KR102203635B1 - Fast Soluble Microneedle patch - Google Patents

Abstract

The present invention relates to a fast-dissolving microneedle having an improved dissolution rate, a microneedle patch including the same, and a method of manufacturing the microneedle. The microneedle according to the present invention is a soluble microneedle forming material, and by applying a synthetic polymer having excellent biocompatibility and excellent solubility, the strength of the microneedles that can penetrate the skin is maintained and the dissolution rate is improved. As the skin transmittance is improved, the ease of use is increased by shortening the use time.

Description

Fast Soluble Microneedle Patch

The present invention relates to a fast-dissolving microneedle having a high dissolution rate and strength sufficient to puncture the skin, a microneedle patch including the same, and a method of manufacturing the microneedle.

Various attempts have been made so far to improve the transdermal delivery efficiency of drugs that are difficult to absorb through the skin due to lack of skin affinity (lipid affinity) or too high molecular weight (over 500 Daltons), and as part of these attempts Needle was introduced.

Because these microneedles penetrate directly into the skin and perforate the skin to administer drugs into the skin, polymers with excellent biocompatibility, especially water-soluble natural polymers that can melt/disintegrate in the skin (e.g., carboxymethyl cellulose, hyaluronic acid) It is common to manufacture microneedles with (ronic acid, chitosan, pullulan, etc.).

However, microneedles made of water-soluble natural polymers do not melt/disintegrate in the skin at a rapid rate, so transdermal delivery efficiency decreases, and they must be adhered to and used for a long time until they melt/disintegrate. There was a problem.

Korean Patent Publication No. 10-0793615

Therefore, the problem to be solved by the present invention is to apply a synthetic polymer having excellent biocompatibility and excellent solubility as a soluble microneedles (microneedle) forming material, while maintaining the strength of a certain or more microneedles that can penetrate the skin, It is to provide a microneedle with improved ease of use by improving the dissolution rate to improve the skin permeability of the drug and shortening the use time.

In order to solve the above problems, the present invention provides a soluble microneedle having an improved dissolution rate while maintaining a certain or more strength capable of penetrating the skin. More specifically, in the soluble microneedle, it provides a fast-dissolving microneedle, characterized in that polyvinyl pyrrolidone (PVP) is included in the microneedle forming material.

The present inventors have made various attempts to develop a dosage form or system capable of efficiently transdermally administering a drug without being limited to the physical and chemical properties of the drug, and considered a microneedle as such a dosage form or system, but has biocompatibility. It was not easy to develop a microneedle (microneedle) that maintains a certain level of strength that can penetrate the skin and at the same time has a fast dissolution rate. When the microneedles are prepared so that they dissolve or collapse quickly in the skin, the strength of the microneedles is weak, so that the skin is not well punctured, and there is a problem in that the drug is not administered into the skin.

Accordingly, the inventors of the present invention produced microneedles having a high dissolution rate while at the same time having a certain strength that can penetrate the skin when polyvinyl pyrrolidone (PVP) is included in the microneedle forming material after various efforts. It was confirmed that the use of these microneedles enables efficient transdermal delivery of the drug without being limited to the physical and chemical properties of the drug, and finally the present invention was completed.

In the microneedle according to the present invention, polyvinylpyrrolidone is included in the microneedle forming material.

The polyvinylpyrrolidone refers to a polymer of N-vinyl-2-pyrrolidone (C.A.S. number: 9003-39-8).

Preferably, the average molecular weight of polyvinylpyrrolidone may be 8,000 to 1,000,000 g/mol, more preferably 10,000 to 400,000 g/mol, and most preferably 50,000 g/mol. When the average molecular weight of polyvinylpyrrolidone is less than 8,000 g/mol, sufficient strength cannot be provided to the microneedle, and when it exceeds 1,000,000 g/mol, it may be difficult to manufacture the microneedle.

More preferably, the polyvinylpyrrolidone may be polyvinylpyrrolidone K30. The polyvinylpyrrolidone K30 has a K value (that is, a value calculated according to the Fikentscherscher equation, 1% solution) of 26 to 35, an average molecular weight of 50,000 g/mol, and a Tg of about 163°C. , Brookfield viscosity (25 ℃, 5% solids) may be about 3 cps. However, it will be understood by those of ordinary skill in the art that the present invention is not limited to these values, and these values may vary depending on the conditions to be measured.

In addition, preferably, in the microneedle according to the present invention, polyvinylpyrrolidone may be included in an amount of less than 15% by weight based on the total weight of the microneedle preparation solution. More preferably, it may be included in an amount of 10% by weight or less. Even more preferably, it may be included in 2 to 10% by weight. When polyvinylpyrrolidone is included in an amount of 15% or more by weight of the total weight of the microneedle preparation solution, there is a problem that the strength of the microneedles rapidly decreases due to the hygroscopicity of the polyvinylpyrrolidone.

Preferably, the material forming the microneedle according to the present invention may be biodegradable or dissolved in the skin. This is because the microneedles must be dissolved or disintegrated after the microneedles are applied to the skin. More preferably, the microneedle according to the present invention is preferably made of a material that dissolves in the skin rather than a biodegradable polymer for the stability of the drug, and such ingredients include hyaluronic acid, sodium carboxymethyl cellulose carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, sugar, or a mixture thereof. As the sugar, xylose, sucrose, maltose, lactose, trehalose, or a mixture thereof may be used.

Among the above-described microneedle forming materials, when comprehensively considering the skin penetration strength of the microneedle and the dissolution rate in the skin, and in particular, comprehensively considering the compatibility with polyvinylpyrrolidone, the microneedle The material for forming the needle is preferably a mixture of hyaluronic acid, sodium carboxymethyl cellulose, and sugar in addition to polyvinylpyrrolidone, and in such a mixture, the sugar is even more preferably trehalose.

Preferably, the microneedle according to the present invention may be formed to contain 1 to 20% by weight of polyvinylpyrrolidone based on the total weight of the microneedle preparation solution. More preferably, a mixture of 1 to 20% by weight of polyvinylpyrrolidone, 1 to 30% by weight of hyaluronic acid, 1 to 30% by weight of sodium carboxymethyl cellulose, and 1 to 40% by weight of sugar based on the total weight of the microneedle preparation solution It can be formed including. Even more preferably, a mixture of 5 to 10% by weight of polyvinylpyrrolidone, 5 to 20% by weight of hyaluronic acid, 5 to 20% by weight of sodium carboxymethyl cellulose, and 10 to 30% by weight of sugar based on the total weight of the microneedle preparation solution It can be formed including.

In addition, preferably, the microneedles according to the present invention have a weight ratio of polyvinylpyrrolidone to the total weight of the mixture of hyaluronic acid, sodium carboxymethyl cellulose and sugar is 2-20: 1 (a mixture of hyaluronic acid, sodium carboxymethyl cellulose and sugar : Polyvinylpyrrolidone), more preferably 4-10: 1. If it is less than 2:1, the strength of the microneedles becomes too weak, and if it is more than 20:1, the dissolution rate of the microneedles may hardly be improved.

The material forming the microneedle may be dissolved in a solvent to exhibit viscosity, for example, water, anhydrous or hydrated lower alcohol having 1-4 carbon atoms, acetone, ethyl acetate, chloroform, dichloromethane, 1, 3- Butylene glycol, nucleic acid, diethyl ether or butyl acetate may be used, but water may be preferably used.

The microneedle according to the present invention may further include a plasticizer, a solubilizer, a surfactant, a preservative, an anti-inflammatory agent, etc. in addition to the aforementioned microneedle structure-forming material. As such a plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin are used alone. It can be used as or mixed. Preferably, glycerin was more preferable as a result of several evaluations in terms of physical properties and durability of the microneedle and compatibility with other materials forming the microneedle. As such a solubilizing agent, various components known in the art can be appropriately selected and used. Preferably, HCO-40 may be used as a result of various evaluations in terms of physical properties and durability of the microneedle and compatibility with other materials forming the microneedle.

In the present invention, the diameter and/or length of the microneedles is not limited to a specific size. However, for the purposes of the present invention, the upper and lower lengths of the microneedles required to pass through the stratum corneum of the skin are preferably 10 to 2,000 micrometers, and more preferably 100 to 1,000 micrometers. However, the length of the microneedles may be changed and used by a person skilled in the art in consideration of the purpose of use of the microneedles, the depth of the target skin layer, and the type of drug, and is not limited to the length.

The microneedle according to the present invention may be manufactured using various methods known in the art. For example, it may be manufactured using the materials described in Korean Patent Publication No. 10-0793615, International Patent Application Publication No. WO 02/064193, Korean Patent Application Publication No. 10-2011-0065361, and the like. More preferably, the microneedles according to the present invention may be manufactured by a solution casting method.

One or more drugs may be included in the microneedle according to the present invention. The term,'drug', may be used in the present specification with the same meaning as'active ingredient'.

The drug may be incorporated into, for example, microparticles, nanoparticles, or emulsion formulations, or/and may be included in a form coated on the outside of the microneedle. For example, the drugs may be internalized or included in a coated form at the same time, and drugs included in such different ways may be different from each other or may be the same. The term, microparticles, refers to micro-sized microspheres in which a drug is encapsulated, and nanoparticles refer to nano-sized microspheres in which a drug is encapsulated. In addition, the term emulsion formulation refers to a form in which a drug is emulsified in a material forming a microneedle. Emulsion formulations can be prepared in an oil-in-water or water-in-oil emulsion type and multiple emulsion type. The method of preparing the emulsion is preferably by dispersing the drug directly in the microneedle-forming material without an emulsifier to prepare an emulsion containing the drug, or may include the drug using various natural or synthesized emulsifiers. When using an emulsifier, more preferably, as a natural emulsifier, it can be stabilized using lecithin, borax, stearic acid, amazole soft, heliogel, beeswax, xanthan gum, emulsifying wax or solubilizer, and a synthetic emulsifier As an oil-in-water emulsifier for silk, PEG-8 dilaurate, PEG-150 distearate, PEG-8 stearate, PEG-40 distearate, PEG-100 distearate From the group consisting of thearate and water-in-oil emulsifiers, such as Sorbitan stearate, Sorbitan oleate, Sorbitan sesquioleate, and Sorbitan trioleate. It can be selected or combined to prepare an emulsion containing a drug. For example, a fat-soluble drug is emulsified in a water-soluble microneedle-forming material in an oil-in-water type with a homogenizer, or a water-soluble drug is emulsified in a fat-soluble microneedle-forming material such as chitosan or biodegradable plastics in a water-in-oil type with a homogenizer. I can get angry. In addition, using a multi-emulsion method, a second emulsion of a water-in-oil emulsion solution of a fat-soluble drug and a water-soluble drug in a mixture of a microneedle-forming material and a water-soluble drug is emulsified into an oil-in-water type, or a fat-soluble microneedle-forming material and a fat-soluble drug The mixture can be prepared by emulsifying a water-in-water emulsion solution of a water-soluble drug and a fat-soluble drug in a second emulsion to emulsify in an oil-in-water type. The size of the emulsion of the drug to be produced varies depending on the homogeneous rate of preparation of the emulsion. Microparticles or nanoparticles are, for example, solvent exchange method (Solvent exchange method), solvent evaporation method (Solvent evaporation method), membrane permeation method (Membrane dialysis method), spray drying method (Spray drying method), etc. Microparticles that can be used in can be produced. For example, methods described in Journal of Controlled Release 70 (2001) 1-20 and International Journal of PharmTech Research, 3 (2011) 1242-1254 may be used, but are not limited thereto. The material forming nanoparticles or microparticles may be the same as the material forming microneedles, but is preferably different. More preferably, there may be a difference in the rate of dissolution or disintegration in the skin between the material forming the microneedles and the material forming the nanoparticles/microparticles, and the rate at which the material forming the microneedles dissolves or collapses in the skin. May be faster than the rate of dissolution or disintegration in the skin of the substance forming nanoparticles/microparticles, whereby the nanoparticles/microparticles are retained after the microneedles are dissolved or collapsed, and the drug impregnated in the microparticles is slowly released. Can be. For example, materials that form nano/microparticles are poly(lactic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyortho. Ester, polyether ester, polycaprolactone, mono-methoxy polyethylene glycol-polycaprolactone (MPEG-PCL), polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, or their The copolymer may be used alone or in combination, but is not limited thereto.

Drugs that can be used in the present invention are not particularly limited. For example, a compound, a natural product, a protein drug, a peptide drug, a nucleic acid molecule drug, a cosmetic ingredient (eg, a wrinkle improving agent, an aging inhibitor, a whitening agent, etc.) may be included. More preferably, in consideration of compatibility and efficiency with the microneedle forming material, niacinamide may be included as an active ingredient.

In addition, the present invention provides not only the above microneedle itself, but also a microneedle patch to which a plurality of such microneedles are attached. The size of the patch is not limited to a specific size, and may be appropriately adjusted according to the amount of the drug to be absorbed into the skin or the attachment site.

The present invention also includes the step of preparing a microneedle containing a drug using the aforementioned microneedle forming material, a microneedle capable of stably enclosing a drug and effectively delivering it into the skin, thereby exhibiting excellent effects. Provides a manufacturing method.

The present invention also provides a method of skin administration characterized by using the microneedle according to the present invention.

The present invention provides a soluble microneedle having an improved dissolution rate. As a soluble microneedle (fine needle) forming material, a synthetic polymer with excellent biocompatibility and excellent solubility is applied to maintain the strength of the microneedles above a certain level that can penetrate the skin, while improving the dissolution rate to increase the skin permeability of the drug. It provides a microneedle with increased ease of use by improving and shortening the use time.

The following drawings attached to the present specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the content of the above-described invention, so the present invention is limited to the matters described in such drawings. It is limited and should not be interpreted.
1 is a view showing an example of several methods of manufacturing a microneedle (microneedle) according to the present invention. Soluble microneedles can be manufactured by a solution casting method, and after casting the solution in which the microneedle forming material is dissolved into a mold, filling the mold with vacuum and/or centrifugation, and drying It can be manufactured. As the material forming the microneedle (microneedle) structure, various materials well known to those skilled in the art may be used, and general biocompatible synthetic polymers, natural water-soluble polymers, biodegradable polymers, etc. may be used. have.
2 is a graph showing the result of confirming the ratio of the microneedles passing through the skin (skin transmittance) when each microneedle is used in order to confirm the strength of the microneedles according to Comparative Examples and Examples 1 to 5.
3 is a diagram showing perforations generated in the skin by each microneedle as a result of applying the microneedles of Comparative Examples, Examples 3 and 5 to the skin.
4 is a graph showing the results of confirming the dissolution rate of microneedles according to Comparative Examples and Examples 1-5.
5 shows the results of confirming the dissolution of the microneedles according to Comparative Example and Example 3 over time with a fluorescence microscope.
6 shows a Franz diffusion cell for evaluating drug release behavior using a microneedle.
7 is a graph showing evaluation results of niacinamide release from microneedles, evaluated using a Franz diffusion cell equipped with pig skin.

Hereinafter, examples, etc. will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

Fast dissolving Micro needle (Fast Soluble Microneedle ) Produce

As shown in Table 1 below, microneedles were prepared. In the present specification, the content of the compositions is expressed in weight percent unless otherwise specified.

Comparative example Produce

Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and trehalose were dissolved in purified water, and then glycerin, HCO-40, and niacinamide were added to prepare a solution.

The prepared solution was cast into a silicon microneedle mold, and then centrifuged at 3000 rpm for 10 minutes, and the solution was filled in a micro mold.

After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedle was separated from the silicone microneedle mold using an adhesive film.

Example Produce

Solution by dissolving Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose), and trehalose in purified water, and then adding glycerin, HCO-40, PVP K-30, and niacinamide. Was prepared.

The prepared solution was cast into a silicon microneedle mold, and then centrifuged at 3000 rpm for 10 minutes to fill the micro mold with the solution.

After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedles were separated from the silicone microneedle mold using an adhesive film.

Microneedle Strength check

Evaluation method: After punching and removing the prepared microneedle on pig skin, Trypan blue was applied for 10 minutes and wiped off. The number of needle holes formed in the skin was counted using a microscope, and the skin transmittance was calculated by comparing with the number of applied microneedles. The experiment was measured 3 times and made into an average.

<Skin transmittance = Number of needle holes / Number of applied needles X 100 (%)>

Comparative Examples, Examples 1, 2, and 3 maintained a skin transmittance of 95% or more, but Examples 4 and 5 had a sharp drop in strength due to the hygroscopicity of pulling moisture in the air of PVP, resulting in a decrease in skin transmittance. I did. The results are shown in FIGS. 2 and 3.

Check dissolution rate

Evaluation method: A microneedle disk of a certain size was prepared, a certain amount (0.2 mL) of water was added dropwise to the center, and the dissolution rate was evaluated by measuring the time at which a hole was formed in the disk. The experiment was measured 5 times and taken as an average. In the case of the example compared to the comparative example, the dissolution rate increased as the content of PVP increased. The results are shown in FIG. 4. As a result of the experiment, in the case of the comparative example, it was dissolved 82 seconds after the contact with water, whereas in the case of the example, it was confirmed that it dissolves within a time period of less than 82 seconds after the contact with water.

Microneedles prepared by adding 0.01% of a fluorescent substance (FITC) were punched into pig skin and removed over time, and then observed with a fluorescence microscope to confirm the degree of dissolution of the microneedles. Compared to the comparative example, in the case of Example 3, it was confirmed that the dissolution of the microneedles increased with time. The results are shown in FIG. 5.

Drug release behavior

Using a Franz diffusion cell, the niacinamide content of the porcine skin tissue and acceptor solution over time was measured using liquid chromatography. Comparative Examples and Examples 1 to 5 were attached to pig skin to compare the skin penetration amount of niacinamide over time.

In the comparative example, the amount permeated through the skin was about 18 ug after 2 hours, but Examples 1 to 4 were 20 ug or more, and in particular, in the case of Example 3, about 53 ug, which was about 3 times higher than that of the comparative example. . In Examples 1 to 3, as the PVP content increased from 2% by weight to 10% by weight, the skin permeation amount increased, which was determined to be because the dissolution rate increased while maintaining the strength of the microneedles enough to puncture the skin. . On the other hand, in the case of Examples 4 to 5, as the content of PVP was increased from 15% by weight to 20% by weight, it was confirmed that the strength of the microneedle was weak and thus the skin could not penetrate, and the skin transmittance was lowered even though the dissolution rate increased.

Claims (8)

In the soluble microneedles comprising a microneedle forming material and polyvinyl pyrrolidone (PVP),
The material for forming the microneedles includes a mixture of hyaluronic acid, sodium carboxymethyl cellulose and sugar,
The microneedles are a mixture of 2 to 10% by weight of polyvinylpyrrolidone, 2 to 10% by weight of hyaluronic acid, 2 to 10% by weight of sodium carboxymethyl cellulose, and 5 to 20% by weight of sugar based on the total weight of the microneedle. Fast-dissolving microneedle, characterized in that it comprises. delete delete The fast-dissolving microneedle of claim 1, wherein the polyvinylpyrrolidone has an average molecular weight of 35,000 to 80,000 g/mol. The fast dissolving microneedle according to claim 4, wherein the polyvinylpyrrolidone is polyvinylpyrrolidone K30. delete delete The fast-dissolving microneedle according to claim 1, wherein the microneedle contains niacinamide as an active ingredient.

Images