KR102164792B1 - Manufacturing method of microneedle patch, microneedle patch manufactued by the method and material delivery system comprising the microneedle patch - Google Patents

Abstract

The present invention relates to a method of manufacturing a microneedle patch, a microneedle manufactured thereby, and a mass transfer system including the same, wherein the method of manufacturing a microneedle patch according to an embodiment of the present invention comprises: manufacturing a mother mold; Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold; Plating the first polymer array mold to manufacture a mold; Manufacturing a mold mother mold by removing the first polymer array mold from the mold mold; Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold; Manufacturing a microneedle patch array by double casting the second polymer array mold; And separating a microneedle patch including a microneedle structure from the microneedle patch array after injection-molding a patch material on the microneedle patch array.

Description

A method of manufacturing a microneedle patch, and a material delivery system including a microneedle and a microneedle patch manufactured therefrom TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method of manufacturing a microneedle patch, a microneedle manufactured thereby, and a mass transfer system including the same.

In the case of injecting a physiologically active substance into human skin, an existing injection needle may be used, but pain at the injection site, damage to the skin, bleeding, and disease infection due to the injection needle may occur.

Accordingly, recently, a method of delivering a physiologically active substance into the skin using a microneedle has been actively studied. The microneedles may have tens to hundreds of micro-diameters to penetrate the stratum corneum of the skin, which is the main barrier layer. Unlike conventional injection needles, microneedles can be characterized by painless skin penetration and no trauma. And, since the microneedles must penetrate the stratum corneum of the skin, some degree of physical hardness may be required. In addition, an appropriate length may be required for the physiologically active substance to reach the epidermal layer of the skin or dermatosis.

However, it is difficult to make a large-area microneedle array having a high aspect ratio (height/diameter), and it is difficult to make a large-area microneedle array with high shape homogeneity even when a large single wafer is used. In addition, when a silicon wafer is used, a pattern having a clean surface can be produced, but it has an advantage of being fragile and is not suitable for mass production.

Therefore, there is a need for a mold that can be used semi-permanently for the production cost and stability of the process.

In addition, in order for the physiologically active substances of hundreds of microneedles to be effectively delivered into the skin, the microneedles must have a high skin transmittance and must be maintained for a certain period of time until dissolution after being inserted into the skin. Recently, a microneedle patch in the form of a patch in which these microneedles are arranged on one side is used, but since the structure of the microneedle itself is very small, even if the patch has adhesiveness, the movement of the body joint is prevented if the microneedle patch is large. It may be affected and cause the problem to fall off easily after attachment.

The present invention is to solve the above-described problems, and an object of the present invention is that it has a high aspect ratio, improves skin penetration, makes it easy to enter the skin, does not fall out easily even after entering, and can efficiently deliver drugs. It is to provide a method of manufacturing a microneedle patch of an area, a microneedle manufactured thereby, and a mass transfer system including the same.

However, the problem to be solved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

One aspect of the present invention, the step of manufacturing a mother mold; Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold; Plating the first polymer array mold to manufacture a mold; Manufacturing a mold mother mold by removing the first polymer array mold from the mold mold; Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold; Manufacturing a microneedle patch array by double casting the second polymer array mold; And separating a microneedle patch including a microneedle structure from the microneedle patch array after injection-molding a patch material into the microneedle patch array.

Another aspect of the invention, the step of manufacturing a mother mold; Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold; Manufacturing a polymer microneedle patch array by double casting the first polymer array mold; Plating the polymer microneedle patch array to manufacture a mold mother mold; Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold; And separating a microneedle patch including a microneedle structure from the second polymer array mold after injection-molding a patch material in the second polymer array mold.

In one embodiment, the manufacturing of the mother mold includes: preparing a first substrate having an intaglio mold and a second substrate having a through hole corresponding to the intaglio mold; And bonding the first substrate and the second substrate.

In one embodiment, the intaglio mold of the first substrate may be manufactured by a wet etching method using at least one solution selected from the group consisting of acids, bases, and organic solvents.

In one embodiment, the through hole of the second substrate is at least selected from the group consisting of reactive ion etching (RIE), inductively coupled plasma (ICP), and ion milling. It may be manufactured by any one dry etching method.

In one embodiment, the first substrate and the second substrate may be silicon wafers.

In one embodiment, the first substrate and the second substrate may have a thickness of 100 μm to 1000 μm, respectively.

In one embodiment, the size of the intaglio mold of the first substrate and the size of the through hole in the second substrate are the same, or the size of the intaglio mold is greater than the size of the through hole, or The size of the mold may be smaller than the size of the through hole.

In one embodiment, the step of manufacturing the first polymer array mold comprises manufacturing a plurality of the first polymer array molds and bonding the plurality of first polymer array molds to each other to be larger than the first polymer array mold. It may further include manufacturing a first polymer array mold having a large area.

In one embodiment, after the step of manufacturing the mold mother mold, it includes performing a physical surface treatment on the surface of the mold mother mold, and the physical surface treatment is performed by electron beam, plasma, corona discharge, and ultraviolet rays. It may include at least one selected from the group consisting of.

In one embodiment, the microneedle structure may be a conical shape, a pyramid shape, or include both.

In one embodiment, the microneedle structure may include an arrow nose shape or an arrowhead end.

In one embodiment, the cross-sectional dimension of the microneedle structure may be 10 nm to 300 μm, and the height may be 100 μm to 1000 μm.

In one embodiment, the aspect ratio of the microneedle structure may be 0.1 to 30.

In one embodiment, the polymer is polyethylene, polypropylene, polyvinyl chloride resin, polyethylene terephthalate (PET), nylon, epoxy, polyimide, polyester, urethane, acrylic, polycarbonate, urea, melanin, chlorinated rubber , Polyvinyl alcohol, polyvinyl ester, vinylidene fluoride-hexafluoropropylene copolymer (PVDF-co-HFP), polyvinylidenefluoride (PVDF), polyacrylonitrile, polymethylmeth Crylate (polymethylmethacrylate), polytetrafluoroethylene (PTFE), styrenebutadiene rubber (SBR), ethylene-propylene-diene copolymer (EPDM), and polydimethlysiloxane (PDMS) ) It may include at least one selected from the group consisting of.

In one embodiment, the patch material may include a biodegradable polymer, an extracellular matrix (ECM) composite, or both.

In one embodiment, the biodegradable polymer is, HA (Hyaluronic Acid), PLA (Poly Lactic Acid), Polyhydroxyalkanoate (PHA), Polyesteramide (PEA), PPDO (poly(p-dioxanone)), PLGA (Poly Lactic- Co-Glycolic Acid), PGA (Polyglycolide Acid), PCL (polycaprolactone), PEG (Poly Ethylene Glycol), PEGDA (Poly Ethylene Glycol Diacrylate), PEGMEA (Poly Ethylene Glycol Methyl Ether Acrylate) and COC (Cyclic Olefin Copolymer) It may include at least one selected from the group.

In one embodiment, the extracellular matrix (ECM) composite is collagen (type I to V), proteoglycan, glycosaminoglycan (GAG), glycoprotein, cytokine, cell-surface related protein, cell Adhesion molecule (CAM), endothelial ligand, matrikine, cadherin, immunoglobulin, fibrillar collagen, non-fibrous collagen, basement membrane collagen, multiplexin, proteoglycan rich in bovine-leucine, Decorin, biglycan, fibromodulin, keratocan, lumican, epipican, heparin sulfate proteoglycan, perlecan, agrin, testican, syndecan, glypican, serglycine, selectin, lectican, agre Can, versican, neurocan, brevican, cytoplasmic domain-44 (CD-44), macrophage stimulating factor, amyloid precursor protein, heparin, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparin sulfate, hyaluronic acid , Fibronectin, tenaskin, elastin, fibrilin, laminin, nidogen/enactin, fibulin I, fibulin II, integrin, permeable membrane molecules, thrombospondin, osteopontin, and angiotensin converting enzyme (ACE) It may include at least one selected from the group.

In one embodiment, the patch material may be cured by at least one selected from the group consisting of heat, radiation, electricity, pressure, and UV.

Another aspect of the present invention provides a microneedle patch manufactured by the method of manufacturing a microneedle patch according to the above.

Another aspect of the present invention provides a mass transfer system including the microneedle patch according to the above.

In one embodiment, the material may include at least one selected from the group consisting of drugs, nanoparticles, molecules, genomes, protein microorganisms, and cells.

In the method of manufacturing a microneedle patch of the present invention, a variety of microneedle patch designs can be easily made with a mold that can be used semi-permanently for production cost and process stability.

The microneedle patch of the present invention may have a large area so that the microneedle has a high aspect ratio and can be attached to a wide surface of pain such as a joint, a shoulder, and a waist. In addition, since the penetration of the skin is improved, it is easy to enter into the skin, and even after entering, it is difficult to fall out, and a large-area microneedle patch can be manufactured.

In the material delivery system of the present invention, a chemical (drug) is effectively injected into the skin by a microneedle patch, and a nanoparticle (or a ligand or an antibody is incorporated), a compound or a microorganism (bacteria, etc.), a molecule (protein , Enzymes, hormones, etc.), genomes (DNA, RNA), proteins and cells (stem cells), etc.

1 is a flowchart showing a manufacturing process of a microneedle patch according to an embodiment of the present invention.
2 is a process chart showing detailed steps of step (a) of FIG. 1.
3 is a view showing a step of performing a physical surface treatment on the surface of the mold mother mold according to an embodiment of the present invention.
4 is a diagram showing another embodiment of step (g) of FIG. 1.
5 is a top view of an exemplary shape of a microneedle structure according to an embodiment of the present invention.
6 is a side view of an exemplary shape of a microneedle structure according to an embodiment of the present invention.
7 is a flowchart showing a manufacturing process of a microneedle patch according to another embodiment of the present invention.
8 is a process chart showing detailed steps of step (a) of FIG. 7.
9 is a view showing a step of performing a physical surface treatment on the surface of the mold mother mold according to an embodiment of the present invention.
10 is a diagram showing another embodiment of step (f) of FIG. 7.
11 is a micrograph of a second polymer array mold according to an embodiment of the present invention.
12 is a micrograph of a microneedle patch array according to an embodiment of the present invention.
13 is a diagram showing one structure of a microneedle patch according to an embodiment of the present invention ((a) design design, (b) SEM image).

Hereinafter, exemplary embodiments will be described in detail with reference to the accompanying drawings. However, since various changes may be made to the embodiments, the scope of the rights of the patent application is not limited or limited by these embodiments. It should be understood that all changes, equivalents, or substitutes to the embodiments are included in the scope of the rights.

The terms used in the examples are used for illustrative purposes only and should not be interpreted as limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In the present specification, terms such as "comprise" or "have" are intended to designate the presence of features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, but one or more other features. It is to be understood that the presence or addition of elements or numbers, steps, actions, components, parts, or combinations thereof, does not preclude in advance.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiment belongs. Terms as defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and should not be interpreted as an ideal or excessively formal meaning unless explicitly defined in this application. Does not.

In addition, in the description with reference to the accompanying drawings, the same reference numerals are assigned to the same components regardless of the reference numerals, and redundant descriptions thereof will be omitted. In describing the embodiments, when it is determined that a detailed description of related known technologies may unnecessarily obscure the subject matter of the embodiments, the detailed description thereof will be omitted.

Hereinafter, a method of manufacturing a microneedle patch of the present invention, a microneedle manufactured thereby, and a mass transfer system including the same will be described in detail with reference to examples and drawings. However, the present invention is not limited to these examples and drawings.

One aspect of the present invention, the step of manufacturing a mother mold; Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold; Plating the first polymer array mold to manufacture a mold; Manufacturing a mold mother mold by removing the first polymer array mold from the mold mold; Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold; Manufacturing a microneedle patch array by double casting the second polymer array mold; And separating a microneedle patch including a microneedle structure from the microneedle patch array after injection-molding a patch material into the microneedle patch array.

1 is a flowchart showing a manufacturing process of a microneedle patch according to an embodiment of the present invention. Referring to Figure 1, the manufacturing process of the microneedle patch according to an embodiment of the present invention, the mother mold manufacturing step (Fig. 1 (a)), the first polymer array mold manufacturing step (Fig. 1 (b)) , Mold mold manufacturing step (Fig. 1(c)), mold mother mold manufacturing step (Fig. 1(d)), second polymer array mold manufacturing step (Fig. 1(e)), microneedle patch array manufacturing step (FIG. 1(f)) and a microneedle patch separation step (FIG. 1(g)).

In one embodiment, the manufacturing of the mother mold includes: preparing a first substrate having an intaglio mold and a second substrate having a through hole corresponding to the intaglio mold; And bonding the first substrate and the second substrate.

2 is a process chart showing detailed steps of step (a) of FIG. 1. In the manufacturing step of the mother mold 110 shown in FIG. 1A, as shown in FIG. 2, a first substrate 110a having an intaglio mold 112 that is a part penetrating into the skin and the first substrate 110a 1 A second substrate 110b having a through hole 114 corresponding to an intaglio mold of the substrate 110a is prepared.

In one embodiment, the intaglio mold 112 of the first substrate 110a may be manufactured by a wet etching method using at least one solution selected from the group consisting of acids, bases, and organic solvents.

In one embodiment, the through hole 114 of the second substrate 110b is formed by reactive ion etching (RIE), inductively coupled plasma (ICP), and ion milling. It may be manufactured by at least one dry etching method selected from the group consisting of.

In one embodiment, the first substrate 110a and the second substrate 110b may be silicon wafers.

In one embodiment, the first substrate 110a and the second substrate 110b may have a thickness of 100 μm to 1000 μm, respectively. The thickness of the first substrate 110a and the second substrate 110b may be the height of the microneedle.

In one embodiment, the size of the intaglio mold 112 of the first substrate 110a and the size of the through hole 114 of the second substrate 110b are the same, or the intaglio mold ( The size of 112 may be larger than the size of the through hole 114, or the size of the intaglio mold 112 may be smaller than the size of the through hole 114.

In one embodiment, as shown in the figure below of FIG. 2, the prepared first substrate 110a and the second substrate 110b are bonded. The first substrate 110a and the second substrate 110b may be bonded through chemical bonding using epoxy.

In one embodiment, in the manufacturing step of the first polymer array mold 120 shown in FIG. 1B, the first polymer is separated by filling and curing the polymer in the mother mold 110, and then separating the cured polymer. It may be to manufacture the array mold 120.

In one embodiment, the polymer is polyethylene, polypropylene, polyvinyl chloride resin, polyethylene terephthalate (PET), nylon, epoxy, polyimide, polyester, urethane, acrylic, polycarbonate, urea, melanin, chlorinated rubber , Polyvinyl alcohol, polyvinyl ester, vinylidene fluoride-hexafluoropropylene copolymer (PVDF-co-HFP), polyvinylidenefluoride (PVDF), polyacrylonitrile, polymethylmeth Crylate (polymethylmethacrylate), polytetrafluoroethylene (PTFE), styrenebutadiene rubber (SBR), ethylene-propylene-diene copolymer (EPDM), and polydimethlysiloxane (PDMS) ) It may include at least one selected from the group consisting of.

In one embodiment, the step of manufacturing the first polymer array mold comprises manufacturing a plurality of the first polymer array molds and bonding the plurality of first polymer array molds to each other to be larger than the first polymer array mold. It may further include manufacturing a first polymer array mold having a large area.

In an embodiment, a plurality of the first polymer array molds 120 may be manufactured, and the plurality of first polymer array molds 120 may be bonded to each other to manufacture a large-area first polymer array mold. For example, a large-area first polymer array mold having a size of 200 mm × 200 mm or more may be manufactured through flat splicing of the plurality of first polymer array molds 120. Accordingly, a first polymer array mold having a large area can be manufactured and used as a mold array mold, and accordingly, it is economical in the manufacturing process and ease of use can be increased.

In one embodiment, the mold mold manufacturing step shown in (c) of FIG. 1 may be to manufacture the mold mold 130 by plating a metal 130a on the first polymer array mold 120. The mold mold 130 may be manufactured by a metal growth process as well as electroplating.

In one embodiment, the metal 130a may include, for example, at least one selected from the group consisting of nickel, iron, copper, silver, gold, and zinc tin-lead alloys.

In one embodiment, the silicone mold is fragile and cannot be deformed into other shapes, so it is unsuitable for use as a mass production mold, but the mold mold 130 can be used semi-permanently and can be deformed so that a large amount of molds are performed through processes such as injection. Production is possible.

In one embodiment, the surface chemical cleaning of the mold mold 130 may include at least one selected from the group consisting of PDMS developer, acetone, MeOH, and IPA.

In one embodiment, the mold mother mold manufacturing step shown in (d) of FIG. 1 is to manufacture the mold mother mold 130 by removing the first polymer array mold 120 from the mold mold 130. Can be.

In one embodiment, after the step of manufacturing the mold mother mold (step (d) of FIG. 1 ), comprising performing a physical surface treatment on the surface of the mold mother mold 130, the physical surface The treatment may include at least one selected from the group consisting of electron beam, plasma, corona discharge, and ultraviolet light.

3 is a view showing a step of performing a physical surface treatment on the surface of the mold mother mold according to an embodiment of the present invention. Referring to FIG. 3, it may be to perform surface treatment on the mold mother mold 130 by using an electron beam. Surface treatment with an electron beam improves surface roughness, shape reproducibility, and ease of molding. In addition, by improving the flatness of the surface, the surface friction is reduced, so that the shape of the mold is uniform, and the polymer mold is easily separated, thereby increasing the usability.

In one embodiment, the manufacturing step of the second polymer array mold shown in (e) of FIG. 1 is a second polymer array mold by filling and curing a polymer in the mold mother mold 130 and separating the cured polymer. It may be to manufacture (140).

In one embodiment, the polymer of the second polymer array mold 140 may be the same or different polymers used when manufacturing the first polymer array mold 120.

In one embodiment, the second polymer array mold 140 can be mass-produced by the mold mother mold 130, and thus can be manufactured in hundreds to thousands or more. For example, it can produce more than 100 copies. The second polymer array mold 140 can be mass-produced in a short time through the mold mother mold 130 and the production cost can be drastically reduced.

In one embodiment, the manufacturing step of the microneedle patch array shown in FIG. 1F may be to manufacture the microneedle patch array 140a by double casting the second polymer array mold 140. The double casting may be performed using the same polymer or a different polymer as the polymer of the second polymer array mold 140.

In one embodiment, the step of separating the microneedle patch shown in (g) of FIG. 1 is a microneedle structure from the microneedle patch array after injection-molding the patch material 150 on the microneedle patch array 140a. It may be to separate the microneedle patch 150 including.

In one embodiment, the patch material may be used according to the purpose. When injecting by coating a drug on the surface, a hard material such as a polymer can be used when it is hardened, and a biomaterial with relatively low hardness when a material mixed with the drug is used, such as an ECM mixture Or you can use biocompatible materials

In one embodiment, the patch material may include a biodegradable polymer, an extracellular matrix (ECM) composite, or both.

In one embodiment, the biodegradable polymer is, HA (Hyaluronic Acid), PLA (Poly Lactic Acid), Polyhydroxyalkanoate (PHA), Polyesteramide (PEA), PPDO (poly(p-dioxanone)), PLGA (Poly Lactic- Co-Glycolic Acid), PGA (Polyglycolide Acid), PCL (polycaprolactone), PEG (Poly Ethylene Glycol), PEGDA (Poly Ethylene Glycol Diacrylate), PEGMEA (Poly Ethylene Glycol Methyl Ether Acrylate) and COC (Cyclic Olefin Copolymer) It may include at least one selected from the group.

In one embodiment, the extracellular matrix (ECM) composite is collagen (type I to V), proteoglycan, glycosaminoglycan (GAG), glycoprotein, cytokine, cell-surface related protein, cell Adhesion molecule (CAM), endothelial ligand, matrikine, cadherin, immunoglobulin, fibrillar collagen, non-fibrous collagen, basement membrane collagen, multiplexin, proteoglycan rich in bovine-leucine, Decorin, biglycan, fibromodulin, keratocan, lumican, epipican, heparin sulfate proteoglycan, perlecan, agrin, testican, syndecan, glypican, serglycine, selectin, lectican, agre Can, versican, neurocan, brevican, cytoplasmic domain-44 (CD-44), macrophage stimulating factor, amyloid precursor protein, heparin, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparin sulfate, hyaluronic acid , Fibronectin, tenaskin, elastin, fibrilin, laminin, nidogen/enactin, fibulin I, fibulin II, integrin, permeable membrane molecules, thrombospondin, osteopontin, and angiotensin converting enzyme (ACE) It may include at least one selected from the group.

In one embodiment, the patch material may be cured by at least one selected from the group consisting of heat, radiation, and UV. Depending on the type of the patch material, the step of curing the patch material by thermal curing, radiation irradiation, and UV irradiation during a curing process may be performed.

In one embodiment, in step (g) of FIG. 1, since the microneedle patch array 140a is made of a hard material, a force is applied to one of the microneedle patch array 140a or the microneedle patch 150, The material is pulled up or the polymer mold 140a is pulled down. This may be, for example, a method used to manufacture a bell tower microneedle patch or to manufacture an arrow nose-shaped or arrowhead end microneedle with a soft material.

4 is a diagram showing another embodiment of step (g) of FIG. 1. Referring to FIG. 4, the microneedle patch mold 140b may be manufactured using a disposable biomaterial. The disposable biomaterial may be dissolved in heat or chemicals, and the microneedle patch mold 140b may melt the microneedle patch mold 140b while leaving the microneedle patch 150 as it is.

In one embodiment, the manufactured microneedle patch 150 may include a microneedle structure.

5 is a top view of an exemplary shape of a microneedle structure according to an embodiment of the present invention. Referring to FIG. 5, the microneedle structure may be conical, pyramidal, or including both. The shape of the microneedle structure may be a shape when the microneedle structure is viewed from above. The microneedle structure may be formed in one shape of a moon horn shape or a pyramid shape, but may be formed by alternately arranging a moon horn shape and a pyramid shape.

In one embodiment, the microneedle structure may include an arrow nose shape or an arrowhead end.

6 is a side view of an exemplary shape of a microneedle structure according to an embodiment of the present invention. 6, when the size of the intaglio mold 112 of the first substrate 110a and the size of the through hole 114 of the second substrate 110b are the same, the bell tower when viewed from the side You can be an older brother. For example, when the size of the intaglio mold 112 is larger than the size of the through hole 114, it may be an arrow nose shape or a microneedle having an arrowhead end when viewed from the side.

In one embodiment, when the area of the microneedle patch is small, the probability of falling out of the skin is small, but when the area of the microneedle patch is large, the probability of falling out of the skin is high because the motility of the body is affected. When the microneedle structure has an arrow nose shape or an arrowhead end, it has an arrowhead shape, so it does not come off easily once it enters, thereby increasing skin surface fixation, and drug delivery can be made stably for a certain period of time.

In one embodiment, drug delivery may be more efficient by increasing the surface area of the microneedle structure.

In one embodiment, the cross-sectional dimension of the microneedle structure may be 10 nm to 300 μm, and the height may be 100 μm to 1000 μm. The cross-section of the microneedle structure may be determined by the size of the intaglio mold 112 and the through hole 114 of the first substrate 110a. The intaglio mold 112 may have a cross-sectional dimension that changes according to the etching time and the width (length). The height of the microneedle structure may be determined by thicknesses of the first and second substrates 110a and 110b.

In one embodiment, the aspect ratio of the microneedle structure may be 0.1 to 30. The thickness of the first substrate 110a and the second substrate 110b and the aspect ratio of the microneedles may be finally adjusted by the intaglio mold 112 and the through hole 114. Therefore, by the method of manufacturing the microneedle of the present invention, it is possible to easily adjust the height of the microneedle and to make a microneedle having a high aspect ratio.

In the method of manufacturing a microneedle patch of the present invention, a variety of microneedle patch designs can be easily made with a mold that can be used semi-permanently for production cost and process stability.

Another aspect of the invention, the step of manufacturing a mother mold; Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold; Manufacturing a polymer microneedle patch array by double casting the first polymer array mold; Plating the polymer microneedle patch array to manufacture a mold mother mold; Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold; And separating a microneedle patch including a microneedle structure from the second polymer array mold after injection-molding a patch material in the second polymer array mold.

7 is a flowchart showing a manufacturing process of a microneedle patch according to another embodiment of the present invention. Referring to Figure 7, the manufacturing process of the microneedle patch according to another embodiment of the present invention, the mother mold manufacturing step (Fig. 7 (a)), the first polymer array mold manufacturing step (Fig. 7 (b)) , Polymer microneedle patch array manufacturing step (Fig. 7(c)), mold mother mold manufacturing step (Fig. 7(d)), second polymer array mold manufacturing step (Fig. 7(e)) and microneedle patch It includes a separation step (Fig. 7 (f)).

The manufacturing process of the microneedle patch according to another embodiment of the present invention of FIG. 7 is almost the same as the manufacturing process of the microneedle patch of FIG. 1, but the step (c) of FIG. 1 is double-casting in FIG. It may be modified in the manufacturing step (Fig. 7 (c)). Therefore, in this case, step (f) of FIG. 1 may be omitted.

In one embodiment, except for steps (c) and (e) of FIG. 7, the parts described with the process chart in FIG. 1 are the same, and thus detailed descriptions of the same steps will be omitted.

In one embodiment, the manufacturing of the mother mold includes: preparing a first substrate having an intaglio mold and a second substrate having a through hole corresponding to the intaglio mold; And bonding the first substrate and the second substrate.

8 is a process chart showing detailed steps of step (a) of FIG. 7. In the manufacturing step of the mother mold 210 shown in FIG. 7A, as shown in FIG. 8, a first substrate 210a having an intaglio mold 212 which is a part penetrating into the skin and the first substrate 210a 1 A second substrate 210b having a through hole 214 corresponding to the intaglio mold 212 of the substrate 210a is prepared.

In one embodiment, as shown in the figure below of FIG. 8, the prepared first substrate 210a and the second substrate 210b are bonded. The first substrate 210a and the second substrate 210b may be bonded through chemical bonding using epoxy.

In one embodiment, the types of the intaglio mold 212 of the first substrate 210a, the through hole 214 of the second substrate 210b, the first substrate 210a, and the second substrate 210b , Thickness, bonding step, etc. are as described in FIG. 1.

In one embodiment, in the manufacturing step of the first polymer array mold 220 shown in FIG. 7B, the mother mold 210 is filled with a polymer and cured, and then the cured polymer is separated to form a first polymer. It may be to manufacture the array mold 220.

In one embodiment, the polymer is polyethylene, polypropylene, polyvinyl chloride resin, polyethylene terephthalate (PET), nylon, epoxy, polyimide, polyester, urethane, acrylic, polycarbonate, urea, melanin, chlorinated rubber , Polyvinyl alcohol, polyvinyl ester, vinylidene fluoride-hexafluoropropylene copolymer (PVDF-co-HFP), polyvinylidenefluoride (PVDF), polyacrylonitrile, polymethylmeth Crylate (polymethylmethacrylate), polytetrafluoroethylene (PTFE), styrenebutadiene rubber (SBR), ethylene-propylene-diene copolymer (EPDM), and polydimethlysiloxane (PDMS) ) It may include at least one selected from the group consisting of.

In an embodiment, in the manufacturing of the first polymer array mold, a plurality of the first polymer array molds are manufactured, and the plurality of first polymer array molds are connected to each other to be larger than the first polymer array mold. It may further include manufacturing a first polymer array mold having a large area.

In one embodiment, a plurality of the first polymer array molds 220 may be manufactured, and the plurality of first polymer array molds 220 may be bonded to each other to manufacture a first polymer array mold having a large area.

In one embodiment, the manufacturing step of the polymer microneedle patch array illustrated in FIG. 7C may be to manufacture the polymer microneedle patch array 220a by double casting the first polymer array mold 220. have. The polymer of the polymer microneedle patch array 220a may be the same as or different from the polymer used to manufacture the first polymer array mold 220.

In one embodiment, the manufacturing step of the mold mother mold shown in FIG. 7D may be to manufacture the mold mother mold 230 by plating a metal 230a on the polymer array mold 220. The mold mother mold 230 may be manufactured by a metal growth process as well as electroplating.

In one embodiment, the metal 230a may include, for example, at least one selected from the group consisting of nickel, iron, copper, silver, gold, and zinc tin-lead alloys.

9 is a view showing a step of performing a physical surface treatment on the surface of the mold mother mold according to an embodiment of the present invention. Referring to FIG. 9, it may be to perform surface treatment on the mold mother mold 230 using an electron beam. Surface treatment with an electron beam improves surface roughness, shape reproducibility, and ease of molding. In addition, by improving the flatness of the surface, the surface friction is reduced, so that the shape of the mold is uniform, and the polymer mold is easily separated, thereby increasing the usability.

In one embodiment, the second polymer array mold manufacturing step shown in (e) of FIG. 7 is a second polymer array mold by filling and curing a polymer in the mold mother mold 230 and separating the cured polymer. It may be to manufacture (240). The polymer of the second polymer array mold 240 may be the same as or different from the polymer used to manufacture the first polymer array mold 220 or the polymer microneedle patch array 220a.

In one embodiment, in the step of separating the microneedle patch shown in FIG. 7(f), after injection-molding the patch material into the second polymer array mold 240, the microneedle patch is removed from the second polymer array mold 240. It may be to separate the microneedle patch 250 including the needle structure.

In one embodiment, the patch material may be used according to the purpose. When injecting by coating a drug on the surface, a hard material such as a polymer can be used when it is hardened, and a biomaterial with relatively low hardness when a material mixed with the drug is used, such as an ECM mixture Or you can use biocompatible materials

In one embodiment, the patch material may include a biodegradable polymer, an extracellular matrix (ECM) composite, or both. Each specific material is as described in FIG. 1.

In one embodiment, the patch material may be cured by at least one selected from the group consisting of heat, radiation, electricity, pressure, and UV. Accordingly, a step of curing by thermal curing, irradiation of radiation, electric shock, pressure, and UV irradiation may be performed during the curing process according to the kind of the patch material.

In one embodiment, in step (f) of FIG. 7, since the second polymer array mold 240 is made of a hard material, force is applied to one of the second polymer array mold 240 or the microneedle patch 250. , The microneedle patch 250 is pulled out or the second polymer array mold 240 is pulled out. This may be, for example, a method used to manufacture a bell tower microneedle patch or to manufacture an arrow nose-shaped or arrowhead end microneedle with a soft material.

10 is a diagram showing another embodiment of step (f) of FIG. 7. Referring to FIG. 10, the second polymer array mold 240a may be manufactured using a disposable biomaterial. The disposable biomaterial may be melted in heat or chemicals, and the second polymer array mold 240a may melt the second polymer array mold 240a while leaving the microneedle patch 250 intact.

Another aspect of the present invention provides a microneedle patch manufactured by the method of manufacturing a microneedle patch according to the above.

The present invention is characterized in that by adjusting the height of the microneedle structure formed on the microneedle patch, the drug tip formed at the end of the microneedle structure can be introduced into the desired skin tissue. In general, the skin is formed from the surface of the stratum corneum, epidermal layer, dermal layer, subcutaneous fat layer, and muscle layer. For example, when a drug tip is to be injected into the epidermal layer, the height of the microneedle structure may be set to a height of less than 50 μm. In addition, when the drug tip is to be incorporated into the dermal layer, the height of the microneedle structure may be set in the range of 0.010 mm to 3.0 mm in correspondence with the height of the epidermal layer.

The microneedle patch of the present invention may have a large area so that the microneedle has a high aspect ratio and can be attached to a wide surface of pain such as a joint, a shoulder, and a waist. In addition, since the penetration of the skin is improved, it is easy to enter into the skin, and even after entering, it is difficult to fall out, and a large-area microneedle patch can be manufactured.

Another aspect of the present invention provides a drug delivery system including the microneedle patch according to the above. In one embodiment, the material may include at least one selected from the group consisting of drugs, nanoparticles, molecules, genomes, proteins, microorganisms, and cells.

The material delivery system of the present invention effectively injects a chemical (drug) into the skin by a microneedle patch, and nanoparticles (or including a form in which ligand and antibody are bound), molecules, genomes (DNA, RNA), proteins, It is possible to deliver the chemical to be delivered in an accurate quantity to a desired place in the body such as microorganisms and cells (stem cells).

Hereinafter, the present invention will be described in detail with reference to the following Examples and Comparative Examples. However, the technical idea of the present invention is not limited or limited thereby.

[Example]

1.silicone mother mold

In order to manufacture a large area array, a large area silicon array wafer having a single needle design was manufactured by combining two wafers each patterned. A wafer having an intaglio mold was prepared in a 190 µm square-pyramidal array through wet etching using KOH. As for the wafer having through holes corresponding to the square pyramid shape, a square hole array having a height of 410 μm passing through the wafer through dry etching using deep RIE was manufactured.

Then, two wafers were prepared in one array mold through epoxy chemical bonding (active area: 100 mm × 100 mm in 6 inch wafer). The size of the microneedle was 600 ± 7 μm in height, and the pitch was 900 μm.

The core technology for manufacturing high-aspect ratio ultra-precision microneedles is a technology that makes the pattern high, and the two wafer bonding process does not require any additional processes for height adjustment, and difficult process optimization is not required. It was completed with a shape precision within 2.5 nm (2.3 ± 0.2 nm) using an ion etching technique. The microneedle size tolerance was within 2.0%. Finally, a mother mold was manufactured so that the shape of the microneedle became an arrowhead when viewed from the side.

2. First Polymer Array Mold

A polymer mold of a mold array for patch fabrication was manufactured in a size of 100 x 100 mm using a 6 inch wafer.

3. Nickel electroplating

A nickel mold was manufactured by performing large-area nickel electroplating on the first polymer array mold.

4. Mold Mother Mold

A mold array mold was prepared for manufacturing a polymer mold of a large area patch. For surface chemical cleaning, PDMS developer, acetone, MeOH, and IPA were used. The manufactured mold mold can be used semi-permanently and can be transformed, so it can be mass-produced through processes such as injection.

5. Surface treatment of e-beam

Electron beam surface treatment was performed to improve surface roughness, shape reproducibility, and ease of molding. By improving the flatness of the surface, the friction of the surface is reduced, so that the shape of the mold is uniform, and the polymer mold falls well. The surface shape tolerance was 2.6±0.2 nm as a result of AFM measurement.

6. Second Polymer Array Mold

As a mold for microneedle patch, a second polymer array mold was manufactured. Through the mold mold, it was possible to mass-produce the polymer array mold for microneedle patch in a short time.

11 is a micrograph of a second polymer array mold according to an embodiment of the present invention. In the second polymer array mold, the shape of the microneedle structure is seen as a relief.

7. Microneedle Patch Array

Different processes were designed according to the kind of patch material. In Step 1, when the patch is a sufficiently hard material (for synthetic polymer or drug coating), it was manufactured using a polymer mold (patch removal after fixing the mold). In step 2, when the material of the patch is a biomaterial, when there is a limitation in removing it from the mold due to weak mechanical properties, a patch was manufactured using a disposable degradable synthetic mold (remove the mold after fixing the patch).

12 is a micrograph of a microneedle patch array according to an embodiment of the present invention. In the microneedle patch array, the structure of the microneedle appears to be intaglio.

A large-area microneedle patch was manufactured in the shape of a square pyramid at the end of an arrowhead with a design optimized for the patch mold manufacturing process using two wafer bonding techniques. 13 is a diagram showing one structure of a microneedle patch according to an embodiment of the present invention ((a) design design, (b) SEM image). 13B is an SEM image of a final microneedle patch made of a hydrogel composite.

As described above, although the embodiments have been described by the limited drawings, a person of ordinary skill in the art can apply various technical modifications and variations based on the above. For example, even if the described techniques are performed in a different order from the described method, and/or the described components are combined or combined in a form different from the described method, or are replaced or substituted by other components or equivalents. Appropriate results can be achieved.

Therefore, other implementations, other embodiments and claims and equivalents fall within the scope of the following claims.

110, 210: mother mold
110a, 210a: first substrate
110b, 210b: second substrate
112, 212: intaglio mold
114, 214: through hole
120, 220: first polymer array mold
130, 230: mold mother mold
130a, 230a: metal
140, 240, 240a: second polymer array mold
140a, 140b, 220a: microneedle patch array
150, 250: microneedle patch

Claims (22)

Manufacturing a mother mold;
Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold;
Plating the first polymer array mold to manufacture a mold;
Manufacturing a mold mother mold by removing the first polymer array mold from the mold mold;
Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold;
Manufacturing a microneedle patch array by double casting the second polymer array mold; And
Separating a microneedle patch including a microneedle structure from the microneedle patch array after injection-molding a patch material on the microneedle patch array;
Including,
The step of manufacturing the mother mold,
Providing a first substrate having an intaglio mold and a second substrate having a through hole corresponding to the intaglio mold; And
Bonding the first substrate and the second substrate;
Including,
The size of the intaglio mold of the first substrate and the size of the through hole of the second substrate are the same, or the size of the intaglio mold is greater than the size of the through hole,
The step of manufacturing the first polymer array mold,
Further comprising manufacturing a plurality of the first polymer array molds and bonding the plurality of first polymer array molds to each other to manufacture a first polymer array mold having a larger area than the first polymer array mold,
The microneedle structure includes a bell tower type, an arrow type, or both,
The arrow shape includes an arrow nose shape or an arrowhead end,
The aspect ratio of the microneedle structure is 2.55 to 30,
Method of manufacturing a microneedle patch.
Manufacturing a mother mold;
Filling and curing the mother mold and then separating the cured polymer to prepare a first polymer array mold;
Manufacturing a polymer microneedle patch array by double casting the first polymer array mold;
Plating the polymer microneedle patch array to manufacture a mold mother mold;
Filling and curing a polymer in the mold mother mold and separating the cured polymer to prepare a second polymer array mold; And
Separating a microneedle patch including a microneedle structure from the second polymer array mold after injection-molding a patch material on the second polymer array mold;
Including,
The step of manufacturing the mother mold,
Providing a first substrate having an intaglio mold and a second substrate having a through hole corresponding to the intaglio mold; And
Bonding the first substrate and the second substrate;
Including,
The size of the intaglio mold of the first substrate and the size of the through hole of the second substrate are the same, or the size of the intaglio mold is greater than the size of the through hole,
The step of manufacturing the first polymer array mold,
Further comprising manufacturing a plurality of the first polymer array molds and bonding the plurality of first polymer array molds to each other to manufacture a first polymer array mold having a larger area than the first polymer array mold,
The microneedle structure includes a bell tower type, an arrow type, or both,
The arrow shape includes an arrow nose shape or an arrowhead end,
The aspect ratio of the microneedle structure is 2.55 to 30,
Method of manufacturing a microneedle patch.
delete The method according to claim 1 or 2,
The intaglio template of the first substrate is prepared by a wet etching method using at least one solution selected from the group consisting of acids, bases and organic solvents.
Method of manufacturing a microneedle patch.
The method according to claim 1 or 2,
The through-hole of the second substrate is at least one dry etching method selected from the group consisting of reactive ion etching (RIE), inductively coupled plasma (ICP), and ion milling. Which is manufactured with,
Method of manufacturing a microneedle patch.
The method according to claim 1 or 2,
The first substrate and the second substrate is a silicon wafer,
Method of manufacturing a microneedle patch.
The method according to claim 1 or 2,
The thickness of the first substrate and the second substrate is, respectively, 100 ㎛ to 1000 ㎛,
Method of manufacturing a microneedle patch.
delete delete The method according to claim 1 or 2,
After the step of manufacturing the mold mother mold,
Including the step of performing physical surface treatment on the surface of the mold mother mold,
The physical surface treatment includes at least one selected from the group consisting of electron beam, plasma, corona discharge, and ultraviolet rays,
Method of manufacturing a microneedle patch.
The method according to claim 1 or 2,
The microneedle structure is a conical shape, a pyramid shape, or including both,
Method of manufacturing a microneedle patch.
delete The method according to claim 1 or 2,
The cross-sectional dimension of the microneedle structure is 10 nm to 300 μm, and the height is 100 μm to 1000 μm,
Method of manufacturing a microneedle patch.
delete The method according to claim 1 or 2,
The polymer is polyethylene, polypropylene, polyvinyl chloride resin, polyethylene terephthalate (PET), nylon, epoxy, polyimide, polyester, urethane, acrylic, polycarbonate, urea, melanin, chlorinated rubber, polyvinyl alcohol, poly Vinyl ester, vinylidene fluoride-hexafluoropropylene copolymer (PVDF-co-HFP), polyvinylidenefluoride (PVDF), polyacrylonitrile, polymethylmethacrylate, Selected from the group consisting of polytetrafluoroethylene (PTFE), styrene butadiene rubber (SBR), ethylene-propylene-diene copolymer (EPDM), and polydimethlysiloxane (PDMS) That includes at least any one of,
Method of manufacturing a microneedle patch.
The method according to claim 1 or 2,
The patch material is a biodegradable polymer, an extracellular matrix (ECM) composite or both,
Method of manufacturing a microneedle patch.
The method of claim 16,
The biodegradable polymers are HA (Hyaluronic Acid), PLA (Poly Lactic Acid), Polyhydroxyalkanoate (PHA), Polyesteramide (PEA), PPDO (poly(p-dioxanone))), PLGA (Poly Lactic-Co-Glycolic Acid), At least one selected from the group consisting of PGA (Polyglycolide Acid), PCL (polycaprolactone), PEG (Poly Ethylene Glycol), PEGDA (Poly Ethylene Glycol Diacrylate), PEGMEA (Poly Ethylene Glycol Methyl Ether Acrylate) and COC (Cyclic Olefin Copolymer) Containing one,
Method of manufacturing a microneedle patch.
The method of claim 16,
The extracellular matrix (ECM) composite is collagen (type I to V), proteoglycan, glycosaminoglycan (GAG), glycoprotein, cytokine, cell-surface related protein, cell adhesion molecule (CAM), Endothelial ligand, matrikine, cadherin, immunoglobulin, fibrillar collagen, non-fibrous collagen, basement membrane collagen, multiplexin, bovine-leucine-rich proteoglycan, decorin, biglycan, Fibromodulin, Keratocan, Lumican, Epican, Heparin Sulfate Proteoglycan, Perlecan, Agrin, Testican, Syndecan, Glypican, Serglycine, Selectin, Retican, Agrecan, Versican, Neurocan, brevican, cytoplasmic domain-44 (CD-44), macrophage stimulating factor, amyloid precursor protein, heparin, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparin sulfate, hyaluronic acid, fibronectin, tenaskin, At least any selected from the group consisting of elastin, fibrillin, laminin, nidogen/enactin, fibulin I, fibulin II, integrin, permeable membrane molecule, thrombospondin, osteopontin, and angiotensin converting enzyme (ACE) Containing one,
Method of manufacturing a microneedle patch.
The method according to claim 1 or 2,
The patch material is cured by at least one selected from the group consisting of heat, radiation, electricity, pressure and UV,
Method of manufacturing a microneedle patch.
A microneedle patch manufactured by the method of manufacturing a microneedle patch according to claim 1 or 2.
A mass delivery system comprising the microneedle patch of claim 20.
The method of claim 21,
The material is one comprising at least one selected from the group consisting of drugs, nanoparticles, molecules, genomes, proteins, microorganisms, and cells,
Mass transfer system.

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