KR20170103273A - Micro-needles and methof of mamufacture - Google Patents

Micro-needles and methof of mamufacture Download PDF

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KR20170103273A
KR20170103273A KR1020160025840A KR20160025840A KR20170103273A KR 20170103273 A KR20170103273 A KR 20170103273A KR 1020160025840 A KR1020160025840 A KR 1020160025840A KR 20160025840 A KR20160025840 A KR 20160025840A KR 20170103273 A KR20170103273 A KR 20170103273A
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poly
cavity
chemical liquid
hormone
tip
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KR101785833B1 (en
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박정환
김지연
박지현
이원준
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가천대학교 산학협력단
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Priority to PCT/KR2017/001626 priority patent/WO2017150824A1/en
Priority to US15/448,182 priority patent/US10967164B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/202—IL-3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Disclosed in the present invention is a manufacturing method of a microneedle which comprises the following steps: preparing a chemical liquid; forming a plurality of tips with the chemical liquid; and forming a cavity in the plurality of tips. According to this configuration, a microneedle having a cavity can be manufactured, and a predetermined amount of medicines can be injected within a short period of time.

Description

[0001] MICRO-NEEDLES AND METHOF OF MAMUFACTURE [0002]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a micro needle and a method for manufacturing the micro needle, and more particularly, to a micro needle which can dose a medicine in a shortened time and a method for manufacturing the same.

The transdermal drug delivery system has a limitation in the size of the drug molecular weight that can be delivered. Therefore, various active transdermal drug delivery systems have recently been proposed. Among them, the micro needle method of passing the keratin through the skin directly to the skin layer is receiving the most attention.

In recent years, molten microneedles based on water-soluble polymers have been developed and a method has been developed in which medicines are administered at the same time that the tip penetrates into the skin. These molten microneedles are excellent in dosage because they are not melted by body fluids after administration to the skin and remain on the tips, but it takes a long time of more than 60 minutes for the medicines in the tips to be completely transferred. As a result, there is a problem in that a drug contained in the tip depends on the complete melting of the tip, so that a certain amount of drug is difficult to be delivered to the skin. Accordingly, in recent years, various studies for improving the dosage of micro needle have been continuously carried out.

Korean Patent Laid-Open No. 10-2015-0127876

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to provide a microneedle and a method of manufacturing the microneedle which can shorten the medication time and improve the dosage of medicines.

According to an aspect of the present invention, there is provided a microneedle comprising a plurality of tips formed of a medicament penetrating into a skin to be melted and a base for supporting the plurality of tips, Is formed.

According to one aspect, the cavity is formed between the base and the tip, and is formed on the inside, outside or side of the tip.

The method of manufacturing a microneedle according to the present invention includes the steps of providing a chemical liquid, forming a plurality of tips with the chemical liquid, and forming cavities in the plurality of tips.

According to one aspect of the present invention, the cavity forming step includes filling the at least one tip groove provided in the molding with the drug solution, centrifuging the drug solution filled in the tip groove, and drying the drug solution, And removing the molding.

According to one aspect of the present invention, the cavity forming step includes a step of applying the chemical solution to a support, drawing the chemical solution in a vertical direction from the support until the cavity is formed, and drying the chemical solution .

According to one aspect, the chemical liquid is formed by mixing a biocompatible material with purified water.

According to one aspect, the biocompatible material is selected from the group consisting of hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, (PGA), polylactide-glycolidide copolymer (PLGA), hyaluronic acid (PEG), polyglycolide (PEG) Alginic acid, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, Polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly (butyric acid), poly (ethylene glycol) Polyacrylic acid, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinylimidazole), chlorosulfonate Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone ), Carboxymethylcellulose, cyclodextrin, and copolymers of monomers forming such polymers and celluloses.

According to one aspect, the chemical liquid is formed by mixing a biocompatible material and an additive for increasing the mechanical strength.

According to one aspect, the additive is selected from the group consisting of trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melitose, dextran, sorbitol, xylitol, palatinite, mannitol, poly Poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester, polycaprolactone e), polyester amide, poly (butyric acid), poly (valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, Polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulfonate, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyridine (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, Or a copolymer of monomers to be formed.

According to one aspect, the drug solution is formed by mixing a biocompatible material with an effective ingredient.

According to one aspect, the active ingredient is selected from the group consisting of a protein / peptide medicament, a hormone, a hormone analog, an enzyme, an enzyme inhibitor, a signal transduction protein or a part thereof, an antibody or a part thereof, a single chain antibody, Structural proteins, regulatory proteins, toxin proteins, cytokines, transcription factors, blood coagulation factors, and vaccines.

According to one aspect, the protein / peptide medicament is selected from the group consisting of insulin, insulin sensitization factor 1 (IGF-1), growth hormone, erythropoietin, granulocyte-colony stimulating factors (G-CSFs), granulocyte / macrophage- stimulating factors, interferon alpha, interferon beta, interferon gamma, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, interleukin-2, epidermal growth factors, calcitonin, The compounds of the invention may be used in combination with other therapeutic agents such as ACTH (adrenocorticotropic hormone), TNF (tumor necrosis factor), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, Dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II (GHRH-II), gonadolerin gonadorelin, goserelin, histrelin, leuprorelin, lypressin, , Octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine, thymocyte, The compounds of the present invention may be used in combination with other drugs such as triptorelin, bivalirudin, carbetocin, cyclosporine, exedine, lanreotide, luteinizing hormone-releasing hormone (LHRH) nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and chicotanide.

According to one aspect, the chemical solution includes a solvent capable of dissolving the biocompatible material, and a mixed solution is used.

According to one aspect, the solvent is selected from the group consisting of DI water, methanol, ethanol, chloroform dibutyl phthalate, dimethyl phthalate, ethyl lactate, lactic acid, glycerin, isopropyl alcohol, lactic acid, propylene glycol and the like.

According to the present invention having the above-described configuration, firstly, since the melting rate of the tip formed with the cavity can be improved, it is possible to inject a predetermined amount of drug within a short period of time.

Second, by adjusting the volume of the cavity by changing the forming conditions of the cavity, it is possible to cope with various medicines.

Third, by forming the cavity by a centrifugal separation or a drawing method, the production is simple and mass production is possible.

Fourth, it is possible to supply a fixed quantity of medicines to a local site, thereby contributing to improvement of therapeutic properties.

Fifth, since the cavity can be formed variously on the inside, outside or side of the needle, it is advantageous in securing variety.

1 is a cross-sectional view schematically showing a microneedle according to a preferred embodiment of the present invention,
FIG. 2 is a cross-sectional view schematically showing a state where the micro needles shown in FIG. 1 are penetrated into the skin,
3 is a flowchart schematically showing a method of manufacturing a micro needle according to the present invention,
FIG. 4 is a flowchart schematically showing concrete steps of the cavity forming step shown in FIG. 3,
FIG. 5 is a view sequentially illustrating a cavity forming operation corresponding to the cavity forming step shown in FIG. 4;
6 is a flowchart schematically showing concrete steps of a cavity forming step according to another embodiment;
FIG. 7 is a view sequentially showing a cavity forming operation corresponding to the cavity forming step according to another embodiment shown in FIG. 6;
FIG. 8 is a graph comparing images of the present invention and the conventional micro needle according to the force applied to the skin,
FIG. 9 shows images obtained by photographing the degree of melting of the micro needle according to the present invention, which is administered to the skin, with an optical microscope over time,
FIG. 10 shows images obtained by photographing the degree of melting of conventional micro-needles administered to the skin with an optical microscope over time,
FIG. 11 shows images obtained by electron microscopy of the degree of melting of the micro needle according to the present invention administered to the skin over time,
12 shows images obtained by electron microscopy of the degree of melting of conventional micro-needles administered to the skin over time,
13 is a graph showing a decrease length of a molten tip according to the present invention and a conventional microneedle over time,
14 is a graph showing the length reduction rate of the molten tip according to the present invention and the conventional micro needle according to time,
15 is a view showing an example of a microneedle in which the positions of cavities of the present invention are variously formed.

Hereinafter, a preferred embodiment of the present invention will be described with reference to the accompanying drawings.

Referring to FIGS. 1 and 2, a micro needle 1 according to a preferred embodiment of the present invention includes a tip 2 and a base 3.

The tip (2) comprises a plurality of tips (2) formed of a medicament that penetrates and melts into the skin (S). The tip (2) has a sharp edge shape to facilitate penetration into the skin. In the present embodiment, the tip 2 is shown to have a polygonal cone shape such as a cone or a quadrangular pyramid, but the present invention is not limited thereto. In addition, the number of the tips 2 is not limited to the illustrated example. Meanwhile, the plurality of tips 2 are each provided with a cavity, which is an empty space, and the structure of the tip 2 including the cavity 4 will be described in detail later.

The base (3) supports a plurality of tips (2). That is, the base 3 is the body of the microneedle 1 that simultaneously supports the plurality of tips 2. 2, the surface of the base 3 on which the tip 2 is provided is attachable to the skin S.

For reference, the tip 2 according to the present invention has a cavity 4, which is an empty space, between the base 3 and the tip. 2, even if the base 3 is separated from the skin S, the tip 3 can be easily inserted into the skin S, (2) does not remain.

Meanwhile, in the present embodiment, the cavity 4 is formed inside the tip 2, but the present invention is not limited thereto. That is, various modifications are possible on the outer side or the side surface of the tip 2. For example, there is a case where the cavity is formed at the center as shown in Fig. 15 (a), but there may be a case where the cavity is formed on one side of the tip as shown in Fig. 15 (b) May be formed on both sides of the tip.

The manufacturing method of the microneedle 1 according to the present invention is shown in Fig.

3 to 5, a method of manufacturing a microneedle 1 according to an embodiment of the present invention includes a chemical solution preparing step 10, a tip forming step 20, and a cavity forming step 30.

The chemical liquid preparing step 10 prepares a chemical liquid 7 (see FIG. 5) for forming the micro needle 1 (10). Here, the chemical solution 7 is formed of a water-soluble polymer containing hyaluronic acid in purified water. More specifically, the chemical solution 7 is a mixed solution of 10% of a hyarronic acid mixed with approximately 9 ml of purified water and 1 g of hyaruronic acid.

More specifically, the chemical solution 7 is prepared by mixing a biocompatible material with purified water. Wherein the biocompatible material is selected from the group consisting of hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin Carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polylactide-glycolidide copolymer (PLGA), hyaluronic acid, (S) selected from the group consisting of alginic acid, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polyanhydride polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly (butyric acid), poly (valeric acid) ), Polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinylimidazole), chlorosulfonate polyolefin chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC) Carboxymethylcellulose, cyclodextrin, and copolymers of monomers that form such a polymer and celluloses.

The chemical solution 7 is formed by mixing a biocompatible material with an additive for increasing the mechanical strength. The additive may be selected from the group consisting of trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melitose, dextran, sorbitol, xylitol, palatinite, mannitol, poly (lactide) But are not limited to, poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester, polycaprolactone, Polyacrylates, ethylene-vinyl acetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl chlorides, Polyvinylpyrrolidone, poly (vinylimidazole), chlorosulfonate, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), poly (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, and monomers forming these polymers Or a combination of two or more substances selected from the group consisting of.

Further, the chemical liquid 7 is formed by mixing a biocompatible material and an active ingredient. Such active ingredients include, but are not limited to, protein / peptide drugs, hormones, hormone analogs, enzymes, enzyme inhibitors, signaling proteins or parts thereof, antibodies or portions thereof, single chain antibodies, binding proteins or binding domains thereof, , Adhesion proteins, structural proteins, regulatory proteins, toxin proteins, cytokines, transcriptional regulatory factors, blood coagulation factors, and vaccines. More specifically, the protein / peptide medicament may be selected from the group consisting of insulin, insulin sensitization factor 1 (IGF-1), growth hormone, erythropoietin, granulocyte-colony stimulating factors (G-CSFs), granulocyte / macrophage- interleukin-1, interleukin-2, EGFs (epidermal growth factors), calcitonin, interleukin-1, interleukin- , Adrenocorticotropic hormone (ACTH), tumor necrosis factor (TNF), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, , Dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II (GHRH-II), konadorerin gonadorelin, goserelin, histrelin, leuprorelin, lypress, inhaled glucocorticoid receptor antagonists, such as oxytocin, octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine, ), Triptorelin, bivalirudin, carbetocin, cyclosporine, exedine, lanreotide, luteinizing hormone-releasing hormone (LHRH) Nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and chiconotide.

Further, the chemical solution (7) uses a mixed solution including a solvent capable of dissolving a biocompatible material. The solvent may be selected from the group consisting of DI water, methanol, ethanol, chloroform dibutyl phthalate, dimethyl phthalate, ethyl lactate, Organic solvents such as glycerin, isopropyl alcohol, Lactic acid, propylene glycol and the like.

The tip forming step 30 forms a plurality of tips 2 with the chemical solution 7 (20). In the tip 2 thus formed, a cavity 4, which is an empty space, is formed (30). This forming step 30 of the cavity 4 will be described in more detail with reference to Figs. 4 and 5. Fig.

4 and 5, the tip forming step 30 may be performed by forming a chemical solution 7 in the tip groove 6 of the molding 5 corresponding to the shape of the tip 2 of the micro needle 1 to be formed Centrifuging the chemical solution 7 filled in the tip grooves 6 and removing the mold 5 after the step of drying 33 are included in the step of filling the tip grooves 6,

A step 31 of filling the tip groove 6 of the molding 5 with the chemical solution 7 is performed by preparing a molding 5 provided with a tip groove 6 as shown in FIG. The chemical solution 7 is applied. At this time, it is illustrated that the chemical liquid (7) is approximately 0.14 g. 5 (c), the chemical liquid 7 applied in this way is dispensed and filled with the chemical liquid 7 into the tip grooves 6.

By centrifuging the chemical solution 7 filled in the tip groove 6, the cavity 4 is formed by centrifugal force as shown in Fig. 5 (d). In the present embodiment, it is exemplified that it takes about 20 minutes at a temperature of 25 DEG C and a speed of about 3000 rpm. At this time, the cavity 4 is formed on the upper surface of the chemical solution 7 filled in the tip groove 6, so that the cavity 4 is formed between the base 3 and the tip groove 6.

When the cavity 4 is formed in the chemical solution 7 filled in the tip groove 6 by centrifugal separation as described above, the chemical solution 7 is dried and the molding 5 is removed as shown in FIG. 5 (e) (33). At this time, the chemical liquid (7) is naturally dried at room temperature. Such a cavity 4 is provided inside the tip 2, so that it can not be recognized even when observed with an electron microscope.

The cavity 4 is filled with the evaporation rate of the solvent 7 contained in the chemical solution 7 or the mixed solution of the hyarronic acid and the concentration of the chemical solution 7 and the concentration of the solution 7 filled in the tip groove 6 of the molding 5 The formation conditions may vary depending on the amount of the chemical solution 7. [ Accordingly, the volume of the cavity 4 can be varied by varying the conditions of the chemical liquid 7 forming the micro needle 1, and the present invention is applicable to various pharmaceutical conditions.

6, another embodiment for forming the cavity 4 is shown. As shown in FIG. 6, the forming step 130 of the cavity 4 according to another embodiment includes a chemical solution applying step 131, a drawing step 132 and a drying step 133.

The application step 131 of the chemical solution 7 applies the chemical solution 7 to the support table 8 as shown in Fig. 7 (a). Here, the chemical solution (7) is exemplified as a mixed solution of 8% of hyaruronic acid in which 9.2 ml of purified water is mixed with 0.8 g of hyaruronic acid. Further, the support table 8 includes a substrate, and approximately 10 liters of the chemical solution 7 is applied.

Thereafter, as shown in Figs. 7B to 7D, the chemical solution 7 is drawn vertically from the support table 8 until the cavity 4 is formed (132). At this time, in the drawing operation, the drawing member 8 such as a tweezer exemplifies that the chemical solution 7 is lifted up in the vertical direction. The cavity 4 is formed by the viscosity of the chemical liquid 7 through the drawing step 132. The chemical liquid 7 in which the cavity 4 is formed is heated at a temperature of 50 DEG C and at a wind speed of 300 L / The micro needles 1 are finally manufactured as shown in FIG. 7 (e) by drying 133 for 15 seconds.

The degree to which the micro needle 1 formed by the above-described structure is inserted after being inserted into the skin S is compared in Fig.

8 (a), 8 (b) and 8 (c) show that the micro needles 1 provided with the cavities 4 according to the present invention are pressed against the skin S for 10 seconds with a force of 10 N, 20 N and 30 N, respectively State. 8 (d), 8 (e) and 8 (f) show that the microneedles (not shown) in which the conventional cavities are not provided are pressed against the skin S for 10 seconds with a force of 10 N, 20 N and 30 N, respectively State. At this time, the skin (S) was prepared by defrosting the porcine skin stored at -20 ° C for 1 hour and 30 minutes to 2 hours at 32 ° C, fixing the skin of the pig to the fixing plate for 15 minutes, Respectively.

Referring to FIG. 8, in the case of the micro needle 1 according to the present invention and the conventional micro needle (not shown), approximately 80% or more of the medicine was administered to the skin S when applying a force of 10 N. In addition, almost all drugs are administered to the skin (S) when a force of 30 N is applied. Accordingly, even when the cavity 4 is provided on the microneedle 1 as in the present invention, it can be confirmed that the mechanical strength for piercing the skin S is not greatly affected.

9 and 10, the degree of melting of the micro needle 1 administered to the skin S is compared with the conventional one. 9A to 9F are images obtained by photographing the degree of melting of the microneedle 1 provided with the cavity 4 according to the present invention by an optical microscope and FIGS. Is an image obtained by photographing a degree of melting of a micro needle (not shown) with an optical microscope. 9 and 10 are images obtained by photographing the melted state of the drug by optical microscope at 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes and 60 minutes, respectively.

9 and 10, the micro needle 1 according to the present invention is completely melted, while the conventional micro needle 1 remains unmelted. That is, it can be seen that the present invention increases the melting rate of the tip 2 by rapidly melting to the point of the tip 2 where the cavity 4 is present. At this time, when the upper part of the tip 2 in which the cavity 4 exists is completely melted, the present invention is crushed to the side of the base 3 without being separated from the base 3.

Fig. 11 is an image obtained by photographing the degree of melting of the micro needle 1 according to the present invention with an electron microscope over time, Fig. 12 is an image obtained by photographing the melting degree of a conventional micro needle (not shown) with an electron microscope Image. (A) to (f) of FIG. 11 and FIG. 12 respectively show the melted state of the drug at 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes and 60 minutes.

11 and 12, irrespective of the presence or absence of the cavity 4, the degrees of melting are similar to each other for up to 5 minutes. However, since the microneedles 1 according to the present invention are melted to the point where the cavities 4 are present, The melting rate of the melt is fast. That is, the tip 2 of the microneedle 1 according to the present invention is completely melted for the same hour, while the conventional microneedles are not completely melted.

13 and 14 are graphs comparing the present invention with the conventional dissolution degree. As shown in FIGS. 13 and 14, it can be seen that the time required for the tip 2 to dissolve after being inserted into the skin S is faster than in the prior art. Here, the depth at which the drug of the tip (2) is administered to the skin (S) is about 1/2 to 2/3 of the total length of the tip (2). Therefore, in delivering a fixed amount of drug within a short period of time, the advantage of the present invention over the prior art is confirmed through FIG. 13 and FIG.

Although the present invention has been described with reference to the preferred embodiments thereof, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the invention as defined in the following claims. It can be understood that

1: Micro needle
2: Tips
3: Base
4: cavity

Claims (15)

A plurality of tips formed into a medicament that penetrates into the interior of the skin and melts; And
A base for supporting the plurality of tips;
/ RTI >
Wherein a plurality of tips are formed with cavities.
The method according to claim 1,
The cavity is formed between the base and the tip, and is formed on the inside, outside or side of the tip.
Preparing a chemical liquid;
Forming a plurality of tips with the chemical liquid; And
Forming a cavity in the plurality of tips;
≪ / RTI >
The method of claim 3,
In the cavity forming step,
Filling the at least one tip groove provided in the molding with the chemical solution;
Centrifuging the drug solution filled in the tip groove; And
Drying the chemical solution, and then removing the molding;
≪ / RTI >
The method of claim 3,
In the cavity forming step,
Applying the chemical liquid to a support;
Drawing the drug solution in a vertical direction from the support until the cavity is formed; And
Drying the chemical liquid;
≪ / RTI >
3. The method of claim 2,
Wherein the chemical liquid is formed by mixing a biocompatible material with purified water.
The method according to claim 6,
The biocompatible material may be,
But are not limited to, hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin ), Fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), hyaluronic acid, alginic acid, , Chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polyanhydride, But are not limited to, polyorthoesters, polyether esters, polycaprolactones, polyesteramides, poly (butyric acid), poly (valeric acid), polyurethanes, polyacrylates, But are not limited to, ethylene-vinyl acetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinylchlorides, polyvinyl fluorides, poly (vinylimidazoles), chlorosulphonate polyolefins, Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, A method of producing a micro needle including at least one selected from the group consisting of a copolymer of monomers forming such a polymer and a cellulose
3. The method of claim 2,
Wherein the chemical liquid is formed by mixing a biocompatible material and an additive for increasing mechanical strength.
9. The method of claim 8,
The additive may be selected from the group consisting of trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melitose, dextran, sorbitol, xylitol, palatinite, mannitol, poly (lactide) But are not limited to, poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester, polycaprolactone, Polyacrylates, ethylene-vinyl acetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl chlorides, Polyvinylpyrrolidone, poly (vinylimidazole), chlorosulfonate, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), poly (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, and monomers forming these polymers Wherein the microneedles are made of one or two or more substances selected from the group consisting of a combination of two or more substances.
3. The method of claim 2,
Wherein the chemical liquid is formed by mixing a biocompatible material and an active ingredient.
11. The method of claim 10,
The active ingredient may be a protein / peptide drug, a hormone, a hormone analogue, an enzyme, an enzyme inhibitor, a signal transduction protein or a part thereof, an antibody or a part thereof, a single chain antibody, a binding protein or a binding domain thereof, A protein, a toxin protein, a cytokine, a transcription regulator, a blood coagulation factor and a vaccine.
12. The method of claim 11,
The protein / peptide medicament may be selected from the group consisting of insulin, IGF-1 (insulin sensitivity factor 1), growth hormone, erythropoietin, granulocyte-colony stimulating factors (G-CSFs), granulocyte / macrophage- Interferon alpha, interferon beta, interferon gamma, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, interleukin-2, epidermal growth factors, calcitonin, adrenocorticotropic hormone ), TNF (tumor necrosis factor), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, dinorpin A dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II (GHRH-II), gonadorelin, Goserelin, histrelin, leuprorelin, lypressin, octreotide, the compounds of the present invention may be selected from the group consisting of octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine, a triptorelin, a bivalirudin, a carbetocin, a cyclosporin, an exedine, a lanreotide, a luteinizing hormone-releasing hormone (LHRH), a nafarelin, A method for producing a micro needle comprising at least one of a hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and chicotanide.
3. The method of claim 2,
Wherein the chemical liquid comprises a solvent capable of dissolving the biocompatible material, and the mixed solution is used.
14. The method of claim 13,
The solvent may be selected from the group consisting of DI water, methanol, ethanol, chloroform dibutyl phthalate, dimethyl phthalate, ethyl lactate, glycerin An organic solvent such as glycerin, isopropyl alcohol, lactic acid, propylene glycol and the like.
A microneedle fabricated by the microneedle manufacturing method according to any one of claims 2 to 14.

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WO2017150824A1 (en) 2016-03-03 2017-09-08 가천대학교 산학협력단 Microneedle and manufacturing method therefor
KR101925678B1 (en) * 2016-06-15 2018-12-05 가천대학교 산학협력단 Micro-needles and method of mamufacture
KR102166065B1 (en) * 2018-08-06 2020-10-15 주식회사 코스칼드바이오 Biosoluble microniddle array and manufacutring method thereof
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KR101224939B1 (en) 2009-12-07 2013-01-22 가천대학교 산학협력단 Microneedle Having Improved Absorption Rate Of Active Agent
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KR20190091008A (en) * 2018-01-26 2019-08-05 가천대학교 산학협력단 Micro-needle and method of mamufacture
KR20220153885A (en) * 2021-05-12 2022-11-21 주식회사 페로카 Micro-needle patch and manufacturing method for micro-needle patch

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