Porous microneedle, microneedle patch including the same, and method for producing such microneedle

Abstract

To provide a microneedle patch including a porous microneedle or a microneedle array having high mechanical strength and capable of quickly and simply collecting a body fluid such as an intercellular fluid by capillary force.SOLUTION: Provided is a method for producing a porous microneedle or a microneedle array, including: (a) providing a female-shaped mold having a cavity portion with a plurality of mold shapes and a lid member having a core portion; (b) injecting a solution A containing a biodegradable material into the cavity portion to fill the mold shape; (c) inserting the core portion into the cavity portion and covering the female-shaped mold with the lid member; and (d) contacting the solution A injected into the cavity portion with a non-solvent for the biodegradable material to elute the biodegradable material and form a porous microneedle or a porous microneedle array.

Description

[Technical Field]

[0001] The present invention relates to a porous microneedle, a microneedle patch including the same, a method for manufacturing the microneedle, and a method for manufacturing the microneedle patch. [Background technology]

[0002] In recent years, many point-of-care testing (POCT) devices have been developed that enable rapid and easy disease testing and diagnosis, as well as health monitoring. To live a healthy life, it is essential to monitor biomarkers, such as blood glucose and cholesterol levels, which are closely related to lifestyle-related diseases. Conventional testing and diagnosis require blood samples to be collected using a syringe or urine or tear samples to measure multiple biomarkers. However, using a syringe involves pain and bleeding with each measurement, placing a significant burden on the patient. Furthermore, urine and tear samples have a large margin of error compared to the biological information in the blood, resulting in unreliable measurements.

[0003] On the other hand, interstitial fluid present in the skin has attracted attention as a promising alternative sample to blood for measuring biomarkers because it has a composition similar to that of plasma. However, a method for extracting interstitial fluid has not yet been established, and a simple and minimally invasive method for extracting interstitial fluid is needed.

[0004] Microneedles, with their thin needle structure of less than 1 mm in length, are shorter than conventional injection needles and have attracted attention as a painless, minimally invasive biosensor device. Among these, hollow microneedles with a fine hollow structure and expandable microneedles using hydrogels have been reported for the extraction of body fluid samples. However, they are known to have problems such as being made of fragile metals or requiring complex post-processing. In recent years, microneedles made of biocompatible polymers have also been developed, but various challenges remain before microneedle devices can be used for biosensors, including the complex fabrication process and the lack of sufficient mechanical strength. DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a method for producing porous microneedles or an array thereof, and a microneedle patch comprising the same, simply and quickly under a room temperature environment. Another object of the present invention is to provide a microneedle patch equipped with porous microneedles or a microneedle array that has high mechanical strength and allows for quick and easy collection of bodily fluids such as interstitial fluid by capillary force. [Means for solving the problem]

[0006] The present inventors have conducted extensive research aimed at solving the above problems, and have focused on a non-solvent-induced phase separation method (NIPS), which differs from conventional methods for producing porous microneedles, and have found that by using this phase separation method, porous microneedles or arrays thereof, and microneedle patches comprising the same, can be produced simply and quickly in an ambient temperature environment. Furthermore, the present inventors have found that the porous microneedles thus obtained have high mechanical strength, leading to the completion of the present invention.

[0007] That is, the present invention has the following configuration. [1] (a) A step of providing a female mold having a cavity portion with a plurality of mold shapes and a cover member having a core portion. (b) injecting a solution A containing a biodegradable material into the cavity to fill it into the mold shape; (c) inserting the core into the cavity and closing the female mold with a cover; (d) contacting the solution A injected into the cavity with a non-solvent for the biodegradable material to elute the biodegradable material and form porous microneedles or a porous microneedle array; A method for producing a porous microneedle or a porous microneedle array, comprising: [2] The manufacturing method described in [1], wherein when the core part is inserted into the cavity part, a liquid reservoir consisting of a portion of the solution A injected into the cavity part is formed between at least one side surface of the cavity part and at least one side surface of the core part. [3] The manufacturing method according to [1] or [2], which includes a step of dissolving bubbles in solution A by ultrasonic degassing treatment and discharging the bubbles into a liquid tank. [4] The manufacturing method according to any one of [1] to [3], wherein at least one of the female shaped mold and the lid member is pretreated in a vacuum environment, and air bubbles in the solution A are absorbed and removed by at least one of the female shaped mold and the lid member pretreated in a vacuum environment. [5] The manufacturing method according to any one of [1] to [4], wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone. [6] The manufacturing method described in [5], wherein the biodegradable material contains polyglycolic acid. [7] The method according to any one of [1] to [6], wherein the non-solvent is water, a lower aliphatic alcohol, acetone, or a combination thereof. [8] A porous microneedle or a porous microneedle array obtained by the production method according to any one of [1] to [7]. [9] A porous microneedle formed by contacting a solution containing a biodegradable material with a non-solvent for the biodegradable material to dissolve the biodegradable material, wherein the pore diameter increases from the tip to the base of the needle.

[10] The microneedle according to [9], wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

[11] The microneedle according to [9], which has a breaking strength of 60 mN or more.

[12] A microneedle array comprising a plurality of microneedles according to any one of [9] to

[11] provided upright on a microneedle substrate.

[13] Porous microneedles, and Absorbent material capable of absorbing interstitial fluid Equipped with A microneedle patch, wherein the microneedles are formed from a biodegradable material using a non-solvent induced phase separation method.

[14] The microneedle patch described in

[13] , wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

[15] The microneedle patch according to

[13] or

[14] , wherein the pore diameter of the porous microneedle increases from the tip to the base of the needle.

[16] The microneedle patch according to any one of

[13] to

[15] , wherein the absorbent material is a paper substrate.

[17] The microneedle patch according to any one of

[13] to

[16] , wherein the microneedles and the absorbent material are integrated.

[18] The microneedle patch according to any one of

[13] to

[16] , further comprising a microneedle substrate, wherein the microneedles are bonded to the microneedle substrate.

[19] The microneedle patch according to

[18] , wherein the absorbent material is integrated with a microneedle array in which the microneedles are bonded to the microneedle substrate.

[20] (1) A step of providing a female mold having a cavity portion with a plurality of mold shapes, and a cover member having a core portion. (2) A step of injecting a solution A containing a biodegradable material into the cavity portion to fill it into the mold shape; (3) placing an absorbent material capable of absorbing interstitial fluid on the solution A injected into the cavity; (4) inserting the core into the cavity and closing the female mold with a cover; and (5) A step of contacting the solution A injected into the cavity with a non-solvent for the biodegradable material to elute the biodegradable material and form porous microneedles or a porous microneedle array; A method for manufacturing a microneedle patch, comprising:

[21] The manufacturing method according to

[20] , in which the biodegradable resin is eluted by a non-solvent-induced phase separation method.

[22] The method according to

[20] or

[21] , which comprises a step of ultrasonic degassing treatment.

[23] The manufacturing method described in any one of

[20] to

[22] , wherein when the core portion is inserted into the cavity portion, a liquid reservoir consisting of a portion of the solution A injected into the cavity portion is formed between at least one side surface of the cavity portion and at least one side surface of the core portion.

[24] The method of any one of

[20] to

[23] , comprising the steps of dissolving bubbles in solution A by ultrasonic degassing treatment and discharging the bubbles into a liquid tank.

[25] The manufacturing method according to any one of

[20] to

[24] , comprising, in step (a), placing at least one of the female shaped mold and the lid member in a vacuum environment.

[26] The manufacturing method described in any one of

[20] to

[25] , wherein at least one of the female shaped mold and the lid member is pretreated in a vacuum environment, and air bubbles in the solution A are absorbed and removed by at least one of the female shaped mold and the lid member pretreated in a vacuum environment.

[27] The manufacturing method according to any one of

[20] to

[26] , comprising, in step (a), a step of subjecting at least one of the female shaped mold and the lid member to plasma treatment.

[28] The manufacturing method according to any one of

[20] to

[27] , wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

[29] The method according to any one of

[20] to

[28] , wherein the non-solvent is water, a lower aliphatic alcohol, acetone, or a combination thereof.

[30] A microneedle patch obtained by the manufacturing method according to any one of

[20] to

[29] .

[31] The microneedle patch according to

[30] , wherein the microneedles or microneedle array and the absorbent material are integrated. [Effects of the Invention]

[0008] The present invention can provide a method for producing porous microneedles or an array thereof, and a microneedle patch comprising the same, simply and quickly in an ambient temperature environment. Furthermore, the present invention can provide a porous microneedle or microneedle array that has high mechanical strength and allows interstitial fluid to be collected quickly and easily by capillary force, and a microneedle patch equipped with the same. [Brief explanation of the drawings]

[0009] [Figure 1] A schematic diagram of porous membrane generation by the NIPS method is shown. [Figure 2] 1 shows non-limiting examples of a female mold shape and a lid member that can be used in the manufacturing method of the present invention. [Figure 3] 1 shows non-limiting examples of a female mold shape and a lid member that can be used in the manufacturing method of the present invention. [Figure 4] 1 shows a schematic diagram of a non-limiting example of the manufacturing method of the present invention. [Figure 5] 1 shows a schematic diagram of a non-limiting example of an ultrasonic degassing step that can be used in the manufacturing method of the present invention. [Figure 6] 1 shows images of phase separation over time in Example 1. [Figure 7] 1 shows the results of observing the porous microneedle array patch obtained in Example 1 with an optical microscope. [Figure 8] 1 shows an SEM image of the substrate portion of the porous microneedle array patch obtained in Example 1. [Figure 9] 1 shows SEM images comparing the substrate portion before and after phase separation in Example 1. [Figure 10] 1 shows the results of the absorption experiment in Example 1. [Figure 11] 1 shows the evaluation results of the microneedles obtained in Example 2. [Figure 12] 1 shows the evaluation results of the microneedles obtained in Example 3. Modes for carrying out the invention

[0010] I. Microneedle (1) Structure and characteristics of microneedles One embodiment of the present invention is a porous microneedle formed from a biodegradable material using a non-solvent-induced phase separation method. Hereinafter, the porous microneedle formed from a biodegradable material using a non-solvent-induced phase separation method will also be referred to as the "microneedle of the present invention." Here, non-solvent-induced phase separation (NIPS) is a phase separation method commonly used to manufacture porous membranes. A solution in which a polymer is dissolved in a solvent is brought into contact with a non-(poor) solvent, and the solvent in the solution is diffused into the non-solvent, causing the polymer to elute. Figure 1 shows a schematic diagram of porous membrane production using the NIPS method. Figure 1 shows a schematic diagram of the porous membrane formation process. When a polymer solution consisting of a polymer and a solvent is brought into contact with a non-solvent (left panel of Figure 1), a solvent-non-solvent exchange occurs (middle panel of Figure 1), the non-solvent penetrates into the polymer solution, the composition of the solution shifts to B on the ternary phase diagram, and the polymer begins to dissolve. As the non-solvent penetrates further, the composition of the solution shifts, the polymer begins to solidify, and finally the phase separation process ends, resulting in the formation of a porous polymer structure (right panel of Figure 1). That is, one aspect of the microneedle of the present invention is a porous microneedle formed by contacting a solution containing a biodegradable material with a non-solvent for the biodegradable material, thereby dissolving the biodegradable material.

[0011] The microneedles of the present invention are formed using a non-solvent induced phase separation method, which allows for the formation of interconnected channels within the porous microneedles. Furthermore, the microneedle of the present invention preferably has a pore size that increases from the tip to the base of the needle. While not intending to be bound by theory, porosity and pore size tend to change depending on the exchange rate of the solvent and non-solvent, and differences in this exchange rate result in differences in the morphology of the resulting porous body. When the exchange rate of the solvent and non-solvent is high, instantaneous demixing occurs, tending to result in a structure with large pore size and high porosity. On the other hand, when the exchange rate of the solvent and non-solvent is low, delayed demixing occurs, resulting in a structure with small holes and low porosity. The difference between the two is thought to be due to different phase separation pathways. When phase separation is performed in the microneedle of the present invention within the mold (template shape), it is thought that the exchange of solvent and non-solvent at the tip of the microneedle is slowest, and phase separation at the tip is also slowest, resulting in a structure with small pore size and low porosity at the tip of the needle. Therefore, the microneedle of the present invention preferably has a structure (form) in which the tip has a nearly solid structure and is characterized by being break-resistant, while the bottom becomes more porous, thereby providing the microneedle of the present invention with the characteristic that the mechanical strength of the entire needle is maintained despite being porous. That is, one preferred aspect of the microneedle of the present invention is a porous microneedle formed by contacting a solution containing a biodegradable material with a non-solvent for the biodegradable material to dissolve the biodegradable material, and the pore diameter increases from the tip to the base of the needle.

[0012] The biodegradable material constituting the microneedle of the present invention preferably contains at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone, and more preferably contains polyglycolic acid. However, polyglycolic acid has a very high melting point of 220-230°C, which makes it difficult to process, making it difficult to obtain porous microneedles. However, the present invention makes it possible for the first time to practically obtain porous microneedles of polyglycolic acid by using a non-solvent-induced phase separation method. Furthermore, polyglycolic acid is hydrophilic and has high mechanical strength, making it effective as a sensor for testing devices equipped with microneedle patches.

[0013] The microneedles of the present invention may be composed solely of the above-mentioned biodegradable materials, or may contain trace amounts of raw materials used in the method for producing the microneedles of the present invention (e.g., surfactants such as polyvinyl alcohol, methyl cellulose, sorbitan fatty acid esters, sorbitan monooleate, sodium dodecyl sulfate, and hexadecyltrimethylammonium bromide) and other additives (e.g., carboxymethyl cellulose (CMC), hyaluronic acid) within a range that does not impair the function of the microneedles of the present invention. Furthermore, the microneedle of the present invention may be at least partially coated with a coating agent so as not to impair its function. As the coating agent, materials commonly used in this technical field (such as CMC and hyaluronic acid) can be used.

[0014] The porosity of the microneedle of the present invention is usually 20 to 80%, preferably 40 to 60%. Here, the porosity is measured by the water absorption method using a porous membrane, comparing the mass before and after fluid extraction to measure the porosity of the porous microneedle using the following procedure (see P. Liu, et al., J Mater Chem B, 2020). First, the dry mass (W dry ) is recorded, and then the membrane is immersed in deionized (DI) water and the surface water is removed after the absorption is saturated. Then, the mass is immediately measured and W wet Record as Calculate the porosity using the following formula:

[0015]

number

[0016] In equation (1), ρ p is the density of the biodegradable material, and ρ is the density of DI water (1.0 g / cm 3 )

[0017] One index of water absorption capacity is absorption volume, and the microneedle of the present invention has an absorption volume of usually 10 to 150 μL, preferably 60 to 120 μL. Here, the absorption volume is measured by puncturing a microneedle array in which 169 porous PLA MNs are arranged upright in a 1% agarose gel, removing it from the gel after 2 minutes, and measuring its weight.

[0018] Furthermore, the absorption rate of the microneedle of the present invention is generally 0.01 to 0.3 μL / min per microneedle, and preferably 0.2 to 0.3 μL / min. Here, the absorption rate is measured by puncturing a microneedle array in which 169 porous PLA MNs are arranged upright in 1% agarose gel, removing the gel after 2 minutes, and measuring the weight.

[0019] The microneedle of the present invention preferably has a breaking strength of 60 mN or more, more preferably 72 to 148 mN. The microneedle of the present invention has a tip structure that is nearly solid and is characterized by being difficult to break, and therefore has a higher breaking strength than conventional microneedles. That is, one preferred aspect of the microneedle of the present invention is a porous microneedle having a breaking strength of 60 mN or more. Here, the breaking strength is measured by compressing the needle from directly above and measuring the force until the needle is bent halfway.

[0020] (2) Microneedle shape The shape of the microneedle of the present invention can be an approximately conical or pyramidal shape, but a polygonal shape (for example, an approximately pyramidal shape) is preferred as it penetrates the skin more easily than an approximately conical shape.

[0021] The diameter of the tip of the microneedle of the present invention is usually 10 μm to 60 μm, and the diameter or maximum dimension of the base is, for example, about 50 μm to 800 μm. The height of the microneedle determines the depth of penetration into the skin. The microneedle of the present invention is preferably 300 μm or more and 1500 μm or less, in order to reach the dermis without stimulating pain sensation.

[0022] When multiple microneedles are provided, the smaller the intervals are, the better for absorbing the interstitial fluid sample, and intervals of 500 to 5000 μm are preferred.

[0023] Regarding the angle of the tip of the microneedle of the present invention, a larger angle increases the mechanical strength, but a larger tip angle also increases the force required for penetration. A tip angle of 15 to 30° is preferable, as the force required for the microneedle to penetrate is less than 0.2 N.

[0024] (3) Microneedle array The microneedle of the present invention can also be used as a microneedle array in which a plurality of microneedles of the present invention are arranged upright on a microneedle substrate. That is, in another aspect of the present invention, the microneedles of the present invention are a microneedle array in which a plurality of microneedles are erected on a microneedle substrate (hereinafter also referred to as "the microneedle array of the present invention").

[0025] Since the microneedles of the present invention and the microneedle array of the present invention are themselves porous, the microneedle array of the present invention can also be used as a microneedle array patch or a patch-type body fluid collection system without using an absorbent material such as filter paper. Furthermore, the microneedles of the present invention can be provided on an absorbent material capable of absorbing interstitial fluid, as described below, and used as a microneedle array patch or a patch-type body fluid collection system. The microneedle array of the present invention can also be joined to an absorbent material capable of absorbing interstitial fluid and used as a microneedle patch or patch-type body fluid collection system.

[0026] In the microneedle array of the present invention, the microneedles can be arranged vertically and horizontally as desired. The spacing between the microneedles is preferably small in order to absorb samples of interstitial fluid, and is preferably 500 to 2000 μm.

[0027] The microneedle substrate may be formed from the same material as the microneedles, or may be formed from a different material.

[0028] In one embodiment, the microneedle substrate is made of a film or hydrocolloid film containing at least one of polylactic acid resin, polyvinyl alcohol resin, polymethyl methacrylate resin, and polyurethane resin.

[0029] In another embodiment, the microneedle substrate is formed from a biodegradable material, which includes at least one of polylactic acid, polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethyl cellulose. In one preferred embodiment, the microneedle substrate is formed from the same biodegradable material as the microneedles, and the two are integrally constructed. In a preferred embodiment of the microneedle array of the present invention, the microneedle substrate is formed from a biodegradable material using a non-solvent-induced phase separation method, just like the microneedles.

[0030] (4) Method for manufacturing microneedles or microneedle arrays The microneedles of the present invention are formed using a non-solvent-induced phase separation method. The microneedles of the present invention can be obtained by any manufacturing method as long as they are formed using a non-solvent-induced phase separation method, but preferably, the microneedles or microneedle array of the present invention can be obtained by the following manufacturing method. That is, one preferred embodiment of the present invention is (a) providing a female mold having a cavity portion with a plurality of mold shapes and a cover member having a core portion; (b) injecting a solution A containing a biodegradable material into the cavity to fill it into the mold shape; (c) inserting the core into the cavity and closing the female mold with a cover; (d) contacting the solution A injected into the cavity with a non-solvent for the biodegradable material to elute the biodegradable material and form porous microneedles or a porous microneedle array; A method for producing a porous microneedle or a porous microneedle array, comprising: The above-described method for producing porous microneedles or porous microneedle arrays will be referred to below as the "microneedle production method of the present invention."

[0031] The method for producing a microneedle of the present invention will be described below with reference to Fig. 4, but the method for producing a microneedle of the present invention is not limited to this. Fig. 4 is also a non-limiting example of the method for producing a microneedle patch of the present invention, which will be described later, but the method for producing a microneedle of the present invention does not require the step of arranging an absorbent material capable of absorbing interstitial fluid, such as filter paper, as shown in the middle diagram of Fig. 4.

[0032] In step (a), a female mold having a cavity portion with a plurality of mold shapes and a lid member having a core portion are provided. The mold used here is a female micromold prepared from a metal master mold consisting of numerous microneedles, and its material is preferably polydimethylsiloxane (PDMS), SUS, etc. The shape and size of the microneedles of the metal master mold can be appropriately determined according to the shape and size of the desired microneedle.

[0033] The female shape mold has a hollow portion (also referred to herein as a "cavity portion") having a plurality of cavities (also referred to herein simply as a "mold shape") corresponding to the mold shape of the microneedle to be prepared. Here, the mold shape is usually provided at the bottom of the cavity portion. The female shape mold can have a desired number of mold shapes. Furthermore, the female shape mold can be appropriately provided with mold shapes in the vertical and horizontal directions, for example. The interval between the mold shapes is usually 500 to 5000 μm, preferably 1000 to 3000 μm.

[0034] The cavity portion of the female shaped mold used in the microneedle manufacturing method of the present invention has a space for forming the microneedle substrate and a space for inserting the core portion of the above-mentioned cover member.

[0035] The lid member used in the microneedle manufacturing method of the present invention has a core portion. When the lid member is mated with the female-shaped mold (the lid is closed), the core portion is inserted into the cavity portion, and the female-shaped mold can be covered with the lid member. Here, the core portion does not need to fill the entire space of the cavity portion, but has a shape that fills at least a portion of it. The cover member is preferably made of polydimethylsiloxane (PDMS), SUS, or the like.

[0036] Non-limiting examples of a female-shaped mold and a cover member used in the microneedle manufacturing method of the present invention are shown in Figures 2 and 3. The shapes and dimensions of the mold and cover member shown in Figures 2 and 3 are examples, and the female-shaped mold and cover member used in the present invention are not limited to these.

[0037] When the lid member is fitted to the female shaped mold (the lid is closed), the cavity portion of the female shaped mold is preferably divided into two parts: a space for forming a liquid reservoir for discharging air bubbles, and a space for forming the microneedles and substrate. That is, in one preferred aspect of the manufacturing method of the present invention, when the core portion of the lid member is inserted into the cavity portion of the female shaped mold, a space capable of accommodating a portion of the solution A injected into the cavity portion is formed between at least one side surface of the cavity portion and at least one side surface of the core portion.

[0038] In the microneedle manufacturing method of the present invention, at least one of the female shaped mold and the cover member used in step (a) may be pretreated in a vacuum environment (see the upper left diagram in FIG. 4). This process takes advantage of the high gas solubility of PDMS, a suitable material for the female mold and lid. After PDMS is degassed and returned to the atmosphere, it gradually begins to absorb air. This phenomenon allows the air contained in Solution A to be absorbed into the degassed PDMS.

[0039] That is, in one preferred embodiment of the method for producing a microneedle of the present invention, at least one, preferably both, of the female shape mold and the cover member used in step (a) are pretreated in a vacuum environment. In one preferred embodiment of the microneedle manufacturing method of the present invention, step (a) includes placing at least one, preferably both, of the female shape mold and the cover member in a vacuum environment. The vacuum environment is set to a vacuum state of less than 0.01 MPa for about 30 minutes to 1 hour.

[0040] In the microneedle manufacturing method of the present invention, at least one of the female shaped mold and the cover member used in step (a) may be plasma treated (see the upper right diagram in FIG. 4). The surface of PDMS, the preferred material for the female mold and lid, is inherently hydrophobic, meaning it has low affinity with water, a non-solvent. Plasma treatment improves the hydrophilicity of the PDMS surface, allowing the phase separation process to proceed more smoothly.

[0041] That is, in one preferred embodiment of the method for producing a microneedle of the present invention, at least one, preferably both, of the female shape mold and the cover member used in step (a) have been plasma treated. In one preferred embodiment of the method for producing a microneedle of the present invention, step (a) includes a step of plasma treating at least one of, and preferably both of, the female shape mold and the cover member. The plasma treatment conditions are 47 W and 30 to 120 seconds.

[0042] Next, in step (b), solution A containing a biodegradable material is poured into the cavity to fill it into the shape of the mold. Solution A contains a biodegradable material and a solvent that dissolves it.

[0043] The biodegradable material preferably includes at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone, and more preferably includes polyglycolic acid.

[0044] Any solvent can be selected as long as it dissolves the biodegradable resin. When polyglycolic acid is used as the biodegradable resin, hexafluoroisopropanol can be used. When polylactic acid is used as the biodegradable resin, for example, tetrahydrofuran, hexafluoroisopropanol, benzene, acetonitrile, dioxane, dichloromethane, chloroform, dimethyl sulfoxide, and dimethylformamide can be used. When poly(lactide-co-glycolide) copolymer is used as the biodegradable resin, for example, acetone, tetrahydrofuran, hexafluoroisopropanol, acetonitrile, dioxane, dichloromethane, chloroform, dimethyl sulfoxide, and dimethylformamide can be used. When polycaprolactone is used as the biodegradable resin, for example, acetone, tetrahydrofuran, hexafluoroisopropanol, dichloromethane, chloroform, dimethyl sulfoxide, dimethylformamide, and 1-methyl-2-pyrrolidone can be used. When polydioxanone is used as the biodegradable resin, for example, hexafluoroisopropanol can be used. These solvents may be used alone or in combination of two or more, but are preferably used alone from the standpoint of matching with the non-solvent.

[0045] The concentration of the biodegradable resin in solution A is preferably 9% to 13% by weight when polyglycolic acid is used, for example.

[0046] In step (b), the amount of solution A containing a biodegradable material injected into the cavity may be the same as or greater than the amount required to fill the mold shape, but it is preferable to inject a larger amount of solution A into the cavity than is required to fill the mold shape. This allows a liquid bath consisting of part of solution A injected into the cavity to be formed between at least one side surface of the cavity and at least one side surface of the core when the core is inserted into the cavity. Typically, the solution is poured into the core and cavity sections until no large air bubbles remain inside, and solution A is poured into the cavity section so that the liquid tank is also filled with the solution.

[0047] Next, in step (c), the core part is inserted into the cavity part, and the female shaped mold is covered with a cover member (see the second diagram from the left in the middle of FIG. 4). By closing (lidding) the cavity with the core, it becomes possible to control the thickness of the microneedle substrate. Furthermore, when the core is inserted into the cavity, a liquid tank consisting of part of the solution A injected into the cavity can be formed between at least one side surface of the cavity and at least one side surface of the core. Air bubbles in the solution A dissolved by ultrasonic degassing can be discharged into this liquid tank.

[0048] That is, the method for producing a microneedle of the present invention preferably includes a step of performing ultrasonic degassing treatment. By performing ultrasonic degassing, it is possible to accelerate the process of dissolution, absorption, and discharge of bubbles inside Solution A (see Figure 5).

[0049] Furthermore, one preferred aspect of the method for producing a microneedle of the present invention includes a step of dissolving air bubbles in Solution A by ultrasonic degassing treatment and discharging the air bubbles into a liquid tank (see the second image from the right in the top row of Figure 4).

[0050] The conditions for ultrasonic degassing treatment are usually 55 W, 40 kHz, and 3-5 minutes.

[0051] Next, in step (d), the solution A injected into the cavity portion is brought into contact with a non-solvent for the biodegradable material, thereby dissolving the biodegradable material and forming porous microneedles or a porous microneedle array. Preferably, the biodegradable resin is eluted by non-solvent induced phase separation, the details of which are as described above for the microneedle of the present invention.

[0052] A non-solvent for a biodegradable material means a poor solvent for the biodegradable material. Preferred non-solvents that can be used in the production method of the present invention are water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropanol), acetone, or a combination thereof. As described in detail in the structure and characteristics of the microneedles of the present invention, the miscibility of non-solvents and solvents differs, resulting in different diffusion rates when mixed. Therefore, the better the miscibility, the larger the pore size and porosity tend to be. Therefore, it is possible to control the pore size and porosity by selecting the combination of non-solvent and solvent.

[0053] Solution A injected into the cavity can be brought into contact with a non-solvent for the biodegradable material by, for example, immersing the entire female mold covered with a lid member in the non-solvent, which causes phase separation and dissolves the biodegradable material to form porous microneedles or a porous microneedle array. The temperature at which solution A injected into the cavity is brought into contact with the non-solvent for the biodegradable material (i.e., phase separation occurs) is preferably 20 to 50° C. Here, for the same reasons as those detailed in the structure and properties of the microneedle of the present invention, it is possible to change the diffusion rate of the solvent by changing the temperature, and it is possible to control the pore size and porosity by appropriately setting the temperature for phase separation. The time required for phase separation is usually 3 to 5 hours. The non-solvent may be replaced during the phase separation process.

[0054] The obtained porous microneedles or porous microneedle array are washed with alcohol or the like and dried, for example, at room temperature (20-25°C).

[0055] One aspect of the present invention is a porous microneedle or a porous microneedle array obtained by the microneedle manufacturing method of the present invention.

[0056] II. Microneedle Patch Another embodiment of the present invention is a microneedle patch (hereinafter also referred to as "the microneedle patch of the present invention") comprising porous microneedles and an absorbent material capable of absorbing interstitial fluid, the microneedles being formed from a biodegradable material using a non-solvent-induced phase separation method. Each component of the microneedle patch of the present invention will be described in detail below.

[0057] 1. Microneedling The porous microneedles used in the microneedle patch of the present invention are porous microneedles (microneedles of the present invention) formed from a biodegradable material using a non-solvent-induced phase separation method, and details thereof are as described in detail in the section "I. Microneedles."

[0058] In the porous microneedles used in the microneedle patch of the present invention, the biodegradable material preferably contains at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone, and more preferably contains polyglycolic acid.

[0059] In a preferred embodiment of the microneedle patch of the present invention, the porous microneedles have a structure in which the pore size increases from the tip to the base of the needle.

[0060] 2. Absorbent material that can absorb interstitial fluid Examples of absorbents capable of absorbing interstitial fluid for use in the microneedle patch of the present invention (hereinafter also referred to as "absorbents used in the present invention") include (1) paper substrates; or (2) filter paper or nonwoven fabrics (hereinafter also referred to as "absorbent (2)") made from a material selected from the group consisting of glass fiber, cellulose, polyester, polyethylene, rayon, acrylic resin, polyvinyl alcohol, polypropylene, nylon, biodegradable polymers, and combinations of any two or more of these. These filter papers or nonwoven fabrics may contain a binder.

[0061] As the paper substrate, filter paper is preferably used, and the filter paper is preferably filter paper for quantitative analysis as specified by JIS P3801, more preferably filter paper or nitrocellulose membrane with a thickness of 100 to 500 μm.

[0062] Examples of filter paper made from glass fibers include filter paper made from glass fibers used in lateral flow immunoassays by Whatman (trademark). An example of a nonwoven fabric made from glass fibers is glass paper manufactured by Oji F-Tex Co., Ltd. Here, the filter paper and nonwoven fabric made from glass fiber refer to filter paper and nonwoven fabric obtained using glass fiber as a raw material (material). The same applies to other materials. Examples of filter paper made from cellulose include filter paper made from one or more materials selected from the group consisting of regenerated cellulose (RC), cellulose acetate (CA), mixed cellulose esters, nitrocellulose, and the like. Examples of nonwoven fabrics made from cellulose include cotton nonwoven fabrics. An example of a filter paper made from polyester is the polyester filter paper used in lateral flow immunoassays by Whatman (trademark). Examples of nonwoven fabrics made from polyester include polyester long fiber nonwoven fabrics manufactured by Toyobo MC Co., Ltd. Examples of filter paper made from polyethylene include filter paper manufactured by Toho Separator Co., Ltd. Examples of nonwoven fabrics made from polyethylene include polyethylene spunbond nonwoven fabrics manufactured by Maeda Kosen Co., Ltd. Examples of filter paper made from rayon include filter paper manufactured by Toho Separator Co., Ltd. An example of a nonwoven fabric made from rayon is a rayon nonwoven fabric manufactured by Kuraray Kuraflex Co., Ltd. Examples of filter paper made from acrylic resin include acrylic pulp filter paper manufactured by Azumi Filter Paper Co., Ltd. Examples of nonwoven fabrics made from acrylic resin include acrylic fiber nonwoven fabrics manufactured by Nippon Exlan Kogyo Co., Ltd. An example of a filter paper made from polypropylene is a polypropylene filter manufactured by Merck Ltd. An example of a nonwoven fabric made from polypropylene is polypropylene nonwoven wiper manufactured by Nippon Paper Crecia Co., Ltd. An example of a filter paper made from nylon is a polypropylene filter manufactured by Merck Ltd. An example of a filter paper made from a biodegradable polymer is a PVA sponge sheet manufactured by Aion Corporation.

[0063] The absorbent material (2) may be filter paper or nonwoven fabric made from a material consisting of a combination of any two or more selected from glass fiber, cellulose, polyester, polyethylene, rayon, acrylic resin, polyvinyl alcohol, polypropylene, nylon, and biodegradable polymers. The absorbent material (2) may contain a binder, such as polyvinyl alcohol. The absorbent (2) may also be obtained by combining two or more types of filter paper or nonwoven fabric made from materials selected from the group consisting of glass fiber, cellulose, polyester, polyethylene, rayon, acrylic resin, polyvinyl alcohol, polypropylene, nylon, biodegradable polymers, and any combination of two or more of these. In this case, the absorbent obtained by combining two or more types of filter paper or nonwoven fabric may contain a binder. Examples of binders include cellulose-based additives and silk fibroin. Note that lactose, polyol, povidone, starch, and polysaccharide binders are undesirable because they may affect future biomarker measurements.

[0064] The thickness of the absorbent material (2) is preferably 100 to 999 μm.

[0065] The absorbent material used in the present invention can be either a paper substrate or an absorbent material (2). However, when the microneedle patch of the present invention is used as a testing system having an integrated structure of a microneedle and a substrate sensor, it is preferable to use a paper substrate as the absorbent material. Because paper is a porous medium with strong water absorption properties, once the porous microneedles absorb the analyte, the paper substrate can rapidly transport it to the sensing area. In addition, the flexibility of paper increases its usefulness as a patch type for human skin.

[0066] In one aspect of the invention, the absorbent material is a paper-based sensor. The paper-based sensor has at least one measurement area in a paper substrate such as filter paper, and detects the reaction with components in interstitial fluid, such as glucose. The measurement is primarily a colorimetric measurement using enzymes, and can determine the concentration and detection of components in interstitial fluid.

[0067] The measurement areas include an area for measuring the target components (glucose, cholesterol, cortisol, etc.) in the interstitial fluid, and a body fluid reaction area for confirming the collection of body fluid. The region for measuring the component to be detected contains an enzyme, a peroxide reacting substance, or a color-developing dye that reacts with the component.

[0068] For example, the region for measuring glucose contains glucose oxidase (GOx), peroxidase (HRP), and a coloring dye such as tetramethylbenzidine (TMB). In the area of ​​measuring cholesterol, cholesterol oxidase is included. The body fluid reaction area, which confirms the collection of body fluid, contains cobalt chloride, etc.

[0069] A paper-based sensor may have one measurement area, or may have two or more measurement areas.

[0070] 3. Microneedle Patches (1) Structure of the microneedle patch The microneedle patch of the present invention is a microneedle patch comprising porous microneedles and an absorbent material capable of absorbing interstitial fluid, the microneedles being formed from a biodegradable material using a non-solvent-induced phase separation method.

[0071] In the microneedle patch of the present invention, the microneedles themselves can be provided on the absorbent material to form an integrated structure. Furthermore, in the microneedle patch of the present invention, a microneedle array in which a plurality of microneedles are erected on a microneedle substrate can be provided on an absorbent material to form an integrated structure.

[0072] In the microneedle patch of the present invention, a structure in which pre-prepared microneedles are joined to an absorbent material such as a paper substrate by adhering them to each other can be used, but preferably the microneedles and the absorbent material are integrated into one structure.

[0073] Furthermore, in the microneedle patch of the present invention, a structure can be created in which a pre-prepared microneedle array is joined to an absorbent material such as a paper substrate by adhering the two together, but preferably the microneedle array and the absorbent material are integrated into one structure.

[0074] Such a structure in which microneedles or microneedle arrays are integrated with an absorbent material can be realized by directly molding the microneedles or microneedle arrays into the absorbent material, for example, by embedding an absorbent material such as a paper substrate in the manufacturing process of the microneedle patch. By having such a structure, the microneedle substrate has greater strength and flexibility than a microneedle substrate made of a biodegradable resin alone.

[0075] In one aspect of the present invention, the structure in which the microneedles or microneedle array are integrated with the absorbent material is a structure in which a biodegradable resin is incorporated (impregnated) into the inside of the absorbent material such as a paper substrate. Although not intending to be bound by theory, the manufacturing method of the microneedle patch of the present invention described below includes a step of contacting an absorbent material such as a paper substrate with a solution containing a biodegradable resin before forming the microneedles, and then contacting the solution and the absorbent material with a non-solvent. Therefore, it is presumed that the biodegradable resin is incorporated into the layer of the absorbent material during this process.

[0076] By using the microneedle patch of the present invention, interstitial fluid can be collected in place of a blood collection needle, and the operation is painless and simple. Furthermore, the microneedle patch of the present invention can be integrated with a sensor as a medical device, making it possible to detect various biomarkers.

[0077] III. Manufacturing method of microneedle patch Another embodiment of the present invention is (1) A step of providing a female mold having a cavity portion with a plurality of mold shapes and a cover member having a core portion. (2) A step of injecting a solution A containing a biodegradable material into the cavity portion to fill it into the mold shape; (3) placing an absorbent material capable of absorbing interstitial fluid on the solution A injected into the cavity; (4) inserting the core into the cavity and closing the female mold with a cover; and (5) A step of contacting the solution A injected into the cavity with a non-solvent for the biodegradable material to elute the biodegradable material and form porous microneedles or a porous microneedle array; (hereinafter also referred to as "the method for producing the microneedle patch of the present invention")

[0078] The manufacturing method of the present invention will be described below with reference to the schematic diagram of a non-limiting example of the manufacturing method of the present invention shown in FIG. 4 as appropriate, but the manufacturing method of the present invention is not limited to the embodiment shown in FIG.

[0079] In step (1), a female mold having a cavity portion with a plurality of mold shapes and a lid member having a core portion are provided. The mold used here is a female micromold prepared from a metal master mold consisting of numerous microneedles, and its material is preferably polydimethylsiloxane (PDMS), SUS, etc. The shape and size of the microneedles of the metal master mold can be appropriately determined according to the shape and size of the desired microneedle.

[0080] The female shape mold has a hollow portion (also simply referred to as a "cavity portion") having a plurality of cavities (also simply referred to as a "mold shape") corresponding to the mold shape of the microneedle to be prepared. Here, the mold shape is usually provided at the bottom of the cavity portion. The female shape mold can have a desired number of mold shapes. Furthermore, the female shape mold can be appropriately provided with mold shapes in the vertical and horizontal directions, for example. The interval between the mold shapes is usually 500 to 5000 μm, preferably 1000 to 3000 μm.

[0081] The cavity portion of the female-shaped mold used in the manufacturing method of the microneedle patch of the present invention has a space for forming the microneedle substrate, a space for accommodating an absorbent material to be placed on top of the solution A injected into the cavity portion, and a space for inserting the core portion of the above-mentioned lid member.

[0082] The lid member used in the method for manufacturing a microneedle patch of the present invention has a core portion. When the lid member is mated with the female-shaped mold (the lid is closed), the core portion is inserted into the cavity portion, and the female-shaped mold can be covered with the lid member. Here, the core portion does not need to fill the entire space of the cavity portion, but has a shape that fills at least a portion of it. The cover member is preferably made of polydimethylsiloxane (PDMS), SUS, or the like.

[0083] Non-limiting examples of a female-shaped mold and a lid member used in the method for producing a microneedle patch of the present invention are shown in Figures 2 and 3. The shapes and dimensions of the mold and lid member shown in Figures 2 and 3 are examples, and the female-shaped mold and lid member used in the present invention are not limited to these.

[0084] When the lid member is fitted to the female shaped mold (the lid is closed), the cavity portion of the female shaped mold is preferably divided into two parts: a space for forming a liquid reservoir for discharging air bubbles, and a space for forming the microneedles and substrate. That is, in one preferred aspect of the method for manufacturing a microneedle patch of the present invention, when the core portion of the lid member is inserted into the cavity portion of the female shaped mold, a space capable of accommodating a portion of the solution A injected into the cavity portion is formed between at least one side surface of the cavity portion and at least one side surface of the core portion.

[0085] In the method for producing a microneedle patch of the present invention, at least one of the female shape mold and the lid member used in step (1) may be pretreated in a vacuum environment (see the top left diagram in Figure 4). PDMS, a suitable material for the female mold and lid, has tiny cavities inside it. When a vacuum is applied, the air inside the cavities is released, reducing the pressure inside the PDMS. When the pressure is then returned to normal, the pressure inside the PDMS also gradually returns to normal, meaning that it has the property of gradually drawing in the surrounding air. Taking advantage of this property, the air dissolved in Solution A and the air bubbles that form when Solution A is injected into the mold shape can be absorbed and removed by PDMS.

[0086] That is, in one preferred embodiment of the method for producing a microneedle patch of the present invention, at least one, preferably both, of the female shape mold and the cover member used in step (1) are pretreated in a vacuum environment. In one preferred embodiment of the method for producing a microneedle patch of the present invention, step (1) includes placing at least one, preferably both, of the female shape mold and the lid member in a vacuum environment. The vacuum environment is set to a vacuum state of less than 0.01 MPa for about 30 minutes to 1 hour.

[0087] In the method for producing a microneedle patch of the present invention, at least one of the female shape mold and the cover member used in step (1) may be plasma treated (see the upper right diagram in FIG. 4). The surface of PDMS, the preferred material for the female mold and lid, is inherently hydrophobic, meaning it has low affinity with water, a non-solvent. Plasma treatment improves the hydrophilicity of the PDMS surface, allowing the phase separation process to proceed more smoothly.

[0088] That is, in one preferred embodiment of the method for producing a microneedle patch of the present invention, at least one, preferably both, of the female shape mold and the cover member used in step (1) have been plasma treated. In one preferred embodiment of the method for producing a microneedle patch of the present invention, step (1) includes a step of plasma treating at least one of, and preferably both of, the female shape mold and the cover member. The plasma treatment conditions are 47 W and 30 to 120 seconds.

[0089] Next, in step (2), solution A containing a biodegradable material is poured into the cavity to fill it into the mold shape. Solution A contains a biodegradable material and a solvent that dissolves it.

[0090] The biodegradable material preferably includes at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone, and more preferably includes polyglycolic acid.

[0091] Any solvent can be selected as long as it dissolves the biodegradable resin. Examples of solvents that can be used are the same as those described in detail in the method for producing microneedles of the present invention.

[0092] The concentration of the biodegradable resin in solution A is preferably 9% to 13% by weight when polyglycolic acid is used, for example.

[0093] In step (2), the amount of solution A containing a biodegradable material injected into the cavity may be the same as or greater than the amount required to fill the mold shape, but it is preferable to inject a larger amount of solution A into the cavity than is required to fill the mold shape. This allows a liquid bath consisting of part of the solution A injected into the cavity to be formed between at least one side surface of the cavity and at least one side surface of the core when the core is inserted into the cavity. Typically, the solution is poured into the core and cavity sections until no large air bubbles remain inside, and solution A is poured into the cavity section so that the liquid tank is also filled with the solution.

[0094] Next, in step (3), an absorbent material capable of absorbing interstitial fluid is placed on top of the solution A injected into the cavity. Details of the absorbent material capable of absorbing interstitial fluid used in the manufacturing method of the present invention are as described in detail for the microneedle patch of the present invention. Furthermore, in this specification, "placing an absorbent material capable of absorbing interstitial fluid on top of solution A injected into the cavity" means that the absorbent material is placed on top of solution A injected into the cavity within the mold so that the absorbent material comes into contact with the solution.

[0095] The method for manufacturing a microneedle patch of the present invention includes a step of embedding an absorbent material such as a paper substrate during the manufacturing process of the microneedle patch, making it possible to bond or fix the absorbent material. This allows for the integration of the microneedles and the absorbent material such as a paper substrate during the manufacturing process, which was previously difficult. Furthermore, this integration eliminates the need for the step of connecting the microneedles to the paper substrate, which was required in the salt leaching method and the microsphere method of the prior art. Furthermore, the microneedle patch obtained by the microneedle patch manufacturing method of the present invention has greater strength and flexibility than a microneedle substrate made of biodegradable resin alone, and can eliminate the resistance to the flow of body fluids, etc., caused by conventional adhesive layer materials.

[0096] Next, in step (4), the core part is inserted into the cavity part, and the female shaped mold is covered with a cover member (see the second diagram from the left in the middle row of FIG. 4). By closing (lidding) the cavity with the core, it becomes possible to control the thickness of the microneedle substrate. Furthermore, when the core is inserted into the cavity, a liquid tank consisting of part of the solution A injected into the cavity can be formed between at least one side surface of the cavity and at least one side surface of the core. Air bubbles in the solution A dissolved by ultrasonic degassing can be discharged into this liquid tank.

[0097] That is, the method for producing a microneedle patch of the present invention preferably includes a step of performing ultrasonic degassing treatment. By performing ultrasonic degassing, it is possible to accelerate the process of dissolution, absorption, and discharge of bubbles inside Solution A (see Figure 5).

[0098] Furthermore, one preferred aspect of the method for manufacturing a microneedle patch of the present invention includes a step of dissolving air bubbles in solution A by ultrasonic degassing treatment and discharging the air bubbles into a liquid tank (see the second image from the right in the top row of Figure 4).

[0099] The conditions for ultrasonic degassing treatment are usually 55 W, 40 kHz, and 3-5 minutes.

[0100] Next, in step (5), the solution A injected into the cavity portion is brought into contact with a non-solvent for the biodegradable material, thereby dissolving the biodegradable material and forming porous microneedles or a porous microneedle array. Preferably, the biodegradable resin is eluted by non-solvent induced phase separation, the details of which are as described above for the microneedle of the present invention.

[0101] A non-solvent for a biodegradable material means a poor solvent for the biodegradable material. Non-solvents that can be used in the method for producing a microneedle patch of the present invention are preferably water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropanol), acetone, or a combination thereof. As described in detail in the structure and characteristics of the microneedles of the present invention, the miscibility of non-solvents and solvents differs, resulting in different diffusion rates when mixed. Therefore, the better the miscibility, the larger the pore size and porosity tend to be. Therefore, it is possible to control the pore size and porosity by selecting the combination of non-solvent and solvent.

[0102] Solution A injected into the cavity can be brought into contact with a non-solvent for the biodegradable material by, for example, immersing the entire female mold covered with a lid member in the non-solvent, which causes phase separation and dissolves the biodegradable material to form porous microneedles or a porous microneedle array. The temperature at which solution A injected into the cavity is brought into contact with the non-solvent for the biodegradable material (i.e., phase separation occurs) is preferably 20 to 50° C. Here, for the same reasons as those detailed in the structure and properties of the microneedle of the present invention, it is possible to change the diffusion rate of the solvent by changing the temperature, and it is possible to control the pore size and porosity of the microneedle by appropriately setting the temperature for phase separation. The time required for phase separation is usually 3 to 5 hours. The non-solvent may be replaced during the phase separation process.

[0103] The obtained porous microneedles or porous microneedle array are washed with alcohol or the like and dried, for example, at room temperature (20-25°C).

[0104] One aspect of the present invention is a microneedle patch obtained by the method for producing a microneedle patch of the present invention. In addition, in the microneedle patch obtained by the method for producing a microneedle patch of the present invention, the microneedles or microneedle array and the paper substrate are preferably integrated together. [Example]

[0105] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0106] 1.Material Polyglycolic acid: BioDegmer (registered trademark), P09008 (BMG Corporation) Hexafluoroisopropanol: H0242 (Tokyo Chemical Industry Co., Ltd.) PDMS (polydimethylsiloxane): DOWSIL (trademark) SILPOT 184 W / C (Dow Chemical Company Midland)

[0107] 2. Experimental Equipment Ultrasonic cleaner: MCS-2 (AS ONE Corporation) Tabletop vacuum plasma device: YHS-R (Kai Semiconductor Co., Ltd.) Oil rotary vacuum pump: GLS-051 (ULVAC KIKO Co., Ltd.)

[0108] [Example 1] (1) Mold design Non-limiting examples of the design of the female-shaped mold and lid member used in Example 1 are shown in Figures 2 and 3. The shapes and dimensions of the mold and lid member shown in these figures are examples, and the female-shaped mold and lid member used in the present invention are not limited to these. The material of the female mold and the cover member shown in Figure 2 is both PDMS. Furthermore, when the lid member is fitted to the female shaped mold (the lid is closed), the cavity portion of the female shaped mold is divided into two parts: a space for forming a liquid tank to expel air bubbles, and a space for forming the microneedle and substrate.

[0109] (2) Fabrication of PGA porous microneedle array patch PGA was dissolved in hexafluoro-2-propanol (HFIP) as a solvent to prepare a PGA / HFIP solution (10 wt %). As shown in Figure 4, the mold was first treated by placing the PDMS mold and lid in a vacuum (<0.01 MPa) environment for 1 hour, followed by 60 seconds of plasma treatment. Next, the solution (0.2 ml) was poured into the mold using filter paper (Whatman #4) and a syringe, and the mold was then covered with a lid. After 3 minutes of ultrasonic degassing, the covered PDMS mold was immersed in 100 ml of pure water to allow phase separation for 3 hours, after which the 100 ml of pure water was replaced once and the mold was left to soak for 1 hour. Finally, the porous microneedles after phase separation were removed from the mold, washed with 10 ml of alcohol, dried, and the excess material was trimmed off. Figure 6 shows images of the phase separation over time. After 3-4 hours from the start of the phase separation process shown in the images, the visual appearance remains almost unchanged. At this stage, it can be determined that phase separation is complete.

[0110] The porous microneedle array patch obtained above was observed under an optical microscope, and the results are shown in FIG. Figure 7 (a) shows the appearance of the entire porous microneedle array patch, (b) shows the appearance of the needles observed with an optical microscope, and (c) shows the appearance of a single needle observed with an electron microscope. Scanning electron microscope (SEM) images show that the needles are porous, with the pore size increasing from the tip to the base.

[0111] The height of the microneedles was 293.0±3.9 μm, and the breaking strength was measured to be 148 mN. The height of the microneedles was measured using a digital microscope (Keyence VH5500), and the breaking strength was measured using a digital force gauge (IMADA ZTA-5N).

[0112] Figure 8 shows an SEM image of the substrate. The SEM image reveals that the PMAP (porous microneedle array patch) substrate is composed of a PGA-filter paper-PGA layer. A porous structure can also be seen in the gaps in the filter paper layer, revealing that PGA has penetrated into the gaps. In addition, SEM images comparing the substrate area before and after phase separation are shown in Figure 9. Comparing the filter paper area, it can be seen that PGA has soaked into the filter paper after phase separation.

[0113] (3) Absorption experiment An experiment was conducted in which the microneedle obtained above was brought close to a water droplet. The water rose the moment the tip touched the droplet (left image in Figure 10). The results of an absorption experiment using methylene blue (1%) are shown in the right panel of Figure 10. Because PGA is highly hydrophilic, the porous microneedles and substrate were stained, demonstrating that they were capable of absorbing liquid. Also, calculated from the image, it is 1.1 mm 2 It was found that it can absorb water at a rate of 1 / s.

[0114] [Example 2] A porous microneedle array patch was produced under the same conditions as in Example 1, except that ethanol was used as the non-solvent instead of pure water. The evaluation results of the obtained microneedles are shown in FIG. It was also possible to prepare PMAP using ethanol as a non-solvent. The needle height was greater than when water was used, and the difference in mechanical properties between the two was small.

[0115] [Example 3] A porous microneedle array patch was produced under the same conditions as in Example 1, except that the phase separation temperature was changed from room temperature (approximately 20°C) to 40°C. The evaluation results of the obtained microneedles are shown in FIG. PMAP was successfully prepared at different temperatures. Higher temperatures are thought to result in faster diffusion of the solvent into the non-solvent, which may lead to shorter preparation times in the future.

Claims

1. (a) providing a female mold having a cavity portion with a plurality of mold shapes and a lid member having a core portion; (b) injecting a solution A containing a biodegradable material into the cavity to fill it into the mold shape; (c) inserting the core into the cavity and closing the female mold with a cover; and (d) contacting the solution A injected into the cavity with a non-solvent for the biodegradable material to elute the biodegradable material and form porous microneedles or a porous microneedle array; A method for producing a porous microneedle or a porous microneedle array, comprising:

2. The manufacturing method according to claim 1, wherein when the core portion is inserted into the cavity portion, a liquid bath consisting of a portion of the solution A injected into the cavity portion is formed between at least one side surface of the cavity portion and at least one side surface of the core portion.

3. The manufacturing method according to claim 2 , further comprising the step of dissolving bubbles in the solution A by ultrasonic degassing treatment and discharging the bubbles into a liquid tank.

4. 2. The manufacturing method according to claim 1, wherein at least one of the female shaped mold and the lid member is pretreated in a vacuum environment, and air bubbles in the solution A are absorbed and removed by at least one of the female shaped mold and the lid member pretreated in a vacuum environment.

5. The method according to claim 1 , wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

6. The method of claim 5 , wherein the biodegradable material comprises polyglycolic acid.

7. The method of claim 1 , wherein the non-solvent is water, a lower aliphatic alcohol, acetone, or a combination thereof.

8. A porous microneedle or a porous microneedle array obtained by the manufacturing method according to claim 1.

9. A porous microneedle formed by contacting a solution containing a biodegradable material with a non-solvent for the biodegradable material, thereby dissolving the biodegradable material, wherein the pore diameter increases from the tip to the base of the needle.

10. The microneedle according to claim 9, wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

11. The microneedle according to claim 9, having a breaking strength of 60 mN or more.

12. A microneedle array comprising a plurality of microneedles according to claim 9 arranged upright on a microneedle substrate.

13. Porous microneedles, and Absorbent material capable of absorbing interstitial fluid Equipped with A microneedle patch, wherein the microneedles are formed from a biodegradable material using a non-solvent induced phase separation method.

14. The microneedle patch of claim 13, wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

15. The microneedle patch of claim 13, wherein the porous microneedles have pores with increasing diameter from the tip to the base of the needle.

16. The microneedle patch of claim 13 , wherein the absorbent material is a paper substrate.

17. The microneedle patch of claim 13, wherein the microneedles and the absorbent material are integrated.

18. The microneedle patch of claim 13 , further comprising a microneedle substrate, the microneedles being bonded to the microneedle substrate.

19. The microneedle patch of claim 18, wherein the absorbent material is integrated with a microneedle array in which the microneedles are bonded to the microneedle substrate.

20. (1) A step of providing a female mold having a cavity portion with a plurality of mold shapes and a cover member having a core portion. (2) A step of injecting a solution A containing a biodegradable material into the cavity portion to fill it into the mold shape; (3) placing an absorbent material capable of absorbing interstitial fluid on the solution A injected into the cavity; (4) inserting the core into the cavity and closing the female mold with a cover; and (5) A step of contacting the solution A injected into the cavity with a non-solvent for the biodegradable material to elute the biodegradable material and form porous microneedles or a porous microneedle array; A method for manufacturing a microneedle patch, comprising:

21. The method according to claim 20, wherein the biodegradable resin is eluted by a non-solvent-induced phase separation method.

22. The method according to claim 20, further comprising the step of performing ultrasonic degassing treatment.

23. The manufacturing method according to claim 20, wherein when the core portion is inserted into the cavity portion, a liquid bath consisting of a portion of the solution A injected into the cavity portion is formed between at least one side surface of the cavity portion and at least one side surface of the core portion.

24. The manufacturing method according to claim 23, comprising the step of dissolving bubbles in solution A by ultrasonic degassing treatment and discharging the bubbles into a liquid tank.

25. The method of claim 20, wherein step (a) comprises placing at least one of the female shaped mold and the lid member in a vacuum environment.

26. 21. The manufacturing method according to claim 20, wherein at least one of the female shaped mold and the lid member is pretreated in a vacuum environment, and air bubbles in Solution A are absorbed and removed by at least one of the female shaped mold and the lid member pretreated in a vacuum environment.

27. The manufacturing method according to claim 20, wherein step (a) includes a step of plasma treating at least one of the female shaped mold and the lid member.

28. The method of claim 20, wherein the biodegradable material comprises at least one of polyglycolic acid, polylactic acid, poly(lactide-co-glycolide) copolymer, polycaprolactone, and polydioxanone.

29. 21. The method of claim 20, wherein the non-solvent is water, a lower aliphatic alcohol, acetone, or a combination thereof.

30. A microneedle patch obtained by the manufacturing method according to any one of claims 20 to 29.

31. The microneedle patch of claim 30, wherein the microneedles or microneedle array and the absorbent material are integrated.

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