KR20220141235A - Microneedle array and fabrication method thereof - Google Patents

Abstract

Disclosed are a microneedle array which has a specific shape and is designed to allow extremely long microneedles to be disposed at a high density per unit area, so as to have excellent skin penetration ability when applied to the skin as a transdermal patch, and a fabrication method thereof. The microneedle array of the present invention includes a substrate and a plurality of microneedles.

Description

Microneedle array and manufacturing method thereof

The present invention discloses a microneedle array having excellent skin insertion ability and a method for manufacturing the same.

The microneedle is a system for delivering drugs to the epidermis and dermis through the stratum corneum of the skin using microneedles within a length of several hundred micrometers.

In order to increase the drug delivery efficiency, excellent skin insertion ability is required to pass through the stratum corneum, and accordingly, the type and composition ratio of the composition constituting the microneedle as well as structural factors such as the length, number per unit area, and shape of the microneedle are required. design is becoming increasingly important.

KR 10-2018-0127093A proposes a soluble microneedle having a length of 500 to 950 μm, and when a microneedle transdermal patch having a number of soluble microneedles per unit area of the support of 0.2 to 0.5 pieces/mm ² is used, per unit area in the skin It is disclosed that the insertability is very good.

The soluble microneedle follows a method in which a drug is released while the microneedle made of a biodegradable material is decomposed in the body. These soluble microneedles are relatively easy to manufacture and have advantages of low manufacturing cost, but have disadvantages in that mechanical strength and physical stability are low and capacity is limited.

In order to increase the insertion ability per unit area in the skin, it can be achieved by increasing the length of the microneedles and increasing the number of microneedles per unit area, that is, the degree of integration. However, as the length increases, the strength of the microneedles decreases, and as the degree of integration increases, the spacing between the microneedles becomes narrower, resulting in a decrease in insertability called the bed nail effect.

The main method for the manufacture of soluble microneedles is to dissolve a drug in a biocompatible polymer, then drop it on a mold having an intaglio structure, dry it, and remove the mold.

This manufacturing method has limitations in increasing the length and integration degree of the microneedle. Moreover, when the manufacturing method of each sub-unit microneedle is applied to mass production, it is difficult to secure a desired manufacturing cost ratio in terms of cost and manufacturing efficiency for facility construction.

KR 10-2017-0000800A discloses that mass production and continuous process of microneedles are possible by using centrifugal force after injecting a solution into a mold. However, in this method, the microneedle is manufactured by rotating the mold so that the engraved pattern surface of the mold is in the direction of centripetal force, but the shape of the manufactured microneedle is limited because the intaglio pattern surface is curved in the direction of the rotation axis. . In addition, it is judged that the manufacturing step is complicated and the possibility of scale-up to mass production is very low.

KR 10-2018-0127093A (2018.11.28) KR 10-2017-0000800A (2017.01.03)

The present applicant selected the shape, length and density of the microneedle among the parameters related to the ability to insert into the skin and studied the design and manufacturing method of the microneedle. Microneedles with insertability could be manufactured.

Accordingly, the present invention is to provide a microneedle array and a method for manufacturing the same.

The present invention includes a substrate in close contact with the skin; It provides a microneedle array comprising a; a plurality of microneedles having a pointed tip formed at the end and arranged at regular intervals in the vertical and horizontal directions on one surface of the substrate.

In this case, the length of the microneedles from the substrate is 700 to 1,000 μm, and the number of microneedles per unit area of the substrate (1 cm x 1 cm) includes 25 (5x5) to 64 (8x8).

The microneedle has one tip selected from the group consisting of a cone, a triangular pyramid, a quadrangular pyramid, a pentagonal pyramid, a hexagonal pyramid, and a polygonal pyramid.

The microneedle has a cone or quadrangular pyramid tip.

The microneedle array has a yield strength of 1.4 to 2.3 N/needle, and a breaking strength of 50N or more.

In addition, the insertion ability per unit area in the skin of the microneedle is 90% or more.

The microneedle contains a biocompatible polymer.

The biocompatible polymer is hyaluronic acid, carboxymethyl cellulose, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan Polylactide, polyglycolide, polyvinyl alcohol, polylactide-glycolide copolymer, pullulan polyanhydride, polyorthoester, polyether ester, polycaprolactone, polyesteramide, poly(butyric acid) , poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole) , chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cyclodextrin, from the group consisting of cellulose and copolymers thereof. It is one or more selected.

In addition, the present invention is the microneedle array; And it provides a microneedle transdermal patch comprising an adhesive sheet to which at least one microneedle array is attached.

In addition, the present invention,

Dropping a composition for manufacturing microneedles on a mold;

inserting a plurality of molds in which the composition for manufacturing the microneedle is dripped into a multi-stage cartridge;

rotating the multi-stage cartridge;

Drying after drawing out a plurality of molds from the multi-stage cartridge; and

It provides a method of manufacturing a microneedle array comprising the step of taking out the microneedle array from the mold.

At this time, the mold in the multi-stage cartridge during the rotation is performed by disposing in a direction perpendicular to the axis of rotation.

The microneedle array according to the present invention has a plurality of microneedles having a specific shape, and each microneedle has an extremely long length and is designed to exist at a high density per unit area, so that when applied to the skin as a transdermal patch, excellent skin It has the ability to insert.

In addition, by controlling the yield strength and breaking strength of the microneedle by the manufacturing method using centrifugal force, there is no occurrence of breakage when the microneedle array is separated from the mold, and the shape of the tip can also be manufactured without bending.

This manufacturing method is easy to apply to a mass production process through scale-up as it is possible to manufacture a microneedle array from a plurality of molds using a multi-stage cartridge.

1 is a flowchart illustrating a method of manufacturing a microneedle array according to the present invention.
2 is a photograph of a mold having a needle-shaped groove.
3 is a cross-sectional view showing a multi-stage cartridge.
4 is a cross-sectional view showing that the mold is inserted into the multi-stage cartridge.
5 is a cross-sectional view showing the rotation of the multi-stage cartridge in a vertical state.
6 is a three-dimensional drawing image designed to have various numbers per unit area.
7 is an optical microscope image according to the number of microneedles per unit area of a quadrangular pyramid shape.
8 is a picture of a parafilm model to which a microneedle is applied.
9(a) and 9(b) are images and photos of a texture analyzer used to measure yield strength.
10(a) and 10(b) are pictures of a texture analyzer used to measure breaking strength.
11 is a graph showing the final depth at which invasion is possible.
12 is a photograph showing a stained hole on the skin surface per unit area.

The present invention proposes a microneedle array and a method for manufacturing the same, which are designed so that extremely long microneedles exist at a high density per unit area in order to improve the skin insertion ability, and enable the manufacturing of the designed microneedles.

microneedle array

As used herein, the term “microneedle” refers to a needle-shaped structure having a length in micrometers (μm). The microneedle is made with a sharp tip formed at the end, and the drug is delivered through the hole formed by forming a hole in the stratum corneum, the outermost layer of the skin. In addition, since the length of the microneedle is very short and has an appropriate length that does not affect nerve cells, almost no pain occurs.

In addition, the term "microneedle array" as used in the present invention refers to a structure including one or more or a plurality of microneedles so as to pierce the stratum corneum to facilitate transdermal delivery of a therapeutic agent through or into the skin or sampling of a fluid. means

Unless otherwise stated herein, microneedles are soluble microneedles. The soluble microneedle is a microstructure that is completely dissolved into the application site of the skin to deliver the drug.

In order to improve the skin insertion ability of the microneedle,

(1) The length of the microneedle should be long;

(2) The number of microneedles present per unit area should be large,

(3) sufficient strength to withstand insertion into the superficial and/or stratum corneum of the skin;

(4) elasticity and flexibility so as not to cause pain or bleeding locally inserted into the superficial and/or stratum corneum of the skin, and

(5) It should have subcutaneous solubility or biodegradability of the subcutaneously inserted microneedle part.

Therefore, in the present invention, extremely long microneedles were designed to exist at a high density per unit area.

The microneedle array according to the present invention comprises: a substrate in close contact with the skin; It includes a; a plurality of microneedles formed with a sharp tip formed at the end and arranged at regular intervals in the vertical and horizontal directions on one surface of the substrate.

At this time, the length of the microneedles from the substrate is 700 to 1,000 μm, and the number of microneedles per unit area (1 cm x 1 cm) of the substrate expressed in the degree of integration is 25 (5x5) to 64 (8x8).

In addition, the shape of the microneedle of the present invention has one tip selected from the group consisting of a cone, a triangular pyramid, a quadrangular pyramid, a pentagonal pyramid, a hexagonal pyramid, and a polygonal pyramid. If necessary, it may have a polygonal body, such as a cylindrical, triangular, or rectangular body. As an example, the microneedle may be in the form of a cylindrical or quadrangular body in which the tip of the cone or quadrangular pyramid is formed.

Test Example of the present invention Differently, microneedles having various types of pyramids such as cones, triangular pyramids, quadrangular pyramids, pentagonal pyramids and hexagonal pyramids were prepared, and their physical properties and skin insertion ability were measured. As a result, in the case of having a cone and a quadrangular pyramid, the ability to insert into the skin was superior to that of other types of pyramid.

At this time, the shape of the microneedle may not form a stage in the middle, or may form a stage in one, two or three stages in the middle. In addition, the microneedle may be hollow, porous, or include a hollow part.

According to an embodiment of the present invention, it was confirmed that the yield strength and breaking strength characteristics of the microneedles were excellent even when the length and the number per unit area of the microneedles were excellent, and the skin insertion ability was improved.

The length of the microneedles 700 to 1,000 μm measured from the top of the substrate and the number per unit area of the substrate as defined in the present invention are limited in a number of patents. However, it is very difficult to implement the limited length and degree of integration of the microneedle in the conventional molding method. In addition, even if implemented, when the microneedles are formed with a long length or high integration, it is difficult to secure sufficient strength, so that when the microneedles are separated from the mold, the microneedles are broken or it is difficult to insert the microneedles into the skin surface layer and/or the stratum corneum. In addition, in the manufacturing process, when the microneedle is formed with a high degree of integration, it is not easy to manufacture the mold, and even if it is manufactured, the composition for forming the microneedle in the mold is not sufficiently inserted or dripped, so it is difficult to manufacture it in the shape of the tip of a cone or square pyramid.

Additionally, the aspect ratio of the microneedle of the present invention is such that the diameter * length is 1:1.1 to 1:2.5, 1:1.2 to 1:2. The diameter of the microneedle means the diameter of the bottom surface of the microneedle connected to the support. The diameter of the microneedle may be 300 to 700 μm. According to one embodiment, when the diameter of the bottom surface of the microneedle connected to the support is 500 μm, the length of the microneedle has an excellent effect when it has a length of 700 to 1000 μm.

In addition, the angle of the distal tip of the microneedle of the present invention has 40 degrees or less. The angle of the tip of the microneedle is related to skin penetration, and the lower the angle, the better the insertion ability into the skin. The shorter the length of the microneedle, the greater the angle, and in this case, the penetration into the skin is lowered. When the length is extremely long as in the present invention, the tip angle can also be very low, and has a very sharp tip of 40 degrees or less, preferably 5 to 40 degrees.

On the other hand, since the conventional molding method is manufactured on a laboratory scale, when it is applied to mass production, it is difficult to secure a desired manufacturing cost ratio in terms of cost and manufacturing efficiency for facility construction. This is achieved by the method for manufacturing a microneedle array using the centrifugal force of the present invention, which will be described below.

1 is a flowchart illustrating a method of manufacturing a microneedle array according to the present invention. Referring to FIG. 1, the manufacturing method of the microneedle array is shown.

(S1) dripping a composition for manufacturing microneedles on a mold;

(S2) inserting a plurality of molds in which the composition for manufacturing the microneedle is dripped into the multi-stage cartridge;

(S3) rotating the multi-stage cartridge;

(S4) taking out a plurality of molds from the multi-stage cartridge and drying the molds; and

(S5) It is manufactured including the step of withdrawing the microneedle array from the mold.

Hereinafter, each step will be described in detail.

(S1) Step of dripping the composition for manufacturing microneedles into the mold

First, a composition for manufacturing a microneedle is prepared, and then it is dripped onto a mold.

The composition for preparing a microneedle may include a biocompatible polymer and, if necessary, further include a drug component in consideration of the subcutaneous solubility or biodegradability of the microneedle inserted subcutaneously.

Biocompatible polymers include hyaluronic acid (HA), carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine (polylysine), collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polyvinyl alcohol (PVA), polylactide-glycolide copolymer ( PLGA), pullulan polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly(butyric acid), poly( valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfo Chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose ( HPC), cyclodextrin, cellulose, and may be at least one selected from the group consisting of copolymers thereof.

Drugs for microneedles are not limited in the present invention, and chemical drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, nanoparticles, functional cosmetic drugs, and cosmetic ingredients may be used.

Preferably, the drug that can be used in the present invention is, for example, an anti-inflammatory agent, an analgesic agent, an anti-arthritic agent, an antispasmodic agent, an anti-depressant agent, an anti-psychotic agent, a nerve stabilizer, an anti-anxiety agent, an opioid antagonist, an anti-Parkin's disease drug, a cholinergic agent Nest, anticancer drug, antiangiogenic inhibitor, immunosuppressant, antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormone, coronary, cerebrovascular or peripheral vasodilator, contraceptive, antithrombotic , diuretics, antihypertensive agents, cardiovascular disease treatment agents, cosmetic ingredients (eg, anti-wrinkle agents, skin aging inhibitors and skin whitening agents), and the like, but are not limited thereto.

The composition for preparing microneedles of the present invention has a viscosity of 300 to 1000 cPs, and a final concentration of 10 to 25 wt% using a hydrophilic solvent. If the viscosity is less than or exceeding the above range, loss of the casting solution and mass deviation between patches occur, so it is appropriately used within the above range.

The hydrophilic solvent may include, for example, water, ionized water, physiological saline, distilled water, purified water, and sterile purified water, but is not limited thereto, and is preferably purified water.

If necessary, the composition may further include a solubilizer, a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, etc. according to the purpose of use.

The mold has a needle-shaped groove as shown in FIG. 2 .

The engraved mold having a needle-shaped groove may be made of one or more materials selected from the group consisting of silicone-based polymers, fluorine-based polymers, UV-curable polymers, thermosetting polymers, thermoplastic polymers, ceramic oxides, and metallic inorganic materials, but is not limited thereto. does not

For example, the mold may be manufactured using micro-machining technology to arrange needles having a embossed pyramid shape at regular intervals. The micromold uses a mold made of a PDMS material.

For the drop of the composition for manufacturing microneedles, a method commonly used in this field may be used. If necessary, the loss of the drug and the composition can be prevented as much as possible by performing the reduced pressure under vacuum by dropping.

If necessary, one or more surface treatment processes selected from the group consisting of plasma treatment, self-assembly monolayer (SAM) treatment, and surface deposition in the groove to improve release or wetting of the composition filled in the mold may have been treated with Specifically, a hydrophilic surface treatment by plasma treatment and a hydrophobic release treatment by SAM treatment can be performed on a mold having a needle-shaped groove.

(S2) Step of inserting the mold into the multi-stage cartridge

Next, the mold in which the composition for forming microneedles obtained in S1 is dripped is inserted into the multi-stage cartridge.

3 is a cross-sectional view showing the multi-stage cartridge 200 . Although the multi-stage cartridge 200 is shown in a cylindrical shape, it may have various shapes depending on the rotating device.

The multi-stage cartridge 200 includes a cylindrical housing 201 and a guide portion 210 provided with a protruding rib 220 for accommodating a mold on an inner wall thereof. The guide part 210 is fastened to the inner circumferential surface of the housing 201 .

Inside the multi-stage cartridge 200 there is a cavity (A) for accommodating the mold, which has a plurality of compartments by the protruding ribs (220).

As shown in FIG. 4 , a plurality of cavities A exist in a horizontal and vertical direction, and one mold 100 is inserted into one cavity A. The number of the cavities (A) may be at least one or more and up to 30, and the size and number may further increase depending on the device used in the subsequent rotation step.

(S3) Multi-stage cartridge rotation step

In S2, the multi-stage cartridge 200 into which the mold 100 is inserted is mounted on a rotating device and then rotated to apply centrifugal force to the mold 100.

The engraved pattern of the mold 100 has a length equal to the length of the microneedle of 700 to 1,000 μm, which has a microchannel at the capillary level. The movement of the composition is stopped by the capillary pressure of the intaglio pattern through simple dripping, so it is not easy to move the composition to the end of the intaglio pattern. However, by increasing the fluidity of the composition in the mold by centrifugal force due to rotation, the composition can be inserted into the intaglio pattern of the mold 100 .

At this time, as shown in FIG. 5 , the multi-stage cartridge 200 is disposed in the vertical direction with respect to the rotation axis C, so that the centrifugal force F in the vertical direction acts within the mold 100 . If it is rotated by being disposed in a horizontal direction with respect to the rotation axis C, a centrifugal force R in the horizontal direction is applied to each mold 100 so that the intaglio pattern surface is curved in the direction of the rotation axis. The curved microneedle has a problem in that penetration into the skin is lowered. In addition, damage or deformation may occur in the process of separating the microneedle array from the mold 100 due to the curved surface phenomenon.

The centrifugal force is preferably applied at a sufficient level, for example, at 2000 to 5000 rpm for 5 to 30 minutes. In this case, the centrifugal force application device may be any device capable of rotation.

(S4) Mold extraction and drying step

Next, the mold is taken out from the multi-stage cartridge to perform drying.

Drying is not particularly limited in the present invention, and known devices and methods may be used. For example, when the hydrophilic solvent is water, it is dried under reduced pressure at 35 to 50°C.

(S5) microneedle array withdrawal step

Next, the microneedle array is separated from the mold and recovered.

The soluble microneedle array of the present invention prepared as above has a specific range of breaking strength and yield strength.

Breaking strength (or breaking strength) is a parameter related to the elasticity of the microneedle array. When the microneedle array is separated from the mold, a certain level of tensile force is applied to the microneedle array. At this time, if the microneedle array has low elasticity, the microneedle array separated from the mold or the microneedle is damaged.

When a certain level of force is applied to the microneedle array, when the stress disappears at the beginning of the deformation, it returns to its original state by the elastic force. destruction occurs in When the microneedle array of the present invention has a breaking strength of 50 N or more when applied at a tensile rate of 10 mm/min to be similar to the level generated during the manufacturing process, the microneedle array separated from the mold does not break.

Yield strength is the limiting stress at which elastic deformation occurs, and is a parameter related to the microneedle's ability to insert into the skin. That is, when the microneedle has low strength, it cannot penetrate the skin, making drug delivery difficult. For drug delivery, the microneedle's ability to insert into the skin should be inserted at least 90%, and when it has a yield strength of 1.4 to 2.3 N/needle under the conditions of compression displacement: about 1 mm, compression rate: 0.5 mm/sec, the 90% It is possible to achieve the above skin insertion ability.

In addition, since the microneedle array of the present invention can be manufactured using a multi-stage cartridge, it is easy to secure a desired manufacturing cost ratio in terms of cost and manufacturing efficiency for facility construction, so it is possible to solve the problem that mass production of the existing molding method is impossible. have.

In addition, it is possible to manufacture microneedles in which extremely long microneedles are formed with a high degree of integration, and the problem of breakage or deformation in the process of separating the microneedle array from the mold can be fundamentally avoided.

transdermal patch

In the present invention, the term “patch” refers to a formulation that is attached to the skin to deliver a drug into the body, and a transdermal patch refers to a patch capable of delivering a drug through the skin.

The microneedle transdermal patch of the present invention includes a microneedle array; and an adhesive sheet to which at least one microneedle array is attached.

The pressure-sensitive adhesive sheet may include, for example, silicone, polyurethane, polyethylene, polyester, polypropylene, polyvinyl chloride, hydrocolloid, or a mixture thereof.

The microneedle transdermal patch includes a microneedle array on one side, and a plurality of microneedles can be inserted into the skin by pressing. As the microneedle penetrating into the skin dissolves in the skin, the drug is rapidly injected into the skin.

For drug injection, the microneedle's ability to insert into the skin per unit area is 90% or more, preferably 95% or more, and more preferably 97% or more.

The soluble microneedle array according to the present invention has appropriate breaking strength and yield strength, and has excellent skin insertability and skin solubility after transdermal patch preparation, enabling stable drug delivery into the skin. In addition, since the manufacturing process is simple, the production of microneedles at a lower cost is possible, which is suitable for mass production.

[Example]

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1: Mold Manufacturing

After completing the three-dimensional drawing as shown in FIG. 6, a master mold made of resin was manufactured with a three-dimensional printer.

Thereafter, the PDMS solution was mixed well to completely remove air bubbles, and then injected into the master mold, and dried at 80° C. for 8 hours to cure. Then, the mold was separated from the master mold and the cast mold was recovered.

At this time, the engraved pattern of the mold was made so that the microneedle in the shape of a quadrangular pyramid could be formed, and the length was 1000 μm x the diameter was 500 μm. The number of pieces per unit area (1cm*1cm) was manufactured in three types: 10x10, 7x7, and 5x5.

Test Example 1: Microneedle Manufacturing and Evaluation

(1) Preparation of microneedle composition

Carboxymethylcellulose sodium (CMC Na) was used as a biodegradable polymer used as a material of the microneedle structure, and purified water was used as a solvent so that the final concentration was 3% of CMC Na to prepare a microneedle composition.

(2) Microneedle Array Manufacturing

100uL of the microneedle composition prepared in (1) was added dropwise to the mold prepared in Preparation Example 1. The mold was then placed on the cartridge and mounted on a centrifuge. Then, centrifugal force was applied at a speed of 3000 rpm for 15 minutes to inject the composition into the engraved pattern of the mold. In addition, the cartridge was rotated by placing it in a direction perpendicular to the rotation axis at 90 degrees.

Then, after taking out the mold from the cartridge of the centrifuge, it was dried for 4 hours at 40 °C, ≤ 20%RH temperature and humidity conditions.

Then, the microneedle array was separated from the mold.

(3) light microscopy analysis

To confirm the surface shape and microstructure of the microneedle array prepared in the above example, it was observed with an optical microscope (Olympus, SZX7), and the results obtained are shown in FIG. 7 .

Referring to FIG. 7 , it can be seen that the microneedles in the form of a quadrangular pyramid are formed in all of 10x10, 7x7, and 5x5 per unit area (1 cm*1 cm) of the substrate. In the case of the formed microneedle, no bending occurred, and there was no deformation even when separated from the mold. As a result, it can be seen that a microneedle array having a clean pattern can be manufactured as it is in the three-dimensional pattern of FIG. 5 .

[Test Methods]

A method for measuring the physical properties of a microneedle will be described.

(1) Yield strength

As shown in FIG. 8, after connecting to both ends of the base of the microneedle array, the resistance during compression was measured. Each result is an average of three specimens prepared in each Example.

<Yield strength measurement conditions>

Compression displacement: about 1 mm

Compression speed: 0.5 mm/sec

(2) Breaking strength

As shown in FIG. 9 , the strength at which the central part breaks when a tensile force is applied after being connected to both ends of the base of the microneedle array was measured according to the evaluation conditions specified below. Each result is an average of three specimens prepared in each Example.

<Conditions for measuring breaking strength>

Measuring area: 3 cm x 5 cm

Tensile speed: 10 mm/min

(3) The ability to insert into the skin by the parafilm model

In order to measure the skin insertion ability of microneedles, Ryan F. Donnelly's research team used a parafilm model proposed in 'A proposed model membrane and test method for microneedle insertion studies' international journal of pharmaceutics, 2014. Parafilm M ^® is a composite of hydrocarbon and polyolefin, and has a certain strength and elasticity just like skin. It has a thickness of about 125 μm per layer and becomes about 1 mm when 8 layers are stacked, providing depth to the epidermis and dermis. Therefore, it is being used as an appropriate in-vitro model to measure the skin insertion ability of microneedles.

The skin insertion ability evaluation of the microneedle array having a certain elasticity (breaking strength of 50N or more) among the microneedles was performed as shown in FIG. 10 to measure the final depth of invasion.

<parafilm model measurement conditions>

Thickness: about 1000μm (8 sheets)

Measurement time: 2 minutes

Invasive force: 20 N

(4) Measurement of skin insertion ability by pig skin model

The microneedle patch prepared in Example was attached to pig skin (0.8-1.2 mm) that was not exfoliated. After 2 minutes, the microneedle patch was removed, and 0.4% Trypan blue reagent was applied to the pig skin surface for about 10 minutes. After 10 minutes, after removing the remaining reagent, the number of stained holes on the skin surface was observed as shown in the result of FIG. 10 .

<Pig skin model measurement conditions>

Thickness: about 800~1200μm

Measurement time: 2 minutes

Invasive force: 20 N

Test Example 2: Evaluation and analysis of physical properties according to the shape of the microneedle

In order to compare the physical properties according to the shape of the microneedle, the microneedle was manufactured to have a size as shown in Table 1 below. The sample preparation process of the microneedle follows the process of Test Example 1. At this time, the diameter of the cone was 500 μm, and the horizontal * vertical diameter of the sagittal cone was 500 μm. In addition, the diameter of the base section of the triangular pyramid, pentagonal pyramid, and hexagonal pyramid was also set to 500 μm.

rescue sample 1 sample 2 sample 3 sample 4 sample 5 Number (1cm x 1cm) 10x10 (100) 10x10 (100) 10x10 (100) 10x10 (100) 10x10 (100) shape quadrangular pyramid cone triangular pyramid pentagonal hexagonal pyramid length 1000μm 1000μm 1000μm 1000μm 1000μm Yield strength (N/needle) 0.7 0.7 0.3 0.2 0.2 Breaking strength (N) 64.2 62.1 64.0 62.1 65.1 Parafilm Penetration Depth (Ratio) 750μm
(75%) 750μm
(75%) 375μm
(37.5%) 375μm
(37.5%) 375μm
(37.5%) Number of staining holes (ratio) 71
(71%) 72 pieces
(72%) 42 pieces
(42%) 50 pieces
(50%) 48 pieces
(48%)

Referring to Table 1, even when the microneedles of the same length have a quadrangular pyramid and a cone shape, the yield strength is higher than that of the triangular pyramid, pentagonal pyramid, and hexagonal pyramid shapes. In addition, in the parafilm penetration depth test related to the ability to insert into the skin, it can be seen that the microneedle having the tip of a quadrangular pyramid and conical shape is deeply inserted into the skin at about twice the level of microneedles of other shapes.

This was similarly expressed through the ratio of stained holes using the pig skin model.

Test Example 3: Evaluation and analysis of physical properties according to the length of the microneedle

In order to compare the physical properties according to the length of the microneedle, the microneedle was manufactured with the size shown in Table 2 below. The sample preparation process of the microneedle follows the process of Test Example 1, and the shape was designed in the form of a quadrangular pyramid showing excellent results in Test Example 2.

rescue sample 1 sample 2 sample 3 sample 4 Number (1cm x 1cm) 10x10 (100) 10x10 (100) 10x10 (100) 10x10 (100) shape quadrangular pyramid quadrangular pyramid quadrangular pyramid quadrangular pyramid microneedle length 1300μm 1000μm 700μm 400μm Yield strength (N/needle) 0.7 0.7 0.8 0.2 Breaking strength (N) 32.2 64.2 70.1 55.2 Parafilm Penetration Depth (Ratio) - 750 μm (75%) 625μm (89%) 125μm (30%) Number of staining holes (ratio) - 71 (71%) 85 (85%) 20 (20%)

Referring to Table 2, it was confirmed that the skin insertion ability was good when the microneedle length was 700 ~ 1000 μm. However, sample 1 with a long length of microneedle had low elasticity and low breaking strength, so it was impossible to measure because the mold and the microneedle array were damaged when separated.

In the case of the microneedle of Sample 4, it was relatively shorter than the length of the microneedle of Sample 2, indicating a breaking strength of 50N or more, but a very low yield strength of 0.2 N/needle. Also, due to the short length of the microneedle, when examining the test related to the ability to insert into the skin, the result was as low as about 1/3 of that of the microneedle sample 2 having a length of 1000 μm.

Test Example 4: Evaluation and analysis of physical properties according to the number of microneedles per unit area

In order to compare the physical properties according to the number of microneedles per unit area, microneedles were manufactured in sizes as shown in Table 3 below. The sample preparation process of the microneedle follows the process of Test Example 1.

rescue sample 1 sample 2 sample 3 sample 4 sample 5 sample 6 sample 7 Count
(1cm x 1cm) 10x10 (100) 9x9 (81) 8x8 (64) 7x7 (49) 6x6 (46) 5x5 (25) 4x4 (16) shape quadrangular pyramid quadrangular pyramid quadrangular pyramid quadrangular pyramid quadrangular pyramid quadrangular pyramid quadrangular pyramid length 1000μm 1000μm 1000μm 1000μm 1000μm 1000μm 1000μm Yield strength (N/needle) 0.7 1.0 1.5 1.7 2.0 2.1 2.4 Breaking strength (N) 64.2 65.0 62.0 57.1 55.3 52.1 38.7 Parafilm Invasion Depth (Ratio) 750μm
(75%) 750μm
(75%) 1000μm
(100%) 1000μm
(100%) 1000μm
(100%) 1000μm
(100%) 750μm
(75%) Number of staining holes (ratio) 71
(71%) 58
(72%) 62 pieces
(97%) 48 pieces
(98%) 36 pieces
(100%) 25 pieces
(100%) 58
(72%)

rescue sample 8 sample 9 sample 10 sample 11 sample 12 sample 13 sample 14 Number (1cm x 1cm) 10x10 (100) 9x9 (81) 8x8 (64) 7x7 (49) 6x6 (46) 5x5 (25) 4x4 (16) shape cone cone cone cone cone cone cone length 1000μm 1000μm 1000μm 1000μm 1000μm 1000μm 1000μm yield strength
(N/needle) 0.7 1.1 1.4 1.7 2.1 2.1 2.5 Breaking strength (N) 62.1 63.0 60.0 58.1 56.3 54.1 35.7 Parafilm Invasion Depth (Ratio) 750μm
(75%) 750μm
(75%) 1000μm
(100%) 1000μm
(100%) 1000μm
(100%) 1000μm
(100%) 750μm
(75%) Number of staining holes (ratio) 72 pieces
(72%) 60 pieces
(74%) 63
(98%) 47 pieces
(96%) 36 pieces
(100%) 25 pieces
(100%) 58
(72%)

Referring to Table 3, when the number of microneedles per unit area is 25 (5x5) to 64 (8x8), when the same external force is transmitted, the force transmitted per microneedle increases, so that the yield and breaking strength of the microneedles is increased. and skin insertion ability was confirmed to be the best. However, when the number of microneedles is too small, although the strength is good, the breaking strength indicating elasticity is low, so that the tendency of the microneedles to break when separated from the mold was confirmed.

11 is a graph showing the final depth at which invasion is possible. Referring to FIG. 11 , the final depth of the 10x10 microneedles was 750 μm, and the 5×5 and 7×7 microneedles had 1000 μm, indicating that deeper penetration into the skin was possible.

12 is a photograph showing a stained hole on the skin surface per unit area. 12, it can be seen that, when looking at the 10x10 microneedles, some holes were not stained, and in the case of the 5x5 microneedles, all holes were stained.

This trend was similarly shown in Table 4 in the case of the shape of the microneedle as a cone.

100: mold
200: multi-stage cartridge
201: housing
210: guide unit
220: protruding ribs

Claims (12)

a substrate in close contact with the skin;
In the microneedle array comprising a; a plurality of microneedles having a pointed tip formed at the end and arranged at regular intervals in the vertical and horizontal directions on one surface of the substrate,
The microneedle array has a length of 700 to 1,000 μm from the substrate, and the number of microneedles per unit area of the substrate (1 cm x 1 cm) is 25 (5x5) to 64 (8x8).
According to claim 1,
The microneedle has a tip selected from the group consisting of a cone, a triangular pyramid, a quadrangular pyramid, a pentagonal pyramid, a hexagonal pyramid, and a polygonal pyramid, a microneedle array.
According to claim 1,
The microneedle array has a tip of a cone or a quadrangular pyramid.
According to claim 1,
The microneedle array is a soluble microneedle array.
According to claim 1,
The microneedle array has a yield strength of 1.4 to 2.3 N/needle, a microneedle array.
According to claim 1,
The microneedle array has a breaking strength of 50N or more, a microneedle array.
According to claim 1,
The microneedle array has an insertability of 90% or more per unit area in the skin, a microneedle array.
According to claim 1,
The microneedle array comprises a biocompatible polymer.
9. The method of claim 8,
The biocompatible polymer is hyaluronic acid, carboxymethyl cellulose, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan Polylactide, polyglycolide, polyvinyl alcohol, polylactide-glycolide copolymer, pullulan polyanhydride, polyorthoester, polyether ester, polycaprolactone, polyesteramide, poly(butyric acid) , poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole) , chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cyclodextrin, from the group consisting of cellulose and copolymers thereof. One or more selected, microneedle array.
The microneedle array according to any one of claims 1 to 9; and an adhesive sheet to which at least one microneedle array is attached.
Dropping a composition for manufacturing microneedles on a mold;
inserting a plurality of molds in which the composition for manufacturing the microneedle is dripped into a multi-stage cartridge;
rotating the multi-stage cartridge;
Drying after drawing out a plurality of molds from the multi-stage cartridge; and
withdrawing the microneedle array from the mold
The method for manufacturing a microneedle array according to any one of claims 1 to 9.
12. The method of claim 11,
A method of manufacturing a microneedle array, wherein the mold in the multi-stage cartridge is disposed in a direction perpendicular to the axis of rotation during the rotation.

Images