Detachable dissolvable micro-needle and method of preparation thereof

Abstract

The present disclosure relates to a separable soluble microneedle and a method for manufacturing the same, wherein the microneedle comprises a plurality of needle portions impregnated with a drug and a base layer, the base layer comprises a first layer and a second layer adjacent to the needle portions, and the first layer comprises a polymer having a sol-gel transition characteristic when pressure is applied.

Description

Technology Field

[0001] The present disclosure relates to a separable soluble microneedle and a method for manufacturing the same. Background Technology

[0002] Most pharmaceuticals are administered via oral routes or in injectable forms. However, injectables must be administered by medical professionals and have drawbacks such as secondary infection and pain at the injection site. Therefore, micro-needles are currently emerging as a viable option.

[0003] Generally, microneedles refer to microstructures capable of penetrating the stratum corneum of the skin to deliver drugs to the epidermis and dermis. Since microneedles are attached to the skin surface to create microscopic holes in the epidermis and deliver drugs through these openings, they cause significantly less pain than conventional injections and can prevent infection. Furthermore, they enable drug delivery at a speed more than 100 times faster than existing transdermal delivery systems.

[0004] Microneedles can be classified into solid microneedles, coated microneedles, soluble microneedles, hollow microneedles, and hydrogel-forming microneedles depending on the drug delivery strategy.

[0005] Among these, soluble microneedles, which fill a mold with a polymer solution containing drugs, are composed of various polymer materials and can completely dissolve and decompose within the epidermis. As such, they can deliver relatively large amounts of drugs to the human body without leaving medical waste, leading to active research and development in fields such as medicine and cosmetics. The problem to be solved

[0006] The present disclosure is devised to solve the above-mentioned problems, and according to one aspect of the present disclosure, when the skin is punctured with a micro-needle, only the needle portion is separated and injected into the body, thereby providing a separable micro-needle capable of delivering a precise amount of medication intact into the body.

[0007] According to one aspect of the present disclosure, a micro-needle according to one embodiment of the present disclosure can provide a micro-needle that fully delivers a drug into the body when inserted into the skin by applying pressure.

[0008] According to one aspect of the present disclosure, soluble microneedles can provide separable microneedles with excellent mechanical strength capable of penetrating skin. means of solving the problem

[0009] The present disclosure provides a separable soluble microneedle comprising a plurality of needle portions impregnated with a drug and a base layer, wherein the base layer comprises a first layer and a second layer adjacent to the needle portions, and the first layer comprises a polymer having a sol-gel transition characteristic when pressure is applied.

[0010] In one embodiment according to the present disclosure, when pressure is applied to the skin, the detachable soluble micro-needle may be separated so that only the needle portion is absorbed into the body.

[0011] In one embodiment according to the present disclosure, the polymer having the sol-gel transition characteristic of the first layer may comprise modified cellulose to which a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate has been added.

[0012] In one embodiment according to the present disclosure, the needle portion or the second layer is a biodegradable polymer such as chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate, albumin, fullulan, cellulose, pectin, starch, glycogen, polylysine, poly lactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or polycarbonate. It may include at least one of the group consisting of collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the polymer.

[0013] In one embodiment according to the present disclosure, the agent may comprise one or more selected from the group consisting of antiviral agents, antifungal agents, antibiotics, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), transcription regulatory factors, vaccines, epidermal growth factor (EGF), and cell signaling regulatory proteins (AIMP1).

[0014] In one embodiment according to the present disclosure, the thickness of the first layer may be 1 μm or more.

[0015] In one embodiment according to the present disclosure, the needle width:length ratio of the needle portion may be 1:1.2 to 1:10.

[0016] In one embodiment according to the present disclosure, the needle portion may have a length of 100 to 1000 μm.

[0017] In one embodiment according to the present disclosure, the detachable soluble micro needle may further include a protective sheet having an adhesive on one surface on the second layer.

[0018] The present disclosure provides a method for manufacturing a separable soluble microneedle, comprising the steps of: injecting a first solution containing a biodegradable polymer and a drug into a lower mold containing a microneedle indentation up to the indentation portion and then pressurizing and drying; injecting a second solution containing a sol-gel transition polymer into a base layer and then pressurizing and drying to form a first layer; and injecting a third solution containing a biodegradable polymer into the base layer and then pressurizing and drying to form a second layer.

[0019] In one embodiment according to the present disclosure, the step of attaching a protective sheet having an adhesive on one surface to the second layer may be further included.

[0020] In one embodiment according to the present disclosure, the second solution may contain 1 to 10 parts by weight of a sol-gel transition polymer.

[0021] In one embodiment according to the present disclosure, the first solution may contain 5 to 20 parts by weight of a biodegradable polymer. Effects of the invention

[0022] According to one embodiment of the present disclosure, the separable soluble micro-needle of the present disclosure can provide a micro-needle in which only the needle portion can be separated when pressure is applied.

[0023] According to one embodiment of the present disclosure, when the separable soluble micro-needles of the present disclosure are inserted into the skin under pressure, the separated needle portion remains in the dermis of the skin and gradually dissolves, thereby improving the efficiency of delivering drugs into the body.

[0024] According to one embodiment of the present disclosure, the physical strength of the micro-needle is enhanced, and the leakage of the drug when inserted into the skin is minimized, thereby improving drug delivery efficiency.

[0025] According to one embodiment of the present disclosure, the needle portion containing the drug is easy to insert into the skin and does not easily fall out of the skin even after insertion, thereby improving the efficiency of drug delivery. Brief explanation of the drawing

[0026] FIG. 1 is a schematic diagram of a microneedle of one embodiment of the present disclosure. FIG. 2 is a schematic diagram illustrating only the needle portion separated from the micro needle of one embodiment of the present disclosure. FIG. 3 is a schematic diagram illustrating the process of separating only the needle portion from a micro-needle patch with a protective sheet attached according to one embodiment of the present disclosure. Figure 4 shows the appearance of a microneedle manufactured according to one embodiment of the present disclosure before the needle portion is separated. Figure 5 shows the appearance of only the needle portion being separated when pressure is applied to a micro needle manufactured according to one embodiment of the present disclosure. Figure 6 is a microscopic view of the micro-needle manufactured according to one embodiment of the present disclosure, after being inserted into the skin and only the needle portion separated and left on the pig skin. Specific details for implementing the invention

[0027] The advantages and features of the present disclosure and the methods for achieving them will become clear by referring to the embodiments described in detail below. However, the present disclosure is not limited to the embodiments disclosed below but may be implemented in various different forms. These embodiments are provided merely to ensure that the disclosure of the present disclosure is complete and to fully inform those skilled in the art of the scope of the invention, and the present disclosure is defined only by the scope of the claims.

[0028] Unless otherwise defined, all terms used in this specification (including technical and scientific terms) may be used in a meaning that is commonly understood by those skilled in the art to which this disclosure pertains.

[0029] Unless otherwise specifically indicated, the singular form of a term used in this specification may be interpreted to include the plural form.

[0030] The numerical ranges used herein include lower and upper limits and all values ​​within the range, increments logically derived from the form and width of the defined range, all of which are limited values, and all possible combinations of upper and lower limits of the numerical range defined in different forms. Unless otherwise specifically defined in the specification of this disclosure, values ​​outside the numerical range that may occur due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0031] This is an open description having an equivalent meaning to expressions such as 'comprising,' 'having,' 'having,' and 'characteristics' mentioned in this specification, and does not exclude elements, materials, or processes not additionally listed.

[0032] The term “soluble microneedle” as used in this specification refers to a needle-shaped structure having a length in the micrometer range, which releases an loaded drug or medication by dissolving within the body when applied to penetrate the skin.

[0033] As used in this specification, the term “patch” refers to a formulation that delivers a drug into the body by being attached to the skin.

[0034] The “needle portion” of the micro-needle mentioned in this specification refers to the pointed portion that first comes into contact when the micro-needle is inserted into the skin, and refers to the portion impregnated with a drug, and refers to portion 10 in Figure 1 of the present disclosure.

[0035] The “first layer” of the microneedle base layer mentioned in this specification refers to the portion 20 in FIG. 1 as a layer adjacent to the needle portion that includes the sol-gel transition polymer.

[0036] The "second layer" of the micro-needle base layer mentioned in this specification refers to a biodegradable polymer layer applied over the first layer, which means part 30 in FIG. 1.

[0037] As mentioned in this specification, "copolymerization" refers to a reaction in which two or more monomers are mixed and polymerized to synthesize a copolymer. The copolymer may be a random copolymer or a graft copolymer, or a block copolymer.

[0038] Hereinafter, the separable soluble micro-needles of the present disclosure and the method for manufacturing the same will be described in detail. However, this is merely illustrative and the present disclosure is not limited to the specific embodiments described illustratively.

[0039] In the case of existing soluble microneedle products, microneedles are manufactured and used on a hydrocolloid. However, in such cases, the drug remains in the needle hole area, causing side effects or problems in that the target amount of drug cannot be fully delivered into the body.

[0040] Accordingly, the inventor of the present disclosure devised a separable soluble microneedle that can deliver a drug intact into the body by separating only the needle portion of the microneedle when penetrating the skin with the microneedle.

[0041] The micro needle of the present disclosure is a micro needle comprising a plurality of needle portions impregnated with a drug and a base layer, wherein the base layer comprises a first layer and a second layer adjacent to the needle portions, and the first layer may provide a separable soluble micro needle comprising a polymer having a sol-gel transition characteristic when pressure is applied.

[0042] FIG. 1 is a conceptual diagram of a micro needle according to an embodiment of the present invention. Referring to FIG. 1, the micro needle according to the embodiment may include a base layer (50) and a needle portion (10) disposed on the base layer (50).

[0043] The base layer (50) may include a first layer (20) containing a sol-gel transition polymer and a second layer (30) containing a biodegradable polymer.

[0044] Here, "gel" refers to a porous solid state in which liquid-type colloids become concentrated and solid components begin to bind to each other, and liquid materials such as water are dispersed within a network structure formed by solid materials, and "sol" refers to a colloidal suspension in which fine solid particles are scattered in a stable state within a liquid.

[0045] The polymer having the above sol-gel transition characteristics is a biodegradable sol-gel transition polymer, which refers to a polymer material that exhibits unique behavior in which it changes from a gel to a sol or changes from a sol to a gel due to stimulation by the surrounding environment, such as temperature, light, mechanical pressure, or pH.

[0046] The sol-gel transition polymer used in one embodiment of the present disclosure may be any polymer having the characteristic of changing into a sol or a gel in response to known pressure.

[0047] When pressure is applied to the skin of the above-described separable soluble micro-needles, the first layer (20) of the base layer (50) changes from a solid (gel) to a liquid (sol), causing only the needle portion (10) to separate. Therefore, when the micro-needles are inserted into the skin, only the needle portion (10) containing the drug is separated, allowing the drug to be absorbed into the body.

[0048] In conventional soluble micro-needles where the needle portion (10) is not separated from the base layer (50), the drug in the needle portion (10) remains in the needle hole area, so the desired amount of drug cannot be fully delivered into the body, and when the protective sheet is removed from the skin, the needle portion (10) containing the drug also comes off together.

[0049] The detachable soluble micro-needles of the present disclosure solve the above problems, so that when the micro-needles are inserted into the skin under pressure, the needle portion (10) is inserted into the skin while detached, allowing the drug to be fully absorbed into the body. Furthermore, even if the protective sheet is subsequently removed from the skin, the drug in the needle portion (10) remains in the body, allowing the drug to be fully delivered into the body.

[0050] FIG. 3 is a schematic diagram illustrating the process of separating only the needle portion from a micro-needle patch with a protective sheet attached according to one embodiment of the present disclosure.

[0051] Referring to FIG. 3, the micro-needles are inserted into the skin by applying pressure. When pressure is applied, the first layer (20) transitions from a gel (solid) state to a sol (liquid) state, causing only the needle portion (10) to be separated. Therefore, when pressure is no longer applied, even if the skin that was pressed returns to its original state, the needle portion (10) remains in the dermis of the skin separated from the base layer (50). The separated needle portion (10) remains in the dermis of the skin and gradually dissolves, allowing the intended amount of medication to be fully delivered into the body.

[0052] In another embodiment of the present disclosure, the polymer having the sol-gel transition characteristic of the first layer (20) of the base layer (50) may comprise surface-modified cellulose to which a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate has been added.

[0053] Cellulose is characterized by high hydrophilicity due to the large number of hydroxyl groups (-OH) present on its surface, and because it consists of a mixture of crystalline and amorphous regions, the crystalline portions possess high mechanical properties. Therefore, cellulose is a polymer that can be chemically modified in various ways by utilizing the surface hydroxyl groups (-OH) in its amorphous portions.

[0054] The cellulose having the sol-gel transition characteristics of the present disclosure may be formed by radical polymerizing a solution containing 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate into cellulose into which a living radical polymerization initiation site has been introduced.

[0055] The surface-modified cellulose may be one in which hydroxyl groups (-OH) remaining on the surface of the cellulose after the radical polymerization reaction are oxidized to carboxylic acids.

[0056] The above 2-methacryloyloxyethyl phosphorylcholine is a hydrophilic equivalent that has a chemical structure similar to that of biological cells and possesses excellent anti-biodegradation properties, making it a biocompatible polymer that can be safely used in the human body. The above-mentioned stearyl methacrylate is a hydrophobic equivalent.

[0057] Thus, the surface-modified cellulose is a cellulose in which a polymer having amphoteric ions and hydrophobic chains are introduced to the surface, and due to the interaction of the hydrophobic chains of the stearyl methacrylate, the cellulose forms a gel phase, and the hydrophilic chains of the 2-methacryloyloxyethylphosphorylcholine impart cationic hygroscopicity to the polymer, thereby promoting complete hydration into water molecules and forming a sol.

[0058] The surface-modified cellulose normally exhibits a gel structure due to hydrophobic chains, but when pressure is applied and a low deformation of 10% occurs, a shear thinning phenomenon is observed in which the gel transitions to a sol due to hydrophilic chains.

[0059] Accordingly, when the separable soluble micro-needle of the present disclosure is inserted into the skin by applying pressure, the first layer (20) containing the sol-gel transition cellulose changes from a gel (solid) state to a sol (liquid) state, and only the needle portion (10) can be separated.

[0060] In one embodiment of the present disclosure, the second layer (30) of the needle portion (10) or the base layer (50) is a biodegradable polymer such as chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate, albumin, fullulan, cellulose, pectin, starch, glycogen, polylysine, poly lactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol, Polycarbonate, collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the polymer may comprise at least one of the group consisting of these, but is not necessarily limited thereto.

[0061] Specifically, it may include one or more selected from the group consisting of hyaluronic acid, polyvinyl alcohol (PVA), carboxymethylcellulose (CMC), chitosan, gelatin, and hydroxypropyl methylcellulose (HPMC).

[0062] More specifically, it may contain polyvinyl alcohol (PVA) and hyaluronic acid in a ratio of 4:1. The term hyaluronic acid is used to mean not only hyaluronic acid but also hyaluronic acid salts and mixtures thereof.

[0063] To improve the mechanical properties of the needle part (10), it may further include additives such as a crosslinking agent, a viscosizing agent, and a solubilizing agent.

[0064] The above additive may further include one or more selected from the group consisting of xanthan gum, fucoidan, carrageenan, carbopol, sucrose, maltose, lactose, cellobiose, hyaluronic acid, gellan gum, microfibrillated cellulose, gum ghatti, carrageenan, karaya gum, carboxymethyl cellulose, and cyclodextrin, but is not necessarily limited thereto.

[0065] For the interaction between the drug of the needle portion (10) and the biodegradable polymer, the needle portion (10) may additionally include a surfactant. As the surfactant, any known surfactant that can be added to a drug by a person skilled in the art may be used without limitation.

[0066] Specifically, it may include one or more selected from the group consisting of sodium lauryl sulfate, sorbitan, polyglycerin ester, lecithin, saponin, glucose, and sugar ester, but is not necessarily limited thereto.

[0067] The needle portion (10) and the second layer (30) of the base layer (50) may be made of the same biodegradable polymer.

[0068] The biodegradable polymer included in the above needle portion (10) can have its molecular weight adjusted according to the properties of the drug. If the drug needs to be released slowly from the affected area over a long period of time depending on the properties of the drug, the molecular weight of the above biodegradable polymer can be designed to be relatively large so that it dissolves in the dermis of the skin over a long period of time and is slowly released into the body.

[0069] In order for it to dissolve over a long period of time, the molecular weight of the biodegradable polymer included in the needle part (10) may be 10,000 to 300,000 Da. More specifically, it may be 30,000 to 200,000 Da.

[0070] The molecular weight of the biodegradable polymer included in the second layer (30) above may be 5,000 to 200,000 Da.

[0071] In one embodiment of the present disclosure, the agent may comprise one or more agents selected from the group consisting of antiviral agents, antifungal agents, antibiotics, polydeoxyribonucleotides (PDRN), polynucleotides (PN), extracellular matrix (ECM), transcription regulators, vaccines, epidermal growth factor (EGF), and cell signaling regulatory proteins (AIMP1).

[0072] Specifically, the above antibiotic may include one or more antibiotics selected from the group consisting of penicillin-based antibiotics, cephalosporin-based antibiotics, macrolide-based antibiotics, lincoamide-based antibiotics, tetracycline-based antibiotics, and metronidazole, but is not necessarily limited thereto.

[0073] Specifically, the above antiviral agent may include one or more selected from the group consisting of sodium azulenesulfonate, cetylpyridinium chloride, acyclovir, triamcinolone acetonide, beclomethasone dipropionate (BMDP), betamethasone valeric acid, triamcinolone, triamcinolone acetonide, dexamethasone, fluocinolone acetonide, fluocinonide, flumethasone, hydrocortisone, prednisolone, and prednisone, but is not necessarily limited thereto.

[0074] Specifically, the above antifungal agent may be an azole-based, arylamine-based, polyene-based, or echinocandin-based antifungal agent.

[0075] More specifically, the agent used in the present disclosure may be NeoPep-S, a peptide derived from epidermal growth factor (EGF) or cell signaling regulatory protein (AIMP1). Even more specifically, the agent may comprise epidermal growth factor (EGF), 5-aminolevulinate hydrochloride, and Chlorin E6.

[0076] The above-mentioned agents are not limited thereto and may be used as drugs, vaccines, nutrients, or cosmetics depending on the application.

[0077] In one embodiment of the present disclosure, the ratio of the drug and the biodegradable polymer of the needle portion (10) can be appropriately selected and manufactured by a person skilled in the art according to the type and composition of the drug. If the ratio of the biodegradable polymer content is too low, the strength of the micro needle may be reduced, making it difficult to insert into the skin, and if the ratio of the biodegradable polymer content is too high, the ratio of sufficient drug may be low, making it difficult to deliver sufficient drug into the body.

[0078] In one embodiment of the present disclosure, the thickness of the first layer (20) may be 1 μm or more.

[0079] Since the sol-gel transition polymer of the first layer (20) has reactivity that transitions from gel to sol for a certain strain, the first layer (20) can be made of 1 μm or more to prevent it from changing into a sol state due to the weight of the second layer (30) during or after the manufacturing process.

[0080] The micro needles of the present disclosure may be designed with different lengths for the first layer (20) of the needle portion (10) depending on the skin thickness, age, gender, race, and degree of obesity of each body part. The shape of the needle portion (10) may be a pointed shape toward the end of the needle portion, and may be a conical shape or a polygonal pyramidal shape, but is not limited thereto.

[0081] In one embodiment of the present disclosure, the needle portion (10) may be 50 to 2000 μm, and more specifically, 70 to 1500 μm. More specifically, it may be in the range of length from 100 to 1000 μm. It is not necessarily limited thereto, and the length of the needle portion (10) may be designed to be an appropriate length to maximize the drug effect according to the skin thickness of each body part.

[0082] Since microneedles are characterized by painless penetration of the skin, they must have sufficient strength to penetrate the stratum corneum and epidermis, which are 10-20㎛ thick. If they do not have sufficient strength, they may bend or break during the insertion process, resulting in the inability to deliver drugs into the body.

[0083] The needle width to length ratio of the above needle part may be 1:1 to 1:20. More specifically, it may be 1:1.2 to 1:10.

[0084] If the width of the needle part is greater than its length, it cannot puncture the skin, and if the ratio of the needle part width to length exceeds 1:20, the needle may break or bend upon puncturing the skin, making it difficult to deliver the drug into the body.

[0085] In one embodiment of the present disclosure, the separable soluble micro needle may further include a protective sheet on the second layer (30).

[0086] Since the raw material of the micro-needle is made of biodegradable polymer, it is highly susceptible to moisture. Therefore, a protective sheet with a waterproof function can be attached to one side of the micro-needle after drying is complete to prevent the micro-needle from being damaged by moisture.

[0087] The above protective sheet may include various adhesives that can adhere to one surface without causing damage to the skin, such as hydrophobic adhesives, silicone adhesives, acrylic adhesives, and hydrophilic adhesives. More specifically, the adhesive included on one surface of the above protective sheet may be at least one of cellulose-based resins, polyester-based resins, polyethylene, resin hydrocolloids, and polyurethanes, or a combination thereof.

[0088] The above protective sheet is formed along the edge of the base layer (50). Accordingly, the shape of the protective sheet may follow the shape of the base layer (50), and the shape of the base layer (50) may have a different shape depending on the area where the micro-needles are inserted. It may be circular, elliptical, square, polygonal, or mask-shaped, and is not specifically limited to the shape.

[0089] In addition, the present disclosure may provide a method for manufacturing the micro-needles. The types of biodegradable polymers, protective sheets, agents, etc. used in the manufacturing method are the same as those described above.

[0090] The present disclosure may provide a method for manufacturing a separable soluble microneedle comprising: a step of injecting a first solution containing a biodegradable polymer and a drug into a lower mold containing a microneedle indentation up to the indentation portion and then pressurizing and drying; a step of injecting a second solution containing a sol-gel transition polymer into a base layer (50) and then pressurizing and drying to form a first layer (20); and a step of injecting a third solution containing a biodegradable polymer into the base layer (50) and then pressurizing and drying to form a second layer (30).

[0091] Since the solutions are applied to the above-mentioned intaglio mold and then subjected to a pressurization step, the solution can be completely injected into the intaglio needle shape, and the probability of generating defective micro-needles may be reduced. The above-mentioned intaglio mold may be provided with a coating portion to easily separate the generated micro-needles.

[0092] In another embodiment of the present disclosure, the step of attaching a protective sheet on the base layer (50) may be further included. After attaching the protective sheet, which has an adhesive on one surface, onto the second layer (30), it can be removed from the intaglio mold.

[0093] The sol-gel transition polymer of the second solution above may comprise cellulose surface-modified with a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate.

[0094] The solvent of the second solution may be a hydrophilic solvent, and the hydrophilic solvent may be purified water, distilled water, water, or ionized water, and specifically, may be water.

[0095] In one embodiment of the present disclosure, the sol-gel transition polymer of the second step may be included in an amount of 1 to 20 parts by weight of the solution, and more specifically, in an amount of 1 to 10 parts by weight.

[0096] When the above sol-gel transition polymer is included in a solution in an amount of less than 10 parts by weight, the drying time is too long, and when it is included in an amount of more than 10 parts by weight, a problem arises in that it is difficult to discharge from a precision dispensing device.

[0097] In one embodiment of the present disclosure, the biodegradable polymer is chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate, albumin, fullulan, cellulose, pectin, starch, glycogen, polylysine, polylactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one of the group consisting of collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the polymer, but is not necessarily limited thereto.

[0098] The solvent of the first solution is determined by the drug and the biodegradable polymer, and may use inorganic or organic solvents such as purified water, distilled water, methanol, ethanol, glycerin, isopropyl alcohol, and propylene glycol. The solvent is not necessarily limited to these, and various solvents known to those skilled in the art may be appropriately selected and used as long as they can dissolve the biodegradable polymer and the drug.

[0099] In one embodiment of the present disclosure, the biodegradable polymer of the first solution or the third solution may be included in an amount of 1 to 40 parts by weight of the solution. More specifically, it may be included in an amount of 5 to 30 parts by weight. Even more specifically, it may be included in an amount of 5 to 20 parts by weight.

[0100] If the biodegradable polymer is included in the solution in an amount of 5 parts by weight or less, the micro-needles produced after pressurized drying have low strength and cannot puncture the skin, and if it is included in an amount exceeding 20 parts by weight, the viscosity is high and cannot be injected into the inside of the mold during extrusion, making it difficult to produce micro-needles with a pointed tip capable of puncturing the skin.

[0101] The above solution may further contain additives such as solubilizers, plasticizers, surfactants, preservatives, anti-inflammatory agents, etc., depending on the intended use. Various ingredients known in the art may be appropriately selected and used.

[0102] The above additive may be included in an amount of 1 to 20 parts by weight relative to the weight of the first solution or the third solution. More specifically, it may be included in an amount of 1 to 10 parts by weight.

[0103] To facilitate understanding of the present disclosure, it will be described in detail below through examples and the like. However, the embodiments according to the present disclosure are not limited to the embodiments described herein and may be modified in various other forms, and the scope of the present disclosure should not be interpreted as being limited to the following embodiments. The embodiments of the present disclosure are provided to more completely explain the present disclosure to those with average knowledge in the art, and are provided merely to sufficiently convey the concept of the present disclosure to those skilled in the art.

[0104] Preparation Example 1: Preparation of separable soluble microneedles.

[0105] <1-1> Synthesis of Sol-Gel Transition Polymers

[0106] 3-aminopropyltriethoxy silane was added to a dispersion solution in which cellulose was fixed in a toluene solution and reacted with the hydroxyl groups (-OH) of the particles to obtain cellulose with introduced amine groups (-NH2).

[0107] Trichloroacetyl isocyanate was added to the cellulose with the above-mentioned amine group (-NH2) introduced and subjected to a condensation reaction to obtain cellulose with a trichloroacetyl group (-COCCl3) introduced on the surface.

[0108] After drying the above cellulose, it was dispersed again in ethanol, and poly(stearyl methacrylate) and 2-methacryloyloxyethyl phosphorylcholine were added to the dispersion to carry out a living radical polymerization reaction. The surface-modified cellulose was redispersed in water, NaBr was added, and the mixture was stirred at room temperature. Subsequently, the pH was adjusted to 10 using NaCl and NaOH, and the mixture was stirred at room temperature. Due to the oxidation reaction, the hydroxyl groups on the surface of the cellulose were oxidized to carboxylic acids.

[0109] The above cellulose and the above poly(stearyl methacrylate were purchased from Sigma-Aldrich, and the above 2-Methacryloyloxyethyl phosphorylcholine was purchased from Merck.

[0110] <1-2> Preparation of Separable Dissolvable Microneedles.

[0111] A first solution to form the needle portion was prepared by adding 8% polyvinyl alcohol, 2% by weight of hyaluronic acid, and 5 ppm of epidermal growth factor (EGF) to distilled water and stirring at room temperature for 30 minutes.

[0112] The polymer prepared in Example 1 was dispersed in water at a weight of 4% with cellulose surface-modified with a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate, and then stirred at room temperature to prepare a second solution to form the first layer.

[0113] A third solution was prepared by adding 5 parts by weight of hyaluronic acid to water and stirring.

[0114] After preparing an intaglio mold shaped like a micro-needle, the first solution was injected into the intaglio portion of the mold using a Musashi precision dispensing device. 2 mg was dispensed per needle, with 1 mg dispensed at a time. Subsequently, pressurized drying was performed for 1 hour with the pressure set to 8 bar, exhaust pressure to 1 bar, drying temperature to 20-25°C, and humidity to 15-20%. Afterward, the second solution was dispensed onto the base layer to a thickness of 1 μm using a precision dispensing device. At this time, 1 mg was dispensed at a time. Pressurized drying was performed for 1 hour under the same conditions as above. The third solution was dispensed to a thickness of 50 μm using a precision dispensing device and then sufficiently pressurized dried for 24 hours.

[0115] After attaching a protective sheet containing a hydroxy colloid adhesive to the above micro needles, the micro needles were detached from the intaglio mold.

[0116] Experimental Example 1: Separation test of the needle part.

[0117] Using the micro-needles prepared in the preparation example, a test was conducted to see if the first layer transitions from solid to liquid and the needle portion separates when pressure is applied.

[0118] Figure 4 is a schematic diagram showing the appearance of the needle portion of the manufactured micro-needle before separation. Figure 5 is a schematic diagram showing the appearance of only the needle portion separated when pressure is applied to the manufactured micro-needle.

[0119] 10 N / cm² for 5 seconds on manufactured detachable soluble microneedles 2 It was confirmed that when the force of pressure was applied, the first layer (20) changed from a gel (solid) state to a sol (liquid) state, and only the needle part (10) was separated.

[0120] Experimental Example 2: Skin perforation test.

[0121] A test was conducted to determine whether the micro-needles prepared according to the preparation example could puncture the skin. After attaching the detachable dissolvable micro-needles to pig skin, 10 N / cm² was applied for 5 seconds. 2 After perforating the skin by pressing with force, the base layer and adhesive sheet were removed. Then, it was observed with an optical microscope.

[0122] Figure 6 is a microscopic view of a micro-needle manufactured according to one embodiment of the present disclosure, after being inserted into the skin and only the needle portion separated and left on the skin.

[0123] Referring to Fig. 6, when the micro-needle prepared according to the preparation example was pressed and inserted into the pig skin layer, it was confirmed that the needle portion penetrated the pig skin layer. It was also confirmed that only the needle portion was inserted separately.

[0124] Although embodiments of the present disclosure have been described above with reference to the attached drawings, those skilled in the art will understand that the present disclosure may be implemented in other specific forms without changing its technical concept or essential features. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. Explanation of the symbols

[0125] 1: Separable dissolvable microneedles 10: Needle part 20: Layer 1 30: Layer 2 50: Base layer

Claims

Claim 1 A microneedle comprising a plurality of needle portions impregnated with a drug and a base layer, wherein the base layer comprises a first layer and a second layer adjacent to the needle portions, and the first layer comprises a polymer having sol-gel transition characteristics when pressure is applied, and the polymer having sol-gel transition characteristics exhibits reactivity of transitioning from gel to sol in response to shear strain. Claim 2 In claim 1, the separable soluble micro needle is such that when pressure is applied to the skin, only the needle portion separates and the drug is absorbed into the body. Claim 3 A separable soluble microneedle according to claim 1, wherein the polymer having the sol-gel transition characteristic of the first layer comprises modified cellulose to which a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate has been added. Claim 4 In claim 1, the needle portion or the second layer is a biodegradable polymer such as chitosan, collagen, gelatin, hyaluronic acid, fibrin, agarose, heparin, chondroitin sulfate, albumin, fullulan, cellulose, pectin, starch, glycogen, polylysine, polylactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and polycarbonate. A separable soluble microneedle comprising at least one of the group consisting of collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the polymers. Claim 5 A separable soluble microneedle according to claim 1, wherein the agent comprises one or more selected from the group consisting of antiviral agents, antifungal agents, antibiotics, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), transcription regulators, vaccines, epidermal growth factor (EGF), and cell signaling regulatory proteins (AIMP1). Claim 6 A separable soluble microneedle according to claim 1, wherein the thickness of the first layer is 1 μm or more. Claim 7 A separable soluble microneedle according to claim 1, wherein the needle width:length ratio of the needle portion is 1:1.2 to 1:

10. Claim 8 A separable soluble microneedle according to claim 1, wherein the needle portion has a length of 100 to 1000 μm. Claim 9 A detachable soluble microneedle patch comprising a protective sheet having an adhesive on one surface on a second layer of a detachable soluble microneedle according to any one of claims 1 to 8. Claim 10 A method for manufacturing a separable soluble microneedle, comprising: a step of injecting a first solution containing a biodegradable polymer and a drug into a lower mold containing microneedle indentations up to the indentation portion and then pressurizing and drying; a step of injecting a second solution containing a sol-gel transition polymer into a base layer and then pressurizing and drying to form a first layer; a step of injecting a third solution containing a biodegradable polymer into the base layer and then pressurizing and drying to form a second layer; wherein the sol-gel transition polymer exhibits reactivity of transitioning from gel to sol with respect to shear strain. Claim 11 A method for manufacturing a separable soluble micro-needle, wherein, in claim 10, the step of attaching a protective sheet containing an adhesive on one surface to the second layer is further included. Claim 12 A method for manufacturing a separable soluble microneedle according to claim 10, wherein the second solution comprises 1 to 10 parts by weight of a sol-gel transition polymer. Claim 13 A method for manufacturing a separable soluble microneedle according to claim 10, wherein the first solution comprises 5 to 20 parts by weight of a biodegradable polymer.

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