KR102491166B1 - Method of forming micro pattern using capillary force and electrostatic force and micro needle including the micro pattern - Google Patents

Abstract

The present application includes the steps of applying a polymer compound resist on a substrate; contacting the polymer compound resist with a template having a micro pattern structure to form a lower structure of the micro pattern on the polymer compound resist; forming an upper structure of the fine pattern on the lower structure of the fine pattern by applying a voltage to the substrate; and curing the polymer compound resist.

Description

Method for forming micropatterns using capillary force and electrostatic force, and microneedles including micropatterns

The present disclosure relates to a method for forming a micropattern using capillary force and electrostatic force, and a microneedle including the micropattern.

In the effect of pharmaceuticals, it is very important not only the effect of the drug itself but also the characteristics of the dosage form and which route of administration to use. Most pharmaceuticals are administered using the oral administration route, but the oral administration route has a disadvantage in that drug efficacy may be reduced when the first pass effect in the liver and gastrointestinal motility are reduced.

If absorption in the gastrointestinal tract is not possible, the drug is administered using an injection formulation. However, injection formulations must be administered by a skilled medical staff with administration skills, are painful, and are economically expensive. In addition, there is a possibility that glass fragments or rubber stopper fragments may be mixed when opening the ampoule or vial. Due to the disadvantages of these oral administration routes and injection formulations, various drug delivery systems through new routes of administration have been studied.

Among them, the method using a microneedle can pierce the epidermal layer of the skin without pain, and can deliver a drug that is difficult to deliver through an oral administration route because the drug is administered through the skin. In addition, it is a transdermal drug delivery system (TDDS, Transdermal Drug Delivery System) that can initiate action more quickly by facilitating the absorption of drugs into the bloodstream and has the advantage of being able to self-administer.

So far, transdermal drug delivery systems have been used for treatments such as arthritis, vaccines, osteoporosis, immune skin diseases, and insulin patches, and anti-cancer drugs and patches for special diseases are also being developed. Fabrication of microneedles is important.

Conventional microneedle manufacturing methods have problems such as unfilling, bubble formation, and deformation during drying in the process of manufacturing the height of 250 μm to 1,000 μm required for transdermal drug delivery. Therefore, there is a limit to manufacturing a microneedle having an optimized height and having an appropriate aspect ratio that effectively delivers drugs and is painless.

In the case of DEN (Droplet Extension) technology of Raphas, a leading microneedle company in Korea, a drug is dropped in the form of a droplet and the drug is stretched like a stick using the viscosity of the drug to form a microneedle. This process can be manufactured in 5 minutes without a heating process and has the advantage that little loss or transformation of active ingredients occurs. there is.

In the case of microneedles manufactured by the tensile method or the tensile blowing method, if a high molecular weight polymer material of 1,000 kDa to 2,500 kDa is used, it is impossible to prepare a viscous solution, and if a polymer material with a low molecular weight of 500 Da to 50 kDa is used, it is biodegradable. It is difficult to form the structure of the magnetic microneedles, and there are problems in that the strength is weakened. In addition, in the drawing process using the tensile method, the microneedle is affected by the tensile force depending on the temperature and humidity, and the shape is not uniform when obtaining the microneedle, and the reproducibility is poor because of the limitation that the viscosity must be adjusted accordingly when the material is changed.

In addition, water-soluble microneedles have difficulty in filling the mold with the drug due to their water-soluble nature, and air-pockets generated during the solidification process degrade the quality of the microneedle patch.

Conventional molding techniques are manufactured by putting a solution of a drug or cosmetic ingredient in a microneedle mold and pressurizing it at 70 kPa or less, and there is a limitation in that microneedles must be pulled out one by one from the mold. In addition, in the case of a drying process for solidifying the microneedles, a complicated drying process such as heat drying and a solidification process by blowing is required, resulting in a decrease in productivity.

In addition, in the process of filling the mold with the solution and drying it with heat, the active ingredient of the drug is lost, and in the process of drying the filling solution filled in the mold with heat, the shrinkage of the filling solution occurs, so that the microneedle structure is not perfectly formed. A problem arises.

In order to apply the various functions of microneedles, it is necessary to develop a microneedle patch over a large area. In the case of a solid microneedle, after applying a drug to the skin, a roller-type microneedle can be used to penetrate the substance subcutaneously over a large area. In the case of , there is a limit to large-area production due to the uniformity of the large-area mold fabrication and the microneedle structure formed, and the formation of air pockets limits the fabrication of large-area uniform microneedles.

In addition, existing microneedles are manufactured on a flat plate and are limited in complex structures, and microneedles produced by drawing lithography have difficulty in large-area production because the process is complicated and time-consuming to transfer onto a desired patch.

Therefore, it is required to develop a method for manufacturing a microneedle having an aspect ratio required for transdermal drug delivery, and having high reproducibility and productivity, and a microneedle that can be manufactured in a large area without losing active ingredients of the drug during the production process. A manufacturing method is required.

Korean Patent Publication No. 10-2020-0079376 is a patent on a microneedle and a manufacturing method thereof. The patent describes a method of manufacturing microneedles using a mold, but does not specify a process of forming a microneedle tip by filling air pockets formed on the top of a pattern with resist using electrostatic force.

The present invention is intended to solve the above-mentioned problems of the prior art, and unlike conventional methods in which there was difficulty in forming the upper structure of the fine pattern due to the formation of the air pocket in the process of forming the fine pattern, the air pocket It is an object of the present invention to provide a method for forming a micropattern in which an upper structure of the micropattern is formed by filling a resist of a polymer compound with an electrostatic force.

In addition, it is an object of the present invention to provide microneedles manufactured by the method for forming a micropattern.

In addition, an object of the present invention is to provide a drug delivery system including the microneedle.

As a technical means for achieving the above technical problem, the first aspect of the present application is a step of applying a polymer compound resist on a substrate; contacting the polymer compound resist with a template having a micro pattern structure to form a lower structure of the micro pattern on the polymer compound resist; forming an upper structure of the fine pattern on the lower structure of the fine pattern by applying a voltage to the substrate; and curing the polymer compound resist.

According to one embodiment of the present application, in the step of forming the lower structure of the micropattern, an air pocket is formed on the lower structure, and the air pocket is filled with the polymer compound resist by applying the voltage, thereby forming an upper portion of the micropattern. It may include forming a structure, but is not limited thereto.

According to one embodiment of the present application, the step of forming the lower structure of the micropattern may include forming the lower structure by sucking the resist into the micropattern structure by capillary force, but is limited thereto not.

According to one embodiment of the present application, the voltage may include, but is not limited to, 1.0 kV or more and 3.0 kV or less.

According to one embodiment of the present application, it may include an insulating layer disposed on the substrate, but is not limited thereto.

According to one embodiment of the present application, an electrode for applying a voltage may be disposed on a mold having the fine pattern structure, but is not limited thereto.

According to one embodiment of the present application, the step of removing the template having the fine pattern structure may be further included, but is not limited thereto.

According to one embodiment of the present application, the template having the fine pattern structure is polydimethylsiloxane (PDMS), polyethylene, polypropylene, polyvinyl chloride resin, polyethylene terephthalate (PET), nylon, epoxy, polyimide, poly Ester, urethane, acrylic, polycarbonate, urea, melanin, chlorinated rubber, polyvinyl alcohol, polyvinyl ester, vinylidenefluoride-hexafluoropropylene copolymer (PVDF-co-HFP), polyvinylidenefluoride : PVDF), polyacrylonitrile, polymethylmethacrylate, polytetrafluoroethylene (PTFE), styrenebutadiene rubber (SBR) or ethylene-propylene copolymer -diene copolymer: EPDM), but is not limited thereto.

According to one embodiment of the present application, the fine pattern structure may include a pattern selected from a pyramid, prism, tetrahedron, hemisphere, aspherical surface, and combinations thereof, but is not limited thereto.

According to one embodiment of the present application, the polymer compound resist may include a thermoplastic polymer, but is not limited thereto.

According to one embodiment of the present application, the thermoplastic polymer is polystyrene (PS), ABS resin (acrylonitrile butadiene-styrene), polyoxymethylene (POM), polymethyl methacrylate (PMMA), cellulose acetate (CA), polytetra Fluoroethylene (PTFE), polychlorotrifluoroethylene (PCTEF), polyvinyl fluoride (PVF), polyvinylidene fluoride (PVDF), polymethylpentene (PMP), polyamide (PA), polycarbonate (PC) , polyethylene (PE), polyethylene terephthalate (PET), polyimide (PI), polyphenylene oxide (PPO), polypropylene (PP), polysulfone (PSul), polyvinylidene chloride (PVDC), polyvinyl chloride (PVC), and may include those selected from the group consisting of combinations thereof, but are not limited thereto.

According to one embodiment of the present application, the polymer compound resist may include a water-soluble polymer, but is not limited thereto.

According to one embodiment of the present application, the water-soluble polymer is carboxymethyl cellulose, hyaluronic acid, chondroitin sulfate, glycogen, dextrin, dextran, Dextran sulfate, hydroxypropyl methylcellulose, alginic acid, chitin, chitosan, pullulan, collagen, gelatin and It may include those selected from the group consisting of hydrolysates thereof, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, and combinations thereof, but are limited thereto It is not.

According to one embodiment of the present application, the curing of the polymer compound resist may include, but is not limited to, simple cooling or lyophilization.

In addition, a second aspect of the present disclosure provides a microneedle including a micropattern manufactured according to the first aspect.

In addition, a third aspect of the present application provides a drug delivery system comprising the microneedle according to the second aspect.

The above-described problem solving means are merely exemplary and should not be construed as intended to limit the present disclosure. In addition to the exemplary embodiments described above, additional embodiments may exist in the drawings and detailed description of the invention.

The conventional method of manufacturing microneedles is manufactured by putting a drug or cosmetic ingredient solution into a microneedle mold and pressurizing it, and has a disadvantage in that microneedles must be pulled out from the mold one by one.

In addition, in the drawing process using the tensile method, microneedles have poor reproducibility due to the influence of tensile force according to temperature and humidity, the non-uniformity of the shape when microneedles are obtained, and the need to adjust the viscosity according to the material used.

In addition, in the drying process of solidifying the microneedles, a complicated drying process such as heat drying and solidification process by blowing is required, resulting in a decrease in productivity.

In the method of forming a micropattern according to the present disclosure, a micropattern structure up to several nanometers may be formed by using capillary force generated simultaneously with contact between a resist and a mold. However, according to Bernoulli's principle, as the resist rises from the bottom to the top of the micro-pattern structure, the volume decreases and the pressure increases, so air pockets may be formed, which may be a problem in forming a micro-pattern structure having a high aspect ratio.

In order to solve this problem, the method of forming a fine pattern according to the present invention forms a fine pattern structure with a height of several hundred μm by filling air pockets formed on the top of the fine pattern with a resist by electrostatic force generated by a high voltage, thereby forming a fine pattern structure having a high aspect ratio. A fine pattern structure can be formed.

In addition, despite the use of chemical components sensitive to temperature and humidity, the influence of a high-voltage magnetic field dominates, making it easy to form fine patterns, ensuring reproducibility of microneedles, and controlling external factors occurring during the process. It has the advantage of reducing costs.

In addition, the higher the viscosity of the drug, the more difficult it is to form a fine pattern. However, it is possible to form a fine pattern having a high aspect ratio by increasing the voltage to offset the cohesive force and attracting the material.

In addition, the yield is high through a relatively simple process, the mold made of polydimethylsiloxane (PDMS) can be recycled, and there are advantages in that shape change does not easily occur even in repeated production.

In the conventional method of forming micropatterns, the active ingredient of the drug is lost in the process of solidifying by filling the mold with a solution and drying it with heat, and shrinkage of the filling solution occurs, so that the microneedle structure is not perfectly formed. Occurs.

According to the solution to the above problem of the present application, a pattern with a pattern shrinkage of less than 10% can be produced by adopting a freeze-drying method to compensate for the change in the active ingredient of the drug and the deformation of the microneedle structure, which are disadvantages of heat drying and blow drying. there is.

In addition, when dried using freeze-drying and then separated from the mold, the yield is high because there are no defects and loss due to heat during manufacture.

In addition, freeze-drying has the advantage of minimizing deformation by selectively removing moisture while maintaining the internal microfiber matrix as it is, and manufacturing drugs and skin care agents that have not been used because they are sensitive to heat with microneedles.

In addition, when the rapid cooling is performed, the water molecules in the solution expand less and the molecular structure is less affected, and the change in the outer shape of the microneedle and the formation of internal pores are prevented.

In addition, according to the solution to the above-described problem, a large-area mold having a fine pattern of 5 cm × 5 cm to 30 cm × 30 cm can be made using polydimethylsiloxane (PDMS). The electrode substrate can be formed in a large area of a desired size, and a uniform microneedle pattern can be formed because a high voltage electric field can be applied uniformly over the entire area of the electrode plate. In addition, the structure can be formed on the patch on which the microneedles will be placed, and it can also be fabricated on the flexible patch.

In addition, it is possible to manufacture outside of a clean room, so it is not limited by space, and after manufacturing a mold of the desired shape such as a screw or sphere, insert a filler and apply a high voltage electric field for 5 to 10 minutes. A microneedle having a desired shape can be obtained.

However, the effects obtainable herein are not limited to the effects described above, and other effects may exist.

1 is a flowchart illustrating a process of forming a micro-pattern structure according to an exemplary embodiment of the present disclosure.
Figure 2 (a) is a simplified flow chart of a process of forming a micro-pattern structure according to an embodiment of the present application, and Figure 2 (b) is a detailed flow chart of a process of forming a micro-pattern structure according to an embodiment of the present application It is a flow chart.
3 is a flowchart of a process of manufacturing a mold having a fine pattern structure according to an embodiment of the present disclosure and an actual image of the mold.
Figure 4 (A) is a flow chart of a process of forming a micro-pattern structure with a resist made of a thermoplastic polymer according to an embodiment of the present application, and Figure 4 (B) is an actual image of the formed micro-pattern.
Figure 5 (A) is a flow chart of a process of forming a micro-pattern structure with a resist made of a water-soluble polymer according to an embodiment of the present application, and Figure 5 (B) is an actual image of the formed micro-pattern.
6 is an image of a lower structure of a micropattern formed by capillary force and an upper structure of a micropattern formed by electrostatic force according to an experimental example of the present application.
7 is a scanning electron microscope image of a micro-pattern structure over time after freeze-drying according to an experimental example of the present application.
8(A) is an image of a micropattern structure when micropattern formation is performed without water treatment according to a comparative example of the present application, and FIG. 8(B) is an image of an optimized structure according to an embodiment of the present application. This is an image of the micropattern structure when the reaction proceeds under the conditions.

Hereinafter, embodiments of the present application will be described in detail so that those skilled in the art can easily practice with reference to the accompanying drawings.

However, the present disclosure may be implemented in many different forms and is not limited to the embodiments described herein. And in order to clearly describe the present application in the drawings, parts irrelevant to the description are omitted, and similar reference numerals are attached to similar parts throughout the specification.

Throughout this specification, when a part is said to be "connected" to another part, this includes not only the case of being "directly connected" but also the case of being "electrically connected" with another element in between. do.

Throughout the present specification, when a member is referred to as being “on,” “above,” “on top of,” “below,” “below,” or “below” another member, this means that a member is located in relation to another member. This includes not only the case of contact but also the case of another member between the two members.

Throughout the present specification, when a certain component is said to "include", it means that it may further include other components without excluding other components unless otherwise stated.

As used herein, the terms "about," "substantially," and the like are used at or approximating that number when manufacturing and material tolerances inherent in the stated meaning are given, and are intended to assist in the understanding of this disclosure. Accurate or absolute figures are used to prevent undue exploitation by unscrupulous infringers of the stated disclosure. In addition, throughout the present specification, “steps of” or “steps of” do not mean “steps for”.

Throughout the present specification, the term "combination thereof" included in the expression of the Markush form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the Markush form, and the components It means including one or more selected from the group consisting of.

Throughout this specification, reference to "A and/or B" means "A or B, or A and B".

Hereinafter, a method of forming a micropattern using capillary force and electrostatic force of the present application, a microneedle including the micropattern, and a drug delivery system including the microneedle will be described in detail with reference to embodiments, examples, and drawings. do. However, the present application is not limited to these embodiments and examples and drawings.

As a technical means for achieving the above technical problem, the first aspect of the present application is a step of applying a polymer compound resist on a substrate; contacting the polymer compound resist with a template having a micro pattern structure to form a lower structure of the micro pattern on the polymer compound resist; forming an upper structure of the fine pattern on the lower structure of the fine pattern by applying a voltage to the substrate; and curing the polymer compound resist.

Hereinafter, a method of forming a fine pattern according to the present disclosure will be described with reference to FIGS. 1 and 2 .

1 is a flowchart illustrating a process of forming a micro-pattern structure according to an exemplary embodiment of the present disclosure.

Figure 2 (a) is a simplified flow chart of a process of forming a micro-pattern structure according to an embodiment of the present application, and Figure 2 (b) is a detailed flow chart of a process of forming a micro-pattern structure according to an embodiment of the present application It is a flow chart.

First, the polymer compound resist 200 is applied on the substrate 100 (S100).

The substrate 100 may be, for example, silicon.

According to one embodiment of the present application, the polymer compound resist 200 may include a thermoplastic polymer, but is not limited thereto.

According to one embodiment of the present application, the thermoplastic polymer is polystyrene (PS), ABS resin (acrylonitrile butadiene-styrene), polyoxymethylene (POM), polymethyl methacrylate (PMMA), cellulose acetate (CA), polytetra Fluoroethylene (PTFE), polychlorotrifluoroethylene (PCTEF), polyvinyl fluoride (PVF), polyvinylidene fluoride (PVDF), polymethylpentene (PMP), polyamide (PA), polycarbonate (PC) , polyethylene (PE), polyethylene terephthalate (PET), polyimide (PI), polyphenylene oxide (PPO), polypropylene (PP), polysulfone (PSul), polyvinylidene chloride (PVDC), polyvinyl chloride (PVC), and may include those selected from the group consisting of combinations thereof, but are not limited thereto.

When the polymeric compound resist 200 is a thermoplastic polymer, the surface of the resist 200 is heated above the glass transition temperature of the thermoplastic polymer to make the resist 200 into a liquid phase, and then fine patterns can be fabricated.

According to one embodiment of the present application, the polymer compound resist 200 may include a water-soluble polymer, but is not limited thereto.

According to one embodiment of the present application, the water-soluble polymer is carboxymethyl cellulose, hyaluronic acid, chondroitin sulfate, glycogen, dextrin, dextran, Dextran sulfate, hydroxypropyl methylcellulose, alginic acid, chitin, chitosan, pullulan, collagen, gelatin and It may include those selected from the group consisting of hydrolysates thereof, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, and combinations thereof, but are limited thereto It is not.

When the polymer compound resist 200 is a water-soluble polymer, heat treatment is performed to evaporate moisture to harden the resist 200, and then a certain amount of water is sprayed on the surface of the resist 200 to make only the surface portion in a liquid phase. After that, fine patterns can be produced.

Next, the polymer compound resist 200 is brought into contact with the mold 300 having a micro-pattern structure to form the micro-pattern lower structure 210 on the polymer compound resist 200 (S200).

According to one embodiment of the present application, the fine pattern structure may include a pattern selected from a pyramid, prism, tetrahedron, hemisphere, aspherical surface, and combinations thereof, but is not limited thereto.

According to one embodiment of the present application, the template 300 having the fine pattern structure is polydimethylsiloxane (PDMS), polyethylene, polypropylene, polyvinyl chloride resin, polyethylene terephthalate (PET), nylon, epoxy, poly Mead, polyester, urethane, acrylic, polycarbonate, urea, melanin, chlorinated rubber, polyvinyl alcohol, polyvinyl ester, vinylidene fluoride-hexafluoropropylene copolymer (PVDF-co-HFP), polyvinylidene fluoro polyvinylidenefluoride (PVDF), polyacrylonitrile, polymethylmethacrylate, polytetrafluoroethylene (PTFE), styrenebutadiene rubber (SBR) or ethylenepropylenediene copolymer ( ethylene-propylene-diene copolymer: EPDM), but is not limited thereto.

According to one embodiment of the present application, the forming of the lower structure 210 of the fine pattern may include forming the lower structure 210 by sucking the resist 200 into the fine pattern structure by capillary force. It may include, but is not limited thereto.

Capillary force refers to a phenomenon in which a liquid climbs a narrow tube without external help such as gravity. This is caused by the surface tension of the liquid and the adsorption force between the liquid and the solid when the diameter of the capillary is sufficiently small.

When the mold 300 having a micro-pattern structure and the polymer compound resist 200 applied on the substrate 100 come into contact, the polymer compound resist 200 is sucked into the micro-pattern structure by capillary force, and the bottom of the micro-pattern Structure 210 is formed.

In addition, according to Bernoulli's principle, as the polymer compound resist 200 rises from the bottom to the top of the micropattern structure, the volume decreases and the pressure increases, so air pockets 220 may be formed.

Therefore, only the lower structure 210 of the pyramidal micropattern is formed by the capillary force, and the upper structure 230 of the micropattern is not yet formed.

Subsequently, a voltage is applied to the substrate 100 to form an upper structure 230 of the fine pattern on the lower structure 210 of the fine pattern (S300).

According to one embodiment of the present application, in the step of forming the lower structure 210 of the fine pattern, an air pocket 220 is formed on the lower structure 210, and the air pocket 220 is formed by applying the voltage. The upper structure 230 of the fine pattern may be formed by filling the polymer compound resist 200, but is not limited thereto.

According to one embodiment of the present application, the electrode 310 for applying a voltage may be disposed on the mold 300 having the fine pattern structure, but is not limited thereto.

According to one embodiment of the present application, the voltage may include, but is not limited to, 1.0 kV or more and 3.0 kV or less.

Since the substrate 100 and the electrode 310 are connected and a high voltage of 1.0 kV or more and 3.0 kV or less is applied, an arc discharge can easily occur. An arc discharge is a discharge in which a potential difference is generated between electrodes and the electrodes are heated to emit hot electrons and emit intense light.

In order to prevent arc discharge from occurring, an insulating layer 110 may be additionally disposed on the substrate 100, but is not limited thereto. The insulating layer 110 may have a thickness of, for example, 3 mm or less.

When a voltage is applied to the substrate 100 and the electrode 310, the surface of the mold 300 having a fine pattern is charged, and the charge of the resist 200 moves due to the potential difference, and the air pocket 220 is filled with the resist 200 to form an upper structure 230 of fine patterns.

Through this method, for example, a pyramid-shaped fine pattern can be formed.

Conventional methods of forming micropatterns have limitations in forming micropattern structures having a high aspect ratio by forming air pockets on top of the pattern structures. However, since the method of forming a fine pattern according to the present disclosure fills formed air pockets with a resist using electrostatic force, it is possible to form a fine pattern structure having a high aspect ratio. Specifically, a fine pattern structure having a length of 200 μm in width and 250 μm in length and an aspect ratio reaching 1.25 may be formed, but is not limited thereto.

Subsequently, the polymer compound resist 200 is cured (S400).

According to one embodiment of the present application, the step of curing the polymer compound resist 200 may include simple cooling or freeze drying, but is not limited thereto.

As described above, the polymer compound used for the polymer compound resist 200 may be a thermoplastic polymer or a water-soluble polymer. Curing methods may be performed differently depending on the type of polymer compound used.

For example, when the resist 200 is manufactured using a thermoplastic polymer, curing is performed through simple cooling, and when the resist 200 is manufactured using a water-soluble polymer, hardening may be performed by lyophilization. .

Freeze-drying is a method of freezing the material to be dried by rapidly lowering the temperature of the vessel, and then sublimating the solidified solvent contained in the material into water vapor by making the pressure inside the vessel close to vacuum.

Through this method, a fine pattern structure having a pattern shrinkage of less than 10% can be formed.

According to one embodiment of the present application, the step of removing the template 300 having the fine pattern structure may be further included, but is not limited thereto.

After curing the fine pattern, the mold 300 having the fine pattern structure may be removed from the formed fine pattern structure to obtain the fine pattern structure.

In addition, a second aspect of the present disclosure provides a microneedle including a micropattern manufactured according to the first aspect.

With respect to the microneedle according to the second aspect of the present application, detailed descriptions of parts overlapping with those of the first aspect of the present application have been omitted. The same can be applied.

The mold for preparing the microneedle pattern may be, for example, a large-area mold having a size of 5 cm × 5 cm to 30 cm × 30 cm made of polydimethylsiloxane (PDMS). The electrode substrate can be formed in a large area of a desired size, and a uniform microneedle pattern can be formed because a high voltage electric field can be applied uniformly over the entire area of the electrode plate. In addition, the structure can be formed on the patch on which the microneedles will be placed, and it can also be fabricated on the flexible patch.

The microneedle according to the present disclosure may be a microneedle having a high aspect ratio having a sufficient height to deliver a drug through the skin, but is not limited thereto.

In addition, a third aspect of the present application provides a drug delivery system including the microneedle according to the second aspect.

With respect to the drug delivery system according to the third aspect of the present application, detailed descriptions of parts overlapping with the second aspect of the present application have been omitted. The same can be applied to

The transdermal drug delivery system through the microneedle has the advantage of being painless and of excellent patient convenience. there is.

In addition, various clinical trials are in progress for the purpose of drug development by various companies to confirm the improvement of safety, efficacy and convenience of taking. Additional clinical confirmation and commercialized manufacturing methods are continuously being studied for innovative effects such as changing the administration route of the current injectable formulation to a transdermal drug delivery system, improving the convenience of taking the drug, and improving the efficacy of the drug.

The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present application.

[Example 1: Production of mold]

3 is a flowchart illustrating a process of manufacturing a mold having a micro-pattern structure and an image of a mold having a micro-pattern structure actually manufactured according to an embodiment of the present disclosure.

Referring to FIG. 3 , the manufacturing process of the mold having the fine pattern structure includes (a) preparing a master pattern; (b) injecting polydimethylsiloxane (PDMS) on the master pattern; (c) disposing silicon to be used as an electrode on a polydimethylsiloxane mold; (d) curing the polydimethylsiloxane.

The master pattern in (a) of FIG. 3 can be used semi-permanently, and the pattern can be obtained through etching.

In order to prepare a mold having the micropattern structure, polydimethylsiloxane was prepared by mixing a silicone elastomer base and a silicone elastomer curing agent in a ratio of 10:1.

The prepared polydimethylsiloxane was injected into the master pattern as shown in (b) of FIG. 3, and silicon to be used as an electrode was placed on the prepared polydimethylsiloxane template as shown in (c) of FIG.

In the process of disposing the electrode on the mold, the electrode may be disposed in the step of manufacturing the mold, or the electrode may be attached to the mold after fabrication is completed.

Thereafter, it was maintained for 20 minutes to 2 hours in a vacuum (1 Torr or more) to remove generated bubbles. The mold from which the air bubbles were removed was cured at a temperature of 50° C. to 100° C. for 1 hour to 5 hours to prepare a mold having a fine pattern.

At this time, the mold having the fine pattern may have various heights or shapes, and in the embodiment, a mold having a pattern of a pyramid shape (200 μm × 200 μm × 250 μm) was manufactured.

The thickness of the mold having the fine pattern was manufactured to be 3 mm or less.

[Example 2: Formation of fine patterns using thermoplastic polymers]

In Example 2, a polymer compound resist was prepared with polystyrene, a thermoplastic polymer, using an organic solvent such as toluene, chloroform, benzene, or acetone as a solvent for the polymer compound resist, and a fine pattern structure was formed on the resist.

Figure 4 (A) is a flow chart showing a method of forming a micro pattern step by step according to an embodiment of the present application, Figure 4 (B) is an actual image of the fabricated micro pattern structure.

Referring to (A) of FIG. 4 , a mold made of polydimethylsiloxane having a silicon electrode disposed thereon prepared in Example 1 was used. In addition, glass was disposed on the silicon substrate as an insulating layer, and the polymer compound resist was applied on the insulating layer.

In addition, the resist was heated to a temperature higher than the glass transition temperature to form a pattern. It is possible at a temperature of 50 ° C to 200 ° C, and in more detail, heat of 100 ° C to 120 ° C can be applied.

At the initial stage of fine pattern replication, the resist rises by capillary force to form a lower structure of the fine pattern, and air pockets are formed on the lower structure of the fine pattern.

In addition, power of 1.5 kV and 5 ㎂ is supplied to the substrate and the electrode disposed on the mold having the fine pattern to charge the surface of the mold made of polydimethylsiloxane, and the charge of the resist is moved by the potential difference And the air pocket is filled with the resist.

The time for forming the fine pattern with the high voltage varies depending on the shape of the fine pattern, and may be maintained for 1 minute to 24 hours.

In addition, the formed fine pattern structure was cured through a simple cooling process at room temperature to cure the resist.

In addition, the mold was removed from the formed fine pattern structure to complete the fine pattern structure.

4(B) is an actual image of the micro-pattern structure fabricated according to Example 2.

Referring to (B) of FIG. 4 , it can be confirmed that a pyramidal micropattern structure is formed. In addition, it can be confirmed that the upper structure of the fine pattern is well formed.

[Example 3: Formation of fine patterns using water-soluble polymers]

Unlike Example 2, in Example 3, a polymer compound resist was prepared using water-soluble carboxymethylcellulose and hyaluronic acid, which are water-soluble polymers in which water is used as a solvent for the polymer compound resist. Unlike Example 2, there is a process of water treatment of the polymer compound resist before pattern formation, and lyophilization is used in the cooling process.

Figure 5 (A) is a flow chart showing a method of forming a micro pattern step by step according to an embodiment of the present application, Figure 5 (B) is a real image of the fabricated micro pattern structure.

Referring to (A) of FIG. 5 , a mold made of polydimethylsiloxane having a silicon electrode disposed thereon prepared in Example 1 was used. Glass was disposed as an insulating layer on a silicon substrate, and the polymer compound resist was applied on the insulating layer.

After coating, the resist was heat-treated to evaporate moisture and hardened, and then a certain amount of water was sprayed on the surface of the applied resist to make only the surface of the resist liquid.

In addition, at the beginning of pattern replication, the resist rises by capillary force to form a lower structure of the fine pattern, and air pockets are formed on the lower structure of the fine pattern.

In addition, power of 1.5 kV and 5 ㎂ is supplied to the electrode and the substrate to charge the surface of the mold made of the polydimethylsiloxane, and the charge of the resist is moved by the potential difference, and the air pocket is filled with the resist .

The time for forming the pattern with the high voltage varies depending on the shape of the pattern, and may be maintained for 1 minute to 24 hours.

In addition, the formed micro-pattern structure was put into a refrigerant such as liquid nitrogen or dry ice together with the mold to lower the temperature to -18° C. or less to freeze the formed micro-pattern structure.

Freeze-drying proceeds in three steps, including a freezing step, a sublimation step and a drying step.

In the freezing step, the formed fine pattern structure was rapidly cooled at a temperature between -196°C and -20°C.

Specifically, freeze-drying was performed using liquid nitrogen (-196°C), dry ice (-78.5°C), and a refrigerator (-20°C). Freeze-drying was possible in all three cases, but the shrinkage rate of the micropatterns after freeze-drying increased as the temperature approached 0 °C.

Through this, it was confirmed that rapid cooling at a cryogenic temperature is not necessarily required during freeze-drying, but it is easier to form a fine pattern structure of a desired shape as freeze-drying is performed at a lower temperature.

In the sublimation step, the frozen micropattern structure was maintained at a low pressure (1 Torr or more) and at a low temperature of minus 20° C., and carboxymethyl cellulose or hyaluronic acid remained due to sublimation of water as a solvent.

The drying step is a step of removing the residual solvent of the frozen solute. As a step of removing only the solvent without affecting the solute, it can be continued for 1 to 10 days.

In addition, the mold was removed from the formed fine pattern structure to complete the fine pattern structure.

5(B) is an actual image of the micro-pattern structure fabricated according to Example 3.

Referring to (B) of FIG. 5 , it can be seen that a pyramidal micropattern structure is formed. In addition, it can be confirmed that the upper structure of the fine pattern is well formed.

[Experimental Example 1]

FIG. 6 is an image of a lower structure of the micropattern formed by capillary force and an upper structure of the micropattern formed by electrostatic force during the formation process of the micropattern when polystyrene was used as a polymer compound resist according to Example 2. FIG.

Referring to FIG. 6 , it can be confirmed that in STEP 1, only the lower structure of the micropattern was formed by capillary force, and an air pocket was formed on the lower structure of the micropattern, thereby forming a quadrangular truncated micropattern structure.

Therefore, in one embodiment of the present application, the air pockets formed on the lower structure of the fine pattern are filled with the resist using electrostatic force to form the upper structure of the fine pattern, and in STEP 2, a pyramid shape, which is the desired shape of the fine pattern, can be manufactured. could

[Experimental Example 2]

7 is a scanning electron microscope image for confirming the pattern reduction rate of carboxymethylcellulose according to the freeze-drying time after fabrication of the micropattern using capillary force and electrostatic force according to the experimental example of the present application.

7 (A) is the original pattern, (B) is a real image of the micropattern when lyophilization was performed on 1 day, (C) is lyophilization on 3 days, and (D) is lyophilization on 4 days.

Referring to (B) of FIG. 7 , it can be seen that the microneedle pattern is deformed when a sufficient drying time is not passed in the lyophilization step.

Referring to (C) and (D) of FIG. 7 , a pattern with a pattern shrinkage rate of less than 10% could be produced compared to the original pattern (A).

Therefore, it could be confirmed that the preferred freeze-drying time in the present invention is 3 to 5 days.

[Comparative Example 1]

8(A) is an image of a micropattern structure when micropattern formation is performed without water treatment according to a comparative example of the present application, and FIG. 8(B) is an image of optimization according to an embodiment of the present application This is an image of the micro-pattern structure when the reaction proceeds under the specified conditions.

Referring to (A) of FIG. 8 , when pattern formation is performed with a resist manufactured using hyaluronic acid, it can be confirmed that a micropattern structure having porosity is formed when a micropattern is formed without going through a water treatment process. could

Therefore, in order to form a micropattern structure without porosity, after heating the resist to evaporate moisture and hardening it, supplying moisture to the surface to make the surface in a liquid state, and then forming a micropattern. could find out

(B) of FIG. 8 shows a method of forming a fine pattern using capillary force and electrostatic force on a surface having a moisture content controlled through the present invention, when freeze-drying is performed by forming a fine pattern under optimized coating conditions, This is the structure of the formed micropattern.

First, after coating a resist made of hyaluronic acid on a glass substrate, it was put on a heater and a temperature of 120° C. was applied to evaporate moisture to cure the resist.

Water was sprayed on the surface of the cured resist to make the surface in a liquid state. Moisture of less than 0.5 ml/cm ² was supplied by spraying, and moisture condensed on the surface was removed with an air gun.

A prefabricated mold is attached to the surface of the liquid phase to form the lower structure of the micropattern by capillary force. Thereafter, an electric field is applied to fill the air pockets formed on the lower portion of the fine pattern with a resist to form an upper structure of the fine pattern.

The formed micropattern structure was freeze-dried like a mold, and after the freeze-drying was finished, the micropattern structure was obtained by removing the mold from the micropattern structure.

Referring to FIG. 8(B), unlike FIG. 8(A), it can be confirmed that the structure of the micropattern does not have a porous characteristic, and the pyramidal micropattern structure to be replicated is formed.

Referring to FIG. 8 , the process of forming a micropattern on a polymer compound resist made using a water-soluble polymer includes applying the resist to a substrate in order not to have porosity, evaporating moisture through heating to harden the resist, It was found that a moisture treatment process of making the surface of the resist in a liquid state by spraying a certain amount of moisture on the surface of the resist was necessary.

In addition, when the amount of moisture supplied during the process of making the surface of the resist into a liquid state is large, patterns having porous characteristics and pattern shrinkage occur. On the other hand, it was confirmed that pattern production was not performed when the amount of supplied moisture was too low. Through this, it was found that spraying an appropriate amount of moisture to the surface of the resist is important in forming a fine pattern.

The above description of the present application is for illustrative purposes, and those skilled in the art will understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present application. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the present application is indicated by the following claims rather than the detailed description above, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts thereof should be construed as being included in the scope of the present application.

100: substrate
110: insulating layer
200: polymer compound resist
210: lower structure of fine pattern
220: air pocket
230: upper structure of fine pattern
300: mold having a fine pattern structure
310: electrode

Claims (16)

coating a polymer compound resist on a substrate;
contacting the polymer compound resist with a mold having a micro pattern structure to form a lower structure of the micro pattern on the polymer compound resist;
forming an upper structure of the fine pattern on the lower structure of the fine pattern by applying a voltage; and
curing the polymer compound resist;
including,
An electrode for applying a voltage is disposed above the mold having the fine pattern structure,
Applying a voltage by connecting the electrode and the substrate with a power supply,
In the step of forming the lower structure of the fine pattern, an air pocket is formed on the lower structure, and the upper structure of the fine pattern is formed by filling the air pocket with the polymer compound resist by applying the voltage,
In the step of forming the lower structure of the fine pattern, the resist is sucked into the fine pattern structure by capillary force to form the lower structure.
A method of forming a fine pattern.
delete delete According to claim 1,
The voltage is 1.0 kV or more and 3.0 kV or less, the method of forming a fine pattern.
According to claim 1,
A method of forming a fine pattern, wherein an insulating layer is disposed on the substrate.
delete According to claim 1,
Further comprising the step of removing the template having the fine pattern structure,
A method of forming a fine pattern.
According to claim 1,
The template having the fine pattern structure is polydimethylsiloxane (PDMS), 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 (polyacrylonitrile), polymethylmethacrylate, polytetrafluoroethylene (PTFE), styrenebutadiene rubber (SBR) or ethylene-propylene-diene copolymer (EPDM) That is, a method of forming a fine pattern.
According to claim 1,
The fine pattern structure includes a pattern selected from a pyramid, a prism, a regular tetrahedron, a hemisphere, an aspherical surface, and combinations thereof.
According to claim 1,
The method of forming a fine pattern, wherein the polymer compound resist includes a thermoplastic polymer.
According to claim 10,
The thermoplastic polymer is polystyrene (PS), ABS resin (acrylonitrile butadiene-styrene), polyoxymethylene (POM), polymethyl methacrylate (PMMA), cellulose acetate (CA), polytetrafluoroethylene (PTFE), poly Chlorotrifluoroethylene (PCTEF), polyvinyl fluoride resin (PVF), polyvinylidene fluoride (PVDF), polymethylpentene (PMP), polyamide (PA), polycarbonate (PC), polyethylene (PE), polyethylene tere Phthalates (PET), polyimide (PI), polyphenylene oxide (PPO), polypropylene (PP), polysulfone (PSul), polyvinylidene chloride (PVDC), polyvinyl chloride (PVC) and combinations thereof Which includes selected from the group consisting of
A method of forming a fine pattern.
According to claim 1,
The method of forming a fine pattern, wherein the polymer compound resist includes a water-soluble polymer.
According to claim 12,
The water-soluble polymer is carboxymethyl cellulose, hyaluronic acid, chondroitin sulfate, glycogen, dextrin, dextran, dextran sulfate, Hydroxypropyl methylcellulose, alginic acid, chitin, chitosan, pullulan, collagen, gelatin and their hydrolysates, polyvinyl alcohol (polyvinyl alcohol), polyvinylpyrrolidone, polyacrylic acid, and combinations thereof,
A method of forming a fine pattern.
According to claim 1,
The step of curing the polymer compound resist is performed by simple cooling or freeze-drying, a method of forming a fine pattern.
delete delete

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