invention.

In order to achieve the above problems, the microneedles need to be soluble in the skin, and to form soluble microneedles, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose), and vinylpyrrolidone can be used. -Vinyl acetate copolymer, polyvinyl alcohol (Polyvinyl alcohol) and polyvinyl pyrrolidone (Polyvinyl pyrrolidone) and other water-soluble polymers; Xylose (Xylose), sucrose (Sucrose), maltose (Maltose), lactose (Lactose), seaweed Sugars such as sugar (Trehalose); or their mixtures. In particular, considering the penetration strength of the microneedle through the skin and the speed of dissolution in the skin, it is preferable to use hyaluronic acid (Oligo-Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) And a mixture of saccharides (more preferably Trehalose), and more preferably the following glycerine (Glycerine). Preferably, the microneedles of the present invention may contain plasticizers, surfactants, preservatives, anti-inflammatory agents, etc. in addition to the above-mentioned components that form the microneedles.

As the above-mentioned plasticizer, for example, Ethylene glycol, Propylene glycol, Dipropylene glycol, Butylene glycol, Glycerine, etc. may be used alone or in combination. Polyol.

Preferably, in the microneedles of the present invention, the content of polyphenols that regulate neurotransmitter release and have wrinkle improvement effects is 0.01-10% by weight, more preferably 0.1-5% by weight, relative to the total weight of the microneedles .

The aforementioned microneedles can contain a high content of polyphenol components, and can provide a transdermal delivery system of polyphenols in which the amount delivered to the skin can be significantly increased compared with the dosage form of a common cosmetic composition.

Due to the poor solubility of polyphenol components, the amount that can be contained in cosmetic compositions in the past is extremely small, and the water content in the microneedle of the present invention is extremely small. Therefore, it is possible to avoid the analysis of polyphenol components, and it is suitable for high content. In the microneedle, and delivered to the skin.

The above-mentioned polyphenols may be selected from Kaempherol, quercetin, myricetin, luteolin, delphinium aglycone, anthocyanin, butyrin, ellagic acid, vitis, hesperidin (Hesperidin) ), Aurantinidin, Europinidin, Pelargonidin, Malvidin, Peonidin, Petunidin, Rosinidin and their Any one or more selected from the group consisting of derivatives of, preferably, any one or more selected from the group consisting of velopeptin, hesperidin (Hesperidin) or derivatives thereof.

In this article, if not specifically limited, the above-mentioned polyphenol derivatives include free form (free acid or panic form) and all prodrugs, polymorphs, hydrates, solvates, All pharmaceutically acceptable forms such as tautomers and stereoisomers, and include all active forms of the above-mentioned compounds. In one embodiment of the present invention, microneedles containing polyphenols hinder the formation of SNARE complexes, thereby hindering membrane fusion, and as a result, hindering the release of neurotransmitters such as acetylcholine, thereby inhibiting muscle cell growth. shrink.

In addition, the present invention provides a microneedle patch system for administration (delivery) of polyphenols or derivatives thereof, to which the above-mentioned microneedles are attached.

The microneedle of the present invention can be manufactured by a method commonly used in the art to manufacture soluble microneedles, and the manufacturing method is not particularly limited.

For example, the method for manufacturing the microneedle of the present invention may include: step S1 of manufacturing a solution containing components that regulate neurotransmitter release (for example, calcium channel blockers, polyphenols or their derivatives, or mixtures thereof); The S2 step of injecting the above solution into the microneedle mold; and the S3 step of drying and separating the microneedles from the above mold.

In addition, the present invention provides a method for transdermal administration of polyphenols, which is characterized by using the microneedle of the present invention. According to this method, solubility and skin transmission rate are improved.

In addition, the present invention provides the use of microneedles for improving wrinkles, wherein the microneedles contain polyphenols that regulate the release of neurotransmitters and have a wrinkle-improving effect.

According to an embodiment of the present invention, the present invention provides a microneedle that contains polyphenols and prevents the formation of SNARE complexes.

According to another embodiment of the present invention, the present invention provides the use of microneedles for improving skin wrinkles, wherein the aforementioned microneedles contain components that regulate neurotransmitter release.

According to another embodiment of the present invention, the present invention provides a microneedle that contains a calcium channel blocker and achieves the effect of improving wrinkles or facial lines through muscle relaxation. More preferably, the substance forming the aforementioned microneedles dissolves in the skin. Therefore, when the microneedles are used on the skin, the calcium channel blocker is released through the dissolution or disintegration of the microneedles, thereby making the aforementioned calcium channel blocker Can be stably delivered to the skin.

The inventor of the present invention has conducted research on various drug delivery systems, and after various efforts, surprisingly found that the inclusion of calcium channel blockers into soluble microneedles in the skin can effectively reduce the transmission of neurotransmitters, thereby hindering The contraction of muscles exerts the effect of improving skin wrinkles or improving facial contours to achieve a lifting effect.

When calcium channel blockers are contained in cosmetic formulations such as creams and lotions and applied, they cannot function normally due to their poor skin penetration ability. However, when the injection method is used, it has the disadvantage that it is not suitable for personal use at home. The inventors explored a solution that not only solves the above-mentioned problems, but also painlessly and conveniently obtains the effect of improving skin wrinkles, and finally completed the present invention.

In order to achieve the above problems, the microneedles need to be soluble in the skin, and to form soluble microneedles, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose), and vinylpyrrolidone can be used. -Vinyl acetate copolymer, polyvinyl alcohol (Polyvinyl alcohol) and polyvinyl pyrrolidone (Polyvinyl pyrrolidone) and other water-soluble polymers; Xylose (Xylose), sucrose (Sucrose), maltose (Maltose), lactose (Lactose), seaweed Sugars such as sugar (Trehalose); or their mixtures. In particular, considering the penetration strength of the microneedle through the skin and the speed of dissolution in the skin, it is preferable to use hyaluronic acid (Oligo-Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) And a mixture of saccharides (more preferably trehalose), and more preferably the following glycerine (Glycerine). Preferably, the microneedles of the present invention may contain plasticizers, surfactants, preservatives, anti-inflammatory agents, etc. in addition to the above-mentioned components that form the microneedles.

As the above-mentioned plasticizer, for example, Ethylene glycol, Propylene glycol, Dipropylene glycol, Butylene glycol, Glycerine, etc. may be used alone or in combination. Polyol.

Preferably, in the microneedle of the present invention, the content of calcium channel blocker that inhibits neurotransmitter release and inhibits skin muscle contraction is 0.0001 to 20% by weight relative to the total weight of the microneedle manufacturing solution, more preferably 0.001 to 5 wt%.

As used herein, "calcium channel blockers" can also be referred to as calcium antagonists, and refer to substances that block the flow of calcium into muscles, thereby inhibiting muscle contraction. The calcium channel blockers mentioned above can be selected from copper gluconate, zinc gluconate, Magnesium Sulfate, magnesium gluconate and magnesium aspartate. One or more organometallic compounds selected from the group consisting of amlodipine, lercanidipine, felodipine, nifedipine, nicardipine, isradipine, nisoldipine and their pharmaceutically acceptable salts Any one or more of dihydropyridine calcium channel blockers selected from the group consisting of; phenalkylamine calcium channel blockers containing verapamil; benzodiazepine calcium channel blockers containing diltiazem ; And, any one or more selected from the group consisting of N-type calcium channel blockers selected from the group consisting of gabapentinoid and zinconotide, and may include all The types of substances that block the flow of calcium into calcium channels and complete the relaxation effect are not particularly limited.

The calcium channel blocker may preferably be magnesium gluconate.

In addition, the present invention provides a microneedle patch system to which the above-mentioned microneedle is attached and contains a component that regulates neurotransmitter release, and preferably provides a microneedle patch for administration (delivery) of calcium channel blockers ( patch) system.

In addition, the present invention provides a method for transdermal administration of a component that regulates the release of neurotransmitters with improved skin transmission rate, which is characterized by using the microneedle of the present invention. Preferably, a method for transdermal administration of calcium channel blockers is provided.

In addition, the present invention provides a microneedle for facial muscle relaxation including the microneedle containing the above-mentioned neurotransmitter release-regulating component, and its use in facial muscle relaxation.

The above-mentioned "facial muscle relaxation use" includes the use of inhibiting the contraction of skin muscles to improve wrinkles; the use of improving facial contours; and the use of preventing skin relaxation to achieve a lifting effect.

According to an embodiment of the present invention, there is provided a method for transdermal administration of components that regulate neurotransmitter release, which utilizes the microneedle of the present invention. Preferably, a method for transdermal administration of a calcium channel blocker for improving wrinkles is provided.

Invention effect

According to the present invention, a microneedle having a skin wrinkle improvement effect is provided.

According to the present invention, there is provided a microneedle for transdermal administration that has a wrinkle improvement effect and can increase the skin permeability of polyphenols. In addition, the present invention also provides a method for transdermal administration of components that regulate neurotransmitter release, which is characterized by using the above-mentioned microneedles.

According to the present invention, there is provided a microneedle having a skin wrinkle improvement effect or a facial contour line improvement effect.

According to the present invention, the active ingredient can be painlessly penetrated into the skin through the microneedle.

According to the present invention, calcium channels of nerve cells can be inhibited and the release of neurotransmitters can be blocked, thereby relaxing muscles and improving wrinkles and facial lines.

In order to help understand the present invention, examples will be given below for detailed description. However, various modifications can be made to the embodiments of the present invention, and the scope of the present invention is not limited to the following embodiments. The embodiments of the present invention are provided to explain the present invention more completely to those of ordinary skill in the art.

＜Manufacture of soluble microneedles＞

The soluble microneedles can be made by the solution casting method, which can be made by casting the solution into a mold, using vacuum or centrifugation (centrifuge) to fill the micro-mold with the solution and then drying it. At this time, the material forming the microneedle structure uses ordinary synthetic water-soluble polymers and natural water-soluble polymers.

<Manufacture of polyphenol microneedles that inhibit the formation of SNARE>

The microneedles with the following composition in Table 1 were manufactured. First, dissolve hyaluronic acid (Oligo-HA™), sodium carboxymethyl cellulose (Na-CMC) and trehalose in purified water, and add glycerin, PEG-40 hydrogenated sesame oil (HCO-40™) and snake Vitisin solution (10% of vitis, 90% of DPG), made a solution of vitis (DPG: dipropylene glycol). The prepared polyphenol dispersion solution was poured into a silicone microneedle mold, centrifuged at 3000 rpm for 10 minutes, and the micro mold was filled with the solution.

After filling the solution, it was placed in a drying oven (70 ℃) to dry for 3 hours. Finally, the microneedles were separated from the silicone mold using an adhesive film. The content in Table 1 below is expressed in% by weight.

The manufacturing process is shown in Figure 1.

Table 1

<Manufacture of polyphenol oil-in-water cream that inhibits the formation of SNARE>

In order to compare the skin permeation amount of the polyphenols immersed in the microneedles, in the comparative example, the polyphenols were immersed in a common oil-in-water cream for comparison.

Table 2

＜Drug release behavior＞

Using a Franz diffusion cell equipped with pig skin, the microneedles produced above were used to evaluate the release of velocin (see Figure 2). As the acceptor solution, a PBS solution containing 30% by weight of DPG was used.

In other words, the Franz diffusion cell was used to measure the content of venereal in pig skin tissue and the acceptor solution over time by liquid chromatography.

The amount of evelourin-containing cream that penetrates through the skin is very small, while the evelourine impregnated in the microneedles directly penetrates the skin through the microneedles, showing a higher amount of skin permeation than the cream.

The amount of permeation through the skin of the cream containing snake vitis is about 1 μg, which is very small, while the polyphenols impregnated in the microneedles directly penetrate the skin through the microneedles. The penetration amount is more than 13 μg, which shows that the amount of penetration is more than 13 μg. The cream has a higher skin permeation rate of about 13 times or more. The results are shown in Fig. 5.

＜Wrinkle improvement effect＞

The sphalacsin cream and the microneedles impregnated with sphalacsin were applied to the wrinkles at the corners of the eyes every day. After 12 weeks, the degree of wrinkle improvement was confirmed by a silicone replica and wrinkle image analysis method (N= 20).

Compared with the cephalosporin cream, the microneedles impregnated with cephalosporin showed an excellent improvement effect more than 5 times. It was confirmed that the effect of improving the wrinkles was outstanding because the cephalosporin was effectively penetrated into the skin through the microneedles. , The results are shown in Figure 6.

＜Experiment to hinder the formation of SNARE complex＞

SDS-PAGE (Sodium dodecyl sulfate-polyacrylamide gel electrophoresis) analysis was performed in order to confirm whether polyphenols such as entropin, kaempferol, and myricetin hinder the formation of SNARE complex. It was confirmed whether the complex formed when SNARE protein SNAP25, SynH3, and Vps protein are mixed at a molar concentration of 1:1:1 is inhibited by polyphenol compounds added at a concentration of 1-50 ppm. Each protein was dropped into a 1 mL tube, polyphenol compounds were added and mixed, and then reacted at room temperature for 30 minutes. After that, electrophoresis was performed on 12% SDS-PAGE to confirm whether the SNARE complex was formed.

It was confirmed that kaempferol, myricetin, and emperoflavone effectively inhibit the formation of SNARE complex in a concentration-dependent manner. The experimental results show that, compared with myricetin, kaempferol and cephalocene have a stronger ability to inhibit the formation of SNARE complex at low concentrations. The inhibitory effects of myricetin, ampelopsin (dihydromyricetin), kaempferol, and A440 on the formation of SNARE were confirmed and shown in Figure 4. (Cell line: C2C12 (muscle cells) + NG108-15 (nerve cells) conditions, concentration: ppm)

＜Muscle contraction inhibition test＞

The C2C12 cells were placed in a culture plate and cultured in DMEM medium with 10% fetal bovine serum and 1% antibiotics. After that, neuroblasts were also added to the same culture plate and cultured together. At the beginning of the cell contraction of C2C12 cells, the number of contractions of C2C12 cells in 30 seconds was measured. After all the medium was removed, the cells were washed three times with PBS. Then, medium without fetal calf serum and 50 ppm of polyphenol compounds were added. , Reacted for 2 hours. After that, the number of contractions of C2C12 cells in 30 seconds was re-measured, and the inhibition of muscle contraction was confirmed.

The confirmation results showed that kaempferol, myricetin, and vegetalin inhibited the release of neurotransmitters from nerve cells, thereby reducing the number of contractions of C2C12 cells. After measurement, it was found that compared with myricetin, the inhibitory effect of kaempferol and kaempferol was relatively high. The results are shown in FIG. 7.

When manufacturing a cosmetic material composition containing the present invention, it may contain less than 0.5% (based on PEG400 5%, water 70%) of the present invention, and it is made by the microneedle manufacturing method of the present invention. In the microneedles, the content of ampelopsin can be increased to about 5% relative to the dry weight of the microneedles. Therefore, it is possible to manufacture products containing high-concentration polyphenols.

＜Manufacture of soluble microneedles＞

The soluble microneedles can be made by the solution casting method. The solution is poured into a mold, and the solution is filled into the micro mold by vacuum or centrifugal separation and then dried.

The material forming the microneedle structure uses ordinary synthetic water-soluble polymers and natural water-soluble polymers.

<Manufacture of soluble microneedles impregnated with magnesium gluconate>

table 3

Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and trehalose were dissolved in purified water, and Glycerin, HCO-40 and magnesium gluconate were added to produce a magnesium gluconate solution. (DPG: Dipropylene glycol)

The prepared dispersion solution of magnesium gluconate was poured into a silicone microneedle mold, centrifuged at 3000 rpm for 10 minutes, and the micro mold was filled with the solution. After filling the solution, place it in a drying oven (70 ℃) to dry for 3 hours, and use an adhesive film to separate the microneedles from the silicone mold.

＜Oil-in-water cream impregnated with magnesium gluconate＞

Table 4

In order to compare the skin permeation amount of magnesium gluconate immersed in microneedles, in the examples, magnesium gluconate was immersed in a common oil-in-water cream for comparison.

＜Drug release behavior＞

Using Franz diffusion cell, and using liquid chromatography to measure the content of magnesium gluconate in pig skin tissue and acceptor solution over time. Apply magnesium gluconate cream to pig skin or paste microneedles impregnated with magnesium gluconate to compare the skin permeation amount of magnesium gluconate over time.

The amount of the cream containing magnesium gluconate through the skin is about 1 μg or less, which is very small, while the magnesium gluconate impregnated in the microneedles directly penetrates the skin through the microneedles, and the penetration amount is more than 20 μg, showing that The amount of skin permeation is about 20 times or more than that of the cream, and the results are shown in FIG. 8.

<External muscle contraction inhibition effect>

It can be confirmed from Fig. 9 that when magnesium gluconate is processed, the higher the concentration of magnesium gluconate, the tendency for the number of muscle contractions to decrease significantly.

＜Wrinkle improvement effect＞

Magnesium gluconate cream and microneedles impregnated with magnesium gluconate were applied to the wrinkles at the corners of the eyes every day. After 12 weeks, they were confirmed by a silicone replica and wrinkle image analysis method (N=20).

From Fig. 10, it can be confirmed that the microneedles impregnated with magnesium gluconate exhibited more than 2 to 3 times the improvement effect compared with the magnesium gluconate cream. It was confirmed that this was because the magnesium gluconate was effectively penetrated by the microneedles. Into the skin, the effect of improving wrinkles is outstanding.

Industrial applicability

The invention can be applied to cosmetics and pharmaceutical applications for improving skin wrinkles.

The microneedle in the present invention can bring an excellent effect of reducing skin wrinkles.

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention. Anyone with ordinary knowledge in the relevant technical field can make some changes and modifications without departing from the spirit and scope of the present invention. The scope of protection of the invention shall be subject to the scope of the attached patent application.

no

The following drawings attached to this specification are used to illustrate the preferred embodiments of the present invention, and together with the foregoing content of the invention, are used to further understand the technical ideas of the present invention. Therefore, they should not be limited to the drawings. The disclosure explains the invention.

Fig. 1 is a diagram showing an example of various methods of manufacturing microneedles of the present invention. Soluble microneedles can be manufactured by solution casting, the solution can be cast into a mold, vacuum and/or centrifugation (centrifuge) can be used to fill the tiny mold with the solution and then dry And made. As a material for forming the microneedle structure, ordinary synthetic water-soluble polymers and natural water-soluble polymers can be used.

Figure 2 shows a Franz diffusion cell used to evaluate the drug release behavior of the microneedle of the present invention.

Fig. 3 is a schematic diagram showing a polyphenol having a similar effect to botulinum according to an exemplary embodiment of the present invention. Among them, myricetin, delphinium aglycone, anthocyanin, kaempferol, quercetin, fisetin, butrine, luteolin, ellagic acid, EGCG (epigallocatechin) can be used. Ester, Epigallocatechin gallate), Vitisin, Hesperidin (Hesperidin) and its derivatives.

Fig. 4 shows the results of confirmation that kaempferol, myricetin, and ampelopsin inhibit the formation of SNARE. (Cell line: C2C12 (muscle cells) + NG108-15 (nerve cells) conditions, concentration: ppm)

Fig. 5 is a graph showing the results of comparison of the content of ampelopsin in pig skin and acceptor solution (acceptor solution).

Fig. 6 is a graph showing the results of confirmation of the wrinkle improvement effect of the scutellarin cream and the scutellarin microneedles using the human body as an object.

Fig. 7 shows the results of confirmation of the muscle contraction inhibitory effects of kaempferol, myricetin, and peperolin.

Fig. 8 is a graph confirming the content of magnesium gluconate in pig skin and acceptor solution (acceptor solution) of magnesium gluconate cream and magnesium gluconate microneedles.

Fig. 9 shows the measurement results of the in vitro (In Vitro) muscle contraction inhibiting effect of magnesium gluconate. The muscle cells and neuroblasts were co-cultured in vitro, and were treated with different concentrations of magnesium gluconate. Ten minutes later, the results of the decrease in the number of muscle contractions were observed.

Fig. 10 is a graph showing the wrinkle improvement index of magnesium gluconate cream and magnesium gluconate microneedles.

Claims (10)

A microneedle containing a component for regulating the release of neurotransmitter, wherein the component for regulating the release of neurotransmitter comprises a polyphenol selected from the group consisting of kaempferol and snake grape At least one. The microneedle according to claim 1, wherein the component for regulating neurotransmitter release further comprises a calcium channel blocker. The microneedle according to claim 1, wherein the polyphenol is ampelopsin. The microneedle according to claim 1, wherein the content of the polyphenol in the microneedle is 0.01-10% by weight relative to the total weight of the microneedle. The microneedle according to claim 2, wherein the calcium channel blocker is composed of an organometallic compound, a dihydropyridine calcium channel blocker, a phenylalkylamine calcium channel blocker, a benzene Any one or more selected from the group consisting of a diazepine calcium channel blocker and an N-type calcium channel blocker; the organometallic compound is composed of copper gluconate, zinc gluconate ), Magnesium Sulfate (Magnesium Sulfate), Magnesium Gluconate (magnesium gluconate) and Magnesium Aspartate (magnesium aspatate) at least one selected from the group; the dihydropyridine calcium channel blocker is composed of ammonia Any one or more selected from the group consisting of clodipine, lercanidipine, felodipine, nifedipine, nicardipine, isradipine, nisoldipine and pharmaceutically acceptable salts thereof; the phenalkylamine The calcium channel blocker has at least verapamil; the benzodiazepine calcium channel blocker has at least diltiazem; and the N-type calcium channel blocker is composed of gabapentinoid and qi Selected from the group consisting of zinconotide. The microneedle according to claim 5, wherein the calcium channel blocker is magnesium gluconate. The microneedle according to claim 1, wherein the microneedle dissolves in the skin. The microneedle according to claim 1, wherein a substance forming the microneedle is hyaluronic acid (Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate Copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, sugars or mixtures thereof. The microneedle according to claim 8, wherein in addition to the microneedle-forming substance, the microneedle further contains a plasticizer. A microneedle for improving skin wrinkles, comprising the microneedle according to any one of claims 1 to 9.

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