KR102093235B1 - Microneedles and methof of mamufacture - Google Patents

Abstract

The present invention relates to a microneedle and a method for manufacturing the same. More specifically, provided are a microneedle and a method for manufacturing the same, wherein the microneedle is easily separated from a coating layer containing an active ingredient, thereby quantitatively and effectively making the active ingredient contained in the coating layer penetrate into the skin.

Description

MICRONEEDLES AND METHOF OF MAMUFACTURE

The present invention relates to a micro-needle and a method for manufacturing the same, and more specifically, it is easy to separate the micro-needle and the coating layer containing the active ingredient, the micro-needle and the active ingredient contained in the coating layer can quantitatively and effectively penetrate into the skin and its It relates to a manufacturing method.

Various drug delivery technologies, such as oral, injectable, transdermal and mucosal permeation, are used. Among these, the transdermal drug delivery technology is a technology for delivering drugs through the skin using a patch, a cream, etc., which has the advantage of avoiding metabolic effects by the intestine and allowing continuous drug administration through a patch.

Common transdermal drug delivery methods include passive transdermal drug delivery systems and active transdermal drug delivery systems.

Passive transdermal drug delivery systems are passive methods that rely on the physico-chemical properties of the drug and apply a cream, patch, or ointment form to the skin.

On the other hand, this passive transdermal drug delivery method has a possible limit only when the molecular weight of the drug delivered through the skin is 500 Da or less.

In addition, the active transdermal drug delivery method delivers the active ingredient by physically penetrating the 10 µm-thick stratum corneum using a microneedle to overcome the skin penetration limit.

These active transdermal drug delivery methods include solid micro needles that apply a cream after piercing the stratum corneum, coated micro needles coated with active ingredients, melted micro needles that are soluble in water, and hollow micro needles that are reduced in size in conventional syringes.

Solid microneedles are difficult to deliver quantitatively, and coating microneedles and molten microneedles have limitations that require a long time to deliver the coated or contained drug to the skin.

Accordingly, in recent years, various studies have been continuously conducted to quickly and effectively deliver a quantitative effective component from a microneedle.

Japanese Patent Publication No. 2017-051312, "Micro Needle Array" Korean Patent Publication No. 10-2018-0011837, "Composition for microstructures containing organic solvents and method for manufacturing microstructures using the same" Korean Patent Publication No. 10-2018-0009729, "Microneedle, manufacturing method thereof, and patch including the same"

The present invention provides a microneedle and a method of manufacturing the microneedle that can easily penetrate into the skin quantitatively and effectively the active ingredient contained in the coating layer by easily separating the microneedle from the coating layer containing the active ingredient.

A method for manufacturing a microneedle according to an embodiment of the present invention includes the steps of providing a microneedle including a tip portion and a base portion supporting the tip portion; Preparing an active ingredient and a coating solution comprising an additive present in an emulsion or molecular state within the active ingredient; Dipping the microneedle in a coating solution to form a coating layer on the tip of the tip portion; And diffusing the additive contained in the coating layer between the tip portion and the coating layer to form an oil film.

In the method for manufacturing a microneedle according to an embodiment of the present invention, the step of diffusing the additive contained in the coating layer between the tip portion and the coating layer to form an oil film may include dispersing the emulsion or molecular dispersion. It can be maintained for 1 minute to 10 hours at a temperature of 5 ℃ to 40 ℃ to allow the additives present in the state to diffuse between the tip portion and the coating layer.

In the method of manufacturing a microneedle according to an embodiment of the present invention, the additive may be an oil and / or a surfactant.

In the method of manufacturing a microneedle according to an embodiment of the present invention, when the additive is oil, the oil is almond oil, canola oil, castor oil, hydrogenei Hydrogenated Castor oil, Coconut oil, Corn oil, Cottonseed oil, Mineral oil, Mineral oil, Almond oil, Canola oil (Canola oil), Castor oil, Hydrogenated Castor oil, Coconut oil, Corn oil, Cottonseed oil, Mineral oil , Mineral oil, light, Mineral oil and Lanolin Alcohols, Olive oil, Peanut oil, Polyoxyethylene castor oil reversible (Polyoxyethylene casto) r oil derivatives), Safflower oil, Sesame oil, Soybean oil, Sunflower oil, Vegetable oil, Hydrogenated, Oleic acid, Linoleic acid, Soy fatty acid, Corn oil mono-di-tridiglycerides, Peppermint oil, Soybean oil, Hydrogenated Hydrogenated soybean oil, Caprylic / capric triglycerides, Glycerin, Alkyl Phenol Ethoxylates (ex: NPE's (nonylphenol ethoxylates), OPE's (octylphenol) ethoxylates), Castor Oil Ethoxylates (CO-5, CO-16, CO-25, CO-36 or CO-40), Hydrogenated Castor Oil Ethoxylates (HCO-16, HCO-25, HCO-36 or HCO-40), Taloamine Ethoxyl Tallow Amine Ethoxylates (trade name: TAM-2, TAM-8 or TAM-15), alcohol ethoxylates-6 to 20 carbon alcohols (Natural and Synthetic Alcohol Ethoxylates-C6-C20 Alcohol Ethoxylates) ( Product Name: Tomadol, Rhodasurf, Neodol 91-2.5, 91-6, 91-8, 23-3, 23-5, 23-7, 23-9, 25-3, 25-5, 25-7, 25-9 , 27-3, 27-5, 27-7, 27-9, 45-7, 45-13, 1-3, 1-5, 1-7, 68-5, 68-20, 68-25, 68 -40), Alcohol Ethoxylate Mixtures-NPE Replacements (NPE replacements) (Tomadol 900, 901, 600, 400 or 1200), Secondary Alcohol Ethoxylates (Tergitol 15-S Series ), Polyethylene Glycols (Polyethylene Glycols; PEG's) (ranging from 200 mw to 4000 mw), Polysorbates ((trade name: Tweens (Ethoxylated)) 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Sorbitan monolaurate ( Sorbitan monolaurate (trade name: Span (Not Ethoxylated) 20), Sorbitan Monopalmitate (Span 40), Sorbitan monostearate (Span 60), Sorbitan Monooleate ) ( Span 80 ), oleyl amine ethoxylates, coco amine ethoxylates, stearyl amine ethoxylates, ethylene oxide / propyl oxide block polymer Ethylene oxide (EO) / propylene oxide (PO) block polymers (Pluronic L61), ethylene oxide / propyl oxide block polymers (Pluronic L62), ethylene oxide / propyl oxide block polymers (Pluronic L61LF), ethylene oxide / propyl oxide Lek block polymer (Pluronic L64), Coco Paper Coco fatty acid ethoxylates, oleic acid ethoxylates, stearic acid ethoxylates, tall oil fatty acid ethoxylates, cocamide mono ethanol consisting of amine (Cocamide MEA (monoethanolamine)), Coca polyimide monoethanolamine (Cocamide DEA (diethanolamine)) and coca polyimide mono isopropoxy Francisco ol amide (Cocamide MIPA (monoisopropanolamine)) may be at least any one of the group.

In the method for manufacturing a microneedle according to an embodiment of the present invention, when the additive is a surfactant, the surfactant is Tergitol, Alpha tocopherol, or a SPAN-type surfactant , Polysorbate (Tween), sodium dodecyl sulfate (SDS), benzalkonium chloride, and glyceryl oleate.

In the method for manufacturing a microneedle according to an embodiment of the present invention, the step of providing a microneedle including the tip portion and a base portion supporting the tip portion includes: supplying a raw material to a mold; Filling the raw material into a tip groove of the mold; And drying the filled raw material and removing the mold.

In the method for manufacturing a microneedle according to an embodiment of the present invention, the step of filling the raw material in the tip groove of the mold may be any one of pressing, spraying, centrifugation, vacuum, ultrasonic, spin coating, or rolling. Can be performed.

In a method for manufacturing a microneedle according to an embodiment of the present invention, the step of providing a microneedle including the tip portion and a base portion supporting the tip portion includes: forming a supporter on a support; Applying and tensioning a raw material to the supporter; And drying.

In the method of manufacturing a microneedle according to an embodiment of the present invention, the step of applying and tensioning a raw material to the supporter may be performed through a drawing process or a dispensing process.

In the method for manufacturing a microneedle according to an embodiment of the present invention, the mold may include at least one of a metal, a water-soluble polymer, a fat-soluble polymer, and an amphiphilic polymer in polydimethylsiloxane (PDMS).

In the method for manufacturing a microneedle according to an embodiment of the present invention, the raw material may be formed of a microneedle material and a water-soluble additive.

In the method of manufacturing a microneedle according to an embodiment of the present invention, the microneedle material is carboxymethylcellulose (CMC), hyaluronic acid (HA), alginic acid, or pectin , Carrageenan, Chondroitin Sulfate, Dextran Sulfate, Chitosan, Polylysine, Carboxymethyl Chitin, Fibrin, Fibrin (Agarose), pullulan, polyanhydride, polyorthoester, polyetherester, polyesteramide, poly butyric acid, Poly valeric acid, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, polyvinyl chloride ide), polyvinyl fluoride, polyvinyl imidazole, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), hydroxypropylmethyl Cellulose (HPMC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose, Cyclodextrin, Maltose, Lactose, Trehalose, Cello Cellobiose, Isomaltose Turanose, Lactulose, poly (lactic acid)) (PLA, Lakeshore Biomaterials, Birmingham, AL), poly (Llactic acid) (L-PLA) , poly (glycolic acid) (PGA), and poly (lactic-co-glycolic acid) (PLGA), PCL (Polycaprolactone), PE (Polyethylene), Polyamide, Polybutylene terephthalate, Polycarbonate, liquid Crystal polymers, polysulfone, polyethersulfone, polyphenylsulfone, and polyetherimide, or monomers forming these polymers It may include at least one of a copolymer and cellulose.

In the method of manufacturing a microneedle according to an embodiment of the present invention, the water-soluble additive is, trehalose, oligosaccharide, sucrose, maltose, lactose, Cellobiose, hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, chitosan Chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacryl Late, at least one of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethyl cellulose, cyclodextrin or gentiobiose It can include any one.

In the method of manufacturing a microneedle according to an embodiment of the present invention, the active ingredient is a drug and a solvent-based liquid state, and the drug may be 0.01 to 99 parts by weight compared to 100 parts by weight of the solvent.

In the method of manufacturing a microneedle according to an embodiment of the present invention, the solvent is purified water (DI water), methanol (Methanol), ethanol (Ethanol), chloroform (Chloroform), dibutyl phthalate (Dibutyl phthalate), dimethyl phthalate It can be at least one of Dimethyl phthalate, Ethyl lactate, Glycerin, Isopropyl alcohol, Lactic acid and Propyleneglycol, or mixtures thereof. have.

In the method for manufacturing a microneedle according to an embodiment of the present invention, the drug may be a water-soluble drug or a poorly soluble drug.

Micro needle according to another embodiment of the present invention, at least one tip portion that can penetrate into the skin; A base portion supporting the at least one tip portion; And a coating layer containing an active ingredient coated on the tip portion of the tip portion, wherein an oil film is formed between the at least one tip portion and the coating layer.

In the microneedle according to another embodiment of the present invention, the oil film may be any one of oil and / or surfactant.

In the microneedle according to another embodiment of the present invention, when the oil film is oil, the oil is almond oil, canola oil, castor oil, hydrogenated castor Hydrogenated Castor oil, Coconut oil, Corn oil, Cottonseed oil, Mineral oil, Mineral oil, Light, Mineral oil Lanolin alcohol ( Mineral oil and Lanolin Alcohols, Olive oil, Peanut oil, Polyoxyethylene castor oil derivatives, Safflower oil, Sesame oil, Soybean oil (Soybean oil), Sunflower oil, Vegetable oil, Hydrogenated (Vegetable oil, hydrogenated), Oleic acid, Linoleic acid, Soy fatty acid, Corn oil mono-di -Tridy Corn oil mono-di-tridiglycerides, peppermint oil, soybean oil, hydrogenated soybean oil, caprylic / capric triglycerides And glycerin (Glycerin).

In a microneedle according to another embodiment of the present invention, when the oil film is a surfactant, the oil film is Tergitol, Alpha tocopherol, a SPAN-type surfactant, polysol It may be at least one of the group consisting of bait (polysorbate (Tween)), sodium dodecyl sulfate (SDS), benzalkonium chloride, and glyceryl oleate.

In the microneedle according to another embodiment of the present invention, the shape of the tip portion may have a conical or polygonal pyramid shape.

According to an embodiment of the present invention, a method for manufacturing a microneedle is formed by forming an oil film between a surface of a microneedle tip portion and a coating layer containing an active material formed on the surface of the tip portion, thereby inducing a change in adhesion between different substances to quantitatively The active ingredient can be delivered intradermally.

The method of manufacturing a microneedle according to an embodiment of the present invention forms an oil film between a tip portion of a microneedle and a coating layer containing an active material formed on the surface of the tip portion, so that an active ingredient is intradermal within seconds without the need for an adhesive and a support. It is delivered to, it can shorten the treatment time.

The method for manufacturing a microneedle according to an embodiment of the present invention can easily coat both the active ingredient contained in the coating layer as well as the water-soluble and poorly soluble, and can be coated with all active ingredients without being limited to a specific active ingredient. have.

The microneedle according to another embodiment of the present invention can deliver a quantitative active ingredient to the blood within a short time within a few seconds, thereby minimizing the discomfort of an operator.

1 is a flowchart illustrating a method of manufacturing a micro needle according to an embodiment of the present invention in order, and FIGS. 2 to 5 are steps of preparing a micro needle in the method of manufacturing a micro needle according to an embodiment of the present invention. 6 is a perspective view sequentially showing steps of forming a coating layer and an oil film in a method of manufacturing a microneedle according to an embodiment of the present invention.
7 shows a cross-section of a microneedle according to an embodiment of the present invention.
8 and Table 2 show the force required for each manufacturing example when the microneedle surface and the coating solution formed on the microneedle surface are separated.
9A to 9C are manufacturing examples 6 of the present invention, FIGS. 10A to 10C are manufacturing examples 9 of the present invention, and FIGS. 11A to 11C are adhesive strength test result images according to manufacturing example 1 of the present invention, respectively.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings and the contents described in the accompanying drawings, but the present invention is not limited or limited by the embodiments.

The terminology used herein is for describing the embodiments and is not intended to limit the present invention. In this specification, the singular form also includes the plural form unless otherwise specified in the phrase. As used herein, "comprises" and / or "comprising" refers to the components, steps, operations and / or elements mentioned above, the presence of one or more other components, steps, operations and / or elements. Or do not exclude additions.

As used herein, "example", "example", "side", "example", etc. should be construed as any aspect or design described being better or more advantageous than another aspect or designs. It is not done.

Also, the term 'or' refers to the inclusive 'inclusive or' rather than the exclusive 'exclusive or'. That is, unless stated otherwise or unclear from the context, the expression 'x uses a or b' means any of the natural inclusive permutations.

Also, the singular expression (“a” or “an”) used in the specification and claims generally means “one or more” unless the context clearly indicates otherwise that it is related to the singular form. It should be interpreted as.

The terminology used in the description below has been selected to be general and universal in the related technical field, but may have other terms depending on the development and / or change of technology, conventions, and preferences of technicians. Therefore, the terms used in the following description should not be understood as limiting the technical idea, but should be understood as exemplary terms for describing the embodiments.

Also, in certain cases, some terms are arbitrarily selected by the applicant, and in this case, detailed meanings will be described in the corresponding description. Therefore, the terms used in the description below should be understood based on the meaning of the term and the entire contents of the specification, not just the name of the term.

Unless otherwise defined, all terms (including technical and scientific terms) used in the present specification may be used as meanings commonly understood by those skilled in the art to which the present invention pertains. In addition, terms defined in the commonly used dictionary are not ideally or excessively interpreted unless specifically defined.

On the other hand, in the description of the present invention, when it is determined that a detailed description of related known functions or configurations may unnecessarily obscure the subject matter of the present invention, the detailed description will be omitted. In addition, terms used in the present specification (terminology) are terms used to properly represent an embodiment of the present invention, which may vary according to a user, an operator's intention, or a custom in a field to which the present invention pertains. Therefore, definitions of these terms should be made based on the contents throughout the present specification.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

1 is a flowchart illustrating a method for manufacturing a microneedle according to an embodiment of the present invention in order, and FIGS. 2 to 5 are steps of preparing a microneedle among the methods for manufacturing a microneedle according to an embodiment of the present invention. 6 is a perspective view sequentially showing steps of forming a coating layer and an oil film in a method of manufacturing a microneedle according to an embodiment of the present invention.

Hereinafter, a method of manufacturing a microneedle according to an embodiment of the present invention will be described with reference to FIGS. 1 to 6.

Referring to FIG. 1, a method for manufacturing a microneedle according to an embodiment of the present invention includes preparing a microneedle (S110), preparing a coating solution (S120), forming a coating layer (S130), and an oil film. It is manufactured through the step of forming (S140).

In the method of manufacturing a microneedle according to an embodiment of the present invention, preparing a microneedle (S110) is a step of manufacturing a microneedle including a tip portion and a base portion supporting the tip portion.

The step (S110) of preparing the microneedles may manufacture the microneedles through the first manufacturing process and the second manufacturing process. Among them, referring to FIGS. 2 and 3 in more detail with respect to the first manufacturing process, the microneedles The step of providing a needle (S110) includes providing a mold 210 having a plurality of tip grooves 220 ((a) of FIG. 3), and supplying a raw material 300a to the mold 210 ( S111 of FIG. 2, (b) of FIG. 3), filling the raw material 300a inside the tip groove 220 of the mold 210 (S112 of FIG. 2, (c) of FIG. 3) and after drying The microneedles 300 composed of the tip part 310 and the base part 320 may be manufactured through the step of removing the mold 210 to prepare the microneedles (S113 of FIG. 2 and (d) of FIG. 3). have.

At this time, the step of filling the raw material 300a inside the tip groove 220 of the mold 210 selects any one of the following processes: pressurization, spray, centrifugation, vacuum, ultrasonic, spin coating or rolling. The material 300a may be filled in the tip groove 220.

Referring to FIGS. 4 and 5 in more detail with respect to the second manufacturing process in the step (S110) of providing a microneedle, the step of providing a microneedle (S110) forms the supporter 240 on the support 230 Step (S114 of FIG. 4, (a) of FIG. 5), coating and tensioning the raw material to the supporter 240 (S115 of FIG. 4, (b) of FIG. 5) and drying (FIG. 4) The microneedle 300 composed of the tip portion 310 and the base portion 320 may be manufactured through S116).

At this time, the step of applying and tensioning the raw material to the supporter (S115) may be manufactured through a process of tensioning through a drawing process of tensioning through a flat plate or the same supporter or a process of tensioning through dispensing.

The tip portion 310 is exemplified as having a sharp shape so as to easily penetrate the skin of a human body or an animal, and has a conical or polygonal shape, but is not limited thereto.

In addition, a plurality of the tip parts 310 are provided in multiple rows and multiple rows. The shape and number of the plurality of tip parts 310 are not limited to the illustrated example.

The base portion 320 is a body of the micro needle 300 supporting a plurality of tip portions 310, and is a kind of patch that is in close contact with the skin while supporting the plurality of tip portions 310.

For reference, the plurality of tip parts 310 may be extended to a length of 50 μm to 2000 μm from the base, and more preferably, to a length of 90 μm to 800 μm from the base.

At this time, the mold 210 includes at least one of a metal, a water-soluble polymer, a fat-soluble polymer, and an amphiphilic polymer in a polydimethylsiloxane (PDMS) mold, and the fat-soluble polymer and the amphiphilic polymer are polyurethane, hydroxypropyl Cellulose (HPC, hydroxy propyl cellulose), hydroxypropyl methyl cellulose (HPMC), PCL (poly capro lactone), polyglycolide (PGA), polylactic acid (PLA), polylactide-glycolide aerial Copolymer (PLGA), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyethylene oxide (PEO), polypropylene oxide (PPO), polyvinyl methyl ether (PVME, poly vinyl methyl ether), polymethyl acrylate (PMA), propylene glycol, polyesteramide, poly Poly butyric acid, acrylamide (acrylamide, acrylic amide), acrylic acid (acrylic acid), hyaluronic acid (HA, hyaluronic acid) and may include at least one of gelatin (gelatin), the metal It may be a silver aluminum biocompatible material.

In addition, the raw material 300a injected into the mold 210 is formed of a biocompatible material and a water-soluble additive.

Here, the biocompatible material, carboxymethyl cellulose (CMC), hyaluronic acid (HA), alginic acid (alginic acid), pectin (Pectin), carrageenan (Carrageenan), chondroitin sulfate (Chondroitin Sulfate) , Dextran sulfate, chitosan, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, polyan Hydride (polyanhydride), polyorthoester, polyetherester, polyesteramide, poly butyric acid, poly valeric acid, polyacrylic Polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, polyvinyl chloride, polyvinyl fluoride, polybi Polyvinyl imidazole, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropyl Cellulose (HPC), carboxymethyl cellulose, Cyclodextrin, Maltose, Lactose, Trehalose, Cellobiose, Isomaltose Turanose ( Turanose) and lactulose (Lactulose), or may include at least one of a copolymer of monomers and cellulose forming the polymer.

In addition, the water-soluble additives, trehalose, oligosaccharide, sucrose, maltose, lactose, cellobiose, hyaluronic acid acid, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, chitosan, polylysine, collagen, gelatin , Carboxymethyl chitin, fibrin, agarose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethyl Cellulose (EC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (carboxymethyl cellulose), cyclodextrin (Cyclodextrin) or may include at least one of gentibiose (gentiobiose).

The step (S120) of preparing a coating solution in the method of manufacturing a microneedle according to an embodiment of the present invention includes an active ingredient and an additive present in an emulsion or molecular state in the active ingredient. This is the step of preparing 420.

More specifically, the active ingredient of the coating solution 420 is a drug and a solvent-based liquid state, the active ingredient may further include hydroxypropyl cellulose (HPC), the drug is 100 parts by weight of the solvent It may be 0.01 parts by weight to parts by weight, preferably parts by weight to parts by weight, and most preferably 1 part to 20 parts by weight.

At this time, the solvent is purified water (DI water), methanol (Methanol), ethanol (Ethanol), chloroform (Chloroform), dibutyl phthalate (Dibutyl phthalate), dimethyl phthalate (Dimethyl phthalate), ethyl lactate (Ethyl lactate) ), Glycerin (Glycerin), isopropyl alcohol (Isopropyl alcohol), lactic acid (Lactic acid), propylene glycol (Propyleneglycol).

The drug may be a water-soluble drug that is easily soluble in water or a poorly soluble drug that is not readily soluble in water.

In general, when forming a coating layer containing a chemical solution on the surface of the microneedle, only a water-soluble drug was possible due to the limitation of the water-soluble-based manufacturing process, but the microneedle having the coating layer formed through the method of manufacturing the microneedle according to an embodiment of the present invention When manufactured, it is also effective to easily coat poorly soluble drugs that are difficult to deliver because they are not soluble in water.

Therefore, the method of manufacturing a microneedle according to an embodiment of the present invention has an advantage of efficiently delivering even poorly soluble drugs that are difficult to apply to the microneedle by a general process.

The water-soluble drug that can be included in the active ingredient in the method of manufacturing a microneedle according to an embodiment of the present invention is a protein / peptide drug, hormone, hormone analog, enzyme, enzyme inhibitor, signal transduction protein or a portion thereof, antibody or a portion thereof, It may include at least one of a single chain antibody, a binding protein or a binding domain thereof, an antigen, an adhesion protein, a structural protein, a regulatory protein, a toxin protein, a cytokine, a transcription regulator, a blood clotting factor, and a vaccine, and more specifically , The protein / peptide medicine is insulin, IGF-1 (insulinlike growth factor 1), growth hormone, erythropoietin, G-CSFs (granulocyte-colony stimulating factors), GM-CSFs (granulocyte / macrophage-colony stimulating factors) , Interferon alpha, interferon beta, interferon gamma, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, interleukin-2, epidermal grow th factors), calcitonin, ACTH (adrenocorticotropic hormone), TNF (tumor necrosis factor), atobisban, buserelin, cetrorelix, deslorelin , Desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, GHRH-II (growth hormone releasing) hormone-II), gonadorelin, goserelin, histrelin, leuprorelin, lypressin, octreotide, oxytocin , Pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine, triptorelin, bivalirudin ( bivalirudin), carbetocin, cyclosporine, exedine, lanreotide, LHRH (luteinizing hormonereleasing hormone), Nafarelin, parathyroid hormone, pramlintide, T20 (enfuvirtide), thymalfasin ziconotide, α-interferon, β-interferon for multiple sclerosis, erythropoietin, polytro Pin β, polytropin α, G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, salmon calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone, filgrastin, heparin, low molecule At least one of heparin and somatropin, Japanese encephalitis vaccine, rotavirus vaccine, influenza vaccine, polio vaccine, chickenpox vaccine, Alzheimer's disease vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, cervical cancer vaccine , Meningococcal vaccine, tetanus vaccine, whooping cough vaccine, Lyme disease vaccine, rabies vaccine, pneumococcal vaccine, yellow fever vaccine, cholera vaccine, vaccinia vaccine, tuberculosis bag , Rubella vaccine, measles vaccine, mumps vaccine, botulinum vaccine, herpesvirus vaccine, other DNA vaccines, hepatitis B vaccine, hyaluronic acid, Coenzymeq10, Chitosan, Botox, Vitamins and vitamin derivatives, hydroxy acid, tetracycline, oxytetracycline, doxycycline, minocycline, benzocaine, mepivacaine, lidocaine (Lidocaine), Prilocaine, Bupivacaine, Etidocaine, Articaine, Procaine, Propoxycaine, Tetracaine, At least one of Ropivacaine, Butacaine, Piperocaine, Cocaine, Chloroprocaine, Proparacaine and DiclonineIt can hamhal.

In the method for manufacturing a microneedle according to an embodiment of the present invention, a poorly soluble drug that may be included in an active ingredient, protein drugs, peptide drugs, nucleic acid molecules and nanoparticles for gene therapy, and effective substances used in cosmetics may be used. have. More specifically, methylprednisolone Sodium Succinate (trade name: A-Methapred), Abacavir sulfate (trade name: Ziagen), Abiraterone acetate (trade name: Zytiga) , Paclitaxel (trade name: Abraxane), Isotretinoin (trade name: Absorica), Fentanyl Sublingual Tablets (trade name: Abstral), clindamycin phosphate 1.2% -benzoyl peroxide 1.2% (Clindamycin phosphate 1.2%) and Benzoyl Peroxide 2.5%) (trade name: Acanya gel), Precose (Acarbose), Zafirlukast (trade name: Accolate), Albuterol sulfate inhalation solution (trade name: AccuNeb), Quinapril Quinapril hydrochloride (trade name: Accupril), isotretinoin (trade name: Accutane), papain and urea (trade name: Accuzyme), acebutolol high Acebutolol hydrochloride (trade name: Sectral), Perindopril erbumine (trade name: Aceon), Acetylcystein injection (trade name: Acetadote), Acetaminophen (trade name: Tylenol) , Acetaminophen-Isometheptene-Dichloralphenazone (trade name: Midrin), Acetazolamide, Acetic acid, Acetyl sulfisoxazole Pediatric Suspension (Acetyl sulfisoxazole) pediatric suspension (trade name: Gantrisin), Acetylcholine chloride intraocular solution (trade name: Miochol-E), Acetylcysteine (trade name: Acetadote), Rabeprazole sodium (trade name: Aciphex), Acitretin (trade name: Soriatane), Aclidinium bromide (trade name: Tudorza pressair), Akravastin-Pseudoephed Hydrochloride (Acrivastine and pseudoephedrine hydrochloride) (trade name: Semprex-d), Corticorelin ovine triflutate (trade name: Acthrel), Permethrin (trade name: Acticin), aclidinium bromide ( Aclidinium bromide (trade name: Tudorza Pressair), Fentanyl citrate (trade name: Actiq), Tetracycline periodontal (trade name: Actisite), Alteplase (trade name: Activase), Pioglitazone hydrochloride and metformin hydrochloride (ACTOPLUS MET®), Cyclosporine A, Triamcinolone, etc., but are not limited thereto.

Forming a coating layer in the method of manufacturing a microneedle according to an embodiment of the present invention (S130) is a step of dipping the microneedle in a coating solution to form a coating layer on the tip of the tip.

Referring to (b) and (c) of FIG. 6 together, by at least partially immersing the tip portion of the tip portion 310 of the micro needle 310 into the coating chamber 410 containing the coating solution 420 prepared in step S120, A coating layer C may be formed on a portion of the tip portion of the tip portion 310.

The step of forming an oil film in the method of manufacturing a microneedle according to an embodiment of the present invention (S140) is the diffusion (diffusion) between the tip portion 310 and the coating layer (C) contained in the coating layer the oil film ( OF, oil film).

In more detail, the step of forming the oil film (OF) by diffusing the additive contained in the coating layer (C) between the tip portion 310 and the coating layer (C) (S140), the emulsion (emulsion) or molecules (molecular) The additives present in a dispersed state are left at a temperature of 5 ° C. to 40 ° C. for 1 minute to 10 hours or more to diffuse between the tip portion 310 and the coating layer (C), more preferably 10 The oil film (OF) may be formed at a temperature of ℃ to 25 ° C. for 1 hour to 5 hours or more.

At this time, the oil film (OF) induces an adhesive force between the tip portion 310 and the coating layer (C), and serves to easily separate the coating layer (C) from the tip portion (310).

Therefore, when the micro-needles 300 are applied to the skin of the body, it is possible to quickly deliver a quantitative active ingredient to the skin, and also has an advantage of shortening the attachment time.

At this time, the additive is an oil and / or a surfactant.

More specifically, when the additive is an oil, the oil is almond oil, canola oil, castor oil, hydrogenated castor oil, coconut Oils (Coconut oil), Corn oil, Cottonseed oil, Mineral oil, Mineral oil, light, Mineral oil and Lanolin Alcohols, Olive Oil, peanut oil, polyoxyethylene castor oil derivatives, safflower oil, sesame oil, soybean oil, sunflower oil ( Sunflower oil, vegetable oil, hydrogenated oil, oleic acid, linoleic acid, soy fatty acid, corn oil mono-di-tridiglyceride (Corn oil) mo no-di-tridiglycerides, Peppermint oil, Soybean oil, Hydrogenated soybean oil, Caprylic / capric triglycerides and Glycerin It may be at least one of the group consisting of.

In addition, when the additive is a surfactant, the surfactant is Tergitol, Alpha tocopherol, a SPAN-type surfactant, polysorbate (Tween), lauryl It may be at least one of the group consisting of sodium dodecyl sulfate (SDS), benzalkonium chloride, and glyceryl oleate.

The method of manufacturing a microneedle according to the above-described exemplary embodiment of the present invention induces a change in adhesion between different materials by forming an oil film between the surface of the microneedle tip portion and the coating layer containing the active material formed on the surface of the tip portion Therefore, there is an advantage in that a quantitative active ingredient can be delivered intradermally.

In addition, the active ingredient is delivered intradermally in a few seconds without the need for an adhesive and a support, which can shorten the treatment time, thereby minimizing the discomfort of the patient.

In addition, since the active ingredient contained in the coating layer is not only water-soluble but also poorly soluble, it can be easily coated, and is not limited to a specific active ingredient, and thus has an advantage of easily coating all active ingredients.

3 is a cross-sectional view showing a microneedle according to another embodiment of the present invention.

Referring to FIG. 3, the microneedle according to another embodiment of the present invention may include at least one tip portion 310 that can penetrate into the skin, a base portion 320 supporting the at least one tip portion 310, and a tip portion of the tip portion It includes a coating layer (C) containing the active ingredient coated on.

At this time, the tip portion 310 may have a conical or polygonal pyramid shape.

In addition, an oil film (OF) is formed between the at least one tip portion 310 and the coating layer (C) to induce a change in the adhesion between different materials, and thus, it is possible to deliver a quantitative active ingredient into the skin. do.

At this time, the additive is an oil and / or a surfactant.

More specifically, when the additive is an oil, the oil is almond oil, canola oil, castor oil, hydrogenated castor oil, coconut Oils (Coconut oil), Corn oil, Cottonseed oil, Mineral oil, Mineral oil, light, Mineral oil and Lanolin Alcohols, Olive Oil, peanut oil, polyoxyethylene castor oil derivatives, safflower oil, sesame oil, soybean oil, sunflower oil ( Sunflower oil, vegetable oil, hydrogenated oil, oleic acid, linoleic acid, soy fatty acid, corn oil mono-di-tridiglyceride (Corn oil) mo no-di-tridiglycerides, Peppermint oil, Soybean oil, Hydrogenated soybean oil, Caprylic / capric triglycerides and Glycerin It may be at least one of the group consisting of.

In addition, when the additive is a surfactant, the surfactant is Tergitol, Alpha tocopherol, a SPAN-type surfactant, polysorbate (Tween), lauryl It may be at least one of the group consisting of sodium dodecyl sulfate (SDS), benzalkonium chloride, and glyceryl oleate.

7 shows a cross-section of a microneedle according to an embodiment of the present invention.

Referring to FIG. 7, a coating layer C is formed on a portion of the tip portion of the tip portion 310 formed on the base portion 320, and an oil film OF is formed between the tip portion 310 and the coating layer C. You can check the structure.

Hereinafter, the present invention will be described in more detail through manufacturing examples. These production examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by these production examples.

 [ Manufacturing example  One]

<Micro You guys  Manufacturing process>

After mixing the polydemic siloxane (PDMS) and the polydemic siloxane curing agent in a ratio of 10: 1, using a vacuum process to remove air bubbles, the master mold is duplicated.

Polycaprolactone (PCL) was used in the mold to remove air bubbles at 100 ° C., and a microneedle was prepared.

<Coating solution manufacturing process>

A coating solution was prepared by mixing 0.139 g of HPC and 0.789 g of ethanol for 1 hour at a temperature of 25 ° C.

<Coating layer formation process>

The microneedles prepared in the microneedle manufacturing process are immersed in the coating solution prepared in the coating solution manufacturing process at a temperature of 25 ° C. for 3 seconds to form a coating layer by dipping a total of 2 times.

< Oil film  Forming process>

The microneedle was prepared by drying and maintaining the microneedle on which the coating layer was formed at a temperature of 25 ° C. for 1 hour to activate oil diffusion in the coating layer to form an oil film.

[ Manufacturing example  2]

[Preparation Example 2] was prepared through the same production process as [Preparation Example 1], except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] was changed to HPC 0.141 g, ethanol 0.789 g, and Span80 0.0094 g. do.

[ Manufacturing example  3]

[Preparation Example 3] is the same as [Preparation Example 1] except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] is changed to HP4 0.1498 g, ethanol 0.789 g, Span80 0.009987 g, and corn oil 0.04994 g. It is manufactured through the manufacturing process.

[ Manufacturing example  4]

[Preparation Example 4] was the same as [Preparation Example 1] except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] was changed to HPC 0.1537 g, ethanol 0.789 g, Span80 0.01025 g, and corn oil 0.07173 g. It is manufactured through the manufacturing process.

[ Manufacturing example  5]

[Preparation Example 5] was the same as [Preparation Example 1] except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] was changed to 0.1599 g of HPC, 0.789 g of ethanol, 0.01066 g of Span80, and 0.10662 g of corn oil. It is manufactured through the manufacturing process.

[ Manufacturing example  6]

[Production Example 6] was prepared through the same production process as [Production Example 1], except that the composition in the manufacturing process of the coating solution of [Production Example 1] was changed to 0.1443 g of HPC, 0.789 g of ethanol, and 0.0289 g of Span80. do.

[ Manufacturing example  7]

[Preparation Example 7] was the same as [Preparation Example 1] except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] was changed to HPC 0.1537 g, ethanol 0.789 g, Span80 0.03074 g, and corn oil 0.05123 g. It is manufactured through the manufacturing process.

[ Manufacturing example  8]

[Preparation Example 8] was the same as [Preparation Example 1] except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] was changed to 0.1578 g of HPC, 0.789 g of ethanol, 0.03156 g of Span80, and 0.07364 g of corn oil. It is manufactured through the manufacturing process.

[ Manufacturing example  9]

[Preparation Example 9] was the same as [Preparation Example 1] except that the composition in the manufacturing process of the coating solution of [Preparation Example 1] was changed to HP644 0.1644 g, ethanol 0.789 g, Span80 0.03288 g and corn oil 0.1096 g. It is manufactured through the manufacturing process.

The coating solution for each manufacturing example according to the above manufacturing examples is summarized in Table 1 below.

[Table 1]

Hereinafter, detailed effects according to Production Examples 1 to 9 of the present invention will be described with reference to FIGS. 8 to 11C.

8 and Table 2 show the force required for each manufacturing example when the microneedle surface and the coating solution formed on the microneedle surface are separated.

[Table 2]

8 and Table 2, it can be seen that as the amount of oil increases, the force required to separate the coating layer from the surface of the microneedle decreases.

9A to 9C are manufacturing examples 6 of the present invention, FIGS. 10A to 10C are manufacturing examples 9 of the present invention, and FIGS. 11A to 11C are images showing adhesion test results according to the manufacturing example 1 of the present invention, respectively.

9A, an image of a microneedle according to Preparation Example 6 of the present invention is shown, and it can be seen that the coating layer was uniformly formed when observed from the side and top.

Referring to Figure 9b, showing the image when the micro-needle prepared according to Preparation Example 6 of the present invention is attached to the tape for 5 seconds and then detached, when observed from the side and top of the microneedle It can be seen that the coating layer was cleanly removed.

In addition, referring to Figure 9c, it can be seen that all of the composition of the coating layer has been moved to the surface of the tape, through which it can be seen that rapid drug delivery is possible.

Referring to Figure 10a, it shows an image of a microneedle according to Preparation Example 9 of the present invention, it can be seen that the coating layer is uniformly formed when viewed from the side and top.

Referring to Figure 10b, showing the image when the micro-needle prepared according to the manufacturing example 9 of the present invention is attached to the tape for 5 seconds and then detached, when observed from the side and top of the microneedle It can be seen that the coating layer was cleanly removed.

In addition, referring to Figure 10c, it can be seen that all of the composition of the coating layer has been moved to the surface of the tape, through which it can be seen that rapid drug delivery is possible.

Referring to FIG. 11A, an image of a microneedle according to Manufacturing Example 1 of the present invention is shown, and similar to FIGS. 9A and 10A above, it can be seen that the coating layer is uniformly formed when observed from the side and top.

However, referring to FIGS. 11B and 11C, when the microneedles manufactured according to Preparation Example 1 of the present invention are attached to a tape for 5 seconds with a force of 1.5 kg and then detached, the coating layer does not move to the surface of the tape and the microneedles If it can be confirmed that it remains intact, it can be confirmed that rapid drug delivery is difficult accordingly.

On the other hand, the embodiments of the present invention disclosed in the specification and drawings are merely presented as specific examples to aid understanding, and are not intended to limit the scope of the present invention. It is obvious to those skilled in the art to which the present invention pertains that other modified examples based on the technical idea of the present invention can be implemented in addition to the embodiments disclosed herein.

Claims (21)

Providing a microneedle including a tip portion and a base portion supporting the tip portion;
Preparing an active ingredient and a coating solution comprising an additive present in an emulsion or molecular state within the active ingredient;
Dipping the microneedle in a coating solution to form a coating layer on the tip of the tip portion; And
The active ingredient contains ethanol as a water-soluble polar solvent,
The active ingredient further comprises hydroxypropyl cellulose (HPC),
The additive includes a water-insoluble oil having a carbon chain structure and a surfactant,
The water-insoluble oil having the carbon chain structure is corn oil
Method for manufacturing a microneedle, characterized by.
According to claim 1,
The step of forming the oil film by diffusing the additive contained in the coating layer between the tip portion and the coating layer,
A method of manufacturing a microneedle, characterized in that the additives existing in the emulsion state are maintained at a temperature of 5 ° C to 40 ° C for 1 minute to 10 hours so as to diffuse between the tip portion and the coating layer.
delete delete According to claim 1,
The surfactant is Tergitol, Alpha tocopherol, a SPAN-type surfactant, polysorbate (Tween), sodium dodecyl sulfate (SDS), A method for manufacturing a microneedle, characterized in that it is at least one of the group consisting of benzalkonium chloride and glyceryl oleate.
According to claim 1,
The step of providing a microneedle including the tip portion and a base portion supporting the tip portion,
Supplying a raw material to the mold;
Filling the raw material into a tip groove of the mold; And
A method for manufacturing a microneedle, comprising drying the filled raw material and removing the mold.
The method of claim 6,
The step of filling the raw material in the tip groove of the mold, a microneedle manufacturing method characterized in that it is performed by any one of the pressing, spraying, centrifugation, vacuum, ultrasonic, spin coating or rolling process.
According to claim 1,
The step of providing a microneedle including the tip portion and a base portion supporting the tip portion,
Forming a supporter on the support;
Applying and tensioning a raw material to the supporter; And
Method of manufacturing a microneedle comprising the step of drying.
The method of claim 8,
The step of applying and tensioning the raw material to the supporter is performed through a drawing process or a dispensing process.
The method of claim 6,
The mold is a poly-dimethylsiloxane (PDMS) metal, water-soluble polymer, fat-soluble polymer and a microneedle manufacturing method characterized in that it comprises at least one of amphiphilic polymers.
The method according to any one of claims 6 to 9,
The raw material is a micro-needle manufacturing method characterized in that formed by a micro-needle material and a water-soluble additive.
The method of claim 11,
The micro needle material,
Carboxymethylcellulose (CMC), hyaluronic acid (HA), alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate , Chitosan, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, polyanhydride, polyorr Polyorthoester, polyetherester, polyesteramide, poly butyric acid, poly valeric acid, polyacrylate, ethylene-vinyl Acetate (ethylene-vinyl acetate) polymer, acrylic substituted cellulose acetate, polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole, chloro Sulfonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose (carboxymethyl cellulose), Cyclodextrin, Maltose, Lactose, Trehalose, Cellobiose, Isomaltose Turanose, Lactulose , poly (lactic acid)) (PLA, Lakeshore Biomaterials, Birmingham, AL), poly (Llactic acid) (L-PLA), poly (glycolic acid) (PGA), and poly (lactic-co-glycolic acid) (PLGA ), PCL (Polycaprolactone), PE (Polyethylene), Polyamide, Polybutylene terephthalate, Polycarbonate, Liquid crystal polymer, Polysulfone, Poly Ethersulfone (polyethersulfo ne), polyphenylsulfone (Polyphenylsulfone) and at least one of polyetherimide (Polyether imide), or a microneedle production characterized in that it comprises at least one of a copolymer of the monomers and cellulose to form such a polymer Way.
The method of claim 11,
The water-soluble additive,
Trehalose, oligosaccharide, sucrose, maltose, lactose, cellobiose, hyaluronic acid, alginic acid ( alginic acid, Pectin, Carrageenan, Chondroitin Sulfate, Dextran Sulfate, Chitosan, Polylysine, Collagen, Gelatin, Carboxymethyl chitin ), Fibrin, agarose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxy Microneedle manufacturing method characterized in that it comprises at least one of propyl cellulose (HPC), carboxymethyl cellulose (carboxymethyl cellulose), cyclodextrin (Cyclodextrin) or gentibiose (gentiobiose).
According to claim 1,
The active ingredient is a drug and a solvent-based liquid state, the drug is a micro-needle manufacturing method, characterized in that 0.01 to 99 parts by weight compared to 100 parts by weight of the solvent.
delete The method of claim 14,
The drug is a microneedle manufacturing method characterized in that the water-soluble drug or poorly soluble drug.
At least one tip portion capable of penetrating into the skin;
A base portion supporting the at least one tip portion; And
The coating layer containing the active ingredient coated on the tip end portion
Including,
An oil film is formed between the at least one tip portion and the coating layer,
The oil film is a water-insoluble oil and a surfactant having a carbon chain structure,
Microneedle, characterized in that the water-insoluble oil having the carbon chain structure is corn oil.
delete delete The method of claim 17,
The surfactant is Tergitol, Alpha tocopherol, a SPAN-type surfactant, polysorbate (Tween), sodium dodecyl sulfate (SDS), A microneedle, characterized in that it is at least one of the group consisting of benzalkonium chloride and glyceryl oleate.
The method of claim 17,
The shape of the tip portion is a micro needle, characterized in that it has a conical or polygonal shape.

Images