Separable-type soluble microneedle and manufacturing method therefor

Abstract

The present disclosure relates to a separable-type soluble microneedle and a manufacturing method therefor, the microneedle comprising: a plurality of needle parts impregnated with a drug; and a base layer, wherein the base layer comprises first and second layers adjacent to the needle parts, and the first layer contains a polymer, which exhibits sol-gel transition characteristics upon application of pressure.

Description

Separable soluble microneedle and method for manufacturing the same

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

[0002] Most medicines are administered orally or in injection form. However, injections must be administered by a healthcare professional and carry risks such as secondary infection and pain at the injection site. Therefore, microneedles are emerging.

[0003] Microneedles are microscopic structures that can penetrate the stratum corneum and deliver drugs into the epidermis and dermis. Microneedles are attached to the skin surface, creating microscopic holes in the epidermis, through which drugs are delivered. Compared to conventional injections, they cause significantly less pain and prevent infection. Furthermore, they can deliver drugs more than 100 times faster than conventional transdermal delivery systems.

[0004] Depending on the drug delivery strategy, microneedles can be divided into solid microneedles, coated microneedles, soluble microneedles, hollow microneedles, and hydrogel forming microneedles.

[0005] Among them, soluble microneedles are composed of various polymer materials that fill the mold with the polymer solution containing the drug. Microneedles can be completely dissolved and decomposed within the epidermis, so no medical waste remains in the body and a relatively large amount of drugs can be delivered to the human body. Therefore, active research and development is being conducted in fields such as medicine and cosmetics.

[0006] The present disclosure has been devised to solve the above problems, and according to one aspect of the present disclosure, when the skin is pierced with a microneedle, only the needle portion is separated and injected into the body, so that a detachable microneedle capable of delivering a fixed amount of drug entirely into the body can be provided.

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

[0008] According to one aspect of the present disclosure, the soluble microneedle can provide a detachable microneedle having excellent mechanical strength sufficient to pierce the skin.

[0009] The present disclosure provides a detachable 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 the property of a sol-gel transition when pressure is applied.

[0010] In one embodiment according to the present disclosure, the detachable soluble microneedle may be such that when pressure is applied to the skin, only the needle portion is detached, allowing the drug to be absorbed into the body.

[0011] In one embodiment according to the present disclosure, the polymer having the characteristics of sol-gel transition of the first layer may include modified cellulose to which a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate is 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, polylactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one member selected from the group consisting of collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the polymers.

[0013] In one embodiment according to the present disclosure, the agent may include at least one selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), transcriptional regulator, vaccine, epidermal growth factor (EGF), and cell signaling regulatory protein (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 microneedle may further include a protective sheet comprising an adhesive on one surface thereof over the second layer.

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

[0019] In one embodiment according to the present disclosure, the method may further include a step of attaching a protective sheet including an adhesive on one surface over the second layer.

[0020] In one embodiment according to the present disclosure, the second solution may comprise 1 to 10 parts by weight of the 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.

[0022] According to one embodiment of the present disclosure, the detachable soluble microneedle of the present disclosure can provide a microneedle in which only the needle portion can be detached when pressure is applied.

[0023] According to one embodiment of the present disclosure, when the detachable dissolvable microneedle of the present disclosure is inserted into the skin by applying pressure, the detached needle portion gradually dissolves while remaining in the skin dermis, thereby improving the efficiency of delivering a drug into the body.

[0024] According to one embodiment of the present disclosure, the physical strength of the microneedle can be enhanced and drug delivery efficiency can be improved by minimizing drug release when inserted into the skin.

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

[0026] Figure 1 is a schematic diagram of a microneedle according to one embodiment of the present disclosure.

[0027] Figure 2 is a schematic diagram showing only the needle portion separated from the microneedle of one embodiment of the present disclosure.

[0028] FIG. 3 is a schematic diagram illustrating a process of separating only the needle portion from a microneedle patch with a protective sheet attached according to one embodiment of the present disclosure.

[0029] Figure 4 is an observation of the appearance of a microneedle manufactured by one embodiment of the present disclosure before the needle portion is separated.

[0030] FIG. 5 shows an observation of a needle portion being separated when pressure is applied to a microneedle manufactured according to one embodiment of the present disclosure.

[0031] Figure 6 is a microscopic view of the microneedle manufactured according to one embodiment of the present disclosure, which is inserted into the skin and then the needle portion is separated and left behind in the pig skin.

[0032] The advantages and features of the present disclosure, and methods for achieving them, will become clearer with reference to the embodiments described in detail below. However, the present disclosure is not limited to the embodiments disclosed below and may be implemented in various different forms. These embodiments are provided solely to ensure the complete disclosure of the present disclosure and to fully inform those skilled in the art of the present disclosure of the scope of the invention. The present disclosure is defined solely by the scope of the claims.

[0033] Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used in a meaning that is commonly understood by a person of ordinary skill in the art to which this disclosure belongs.

[0034] As used herein, the singular forms of terms may be construed to include the plural forms as well, unless otherwise specified.

[0035] The numerical ranges used herein include lower and upper limits and all values ​​within that range, increments logically derived from the shape and width of the defined range, all doubly defined values, and all possible combinations of upper and lower limits of numerical ranges defined in different shapes. Unless otherwise specified in the specification of the present disclosure, values ​​outside the defined range that may arise due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0036] This is an open-ended description having the equivalent meaning of expressions such as 'includes,' 'provides,' 'has,' and 'characterizes,' as mentioned in this specification, and does not exclude elements, materials or processes not listed additionally.

[0037] The term “soluble microneedle” as used herein refers to a needle-like structure having a length in micrometers, which, when applied to penetrate the skin, dissolves in the body and releases a loaded drug or medication.

[0038] The term “patch” as used herein refers to a formulation that is attached to the skin to deliver a drug into the body.

[0039] The “needle portion” of the microneedle referred to in this specification means the sharp portion that first comes into contact with the skin when the microneedle is inserted into the skin, and refers to the portion impregnated with the drug, and means portion 10 in Drawing 1 of the present disclosure.

[0040] The “first layer” of the microneedle base layer referred to in this specification refers to a layer adjacent to the needle portion and including the sol-gel transition polymer, as shown in part 20 in FIG. 1.

[0041] The “second layer” of the microneedle base layer referred to herein is a biodegradable polymer layer applied over the first layer, and refers to portion 30 in FIG. 1.

[0042] The term "copolymerization" as used herein 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, a graft copolymer, or a block copolymer.

[0043] Below, the detachable soluble microneedles of the present disclosure and their manufacturing method will be described in detail. However, these are merely exemplary and the present disclosure is not limited to the specific embodiments described as examples.

[0044] Conventional dissolvable microneedle products are manufactured and used on top of hydrocolloid. However, in these cases, drug residue remains in the needle hole, causing side effects or preventing the intended amount of drug from being fully delivered into the body.

[0045] Accordingly, the inventor of the present disclosure invented a detachable soluble microneedle that can deliver a drug entirely into the body by detaching only the needle portion of the microneedle when penetrating the skin.

[0046] The microneedle of the present disclosure is 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 the property of a sol-gel transition when pressure is applied, which can provide a detachable soluble microneedle.

[0047] Fig. 1 is a conceptual diagram of a microneedle according to one embodiment of the present invention. Referring to Fig. 1, the microneedle according to the embodiment may include a base layer (50) and a needle portion (10) disposed on the base layer (50).

[0048] The above base layer (50) may include a first layer (20) including a sol-gel transition polymer and a second layer (30) including a biodegradable polymer.

[0049] Here, gel refers to a porous solid state in which liquid colloids become concentrated and solid components begin to bond with each other, and liquid materials such as moisture are dispersed within the network structure formed by the solid substances, while sol refers to a colloidal suspension in which fine solid particles are dispersed in a stable state in a liquid.

[0050] The polymer having the above sol-gel transition properties is a biodegradable sol-gel transition polymer, which refers to a polymer material that exhibits a unique behavior of changing from a gel to a sol or changing from a sol to a gel when stimulated by the surrounding environment such as temperature, light, mechanical pressure or pH.

[0051] The sol-gel transition polymer used in one embodiment of the present disclosure may be any polymer having the property of changing into a sol or gel in response to a known pressure. When pressure is applied to the skin, the first layer (20) of the base layer (50) changes from a solid (gel) to a liquid (sol), thereby separating only the needle portion (10). Therefore, when the microneedle is inserted into the skin, only the needle portion (10) containing the drug is separated, allowing the drug to be absorbed into the body.

[0052] The existing soluble micro needles in which the needle portion (10) is not separated from the base layer (50) have a problem in that the drug in the needle portion (10) remains in the needle hole area, so the desired amount of drug cannot be completely delivered into the body, and when the protective sheet falls off from the skin, the needle portion (10) containing the drug also falls off.

[0053] The detachable dissolvable microneedle of the present disclosure solves the above problems. When the microneedle is inserted into the skin under pressure, the needle portion (10) remains detached and inserted into the skin, allowing the drug to be fully absorbed into the body. Furthermore, even if the protective sheet is later removed from the skin, the drug in the needle portion (10) remains within the body, allowing the drug to be fully delivered into the body.

[0054] FIG. 3 is a schematic diagram illustrating a process of separating only the needle portion from a microneedle patch with a protective sheet attached according to one embodiment of the present disclosure.

[0055] Referring to Fig. 3, when the micro needle is inserted into the skin by applying pressure, the first layer (20) transitions from a gel (solid) state to a sol (liquid) state, so that only the needle portion (10) is separated. Therefore, when pressure is no longer applied, even if the pressed skin returns to its original state, the needle portion (10) remains in the skin dermis in a state separated from the base layer (50). The separated needle portion (10) gradually dissolves while remaining in the skin dermis, thereby completely delivering the desired amount of drug into the body.

[0056] In another embodiment of the present disclosure, the first layer (20) may include cellulose having sol-gel transition properties, and the cellulose may include surface-modified cellulose having a copolymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and stearyl methacrylate (SMA).

[0057] Cellulose possesses high hydrophilicity due to the abundance of surface hydroxyl groups (-OH). Its structure, which combines crystalline and amorphous regions, offers excellent mechanical properties. In particular, it has the advantage of being capable of various chemical modifications utilizing the hydroxyl groups in the amorphous region. Therefore, cellulose is a polymer that can be chemically modified in various ways using the surface hydroxyl groups (-OH) in the amorphous region.

[0058] The cellulose having the characteristics of the sol-gel transition of the present disclosure may be formed by radical polymerization of a solution containing 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate into cellulose having an initiation site for a living radical polymerization reaction introduced thereto. The surface-modified cellulose may be obtained by oxidizing hydroxyl groups (-OH) remaining on the surface of cellulose after the radical polymerization reaction into carboxylic acid.

[0059] The above 2-methacryloyloxyethyl phosphorylcholine is a hydrophilic equivalent with a chemical structure similar to living cells and has excellent anti-biofouling properties, making it a biocompatible polymer that can be safely used on the human body. The above stearyl methacrylate is a hydrophobic equivalent containing a long hydrophobic alkyl chain, which can induce the formation of a gel network through hydrophobic interactions between them.

[0060] The surface-modified cellulose is a cellulose in which a polymer having zwitterionic groups and a hydrophobic chain are introduced to the surface, and the cellulose forms a gel phase due to the interaction of the stearyl methacrylate hydrophobic chain, and the 2-methacryloyloxyethyl phosphorylcholine (MPC) hydrophilic chain imparts cationic hygroscopicity to the polymer, promoting complete hydration with water molecules to form a sol.

[0061] The above surface-modified cellulose normally exhibits a gel structure due to hydrophobic chains, but when pressure is applied to cause a low strain of 10%, a shear thinning phenomenon is observed in which it transitions to a sol state due to hydration of hydrophilic MPC chains.

[0062] Accordingly, when the detachable soluble microneedle of the present disclosure is inserted into the skin by applying pressure, the sol-gel transition polymer of the first layer (20), i.e., the surface-modified cellulose, is transferred to a sol state, so that only the needle portion (10) is selectively separated from the base layer (50), and the remaining needle portion is gradually dissolved in the body, thereby completely delivering the drug.

[0063] 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, polylactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, polymethyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol. It may include at least one member selected from the group consisting of, but is not necessarily limited to, Glycol (PEG), polycarbonate, collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the above polymers.

[0064] Specifically, it may include one or two or more selected from the group consisting of hyaluronic acid, polyvinyl alcohol (PVA), carboxymethylcellulose (CMC), chitosan, gelatin, and hydroxypropyl methylcellulose (HPMC).

[0065] Even better, it may contain polyvinyl alcohol (PVA) and hyaluronic acid in a ratio of 4:1. The hyaluronic acid is used to mean not only hyaluronic acid but also hyaluronic acid salts and mixtures thereof.

[0066] In order to improve the mechanical properties of the above needle portion (10), additives such as a crosslinking agent, a viscosity agent, and a solubilizing agent may be further included.

[0067] The above additive may further include one or two 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.

[0068] In order to facilitate interaction between the drug and the biodegradable polymer in the needle portion (10), the needle portion (10) may additionally include a surfactant. As the surfactant, those skilled in the art may use any known surfactant that can be added to a drug without limitation.

[0069] 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.

[0070] The above needle portion (10) and the second layer (30) of the base layer (50) may be made of the same biodegradable polymer.

[0071] The biodegradable polymer included in the needle portion (10) can have its molecular weight adjusted depending on the nature of the drug. If the drug needs to be slowly released from the affected area over a long period of time, depending on the nature of the drug, the molecular weight of the biodegradable polymer can be designed to be relatively large so that it can dissolve in the skin dermis over a long period of time and slowly release the drug into the body.

[0072] In order to be dissolved over a long period of time, the molecular weight of the biodegradable polymer included in the needle portion (10) may be a lower limit of 10,000 Da or more, 20,000 Da or more, 25,000 Da or more, 30,000 Da or more, 35,000 Da or more, 40,000 Da or more, 45,000 Da or more, or 500,000 Da or more, and an upper limit of 800,000 Da or less, 750,000 Da or less, 700,000 Da or less, 650,000 Da or less, 600,000 Da or less, 550,000 Da or less, or 750,000 Da or less, but is not necessarily limited thereto. More preferably, it may be 10,000 to 300,000 Da. More specifically, it may be between 30,000 and 200,000 Da, but is not necessarily limited thereto. Those skilled in the art can effectively control the release rate of the drug by appropriately selecting the molecular weight of the biodegradable polymer to control the dissolution rate in the body.

[0073] Since the molecular weight of the biodegradable polymer included in the needle portion satisfies the above range, the dissolution and decomposition speed of the biodegradable polymer is slow, and as a result, the effective ingredient can be slowly released over a long period of time. That is, rapid release of the effective ingredient from the needle portion of the microneedle is prevented, and the effective ingredient can be delivered to the affected area at a constant concentration for a long period of time. The molecular weight of the biodegradable polymer included in the second layer (30) may be a lower limit of 3,000 Da or more, 4,000 Da or more, 5,000 Da or more, 6,000 Da or more, 7,000 Da or more, 8,000 Da or more, 9,000 Da or more, or 10,000 Da or more, and an upper limit of 200,000 Da or less, 150,000 Da or less, or 100,000 Da or less, but is not necessarily limited thereto. Specifically, it may be 3,000 Da to 200,000 Da, or 5,000 Da to 200,000 Da, and even better, 5,000 Da to 100,000 Da. However, it is not necessarily limited thereto, and a person skilled in the art can appropriately select the molecular weight of the biodegradable polymer included in the second layer by considering the structural stability of the microneedle, securing support when inserted into the skin, and ease of removing the base layer after insertion.

[0074] In one embodiment of the present disclosure, the agent may include at least one agent selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, a polydeoxyribonucleotide (PDRN), a polynucleotide (PN), an extracellular matrix (ECM), a transcriptional regulator, a vaccine, an epidermal growth factor (EGF), and an AIMP1 (cell signaling regulator protein).

[0075] Specifically, the antibiotic may include at least one antibiotic selected from the group consisting of penicillin antibiotics, cephalosporin antibiotics, macrolide antibiotics, lincosamide antibiotics, tetracycline antibiotics, and metronidazole, but is not necessarily limited thereto.

[0076] Specifically, the antiviral agent may include at least one selected from the group consisting of sodium azulenesulfonate, cetylpyridinium chloride, acyclovir, triamcinolone acetonide, beclomethasone dipropionate (BMDP), betamethasone valerate, triamcinolone, triamcinolone acetonide, dexamethasone, fluocinolone acetonide, fluocinonide, flumethasone, hydrocortisone, prednisolone, and prednisone, but is not necessarily limited thereto.

[0077] Specifically, the above antifungal agent may be an azole-based, arylamine-based, polyene-based, or echinocandin-based antifungal agent.

[0078] 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 1 (AIMP1). Even more specifically, the agent may include EGF, 5-aminolevulinic acid hydrochloride, and chlorin E6. These agents exhibit various physiological activities, such as tissue regeneration, photodynamic therapy, and skin treatment, and can be effectively delivered to a target site through microneedles.

[0079] The above agent is not limited to the above examples, and may be a variety of physiologically active substances that can be used as medicines, vaccines, nutrients, or cosmetics depending on the purpose of application.

[0080] In one embodiment of the present disclosure, the ratio of the drug and the biodegradable polymer in the needle portion (10) can be appropriately selected and manufactured by a person skilled in the art according to the type and ingredients of the drug. If the content ratio of the biodegradable polymer is too low, the strength of the microneedle may be reduced, making it difficult to insert into the skin. On the other hand, if the content ratio of the biodegradable polymer is too high, the ratio of the drug may be insufficient, making it difficult to deliver a sufficient amount of the drug into the body.

[0081] In one embodiment of the present disclosure, the thickness of the first layer (20) may be 1 μm or more.

[0082] Since the sol-gel transition polymer of the first layer (20) has a reactivity that transitions from a gel to a sol at a certain strain, the first layer (20) may be formed to have a thickness of 1 ㎛ or more in order to prevent it from changing into a sol state due to the weight of the second layer (30) during or after the manufacturing process.

[0083] The micro needle of the present disclosure can be designed to have a range of lengths of 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 shape that becomes sharper toward the end of the needle portion, and may be a cone shape or a polyhedron shape, but is not limited thereto.

[0084] In one embodiment of the present disclosure, the needle portion (10) may have a lower limit of 50 µm or more, 60 µm or more, 70 µm or more, 80 µm or more, 90 µm or more, or 100 µm or more, and an upper limit of 2,000 µm or less, 1,900 µm or less, 1,800 µm or less, 1,700 µm or less, 1,600 µm or less, 1,500 µm or less, 1,400 µm or less, 1,300 µm or less, 1,100 µm or less, or 1,000 µm or less, but is not necessarily limited thereto. Specifically, the length of the needle portion (10) may be 50 to 2,000 µm, and more specifically, 70 to 1,500 µm. More specifically, the length may range from 100 to 1000 μm, but is not necessarily limited thereto, and the length of the needle portion (10) may be designed to an appropriate length to maximize the drug effect depending on the skin thickness of each body part.

[0085] Microneedles are characterized by their painless penetration of the skin. Therefore, they must be strong enough to penetrate the 10-20㎛ stratum corneum and epidermal layers. If they lack sufficient strength, they can bend or break during insertion, preventing the drug from reaching the body.

[0086] The needle width:length ratio of the above needle portion may be 1:1 to 1:20, 1:1 to 1:18, 1:1 to 1:16, 1:1 to 1:14 or 1:1 to 1:12, and more specifically, 1:1.2 to 1:10.

[0087] If the width of the needle part is greater than its length, it will not be able to puncture the skin, and if the width:length ratio of the needle part is more than 1:20, the needle may break or bend when puncturing the skin, making it difficult to deliver the drug into the body.

[0088] In one embodiment of the present disclosure, the detachable soluble microneedle may further include a protective sheet on the second layer (30).

[0089] Because the raw material for microneedles is made of biodegradable polymers, they are highly susceptible to moisture. Therefore, a waterproof protective sheet can be attached to one side of the dried microneedles to prevent them from being damaged by moisture.

[0090] The protective sheet may include various adhesives on one surface that can adhere to the skin without causing damage, such as hydrophobic adhesives, silicone adhesives, acrylic adhesives, and hydrophilic adhesives. More specifically, the adhesive included on one surface of the protective sheet may be at least one of a cellulose-based resin, a polyester-based resin, polyethylene, a resin hydrocolloid, and polyurethane, or a combination thereof.

[0091] The above protective sheet is formed along the edge of the base layer (50). Therefore, the shape of the protective sheet may be determined according to the shape of the base layer (50), and the shape of the base layer (50) may have a different shape depending on the portion into which the micro needle is inserted. It may be circular, oval, square, polygonal, or mask-shaped, and there is no particular limitation on the shape.

[0092] Additionally, the present disclosure can provide a method for manufacturing the microneedle. The types of biodegradable polymers, protective sheets, and drugs used in the manufacturing method are the same as those described above.

[0093] The present disclosure can provide a method for manufacturing a detachable soluble microneedle, comprising the steps of: injecting a first solution containing a biodegradable polymer and a drug into a lower mold including a microneedle engraving up to the engraved portion and then drying under pressure; injecting a second solution containing a sol-gel transition polymer into a base layer (50) and then drying under pressure to form a first layer (20); and injecting a third solution containing a biodegradable polymer into the base layer (50) and then drying under pressure to form a second layer (30).

[0094] After applying the above solutions to the negative mold, a pressurization step is performed, so that the solutions can be completely injected into the negative needle shape, and the probability of producing defective microneedles can be reduced. The negative mold may be provided with a coating portion to easily separate the produced microneedles.

[0095] In another embodiment of the present disclosure, a step of attaching a protective sheet on the base layer (50) may be additionally included. The protective sheet, which includes an adhesive on one surface thereof, may be attached on the second layer (30) and then removed from the negative mold.

[0096] The sol-gel transition polymer of the second solution may include cellulose surface-modified with a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate.

[0097] 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.

[0098] 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, may be included in an amount of 1 to 10 parts by weight.

[0099] When the above sol-gel transition polymer is included in less than 10 parts by weight of the solution, the drying time takes too long, and when it is included in more than 10 parts by weight, the problem of difficulty in dispensing using precision dispensing equipment occurs.

[0100] 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, poly lactic acid (PLA), polyvinyl alcohol (PVA), polysulfone, polyethersulfone, polyetherester, polyacrylate, poly methyl methacrylate, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polycarbonate. It may include at least one member selected from the group consisting of collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the above polymers, but is not necessarily limited thereto.

[0101] The solvent of the above first solution is determined by the drug and the biodegradable polymer, and may be an inorganic solvent or an organic solvent such as purified water, distilled water, methanol, ethanol, glycerin, isopropyl alcohol, or propylene glycol. The solvent is not necessarily limited thereto, 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.

[0102] 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.

[0103] If the biodegradable polymer is included in less than 5 parts by weight of the solution, the microneedles manufactured after pressure drying have low strength and cannot puncture the skin. If the biodegradable polymer is included in more than 20 parts by weight, the viscosity is high and cannot be injected into the inside of the mold during ejection, making it difficult to manufacture microneedles with a pointed tip.

[0104] 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.

[0105] 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.

[0106] Hereinafter, to aid in understanding of the present disclosure, a detailed description will be given 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 construed as being limited to the following examples. The embodiments of the present disclosure are provided to more fully explain the present disclosure to those of ordinary skill in the art, and are provided only to sufficiently convey the spirit of the present disclosure to those skilled in the art.

[0107] Manufacturing Example 1: Manufacturing of a detachable soluble microneedle.

[0108] <1-1> Synthesis of sol-gel transition polymers

[0109] 3-aminopropyltriethoxy silane was added to a dispersion solution in which cellulose was fixed in a toluene solution, and reacted with the hydroxyl group (-OH) of the particles to obtain cellulose with an amine group (-NH2) introduced therein.

[0110] Trichloroacetyl isocyanate was added to cellulose to which the above amine group (-NH2) was introduced, and a condensation reaction was performed to obtain cellulose to which a trichloroacetyl group (-COCCl3) was introduced on the surface.

[0111] 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 perform a living radical polymerization reaction. The surface-modified cellulose was redispersed in water, and NaBr was added, followed by stirring at room temperature. After that, the pH was adjusted to 10 using NaCl and NaOH, and stirred at room temperature. Due to the oxidation reaction, the hydroxyl groups on the surface of the cellulose were oxidized to carboxylic acid.

[0112] The above cellulose and poly(stearyl methacrylate were purchased from Sigma-Aldrich, and the above 2-Methacryloyloxyethyl phosphorylcholine was purchased from Merck.

[0113] <1-2> Manufacturing of detachable soluble microneedles.

[0114] A first solution for forming the needle portion was prepared by adding 8% by weight of 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.

[0115] The polymer manufactured in Example 1 was dispersed in water by adding 4% by weight of 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.

[0116] A third solution was prepared by adding 5 parts by weight of hyaluronic acid to water and stirring.

[0117] After preparing a negative mold shaped like a microneedle, the first solution was injected into the negative part of the mold using a Musashi precision dispensing device. 2 mg was dispensed per needle, and 1 mg was dispensed per injection. Afterwards, the solution was pressurized and dried for 1 hour under the settings of 8 bar of pressurization, 1 bar of exhaust pressure, 25°C of drying temperature, and 15-20% of humidity. Afterwards, the second solution was dispensed onto the base layer with a thickness of 1 μm using a precision dispensing device. 1 mg was dispensed at a time. Pressure drying was performed for 1 hour under the same conditions as above. The third solution was dispensed with a thickness of 50 μm using a precision dispensing device, and then sufficiently pressurized and dried for 24 hours.

[0118] After attaching a protective sheet containing a hydroxy colloid adhesive to the above micro needles, the micro needles were detached from the negative mold.

[0119] Experimental Example 1: Needle part separation test.

[0120] Using the microneedles manufactured in the manufacturing example, it was tested whether the first layer was transformed from a solid to a liquid and the needle portion was separated when pressure was applied.

[0121] Figure 4 is a schematic diagram showing the appearance of a manufactured microneedle before the needle portion is separated. Figure 5 is a schematic diagram showing the appearance of only the needle portion being separated when pressure is applied to the manufactured microneedle.

[0122] 10 N / cm for 5 seconds on the manufactured detachable soluble microneedle 2 When pressure of the force was applied, it was confirmed that the first layer (20) changed from a gel (solid) state to a sol (liquid) and only the needle portion (10) was separated.

[0123] Experimental Example 2: Skin perforation test.

[0124] The ability of microneedles manufactured according to the manufacturing example to puncture the skin was tested. After attaching the detachable soluble microneedles to pig skin, a force of 10 N / cm was applied for 5 seconds. 2 After pressing the skin with force to puncture it, the base layer and adhesive sheet were removed and observed under an optical microscope.

[0125] Figure 6 is a microscopic view of the microneedle manufactured according to one embodiment of the present disclosure, after inserting it into the skin, leaving only the needle portion separated and remaining in the skin.

[0126] Referring to Fig. 6, when the microneedle manufactured according to the manufacturing example was pressed and inserted into the pig skin layer, it was confirmed that the needle portion penetrated the pig skin layer. In addition, it was confirmed that only the needle portion was inserted separately.

[0127] While the embodiments of the present disclosure have been described above with reference to the attached drawings, those skilled in the art will appreciate that the present disclosure can be implemented in other specific forms without altering the technical spirit or essential features thereof. Therefore, the embodiments described above should be understood to be illustrative in all respects and not restrictive.

[0128] (Explanation of symbols)

[0129] 1: Separable soluble microneedles

[0130] 10: Needle part

[0131] 20: First layer

[0132] 30: Second layer

[0133] 50: Base layer

Claims

1. A microneedle comprising a plurality of needle sections and a base layer impregnated with a drug, The above base layer includes a first layer and a second layer adjacent to the needle portion, A separable soluble microneedle, wherein the first layer comprises a polymer having the property of sol-gel transition when pressure is applied.

2. In paragraph 1, The above detachable soluble micro needle is a detachable micro needle in which, when pressure is applied to the skin, only the needle portion is detached and the drug is absorbed into the body.

3. In paragraph 1, A detachable soluble microneedle comprising a polymer having the characteristics of a sol-gel transition of the first layer, wherein the polymer comprises modified cellulose to which a copolymer of 2-methacryloyloxyethyl phosphorylcholine and stearyl methacrylate is added.

4. In paragraph 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), polycarbonate. A detachable soluble microneedle comprising at least one member selected from the group consisting of collagen-acrylate, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polylactide-co-glycolide (PLGA), and copolymers forming the polymers.

5. In paragraph 1, A detachable soluble microneedle comprising at least one selected from the group consisting of an antiviral agent, an antifungal agent, an antibiotic, polydeoxyribonucleotide (PDRN), polynucleotide (PN), extracellular matrix (ECM), transcriptional regulator, vaccine, epidermal growth factor (EGF), and cell signaling regulatory protein (AIMP1).

6. In paragraph 1, A detachable soluble microneedle, wherein the thickness of the first layer is 1 μm or more.

7. In paragraph 1, A detachable soluble microneedle, wherein the needle width:length ratio of the above needle portion is 1:1.2 to 1:

10.

8. In paragraph 1, A detachable soluble microneedle, wherein the needle portion has a length of 100 to 1000 μm.

9. In any one of paragraphs 1 to 8, A detachable dissolvable microneedle patch further comprising a protective sheet comprising an adhesive on one side thereof on the second layer.

10. A step of injecting a first solution containing a biodegradable polymer and a drug into a lower mold including a microneedle engraving up to the engraved portion and then drying under pressure; A step of forming a first layer by injecting a second solution containing a sol-gel transition polymer into a base layer and then drying under pressure; A method for manufacturing a detachable soluble microneedle, comprising: a step of injecting a third solution containing a biodegradable polymer into a base layer and then drying the base layer under pressure to form a second layer; 11. In paragraph 10, A method for manufacturing a detachable soluble microneedle, further comprising the step of attaching a protective sheet containing an adhesive on one surface thereof on the second layer.

12. In paragraph 10, A method for manufacturing a separate soluble microneedle, wherein the second solution contains 1 to 10 parts by weight of a sol-gel transition polymer.

13. In paragraph 10, A method for manufacturing a separate soluble microneedle, wherein the first solution contains 5 to 20 parts by weight of a biodegradable polymer.

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