TWI645870B - Microstructure for transdermal absorption and process for preparing the same - Google Patents

Abstract

The present invention relates to a microstructure comprising a biocompatible polymer or a binder and a method of producing the same. The inventors optimized the aspect ratio according to the morphology of each microstructure to ensure an optimal tip angle and diameter range for penetration through the skin. In particular, the B-type and C-type microstructures of the present invention minimize penetration resistance due to skin elasticity when attached to the skin, thereby improving the transmittance of the structure (60% or more) and the active ingredient. Absorption rate in the skin. Further, the D-type microstructure of the present invention is applied to a triple structure, thereby maximizing the mechanical strength of the structure and easily penetrating the skin. In the present invention, in the case where a plurality of microstructures are arranged in a Hexagonal arrangement, there is an advantage that all of the microstructures can be subjected to equal pressure when attached to the skin.

Description

Transdermal absorption microstructure and method of producing the same

The present invention relates to a microstructure for transdermal absorption and a method for producing the same. More specifically, it relates to a biodegradable microstructure comprising a biocompatible polymer or a binder and a method for producing the same.

Drug Delivery System (DDS) is a series of techniques for delivering drugs to target sites such as cells and tissues by controlling the absorption and release of drugs. In addition to the usual oral intake, there is percutaneous penetration of locally applicable drugs. A type of delivery system or the like has been continuously studied in order to effectively and safely administer a pharmaceutical substance such as a drug. Among them, in the case of injection therapy, there is a problem that the administration method is cumbersome, and depending on the patient, there is a possibility that pain is accompanied, and there is a limitation in controlling the release rate of the drug in addition to the method of temporarily injecting the drug. In order to improve the shortcomings of this injection therapy, microscopic structures (microneedles) which are much smaller than the needle of the syringe and have little pain have been studied, and are carried out in various fields such as drug delivery, blood collection, biosensors, and skin cosmetics. Its research.

Conventional microneedle manufacturing methods include "MICRONEEDLE DEVICES AND METHODS OF MANUEACTURE AND USE THEREOF" in US Pat. No. 6,334,856 and Korean Patent No. 10-079 "Biodegradable solid microneedle and its manufacturing method" No. 3615.

In the above patent, a microneedle is produced by injecting a biodegradable viscous material into a micro-mold made of a curable polymer and drying it, followed by separation from a mold, thereby producing a microneedle (molding technique), Or after coating a biodegradable viscous substance for forming a biodegradable solid microneedle, the coated biodegradable viscous substance is drawn using a frame patterned with a pillar, dried, and then passed. A microneedle (drawing technique) is produced by the step of cutting the drawn biodegradable viscous material. However, the biodegradable polymer microstructures produced by such a conventional manufacturing method have relatively low mechanical strength, so that there is a problem of bending or being crushed when penetrating the skin. In particular, in the case where a polymer derivative having high elasticity is used as a raw material, when a microstructure is produced by a molding technique or a drawing technique, there is a limitation that it is impossible to uniformly form a desired structure shape, and it is difficult It meets the shortcomings of the mechanical strength of the microstructures required to penetrate the skin.

The hyaluronic acid used in the present invention is a biodegradable polymer. In the case of a structure made of hyaluronic acid, the smaller the average molecular weight, the easier it is to form a structure, and the viscosity is small, and the molecular weight is small. Increase, mechanical strength rises, and viscosity increases. Due to such characteristics, low molecular weight hyaluronic acid is generally used as a raw material of the microstructure, and in the case of using a low molecular weight hyaluronic acid microstructure, when it penetrates the skin, it is liable to be broken or bent. On the other hand, Carboxymethyl cellulose (CMC) is a cellulose derivative which is a biodegradable polymer which is mainly used as a thickening agent in pharmacy and has various molecular weights.

On the other hand, the conventional microstructures are not suitable for penetrating the skin because the angle of the tip portion is too large, even at the angle of the tip, which has a range that easily penetrates the skin. In this case, since there is a structure in which the diameter continuously increases from the tip to the bottom, there is a disadvantage that the skin itself is resistant to a very limited ratio which penetrates only to the entire height of the structure. In the case of a structure having a low aspect ratio (w:h,h/w), it is difficult to penetrate the skin, and in the case of a structure having a high aspect ratio, although it is easy to penetrate the skin, it is relatively low in machinery. Strength and the problem of being broken or bent when penetrating the skin. Further, the conventional microstructure has a structure in which it is difficult to overcome the elasticity and restoring force of the skin itself when penetrating the skin, and thus there is a drawback that it is easy to re-needle after the structure penetrates the skin.

In order to solve the above problems and to produce a microstructure in which the present invention has developed a biocompatible polymer and a method for producing a microstructure using the same, the microstructure uses both low molecular hyaluronic acid. And carboxymethyl cellulose, which has mechanical strength suitable for penetrating the skin, is easily dissolved or spread in the skin, and is therefore suitable for drug delivery or skin beauty.

Throughout this specification, reference has been made to a number of papers and patent documents, and references are cited. The disclosures of the cited papers and the patent documents are hereby incorporated by reference in their entirety in their entireties in the extent of the disclosure of the present disclosure.

The present inventors conducted intensive research and efforts to solve the problems of the above-described plurality of prior art. Finally, the inventors made use of a hydrogel formed of a biocompatible polymer to produce a microstructure, in particular, a microstructure having various tip angles and diameter ranges, thereby developing a microstructure that easily penetrates the skin. body. The present inventors optimized the aspect ratio w:h formed by the diameter w and the height h of the bottom surface of the microstructure to ensure the best end for penetrating the skin. Tip angle. Further, a double or triple structure (microstructures of the B, C, and D types of the present invention) is applied to the microstructure to maximize the mechanical strength, and a hexagonal pattern is applied to align the microstructure so as to adhere to the skin. The entire microstructure can be subjected to uniform pressure, and finally, it is confirmed that the active ingredient loaded on the microstructure can be stably transferred into the living body, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a microstructure comprising a biocompatible polymer or a binder.

Another object of the present invention is to provide a method for producing a microstructure comprising a biocompatible polymer or a binder.

Other objects and advantages of the present invention will be more clearly understood from the following description of the appended claims.

According to an embodiment of the present invention, the present invention provides an aspect ratio w:h comprising a biocompatible polymer or binder and having a diameter w and a height h of the bottom surface of 1:5 to 1:1.5, distal end The angle α of the tip is a microstructure of 10 to 40 degrees.

The inventors of the present invention have intensively studied and worked hard to solve the problems of the prior art described above, and as a result, microstructures have been produced using biocompatible polymers, and in particular, microstructures having various tip angles and diameter ranges have been produced, thereby developing A microstructure that easily penetrates the skin. The inventors have optimized the optimum tip angle for penetrating the skin by optimizing the aspect ratio w:h formed by the diameter w and the height h of the bottom surface of the microstructure. Further, a double or triple structure (microstructures of the B, C, and D types of the present invention) is applied to the microstructure to maximize the mechanical strength, and a hexagonal pattern is applied to align the microstructure so as to adhere to the skin. When all the microstructures are subjected to equal pressure, it is finally confirmed that the microorganisms can be stably transported to the living body. The active ingredient of the microstructure.

The term "biocompatible polymer" in the present specification is selected from the group consisting of hyaluronic acid (HA), Carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, Chondroitin sulfate, dextran sulfate, chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, amylopectin polylactic acid Polyglycolide (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyanhydride, polyorthoester, polyetherester, polycaprolactone, poly Polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, propylene-substituted cellulose acetate, non-degradable polyurethane, polystyrene, Polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxy Propyl methylcellulose (HPMC) Ethyl cellulose (EC), hydroxypropyl cellulose (HPC), cyclodextrin, and cellulose formed a plurality of groups, and copolymers of these monomers consisting of a polymer of one or more polymers.

The term "binder" as used in the present specification is selected from the group consisting of hydrazine, polyurethane, hyaluronic acid, physical binder (gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, ethylene vinyl acetate, and polyisobutylene. More than one binder in the group consisting.

The term "hyaluronic acid" in the present specification also includes hyaluronate (for example, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, and calcium hyaluronate) in addition to hyaluronic acid and their The mixture is included in the meaning to be used. According to an embodiment of the present invention, the hyaluronic acid of the present invention has a molecular weight of 100 to 5000 kDa. According to any of the examples of the invention, the invention The hyaluronic acid has a molecular weight of 100-4500 kDa, 150-3500 kDa, 200-2500 kDa, 220-1500 kDa, 240-1000 kDa or 240-490 kDa.

As the "carboxymethylcellulose" used in the present specification, carboxymethylcellulose of a plurality of known molecular weights can be used. For example, the carboxymethylcellulose used in the present invention has an average molecular weight of 90,000 kDa, 250,000 kDa or 700,000 kDa.

The present invention can provide a variety of microstructures, for example, microneedles, microblades, microknifes, microfibers, microwires, microprobes, microbarbs, microarrays, or microelectrodes. According to an embodiment of the invention, the microstructure of the invention is a microneedle.

According to an embodiment of the present invention, in the present invention, 1-5% (w/v) of a biocompatible polymer or binder is contained. According to a specific example of the present invention, in the present invention, hyaluronic acid or carboxymethylcellulose is contained in a concentration of 3% (w/v).

Unlike the conventional microstructures, one of the largest features of the microstructures of the present invention is a double or triple structure, thereby maximizing mechanical strength. For this reason, by optimizing the aspect ratio w:h formed by the diameter w and the height h of the bottom surface of the microstructure, the distal end angle α of the microstructure, and the diameter range t of the tip, it is easy to penetrate. The microstructure of the skin.

The microstructure of the present invention produced according to the above conditions is in the shape of Type A to D of Figs. 1A to 1D. The type A microstructure has a common conical shape; the type B has a double structure of a cylinder and a cone; the C type has a double structure of a deformed cylinder (conical table) and a cone; and the type D has two deformed cylinders (a truncated cone). And the triple structure of the cone.

According to an embodiment of the present invention, in the present invention, the aspect ratio w:h formed by the diameter w and the height h of the bottom surface of the microstructure is 1:5 to 1:1.5, and the angle α of the distal end is 10 to 40 degree. According to still another example of the present invention, the aspect ratio is 1:5 to 1:2 (refer to Figs. 1A-1D).

In Fig. 1A, a microstructure having a conical A shape can be represented by the diameter w, the height h of the bottom surface, and the angle α of the tip. According to an example of the invention, the aspect ratio w:h of type A is from 1:5 to 1:1.5.

In Fig. 1B, the type B is a microstructure formed by a double structure of a cylinder and a cone, and can be represented by the diameter w and height h _{1 of the} bottom surface of the cone, the angle α of the tip, and the diameter w and height h _{2 of the} bottom surface of the cylinder. According to an example of the present invention, the aspect ratio of type B of w1:h ₁ is 1:5 to 1:1.5, the aspect ratio of w:h ₂ is 1:5 to 1:1.0, and the aspect ratio of w:h is 1. : 5 to 1:2. According to a particular example of the invention, the aspect ratio of w:h ₂ is 1:1.4 and the ratio of h ₁ :h ₂ is 1.1:1. On the other hand, in the B-type microstructure of the present invention, the optimum w:h aspect ratio is 1:3, and the optimum interval between the structures is 1/2 h-2h.

In Fig. 1C, the C type is a microstructure composed of a double structure of a truncated cone and a cone, and can be represented by a diameter w ₁ and a height h _{1 of the} conical bottom surface, an angle α of the tip end, and a diameter w and a height h _{2 of the} bottom surface of the truncated cone. . According to an embodiment of the present invention, the aspect ratio of the type C w ₁ :h ₁ is 1:5 to 1:1.5, and the aspect ratio of w:h ₂ is 1:5 to 1:1.0, and the aspect ratio of w:h is 1:5 to 1:2. According to a particular example of the invention, the aspect ratio of w:h ₂ is 1:1.25 and the ratio of h ₁ :h ₂ is 1.3:1. On the other hand, in the microstructure of the C type of the present invention, the optimum aspect ratio of w:h is 1:3, and the interval between the optimum structures is 1/2h-2h.

In Fig. 1D, the D type is a microstructure composed of two truncated cones and a conical triple structure, and the diameter w _{1 of the} conical bottom surface, the height h ₁ and the angle α of the tip; the diameter w _{2 of the} bottom surface of the upper truncated cone, The height h ₂ is represented by the diameter w and the height h _{3 of the} bottom surface of the lower truncated cone. According to an embodiment of the present invention, the aspect ratio of the type D of w ₁ :h ₁ is 1:5 to 1:1.5, and the aspect ratio of w:h ₂ and w:h ₂ is 1:5 to 1:1.0, w: The aspect ratio of h is 1:5 to 1:2.

According to a particular example of the invention, the aspect ratio of w:h ₂ is 1:1.5, the aspect ratio of w:h ₃ is 1:1, and the ratio of h ₁ :h ₂ :h ₃ is 1.5:1.5:1. On the other hand, in the microstructure of the D type of the present invention, the optimum w:h aspect ratio is 1:3.5 to 1:4, and the optimum interval between the structures is 1/2h-2h.

The microstructure of the present invention can be made to have a height of from 80 μm to 1500 μm. According to a specific example of the present invention, the above microstructure has a height of from 100 μm to 1300 μm.

According to an embodiment of the invention, the distal end tip has a diameter t of 2-20 μm. The above diameter t represents the diameter of the distal end portion of the microstructure observed by magnifying 40 to 250 times with a microscope or an electron microscope.

According to an embodiment of the present invention, the microstructure of the present invention has a mechanical strength (penetration rate, %) of 80 or more. According to still another embodiment of the present invention, the mechanical strength is 80-100. According to another embodiment of the present invention, the above mechanical strength is 90-100. According to still another embodiment of the present invention, the mechanical strength is 95-100.

According to an example of the present invention, in the microstructure of the present invention, the skin penetration rate of the B-D type having a double and triple structure is higher than that of the type A.

According to an embodiment of the present invention, the microstructure of the present invention contains an active ingredient in addition to the biocompatible polymer and the binder. For example, the above-mentioned effective ingredients are drugs, cosmetic ingredients (whitening, cosmetic ingredients such as wrinkles), or a combination thereof. Since the microstructure of the present invention contains an active ingredient, it is effective to deliver an active ingredient into the skin.

According to an embodiment of the present invention, the microstructure of the present invention may further comprise a metal, High molecular polymer or binder.

According to another embodiment of the present invention, in the method for producing a microstructure according to the present invention, the method for producing the microstructure includes the step (a) of supplying a biocompatible polymer or a binder to the micro mold; and the step (b) Inserting the above biocompatible polymer or binder into the pores of the micro mold; step (c), drying the biocompatible polymer or binder; and step (d), for the above micro The mold is separated from the dried biocompatible polymer or binder to form a microstructure.

The manufacturing method of the microstructure of the present invention will be described in detail as follows in each step:

Step (a): supplying a biocompatible polymer or binder to the micro mold

According to the present invention, a biocompatible polymer or binder is first supplied to a micro mold.

As the micro mold of the present invention, a micro mold manufactured by any micro mold manufacturing technique in the art can be utilized. For example, MEMS (Micro-Electro Mechanical System) manufacturing technology, lithography (photolithography, Biodegradable polymer microneedles: Fabrication, mechanisms and transder mal drug delivery, Journal of Controlled Release 104, 51-66, 2005) Manufacturing techniques, soft lithography manufacturing techniques, and the like are used to manufacture the micro-mold of the present invention, but are not limited thereto. Among them, in the case of using soft lithography manufacturing technology, polydimethylsiloxane (PDMS) or poly(methyl methacrylate) (PMMA, Poly(methyl methacrylate)), etc. can be produced. Elastomeric molds are used in the manufacture of microstructures. Technology for manufacturing polydimethyl siloxane molds as a plastic processing technology The desired molding structure can be obtained by various methods such as casting, injection, and hot-embossing. For example, when a photosensitive material is applied onto a substrate such as a ruthenium or glass, and patterned by a photomask, a master mold is finally produced. When the above-mentioned main mold is cast as a mold to cast polydimethyl siloxane and sintered, a polydimethyl siloxane mold which functions as a stamp can be completed.

According to an embodiment of the present invention, the hyaluronic acid has a molecular weight of 240 to 490 kDa, and according to a specific example of the present invention, the hyaluronic acid has an average molecular weight of 360 kDa.

According to the present invention, in the step (a), the solid content of the biocompatible polymer may be contained in an amount of 1 to 30% (w/v) with respect to the total composition of the microstructure.

According to an embodiment of the present invention, in step (a), the concentration of the biocompatible macromolecule is 1-5% (w/v) relative to the total composition of the microstructure, according to a specific example of the present invention, The biocompatible polymer can be contained in a concentration of 3% (w/v).

Step (b): injecting the above biocompatible polymer or binder into the pores of the micro mold

Next, the biocompatible polymer or binder is injected into the pores of the micro mold.

According to an embodiment of the present invention, after supplying the biocompatible polymer to the micro mold, in the present invention, (i) applying a centrifugal force of 800 to 1000 g to the micro mold to perform an implantation step, or (ii) at 500- The implantation step was carried out under a pressure of 860 mmHg.

For example, in the case of performing injection by applying a centrifugal force of 800 to 1000 g to the micro mold, centrifugation for 10-20 minutes may be performed under a centrifugal force of 800 to 1000 g, or Centrifugation was carried out for 15 minutes under a centrifugal force of 900 g. Further, in the case where the injection is performed under vacuum pressure, it may be injected at a pressure of 500 to 860 mmHg for 5 to 20 minutes, or at a pressure of 600 to 760 mmHg for 10 to 30 minutes.

According to a specific example of the present invention, the above biocompatible polymer is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, chitosan, poly Lysine, collagen, gelatin, carboxymethyl chitosan, fibrin, agarose, amylopectin polylactic acid, polyglycolide, polylactic acid-glycolic acid copolymer, polyanhydride, polyorthoester, Polyether ester, polycaprolactone, polyester decylamine, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, propylene substituted cellulose acetate, not Degradation of polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole, chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropyl One or more polymers selected from the group consisting of cellulose, ethyl cellulose, hydroxypropyl cellulose, cyclodextrin, and a copolymer of a plurality of monomers forming these polymers and a cellulose composition. According to a specific example of the present invention, the above binder comprises a material selected from the group consisting of ruthenium, polyurethane, hyaluronic acid, physical binder (gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, ethylene vinyl acetate, and poly More than one substance in the group consisting of isobutylene.

Step (c): drying the above biocompatible polymer or binder

After the step (b) is carried out, the above biocompatible polymer or binder is dried.

According to an embodiment of the present invention, the above step (c) is carried out at (i) normal temperature for 36-60 hours, or at (ii) 40-60 ° C for 5-16 hours, or at (iii) 60-80. It is carried out at a temperature of ° C for 2-4 hours. According to another example of the present invention, the above step (c) may Performing at (i) 20-30 ° C for 42-54 hours, or (ii) 45-55 ° C for 5-7 hours, or (iii) 65-75 ° C for 2 - 4 hours. According to a specific example of the present invention, the above step (c) may be carried out at (i) a temperature of 25 ° C for 48 hours, or at (ii) a temperature of 50 ° C for 6 hours, or at a temperature of (iii) 70 ° C. Implemented for 3 hours. This drying process increases the mechanical strength of the microstructure.

Step (d): Separation of the micro mold and the crosslinked hyaluronic acid hydrogel

After carrying out step (c), the micro-mold of the present invention and the dried biocompatible polymer or binder are separated to form a microstructure.

The method for producing a microstructure according to the present invention allows a plurality of microstructures to be arranged in a quadrangular shape or a hexagonal shape. A plurality of microstructures manufactured by a hexagonal arrangement can be subjected to equal pressure when attached to the skin.

According to an embodiment of the present invention, the plurality of microstructures can be arranged at intervals p of 250 to 1500 μm. In this case, about 25 to 1300 structures can be arranged per cm ² (refer to Table 1).

Since the method for producing a microstructure according to the present invention is directed to the above-described microstructure, the same contents as those in the above-described microstructure are omitted in order to avoid the complexity of the present specification.

According to another embodiment of the present invention, the present invention provides a microstructure having the feature that one of the types A to D of FIGS. 1A to 1D is in the shape of the above-described microstructure. The features of the microstructures of the A to D type shape are as described above, and in order to avoid the description becoming too complicated, the description thereof will be omitted.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides a microstructure comprising a biocompatible polymer or a binder and a method for producing the same.

(b) The inventors optimized the aspect ratio according to the morphology of the microstructure to ensure an optimum tip angle and diameter range for penetrating the skin.

(c) In particular, the B-type and C-type microstructures of the present invention minimize penetration resistance due to skin elasticity when attached to the skin, thereby improving the penetration rate of the structure (60% or more) and Intradermal absorption rate of active ingredients. Further, the D-type microstructure of the present invention is applied to a triple structure, thereby maximizing the mechanical strength of the structure and easily penetrating the skin.

(d) In the present invention, in the case where a plurality of microstructures are arranged in a hexagonal arrangement, there is an advantage that all of the microstructures can be subjected to an equal pressure when attached to the skin.

1A to 1F show a microstructure manufactured by the method for producing a microstructure of the present invention. Wherein, the diameter w of the bottom surface, the height h, the angle α of the distal tip, the diameter t of the distal tip, the interval p between the microstructures, the angular range of the column of the structure (β1 is 85-90 degrees; β2-β4 It is 90-180 degrees).

2A to 2D show electron microscope (SEM) photographs of a micro mold used in the method of producing a microstructure of the present invention. Among them, 2A: A type, 2B: B type, 2C: C type, 2D: Type D.

3A to 3D show micrographs (Sunny SZMN, 40-70 times) of the A to D types of the respective microstructures manufactured by the method of manufacturing the microstructure of the present invention. Among them, 3A: A type, 3B: B type, 3C: C type, 3D: D type.

4A to 4D show photographs of microscopes (SEM, JEOL JSM-7500F) of the A to D type as individual microstructures manufactured by the method of manufacturing the microstructure of the present invention. The arrows in Fig. 4D indicate the positions at which w ₁ , w ₂ and w are measured. Among them, 4A: A type, 4B: B type, 4C: C type, 4D: D type.

5A to 5E show experimental results of mechanical strength of the A type to D type microstructures (5A-5D) and the pyramid shape comparison group (5E) manufactured by the method of manufacturing the microstructure of the present invention.

6A to 6D show experimental results of skin penetration (depth) of a microstructure produced by the method for producing a microstructure of the present invention (electron micrograph of a microstructure after deformation through the skin). Among them, 6A: A type, 6B: B type, 6C: C type, 6D: D type.

Hereinafter, the present invention will be described in more detail by way of examples. The embodiments are only intended to more specifically illustrate the invention, and the scope of the invention is not limited by the scope of the invention, which is obvious to those skilled in the art.

Example

Example 1: Fabrication of Microstructures

1. Manufacturing process of type A microstructure

In the use of lithography manufacturing technology in the manufacture of the main negative mold or main positive mold (positiv e or negative master mold), and then a negative mold is finally produced from the above main mold by using a curable hydrazine (polydimethylsiloxanes).

As a biocompatible polymer, hyaluronic acid is used. It was used by completely dissolving hyaluronic acid (Bloomage Freda Biotechnology Co., Ltd.) having an average molecular weight of 360 kDa (molecular weight range of 240-490 kDa) in purified water at a concentration of 3% (w/v).

After supplying the above hyaluronic acid to the polydimethylsiloxane micro mold, it is injected and dried at normal temperature (25 ° C) for 48 hours, and injected at a temperature of 50 ° C for 6 hours or at a temperature of 70 ° C. It was dried for 3 hours (without performing centrifugation and vacuum process), and then the mold was removed, thereby producing a hyaluronic acid microstructure.

2. Manufacturing process of type B microstructure

After the main negative mold or the main male mold is manufactured by the lithography manufacturing technique using the lithography manufacturing technique, the negative mold is finally produced from the above main mold by using the curable cerium (polydimethyl siloxane).

As a biocompatible polymer, hyaluronic acid is used. It is used by completely dissolving hyaluronic acid having an average molecular weight of 360 kDa (molecular weight range of 240-490 kDa) in purified water at a concentration of 3% (w/v).

After the hyaluronic acid was supplied to the polydimethyl siloxane micro-mold, it was injected into a hole formed in the micro-mold at 900 g for 15 minutes by centrifugation. It was injected and dried at normal temperature (25 ° C) for 48 hours, injected and dried at a temperature of 50 ° C for 6 hours or at a temperature of 70 ° C for 3 hours, after which the mold was removed, thereby producing a hyaluronic acid microstructure. body.

3. Manufacturing process of C type microstructure

After the main negative mold or the main male mold is manufactured by the lithography manufacturing technique using the lithography manufacturing technique, the negative mold is finally produced from the above main mold by using the curable cerium (polydimethyl siloxane).

As a biocompatible polymer, hyaluronic acid is used. It is used by completely dissolving hyaluronic acid having an average molecular weight of 360 kDa (molecular weight range of 240-490 kDa) in purified water at a concentration of 3% (w/v).

After supplying the above hyaluronic acid to the polydimethyl siloxane micro-mold, it was poured into a hole formed in the micro-mold in a vacuum (600-760 mmHg) for 10 to 30 minutes. It was injected and dried at normal temperature (25 ° C) for 48 hours, injected and dried at a temperature of 50 ° C for 6 hours or at a temperature of 70 ° C for 3 hours, after which the mold was removed, thereby producing a hyaluronic acid microstructure. body.

4. Manufacturing process of D type microstructure

A positive master mold is fabricated on a crepe sheet by a photolithographic manufacturing technique, and then a negative mold is fabricated from the above-described main male mold by using a curable cerium (polydimethyl siloxane).

As the biocompatible polymer, carboxymethyl cellulose is used. It was used by completely dissolving carboxymethylcellulose in purified water at a concentration of 3% (w/v).

After supplying the above hyaluronic acid to the polydimethyl siloxane micro-mold, it was poured into a hole formed in the micro-mold in a vacuum (600-760 mmHg) for 10 to 30 minutes. It was injected and dried at normal temperature (25 ° C) for 48 hours, injected and dried at a temperature of 50 ° C for 6 hours or at a temperature of 70 ° C for 3 hours, after which the carboxymethyl cellulose micro was produced by removing the mold. Structure.

5. Specification range of microstructures (Figure 1A to Figure 1F)

Table 1

The angular range of the microstructure column: β1, 85 degrees - 90 degrees / β2 ~ β4, more than 90 degrees (90 degrees - 180 degrees)

Example 2. Mechanical strength test of microstructure

The mechanical strength test of the microstructure produced by the present invention was carried out using the skin of the pig, and when the microstructure was penetrated into the pig skin with a prescribed force, the number of pores occurring in the skin epidermis was confirmed and compared (Fig. 5A) To Figure 5E).

A sample of each type of microstructure was cut after being cut to a specification of 0.7 cm × 0.7 cm (100 or more structures), and a vertical force of 3-5 kg was applied to the skin of the pig and applied for 10 seconds to penetrate the skin. The microstructure was removed after penetrating the skin, and 20 ml of trypane blue (Sigma) was applied to the surface of the penetrating skin for 10 minutes, followed by wiping with a cotton swab and saline (PBS). except. The mechanical strength of the microstructure which can successfully penetrate the skin was observed by measuring the number of pores dyed in the epidermal layer.

Experiments were conducted in the same manner to compare the mechanical strength of pyramid-shaped microstructures.

The mechanical strength test results of the respective microstructures of the present invention are shown in the following table.

The specific specifications of the microstructures used in the above experiments are shown in the following table.

Example 3. Skin penetration rate (depth) experiment of microstructure

The skin penetration rate experiment of the microstructure produced by the present invention was carried out in such a manner that after the structure was penetrated into the skin of the pig with a predetermined force, the degree of deformation of the structure before and after the penetration was confirmed and compared. (Fig. 6A to Fig. 6D).

Samples of each type of microstructure were cut after being cut to a size of 0.7 cm x 0.7 cm, and a vertical force of 3-5 kg was applied to the pig skin and applied for 10 seconds to 30 minutes to penetrate the skin. The insertion site was observed with an optical microscope (Optical Microscope), and observed by an electron microscope (SEM) to confirm the degree of deformation of the microstructure before and after insertion into the skin, and the penetration depth was measured.

The experimental results of the skin penetration rate of the different microstructures of the present invention are shown in the following table.

The specific portions of the present invention have been described in detail above, and it is obvious to those skilled in the art that this detailed description is only a preferred example, and the scope of the present invention is not limited thereto. Therefore, the actual scope of the invention should be defined by the scope of the appended claims and their equivalents.

Claims (17)

A microstructure comprising a biocompatible polymer or a binder having an aspect ratio (w:h) formed by a diameter (w) and a height (h) of the bottom surface of 1:5 to 1: 1.5, the angle (α) of the distal tip is 10 to 40 degrees, wherein the interval between the microstructures is 1/2 h to 2 h, and wherein the microstructure has the structure (i), Ii) or (iii): (i) a microstructure having a double structure connected in the order of a cone and a cylinder from the tip to the bottom of the microstructure, wherein the diameter (w) and height (h ₁ ) of the bottom surface of the cone are between The aspect ratio (w:h ₁ ) is 1:5 to 1:1.5, and the aspect ratio (w:h ₂ ) between the diameter (w) and the height (h ₂ ) of the bottom surface of the cylinder is 1:5 to 1:1. (ii) a microstructure having a dual structure connected in the order of a cone and a truncated cone from the tip to the bottom of the microstructure, wherein the aspect ratio between the diameter (w ₁ ) and the height (h ₁ ) of the conical bottom surface ( w ₁ :h ₁ ) is 1:5 to 1:1.5, and the aspect ratio (w:h ₂ ) between the diameter (w) and the height (h ₂ ) of the bottom surface of the truncated cone is 1:5 to 1:1; (iii) having a cone from the tip to the bottom of the microstructure, the upper circle a triple-structured microstructure in which the frustum and the lower truncated cone are sequentially connected, wherein the aspect ratio (w ₁ :h ₁ ) between the diameter (w ₁ ) and the height (h ₁ ) of the conical bottom surface is 1:5 to 1 : 1.5, the aspect ratio (w ₂ : h ₂ ) between the diameter (w ₂ ) and the height (h ₂ ) of the bottom surface of the upper truncated cone is 1:5 to 1:1, and the diameter of the bottom surface of the lower truncated cone (w) The aspect ratio (w:h) between the heights (h) is 1:5 to 1:2. The microstructure according to claim 1, wherein the biocompatible polymer is selected from the group consisting of hyaluronic acid Acid (Hyaluronic acid: HA), Carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, chitosan, polylysine (polylysine), collagen, gelatin, carboxymethyl chitin, fibrin, agarose, amylopectin polylactic acid, polyglycolide (PGA), polylactic acid-glycolic acid copolymer (PLGA) ), polyanhydide, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid) ), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, propylene substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole, chlorosulfonate Chlorosulfonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC) , hydroxypropyl cellulose (HPC), cyclodextrin and form this One or more copolymers and cellulose polymer group of the plurality of monomers in the polymer composition. The microstructure according to claim 1, wherein the binder is selected from the group consisting of ruthenium, polyurethane, hyaluronic acid, physical binder (gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, and ethylene acetate. More than one substance in the group consisting of vinyl ester and polyisobutylene. The microstructure of claim 1, wherein the microstructure has an aspect ratio of 1:5 to 1:2. The microstructure of claim 1, wherein the microstructure has a height of from 80 μm to 1500 μm. The microstructure according to claim 1, wherein the distal end has a diameter (t) of 2 to 20 μm. The microstructure according to claim 1, wherein the plurality of microstructures are formed in a hexagonal shape. The microstructure of claim 1, wherein the microstructure further comprises a metal, a high molecular polymer or a binder. The microstructure according to claim 1, wherein the microstructure comprises an active ingredient in addition to the biocompatible polymer and the binder. A method for producing a microstructure, comprising: step (a), supplying a biocompatible polymer or a binder to a micro mold; and step (b), (i) applying 800-1000 g to the micro mold Centrifugal force, or (ii) injecting the above biocompatible polymer or binder into the pores of the micro mold under a pressure of 500-860 mmHg; and (c), performing the above biocompatible polymer or binder Drying; and step (d), separating the micro mold and the dried biocompatible polymer or binder to form a microstructure in which the diameter (w) and height (h) of the bottom surface of the microstructure are The aspect ratio (w:h) is 1:5 to 1:1.5, and the distal end angle is 10 to 40 degrees, wherein the interval between the microstructures is 1/2h to 2h, and wherein the micro The structure has a structure (i), (ii) or (iii): (i) a microstructure having a double structure connected in the order of a cone and a cylinder from the tip to the bottom of the microstructure, wherein the diameter of the bottom surface of the cone (w) ) and the height (aspect ratio between ₁ H) ratio (w: h ₁₎ is 1: 5 to 1: 1.5, the diameter of the cylindrical bottom surface (w) and height (h ₂₎ of Aspect ratio (w: h ₂₎ is 1: 5 to 1: 1; (II) having a microstructure double structure of the order of a cone and the truncated cone of the connection from the tip microstructure body to the bottom, wherein the conical bottom surface aspect ratio between the diameter (W ₁₎ and height (H ₁₎ ratio (w _1: h ₁₎ is 1: 5 to 1: 1.5, the aspect ratio between the diameter of the bottom surface of the truncated cone (w) and height (h ₂₎ a ratio (w:h ₂ ) of 1:5 to 1:1; and (iii) a triple-structured microstructure having a cone, an upper truncated cone, and a lower truncated cone connected from the tip to the bottom of the microstructure, wherein the aspect ratio between the diameter of the conical bottom surface (W ₁₎ and height (h ₁₎ than (w _1: h ₁₎ is 1: 5 to 1: 1.5, the diameter of the bottom surface of the upper truncated cone (w ₂₎ and the height (h ₂ ) The aspect ratio (w ₂ :h ₂ ) is 1:5 to 1:1, and the aspect ratio (w:h) between the diameter (w) and the height (h) of the bottom surface of the lower truncated cone is 1 : 5 to 1:2. The method for producing a microstructure according to claim 10, wherein the step (c) is carried out at (i) at room temperature for 36 to 60 hours, or at (ii) 40 to 60 ° C for 5 to 16 hours, or It is carried out at (iii) a temperature of 60-80 ° C for 2-4 hours. The method for producing a microstructure according to claim 10, wherein the biocompatible polymer is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, alginic acid, pectin, carrageenan, chondroitin sulfate, and sulfuric acid. Sugar, chitosan, polylysine, collagen, gelatin, carboxymethyl chitosan, fibrin, agarose, amylopectin polylactic acid, polyglycolide, polylactic acid-glycolic acid copolymer, poly Anhydride, polyorthoester, polyether ester, polycaprolactone, polyester decylamine, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, propylene substituted Cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, Polyvinylimidazole, chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, One or more polymers of a cyclodextrin and a copolymer of a plurality of monomers forming these polymers and a group consisting of cellulose. The method for producing a microstructure according to claim 12, wherein the hyaluronic acid has a molecular weight of 240 to 490 kDa. The method for producing a microstructure according to claim 10, wherein, in the above step (a), the solid content of the biocompatible polymer is 1 to 30 with respect to the total composition of the microstructure. %(w/v). The method for producing a microstructure according to claim 10, wherein the binder is selected from the group consisting of ruthenium, polyurethane, hyaluronic acid, physical binder (gecko), polyacrylic acid, ethyl cellulose, and hydroxymethyl cellulose. And one or more substances selected from the group consisting of ethylene vinyl acetate and polyisobutylene. The method for producing a microstructure according to claim 10, wherein in the method for producing the microstructure, the plurality of microstructures are formed in a hexagonal shape. The method of producing a microstructure according to claim 16, wherein the plurality of microstructures are arranged at intervals (p) of 250 to 1500 μm.