Manufacturing method of microneedle constructs and microneedle constructs

Abstract

The method for manufacturing a microneedle structure of the present invention comprises a method for manufacturing a microneedle structure 10 having a needle-like portion 12 with a hole 13 on one side of a substrate 11 having liquid permeability in the thickness direction, and includes: a forming step in which a protrusion 5 is formed using a composition 3 for forming a needle-like portion containing a first water-insoluble material and a first water-soluble material; a following step in which the aforementioned composition 3 or the protrusion 5 formed in the aforementioned forming step is bonded to the substrate 11; and a removal step in which the protrusion 5 and the substrate 11 are immersed in water to dissolve and remove the first water-soluble material, thereby forming the needle-like portion 12 and the hole 13 from the protrusion 5. According to this method for manufacturing a microneedle structure, a microneedle structure having a substrate and ensuring a channel is provided.

Description

Technical Field

[0001] This invention relates to a method for manufacturing microneedle structures and to microneedle structures themselves. Prior Technology

[0002] In recent years, proposals have been made for administering drugs into the body and collecting bodily fluids from the body through the through-holes formed in microneedles. For example, microneedles with excellent diffusion properties for administering drugs into the body are known to have the following characteristics: a height of 20 μm or more and less than 500 μm, an aspect ratio (h / a) of height h to the maximum length a of the base (h / a) of 2 or more, and are made of mesoporous material (Patent Document 1). Furthermore, in order to more accurately understand the patient's symptoms, a minimally invasive analytical patch has been proposed, which involves inserting tiny microneedles less than 1 mm in length into the patient's skin to collect blood and analyze the blood. Patent Document 2 discloses a low-invasive examination patch that allows patients to easily and continuously monitor their blood glucose levels: a base plate with microchannels is used as a substrate, and on this substrate, an adhesive material for forming needle-like portions is slowly dispensed from a dispenser to form multiple needle-like portions. This examination patch involves inserting a needle-like part into the patient, and using a capillary pump part in the microchannels of the base plate, blood is continuously drawn from the needle-like part through capillary action. The amount of blood drawn is then measured by a sensor in the reaction chamber of the base plate. [Prior Technology Documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 2014-094171 [Patent Document 2] WO2019 / 176126 Publication No. Summary of the Invention

[0004] [The problem the invention aims to solve]

[0005] The substrate used for the aforementioned examination patches needs to have fine capillary pump sections and microchannels formed on it, but it is desirable to manufacture examination patches and microneedle structures that ensure channels more cheaply and easily. Furthermore, even examination patches manufactured by simple methods must be able to form the shape of needles as expected and ensure channels.

[0006] The present invention was made in view of this actual situation, and its purpose is to provide a microneedle structure that can be easily obtained to ensure the microneedle channel, and a method for manufacturing the microneedle structure. [Methods used to solve problems]

[0007] To achieve the above objectives, firstly, the present invention provides a method for manufacturing a microneedle structure, which is a method for manufacturing a microneedle structure having a needle-like portion with a hole on one side of a substrate having liquid permeability in the thickness direction, characterized in that it includes: a forming step, which forms a protrusion using a composition for forming a needle-like portion containing a first water-insoluble material and a first water-soluble material; a following step, which bonds the aforementioned composition or the aforementioned protrusion formed in the aforementioned forming step to the aforementioned substrate; and a removal step, which immerses the aforementioned protrusion and the aforementioned substrate in water to dissolve and remove the aforementioned first water-soluble material, thereby forming the aforementioned needle-like portion and the aforementioned hole from the aforementioned protrusion (Invention 1).

[0008] In the above-mentioned invention (Invention 1), since a substrate with liquid permeability in the thickness direction is used, channels can be easily formed in the microneedle structure. Moreover, since a hole is formed in the protrusion during the removal step after the substrate is bonded to the composition or the aforementioned protrusion formed in the forming step, the hole in the protrusion and the hole in the substrate can be easily connected, and channels can be easily formed in the microneedle structure.

[0009] In the above invention (Invention 1), it is preferred that the substrate having liquid permeability in the thickness direction is a porous substrate, the aforementioned bonding step is a step of bonding the aforementioned protrusion formed by the aforementioned forming step with the sheet containing the second water-soluble material and the aforementioned porous substrate, and the aforementioned removal step is a step of dissolving and removing the aforementioned first water-soluble material and second water-soluble material (Invention 2).

[0010] By incorporating a second water-soluble material into a porous substrate, the absorption of the protrusion's components by the substrate can be suppressed when the substrate is bonded to the formed protrusion. As a result, since excessive voids are not formed, particularly at the root of the protrusion, i.e., the needle-like portion, the collapse of the needle-like portion is suppressed, and a needle-like portion with a shape suitable for bonding with the substrate that serves as a channel can be formed, thereby creating a microneedle structure with good bonding between the needle-like portion and the substrate.

[0011] In the above invention (Invention 2), it is preferred that the aforementioned porous substrate is a substrate made of fibrous material (Invention 3).

[0012] In the above inventions (Inventions 2 and 3), it is preferred that the aforementioned sheet contains a second water-insoluble material (Invention 4).

[0013] In the above invention (Invention 4), it is preferable that the first water-insoluble material and the second water-insoluble material are the same (Invention 5).

[0014] In the above inventions (Inventions 2 to 5), it is preferred that the aforementioned sheet system is formed by impregnating the aforementioned substrate with a second water-soluble material (Invention 6).

[0015] In the above inventions (Inventions 2-6), it is preferred that the substrate composed of the aforementioned fibrous material is nonwoven fabric, textile, knitted fabric or paper (Invention 7).

[0016] In the above invention (Invention 1), it is preferable that the aforementioned substrate is a substrate made of a material that is impermeable to liquids, and has a through hole formed along the thickness direction (Invention 8).

[0017] Because the substrate is liquid-impermeable, liquid absorption is suppressed, allowing liquid to pass through only the through-holes formed along the thickness direction within the substrate. Therefore, bodily fluids obtained from the needle-like portion or medications transported to it do not seep into the substrate, allowing the entire volume to flow through the through-holes. Furthermore, since pores are formed in the protrusions during the removal step after attaching this substrate to the composition or the protrusions formed in the forming step, the pores of the protrusions easily connect with the through-holes in the substrate, facilitating the formation of channels in the microneedle structure.

[0018] In the above inventions (Inventions 1-8), it is preferred to include a filling step, which fills the aforementioned composition for forming the needle-like portion into a mold having a recess (Invention 9).

[0019] In the above invention (Invention 9), it is preferable that in the aforementioned filling step, the composition for forming the needle-like portion includes a solvent, and in the aforementioned forming step, the aforementioned solvent is evaporated (Invention 10).

[0020] In the above inventions (Inventions 1 to 10), it is preferred to have a setting step in which a means for analyzing bodily fluids and / or a means for storing physiologically active substances are set on the side of the aforementioned substrate opposite to the side on which the aforementioned needle-shaped portion is provided (Invention 11).

[0021] Second, the present invention provides a microneedle structure having a needle-like portion with a hole on one side of a porous substrate. The needle-like portion is characterized in that it is made of a first water-insoluble material and is directly disposed on the aforementioned porous substrate, wherein the aforementioned porous substrate contains a second water-insoluble material (Invention 12). [Invention Benefits]

[0022] According to the method for manufacturing a microneedle structure of the present invention, a microneedle structure can be provided that can easily obtain a needle-like portion that ensures a channel, and at the same time form the needle-like portion in a desired shape, and the needle-like portion and the channel are well joined. Simple Explanation of the Diagram

[0023] Figure 1 is a schematic partial cross-sectional view of the microneedle structure of the present invention. Figure 2 is a cross-sectional view of an examination patch using the microneedle structure of the present invention. Figure 3 is a flowchart illustrating the manufacturing method of the microneedle structure. Implementation

[0024] [The form in which the invention is carried out]

[0025] The following describes embodiments of the present invention. [Microneedle Structure] Figure 1 shows a microneedle structure 10 according to one embodiment of the present invention. The microneedle structure 10 includes a plurality of needle-like portions 12 separated from each other at specified intervals on one side of a substrate 11. The microneedle structure 10 can be used as: an examination patch for absorbing interstitial fluid from the skin through the needle-like portions 12 and using the obtained interstitial fluid for examination; a drug delivery patch for delivering a drug from the substrate 11 to the body through the needle-like portions 12, etc.

[0026] (1) The shape, size, spacing, and number of needle-like portions 12 can be appropriately selected according to the purpose of the microneedles. Examples of the shape of the needle-like portions 12 include cylindrical, prismatic, conical, and pyramidal shapes; in this embodiment, it is pyramidal. Examples of the maximum diameter or maximum cross-sectional size of the needle-like portions 12 include, for example, 25 to 1000 μm; examples of the diameter of the front end or the cross-sectional size of the front end include, for example, 1 to 100 μm; and examples of the height of the needle-like portions 12 include, for example, 50 to 2000 μm. Furthermore, multiple rows of needle-like portions 12 are provided in one direction of the substrate 11, and multiple portions are formed simultaneously in each row, arranged in a matrix.

[0027] The needle-like portion 12 is composed of a first water-insoluble material, which is insoluble in water contained in the cleaning solution used in the removal step described later. Considering ease of processing in the manufacturing process, the first water-insoluble material is preferably a water-insoluble resin. The water-insoluble resin is preferably one with a melting point above room temperature and below 250°C, more preferably one with a melting point above 40°C and below 200°C, particularly preferably one with a melting point above 45°C and below 150°C, and even more preferably one with a melting point above 45°C and below 80°C. Because its melting point is above room temperature, and at room temperature, the water-insoluble resin becomes solid and can form the needle-like portion 12, and if the melting point is below 150°C, the freedom of choice in selecting the substrate material increases, and workability is also improved.

[0028] Furthermore, this water-insoluble resin is preferably a water-insoluble biodegradable resin that is unlikely to have any impact on the human body. As a biodegradable resin, aliphatic polyesters and their derivatives are preferred; furthermore, at least one type selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, and copolymers formed by copolymerizing the monomers constituting them is also acceptable. Additionally, biodegradable resins such as polybutylene succinate, aliphatic aromatic copolyesters, and polyhydroxybutyrate can also be used. Furthermore, mixtures of two or more of these biodegradable resins can also be used. Preferably, the first water-insoluble material is a biodegradable resin with a melting point of 60°C, namely polycaprolactone, or a copolymer of caprolactone and monomers constituting other biodegradable resins. The molecular weight of the water-insoluble resin is typically 5,000 to 300,000, preferably 7,000 to 200,000, and more preferably 8,000 to 150,000.

[0029] Each needle-shaped portion 12 has a pore 13 formed on its surface and inside. The pore 13 is formed during the removal of the first water-soluble material in the removal step described later, and bodily fluids, pharmaceutical solutions, etc., can pass through this pore 13. The pore 13 is formed in the needle-shaped portion 12 as a porous structure. If the needle-shaped portion 12 is formed in a way that makes it a porous structure, then channels through which bodily fluids or pharmaceutical solutions can pass are formed inside it as pores 13, so it is better not to mechanically form nano-scale channels. Furthermore, since bodily fluids or pharmaceutical solutions can pass through the entire portion of the needle-shaped portion that has a porous structure, the flow rate can be increased compared to a simple connecting hole. Moreover, in the case where the needle-shaped portion 12 is formed in a way that makes it a porous structure, if the porous structure does not cover part or all of the side of the needle-shaped portion, the pore 13 will also open on the side of the needle-shaped portion 12. In this case, the flow rate of liquid can be increased compared to the case where the opening is only at the front end of the needle-shaped portion 12. As shown in its cross-section, the aperture 13 extends to the substrate 11. While the size of the aperture 13 is determined based on its intended use as an examination patch or similar device employing the microneedle structure 10, from the viewpoint of facilitating liquid penetration, the aperture size is preferably 0.1 to 50.0 μm, more preferably 0.5 to 25.0 μm, and even more preferably 1.0 to 10.0 μm. Furthermore, in this invention, "body fluid" includes blood, lymph, interstitial fluid, etc.

[0030] (2) Substrate The substrate 11 is not particularly limited as long as it is permeable to liquid in the thickness direction. The substrate 11 is preferably a porous material with tiny substrate pores formed internally, extending from one side to the other. As such a porous substrate 11, conventional substrates can be used, such as substrates made of foaming materials like polyurethane resin, porous ceramics, or fibrous materials. The porous substrate 11 is generally insoluble in water or formed of materials that are poorly soluble in water. Preferably, it is a substrate made of easily handled fibrous materials. Here, the term "fibrous material" in this invention refers to fibers such as natural fibers and chemical fibers. Examples of substrates made of fibrous materials include nonwoven fabrics, woven fabrics, knitted fabrics, and paper made from such fibers.

[0031] The porous substrate 11 has pores that communicate with the pores 13 of the needle-like portion 12 to form a connecting hole. The shape of the pores is determined by the material of the substrate. Preferably, the porous substrate 11 has a porosity of 1-70% due to the pores, more preferably 5-50%, and particularly preferably 10-30%. With a porosity within this range, the body fluid absorbed by the needle-like portion 12 can be sufficiently absorbed. As will be described later, the porous substrate 11 preferably contains a second water-insoluble material, and the pores are maintained in the substrate 11 containing the second water-insoluble material. Furthermore, the needle-like portion 12 is directly attached to the substrate 11. For example, when the substrate 11 and the needle-shaped portion 12 are bonded together by an adhesive layer, a gap may be generated between the substrate 11 and the needle-shaped portion 12, which may cause liquid leakage or obstruction of the passage of liquid between the substrate 11 and the needle-shaped portion 12 due to the adhesive layer. However, by directly bonding the substrate 11 and the needle-shaped portion 12, the channels between the two can be easily connected.

[0032] Furthermore, as a substrate with liquid permeability in the thickness direction, the substrate 11 can be made of a liquid-permeable material, or it can be made of a liquid-impermeable material, allowing liquid to pass through the thickness direction of the substrate 11 via through-holes formed therein. Because the substrate 11 is liquid-impermeable, liquid absorption is suppressed, and the liquid only passes through the through-holes within the substrate 11. Therefore, bodily fluids obtained from the needle portion 12 or medications delivered to the needle portion 12 will not leak out of the substrate 11, allowing the entire amount to flow through the through-holes. Thus, when the microneedle structure 10 is used as an examination patch, rapid analysis is possible because bodily fluids can quickly pass through the substrate 11. Furthermore, even when the microneedle structure 10 is used as a drug delivery patch, the medication will not leak out, allowing the entire amount of medication to be rapidly delivered to the skin.

[0033] Materials that are impermeable to liquids can include resin films, metal foils, and glass films, with resin films being preferred. The shape of the through-holes is not particularly limited, but from the viewpoint of generating capillary action and ensuring sufficient flow, a structure with multiple small-diameter through-holes is preferred. The diameter of the through-holes is, for example, less than 2 mm, preferably 0.05 to 1 mm, and more preferably 0.1 to 0.8 mm. The through-holes can be formed by punching, laser perforation, or other methods. Resins used in resin films can include polybutylene terephthalate, polyethylene terephthalate, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, vinyl chloride, acrylic resin, polyurethane, and polylactic acid. The substrate 11 can be a laminated substrate formed by laminating a resin film with through-holes to a porous substrate.

[0034] When an adhesive layer is provided on the surface of the substrate 11 where the needle-like portion 12 is formed, the bonding step described later can be performed at room temperature, or the adhesion between the substrate 11 and the needle-like portion 12 can be improved. In this case, because of the presence of the adhesive layer, a gap is created between the substrate 11 and the needle-like portion 12, which may lead to liquid leakage, or the passage of liquid between the substrate 11 and the needle-like portion 12 may be obstructed due to the adhesive layer. Therefore, it is preferable to provide an adhesive layer in the substrate 11 in such a way that it includes the area through which the liquid should pass, and to provide a non-adhesive layer area in the center.

[0035] Thus, the microneedle structure 10 of this embodiment forms a needle-shaped portion 12 in the desired shape, and the needle-shaped portion 12 is well bonded to the substrate 11 in a manner that allows good liquid permeability of the channel formed by the hole portion 13 of the needle-shaped portion 12 and the substrate hole portion of the substrate 11.

[0036] [Examination Patch] Preferably, the microneedle structure 10 is used in the examination patch 20, which absorbs body fluid from the skin through the needle portion 12 and uses the obtained body fluid for examination. As shown in FIG2, the examination patch 20 has a microneedle structure 10, which has an analytical sheet 21 and a film 22 on the side of the substrate 11 opposite to the side where the needle portion 12 is provided (hereinafter, sometimes referred to as the "back side"). In addition, the microneedle structure 10 can also be used as a drug delivery patch for delivering a drug from the skin to the body through the needle portion 12 from the substrate 11. In this case, the drug delivery patch can be configured such that a sheet containing a physiologically active substance is provided on the back side of the substrate 11 of the microneedle structure 10, and the physiologically active substance from the sheet containing the physiologically active substance is delivered into the skin through the substrate 11 and the needle portion 12.

[0037] The analytical strip 21 is used to analyze and examine bodily fluids such as blood and interstitial fluid obtained from the subcutaneous tissue, and is disposed on the back side of the substrate 11. When the needle-like portion 12 is pierced into the skin of the subject, the bodily fluid flows in from the hole 13 of the needle-like portion 12, is absorbed by the substrate 11, and reaches the analytical strip 21 through the hole of the substrate. The analytical strip 21 can be appropriately selected according to the desired examination content, and can be formed by including components used as analytical means in a substrate such as paper. Examples of such analytical strips 21 include glucose measuring paper that changes color according to the glucose concentration in the bodily fluid. In the case of using glucose measuring paper as the analytical strip 21, it can be used as a blood glucose measurement patch 20, in which the analytical strip 21 absorbs the interstitial fluid taken by the microneedle structure 10 and changes color, and the blood glucose level is measured over time using the degree of this color change.

[0038] The adhesive film 22 is made of a material with biocompatibility. Considering the conformability to the skin to which it is applied, it is preferably made of a material with softness, elasticity, or even contractility, but it is not limited to this material. As a preferred material for the adhesive film 22, elastic woven fabrics can be listed, and conventionally known materials can also be used.

[0039] [Method for Manufacturing Microneedle Constructs] (Filling Step) Figure 3 illustrates a method for manufacturing a microneedle construct 10 according to an embodiment of the present invention. In this embodiment, as shown in Figure 3(a), a liquid composition 3 is filled into a mold 2 having a plurality of recesses 1 (filling step). The recesses 1 are filled with the liquid composition 3.

[0040] The material of mold 2 is not particularly limited, but it is preferably formed of a polysiloxane compound that is easy to mold correctly and whose solidified liquid component 3 is easy to peel off. In this embodiment, it is made of polydimethylsiloxane. The recess 1 is used to form the needle-like portion 12 shown in FIG1, and is configured to form the needle-like portion 12 of the desired shape. In mold 2, multiple recesses 1 are spaced apart from each other and arranged in multiple rows at designated positions.

[0041] The liquid composition 3 comprises: the aforementioned first water-insoluble material (schematically shown as a light gray circle in FIG. 3(a)), a first water-soluble material (schematically shown as a dark gray circle in FIG. 3(a)), and a solvent. Furthermore, in the figures, for illustrative purposes, each material is schematically depicted as a particle and shown as being dispersed in the solvent. The liquid composition 3 only needs to contain at least one of the first water-insoluble material and the first water-soluble material (the composition for forming the needle-like portion) dissolved in the solvent; from the viewpoint of easily forming a porous structure in the needle-like portion 12, it is preferable to contain at least the first water-insoluble material. The liquid composition 3 preferably has a viscosity of 0.1 to 1000 mPa·s, more preferably 0.5 to 100 mPa·s, and particularly preferably 1.0 to 10 mPa·s. Within this range, the liquid composition 3 can be injected into the mold 2 with good workability, and the composition in the filling step also has good filling properties for the recess 1, thus forming the desired needle-like portion 12.

[0042] As the first water-soluble material, it is preferably a water-soluble material with a melting point higher than room temperature. The water-soluble material can be organic or inorganic, and examples include sodium chloride, potassium chloride, sodium sulfate, sodium carbonate, potassium nitrate, alum, sugar, and water-soluble resins. As the water-soluble resin, it is preferably a water-soluble thermoplastic resin, and more preferably one with a melting point higher than room temperature. In addition to the biodegradable resins described later, examples of water-soluble thermoplastic resins include hydroxypropyl cellulose and polyvinylpyrrolidone. Considering further impacts on the human body, the water-soluble thermoplastic resin is more preferably a biodegradable resin. As such a biodegradable resin, at least one can be selected from the group consisting of polyethylene glycol, polypropylene glycol and other polyolefin glycols, polyvinyl alcohol, collagen, and mixtures thereof, with polyethylene glycol being particularly preferred. The molecular weight of polyethylene glycol is preferably 200 to 4,000,000, more preferably 600 to 500,000, and even more preferably 1,000 to 100,000.

[0043] The first water-insoluble material and the first water-soluble material are preferably mixed in a mass ratio of 9:1 to 1:9, more preferably in a mass ratio of 8:2 to 2:8, and most preferably in a mass ratio of 7:3 to 3:7. By forming the liquid composition 3 in this ratio, the needle-like portion 12 with the desired porosity is formed, making it easier to balance the liquid permeability and strength of the needle-like portion 12.

[0044] In this embodiment, in order to contain all the materials and be in a liquid state, the liquid composition 3 includes a solvent. The solvent can be water or an organic solvent, but in the case of dissolving the first water-insoluble material, the liquid composition 3 preferably includes an organic solvent. The organic solvent can be any organic solvent that can dissolve or disperse the aforementioned first water-insoluble material and first water-soluble material. For example, aliphatic hydrocarbons such as hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride and ethylene chloride, alcohols such as methanol, ethanol, propanol, butanol, and 1-methoxy-2-propanol, acetone, methyl ethyl ketone, 2-pentanone, isophorone, and cyclohexanone, esters such as ethyl acetate and butyl acetate, and cellosolve solvents such as ethyl cellosolve.

[0045] The total content of the first water-insoluble material and the second water-insoluble material in all components of the liquid composition 3 is preferably 40% or less by mass, more preferably 35% or less, and particularly preferably 30% or less. By including the components within this range relative to the total amount of the liquid composition 3, the liquid composition 3 can be formed with a desired viscosity that facilitates the fabrication of the needle-shaped portion 12 of the microneedle structure 10. As a result, the needle-shaped portion 12 can be formed in the desired shape.

[0046] Furthermore, the liquid composition 3, as a non-volatile solid component, may include not only the aforementioned first water-insoluble material, namely resin and first water-soluble material, but also other materials.

[0047] Although this embodiment uses a liquid composition 3 formed by dissolving or dispersing various materials in a solvent, the liquid composition 3 may also be composed solely of a composition that does not contain a solvent. Furthermore, the liquid composition 3 may further contain a dispersant. For example, to further improve the strength of the needle-like portion, a water-insoluble material other than resin, such as a silica filler, may be included. In the case of filling a mold with a solvent-free composition, it is preferable to heat the composition to fluidize it.

[0048] (Vibration Step) Next, as a vibration step, it is preferable to place the mold 2 in an ultrasonic cleaning apparatus and subject the mold 2 to ultrasonic vibration. The means of imparting vibration is not limited to an ultrasonic cleaning apparatus, as long as it can impart minute vibrations to the mold 2. By performing this vibration step, as shown in FIG3(b), the liquid composition 3 is promoted to fill the recess 1, and the first water-insoluble material and the first water-soluble material in the recess 1 are further filled to each corner of the recess 1. This filling method avoids defects such as those caused by air bubbles, and allows the formation of needle-shaped portions 12 with high transferability to the shape of the recess 1, and also increases the strength of the needle-shaped portions 12.

[0049] During the ultrasonic treatment, which is a vibration step, heating can be performed simultaneously. In this case, heating is performed at a temperature that promotes evaporation / drying (e.g., 45°C or higher), preferably at a temperature above the melting point of at least one of the first water-insoluble material and the first water-soluble material (e.g., 60°C or higher). By heating at this temperature, surface solidification of the liquid composition 3 is suppressed, evaporation / drying of the organic solvent is promoted, and filling of the recess 1 by the first water-insoluble material and the first water-soluble material in the liquid composition 3 is promoted. In particular, heating at 60°C or higher further promotes the evaporation / drying of the organic solvent and further promotes the filling of the recess 1 by the first water-insoluble material and the first water-soluble material.

[0050] The frequency during the vibration step is preferably selected from a low-frequency range that promotes high filling efficiency, preferably 10~200kHz, more preferably 20~150kHz, and particularly preferably 30~80kHz. Furthermore, the ultrasonic treatment time during the vibration step is preferably 0.5~10 minutes, more preferably 2~7 minutes. By vibrating the mold 2 within this range, the filling of the recess 1 by the first water-insoluble material and the first water-soluble material within the liquid composition 3 is further promoted.

[0051] (Degassing Step) The next step after the vibration step is preferably a degassing step. This degassing process removes air from the recess 1, further promoting the filling of the recess 1 by the first water-insoluble material and the first water-soluble material, while simultaneously promoting the evaporation / drying of the organic solvent. For example, in the embodiments described later, when using ethyl acetate as the solvent, the degassing step is preferably performed at 0.01~0.05 MPa and 20~25°C. By performing degassing within this pressure range, the solidification of the liquid composition 3 on the surface is inhibited, facilitating the evaporation / drying of the organic solvent, and further promoting the filling of the recess 1 by the first water-insoluble material and the first water-soluble material.

[0052] (Heating Step) After this, it is preferable to perform a heating step at 80~120°C. Thus, as shown in FIG3(c), in the case where the solvent is further promoted to evaporate / dry and the material is heated to above the melting point of either the first water-insoluble material or the first water-soluble material, the material becomes molten, thereby promoting the filling of the recess 1 by the first water-insoluble material and the first water-soluble material. Furthermore, in this embodiment, although the heating step is performed after the degassing step, it can also be performed beforehand.

[0053] Afterwards, the solvent evaporates / dries, and the first water-insoluble material and the first water-soluble material contained in the liquid composition 3 are fully filled into the recess 1. With the protrusion 5 already formed in the recess 1, as shown in FIG. 3(d), the sheet 4 is placed in the mold 2. Thus, by fully filling the recess 1 with the first water-insoluble material and the first water-soluble material, the needle-like portion 12 can be formed in the desired shape in this embodiment, and the adhesion between the needle-like portion 12 and the substrate 11 is also good. Thus, in this embodiment, the protrusion 5 is formed through a filling step, followed by a vibration step, a degassing step, and a heating step. Alternatively, the vibration step and / or the degassing step can be omitted. Or, by drying the solvent at room temperature, the protrusion 5 can be formed without the heating step.

[0054] (Sheet) Sheet 4 is formed by containing a second water-soluble material that is soluble in water and a second water-insoluble material that is insoluble in water in the aforementioned porous substrate 11. Because the mold 2 is heated in the previous step, the first water-insoluble material and the first water-soluble material in the recess 1 are in a molten state. If sheet 4 is placed on it, the protrusions 5 formed by the molten first water-insoluble material and the first water-soluble material in the recess 1 will directly adhere to sheet 4. In this case, since sheet 4 contains the second water-insoluble material and the second water-soluble material, the absorption of the molten components in the recess 1 by the substrate 11 can be suppressed. As a result, even if the microneedle structure 10 has a porous substrate 11 and is formed using a liquid material, the collapse of the needle-like portion 12 is suppressed because the root of the protrusion 5 does not form too many voids. Therefore, a needle-like portion 12 with a shape suitable for bonding with the substrate 11 can be formed, and a microneedle structure 10 with good bonding between the needle-like portion 12 and the substrate 11 can be manufactured. Furthermore, since the sheet 4 contains not only a second water-soluble material but also a second water-insoluble material, the adhesion between the sheet 4 and the protrusion 5 is further improved by heat-sealing the molten first water-insoluble material in the recess 1 and the second water-insoluble material contained in the sheet 4.

[0055] As the second water-soluble material, any of the materials listed for the first water-soluble material can be used. However, as described later, to facilitate the impregnation of the porous substrate 11 with the second water-soluble material, a water-soluble resin is preferred, a water-soluble thermoplastic resin is preferred, and a water-soluble biodegradable resin is even more preferred. Preferably, the second water-soluble material is the same as the first water-soluble material. By using the same second water-soluble material as the first water-soluble material, it becomes easier to remove both the second and first water-soluble materials in the subsequent removal step, thus forming the desired pores 13 of the needle-like portions 12.

[0056] The second water-insoluble material may be any of those listed for the first water-insoluble material, but it is preferred that the second water-insoluble material is the same as the first water-insoluble material. By making the second water-insoluble material the same as the first water-insoluble material, the second water-insoluble material and the first water-insoluble material become easier to heat seal, and the adhesion between the protrusion 5 and the sheet 4 is improved.

[0057] Furthermore, as a second water-insoluble material, as described later, a water-insoluble resin is preferred to facilitate the impregnation of the porous substrate 11 with a second water-soluble material. The water-insoluble resin is preferably one with a melting point above room temperature and below 250°C, more preferably one with a melting point above 40°C and below 200°C, and even more preferably one with a melting point above 45°C and below 150°C. The resin used as the second water-insoluble material is also preferably biodegradable.

[0058] For sheet 4, it may contain either a second water-soluble material or a second water-insoluble material, but sheet 4 only needs to contain at least the second water-soluble material in such a way that it does not absorb the first water-insoluble material and the first water-soluble material from the recess 1 from the side of the substrate 11 that is attached to the protrusion 5 (needle-shaped portion 12). That is, sheet 4 only needs to be constructed in such a way that it contains at least the second water-soluble material, and thereby blocks at least a portion of the pores of the porous substrate 11, thereby inhibiting the absorption of the first water-insoluble material and the first water-soluble material. For example, a layer containing the second water-soluble material and the second water-insoluble material may be deposited on the side of the porous substrate 11 that is attached to the protrusion 5. Preferably, the porous substrate 11 is impregnated with the second water-soluble material and the second water-insoluble material. As a method for impregnating a porous substrate 11 with a second water-soluble material and a second water-insoluble material, for example, the porous substrate 11 can be immersed in a solution containing the second water-soluble material and the second water-insoluble material. Alternatively, the solution containing the second water-soluble material and the second water-insoluble material can be coated onto the porous substrate 11 using an inkjet printing method or the like. Drying the solution containing the second water-soluble material and the second water-insoluble material immersed in the porous substrate 11 leaves the second water-soluble material and the second water-insoluble material in the pores of the substrate 11; this is a simple and preferred impregnation method. The solution may contain not only the second water-soluble material and the second water-insoluble material, but also a solvent. The total concentration of the second water-soluble material and the second water-insoluble material in the total components of the solution, by mass, is preferably 1-35%, more preferably 3-30%, and particularly preferably 5-25%. The solution preferably contains a second water-soluble material and a second water-insoluble material in a mass ratio of 9:1 to 1:9. Within this range, it becomes easier to restore the substrate pores of the substrate 11 in the removal step described later, and it is also easier to improve the adhesion between the substrate 11 and the needle-like portion 12.

[0059] When a porous substrate 11 is immersed in a solution containing a second water-soluble material and a second water-insoluble material, for example, the substrate 11 is immersed in the solution at 10-60°C for 1-60 minutes, and then the solvent is evaporated. By drying, the substrate 11 can be impregnated with the second water-soluble material and the second water-insoluble material. In particular, when the substrate 11 is composed of a fibrous material, immersion in the solution allows for easy and sufficient absorption of the second water-soluble material and the second water-insoluble material, thus impregnating the substrate 11.

[0060] In this embodiment, sheet 4 is constructed containing a second water-insoluble material, but is not limited to this. Sheet 4 may also not contain a second water-insoluble material. Because the mold 2 is heated, the first water-insoluble material and the first water-soluble material in the recess 1 are in a molten state. If sheet 4 is placed, the protrusion 5 formed by the molten first insoluble material and the first water-soluble material in the recess 1 will adhere to the surface of the placed sheet 4. When sheet 4 does not contain a second water-insoluble material, for example, by providing any bonding means on the side of the mold 2 of sheet 4, such as providing a bonding part using a conventional adhesive, the adhesion between sheet 4 and the protrusion 5 can be improved.

[0061] (Pressure Application Step) Next, as shown in FIG3(e), a pressure application step is performed to apply pressure to sheet 4. The pressure application method is not particularly limited, and conventional methods can be used. During the pressure application step, a heating step of heating at 60~120°C can also be performed simultaneously. By performing the heating step simultaneously, the adhesion can be further improved. Subsequently, by maintaining a low temperature of -10~3°C, the protrusion 5 in the recess 1 will solidify, and the bonding between the protrusion 5 and sheet 4 will end at the same time. Thus, in this embodiment, the bonding step of bonding the protrusion 5 and sheet 4 is performed by the heating step, the subsequent pressure application step, and the solidification of the protrusion 5. Alternatively, the pressure application step can be omitted, and the protrusion 5 can be bonded to sheet 4 by only the heating step. Or, the protrusion 5 can be bonded to sheet 4 by the above-described bonding method without either the heating step or the pressure application step. As in this embodiment, when the liquid composition 3 contains a solvent, the shape of the composition for forming the needle-like portion is fixed by evaporating the solvent after the filling step (forming step). Therefore, it is not possible to perform the bonding step between the composition for forming the needle-like portion and the substrate 11 before the forming step; the bonding step must be performed after the forming step. However, in this invention, since the sheet 4 contains a water-soluble material, the absorption of the composition for forming the needle-like portion caused by the substrate 11 can be suppressed, and the needle-like portion can be obtained in the desired shape.

[0062] (Removal Step) After the step is completed, as shown in Figure 3(f), a removal step is performed, which separates the solidified protrusion 5 and sheet 4 from the mold 2 and removes the water-soluble material of the protrusion 5 and sheet 4.

[0063] The cleaning solution used in this removal step is water-containing. The removal step is performed, for example, by immersing the assembly of the protrusion 5 and the sheet 4 in the cleaning solution. By immersing in the water-containing cleaning solution, the portions of the first and second water-soluble materials contained in the protrusion 5 and the sheet 4 that are in contact with the outside dissolve and flow into the water, thus being removed. Alternatively, the cleaning solution can be a mixture of water and alcohol, etc. This removal process forms a pore 13 in the protrusion 5, as shown in FIG3(g), and a needle-like portion 12 is formed. This yields a microneedle structure 10. In the removal step, by removing the second water-soluble material, the substrate pores of the substrate 11 that were blocked by the second water-soluble material are at least partially restored, thus the sheet 4 exhibits good liquid permeability. Furthermore, in the case where the sheet 4 contains both the second water-soluble material and the second water-insoluble material, the substrate 11 becomes one containing the second water-insoluble material and whose substrate pores have been restored. In this situation, by dissolving the portion where the first water-soluble material and the second water-soluble material come into contact, the second water-insoluble material remains in the substrate 11, and the pore 13 extending from the needle-like portion 12 to the substrate 11 side further connects with the substrate pore of the substrate 11. The pore 13, which has been connected with the substrate pore, forms a channel for the liquid. In this way, in the microneedle structure 10, the liquid becomes easier to pass through the interface between the needle-like portion 12 and the substrate 11.

[0064] (Modified Example of Protrusion Formation Method) In this embodiment, although the needle-like portion 12 is formed by filling the recess 1 with the liquid composition 3, it is not limited to this. For example, the formation step may also be achieved by preparing the liquid composition 3 with high viscosity and dripping this high-viscosity liquid composition 3 onto the porous substrate 11 using a dispenser or the like, thereby forming the needle-like portion 12. Even in this case, by including at least a first water-soluble material in the substrate 11, it is possible to prevent the liquid composition 3 from being absorbed by the substrate 11 and the needle-like portion 12 from failing to obtain the desired shape.

[0065] In this embodiment, although the needle-like portion 12 is formed by filling the recess 1 with a liquid composition 3 containing a first water-insoluble material, a first water-soluble material, and a solvent, the protrusion 5 can also be formed by melting and filling the recess 1 with a composition containing the first water-insoluble material and the first water-soluble material, but without a solvent. Specifically, this composition is first molded into a suitable shape (e.g., a disc shape) to produce a solid composition. Then, an adhesive layer is pre-applied to a sheet 4, and the adhesive layer of the sheet 4 is bonded to one side of the solid composition. In this way, a bonding step is performed at room temperature to bond the composition before forming the needle-like portion 12 to the substrate 11. Subsequently, the side of the solid composition attached to the substrate opposite to the side attached to the substrate is placed towards the recess 1, and the solid composition is heated and melted while filling the recess 1. Afterward, the protrusion 5 is formed by cooling. In the microneedle structure 10, if the resulting needle portion 12 has a porous structure, the bonding area of ​​the needle portion 12 to the substrate 11 becomes smaller, which is detrimental to the adhesion between them. However, in such a state where the substrate 11 and the solid composition are already bonded, the adhesion between the needle portion 12 and the substrate 11 can be improved by heating during the forming step.

[0066] [Manufacturing Method of Inspection Patch] An inspection patch can be manufactured by placing an analytical sheet 21 at a designated position on the back side of the substrate 11 of the obtained microneedle structure 10 (setting step), and laminating an adhesive film 22 to cover the analytical sheet 21. The lamination method can be a conventional method, for example, by laminating an adhesive film 22 formed on an adhesive film substrate using commonly used rubber-based adhesives, acrylic adhesives, polysiloxane adhesives, etc., after the analytical sheet 21 has been placed on the back side of the substrate 11, thereby manufacturing the inspection patch. The application of reagents to the patch can also be manufactured using the same method.

[0067] [Modified Examples of Microneedle Structures and Manufacturing Methods Thereof] In the embodiments of the microneedle structures and manufacturing methods described above, although multiple needle-shaped portions 12 are directly disposed on the substrate 11, the needle-shaped portions 12 may also have bases, and each needle-shaped portion 12 is disposed on the substrate 11 through the base. The base serves as a base for each needle-shaped portion 12 and, like each needle-shaped portion 12, has a hole. In this case, as long as the base is made of the same material as described for the needle-shaped portions 12, or is formed by the same steps, the needle-shaped portions 12 and the substrate 11 can also achieve good adhesion through the base. In the filling step described above, in order to form the base, simply fill the mold 2 with a liquid composition 3 that is excess compared to the volume corresponding to the recess 1, and allow it to overflow from the recess 1. In this case, by providing a wall portion on the recess 1 forming surface of the mold 2, it is equivalent to providing a liquid storage portion, and the liquid composition overflowing from the recess 1 is accumulated in this liquid storage portion, thereby forming a base.

[0068] In this embodiment, although a sheet 4 made of a porous substrate 11 containing a second water-soluble material that is soluble in water and a second water-insoluble material that is insoluble in water is used, this can be substituted by attaching a resin film with through holes to the protrusions 5. In this case, during the removal step, by dissolving the first water-soluble material, the pore portion 13 extending from the needle-like portion 12 to the substrate 11 side will further connect with the through holes of the substrate 11. The pore portion 13 connected with the through holes forms a liquid channel. Thereby, in the microneedle structure 10, liquid becomes easier to pass from the needle-like portion 12 through the through holes of the substrate 11 to the surface of the substrate 11 opposite to the surface where the needle-like portion 12 is located.

[0069] The present invention will now be described in more detail by way of examples. [Example] A liquid composition with a solid content of 20% was prepared by mixing 100 parts by weight of polyethylene glycol (molecular weight 4000, melting point 40°C) as the first water-soluble material, 100 parts by weight of polycaprolactone (molecular weight 10,000, melting point 60°C) as the first water-insoluble material, and 800 parts by weight of ethyl acetate as the solvent (organic solvent).

[0070] 0.7 ml of the liquid composition is injected into a mold made of polydimethylsiloxane with a recess having the following shape. The area of ​​the mold filled with the liquid composition is a square with four sides of 15 mm, and a reservoir is provided above the recess forming surface. The liquid composition is filled until it is above the recess forming surface, and the needle-like portion has a base. • Concave shape: A square cross-section with four corner weights • Length of one side of the largest cross-section of the concave portion: 500 μm ·Height of recess: 900μm • Spacing between recesses: 1000μm • Number of recesses: 13 in one vertical row, 169 in total across 13 rows. ·Concave arrangement: square grid shape

[0071] Next, the mold was placed in an ultrasonic cleaning device (ultrasonic cleaner AU-10C / manufactured by Aiwa Medical Industry Co., Ltd.) and subjected to ultrasonic treatment for 1 minute at a temperature of 23°C.

[0072] Next, as a degassing step, vacuum drying was carried out for 30 minutes at a reduced pressure of 23°C and 0.05 MPa. After that, it was heated for 30 minutes at 110°C without humidity adjustment.

[0073] On the other hand, a solution with a solid content concentration of 10% was prepared by mixing 100 parts by weight of polyethylene glycol (the same as the first water-soluble material) as the second water-soluble material, 100 parts by weight of polycaprolactone (the same as the first water-insoluble material) as the second water-insoluble material, and 1800 parts by weight of ethyl acetate as the solvent (organic solvent). Furthermore, filter paper (WHATMAN FILTER PAPER GRADE4 / GE Healthcare Life Sciences) used as a porous substrate was immersed in the above solution and then removed and dried at 23°C for 60 minutes to produce a sheet.

[0074] A sheet is placed on the exposed surface of the base, which is located above the protrusion of the recess formed in the heated mold. A 500g weight is then placed on the sheet to apply pressure. Subsequently, after maintaining the temperature at 3°C ​​for 10 minutes, the assembly consisting of the protrusion, base, and sheet is peeled from the mold and immersed in purified water at 23°C for 24 hours to dissolve and remove the first and second water-soluble materials from the protrusion, base, and sheet.

[0075] Subsequently, the first and second water-soluble materials are dissolved and removed. The protrusions, base and sheet are then left to stand for 24 hours at 23°C and 50% relative humidity to allow the water to evaporate and dry, thus creating a microneedle structure.

[0076] As a comparative example, the microneedle structure was fabricated in the same manner as in the examples, except that the step of immersing the porous substrate in the solution was omitted.

[0077] For the microneedle structures obtained from the examples and comparative examples, the root of the needle-like portion was peeled off from the substrate using tweezers, and the interior of the needle-like portion was observed using an optical microscope (magnification: 50x and 100x). In the case of the microneedle structures of the examples, although the resin was filled into the interior of the root of the needle-like portion almost without gaps, in the microneedle structures of the comparative examples, there were gaps, voids, etc., and the filling was not sufficient.

[0078] Next, in the examples and comparative examples, protrusions were formed by cooling the composition. After being peeled from the mold and before being immersed in purified water, the protrusions were observed using an optical microscope (magnification: 50x and 100x) to calculate the number of needle-like portions remaining on the substrate. The proportion of this number of residues to the total number of needle-like portions in the design was calculated as the transfer rate. In the microneedle structures obtained from the examples, a transfer rate of 50% or more indicates good transferability, while the microneedle structures obtained from the comparative examples have a transfer rate of less than 50% and low transferability. [Industrial applicability]

[0079] The microneedle structure of the present invention, for example, can be used as an examination patch by placing an analytical strip on the back side and laminating it with an adhesive film.

[0080] 1: concave part 2: Mold 3: Liquid components 4: film 5: Protrusion 10: Microneedle Structure 11: Substrate 12: Needle-like part 13: Hole 20: Inspect the patch 21: Analysis Slide 22: Adhesive film

Claims

1. A method for manufacturing a microneedle structure, comprising a microneedle structure having a needle-like portion with a hole on one side of a substrate, and the substrate being liquid-permeable in the thickness direction, characterized in that: the substrate is a substrate made of a liquid-impermeable material, and has a through hole formed along the thickness direction by punching or laser perforation, and includes: a forming step, which forms a protrusion using a composition for forming a needle-like portion containing a first water-insoluble material and a first water-soluble material; a following step, which attaches the composition or the protrusion formed in the forming step to the substrate; and a removal step, which immerses the protrusion and the substrate in water to dissolve and remove the first water-soluble material, thereby forming the needle-like portion and the hole from the protrusion.

2. A method for manufacturing a microneedle structure as described in claim 1, wherein, The aforementioned substrate with liquid permeability in the thickness direction is a porous substrate. The aforementioned bonding step is a step of bonding the aforementioned protrusion formed by the aforementioned forming step with the sheet containing the second water-soluble material and the aforementioned porous substrate. The aforementioned removal step is a step of dissolving and removing the aforementioned first water-soluble material and second water-soluble material.

3. A method for manufacturing a microneedle structure as described in claim 2, wherein, The aforementioned porous substrate is a substrate composed of fibrous material.

4. A method for manufacturing a microneedle structure as described in claim 2 or 3, wherein, The aforementioned film contains a second water-insoluble material.

5. A method for manufacturing a microneedle structure as described in claim 4, wherein, The aforementioned first water-insoluble material is the same as the aforementioned second water-insoluble material.

6. A method for manufacturing a microneedle structure as described in claim 2 or 3, wherein, The aforementioned sheet is made by impregnating the aforementioned substrate with a second water-soluble material.

7. A method for manufacturing a microneedle structure as described in claim 3, wherein, The aforementioned substrate composed of fibrous material is nonwoven fabric, textile, knitted fabric or paper.

8. A method for manufacturing a microneedle structure as described in claim 1, wherein, The aforementioned forming steps include a filling step, which fills the aforementioned composition for forming the needle-like portion into a mold having a recess.

9. A method for manufacturing a microneedle structure as described in claim 8, wherein, In the aforementioned filling step, the composition for forming the aforementioned needle-like portion includes a solvent, and in the aforementioned forming step, the aforementioned solvent is evaporated.

10. A method for manufacturing a microneedle structure as described in claim 1, wherein, It includes a setting step in which an analytical means for bodily fluids and / or a means for storing physiologically active substances are set on the side of the aforementioned substrate opposite to the side on which the aforementioned needle-shaped portion is provided.

11. A microneedle structure having a needle-like portion with a hole on one side of a porous substrate, characterized in that the substrate is made of a material that is impermeable to liquids and has through holes formed along the thickness direction by punching or laser perforation, the needle-like portion is made of a first water-insoluble material and is directly disposed on the porous substrate, and the porous substrate contains a second water-insoluble material.

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