Method for manufacturing porous microneedles

Abstract

[Problem] To provide a porous microneedle capable of collecting a body fluid. [Solution] Provided is a porous microneedle including a water-soluble material and microspheres of a biodegradable material, wherein: the microspheres of the biodegradable material are bonded to each other to form a network of interconnected pores; the microneedle may comprise a microneedle substrate including the microspheres and the water-soluble material; and the volume ratio of the water-soluble material and the biodegradalbe material is 1:2 to 3.

Description

Technical Field

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

Background Art

[0002] In recent years, many point-of-care testing (POCT) devices that can quickly and easily inspect and diagnose diseases and monitor health conditions have been developed. In order to lead a healthy life, it is essential to monitor biomarkers, which are biological indicators deeply related to lifestyle-related diseases such as blood glucose levels and cholesterol in the body in daily life. In conventional tests and diagnoses, it is necessary to collect blood with an injection needle or the like or collect samples of urine or tears for measuring multiple biomarkers. However, when using an injection needle, pain and bleeding are involved every time of measurement, imposing a great burden on patients. Also, urine and tears have large errors from the biological information in blood, resulting in measurements lacking reliability.

[0003] On the other hand, interstitial fluid present in the skin has almost the same composition as plasma, and thus has attracted attention as a promising alternative specimen to blood in measuring biomarkers. However, a method for extracting interstitial fluid has not yet been established, and it is necessary to develop a simple and minimally invasive method for extracting interstitial fluid.

[0004] Microneedles have a structure of needles shorter and thinner than conventional injection needles and have attracted attention as minimally invasive biosensor devices without pain. A microneedle (MN) array is an effective approach for puncturing into the dermis layer to extract interstitial fluid painlessly. In particular, biodegradable polymer MNs having a porous structure have attracted great attention in recent years. However, there are still various problems to be solved for practical use, such as complicated processing, long manufacturing time, and difficulty in obtaining sufficient mechanical strength (strength easy to puncture the skin, etc.).

[0005] The present inventors have found that porous microneedles can be manufactured from microspheres of biodegradable polymers such as polylactic acid by heat treatment, and that the porous microneedles obtained in this way have high mechanical strength (Patent Document 1). In the single emulsion method discovered by the present inventors, when forming porous microneedles made from a biodegradable polymer such as polylactic acid (PLA) and a surfactant (water-soluble material) such as polyvinyl alcohol (PVA), PLA particles accumulate and the PVA solution fills the gaps between them. As a result, when dried, the adhesive PVA binds the PLA particles together, allowing the shape to be maintained even after demolding. Furthermore, the heating process allows the entire microneedle to be exposed to ambient temperature, which has the advantage of enabling uniform heating.

[0006] However, when actually producing microneedles using the single emulsion method described above, it was necessary to gradually change the amount of material and the manufacturing process to find the optimal conditions. This meant that if the conditions were different, the amount of material had to be adjusted from scratch. Furthermore, even if optimization was achieved, it was only for one condition. If the length or number of needles, the thickness of the microneedle substrate, etc., were different, it was necessary to adjust the amount of material such as PLA or PVA again from scratch and repeat the prototyping and evaluation process, which was inefficient. Furthermore, because the optimal ratio of biodegradable materials such as PLA and water-soluble materials such as PVA for efficient collection of bodily fluids was not clearly defined, it was difficult to stably prepare porous microneedles that could efficiently collect bodily fluids. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International release 2023 / 021665 [Disclosure of the Invention] [Problems that the invention aims to solve]

[0008] The present invention aims to provide a porous microneedle capable of collecting bodily fluids. Furthermore, the present invention also aims to provide a microneedle composed of a water-soluble material and a biodegradable material in an optimal ratio. [Means for solving the problem]

[0009] The inventors investigated the above-mentioned problems in the production of porous microneedles by the single emulsion method and found that the cause was due to practical optimization by gradually changing the conditions. They discovered that in order to theoretically optimize the process, it is necessary to clarify the deposition state of biodegradable material particles such as PLA and water-soluble material such as PVA that constitute the porous microneedle. They then found that by setting the volume ratio of water-soluble material to biodegradable material within a specific range, the optimal deposition distance from the needle tip of the final microneedle to the biodegradable material particles and water-soluble material can be obtained.

[0010] Furthermore, the inventors have found that by treating porous microneedles obtained by the single emulsion method under specific conditions, porous microneedles from which water-soluble materials have been removed can be obtained, and that these microneedles have a higher sampling capacity than conventional porous microneedles.

[0011] In other words, the present invention has the following configuration. [1] A porous microneedle comprising microspheres of biodegradable material and a water-soluble material, wherein the microspheres of biodegradable material are bonded to each other to form an interconnected network of pores, The microneedle may include a microneedle substrate containing the microspheres and a water-soluble material. The microneedle wherein the volume ratio of the water-soluble material to the biodegradable material is 1:2 to 3. [2] The microneedle according to [1], wherein a water-soluble material is filled into the gaps between the particles of the microsphere, extending from the tip to the bottom of the microneedle (and, if the microneedle includes the microneedle substrate, extending from the tip of the microneedle to the bottom of the microneedle substrate). [3] The microneedle according to [1] or [2], wherein the biodegradable material comprises at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose. [4] The water-soluble material is polyvinyl alcohol (PVA), CMC (carboxymethylcellulose), or starch, as described in any one of [1] to [3]. A microneedle patch comprising porous microneedles as described in any one of items [5][1] to [4]. [6] (a) A step of preparing a biodegradable material microsphere solution or suspension containing biodegradable material microspheres by dissolving a biodegradable material in an organic solvent, mixing the solution A with an aqueous solution containing a water-soluble material and stirring, (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or a microneedle array precursor, and (d) A step of heating the microneedle precursor to a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together with each other. A method for manufacturing a porous microneedle or porous microneedle array, comprising: A method for producing porous microneedles or porous microneedle arrays, wherein the volume ratio of water-soluble material to biodegradable material in the resulting porous microneedles or porous microneedle array is 1:2 to 3. [7] The biodegradable material comprises at least one selected from the group consisting of polylactic acid, polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose, as described in [6]. [8] The water-soluble material is polyvinyl alcohol (PVA), CMC (carboxymethylcellulose), or starch, the method of production according to [6] or [7]. The method according to any one of [6] to [8], wherein the drying of the solution or suspension in step [9](c) is carried out by air drying, a pressurized drying process in which pressure is applied to the solution or suspension while drying, or a combination thereof. The manufacturing method according to [9], wherein in step

[10] (c), the solution or suspension is air-dried, and then subjected to a pressurized drying process in which pressure is applied to the solution or suspension to dry it, thereby obtaining a microneedle precursor or a microneedle array precursor. The manufacturing method according to [9], wherein in step (c), the solution or suspension is subjected to a pressure drying treatment to dry it under pressure, thereby obtaining a microneedle precursor or a microneedle array precursor. A porous microneedle or porous microneedle array obtained by the manufacturing method described in any one of items

[12] [6] to

[11] .

[13] (a) A step of preparing a solution A in which a biodegradable material is dissolved in an organic solvent, and mixing the solution A with an aqueous solution containing a water-soluble material and stirring to prepare a biodegradable material microsphere solution or suspension containing microspheres of the biodegradable material, (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or a microneedle array precursor. (d) A step of heating the microneedle precursor at a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together to obtain porous microneedles or porous microneedle arrays, and A step of treating the porous micro needles or porous micro needle array obtained in the step (e)(d) with water, A method for producing a porous micro needle or porous micro needle array from which a water-soluble material has been removed, which includes

[14] After the step (e), a method for production according to

[13] , including a step of heating the porous micro needle or porous micro needle array treated with (f) water to a temperature not higher than the temperature at which melting begins near the melting point of the biodegradable material.

[15] The method for production according to

[14] , wherein the temperature for treating the porous micro needle or porous micro needle array with water in the step (e) is 20 to 60°C.

[16] The drying of the solution or suspension in the step (c) is carried out by natural drying, pressure drying treatment in which pressure is applied to the solution or suspension during drying, or a combination thereof, according to any one of

[13] to

[15] .

[17] The method for production according to

[16] , wherein after the solution or suspension is naturally dried in the step (c), a pressure drying treatment is carried out in which pressure is applied to the solution or suspension during drying to obtain a micro needle precursor or a micro needle array precursor.

[18] The method for production according to

[16] , wherein a pressure drying treatment is carried out in which pressure is applied to the solution or suspension during drying to obtain a micro needle precursor or a micro needle array precursor.

[19] A porous micro needle or porous micro needle array substantially free of a water-soluble material obtained by the method for production according to any one of

[13] to

[18] .

[20] A porous micro needle formed from microspheres of a biodegradable material, wherein the microspheres of the biodegradable material are bonded to each other to form a network of interconnected pores, and the micro needle substantially contains no water-soluble material.

[21] The micro needle according to

[20] , having an absorption volume of 8 to 150 μL.

[22] The micro needle according to

[20] or

[21] , having a mechanical strength (breaking strength) of 0.1 to 0.5 N. A microneedle patch comprising the porous microneedle according to any one of

[23] to

[22] . [Advantages of the Invention]

[0012] The microneedle and microneedle array according to the first embodiment of the present invention (details will be described later) are composed of a water-soluble material and a biodegradable material in an optimal ratio, so it is possible to provide a porous microneedle capable of efficiently collecting body fluid. In addition, a method for manufacturing a microneedle (or microneedle array) according to the first embodiment of the present invention can provide a microneedle composed of a water-soluble material and a biodegradable material in an optimal ratio. In the method for manufacturing a microneedle (or microneedle array) according to the first embodiment of the present invention, by appropriately adjusting the ratio of the water-soluble material and the biodegradable material at the start of production, a microneedle with stable performance can be manufactured, so it can also be used for mass production of microneedles.

[0013] A method for manufacturing according to the second embodiment of the present invention (details will be described later) can provide a porous microneedle or porous microneedle array from which the water-soluble material has been removed. In addition, the microneedle and microneedle array from which the water-soluble material has been removed according to the second embodiment of the present invention can have a higher collection capacity than conventional porous microneedles. [Brief Description of the Drawings]

[0014] [Figure 1] As a typical example of the single emulsion method, a non-limiting schematic diagram of a method for manufacturing a porous microneedle using PLA and PVA is shown. [Figure 2] Shows various forms (structures) of PLA particles and PVA inside the porous microneedle obtained by the single emulsion method using PLA and PVA. [Figure 3]This shows a 3D-CAD model of a porous microneedle obtained by the single emulsion method using PLA and PVA, where PLA particles are densely deposited. [Figure 4] In a model of porous microneedles obtained by the single emulsion method using PLA and PVA, the results are shown as line graphs plotting the distance from the needle tip on the x-axis and the volume on the y-axis, divided into (1) the range where PLA particles are deposited from the needle tip and (2) the range where only PVA is present. [Figure 5] In Example 1, the table and figure show the simulation results for the amount of material layered in a microneedle array with a needle height of 1200 μm. [Figure 6] In Example 1, when the PLA content is entered into the form in the table shown in Figure 5, it is reflected in each of the 1.0 mL to 0.5 mL cells of the 5% (w / v) PVA solution. [Figure 7] In Example 1, the repeating "pattern shape" was extracted from a densely aggregated state of PLA microparticles with the same diameter of 11 μm, and the results of comparing the volume of the PLA microparticles with the volume of the voids are shown. [Figure 8] In Example 1, a 3D model of the recess in the female mold of the MAP is created, and a schematic diagram is shown in which the volume is checked every 10 μm from 0 μm to 1620 μm from the tip of the needle. [Figure 9A] The results of creating a table of total MAP volumes at different distances from the needle tip in Example 1 are shown below. [Figure 9B] The results of creating a table of total MAP volumes at different distances from the needle tip in Example 1 are shown below. [Figure 9C] The results of creating a table of total MAP volumes at different distances from the needle tip in Example 1 are shown below. [Figure 10] In Example 1, the graph shows the changes in PLA volume and PVA volume (when injected at a volume of 1.0 mL) on the horizontal axis and the vertical axis respectively. [Figure 11] In Example 1, the graph shows the changes over time with the distance from the needle tip on the horizontal axis and the PLA volume and PVA volume (when the injection volume is 1.0 to 0.5 mL) on the vertical axis. [Figure 12] The graph shows the relationship between PLA volume and PVA volume as a function of distance from the needle tip in Example 1, when the needle length is 300 μm and the PLA content is 100 mg. [Figure 13] The stacked image of the MNs cross-section obtained from the simulation of Example 1 is shown. [Figure 14] This shows a non-limiting schematic diagram of the method for producing porous PLA microneedles from which PVA has been removed according to the present invention. [Figure 15] The evaluation results of the porous PLA microneedles obtained in Example 2, from which the PVA has been removed, are shown. [Figure 16] The following are non-limiting schematic diagrams illustrating the detailed structure of the microneedles due to differences in the drying process, specifically for the cases where only natural drying is performed and where natural drying and pressurized drying using a pressure vessel are performed in manufacturing methods 1 and 2 of the present invention. [Figure 17] A non-limiting schematic diagram is shown for the manufacturing method of porous PLA microneedles from which PVA has been removed according to the present invention, in which a pressurized drying treatment using a pressure vessel is performed in step (c) (Example 3). [Figure 18] A schematic diagram of the pressurized drying process using the pressure vessel used in Example 3 is shown. [Figure 19] A non-limiting schematic diagram is shown for the method of producing porous PLA microneedles from which PVA has been removed according to the present invention, in which only a pressurized drying treatment using a pressure vessel is performed in step (c) (Example 4). [Modes for carrying out the invention]

[0015] I. First Embodiment of the Present Invention One aspect of the first embodiment of the present invention is a porous microneedle comprising microspheres of a biodegradable material and a water-soluble material, wherein the microspheres of the biodegradable material are bonded to each other to form a network of interconnected pores, and the microneedle may include a microneedle substrate comprising the microspheres and the water-soluble material, and the volume ratio of the water-soluble material to the biodegradable material is 1:2 to 3 (hereinafter also referred to as "microneedle 1 of the present invention").

[0016] Another aspect of the first embodiment of the present invention is: (a) A step of preparing a biodegradable material microsphere solution or suspension containing biodegradable material microspheres by dissolving a biodegradable material in an organic solvent, mixing the solution A with an aqueous solution containing a water-soluble material, and stirring. (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or a microneedle array precursor, and (d) A step of heating the microneedle precursor to a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together with each other. The water-soluble material and the biodegradable material have a volume ratio of 1:2 to 3. This is a method for manufacturing porous microneedles or porous microneedle arrays (hereinafter also referred to as "Manufacturing Method 1 of the present invention").

[0017] Hereinafter, Embodiment 1 of the present invention will be described in detail, including the microneedle 1 of the present invention and the manufacturing method 1 of the present invention.

[0018] 1. Microneedle 1 of the present invention (1) Structure and characteristics of microneedles The microneedle 1 of the present invention is a porous microneedle containing microspheres of biodegradable material and a water-soluble material, and is characterized in that the volume ratio of the water-soluble material to the biodegradable material is 1:2 to 3.

[0019] While not intended to be constrained by theory, the single emulsion method discovered by the inventors allows for the formation of porous microneedles made from biodegradable polymers such as polylactic acid (PLA) and surfactants (water-soluble materials) such as polyvinyl alcohol (PVA). As a result, PLA particles accumulate, and the PVA solution fills the gaps between them. When dried, the adhesive PVA binds the PLA particles together, allowing the shape to be maintained even after demolding. Furthermore, the heating process allows the entire microneedle to be exposed to ambient temperature, providing the advantage of uniform heating. Figure 1 shows a non-limiting schematic diagram of a method for manufacturing porous microneedles using PLA and PVA, which is a typical example of the single emulsion method disclosed in Patent Document 1. However, when actually producing microneedles using the single emulsion method described above, it was necessary to gradually change the amount of material and the manufacturing process to find the optimal conditions. This meant that if the conditions were different, the amount of material had to be adjusted from scratch. Furthermore, even if optimization was achieved, it was only for one condition. If the length or number of needles, the thickness of the microneedle substrate, etc., were different, it was necessary to adjust the amount of material such as PLA or PVA again from scratch and repeat the prototyping and evaluation process, which was inefficient.

[0020] Furthermore, in porous microneedles obtained by the single emulsion method using PLA and PVA, for example, the PLA, which has a melting point of 170°C, is coated with PVA, which has a higher melting point. Therefore, heating to 180°C, slightly higher than the melting point of PLA, partially turns the PLA particles into a liquid or rubbery state, causing them to bond together. However, the optimal ratio of PLA to PVA for efficient collection of bodily fluids was not clearly defined. If the amount of PVA was insufficient compared to the amount of PLA particles, the PVA could not coat the PLA particles on the back side of the microneedle. When heated to 180°C, above the melting point of PLA, the uncoated PLA particles melted, blocking the pore network (capillaries) and preventing the collection of bodily fluids (right-hand diagram in Figure 2). Furthermore, if the amount of PVA is large relative to the amount of PLA particles, a layer of PVA alone will form covering the PLA particle deposit layer on the back side of the microneedle. This makes it difficult for the body fluid to dissolve the PLA, making rapid sample collection difficult. Also, if the layer of PVA alone is thick, heat does not easily reach the PLA particles inside on the back side. When the needle side reaches the temperature at which the PLA particles partially become liquid or rubbery and bond together, the back side has not yet reached the temperature at which the PLA particles partially become liquid or rubbery and bond together, resulting in uneven heating (left side of Figure 2). Furthermore, since water-soluble PVA dissolves in body fluids during puncture and is absorbed along with biomarkers in the body fluids, there was a possibility that the analysis results might be affected depending on the biomarker. Furthermore, since the time required for PVA to dissolve is added to the time taken for fluid collection, there was a need for further time reduction, even though the procedure was already quick.

[0021] Thus, in the single emulsion method for producing porous microneedles (porous MNs), the optimal ratio of biodegradable materials such as PLA and water-soluble materials such as PVA was not clearly defined, making it difficult to stably prepare porous microneedles capable of efficiently collecting bodily fluids. The inventors of this invention found that the reason for this is that they are performing practical optimization by gradually changing the conditions, and that in order to optimize theoretically, it is necessary to clarify the deposition state of biodegradable material particles such as PLA and water-soluble material such as PVA that constitute the porous microneedles.

[0022] Therefore, the inventors first created a model of densely deposited PLA particles in 3D-CAD for porous microneedles obtained by the single emulsion method using PLA and PVA. From the pattern shape, they confirmed the volume ratio of the pattern shape, PLA particles, and interparticle voids, and found that it was "1:0.7404:0.2596" (see Figure 3, Example). From this, it can be seen that the volume ratio of PLA to PVA is 2.85:1 (mass ratio of 3:1) (Figure 3).

[0023] TIFF0007901820000001.tif54159

[0024] Furthermore, the line graph was converted into a bar graph so that it could be displayed in the shape of a needle, with the distance from the needle tip on the x-axis and the volume on the y-axis (see Example, Figure 13). Then, a simulation was created based on the calculated volume ratio. After inputting the content of the optimized conditions, the feather weight was subtracted, and the PVA amount was input again. It was confirmed that the PLA and PVA deposition amounts were equal. The term "feathers" here primarily refers to the precipitated PVA, which will be discussed later.

[0025] Thus, the inventors investigated the optimization of material ratios using porous microneedles formed from PLA particles and PVA as an example, and found that even if the needle height and number of porous MNs, the thickness of the microneedle substrate, etc., differ, the volume ratio of water-soluble material to biodegradable material in the finished MNs product is 1:2 to 3, preferably 1:2.85 (weight ratio is "1:3").

[0026] In the case of PVA, because it has surface activity, when PLA particles and a PVA solution are mixed and injected into the female mold, a thin layer of PVA precipitates on the sides of the recesses of the female mold during the drying process. Here, precipitation includes the residue of PVA after the water evaporates during drying. The precipitated thin layer of PVA is PVA that has spread and solidified on the sides of the recesses of the female mold. This thin layer of PVA can occur around the entire circumference of the female mold's sides. The precipitated PVA may also contain other components (e.g., biodegradable materials such as PLA, carboxymethylcellulose (CMC), hyaluronic acid). Since the precipitated PVA is unnecessary in the final product, it can be discarded. By measuring the weight of the precipitated PVA at this time and adding it to the amount of PVA initially injected into the mold, the resulting mixture of PVA and PLA particles in the final product will have a volume ratio of 1:2 to 3, preferably 1:2.85, and a mass ratio of 1:3. In this way, by taking into account the amount of PVA discarded during the manufacturing process, it is also possible to calculate the optimal amounts of PLA material and PVA material to start the manufacturing process. The precipitated PVA can be disposed of by separating the portion containing the precipitated PVA from the microneedle. The separated portion may contain other components (e.g., PLA, carboxymethylcellulose (CMC), hyaluronic acid). Separation can be achieved by cutting, for example, with a blade. The resulting microneedle (precursor) has a mixture of PVA and PLA particles in a volume ratio of 1:2 to 3, preferably 1:2.85, and a mass ratio of 1:3. By measuring the weight of the PVA or PLA contained in the separated material and adding this weight to the weight of the PVA or PLA in the resulting microneedles, the amount of PVA or PLA to be initially injected into the female mold can be calculated. Alternatively, the weight of the separated material can be considered as the weight of the PVA, and this weight can be added to the weight of the PVA or PLA in the resulting microneedles.

[0027] In the microneedle 1 of the present invention, the biodegradable material comprises at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose. The biodegradable material is preferably polylactic acid or polyglycolic acid, and more preferably polylactic acid.

[0028] In the microneedle 1 of the present invention, the water-soluble material is polyvinyl alcohol (PVA), CMC (carboxymethylcellulose), or starch, and is preferably polyvinyl alcohol.

[0029] The microneedle 1 of the present invention may include a microneedle substrate. That is, the microneedle 1 of the present invention can also be used as a microneedle array in which a plurality of microneedles of the present invention are erected on a microneedle substrate. That is, in another embodiment of the present invention, the microneedle of the present invention is a microneedle array in which a plurality of microneedles are erected on a microneedle substrate (hereinafter also referred to as "microneedle array 1 of the present invention").

[0030] Since the microneedle 1 and microneedle array 1 of the present invention are porous themselves, the microneedle array of the present invention can be used as a microneedle array patch or a patch-type bodily fluid collection system without using absorbent materials such as filter paper. Furthermore, the microneedle 1 of the present invention can also be placed on an absorbent material capable of absorbing interstitial fluid and used as a microneedle array patch or a patch-type bodily fluid collection system. Furthermore, the microneedle array 1 of the present invention can be combined with an absorbent material capable of absorbing interstitial fluid and used as a microneedle patch or a patch-type bodily fluid collection system.

[0031] In the microneedle array 1 of the present invention, microneedles can be appropriately arranged vertically and horizontally. While smaller spacing between microneedles is preferable for absorbing interstitial fluid samples, a spacing of 500 to 2000 μm is preferred.

[0032] The microneedle substrate may be made from the same material as the microneedles, or it may be made from a different material.

[0033] In one embodiment, the microneedle substrate is composed of a film or hydrocolloidal film comprising at least one of polylactic acid resin, polyvinyl alcohol resin, polymethyl methacrylate resin, and polyurethane resin.

[0034] In another embodiment, the microneedle substrate is formed from a biodegradable material. The biodegradable material includes at least one of polylactic acid, polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose. In one preferred embodiment, the microneedle substrate is formed from the same biodegradable and water-soluble material as the microneedles, and the two are integrally constructed.

[0035] In the microneedle 1 of the present invention, the water-soluble material is contained in the gaps between the particles of the microsphere, extending from the tip to the bottom of the microneedle (and, if the microneedle is equipped with a microneedle substrate made of a biodegradable material and a water-soluble material, extending from the tip to the bottom of the microneedle substrate). Furthermore, if the water-soluble material is an adhesive such as PVA, the PVA plays a role in fixing (maintaining) the positions (spacing) between the particles of the biodegradable material such as PLA.

[0036] In the microneedle 1 of the present invention, the optimal volume ratio of the final amount of biodegradable material particles to the amount of water-soluble material is determined. If the amount of water-soluble material such as PVA is small compared to the amount of biodegradable material particles, a layer of only biodegradable material will form on the microneedle, and the water-soluble material will not be able to coat the biodegradable material particles. When heated at a temperature above the melting point of the biodegradable material, the biodegradable material particles that were not coated will melt and clog the pore network (capillaries), solving the problem of not being able to collect bodily fluids. Furthermore, if the amount of water-soluble material is large compared to the amount of biodegradable material particles, a layer of water-soluble material will form covering the layer of biodegradable material particles, and it will take time for the bodily fluids to dissolve the biodegradable material, solving the problem of difficulty in collecting bodily fluids in a short time. Furthermore, if the single layer of biodegradable material is thick, heat does not easily reach the biodegradable material particles inside on the back side. This solves the problem that when the needle side reaches the temperature at which the biodegradable material particles partially become liquid or rubbery and bond with each other, the back side has not yet reached the temperature at which the biodegradable material particles partially become liquid or rubbery and bond with each other, resulting in uneven heating. Furthermore, the present invention does not prohibit the formation of a single layer of water-soluble material (for example, a single layer of PVA) in the microneedle.

[0037] The microneedle 1 of the present invention may consist only of the above-mentioned biodegradable material and water-soluble material, or it may contain other additives (e.g., carboxymethylcellulose (CMC), hyaluronic acid) as trace components in an amount that does not impair the function of the microneedle of the present invention. Furthermore, the microneedle 1 of the present invention may be coated with a coating agent, at least a portion of which is coated, so as not to impair its function. As the coating agent, materials commonly used in the art (such as CMC or hyaluronic acid) can be used.

[0038] The porosity of the microneedle 1 of the present invention is typically 10 to 40%, preferably 20 to 30%. Here, the porosity is determined by comparing the mass before and after fluid extraction using a water absorption method with a porous membrane, and measuring the porosity of the porous microneedle in the following procedure (see P. Liu, et al., J Mater Chem B, 2020). First, the dry mass (W) of the porous membrane. dry ) is recorded, then the membrane is immersed in deionized (DI) water, and surface water is removed after absorption saturation. The mass is then immediately measured, W wet Record it as follows. Calculate the void ratio using the following formula.

[0039]

number

[0040] In equation (1), ρ p ρ0 is the density of the biodegradable material, and ρ0 is the density of water (1.0 g / cm³). 3 )

[0041] The microneedle 1 of the present invention has excellent water absorption capacity, such as water absorption rate. When the microneedle precursor is heated at a high temperature, the microspheres partially become liquid or rubbery due to the heat treatment, and bond together to form a strong interconnected micropore network, allowing for efficient extraction of interstitial fluid from the skin by capillary force.

[0042] Absorption volume is one indicator of water absorption capacity, and the microneedle 1 of the present invention has an absorption volume of typically 8 to 150 μL, preferably 20 to 120 μL. Here, the absorption volume is measured by puncturing a microneedle array consisting of 169 porous PLA MN needles erected in a 1-2% agarose gel, removing the needles from the gel after 2 minutes, and measuring their weight.

[0043] Furthermore, the microneedle 1 of the present invention has an absorption rate of typically 0.01 to 0.3 μL / min per microneedle, preferably 0.2 to 0.3 μL / min. Here, the absorption rate is measured by puncturing a microneedle array consisting of 169 porous PLA MN needles erected in a 1-2% agarose gel, removing the needles from the gel after 2 minutes, and measuring their weight.

[0044] The microneedle 1 of the present invention has a strength of 0.1 N or more, preferably 0.3 N or more, at the yield point load measured under the following conditions. Conditions: A compressive load is applied axially to a single microneedle, and the load at the yield point obtained from the load-displacement curve is measured as the fracture strength. The microneedles of the present invention possess such high mechanical strength that it becomes possible to realize the inspection device of the present invention.

[0045] (2) Shape of the microneedle The shape of the microneedle 1 of the present invention can be a substantially conical shape or a substantially pyramidal shape, but a polygonal shape (for example, a substantially pyramidal shape) is preferable because it penetrates the skin more easily than a substantially conical shape.

[0046] The tip diameter of the microneedle 1 of the present invention is typically 10 μm to 60 μm. The base diameter or maximum dimension is, for example, about 50 μm to 800 μm. Furthermore, the height of the microneedle determines the depth of penetration into the dermis. In the microneedle of the present invention, considering that it reaches the dermis, it is preferably 300 μm to 2500 μm, and considering that it does not stimulate pain receptors, it is even more preferably 300 μm to 1500 μm.

[0047] When multiple microneedles are provided, a smaller spacing is preferable for absorbing the interstitial fluid sample, but a spacing of 500 to 2000 μm is preferable.

[0048] Regarding the tip angle 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 because the force required for the microneedle to penetrate is less than 0.1 N.

[0049] Embodiment 1 of the present invention includes a microneedle patch comprising the microneedle 1 and / or the microneedle array 1 of the present invention (hereinafter also referred to as "microneedle patch 1 of the present invention"). Furthermore, the microneedle 1 and / or microneedle array 1 of the present invention may be further provided with filter paper as a means for storing the collected interstitial fluid. The filter paper may be equipped with a sensor that detects biomarkers from the collected interstitial fluid.

[0050] 2. Manufacturing method of the present invention 1 One embodiment of Embodiment 1 of the present invention is (a) A step of preparing a biodegradable material microsphere solution or suspension containing biodegradable material microspheres by dissolving a biodegradable material in an organic solvent, mixing the solution A with an aqueous solution containing a water-soluble material, and stirring. (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or a microneedle array precursor, and (d) A step of heating the microneedle precursor to a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together with each other. A method for manufacturing a porous microneedle or porous microneedle array, comprising: The manufacturing method is such that the volume ratio of water-soluble material to biodegradable material in the resulting porous microneedle or porous microneedle array is 1:2 to 3.

[0051] The biodegradable material comprises at least one selected from the group consisting of polylactic acid, polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose, preferably polylactic acid or polyglycolic acid, and more preferably polylactic acid.

[0052] The water-soluble material is polyvinyl alcohol (PVA), CMC (carboxymethylcellulose), or starch, and is preferably polyvinyl alcohol.

[0053] The particle size of the biodegradable material microspheres is preferably 5 to 30 μm. A particle size within this range is preferable in terms of achieving both mechanical strength and fluid performance.

[0054] A solution or suspension of biodegradable material microspheres means a liquid in which biodegradable material microspheres are dissolved or dispersed in water or an organic solvent. Preferably, it is a suspension of biodegradable material microspheres, and more preferably, a suspension in which biodegradable material microspheres are dispersed in water.

[0055] The organic solvent is not particularly limited as long as it is a solvent that dissolves biodegradable materials, but examples include dichloromethane and acetone.

[0056] The concentration of biodegradable material in solution A is, for example, 0.05-0.1% (w / v).

[0057] Solution A, and / or the aqueous solution containing the water-soluble material, may also contain other additives (e.g., carboxymethylcellulose (CMC), hyaluronic acid) to the extent that they do not impair the function of the resulting porous microneedles.

[0058] The solution obtained by mixing solution A with an aqueous solution can have its organic solvent evaporated by stirring at room temperature at a concentration of 500-1500 ppm using a magnetic stirrer or the like.

[0059] In step (b), a solution or suspension of biodegradable material microspheres is injected into a female mold. The mold used here is a female micromold prepared from a metal master mold consisting of numerous microneedles, and the material used 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 microneedles.

[0060] The mold may only have the shape of the template for the microneedle to be prepared. In this case, a single microneedle can be obtained. Furthermore, the mold can be provided with a cavity having a shape in which a microneedle substrate and multiple microneedles are joined together. In this case, a microneedle array can be obtained in which multiple microneedles are joined to the microneedle substrate and erected. The micromold itself can have any desired number of cavities. Furthermore, cavities in the micromold itself can be appropriately provided both vertically and horizontally. The spacing between these cavities is preferably 500 to 2000 μm.

[0061] It is preferable to inject a solution or suspension of biodegradable material microspheres into the female mold cavity, and then leave it in a vacuum or apply centrifugal force to fill or deposit the microspheres into the cavity.

[0062] In step (c), the water, solvent, and dispersant are evaporated by drying the solution or suspension of the biodegradable material microspheres. As a drying method, the temperature can be controlled by installing piping inside the female micromold, or the entire micromold can be dried by placing it in a dryer such as a convection oven. The drying temperature is preferably 20 to 100°C, and the drying time can be determined as appropriate, for example, 1 to 48 hours.

[0063] Furthermore, in step (c), the method for drying the solution or suspension of biodegradable material microspheres can be natural drying, pressurized drying in which pressure is applied to the solution or suspension, or a combination thereof.

[0064] The above drying methods can be selected arbitrarily, but in particular, when manufacturing microneedles with a large height (needle height) (which may vary slightly depending on the manufacturing conditions, but for example, a needle height of 800 μm or more), it is preferable to use pressurized drying or a combination of natural drying and pressurized drying. By using these drying methods, even when the needle height of the microneedles is large, it is possible to obtain microneedles in which bending of the needle tip is suppressed.

[0065] While not intended to be theoretically restrictive, Figure 16 shows a non-restrictive schematic diagram illustrating the differences in the detailed structure of microneedles due to the drying process, specifically for cases where only natural drying is performed and cases where natural drying and pressure drying using a pressure vessel are performed. In the drying process of (c), if the solution or suspension of biodegradable material microspheres is air-dried only, it is thought that the microspheres such as PLA fine particles are stacked by gravity, the gaps between them are filled with a water-soluble material such as PVA, and the fine particles are fixed after drying (see the upper left diagram of Figure 16). In this case, the gaps filled by the water-soluble material are relatively large, and in the heating process of (d) after the process of (c), the microsphere particles partially become liquid or rubbery and bond with each other, so it is thought that the gaps become slightly smaller, but the majority of the gap space is maintained. Furthermore, in the second embodiment of the present invention described later, even when the microneedle is heated after the water-soluble material has been removed, and even after the water-soluble material has been removed again, relatively large gaps remain between the microsphere particles. When there are gaps between relatively large microsphere particles (including gaps filled with water-soluble material and gaps after the water-soluble material has been removed), there is generally no problem if the needle height of the microneedle is small, but as the needle height increases, the needle tip is more likely to bend. In contrast, in the drying process of (c), if a pressurized drying treatment is performed in which pressure is applied to the solution or suspension of biodegradable material microspheres while drying, or if a combination of natural drying and pressurized drying is performed, it is thought that after the microspheres such as PLA fine particles are stacked by gravity, the pressure pushes in the solution of water-soluble material such as PVA, which in turn pushes in each individual particle, and the pressure further pushes in the particles themselves, resulting in a dense layer where the water-soluble material such as PVA in the gaps dries and fixes the particles (see the lower left diagram of Figure 16). In this case, the gaps filled by the water-soluble material are small, and in the heating process of (d) after the process of (c), the microsphere particles partially enter a liquid phase or rubbery state and bond with each other, so it is thought that the gaps become even smaller.

[0066] In one preferred embodiment of the manufacturing method 1 of the present invention, in step (c), after the solution or suspension is air-dried, a pressurized drying treatment is performed on the solution or suspension while applying pressure to obtain a microneedle precursor or a microneedle array precursor.

[0067] Furthermore, in another preferred embodiment of the manufacturing method 1 of the present invention, in step (c), a pressurized drying treatment is performed on the solution or suspension while applying pressure to obtain a microneedle precursor or a microneedle array precursor.

[0068] Pressurized drying is preferably carried out using a pressure vessel. Furthermore, when drying in a pressure vessel, if the vessel is sealed, the water vapor during the drying process cannot escape to the outside of the vessel, making drying impossible. Therefore, it is preferable to allow air leakage. This makes it possible to discharge the water vapor to the outside of the pressure vessel.

[0069] When performing pressurized drying using a pressure vessel, it is preferable to dry the drying time at room temperature for approximately 72 to 96 hours. Furthermore, when combining natural drying and pressurized drying using a pressure vessel, it is preferable that natural drying takes about 18 to 24 hours at room temperature, and pressurized drying using a pressure vessel (preferably with air leakage) takes about 24 to 36 hours. By limiting the drying time to this extent, it becomes possible to manufacture microneedles with a uniform structure and small gaps between the microsphere particles.

[0070] The pressure inside the pressure vessel is preferably in the range of 0.1 MPa to 0.5 MPa, but it is even more preferable to set it at around 0.2 MPa from the viewpoint of balancing it with promoting drying. The pressure inside the pressure vessel can be adjusted by changing the air pressure supplied by the compressor.

[0071] Furthermore, when performing pressurized drying using a pressure vessel, it is preferable to install a cover so as to cover part or all of the female mold into which the biodegradable material microsphere solution or suspension has been injected. This prevents the microneedles from being directly subjected to air pressure from the compressor, and thus allows for the production of homogeneous microneedles without being affected by air pressure that may vary depending on the position within the mold. Furthermore, the drying time can be accelerated by placing silica gel inside the pressure vessel.

[0072] After drying, water evaporates from the solution or suspension of biodegradable material microspheres to obtain a microneedle precursor or microneedle array precursor composed of biodegradable material microspheres. At this stage, the microneedle precursor may be removed from the mold and subjected to the next step (d). Alternatively, at this stage, the microneedle precursor may be subjected to the heating step of the next step (d) with the microneedle precursor still inside the mold.

[0073] In step (d), the microneedle precursor is heated to a predetermined temperature. In the microneedle precursor, the individual microspheres maintain their shape and do not have a bonded form with each other. In the manufacturing method of the present invention, the microneedle precursor or microneedle array precursor is heated at a high temperature to bond the microspheres with each other. The heating temperature at this stage must be such that the microspheres deform and bond with each other, and this temperature varies depending on the type of biodegradable resin. For example, in the case of polylactic acid, the temperature is preferably 170-200°C, more preferably 170-190°C. Furthermore, in the case of polyglycolic acid, the temperature is preferably 170 to 250°C. Furthermore, in the case of poly(lactide-co-glycolide) copolymers, the temperature is preferably 50 to 200°C. In the case of PEG copolymers, the temperature is preferably 30 to 200°C. In the case of polyhydroxybutyric acid, the temperature is preferably 100 to 200°C. In the case of ethylcellulose, the temperature is preferably 80 to 300°C. For example, the heating time is 10 to 120 minutes.

[0074] The porous microneedles obtained by the manufacturing method of the present invention described above are formed by partially liquidizing or rubberizing the microspheres and bonding them together, thereby creating a continuous network of interconnected (communicating) pores, and thus forming a robust pore structure.

[0075] In the manufacturing method 1 of the present invention, the volume ratio of water-soluble material particles to biodegradable material particles in the resulting porous microneedle or porous microneedle array is 1:2 to 3. In the manufacturing method 1 of the present invention, "the resulting porous microneedle or porous microneedle array" refers to the porous microneedle or porous microneedle array obtained after the heating step of step (d) (i.e., the porous microneedle or porous microneedle array obtained by the manufacturing method 1 of the present invention). Here, the optimal amounts of water-soluble and biodegradable materials at the start of manufacturing are calculated, taking into account the amounts of water-soluble and biodegradable materials that will be discarded during the manufacturing process. For example, if the water-soluble material is PVA, because it has surface activity, PLA will precipitate on the sides of the recesses of the female mold during the drying process after mixing biodegradable material particles and PVA solution in the female mold and injecting the mixture. Since the precipitated PVA is not needed in the final product, it is discarded. However, the weight of the precipitated PVA at this time is measured and fed back into the amount of PVA initially injected into the female mold, and added to it. This is done to adjust the composition of the mixed portion of PVA and biodegradable material particles in the final product so that the volume ratio is 1:2 to 3, preferably 1:2.85 (mass ratio of 1:3).

[0076] An example of a method for calculating the optimal amounts of water-soluble and biodegradable materials at the start of manufacturing is described below for porous microneedles formed from PLA particles and PVA. The procedure is as follows: 1. Determine the height of the microneedle to be manufactured (microneedle needle height + microneedle substrate thickness).

[0077] 2. Using simulation, input the amount of PLA so that it corresponds to the thickness of the BackLayer (microneedle substrate) that the PLA microparticles are expected to form. For example, we can determine the amount of PLA such that the layer height of the PLA is the same as the height of the microneedle being manufactured.

[0078] 3. Next, input the amount of PVA into the simulation so that the ratio of PVA amount:PLA amount = 1:2 (by weight), and check where the amount of PVA deposition is located relative to the amount of PLA microparticle deposition. For example, when you input the amount of PVA, you determine the amount of PVA by checking whether the height of the PVA deposit displayed on the MAP is the same as, or higher / lower than, the PLA layer height.

[0079] 4. Fabricate a prototype microneedle under the above conditions and confirm that the pore network of the microneedle is not collapsed. (You may also check conditions such as strength, absorption volume, and the presence or absence of a PVA layer alone.) After the microneedles have dried, the weight of the thin, film-like PVA that has actually precipitated (formed) on the sides of the recesses of the female mold, which is then separated from the microneedles (also called "feathers"), is measured. This weight of the feathers (which are mostly PVA) is then fed back into the initially determined amount of PVA to adjust it to the appropriate amount.

[0080] In this way, the optimal volume ratio of water-soluble materials to biodegradable materials at the start of manufacturing can be determined.

[0081] As one non-limiting example, consider the case where the needle height is 800 μm, the thickness of the microneedle substrate is 150 μm, and there is only one cavity (recess) in the female mold. The amount of PLA and PVA required to fill this cavity is 30 mg of PLA, 25 mg of PVA, and the weight of the blade is 15 mg. Since the blade is composed almost entirely of PVA, there is 10 mg of PVA remaining in the microneedle. The weight ratio of PVA to PLA at the start of manufacturing was 2.5:3. This is the ratio of microneedles (precursors) in a step prior to the separation of PVA (precipitated PVA), which is separated later. After the separation process of the precipitated PVA, the volume ratio of PVA:PLA in the obtained microneedles (precursors) is 1:2 to 3. After the heating process, the volume ratio of PVA:PLA in the resulting microneedles is 1:2 to 3.

[0082] Another aspect of the present invention is a porous microneedle or porous microneedle array obtained by the manufacturing method 1 of the present invention. Furthermore, Embodiment 1 of the present invention includes a microneedle patch comprising porous microneedles and / or porous microneedle arrays obtained by the manufacturing method 1 of the present invention (hereinafter also referred to as "microneedle patch 1A of the present invention").

[0083] By using the microneedle patch 1 or 1A of the present invention, interstitial fluid can be collected instead of using a blood collection needle, and the procedure is painless and easy. Furthermore, the microneedle patch 1 or 1A of the present invention can be integrated with a sensor as a medical device, enabling the detection of various biomarkers.

[0084] The manufacturing method 1 of the present invention can be used for the manufacture of microneedles. Furthermore, since the manufacturing method 1 of the present invention can produce microneedles with stable performance, the manufacturing method 1 of the present invention can also be used for mass production of microneedles. The microneedle 1 and / or microneedle array 1 of the present invention can also be used for drug delivery.

[0085] II. Second Embodiment of the Invention One aspect of a second embodiment of the present invention is: (a) A step of preparing a biodegradable material microsphere solution or suspension containing biodegradable material microspheres by dissolving a biodegradable material in an organic solvent, mixing the solution A with an aqueous solution containing a water-soluble material, and stirring. (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or a microneedle array precursor. (d) A step of heating the microneedle precursor at a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together to obtain porous microneedles or porous microneedle arrays, and (e)(d) A process of treating the porous microneedle or porous microneedle array obtained in step (e)(d) with water. This is a method for producing porous microneedles or porous microneedle arrays from which water-soluble materials have been removed (hereinafter also referred to as "production method 2 of the present invention").

[0086] 1. Manufacturing method of the present invention 2 The manufacturing method 2 of the present invention makes it possible to produce porous microneedles or porous microneedle arrays from which water-soluble materials have been removed.

[0087] Steps (a) to (d) in manufacturing method 2 of the present invention are basically the same as steps (a) to (d) in manufacturing method 1 of the present invention. However, in manufacturing method 2 of the present invention, the volume ratio of water-soluble material to biodegradable material in the porous microneedle or porous microneedle array obtained through the heating step of step (d) does not need to be 1:2 to 3, but the volume ratio is preferably 1:2 to 3, and more preferably 1:2.85 (1:3 by mass ratio).

[0088] In the manufacturing method 2 of the present invention, in step (c), the method for drying the solution or suspension of biodegradable material microspheres can be natural drying, a pressurized drying treatment in which pressure is applied to the solution or suspension while drying, or a combination thereof.

[0089] The above drying methods can be arbitrarily selected, but in particular, when manufacturing microneedles with a large height (needle height) (which may vary slightly depending on the manufacturing conditions, but for example, a needle height of 800 μm or more), it is preferable to use pressurized drying or a combination of natural drying and pressurized drying. By using these drying methods, even when the needle height of the microneedles is large, it is possible to obtain microneedles in which bending of the needle tip is suppressed. The reason for this is described in detail in Manufacturing Method 1 of the present invention.

[0090] In one preferred embodiment of the manufacturing method 2 of the present invention, in step (c), after the solution or suspension is air-dried, a pressurized drying treatment is performed on the solution or suspension to dry it under pressure to obtain a microneedle precursor or a microneedle array precursor.

[0091] Furthermore, in another preferred embodiment of the manufacturing method 2 of the present invention, in step (c), a pressurized drying treatment is performed on the solution or suspension while applying pressure to obtain a microneedle precursor or a microneedle array precursor.

[0092] Pressurized drying is preferably carried out using a pressure vessel. Furthermore, when drying in a pressure vessel, if the vessel is sealed, the water vapor during the drying process cannot escape, making drying impossible. Therefore, it is preferable to allow air leakage. This makes it possible to discharge the water vapor to the outside of the pressure vessel.

[0093] When performing pressurized drying using a pressure vessel, it is preferable to dry the drying time at room temperature for approximately 72 to 96 hours. Furthermore, when combining natural drying and pressurized drying using a pressure vessel, it is preferable that natural drying takes about 18 to 24 hours at room temperature, and pressurized drying using a pressure vessel (preferably with air leakage) takes about 24 to 36 hours. By limiting the drying time to this extent, it becomes possible to manufacture microneedles with a uniform structure and small gaps between the microsphere particles.

[0094] The pressure inside the pressure vessel is preferably in the range of 0.1 MPa to 0.5 MPa, but it is even more preferable to set it at around 0.2 MPa from the viewpoint of balancing it with promoting drying. The pressure inside the pressure vessel can be adjusted by changing the air pressure supplied by the compressor.

[0095] Furthermore, when performing pressurized drying using a pressure vessel, it is preferable to install a cover so as to cover part or all of the female mold into which the biodegradable material microsphere solution or suspension has been injected. This prevents the microneedles from being directly subjected to air pressure from the compressor, and thus allows for the production of homogeneous microneedles without being affected by air pressure that may vary depending on the position within the mold. Furthermore, the drying time can be accelerated by placing silica gel inside the pressure vessel.

[0096] In step (e) of the manufacturing method 2 of the present invention, the porous microneedle or porous microneedle array obtained in step (d) is treated with water. Treatment with water can be carried out, for example, by immersing (soaking) porous microneedles or porous microneedle arrays in a hot bath. By treating porous microneedles or porous microneedle arrays with water, the water-soluble material dissolves in the water, resulting in porous microneedles or porous microneedle arrays from which the water-soluble material has been removed.

[0097] The water treatment temperature (preferably the immersion temperature) should be a temperature that does not significantly affect the biodegradable material, and preferably a temperature below the glass transition temperature. If the biodegradable material is PLA, the glass transition temperature of PLA is 50-60°C, so a temperature of 20-60°C, which is below the glass transition temperature, is desirable. Furthermore, the water treatment can be carried out over a predetermined period of time, for example, 20 to 60 minutes (preferably by immersion in water).

[0098] In the manufacturing method 2 of the present invention, the volume ratio of the voids from which the water-soluble material has been removed and the biodegradable material in the porous microneedle or porous microneedle array obtained by further step (e) is preferably 1:2 to 3, and more preferably 1:2.85 (1:3 by mass ratio).

[0099] In the manufacturing method 2 of the present invention, following step (e), the step of (f) heating the porous microneedles or porous microneedle array treated with water (i.e., porous microneedles or porous microneedle array from which the water-soluble material has been removed) may be further included. The heating temperature should preferably be near the melting point of the biodegradable material, and if the biodegradable material is PLA, it should preferably be 160°C or lower. This heating temperature may be slightly lower than the heating temperature of the first heating step.

[0100] In the manufacturing method 2 of the present invention, porous microneedles or porous microneedle arrays from which water-soluble materials have been removed can be obtained by treatment with water, without going through the reheating step described above. On the other hand, if the mechanical strength of the microneedles decreases due to the removal of the water-soluble material, in manufacturing method 2 of the present invention, after removing the water-soluble material from the porous microneedles or porous microneedle array, the microneedles are heated to slightly deform the biodegradable material, thereby increasing the bonding strength between the particles of the biodegradable material, and thus a high yield can be obtained while maintaining mechanical strength. By removing water-soluble materials, the particles of the biodegradable material become easier to bond together. Furthermore, since the heating temperature is near the melting point of the biodegradable material, the particles of the biodegradable material do not completely melt. Instead, the particles bond together while maintaining their pore network (capillaries), thus providing mechanical strength.

[0101] In the manufacturing method 2 of the present invention, the volume ratio of the voids from which the water-soluble material has been removed and the biodegradable material in the porous microneedle or porous microneedle array obtained by further step (f) is preferably 1:2 to 3, and more preferably 1:2.85 (1:3 by mass ratio).

[0102] Another aspect of the second embodiment of the present invention is a porous microneedle or porous microneedle array that is substantially free of water-soluble material obtained by the manufacturing method 2 of the present invention.

[0103] Furthermore, another aspect of the second embodiment of the present invention is a porous microneedle formed from microspheres of a biodegradable material, wherein the microspheres of the biodegradable material are bonded to one another to form an interconnected network of pores, and the microneedle substantially does not contain any water-soluble material (hereinafter also referred to as "microneedle 2 of the present invention").

[0104] The microneedle 2 of the present invention may include a microneedle substrate. That is, the microneedle 2 of the present invention can also be used as a microneedle array in which a plurality of microneedles of the present invention are erected on a microneedle substrate. That is, in another embodiment of the present invention, the microneedle 2 of the present invention is a microneedle array in which a plurality of microneedles are erected on a microneedle substrate (hereinafter also referred to as "microneedle array 2 of the present invention"). Details such as the microneedle substrate and shape in the microneedle array 2 of the present invention are the same as those described in detail in the microneedle array 1 of the present invention.

[0105] The microneedle 2 of the present invention preferably has an absorption volume of 8 to 150 μL. Furthermore, the absorption volume varies depending on the volume of the microneedle; for example, the volume of biodegradable material is 80 mm³. 3 In this case, the absorption volume is theoretically 28.07 mm 3 This translates to an absorption of 28.07 μL. Here, the absorption volume can be measured by puncturing a microneedle array consisting of 289 porous PLA MN needles erected in a 1%-2% agarose gel, removing the needles from the gel after 2 minutes, and measuring their weight.

[0106] Furthermore, the absorption volume in the resulting microneedle is approximately equal to the volume of the (removed) water-soluble material and approximately equal to the volume of the non-biodegradable material portion. In addition, the volume of the continuous pore network is approximately equal to the volume of the water-soluble material. Therefore, when the volume ratio of water-soluble material to biodegradable material is 1:2 to 3, the volume ratio of absorption to biodegradable material will also be 1:2 to 3. The absorption volume can also be determined using the porosity measurement method described above.

[0107] The microneedle 2 of the present invention preferably has a mechanical strength (breaking strength) of 100mN to 500mN (0.1 to 0.5N), and more preferably 100mN to 300mN (0.1 to 0.3N).

[0108] Another aspect of the second embodiment of the present invention is a microneedle patch comprising the microneedle 2 or microneedle array 2 of the present invention and an absorbent material capable of absorbing interstitial fluid (hereinafter also referred to as "microneedle patch 2 of the present invention").

[0109] The absorbent material capable of absorbing interstitial fluid in the microneedle patch 2 of the present invention, the structure of the microneedle patch, etc., are the same as those described in detail in the microneedle patch 1 of the present invention. [Examples]

[0110] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0111] [Example 1] The amount of material layered in a MAP (microneedle array patch, meaning a microneedle patch equipped with a microneedle array) with a needle height of 1200 μm was simulated using the table and figure shown in Figure 5. Here, we show the MAP layering diagram for a material formulation where the PLA content remains constant even when the injection volume of 5% (w / t) PVA solution is changed from 1.0 to 0.5 mL. The calculation process and calculation form are described in detail below. TIFF0007901820000003.tif21156

[0112] 1-1. Calculation of Volume (1) Entering the PLA content into the form in the table shown in Figure 5 will reflect this in each of the 1.0 mL to 0.5 mL cells of the 5% (w / v) PVA solution (see Figure 6). (2) The densities of PLA and PVA were entered. (3) The PLA volume and the PVA volume for each injection amount were calculated using the formula "Volume = Mass (Content) ÷ Density".

[0113] 1-2. Volume ratio of voids in PLA microparticles (microspheres) (4) Repeating "pattern shapes" were extracted from a densely packed collection of PLA microparticles with the same diameter of 11 μm, and the volume of the PLA microparticles and the voids were compared (see Figure 7). Here, comparing the case where PLA microparticles are poured into the female mold with the case where molten resin (not microparticles) is poured, it is shown that pouring 0.7404 times the amount of PLA microparticles compared to the amount of molten resin results in the same deposition distance from the needle tip. Furthermore, since PVA fills the voids in the PLA microparticles, the deposition distance from the needle tip becomes the same with 0.2596 times the amount of PVA compared to the amount of molten resin.

[0114] 1-3. Calculate the total volume of the map using 3D CAD. (5) A 3D model of the recess in the female mold of the MAP was created, and the volume was confirmed at 10 μm intervals from 0 μm to 1620 μm from the needle tip (see Figure 8). Here, if numerical calculations alone are used, it may be impossible to calculate the correct volume ratio depending on the shape of the microneedle. However, using a 3D-CAD model has the advantage of being able to calculate regardless of the shape, whether it is elliptical or curved. The volume may also be determined by methods other than the 3D model (for example, by a formula).

[0115] 1-4. Create a table listing the total volume of the MAP at different distances from the needle tip. (6) A table was created listing the volumes at 10 μm intervals from the needle tip, and the corresponding volumes of PLA and PVA were also recorded. (7) Since the volume ratio of PLA to PVA is "0.7404:0.2596" from "Volume ratio of voids in PLA microparticles (1-2)", it was set so that "0.7404 times the volume of the whole MAP is the PLA volume" from the volume of the whole MAP (pretreatment). (8) Since there is an upper limit to the amount of PLA, when the volume increases and reaches the upper limit value, the IF function is used to prevent it from exceeding the upper limit value [Upper limit setting]. =IF(PLA volume [pretreatment] < PLA volume upper limit, PLA volume [pretreatment], PLA volume upper limit) (9) The PVA volume [pretreatment1] is "the state where the PLA volume [pretreatment] is subtracted from the volume of the whole MAP" (10) The PVA volume [pretreatment2] is "the state where the PLA volume [upper limit setting] is subtracted from the volume of the whole MAP" (11) Since there is also an upper limit to the amount of PVA, when the volume increases and reaches the upper limit value, the IF function is used to prevent it from exceeding the upper limit value [Upper limit setting] =IF(PVA volume [pretreatment2] < PVA volume upper limit, PVA volume [pretreatment2], PVA volume upper limit) … 6 types from 1.0 mL to 0.5 mL Table of the volume of the whole MAP at the distance from the needle tip is shown in Fig. 9.

[0116] 1-5. Calculate the thickness of the Backlayer and the thickness of the PVA single layer Here, the thickness of the Backlayer refers to the thickness of the microneedle substrate. (12) The distance from the needle tip to the back surface of PLA is read by the INDEX function as the distance from the needle tip when the maximum value is reached for the first time in the PLA volume [upper limit setting]. =INDEX(distance from the needle tip, MATCH(MAX(PLA volume [upper limit setting]) , PLA volume [upper limit setting], 0), 1) (13) The distance from the needle tip to the back surface of PVA is read by the INDEX function as the distance from the needle tip when the maximum value is reached for the first time in the PVA volume [upper limit setting] and from the volume of the whole MAP. =INDEX(Distance from needle tip:Total MAP volume,MATCH(MAX(PVA volume [Upper limit]),PVA volume [Upper limit],0),1) ...6 types from 1.0mL to 0.5mL (14) The distance from the needle tip to the back surface of the Backlayer is read using the INDEX function, which is the distance from the needle tip when the PVA volume [upper limit setting] first reaches its maximum value. =MAX(Distance from needle tip to PLA back surface:Distance from needle tip to PVA back surface) (15) The thickness of the back layer was displayed as the distance from the needle tip to the back surface of the back layer minus the needle height of 1200 μm. If no back layer was present, "None" was displayed. =IF(Distance from needle tip to back layer surface - needle length <= 0,"None",Distance from needle tip to back layer surface - needle length) (16) The thickness of the PVA single layer is calculated using the IF function by subtracting the distance from the needle tip to the PLA back surface from the distance from the needle tip to the PVA back surface. If the PLA back surface is greater than zero, it means that there is no PVA single layer, so it is displayed as "none". =IF(Distance from needle tip to PVA back surface - Distance from needle tip to PLA back surface <= 0 "None", (Distance from needle tip to PVA back surface - Distance from needle tip to PLA back surface) The calculated thicknesses of the back layer and the PVA single layer are shown in Table 1 below.

[0117] [Table 1]

[0118] 1-6. Changes in PLA volume and PVA volume with respect to distance from needle tip (17) The graph shows the changes in PLA volume and PVA volume (when injected at a volume of 1.0 mL) with the distance from the needle tip on the horizontal axis and the vertical axis (see Figure 10).

[0119] (18) The graph shows the changes in PLA volume and PVA volume (when the injection volume is 1.0 to 0.5 mL) with the distance from the needle tip on the horizontal axis and the vertical axis (see Figure 11).

[0120] Furthermore, Figure 12 shows a graph of the PLA volume and PVA volume as a function of distance from the needle tip when the needle length is 300 μm and the PLA content is 100 mg.

[0121] 1-7. Stacked image of MNs cross-section (19) The graph in "1-6. Changes in PLA volume and PVA volume with respect to distance from the needle tip" was converted into a layered image that is easier to understand intuitively. ⇒ By creating and layering four types of layers, a layered image of the MAP cross-section was represented (see Figure 13).

[0122] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0123] 1.Material Polylactic acid (PLA): MAGIX PLA 30 Clear (Muto Industries) Polyvinyl alcohol: 363073-500G (SIGMA-ALDRICH) Dichloromethane: 135-02446 (Fujifilm Wako Pure Chemical Industries)

[0124] 2. Laboratory equipment Optical microscope: Stemi305 (Carl Zeiss) Optical microscope (microsphere observation): IX71 (OLYMPUS) Force measurement: MX2-500N-FA-V45(IMADA) Vacuum applications: Vacuum desiccator (SANPLATEC); Oil rotary vacuum pump GLS-051 (ULVAC) Electronic balance: SECURA 125-1SJP (Sartorius) Hot Plate: Hot Plate / Stirrer LSH-4D (AS ONE) Constant temperature drying oven: OFP-300V (AS ONE) Desiccator: DCD-PSPS (AS ONE)

[0125] [Example 2] Fabrication of porous microneedles with a needle height of 300 μm using polylactic acid microspheres. Porous PLA microneedles were fabricated using polylactic acid (PLA) microspheres, following the procedure described in the schematic diagram of the preparation method for porous microneedles of the present invention, shown in the upper and middle sections of Figure 14. As shown in Figure 14 (top panel), a 6.7% (w / v) PLA solution was prepared as the organic phase in dichloromethane (DCM). Next, the organic phase was added to an aqueous phase containing 5% (w / v) polyvinyl alcohol (PVA) as a water-soluble material, and stirred at 1000 rpm for 6 hours, resulting in the acquisition of PLA microspheres in the PVA solution.

[0126] Once the PLA microspheres were formed, their spherical shape was stably maintained in the surrounding environment. The fabricated microspheres had a diameter of 15.5 ± 6.9 μm. The diameter of the microspheres was measured by optical microscopy.

[0127] Next, a PLA microsphere solution was injected into a PDMS female mold prepared from a metal master mold consisting of 289 pyramidal microneedles, each 300 μm long. Then, a vacuum was applied to fill the cavity with the microsphere solution. Next, the entire mold was left in a desiccator at 20°C and 20% RH for 36 hours to allow the moisture to evaporate naturally. Afterward, the microspheres were demolded from the PDMS female mold and the ends (wings, etc.) were cut off. Then, a heat treatment at 180°C was applied for 30 minutes to bond the microspheres together.

[0128] Next, to remove the PVA, the microneedle was placed in water on a hot plate set to 60°C for 20 minutes to dissolve the PVA into the water.

[0129] Finally, a heat treatment was applied for 30 minutes at 160°C, a temperature near the melting point of PLA where it begins to melt. This reheating process restored the strength that had decreased when the PVA was removed in the previous step, and strongly bonded the microspheres together.

[0130] Furthermore, plasma treatment was performed to improve the hydrophilicity of the microneedle surface (see Figure 15).

[0131] Evaluation of porous PLA microneedles with PVA removed. Shape and dimensions The dimensional measurements were 261.3 ± 4.8 μm and 10.3 ± 0.7 μm (n=5). The fabrication results showed that the shape and sharp tip were maintained even after heat treatment, but the MN height and tip diameter decreased slightly. This shrinkage was thought to be due to the deformation and bonding of the PLA microspheres inside the MNs.

[0132] Absorption capacity of porous PLA microneedles with PVA removed The study was conducted using a 2% (w / v) agarose gel coated with aluminum foil mimicking human skin. A force of 100g was applied to the MN array and allowed to permeate the agarose gel for 5 minutes. The absorption amount was 14 ± 1 μL (n=4).

[0133] The strength of the microneedles was measured using a force measuring device and found to be between 0.2N and 0.3N (n=8).

[0134] [Example 3] Fabrication of porous microneedles with a needle height of 800 μm using polylactic acid microspheres (1) By modifying the method of Example 2, a porous microneedle with a needle height of 800 μm was fabricated. Porous PLA microneedles were fabricated using polylactic acid (PLA) microspheres, following the procedure described in the schematic diagram of the preparation method for porous microneedles of the present invention shown in the upper and middle sections of Figure 17. As shown in Figure 17 (top panel), a 6.7% (w / v) PLA solution was prepared as the organic phase in dichloromethane (DCM). Next, the organic phase was added to an aqueous phase containing 5% (w / v) polyvinyl alcohol (PVA) as a water-soluble material, and stirred at 1000 rpm for 6 hours, resulting in the acquisition of PLA microspheres in the PVA solution.

[0135] Once the PLA microspheres were formed, their spherical shape was stably maintained in the surrounding environment. The fabricated microspheres had a diameter of 15.5 ± 6.9 μm. The diameter of the microspheres was measured by optical microscopy.

[0136] Next, a PLA microsphere solution was injected into a PDMS female mold prepared from a metal master mold consisting of 81 pyramidal microneedles, each 800 μm long. Then, a vacuum was applied to fill the cavity with the microsphere solution. Next, the entire mold was left in a desiccator at 30°C and 20% RH for 24 hours to allow the moisture to evaporate naturally. After that, the entire mold was placed in a pressure vessel and left in an environment of 20°C and 0.2 MPa for 24 hours to allow the moisture to evaporate. The process in Example 3 differs from that in Example 2 in this drying step. In order to promote drying in the pressure vessel, a pressure of 0.3 MPa was applied to the pressure vessel while an air leak of 0.1 MPa was performed to maintain the pressure inside the pressure vessel at 0.2 MPa. Figure 18 shows a schematic diagram of the pressurized drying process using the pressure vessel used in this example. Afterward, the microspheres were demolded from the PDMS female mold and the ends (wings, etc.) were cut off. Then, a heat treatment at 180°C was applied for 30 minutes to bond the microspheres together.

[0137] Next, to remove the PVA, the microneedle was placed in water on a hot plate set to 60°C for 20 minutes to dissolve the PVA into the water.

[0138] Finally, a heat treatment was applied for 30 minutes at 160°C, a temperature near the melting point of PLA where it begins to melt. This reheating process restored the strength that had decreased when the PVA was removed in the previous step, and strongly bonded the microspheres together.

[0139] Furthermore, plasma treatment was performed to improve the hydrophilicity of the microneedle surface (see Figure 15).

[0140] Evaluation of porous PLA microneedles with PVA removed. Shape and dimensions The dimensional measurements were 719.3 ± 6.8 μm and 19.2 ± 1.0 μm (n=5). The fabrication results showed that the shape and sharp tip were maintained even after heat treatment, but the MN height and tip diameter decreased slightly. This shrinkage was thought to be due to the deformation and bonding of the PLA microspheres inside the MNs.

[0141] Absorption capacity of porous PLA microneedles with PVA removed The study was conducted using a 2% (w / v) agarose gel coated with aluminum foil mimicking human skin. A force of 100g was applied to the MN array and allowed to permeate the agarose gel for 5 minutes. The absorption amount was 17±1 μL (n=4).

[0142] The strength of the microneedles was measured using a force measuring device and found to be between 0.2N and 0.3N (n=8).

[0143] [Example 4] Fabrication of porous microneedles with a needle height of 800 μm using polylactic acid microspheres (2) By modifying the method of Example 2, a porous microneedle with a needle height of 800 μm was fabricated. Porous PLA microneedles were fabricated using polylactic acid (PLA) microspheres, following the procedure described in the schematic diagram of the preparation method for porous microneedles of the present invention, shown in the upper and middle sections of Figure 19. As shown in Figure 19 (top panel), a 6.7% (w / v) PLA solution was prepared as the organic phase in dichloromethane (DCM). Next, the organic phase was added to an aqueous phase containing 5% (w / v) polyvinyl alcohol (PVA) as a water-soluble material, and stirred at 1000 rpm for 6 hours, resulting in the acquisition of PLA microspheres in the PVA solution.

[0144] Once the PLA microspheres were formed, their spherical shape was stably maintained in the surrounding environment. The fabricated microspheres had a diameter of 15.5 ± 6.9 μm. The diameter of the microspheres was measured by optical microscopy.

[0145] Next, a PLA microsphere solution was injected into a PDMS female mold prepared from a metal master mold consisting of 81 pyramidal microneedles, each 800 μm long. Then, a vacuum was applied to fill the cavity with the microsphere solution. Next, the entire mold was placed in a pressure vessel and left for 96 hours at a temperature of 20°C and a pressure of 0.2 MPa to evaporate the moisture. The process in Example 4 differs from that in Example 2 in this drying step. In order to promote drying in the pressure vessel, a pressure of 0.3 MPa was applied to the pressure vessel while an air leak of 0.1 MPa was maintained to keep the pressure inside the pressure vessel at 0.2 MPa. Figure 18 shows a schematic diagram of the pressurized drying process using the pressure vessel used in this example. Afterward, the microspheres were demolded from the PDMS female mold and the ends (wings, etc.) were cut off. Then, a heat treatment at 180°C was applied for 30 minutes to bond the microspheres together.

[0146] Next, to remove the PVA, the microneedle was placed in water on a hot plate set to 60°C for 20 minutes to dissolve the PVA into the water.

[0147] Finally, a heat treatment was applied for 30 minutes at 160°C, a temperature near the melting point of PLA where it begins to melt. This reheating process restored the strength that had decreased when the PVA was removed in the previous step, and strongly bonded the microspheres together.

[0148] Furthermore, plasma treatment was performed to improve the hydrophilicity of the microneedle surface (see Figure 15).

[0149] Evaluation of porous PLA microneedles with PVA removed. Shape and dimensions The dimensional measurements were 713.6 ± 16.2 μm and 23.1 ± 4.5 μm (n=5). The fabrication results showed that the shape and sharp tip were maintained even after heat treatment, but the MN height and tip diameter decreased slightly. This shrinkage was thought to be due to the deformation and bonding of the PLA microspheres inside the MNs.

[0150] Absorption capacity of porous PLA microneedles with PVA removed The study was conducted using a 2% (w / v) agarose gel coated with aluminum foil mimicking human skin. A force of 100g was applied to the MN array and allowed to permeate the agarose gel for 5 minutes. The absorption amount was 12.5 ± 1.5 μL (n=4).

[0151] The strength of the microneedles was measured using a force measuring device and found to be between 0.2N and 0.3N (n=8).

Claims

1. A porous microneedle comprising microspheres of biodegradable material and a water-soluble material, wherein the microspheres of biodegradable material are bonded to each other, forming an interconnected network of pores. The microneedle may include a microneedle substrate containing the microspheres and a water-soluble material. The volume ratio of the water-soluble material to the biodegradable material, based on the volume obtained from the repeating pattern shape in a state where fine particles of the biodegradable material of the same diameter are densely aggregated, is 1:2.

85. The water-soluble material is contained in the gaps between the particles of the microsphere, extending from the tip to the bottom of the microneedle (and, if the microneedle is provided with a microneedle substrate, extending from the tip of the microneedle to the bottom of the microneedle substrate). A microneedle in which there is no separate layer of water-soluble material covering the deposited layer of microspheres on the back side of the microneedle.

2. The microneedle according to claim 1, wherein the biodegradable material comprises at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose.

3. The microneedle according to claim 1, wherein the water-soluble material is polyvinyl alcohol (PVA), CMC (carboxymethylcellulose), or starch.

4. A microneedle patch comprising a porous microneedle as described in any one of claims 1 to 3.

5. (a) A step of preparing a solution A in which a biodegradable material is dissolved in an organic solvent, mixing the solution A with an aqueous solution containing a water-soluble material and stirring to prepare a biodegradable material microsphere solution or suspension containing microspheres of the biodegradable material, by feeding back and adding the weight of the water-soluble material discarded in step (c), so that in the microneedle precursor or microneedle array precursor from which the water-soluble material was discarded in step (c), the volume ratio of the water-soluble material to the biodegradable material, based on the volume obtained from the repeating pattern shape in a state in which fine particles of the biodegradable material of the same diameter are densely aggregated, is 1:2.

85. (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or microneedle array precursor, and discarding the water-soluble material deposited on the side surface of the recess of the female mold from the obtained microneedle precursor or microneedle array precursor, and (d) A step of heating the microneedle precursor or the microneedle array precursor to a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together with each other. A method for manufacturing a porous microneedle or porous microneedle array, comprising: In the resulting porous microneedle or porous microneedle array, the volume ratio of the water-soluble material to the biodegradable material, based on the volume obtained from the repeating pattern shape within a densely aggregated state of fine particles of the biodegradable material of the same diameter, is 1:2.

85. The water-soluble material is embedded in the voids between the particles of the microspheres, extending from the tip to the bottom of the porous microneedle, or from the tip of the microneedle in a porous microneedle array to the bottom of the microneedle substrate. No single layer of water-soluble material is generated covering the deposited layer of microspheres on the back side of the porous microneedle or porous microneedle array. The said manufacturing method.

6. The method for producing the biodegradable material according to claim 5, wherein the biodegradable material comprises at least one selected from the group consisting of polylactic acid, polyglycolic acid, poly(lactide-co-glycolide) copolymer, PEG copolymer, polyhydroxybutyric acid, and ethylcellulose.

7. The method for producing the product according to claim 5, wherein the water-soluble material is polyvinyl alcohol (PVA), CMC (carboxymethylcellulose), or starch.

8. The method according to claim 5, wherein the drying of the solution or suspension in step (c) is carried out by natural drying, a pressurized drying process in which pressure is applied to the solution or suspension while drying, or a combination thereof.

9. The manufacturing method according to claim 8, wherein in step (c), after the solution or suspension is air-dried, a pressurized drying treatment is performed on the solution or suspension to dry it under pressure, thereby obtaining a microneedle precursor or a microneedle array precursor.

10. The manufacturing method according to claim 8, wherein in step (c), a pressurized drying treatment is performed on the solution or suspension to dry it under pressure, thereby obtaining a microneedle precursor or a microneedle array precursor.

11. (a) A step of preparing a solution A in which a biodegradable material is dissolved in an organic solvent, mixing the solution A with an aqueous solution containing a water-soluble material and stirring to prepare a biodegradable material microsphere solution or suspension containing microspheres of the biodegradable material, by feeding back and adding the weight of the water-soluble material discarded in step (c), so that in the microneedle precursor or microneedle array precursor from which the water-soluble material was discarded in step (c), the volume ratio of the water-soluble material to the biodegradable material, based on the volume obtained from the repeating pattern shape in a state in which fine particles of the biodegradable material of the same diameter are densely aggregated, is 1:2.

85. (b) A step of injecting the solution or suspension into a female mold, (c) A step of drying the solution or suspension to obtain a microneedle precursor or microneedle array precursor, and discarding the water-soluble material deposited on the side surface of the recess of the female mold from the obtained microneedle precursor or microneedle array precursor. (d) The microneedle precursor is heated to a predetermined temperature so that the microspheres partially become liquid or rubbery and bond together with each other. The volume ratio of the water-soluble material to the biodegradable material, based on the volume obtained from the repeating pattern shape in a state where fine particles of the biodegradable material of the same diameter are densely aggregated, is 1:2.

85. The water-soluble material is embedded in the voids between the particles of the microspheres, extending from the tip to the bottom of the porous microneedle, or from the tip of the microneedle in a porous microneedle array to the bottom of the microneedle substrate. No single layer of water-soluble material is generated covering the deposited layer of microspheres on the back side of the porous microneedle or porous microneedle array. A step of obtaining a porous microneedle or a porous microneedle array, and (e) A step of treating the porous microneedle or porous microneedle array obtained in step (d) with water. A method for producing porous microneedles or porous microneedle arrays in which water-soluble material is removed and the portion containing the water-soluble material becomes a void.

12. The manufacturing method according to claim 11, further comprising the step of (f) heating the porous microneedles or porous microneedle array treated with water at a temperature below the melting point of the biodegradable material.

13. The manufacturing method according to claim 11, wherein in step (e), the temperature at which the porous microneedle or porous microneedle array is treated with water is 20 to 60°C.

14. The method according to claim 11, wherein the drying of the solution or suspension in step (c) is carried out by natural drying, a pressurized drying process in which pressure is applied to the solution or suspension while drying, or a combination thereof.

15. The manufacturing method according to claim 14, wherein in step (c), after the solution or suspension is air-dried, a pressurized drying treatment is performed on the solution or suspension to dry it under pressure, thereby obtaining a microneedle precursor or a microneedle array precursor.

16. The manufacturing method according to claim 14, wherein in step (c), a pressurized drying treatment is performed on the solution or suspension to dry it under pressure, thereby obtaining a microneedle precursor or a microneedle array precursor.

17. The method according to any one of claims 11 to 16 for producing a porous microneedle or porous microneedle array that is substantially free of water-soluble material.

18. The method according to claim 17, for producing a porous microneedle or porous microneedle array in which microspheres of biodegradable material are bonded to each other to form a network of interconnected pores.

19. The method according to claim 18, for manufacturing a porous microneedle or porous microneedle array having a mechanical strength (breaking strength) of 0.2 to 0.3 N.

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