Microneedles containing a fine fiber network structure

Abstract

The present invention relates to a microneedle including a fine fiber network structure, and more particularly to a microneedle that contains an insoluble fine fiber network structure in a soluble microneedle base, thereby enabling a large amount of aqueous drug solution to be delivered to the skin, regardless of the type of drug, through a drug injection hole on the back of the patch, even without the needle containing the drug.

Description

[Technical Field]

[0001] This application claims priority based on Korean Patent Application No. 10-2020-0080091 filed on June 30, 2020, and Korean Patent Application No. 10-2021-0055845 filed on April 29, 2021, the entire contents of which are incorporated herein by reference in their entirety in their specifications and drawings. The present invention relates to a microneedle patch comprising a fine fiber network structure. [Background technology]

[0002] In transdermal drug delivery systems, the stratum corneum, the outermost layer of skin with a thickness of 10–15 μm, serves as the most important barrier. Microneedles, measuring less than several hundred μm in length, can physically penetrate the skin with minimal penetration, allowing for convenient, painless, and effective drug delivery. This has led to extensive research in various fields, such as cosmetics and biomedicine. Starting with silicone microneedles manufactured using semiconductor processing technology by the Prausnitz group at Georgia Institute of Technology (USA) in 1998, various solid microneedles manufactured from metal, ceramic, or glass create temporary microchannels in the skin to deliver drugs coated on the needle or topically applied to the skin. However, if the needle breaks within the skin or small particles remain in the body, it can potentially induce an inflammatory response. Dissolving microneedles, manufactured from water-soluble polymers, are loaded with drugs and release the drug as the needle dissolves after penetrating the skin. Although microneedles have various advantages over solid microneedles, such as being easier to manufacture and leaving no residue on the skin, the active compounds that can be loaded are limited to hydrophilic substances. Also, because microneedles are several hundred μm in size, the amount of drug that can be loaded inside is limited, and only a small amount of drug can be delivered, which is insufficient to achieve efficacy. Furthermore, there is a problem that unstable active substances may be denatured during the microneedle manufacturing process.

[0003] Therefore, several studies have been reported to improve the drug loading capacity of dissolving microneedles. Studies have been reported in which the same drug was loaded into both dissolving microneedles and a topical formulation, and the topical formulation was applied before the needle was applied, thereby increasing the efficiency of drug delivery compared to using a needle alone (see Non-Patent Documents 1 and 2). Another system has been reported in which horse oil is applied to the end of a dissolving microneedle patch containing a hydrophilic drug, delivering both the drug and horse oil phases simultaneously. However, these methods do not significantly improve the drug delivery capacity, and there are significant inconveniences in their use, such as the need to wait for the formulation applied to the skin to dry properly before applying the needle, or the need to apply the oil phase to the needle before applying it to the skin.

[0004] In this specification, a number of documents are referenced and citations are provided, the disclosure contents of which are incorporated herein by reference in their entirety to more clearly explain the state of the art to which the present invention pertains and the content of the present invention. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Korean Patent Publication No. 10-2017-0103698 [Non-patent literature]

[0006] [Non-Patent Document 1] Molecular pharmaceutics 14(2017)2024-2031 [Non-patent document 2] Journal of cosmetic dermatology 18(2019)1083-1091 [Non-patent document 3] Journal of cosmetic dermatology 18(2019)936-943 Summary of the Invention [Problem to be solved by the invention]

[0007] In order to solve the above problems, the present inventors have confirmed that when a microneedle patch is manufactured by adding an insoluble fine fiber network structure to soluble microneedles, various types of drugs additionally supplied after the skin is perforated by the microneedle patch can not only be quickly diffused along the network structure formed by the fine fiber structure, but can also be delivered deep into the skin in large amounts throughout the entire area of ​​the patch, leading to the completion of the present invention.

[0008] Therefore, an object of the present invention is to provide a microneedle including a fine fiber network structure, and more specifically, to provide a microneedle that can deliver a large amount of aqueous drug solution to the skin through the back of the patch, regardless of the type of drug, by incorporating an insoluble fine fiber network structure into a soluble microneedle base.

[0009] More specifically, the object of the present invention is to provide the following embodiments: Embodiment 1. A microneedle comprising a microfiber network structure and a microneedle-forming material.

[0010] Embodiment 2: The microneedle of embodiment 1, wherein the fine fibers forming the network structure are one or more selected from the group consisting of cellulose fibers, acrylic fibers, chitosan fibers, polyethylene fibers, polypropylene fibers, polyethylene terephthalate fibers, polyimide fibers, and polyamide fibers.

[0011] Embodiment 3: In any one of the preceding embodiments, the microneedle includes a needle portion having a plurality of needles formed thereon, and a substrate portion to which the plurality of needles are attached, and the microfiber network structure is contained within the substrate portion.

[0012] Embodiment 4. The microneedle of any one of the preceding embodiments, wherein the fine fiber network structure is not contained within the needle portion.

[0013] Embodiment 5. The microneedle of any one of the preceding embodiments, wherein the microneedle-forming material swells or dissolves within the skin.

[0014] Embodiment 6. The microneedle of any one of the preceding embodiments, wherein the microneedle-forming material comprises a water-soluble polymer.

[0015] Embodiment 7. The microneedle of any one of the preceding embodiments, wherein the microneedle-forming material comprises one or more selected from the group consisting of hyaluronic acid or a salt thereof, carboxymethylcellulose or a salt thereof, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, and sugars.

[0016] Embodiment 8: The microneedle of any one of the preceding embodiments, wherein the content of the microfiber network structure contained within the microneedle is 0.01 wt % or more and less than 13.6 wt % of the total weight of the microneedle.

[0017] Embodiment 9. The microneedle of any one of the preceding embodiments, wherein a drug injection hole is formed in the substrate portion of the microneedle.

[0018] Embodiment 10: A microneedle in any one of the preceding embodiments, in which when a drug is injected through the drug injection hole, the drug spreads over the entire area of ​​the microneedle patch due to the fine fiber network structure contained within the substrate portion.

[0019] Embodiment 11. The microneedle of any one of the preceding embodiments, wherein the fine fiber network structure is an aqueous dispersion of an oxidized biocellulose fine fiber network.

[0020] Embodiment 12. The microneedle of any one of the preceding embodiments, wherein the oxidized biocellulose has 0.8 mmol / g or more of the total alcohol groups contained in the biocellulose before oxidation substituted with carboxyl groups.

[0021] Embodiment 13. A microneedle kit including a microneedle according to any one of the preceding embodiments and a drug separately provided.

[0022] Embodiment 14. A method for efficiently injecting an active ingredient into the skin for cosmetic purposes, comprising the steps of: preparing a microneedle according to any one of the preceding embodiments; and injecting the active ingredient through a drug injection hole formed in a substrate portion of the microneedle.

[0023] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, the claims and the drawings. [Means for solving the problem]

[0024] One aspect of the present invention provides a microneedle comprising a fine fiber network structure and a microneedle-forming material.

[0025] As a means of solving the above problem, a soluble microneedle-forming material was mixed with a water-insoluble fine fiber network structure, and a microneedle patch was manufactured using a micromolding method, which is a conventional method for manufacturing soluble microneedles.

[0026] Because the microfiber network structure has a three-dimensional entangled network structure, it cannot enter the mold cavity for forming the needle part and is uniformly dispersed only on the back surface of the substrate part, thereby producing a double-layered microneedle patch including (i) a needle part in which multiple needles that swell or dissolve with moisture in the skin are formed, and (ii) a substrate part in which the insoluble microfiber network structure is impregnated with a microneedle-forming substance.

[0027] That is, the needle portion is composed only of water-soluble components, while the substrate portion, while insoluble in water due to its microfiber network structure, acts as a reservoir that instantly absorbs the drug solution injected through the solution injection hole on the back of the substrate and continuously delivers it to the microneedles. Furthermore, the needle portion at the bottom of the substrate simultaneously dissolves in the body fluids in the skin and the drug solution, forming a channel along which a large amount of drug can quickly penetrate into the skin. As a result, we developed a system that can deliver a large amount of drug without the effort of maintaining drug stability and pre-treatment processes (e.g., drug surface modification and coating) required for drug loading into the microneedles.

[0028] Therefore, the present invention provides a microneedle patch comprising a needle portion having a plurality of needles formed thereon and a base portion to which the plurality of needles are attached, wherein the microfiber network structure is contained within the base portion and not within the needle portion.

[0029] In a preferred embodiment, a drug injection hole may be formed in the substrate portion of the microneedle, and when a drug is injected through the drug injection hole, the fine fiber network structure contained in the substrate portion has the effect of spreading the drug over the entire area of ​​the microneedle patch.

[0030] In the microneedle patch of the present invention, the diameter of the fine fibers forming the network structure may be 1 nm to 100 nm or less, preferably 20 nm to 80 nm or less, and may include, but is not limited to, polymer fibers with an aspect ratio of 4 to 5000, carbon fibers, conductive polymer fibers, etc.

[0031] If the content of fine fibers is less than 0.01 wt% of the dry weight of the microneedle patch, the ability to quickly absorb aqueous drug solutions will be reduced, and if more than 13.6% is added, it will be difficult to manufacture needles with sharp tips. Therefore, the content of the fine fiber network structure is preferably 0.01 wt% or more but less than 13.6 wt%.

[0032] The fine fibers forming the network structure preferably refer to fibers that are water-dispersible or modified to be water-dispersible, and may be, for example, one or more selected from the group consisting of cellulose fibers, acrylic fibers, chitosan fibers, polyethylene fibers, polypropylene fibers, polyethylene terephthalate fibers, polyimide fibers, and polyamide fibers, but are not limited thereto.

[0033] Preferably, the microfiber network structure may be an aqueous dispersion of an oxidized biocellulose microfiber network, which has high water absorption capacity and water retention capacity and is insoluble. Biocellulose is a cellulose microfiber synthesized from bacteria, and has excellent properties such as a smaller fiber diameter, high physical strength, and high crystallinity compared to plant-derived cellulose. However, it is difficult to apply it to cosmetic formulations because it is mainly in the form of a gel or sheet. In Patent Document 1, the present inventors developed a water-dispersible aqueous dispersion of biocellulose microfibers by substituting the alcohol groups of biocellulose with carboxyl groups.

[0034] Therefore, when biocellulose is used as the fine fibers forming the fine fiber network structure, oxidized biocellulose in which some or all of the alcohol groups are substituted with carboxyl groups should be used, and preferably, biocellulose in which 0.8 mmol / g or more of the total alcohol groups contained in the biocellulose are substituted with carboxyl groups can be used. When non-oxidized general biocellulose is used, the strong hydrogen bonds between the fibers cause the formation of aggregates in the water-soluble substance (microneedle-forming substance), making it impossible to form a network structure. In other words, when non-oxidized general biocellulose is used, it is not possible to form a network structure, making it impossible to form needles, or there is a risk of the microcellulose getting into the needles and leaving residue on the skin.

[0035] In the microneedles of the present invention, the microneedle-forming substance is one that swells or dissolves in the skin, and may include, but is not limited to, water-soluble polymers such as hyaluronic acid or its salts, carboxymethylcellulose or its salts, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof.

[0036] More specifically, the microneedle-forming material is a water-soluble material that can swell or dissolve well in the skin, and may include hyaluronic acid or its salt, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, sugars, or mixtures thereof.

[0037] The microneedle-forming material may further contain a plasticizer, a surfactant, a preservative, etc., taking into consideration the skin penetration strength of the microneedles, the dissolution rate in the skin, and the like.

[0038] As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin can be used alone or in combination.

[0039] Furthermore, the microneedles of the present invention, which include a fine fiber network structure and a microneedle-forming material, may further include a drug therein. That is, the present invention does not exclude the case where a drug is included inside a dissolving microneedle, as in the prior art.

[0040] The structure and shape of the microneedle of the present invention, when viewed from the base to the tip, can be any shape, such as a square pyramid, a triangular pyramid, a stepped pyramid, a microblade, or a bullet, tapering from a wide base, and the length is preferably within the range of 20 μm to 2 mm, but is not limited to these.

[0041] Another aspect of the present invention provides a microneedle kit including the microneedle and a liquid-phase drug separately provided.

[0042] Yet another aspect of the present invention provides a method for efficiently injecting cosmetic drugs into the skin for cosmetic purposes, comprising the steps of: preparing a microneedle comprising a fine fiber network structure and a microneedle-forming material, and having a drug injection hole formed in a substrate portion of the microneedle; and injecting a cosmetic drug through the drug injection hole formed in the substrate portion of the microneedle.

[0043] According to the microneedle patch including the microfiber network structure provided by the present invention, when a drug (preferably an aqueous drug solution) is injected through the drug injection hole on the back of the patch, the microfibers act as a reservoir that quickly absorbs the injected drug solution and continuously delivers it to the microneedles, allowing a large amount of drug to be delivered to the skin through microchannels formed from the microneedles dissolved in body fluids and the drug solution. Furthermore, since the drug is not loaded within the needles, there is no risk of drug denaturation during the needle manufacturing process or limitations on the amount of drug loaded, making it useful for applications in the cosmetics and pharmaceutical industries.

[0044] Preferably, all components described in the present invention do not exceed the maximum usage amount specified in the relevant laws, regulations, and standards of Korea, China, the United States, Europe, Japan, etc. (e.g., Regulations on Cosmetic Safety Standards (Korea), Cosmetic Safety Technical Standards (China)). That is, preferably, the microneedles according to the present invention, the drugs used in the present invention, and the microneedle kits containing the drugs contain the components according to the present invention within the content limits permitted by the relevant laws, regulations, and standards of each country. [Effects of the Invention]

[0045] When microneedles are manufactured by adding a microfiber network structure to a water-soluble microneedle-forming material, the microfiber structure has a three-dimensional entangled network structure, so it cannot enter the mold cavity where the needles are formed and is uniformly dispersed only on the back surface of the substrate. As a result, a microneedle patch having a dual structure of a water-soluble needle portion and an insoluble substrate portion can be provided by a single casting using molding technology, a conventional microneedle manufacturing method.

[0046] Meanwhile, when a drug injection hole is formed on the back surface of the substrate portion of the microneedle according to the present invention and a drug is injected through it, the fine fibers quickly absorb the drug and act as a reservoir that continuously delivers it to the microneedle portion, allowing a large amount of drug to be delivered to the skin through the microchannels formed from the microneedles that swell or dissolve due to moisture in the skin.

[0047] In addition, when a drug injection hole is formed on the back of the substrate and the drug is injected through it, it is not necessary to contain the drug inside the needle, which has the effect of solving the problem of the drug denaturing during the manufacturing process of the microneedle or the drug loading amount being limited due to the size of the microneedle. [Brief explanation of the drawings]

[0048] [Figure 1] 1 is a schematic diagram showing the manufacturing process of a microneedle patch including a fine fiber network structure. FIG. [Figure 2] FIG. 1 is a schematic diagram illustrating the drug delivery principle of a microneedle patch including a fine fiber network structure.

[0049] [Figure 3] 1 is a photograph showing the microstructure of a microfiber network structure according to an embodiment of the present invention and a microneedle patch manufactured in Example 1. [Figure 4] 1 shows the shape of the microneedle patch produced in Comparative Example 1.

[0050] [Figure 5] 1 is a photograph showing the difference in solubility in water and structural properties between Example 1 and Comparative Example 2. [Figure 6] 1 shows the results of applying Example 1 and Comparative Example 2 to pig skin to confirm the skin perforation rate of the microneedles.

[0051] [Figure 7]The results show that Example 1 and Comparative Example 2 were attached to pig skin and an aqueous solution of a model drug was applied, and the horizontal / vertical delivery of the drug was confirmed. [Figure 8] 1 shows the results of analyzing the amount of drug permeated through the skin when Example 1 and Comparative Example 2 were attached to pig skin and an aqueous solution of a model drug was applied. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention will be described in more detail below with reference to examples. It will be obvious to those skilled in the art that the following examples are merely for the purpose of explaining the present invention in more detail, and that the scope of the present invention is not limited by these examples.

[0053] Example Experimental Example 1. Fabrication of a microneedle patch containing a fine fiber aqueous dispersion network The mixture for the microneedle patch used during synthesis consisted of 1.5% Aqua Cellulose Solution (registered trademark, a water-insoluble biocellulose microfiber dispersion in which the alcohol groups of biocellulose are replaced with carboxyl groups, provided by The Garden of Natural Solution; distilled water 95.5%; hexanediol 3%), water-soluble hyaluronic acid, carboxymethylcellulose, trehalose, glycerin, and distilled water (see Table 1). The mixture was applied to a silicone mold and vacuum-sealed for 30 minutes, followed by drying at 50°C for 3 hours. The dried patch was separated from the mold, and a 6 mm diameter drug injection hole was punched in the center of the patch (see Figure 1).

[0054] [Table 1]

[0055] In Table 1, Example 1 is a microneedle patch containing a fine fiber water dispersion network (7.5% by dry weight).

[0056] Comparative Example 1 is a microneedle patch containing a fine fiber water dispersion network (13.6% by dry weight).

[0057] Comparative Example 2 is a dissolving microneedle patch that does not contain a fine fiber aqueous dispersion network. Scanning electron microscope photographs showing the structure of the biocellulose microfibers used in Example 1 and Comparative Example 1, and a scanning electron microscope photograph of the microneedle patch produced in Example 1, are shown in Figure 3. When measuring the microstructure of the microneedle patch produced in Example 1, it was confirmed from Figure 3 that almost no microfibers were observed on the surface of the needles and the front surface of the patch, but that the back surface of the patch had a double structure in which microfibers were uniformly distributed over the entire area (see Figure 3).

[0058] Furthermore, it was confirmed that the weight of the biocellulose microfiber aqueous dispersion that can be used to produce a microneedle patch (enables the tip of the microneedle to be formed well) is less than 13.6%, and that if more than this is added, the needles will not have a sharp tip and cannot be used (see Comparative Example 1 in Table 1 and Figure 4).

[0059] Experimental Example 2: Confirmation of the structural characteristics of the microneedle patch containing fine fibers To compare the structure and dissolution characteristics of the microneedle patch containing fine fibers (Example 1) prepared in Experimental Example 1 and the microneedle patch not containing fine fibers (Comparative Example 2), a small amount of water (0.1 mL) was dropped onto each patch before the drug injection holes were formed, and the change in shape was observed. As a result, in the case of Comparative Example 2, the entire patch including the needles dissolved in water and lost its shape (see Figure 5C and D), whereas in Example 1, only the needles dissolved, and the shape of the patch substrate was maintained (see Figure 5A and B).

[0060] Experimental Example 3: Comparison of skin perforation rates between microneedle patches containing fine fibers and those without. The microneedle patch containing the microfibers prepared in Experimental Example 1 (Example 1) and the microneedle patch not containing the microfibers (Comparative Example 2) were attached to pig skin and applied with a force of 20 N for 10 seconds. The patches were then removed, and the microchannels formed in the skin were stained with an aqueous trypan blue solution to compare the skin perforation rates. As a result, regardless of whether the patch contained microfibers or not, the skin perforation rate was over 90% (see Figure 6).

[0061] Experimental Example 4. Visualization of drug delivery ability of microneedle patches containing fine fibers A microneedle patch containing the microfibers prepared in Experimental Example 1 (Example 1) and a microneedle patch not containing the microfibers (Comparative Example 2) were attached to pig skin, and a model drug, rhodamine B, aqueous solution (300 μg / mL, 100 μL), was injected into the pore structure of the patch to compare the horizontal distribution of the drug solution. In Comparative Example 2 (see FIG. 7B), rhodamine B was distributed only in a portion of the microneedle patch, whereas in Example 1 (see FIG. 7A), rhodamine B was observed to be uniformly distributed throughout the entire patch area. Furthermore, a fluorescein aqueous solution (50 μg / mL, 2 mL) was applied to both the pig skin to which Example 1 was applied and the unattached pig skin. After removing the patch and residual solvent, the skin was sliced ​​to examine the vertical distribution of the drug. When the drug was applied without the microneedle patch, weak fluorescein fluorescence was observed only on the surface of the pig skin (see E and F in Figure 7), whereas in Example 1, strong fluorescence was observed deep into the skin (see C and D in Figure 7). As a result, it was confirmed that the microneedle patch containing fine fibers can deliver drugs deep into the skin over the entire area of ​​the patch.

[0062] Experimental Example 5: Evaluation of the amount of drug permeated through the skin using a microneedle patch containing fine fibers The patches prepared in Experimental Example 1 and Comparative Example 2 were attached to pig skin, and the receptors were attached to a plant cell filled with phosphate-buffered saline (pH 7.4, Gibco). A model drug, rhodamine B aqueous solution (300 μg / mL, 100 μL), was injected into the pore structure of each patch. The drug was allowed to permeate for 17 hours at 37°C and 50% relative humidity. The patch and unabsorbed solution were then removed, and the amount of drug permeated into the skin and receptors was analyzed (see Figure 8A). Additionally, a fluorescein aqueous solution (50 μg / mL, 2 mL) was applied to both the pig skin treated with Example 1 and the bare pig skin, and the amount of drug permeated was analyzed using the same procedure as above (see Figure 8B). As a result, even without the drug loaded on the needles, a significantly greater amount of drug was delivered into the skin than when only the model drug aqueous solution was applied without the patch. Furthermore, it was confirmed that an even greater amount of drug could be delivered than in Comparative Example 2.

Claims

1. A method for producing a microneedle comprising a fine fiber network structure and a microneedle-forming material, i) mixing oxidized bio-cellulose fine fibers with a microneedle-forming material; ii) applying the mixture of the microneedle-forming material and the oxidized biocellulose fine fibers to a mold to form microneedles; iii) separating the formed microneedles from the mold; The microneedle includes a needle portion having a plurality of needles formed thereon and a base portion to which the plurality of needles are attached, the microfiber network structure being contained within the base portion and not contained within the needle portion; and iv) forming a drug injection hole in the substrate portion of the microneedle; A method for producing a microneedle, in which some or all of the alcohol groups of the oxidized biocellulose are substituted with carboxyl groups.

2. The method for producing microneedles according to claim 1 , wherein the microneedle-forming substance swells or dissolves within the skin.

3. The method for producing microneedles according to claim 1 , wherein the microneedle-forming substance comprises a water-soluble polymer.

4. The method for producing microneedles according to claim 1, wherein the microneedle-forming substance comprises one or more selected from the group consisting of hyaluronic acid or a salt thereof, carboxymethylcellulose or a salt thereof, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, and sugars.

5. The method for manufacturing a microneedle according to claim 1, wherein the content of the microfiber network structure contained in the microneedle is 0.01 wt % or more and less than 13.6 wt % of the total weight of the microneedle.

6. The method for manufacturing a microneedle according to claim 1 , wherein when a drug is injected through the drug injection hole, the drug spreads over the entire area of ​​the microneedle patch due to the fine fiber network structure contained in the substrate portion.

7. The method for manufacturing a microneedle according to claim 1, wherein the oxidized biocellulose has 0.8 mmol / g or more of the total alcohol groups contained in the biocellulose before oxidation substituted with carboxyl groups.

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