HK1252001B - Microstructure for percutaneous absorption, and method for preparing same - Google Patents

Description

Microstructure for percutaneous absorption and preparation method thereof

Technical Field

This patent application claims priority to Korean Patent Application No. 10-2015-0187700 filed with the Korean Intellectual Property Office on December 28, 2015, the disclosure of which is hereby incorporated by reference into this specification.

The present invention relates to a microstructure for percutaneous absorption and a preparation method thereof, and more particularly to a degradable microstructure containing a biocompatible polymer or a binder and a preparation method thereof.

Background Art

Drug delivery systems (DDS) are a series of technologies that deliver drugs to target sites such as cells and tissues by controlling their absorption and release. In addition to conventional oral administration, there are also transdermal delivery systems that can apply drugs topically, and research continues on their use for the effective and safe administration of pharmaceutical substances such as drugs. However, injection therapy has the following problems: the administration method is cumbersome and can be painful for the patient, and there are limitations on controlling the drug release rate beyond the temporary injection of the drug. To overcome the shortcomings of this injection therapy, research has been conducted on microstructures (microneedles) that are much smaller than syringe needles and less painful, and these are being used in a variety of fields, including drug delivery, blood collection, biosensors, and skin care.

Existing methods for preparing microneedles include U.S. Patent No. 6,334,856, “MICRONE EDLE DEVICES AND METHODS OF MANUFACTURE AND USE THEREOF,” and Korean Patent No. 10-0793615, “BIODｅｄｉｎｇ SOLID MICｒｅｎｅｕｒｏｌｅｕｍ ｍｅｔｈｏｄ ａｎｄ ｍｅｔｈｏｄ ｆｏｒ ｓｏｌｕｔｉｏｎ ｏｆ ...ｓａｎｄ ｍｅｔｈｏｄ.”

The above patents prepare microneedles by the following steps: injecting a biodegradable viscous substance into a micro-mold prepared by utilizing a curable polymer and drying it, then separating the microneedles from the mold (molding technology), or applying a biodegradable viscous substance for forming a biodegradable solid microneedle, drawing the biodegradable viscous substance applied by a frame patterned with pillars (pillars) and drying it, and then cutting the drawn degradable substance (drawing technology). However, due to the relatively low mechanical strength of the degradable polymer microstructures prepared by such existing preparation methods, there is a problem of bending or being broken during the penetration process of the skin. In particular, when a polymer derivative with high elasticity is used as a raw material, when preparing the microstructure by utilizing a molding technology or a drawing technology, there is a limitation that the structure of the desired shape cannot be uniformly formed, and there is a disadvantage that the mechanical strength of the microstructure required for skin penetration is difficult to meet.

The hyaluronic acid used in the present invention is a biodegradable polymer, and in the case of the structure prepared by hyaluronic acid, mean molecular weight is less, and more easily forms structure and viscosity is low, and the larger mechanical strength of molecular weight is higher, but viscosity becomes stronger. Due to this characteristic, generally speaking, low-molecular hyaluronic acid is used as the raw material of microstructure, but, in the case of using low-molecular hyaluronic microstructure, the problem of breaking or bending easily occurs in the skin penetration process. On the other hand, carboxymethyl cellulose (carboxymethyl cellulose, CMC) is mainly used as thickening agent (thickening agent) in pharmaceutics as cellulose derivative, is the biodegradable polymer with multiple molecular weight.

On the other hand, the angle of the tip of the existing microstructure is too large to be suitable for skin penetration, or even if the angle of the tip has a range that allows for easy skin penetration, it forms a structure that continuously increases from the tip to the bottom edge. Due to the resistance of the skin itself, it has the disadvantage of only penetrating to a very limited ratio of the height of the entire structure. In the case of a structure with a low aspect ratio (w:h, h/w), skin penetration itself is very difficult. In the case of a structure with a high aspect ratio, skin penetration is easy, but due to the relatively low mechanical strength, there is a problem of breaking or bending when penetrating the skin. In addition, since the existing microstructure has a structure that is difficult to overcome the elasticity and restoring force of the skin itself when penetrating the skin, it has the disadvantage of being easy to escape again after penetrating the skin.

In order to solve the above-mentioned problems, the present invention develops a method for preparing a microstructure using low-molecular-weight hyaluronic acid and carboxymethyl cellulose, which has mechanical strength suitable for skin penetration and is easily dissolved or swelled in the skin, thereby being suitable for drug delivery or skin beauty. A biocompatible polymer and a method for preparing a microstructure using the biocompatible polymer as the main material are developed.

Throughout this specification, reference is made to various papers and patent documents, and their citations are shown. The disclosures of the cited papers and patent documents are fully incorporated into this specification as references to further clarify the state of the art and the content of the present invention.

Summary of the Invention

Technical issues

The present inventors have made intensive research efforts to solve the problems of the above-mentioned prior art. As a result, the present inventors have prepared microstructures by using hydrogels formed by biocompatible polymers. In particular, the present inventors have developed microstructures that are easy to penetrate the skin by preparing microstructures with various ranges of tip angles and diameters. The present inventors have ensured the best tip angle for penetrating the skin by optimizing the aspect ratio (w:h) formed by the diameter (w) and height (h) of the bottom surface of the microstructure. In addition, a double or triple structure (type B, C and D microstructures of the present invention) is applied to the microstructure to maximize the mechanical strength, and a hexagonal pattern is applied to the arrangement of the microstructures so that uniform pressure is applied to the entire microstructure when the skin is attached. Finally, the present invention is completed by confirming that the active ingredients carried by the microstructure can be stably delivered to the biological body.

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

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

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, the scope of the claims and the accompanying drawings.

Solutions to the Problem

According to one embodiment of the present invention, the present invention provides a microstructure comprising a biocompatible polymer or a binder, wherein the aspect ratio (w:h) formed by the diameter (w) and height (h) of the bottom surface is 1:5 to 1:1.5, and the angle (α) of the distal tip is 10° to 40°.

The present inventors have made a lot of efforts to solve the problems of the prior art as described above. As a result, they have developed microstructures that are easy to penetrate the skin by preparing microstructures using biocompatible polymers, and in particular, by preparing microstructures with various ranges of tip angles and diameters. The present inventors ensured the optimal tip angle for penetrating the skin by optimizing the aspect ratio (w:h) formed by the diameter (w) and height (h) of the bottom surface of the microstructure. In addition, a double or triple structure (type B, C and D microstructures of the present invention) is applied to the microstructure to maximize the mechanical strength. The arrangement of the microstructures adopts a hexagonal model so that uniform pressure is applied to the entire microstructure when the skin is attached. Ultimately, it was confirmed that the active ingredients carried by the microstructure can be stably delivered into the living body.

The term "biocompatible polymer" in this specification is selected from hyaluronic acid (HA), carboxymethyl cellulose, alginic acid, pectin, carrageenan, chondroitin (sulfuric acid), dextran (sulfuric acid), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactic acid, polyglycolide (PGA), polylactide-co-glycolide (PLGA), pullulan polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic acid-substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonic acid polyolefin (chlorosulfonic acid polyolefin), One or more polymers selected from the group consisting of polyolefins, polyethylene oxide, polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), cyclodextrin, copolymers of multiple monomers forming these polymers, and cellulose.

The term "binder" in this specification refers to one or more binders selected from the group consisting of silicone, polyurethane, hyaluronic acid, physical adhesive (gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, ethylene vinyl acetate and polyisobutylene.

The term "hyaluronic acid" in this specification is not only used to represent hyaluronic acid, but also includes all hyaluronates (e.g., sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate and calcium hyaluronate) and mixtures thereof. According to an example of the present invention, the molecular weight of the hyaluronic acid of the present invention is 100 to 5000 kDa. According to an example of the present invention, the molecular weight of the hyaluronic acid of the present invention is 100 to 4500, 150 to 3500, 200 to 2500 kDa, 220 to 1500 kDa, 240 to 1000 kDa or 240 to 490 kDa.

As used herein, "carboxymethyl cellulose (CMC)" may be any of various known carboxymethyl celluloses of various molecular weights. For example, the carboxymethyl cellulose used in the present invention may have an average molecular weight of 90,000 kDa, 250,000 kDa, or 700,000 kDa.

The present invention can provide a variety of microstructures, such as microneedles, microblades, microknives, microfibers, microwires, microprobes, microbarbs, microarrays, or microelectrodes. According to one embodiment of the present invention, the microstructure is a microneedle.

According to one embodiment of the present invention, the biocompatible polymer or binder of the present invention is contained at 1-5% (w/v). According to a specific embodiment of the present invention, the concentration of the hyaluronic acid or carboxymethyl cellulose of the present invention is 3% (w/v).

One of the greatest features of the microstructures of this invention is that, unlike existing ones, they utilize a double or triple structure to maximize mechanical strength. To achieve this, the aspect ratio (w:h) formed by the diameter (w) and height (h) of the microstructure's base, the angle (α) at the tip of the microstructure's end, and the diameter range (t) of the tip were optimized to create a microstructure that easily penetrates the skin.

The microstructures of the present invention prepared under the above conditions are represented by the shapes of types A to D in Figures 1a to 1d. Type A microstructures are ordinary conical; Type B is a dual structure of a cylinder and a cone; Type C is a dual structure of a deformed cylinder (truncated cone) and a cone; and Type D is a triple structure of two deformed cylinders (truncated cones) and a cone.

In one embodiment of the present invention, the aspect ratio (w:h) formed by the diameter (w) and height (h) of the bottom surface of the microstructure of the present invention is 1:5 to 1:1.5, and the angle (α) of the tip is 10° to 40°. According to another embodiment of the present invention, the aspect ratio is 1:5 to 1:2 (see Figures 1a to 1d).

In Figure 1a, type A is a conical microstructure, which can be represented by the base diameter (w), height (h), and tip angle (α). In one embodiment of the present invention, the aspect ratio (w:h) of type A is 1:5 to 1:1.5.

In Figure 1b, type B is a microstructure composed of a dual structure of cylinders and cones, which can be represented by the diameter (w), height ( _h1 ), and angle (α) of the cone's base; and the diameter (w) and height ( _h2 ) of the cylinder's base. According to one embodiment of the present invention, the aspect ratio of type B, _w1 : _h1, is 1:5 to 1:1.5, the aspect ratio of w: _h2 is 1:5 to 1:1.0, and the aspect ratio of w:h is 1:5 to 1:2. According to a specific embodiment of the present invention, the aspect ratio of w: _h2 is 1:1.4, and the ratio of _h1 : _h2 is 1.1:1. On the other hand, the optimal w:h aspect ratio of the type B microstructure of the present invention is 1:3, and the optimal structure pitch range is 1/2h to 2h.

In Figure 1c, a C-type microstructure is a dual structure of a truncated cone and a cone, which can be represented by the diameter (w ₁ ), height (h ₁ ), and angle (α) of the cone's base; and the diameter (w) and height (h ₂ ) of the truncated cone's base. According to one embodiment of the present invention, the C-type microstructure has an aspect ratio of w ₁ :h ₁ of 1:5 to 1:1.5, a ratio of w :h ₂ of 1:5 to 1:1.0, and a ratio of w :h 2 of 1:5 to 1:2. According to a specific embodiment of the present 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, the optimal w :h aspect ratio in the C-type microstructure of the present invention is 1:3, and the optimal inter-structure spacing is 1/2h to 2h.

In Figure 1d, type D is a microstructure composed of a triple structure of two truncated cones and a cone. This can be represented by the cone base diameter ( _w1 ), height ( _h1 ), and apex angle (α); the upper truncated cone base diameter ( _w2 ), height ( _h2 ); and the lower truncated cone base diameter (w) and height ( _h3 ). According to one embodiment of the present invention, the D-type has an aspect ratio of _w1 : _{h1 of} 1:5 to 1:1.5, an aspect ratio of w: _h2 and w: _h2 of 1:5 to 1:1.0, and an aspect ratio of w:h of 1:5 to 1:2.

According to a specific embodiment of the present invention, the w: _h2 aspect ratio is 1:1.5, the w: _h3 aspect ratio is 1:1, and the _h1 : _h2 : _h3 ratio is 1.5:1.5:1. On the other hand, in the D-type microstructures of the present invention, the optimal w:h aspect ratio is 1:3.5 to 1:4, and the optimal inter-structure spacing ranges from 1/2h to 2h.

The microstructure of the present invention can be prepared with a height of 80 μm to 1500 μm. According to a specific embodiment of the present invention, the height of the microstructure is 100 μm to 1300 μm.

According to one embodiment of the present invention, the diameter (t) of the tip of the terminal is 2 to 20 μm. The diameter (t) refers to the diameter of the cross-section of the tip of the terminal of the microstructure observed with a microscope or electron microscope at 40 to 250 times magnification.

According to one embodiment of the present invention, the mechanical strength (permeability, %) of the microstructure of the present invention is greater than 80. In another embodiment of the present invention, the mechanical strength is 80 to 100. In another embodiment of the present invention, the mechanical strength is 90 to 100. In another embodiment of the present invention, the mechanical strength is 95 to 100.

According to one embodiment of the present invention, the skin permeability of the B-D type microstructure having a double or triple structure is higher than that of the A type microstructure.

According to one embodiment of the present invention, the microstructure of the present invention further comprises an active ingredient in addition to the biocompatible polymer and the binder. For example, the active ingredient is a drug, a cosmetic ingredient (such as a whitening, wrinkle improvement, or other cosmetic ingredient), or a combination thereof. The microstructure of the present invention comprises the active ingredient, thereby effectively delivering the active ingredient to the skin.

According to an embodiment of the present invention, the microstructure of the present invention may further include metal, high molecular polymer or binder.

According to another embodiment of the present invention, the present invention provides a method for preparing a microstructure, comprising: step (a) providing a biocompatible polymer or adhesive to a micromold; step (b) injecting the biocompatible polymer or adhesive into the holes of the micromold; step (c) drying the biocompatible polymer or adhesive; and step (d) forming a microstructure by separating the micromold and the dried biocompatible polymer or adhesive.

The method of the present invention is described in detail in each step as follows:

Step (a): providing a biocompatible polymer or adhesive to the micro mold

In the present invention, first, a biocompatible polymer or a binder is provided to the micro mold.

The micro-mold of the present invention can be prepared using any micro-mold preparation method known in the art. For example, micro-electromechanical system (MEMS) preparation methods, photolithography (Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery, Journal of Controlled Release 104, 51-66, 2005) preparation methods, and soft lithography preparation methods can be used to prepare the micro-mold of the present invention, but are not limited thereto. In the case of soft lithography preparation methods, an elastomeric mold, such as polydimethylsiloxane (PDMS) or poly(methyl methacrylate) (PMMA), can be prepared and used in the preparation of the microstructure. The technology for preparing the polydimethylsiloxane mold is a plastic processing technology, and the desired mold structure can be obtained by various methods such as casting, injection molding, and hot-embossing. For example, a photosensitive material is coated on a substrate such as a silicon wafer or glass and patterned using a photomask to create a master. Using this master as a template, polydimethylsiloxane is cast and sintered to create a polydimethylsiloxane mold that functions as a stamp.

According to one embodiment of the present invention, the molecular weight of the hyaluronic acid is 240-490 kDa. According to a specific embodiment of the present invention, the average molecular weight of the hyaluronic acid is 360 kDa.

According to the present invention, in step (a), the solid content of the biocompatible polymer may be 1 to 30% (w/v) relative to the total microstructure components.

According to one embodiment of the present invention, in step (a), the concentration of the biocompatible polymer is 1-5% (w/v) relative to the total microstructure components. In a specific embodiment of the present invention, the concentration may be 3% (w/v).

Step (b): injecting biocompatible polymer or adhesive into the holes of the micro mold

Next, the biocompatible polymer or adhesive is injected into the holes of the micro mold.

According to one embodiment of the present invention, the injection of the present invention can be performed by (i) applying a centrifugal force of 800-1000 g to the micro mold after providing the biocompatible polymer to the micro mold, or (ii) performing the injection under a pressure of 500-860 mmHg.

For example, when the micromold is subjected to a centrifugal force of 800-1000 g, centrifugation can be performed at 800-1000 g for 10-20 minutes, or at 900 g for 15 minutes. Furthermore, when the micromold is subjected to vacuum pressure, the micromold can be injected at a pressure of 500-860 mmHg for 5-20 minutes, or at a pressure of 600-760 mmHg for 10-30 minutes.

According to a specific embodiment of the present invention, the biocompatible polymer is one or more polymers selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan, polylactic acid, polyglycolide, polylactide-glycolide copolymer, pullulan polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyamide ester, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic acid-substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonic acid polyolefin, polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, cyclodextrin, copolymers of multiple monomers forming these polymers, and cellulose. According to a specific embodiment of the present invention, the binder comprises one or more substances selected from the group consisting of silicone, polyurethane, hyaluronic acid, physical adhesive (gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, ethylene vinyl acetate and polyisobutylene.

Step (c): Drying of the biocompatible polymer or binder

After step (b), the biocompatible polymer or adhesive is dried.

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

Step (d): Separating the hyaluronic acid hydrogel cross-linked with the micromold

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

In the method for preparing the microstructure of the present invention, a plurality of microstructures can be formed by arranging in a quadrilateral or hexagonal manner. When the skin is attached, the microstructures prepared by using the hexagonal arrangement can transmit uniform pressure throughout the microstructure.

According to one embodiment of the present invention, the plurality of microstructures can be arranged at a pitch (p) of 250 to 1500 μm. In this case, approximately 25 to 1300 microstructures can be arranged per 1 cm ² (see Table 1).

Since the above-mentioned microstructures are common in the microstructure production method of the present invention, description of the common contents with the above-mentioned microstructures is omitted to avoid excessive complexity of this specification.

In another embodiment of the present invention, a microstructure is provided, characterized in that the shape is one of the shapes A to D in Figures 1a to 1d. The features of the microstructures of shapes A to D are as described above, and their description is omitted to avoid excessive complexity in this specification.

Effects of the Invention

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 preparing the same.

(b) The present inventors ensured the optimal tip angle and diameter range for skin penetration by optimizing the aspect ratio according to the morphology of each microstructure.

(c) In particular, Type B and Type C microstructures of the present invention minimize the penetration resistance caused by skin elasticity when attached to the skin, thereby increasing the permeability of the structure (60% or more) and the absorption rate of the active ingredient into the skin. Furthermore, Type D microstructures of the present invention maximize the mechanical strength of the structure by utilizing a triple structure, thereby facilitating skin penetration.

(d) In the present invention, when a hexagonal arrangement is applied to a plurality of microstructures, uniform pressure can be applied to the entire microstructure when the skin is attached.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1a to 1f illustrate microstructures prepared according to the method of the present invention, including the bottom diameter (w), height (h), tip angle (α), tip diameter (t), spacing between microstructures (p), and the range of microstructure pillar angles (β ₁ : 85-90°; β ₂ -β ₄ : 90-180°).

Figures 2a to 2d are scanning electron microscope (SEM) images of micro molds used in the method of the present invention: 2a: Type A, 2b: Type B, 2c: Type C, 2d: Type D.

3a to 3d are microscope photographs (Sunny SZMN, 40-70 times) showing types A to D of microstructures prepared according to the method of the present invention, respectively: 3a: Type A, 3b: Type B, 3c: Type C, 3d: Type D.

Figures 4a to 4d are electron microscope (SEM, JEOL JSM-7500F) photographs of microstructures of types A to D, respectively, prepared according to the method of the present invention. The arrows in Figure 4d indicate the measurement points for w ₁ , w ₂ , and w . 4a: Type A, 4b: Type B, 4c: Type C, 4d: Type D.

5a to 5e show the mechanical strength test results of type A to type D microstructures (5a-5d) and a pyramid-shaped comparison group (5e) prepared according to the method of the present invention.

Figures 6a to 6d show the experimental results of the skin penetration (depth) of microstructures prepared according to the method of the present invention (electron microscopic images of deformed microstructures after penetration into the skin). Figure 6a: Type A, Figure 6b: Type B, Figure 6c: Type C, and Figure 6d: Type D.

DETAILED DESCRIPTION

The present invention is further described in detail below by way of examples. These examples are only used to further illustrate the present invention. According to the gist of the present invention, the scope of the present invention is not limited to these examples, which will be apparent to those skilled in the art.

Example

Example 1: Preparation of microstructures

1. Preparation process of type A microstructure

After a positive or negative master mold is prepared on a silicon wafer using photolithography, a final negative mold is prepared from the master mold using curable silicone (polydimethylsiloxane).

Hyaluronic acid (HA) with an average molecular weight of 360 kDa (molecular weight range 240-490 kDa) (Bloomage Freda Biotechnology Co., Ltd., China) was used as a biocompatible polymer and completely dissolved in purified water at a concentration of 3% (w/v).

After providing the above-mentioned hyaluronic acid to the polydimethylsiloxane micromold, it was injected and dried at room temperature (25°C) for 48 hours, at 50°C for 6 hours, or at 70°C for 3 hours (without centrifugation and vacuum process), and then the mold was removed to prepare a hyaluronic acid microstructure.

2. Preparation process of type B microstructure

After a positive or negative master mold is prepared on a silicon wafer using a photolithography method, a negative mold is prepared from the master mold using curable silicone (polydimethylsiloxane).

Hyaluronic acid was used as the biocompatible polymer. Hyaluronic acid with an average molecular weight of 360 kDa (molecular weight range of 240 to 490 kDa) was completely dissolved in purified water at a concentration of 3% (w/v).

The hyaluronic acid was placed in a polydimethylsiloxane micromold and then injected into the pores formed in the micromold using a centrifuge at 900g for 15 minutes. After drying and injection at room temperature (25°C) for 48 hours, at 50°C for 6 hours, or at 70°C for 3 hours, the mold was removed to produce a hyaluronic acid microstructure.

3. Preparation process of C-type microstructure

After a positive or negative master mold is prepared on a silicon wafer using a photolithography method, a negative mold is prepared from the master mold using curable silicone (polydimethylsiloxane).

Hyaluronic acid was used as the biocompatible polymer. Hyaluronic acid with an average molecular weight of 360 kDa (molecular weight range of 240 to 490 kDa) was completely dissolved in purified water at a concentration of 3% (w/v).

After applying the hyaluronic acid to a polydimethylsiloxane micromold, the hyaluronic acid was injected into the pores formed in the micromold under a vacuum (600-760 mmHg) for 10-30 minutes. After drying and injection at room temperature (25°C) for 48 hours, at 50°C for 6 hours, or at 70°C for 3 hours, the mold was removed to produce a hyaluronic acid microstructure.

4. Preparation process of type D microstructure

After a positive or negative master mold is prepared on a silicon wafer using a photolithography method, a negative mold is prepared from the master mold using curable silicone (polydimethylsiloxane).

Carboxymethyl cellulose was used as the biocompatible polymer and was completely dissolved in purified water at a concentration of 3% (w/v).

After the carboxymethyl cellulose was applied to a polydimethylsiloxane micromold, it was injected into the pores formed in the micromold under a vacuum (600-760 mmHg) for 10-30 minutes. After drying and injection for 48 hours at room temperature (25°C), 6 hours at 50°C, or 3 hours at 70°C, the mold was removed to produce a hyaluronic acid microstructure.

5. Specification range of microstructures (Figures 1a to 1f)

Table 1

*Microstructure column angle range: β ₁ , 85° to 90° / β ₂ to β ₄ , exceeding 90° (90° to 180°)

Example 2. Mechanical strength test of microstructure

The mechanical strength of the microstructures prepared by the present invention was tested using pig skin. When the microstructures were infiltrated into pig skin with a predetermined force, the number of pores generated in the epidermis was confirmed and compared ( FIG. 5 a to FIG. 5 e ).

Each type of microstructure sample was cut into 0.7 cm x 0.7 cm pieces (100 or more structures) and then used to penetrate pig skin with a vertical force of 3 to 5 kg for 10 seconds. After skin penetration, the microstructure was removed and applied to the skin surface soaked with 20 ml of trypan blue (Sigma). The skin was stained for 10 minutes and then wiped clean with a cotton swab and physiological saline (phosphate buffered saline (PBS)). The mechanical strength of the microstructure that successfully penetrated the skin was evaluated by measuring the number of stained pores in the epidermis.

The mechanical strength was compared by conducting experiments on pyramid-shaped microstructures using the same method.

The mechanical strength of the microstructure according to the present invention is shown in the following table.

Table 2

The detailed specifications of the microstructures used in the above experiments are as follows.

Table 3

Example 3. Skin penetration (depth) experiment of microstructures

After the structures were infiltrated into pig skin with a predetermined force, the skin permeability of the microstructures prepared by the present invention was compared by confirming the degree of deformation of the structures before and after the penetration ( FIG. 6 a to FIG 6 d ).

Each type of microstructure sample was cut into 0.7 cm x 0.7 cm pieces and then penetrated into pig skin with a vertical force of 3 to 5 kg for 10 seconds to 30 minutes. The insertion site was observed using an optical microscope, and the degree of deformation of the microstructures before and after insertion was confirmed using a scanning electron microscope (SEM) to determine the penetration depth.

The skin permeability test results of the microstructures according to the present invention are shown in the following table.

Table 4

While specific aspects of the present invention have been described in detail above, it should be understood by those skilled in the art that these specific descriptions are merely preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention should be defined in accordance with the appended claims and their equivalents.

Claims (12)

1. A microneedle, characterized in that it comprises a biocompatible polymer or binder, The aforementioned biocompatible polymer or binder is hyaluronic acid with a molecular weight of 240–490 kDa. Multiple microneedles are arranged in a hexagonal shape. The aforementioned microneedle has a triple-tower structure, with the following parts arranged sequentially from the tip to the bottom: cone, upper truncated cone, and The lower part is a truncated cone. in, The aspect ratio _w1 :h1 between the diameter w1 of the base of the aforementioned cone and the height _h1 of the aforementioned cone _{is 1} :5 to 1:1.5; The aspect ratio _{w2 : h2} between the diameter _w2 of the base of the upper truncated cone and the height h2 of the upper truncated cone is 1:5 to 1:1.0; and The aspect ratio w:h between the diameter w of the base of the lower truncated cone and the height h of the microneedle is 1:5 to 1:2. The spacing between the microneedles ranges from 1/2h to 2h. The diameter t of the tip is 2–20 μm. The angle α of the tip ranges from 10° to 40°, and The angle _β3 between the upper frustum and the cone and the angle _β4 between the upper frustum and the lower frustum are obtuse angles, and _β3 is greater than _β4 . 2. The microneedles according to claim 1, characterized in that the biocompatible polymer further comprises one or more polymers selected from the group consisting of carboxymethyl cellulose, alginate, pectin, carrageenan, chondroitin (sulfuric acid), dextran (sulfuric acid), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactic acid, polyglycolic acid, polylactide-glycolic acid copolymer, pullulan polyanhydride, polyorthoester, polyether ester, polycaprolactone, polyamide ester, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic acid-substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazolium), chlorosulfonic acid polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, cyclodextrin, copolymers of multiple monomers forming these polymers, and cellulose. 3. The microneedles according to claim 1, wherein the binder further comprises one or more substances selected from the group consisting of silicone, polyurethane, physical adhesive (Gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, ethylene vinyl acetate and polyisobutylene. 4. The microneedle according to claim 1, wherein the height of the microneedle is 80 μm to 1500 μm. 5. The microneedle according to claim 1, wherein the microneedle further comprises a metal, a polymer, or a binder. 6. The microneedle according to claim 1, wherein the microneedle further comprises effective components other than biocompatible polymers and binders. 7. A method for preparing microneedles according to claim 1, characterized in that it comprises: Step (a) involves providing a biocompatible polymer or binder to the micromold; Step (b): Inject the above-mentioned biocompatible polymer or binder into the pores of the micromold; Step (c) involves drying the aforementioned biocompatible polymer or binder; and Step (d) involves forming microneedles by separating the aforementioned micromold from a dried biocompatible polymer or binder. The aforementioned biocompatible polymer or binder is hyaluronic acid with a molecular weight of 240–490 kDa. Multiple microneedles are arranged in a hexagonal shape, and The injection is performed inside the micromold under a pressure of 500–760 mmHg. 8. The method according to claim 7, characterized in that step (c) above... (i) Conduct at room temperature for 36–60 hours. (ii) Perform at a temperature of 40–60°C for 5–16 hours, or (iii) Perform at a temperature of 60–80°C for 2–4 hours. 9. The method for preparing microneedles according to claim 7, characterized in that the above-mentioned biocompatible polymer further comprises one or more polymers selected from the group consisting of carboxymethyl cellulose, alginate, pectin, carrageenan, chondroitin (sulfuric acid), dextran (sulfuric acid), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibroin, agarose, pullulan polylactic acid, polyglycolic acid, polylactide, polylactide-glycolic acid copolymer, pullulan polyanhydride, polyorthoester, polyether ester, polycaprolactone, polyamide ester, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic acid-substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazolium), chlorosulfonic acid polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, cyclodextrin, copolymers of multiple monomers forming these polymers, and cellulose. 10. The method according to claim 7, wherein in step (a) above, the solid content of the biocompatible polymer is 1 to 30% (w/v) relative to the total microneedle composition. 11. The method according to claim 7, wherein the adhesive further comprises one or more substances selected from the group consisting of silicone, polyurethane, physical adhesive (Gecko), polyacrylic acid, ethyl cellulose, hydroxymethyl cellulose, ethylene vinyl acetate and polyisobutylene. 12. The method according to claim 7, wherein the plurality of microneedles are arranged at a spacing p of 250 to 1500 μm.