Microneedle structure and method for producing microneedle structure

Abstract

A microneedle structure 10 equipped with needle-shaped parts 12 having a hole formed therein and a substrate 11 provided with said needle-shaped parts on one surface thereof. The needle-shaped parts 12 have a porous structure formed therein, and the value of the tip strength of the needle-shaped parts 12 is 40mN or higher. This method for producing a microneedle structure produces said microneedle structure 10. As a result, it is possible to provide: a microneedle structure having needle-shaped parts for which loss thereof and damage thereto is suppressed during use; and a method for producing said microneedle structure.

Description

Microneedle structure and method for manufacturing the microneedle structure

[0001] The present invention relates to a microneedle structure and a method for manufacturing a microneedle structure.

[0002] In recent years, microneedles have been proposed that deliver drugs to the body or collect body fluids from the body through through-holes formed in the microneedles. For example, a microneedle is known that includes a biocompatible matrix in the form of a microneedle and porous particles provided on the surface or at least in part inside the biocompatible matrix (Patent Document 1).

[0003] JP 2014-094171 A

[0004] In Patent Document 1, the biocompatible material constituting the microneedle swells or is absorbed into biological tissue within a few seconds to a few hours after insertion into the skin, and therefore the microneedle is assumed to be absorbed in the body. However, from a safety standpoint, it is desirable to remove the inserted microneedle so as to leave as little of it in the skin as possible. Here, for example, when attempting to remove a microneedle containing porous particles as shown in Patent Document 1 from the skin after insertion, there is a problem that the microneedle may be damaged. Furthermore, there is a possibility that the microneedle may be damaged when puncturing the skin, reducing the efficiency of drug delivery, etc.

[0005] The present invention has been made in consideration of the above-described circumstances, and aims to provide a microneedle structure having a needle-shaped portion that is prevented from being chipped or broken during use, and a method for manufacturing such a microneedle structure.

[0006] In order to achieve the above object, firstly, the present invention provides a microneedle structure comprising a needle-shaped portion having a hole formed therein and a substrate having the needle-shaped portion on one side thereof, wherein a porous structure is formed in the needle-shaped portion, and the needle-shaped portion has a tip strength of 40 mN or more as measured by the following evaluation method (evaluation method: the microneedle structure is placed on a stage with the needle-shaped portion facing upward, and observed under a microscope. One needle-shaped member with a sharp tip shape is selected, and the actuator of a digital force gauge is adjusted to the position of the selected needle-shaped portion). An attachment (made of iron, 2 mm diameter) is lowered at a rate of 5 mm / min to measure the force applied to the attachment (measurement environment temperature: 23°C, measurement environment relative humidity: 50%), and on the graph outputting the measured forces, when a decrease in force is first observed, the maximum force value indicated at the position before the decrease in force is read, or, if no decrease in force is observed before the attachment has been lowered 100 μm, the force value at the time the attachment has been lowered 100 μm is read, and this value is taken as the tip strength of the needle-like portion (Invention 1).

[0007] In the above invention (Invention 1), the tip strength of the needle-shaped portion is 40 mN or more, which makes it possible to prevent the needle-shaped portion from breaking when piercing the skin.

[0008] In the above invention (Invention 1), it is preferable that the hole opens on a side surface of the needle-shaped portion (Invention 2).

[0009] In the above invention (Invention 1), it is preferable that the needle-shaped portion contains a high-melting point resin having a melting point exceeding 130°C, the substrate includes a layer containing a heat-resistant resin, and is capable of passing liquid in the thickness direction (Invention 3).

[0010] In the above invention (Invention 3), the high-melting-point resin is preferably a water-insoluble resin (Invention 4).

[0011] In the above invention (Invention 3), the high-melting-point resin is preferably a biodegradable resin (Invention 5).

[0012] In the above invention (Invention 3), the high melting point resin is preferably a copolymer of at least one monomer selected from polylactic acid and polyglycolic acid with another monomer (Invention 6).

[0013] In the above invention (Invention 3), the layer containing the heat-resistant resin preferably contains at least one heat-resistant organic polymer selected from polymethyl methacrylate, polystyrene, polyacrylonitrile, polyphenylene oxide, polyethylene naphthalate, polyphenylene sulfide, polytetrafluoroethylene, polycarbonate, allyl resin, polyether ether ketone, acetyl cellulose resin, polysulfone, polyethersulfone, polyimide, and polyamideimide, a copolymer obtained by copolymerizing a monomer that is a raw material of the heat-resistant organic polymer with any other monomer, or a silicone resin (Invention 7).

[0014] In the above invention (Invention 3), it is preferable that the substrate and the needle-shaped portion are directly bonded via a base portion made of the same material as the needle-shaped portion (Invention 8).

[0015] In the above invention (Invention 1), the needle-shaped portion preferably contains a low-melting-point resin having a melting point of 130° C. or less (Invention 9).

[0016] In the above invention (Invention 1), it is preferable that the needle-shaped portion contains a high-melting-point resin and also contains a low-melting-point resin whose melting point is 130° C. or less (Invention 10).

[0017] Secondly, the present invention provides a method for manufacturing a microneedle structure comprising a needle-shaped portion having a hole formed therein and a substrate having the needle-shaped portion on one side thereof, characterized in that the method includes a forming step of heating a composition containing a high-melting point resin having a melting point exceeding 130°C and forming protrusions on the substrate using the composition (Invention 11).

[0018] In the above invention (Invention 11), it is preferable that the high-melting point resin is a water-insoluble resin, the composition is a mixture containing the water-insoluble resin and a water-soluble material, and after the forming step, there is a removal step of removing the water-soluble material from the formed protrusions with a solution containing water to form holes in the protrusions (Invention 12).

[0019] Thirdly, the present invention provides a method for manufacturing a microneedle structure comprising a needle-shaped portion having a hole formed therein and a substrate having the needle-shaped portion on one side thereof, the method comprising a bonding step of heating a composition containing a high-melting point resin having a melting point of more than 130°C and bonding the heated composition to the substrate (Invention 13).

[0020] 1A to 1C are explanatory diagrams showing the steps of a method for manufacturing a microneedle structure according to an embodiment; FIG. 1B is a schematic cross-sectional view of a microneedle structure according to an embodiment; FIG. 1C is a partial enlarged view of a needle-shaped portion of a microneedle structure according to an embodiment; FIG. 1D is a schematic partial cross-sectional view of a test patch using a microneedle structure according to an embodiment; FIG. 1E is an explanatory diagram showing the steps of a method for manufacturing a microneedle structure according to an embodiment; FIG. 1F is an explanatory diagram showing the steps of a method for manufacturing a microneedle structure according to an embodiment;

[0021] An embodiment of the present invention will be described below. [Microneedle Structure] Fig. 1 shows a microneedle structure 10 according to one embodiment of the present invention. The microneedle structure 10 includes a plurality of needle-shaped portions 12 spaced apart at a predetermined interval on one side of a substrate 11. The substrate 11 has through-holes 15 formed therein. Each of the needle-shaped portions 12 has a plurality of holes 13 formed therein. The microneedle structure 10 can be used as a test patch that absorbs body fluid from within the skin through the holes 13 in the needle-shaped portions 12 and performs a test using the body fluid obtained through the substrate 11, or as a drug administration patch that administers a drug into the body through the skin via the holes 13 in the substrate 11 and the needle-shaped portions 12. In the present invention, body fluid includes blood, lymph, interstitial fluid, etc.

[0022] (1) Needle-shaped portion The shape, size, formation pitch, and number of the needle-shaped portions 12 can be appropriately selected depending on the intended use of the microneedle, etc. Examples of the shape of the needle-shaped portion 12 include a cylindrical shape, a prismatic shape, a conical shape, and a pyramidal shape, and in this embodiment, the needle-shaped portion 12 is a pyramidal shape. The maximum diameter or maximum cross-sectional dimension of the needle-shaped portion 12 is, for example, 25 to 1000 μm, the tip diameter or cross-sectional dimension of the tip is, for example, 1 to 100 μm, and the height of the needle-shaped portion 12 is, for example, 50 to 2000 μm. Furthermore, the needle-shaped portions 12 are provided in multiple rows in one direction of the substrate 11, and multiple needle-shaped portions 12 are formed in each row and arranged in a matrix.

[0023] In this embodiment, the needle-shaped portion 12 has a tip strength of 40 mN or more as measured by the following evaluation method. Evaluation method: The microneedle structure is placed on a stage with the needle-shaped portion facing up, observed under a microscope, and one needle-shaped body with a sharp tip shape is selected. The attachment of the digital force gauge (made of iron, 2 mmφ) is lowered at a descent rate of 5 mm / min to match the position of the needle-shaped portion, and the force applied to the attachment is measured (measurement environment temperature: 23 ° C., measurement environment relative humidity: 50%). On the graph outputting the measured force, when the first drop in force is observed, the maximum force indicated at the position before the drop in force is read, or if no drop in force is observed until the attachment's drop distance reaches 100 μm, the force value at the time the attachment's drop distance reaches 100 μm is read, and this value is the tip strength of the needle-shaped portion.

[0024] For details of the method for evaluating tip strength, for example, a method for evaluating tip strength employing the procedures, apparatus, etc. described in the Examples below can be mentioned. When the tip strength of the needle-shaped portion 12 is within this range, it is possible to prevent the needle-shaped portion 12 from breaking when piercing the skin with the needle-shaped portion 12. From this perspective, the tip strength of the needle-shaped portion is preferably 40 to 500 mN, more preferably 60 to 450 mN, even more preferably 85 to 400 mN, and even more preferably 100 to 350 mN.

[0025] In the first embodiment (hereinafter simply referred to as the "first embodiment") of the resin constituting the needle-shaped portion 12 of this embodiment, the needle-shaped portion 12 is preferably made of a high-melting-point resin. High-melting-point resins preferably have a melting point of over 130°C, more preferably 135 to 240°C, more preferably 140 to 220°C, and most preferably 145 to 200°C. High-melting-point resins are less likely to soften at temperatures near room temperature, at which the microneedle structure 10 is used. Therefore, by including a high-melting-point resin with a melting point exceeding 130°C, the needle-shaped portion 12 can maintain sufficient strength. As described below, in a structure in which multiple holes 13 are opened on the side surface of the needle-shaped portion 12, it is possible to increase the rate at which fluid is absorbed or released from the needle-shaped portion 12 compared to a structure in which holes are opened only at the top of the needle-shaped portion. However, the needle-shaped portion 12 becomes brittle and its strength is likely to decrease. However, in this embodiment, the needle-shaped portion 12 is formed from a composition containing a high-melting point resin with a melting point exceeding 130°C, which increases the strength and prevents the needle-shaped portion 12 from breaking when, for example, the needle-shaped portion 12 is pierced into the skin.

[0026] Such a high-melting-point resin is preferably a water-insoluble high-melting-point resin. Being water-insoluble means that when applied to a living body, it does not dissolve in body fluids, allowing the shape of the microneedle structure 10 to be maintained for the desired application time, and also makes it possible to easily form minute holes 13, as described below. In this embodiment, the needle-shaped portion 12 is made of a water-insoluble material containing a water-insoluble high-melting-point resin. Examples of water-insoluble high-melting-point resins other than the biodegradable resins described below include polypropylene, polyvinylidene fluoride, acetal resin, polycarbonate, etc.

[0027] The molecular weight of the high-melting-point resin is usually 5,000 to 1,000,000, preferably 7,000 to 500,000, and more preferably 9,000 to 300,000. Within this range, the needle-shaped portion 12 can be preferably formed.

[0028] Furthermore, the high-melting-point resin is preferably a high-melting-point biodegradable resin. Here, biodegradable resins are those that are eventually decomposed into CO2 by the action of microorganisms present in nature after use.２ It is a plastic that completely decomposes into water and, by being a biodegradable resin, its impact on living organisms can be reduced. Aliphatic polyesters and their derivatives are preferably used as such biodegradable resins, and specific examples include polyglycolic acid (melting point: 218°C), polylactic acid (melting point: 170°C), and polyhydroxybutyric acid (melting point: 175°C). Copolymers composed of two or more monomers selected from the group consisting of glycolic acid, lactic acid, and caprolactone are also suitable. Such copolymers preferably have glycolic acid or lactic acid as the main monomer component, in order to achieve a melting point exceeding 130°C. High-melting-point biodegradable resins are preferably polyglycolic acid, polylactic acid, or a copolymer of glycolic acid and lactic acid, with polylactic acid being more preferred.

[0029] In a second embodiment (hereinafter simply referred to as the "second embodiment") of the present embodiment, the resin constituting the needle-shaped portion 12 may be a low-melting-point resin. Low-melting-point resins are preferably materials that are solid at room temperature and have a melting point of 130°C or less, more preferably materials with a melting point below 130°C, particularly materials with a melting point of 40 to 120°C, and most preferably materials with a melting point of 45 to 100°C. Being solid at room temperature allows the shape of the needle-shaped portion 12 to be maintained at room temperature. Furthermore, a melting point of 130°C or less eliminates the need for high-temperature heating when melting the resin to form the needle-shaped portion 12, resulting in low cost and excellent workability. Additionally, even if the resin is bonded to the substrate 11 in a molten state or heated while the resin and the substrate are bonded, the resin can be melted at a low temperature, preventing softening, deformation, or burning of the substrate 11, and providing a high degree of freedom in selecting the substrate 11. Furthermore, even when a nonwoven fabric or a resin film made of synthetic fibers or the like with a low heat resistance temperature is used as the substrate 11, deterioration of the substrate 11 due to softening of the synthetic fibers or the like can be prevented. From this viewpoint, the proportion of the low-melting-point resin to the total mass of the resin components contained in the needle-shaped portion 12 is preferably 50 mass% or more, and more preferably 70 mass% or more.

[0030] The low-melting-point resin constituting the needle-shaped portion 12 may further be a water-insoluble resin. Being water-insoluble means that when applied to a living body, it will not dissolve in body fluids, making it possible to maintain the shape of the microneedle structure 10 for the desired application time, and also makes it possible to easily form minute holes 13, as will be described later. Examples of water-insoluble resins include polyolefin-based resins such as polyethylene and α-olefin copolymers, olefin copolymer-based resins such as ethylene-vinyl acetate copolymer-based resins, polyurethane-based elastomers, and acrylic copolymer-based resins such as ethylene-ethyl acrylate copolymers.

[0031] The low-melting-point resin constituting the needle-shaped portion 12 may also be a biodegradable resin. Examples of such biodegradable resins include aliphatic polyesters and their derivatives, and further include homopolymers of at least one monomer selected from the group consisting of glycolic acid, lactic acid, and caprolactone, or copolymers of two or more monomers. Polybutylene succinate (melting point: 84-115°C) and aliphatic aromatic copolyesters (melting point: 110-120°C) can also be used as low-melting-point biodegradable resins. Specifically, examples of polybutylene succinate that can be used include BioPBS, available from Mitsubishi Chemical Corporation, and examples of aliphatic aromatic copolyesters include Ecoflex, available from BASF.

[0032] The biodegradable resin may also be a resin whose monomer has an acid dissociation constant of 4 or more. Having a monomer acid dissociation constant of 4 or more can reduce the impact on the living body when the microneedle structure 10 is applied to the living body. Note that, when the monomer is a cyclic ester, the acid dissociation constant of the monomer referred to here is the acid dissociation constant of the hydroxycarboxylic acid resulting from the ring-opening of the cyclic ester. The acid dissociation constant of the monomer is preferably 4.0 or more, more preferably 4.5 or more. The acid dissociation constant of the monomer is preferably 25 or less, more preferably 15 or less. Examples of monomers constituting such biodegradable resins with an acid dissociation constant of 4 or more include caprolactone. In low-melting biodegradable resins, the constituent units derived from the monomers having an acid dissociation constant of 4 or more preferably account for 70% by mass or more of all constituent units, more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0033] The molecular weight of the resin constituting the needle-shaped portion 12 is usually 5,000 to 300,000, preferably 7,000 to 200,000, and more preferably 8,000 to 150,000.

[0034] Most preferably, the low-melting-point resin constituting the needle-shaped portion 12 is a water-insoluble, low-melting-point resin that is biodegradable and has an acid dissociation constant of 4 or more, such as polycaprolactone or a copolymer of caprolactone and another polymer.

[0035] In the second embodiment, the resin constituting the needle-shaped portion 12 is preferably a low-melting resin and has a weight-average molecular weight of 40,000 or more, that is, a high-molecular-weight low-melting resin.

[0036] The weight average molecular weight of the high molecular weight, low melting point resin is preferably 40,000 or more, more preferably 40,000 to 200,000, and even more preferably 60,000 to 150,000. By having it in this range, the tip strength of the needle-like portion 12 can be easily improved.

[0037] In the second embodiment, it is also preferable that the needle-shaped portion 12 further contains a filler. By containing a filler in the needle-shaped portion 12, it is possible to further improve the mechanical strength of the needle-shaped portion 12. The filler is preferably contained so as to be dispersed in the resin of the needle-shaped portion 12.

[0038] The filler is preferably made of a resin, and preferably made of one selected from the group consisting of natural organic polymers or modified products thereof, and biodegradable resins. Resin fillers can also be used that contain inorganic components, such as organic-inorganic hybrid fillers in which inorganic substances are attached to the surfaces of resin particles. However, in consideration of the effects on living organisms, fillers are preferably made of only resin and organic components, and more preferably made of only resin. Examples of natural organic polymers include cellulose, and examples of fillers made of natural organic polymers or modified products thereof include cellulose fiber and spherical cellulose acetate microparticles.

[0039] While the biodegradable resins described above can be used, when a low-melting-point biodegradable resin is used as the resin constituting the needle-shaped portion 12, it is preferable to use a different biodegradable resin. From the viewpoint of further improving the mechanical strength of the filler, as described below, a biodegradable resin with a melting point above 130°C or no melting point is preferred. Examples of such biodegradable resins include polylactic acid (melting point: 170°C), polyglycolic acid (melting point: 218°C), polyhydroxybutyric acid (melting point: 175°C), and cellulose acetate diacetate (melting point: 230-300°C). Biodegradable resins such as cellulose acetate diacetate also qualify as modified natural organic polymers.

[0040] From the viewpoint of further improving the mechanical strength of the needle-shaped portion 12, the filler is preferably made of a resin having a melting point of more than 130°C or no melting point. A resin having a melting point of more than 130°C is less likely to soften at temperatures around room temperature where the microneedle structure 10 is used. Therefore, by making the filler from a resin having a melting point of more than 130°C, it is easy to obtain sufficient strength for the microneedle structure 10. Furthermore, when the filler 12 is made of a resin having a melting point of more than 130°C, adding such a resin that is difficult to melt in the form of a filler is preferable because, when mixed with the low-melting point resin, the filler made of the resin that is difficult to melt is dispersed in the composition, and the composition can be kneaded at a low temperature without melting. Other than the biodegradable resins mentioned above, examples of resins having a melting point of more than 130°C or no melting point include polypropylene (melting point: 155°C), polybutylene terephthalate (223°C), polyethylene terephthalate (melting point: 260°C), polytetrafluoroethylene (melting point: 327°C), melamine resin (melting point: none), and unmodified cellulose (melting point: none).

[0041] From the same viewpoint, it is also preferable that the filler is made of a resin having a glass transition temperature of -10°C or higher. It is also preferable that the filler is made of a resin having a glass transition temperature of 80°C or lower. When the filler is made of a resin having a glass transition temperature of 80°C or lower, the filler is likely to soften during melting and is easily compatible with the low-melting-point resin, even when melting is performed at a low temperature. This makes it easier to improve the strength of the needle-shaped portion 12 to be produced. Note that when the resin contained in the filler is crosslinked, it is the polymer before crosslinking that has a glass transition temperature of -10°C or higher or 80°C or lower. Examples of resins having a glass transition temperature (Tg) of -10°C or higher and 80°C or lower include polypropylene (Tg: 0°C), polybutylene terephthalate (Tg: 50°C), polyethylene terephthalate (Tg: 69°C), polymethyl methacrylate (Tg: 60°C), polylactic acid (Tg: 60°C), polyglycolic acid (Tg: 40°C), and polyhydroxybutyric acid (Tg: 15°C). Of these, biodegradable resins are preferred, as described above, and polylactic acid, polyglycolic acid, polyhydroxybutyric acid, or copolymers of these polymer monomers are preferred. The filler is more preferably made of a resin having a glass transition temperature of 10 to 80°C, and even more preferably made of a resin having a glass transition temperature of 30 to 75°C.

[0042] The filler is preferably contained in an amount of 3 to 50% by mass, more preferably 5 to 43% by mass, and even more preferably 10 to 35% by mass, relative to the total mass of the needle-shaped portion 12. If the filler content is 50% by mass or less, it becomes easier to maintain the shape of the needle-shaped portion 12 and improve processability during manufacturing. If the filler content is 3% by mass or more, it becomes easier to increase the strength of the needle-shaped portion 12. By containing the filler in this range, it becomes easier to form a needle-shaped portion 12 with the desired porosity and maintain liquid permeability, while also increasing the strength of the needle-shaped portion 12 due to the filler. Two or more types of the above-mentioned fillers may also be contained. Even in this case, it is preferable to contain the filler so that the total amount of the filler relative to the resin constituting the needle-shaped portion 12 falls within the above-mentioned content range.

[0043] The shape of the filler may be plate-like (flake-like), fibrous, spherical, or amorphous, with fibrous being preferred. A fibrous filler is preferred because it is more compatible with the molten low-melting-point resin and therefore more likely to improve the strength of the resulting needle-shaped portion 12. Examples of fibrous fillers include metal fiber fillers, carbon fibers, carbon nanofibers, and cellulose fibers. When the filler has a shape other than fibrous, such as a spherical or amorphous shape, as described above, the filler is made of a resin with a glass transition temperature of 80°C or lower, which makes the filler more compatible with the low-melting-point resin. The particle diameter of the filler is 0.3 to 150 μm, preferably 0.5 to 125 μm, and more preferably 1 to 100 μm. A filler particle diameter of 0.3 to 150 μm makes it easier to disperse the filler in a composition containing a low-melting-point resin and further improves the strength of the resulting microneedle structure 10. The particle diameter of the filler is the average of seven measurements of the longest part of the particle length when the filler in the microneedle structure 10 is observed with a scanning electron microscope (SEM). When the filler is fibrous, the particle diameter refers to the fiber length.

[0044] As described above, in the first embodiment, the needle-shaped portion 12 is made of a high-melting-point resin. However, the needle-shaped portion 12 may contain a resin other than the high-melting-point resin. In this case, the proportion of the high-melting-point resin relative to the total mass of the resin components contained in the needle-shaped portion 12 is preferably 30% by mass or more, more preferably 50% by mass or more, and even more preferably 70% by mass or more, from the viewpoint of efficiently achieving the effect of increasing the strength of the needle-shaped portion 12. Resins other than the high-melting-point resin contained in the needle-shaped portion 12 include low-melting-point resins having a melting point of less than 130°C. Examples of low-melting-point resins include polycaprolactone (melting point: 60°C), polybutylene succinate (melting point: 84 to 115°C), and aliphatic aromatic copolyester (melting point: 110 to 120°C). Furthermore, the low-melting-point resin contained in the needle-shaped portion 12 together with the high-melting-point resin may be the same low-melting-point resin used in the second embodiment described above, but with a melting point of 130°C or less. The needle-shaped portion 12 contains a high-melting point resin and a low-melting point resin, which allows the resin to melt at low temperatures while improving the tip strength of the needle-shaped portion 12. In this case, the high-melting point resin and the low-melting point resin may be in a kneaded state, but by using a high-melting point resin as the resin used for the filler described above and mixing the high-melting point resin with the low-melting point resin in the form of a filler, it becomes easier to mix the high-melting point resin and the low-melting point resin at low temperatures.

[0045] The needle-shaped portion 12 has holes 13 formed therein as flow paths through which liquid flows. One or more holes 13 are formed in each needle-shaped portion 12, and one or more holes 13 open on the surface of the needle-shaped portion 12. In this embodiment, the needle-shaped portion 12 has a porous structure. Forming at least a portion of the needle-shaped portion 12 to have a porous structure allows body fluids or medicinal fluids to pass through the holes 13 of the porous structure, which is preferable because it eliminates the need to mechanically form nano-order flow paths. Furthermore, since body fluids or medicinal fluids can flow through all flow paths in the portion of the needle-shaped portion 12 where the porous structure is formed, the flow rate can be increased compared to when a simple single communicating hole is formed. However, forming at least a portion of the needle-shaped portion 12 to have a porous structure in this manner may result in the needle-shaped portion 12 becoming brittle. For example, if the porous structure is not covered in part or all of the side surface of the needle-shaped portion 12, the holes 13 will also open on the side surface of the needle-shaped portion 12. In this case, the amount of liquid that flows can be increased compared to when the opening is only at the tip of the needle-shaped portion 12. If the needle-shaped portion 12 has a porous structure or if the holes 13 are opened on the side surface of the needle-shaped portion 12, the needle-shaped portion 12 may become brittle, but in this embodiment, the needle-shaped portion 12 is formed to have a tip strength within a predetermined range, and therefore, the needle-shaped portion 12 can be formed to be less likely to chip or break without becoming brittle.

[0046] As a method for forming the porous structure, which will be described in detail later, from the viewpoint of forming the pores 13 as a continuous structure, it is preferable to form the porous structure simultaneously with the formation of the needle-shaped portion 12, or to form the protrusion 32 (not shown in FIG. 1 , which will be described later) without a porous structure and then form the porous structure in the protrusion 32. In the latter case, for example, the porous structure may be obtained by mixing two or more different materials to form the protrusion 32, and then removing at least one of the materials to form the pores 13. When the needle-shaped portion 12 contains a filler, this method for forming the porous structure allows the filler to be contained in a dispersed state in the resin of the needle-shaped portion 12. In this embodiment, the needle-shaped portion 12 is manufactured by producing the protrusion 32 made of a water-insoluble high-melting-point resin and a water-soluble material in a manufacturing process described later, and then removing the water-soluble material to form the pores 13, while the water-insoluble high-melting-point resin remains to form the porous needle-shaped portion 12.

[0047] In one aspect of this embodiment, the pores 13 are voids formed by removing the water-soluble material from the protrusions 32, which are made of a water-insoluble high-melting point resin or low-melting point resin and a water-soluble material, and body fluids and medicinal solutions pass through these pores 13 as flow paths. As shown in the cross section of the needle-shaped portion 12, the pores 13 are formed by the removal of the water-soluble material, resulting in multiple voids that are interconnected. Some pores 13 form flow paths that connect the surface of the needle-shaped portion 12 to one side of the substrate 11. The size of the opening of the pores 13 is determined depending on the application, such as a test patch using the microneedle structure 10. From the perspective of facilitating the passage of liquids, the size of the opening 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. The water-soluble material and its content are appropriately selected in the manufacturing process to achieve such an opening diameter. In one aspect of this embodiment, the needle-shaped portion 12 is formed into a porous structure by removing the water-soluble material from the protrusion portion 32, which is made of a water-insoluble high-melting point resin or low-melting point resin and a water-soluble material. However, this is not limited to this, and it is also possible to form the needle-shaped portion 12 using a porous high-melting point resin, to form a porous structure simultaneously with the formation of the needle-shaped portion 12 using a foaming material, or to form a porous structure by sintering a particulate composition containing a high-melting point resin.

[0048] Furthermore, the needle-shaped portions 12 may have a base 14 provided between one surface of the substrate 11 and at least the region where the needle-shaped portions 12 are formed. In this embodiment, the base 14 is provided in the form of a layer over the entire one surface of the substrate 11. The base 14 serves as the foundation for each needle-shaped portion 12, and has holes 13 similar to the individual needle-shaped portions 12. The base 14 is formed to a thickness of, for example, 0.1 to 500 μm. Having a thickness of this order of magnitude increases the strength of the substrate 11 and achieves favorable adhesion between the needle-shaped portions 12, the base 14, and the substrate 11.

[0049] The base 14 also preferably has a porous structure similar to the needle-shaped portion 12, and it is more preferable to use a material with the same porous structure as the needle-shaped portion 12. When a porous structure is used for the base 14, a flow path through which liquid flows is formed therein, eliminating the need to mechanically form the holes 13; liquid from the needle-shaped portion 12 can pass through the holes 13 of the base 14 and fill the through-holes 15, which is preferable. In this embodiment, the base 14 is made of the same high-melting-point resin as the material described for the needle-shaped portion 12 and is formed using the same process, which not only simplifies production but also allows for better adhesion between the needle-shaped portion 12 and the substrate 11 via the base 14, which is preferable. Furthermore, in this embodiment, the base 14 is provided over the entire one side of the substrate 11, so that the base 14 remains attached to the substrate 11 even in areas where the needle-shaped portion 12 is not formed, further improving the overall strength of the microneedle structure 10.

[0050] (2) Substrate In the case of the first embodiment described above, i.e., when the needle-shaped portion 12 contains a high-melting point resin, the substrate 11 preferably has a layer containing a heat-resistant resin and is configured to allow liquid to pass through in the thickness direction. The layer containing the heat-resistant resin only needs to contain the heat-resistant resin to an extent that it can exhibit heat resistance. The ratio of the heat-resistant resin content to the total mass of the resin components contained in the layer containing the heat-resistant resin is preferably 50% by mass or more, more preferably 65% ​​by mass or more, and even more preferably 80% by mass or more. Examples of heat-resistant resins include heat-resistant organic polymers and silicone resins. The glass transition temperature of the heat-resistant organic polymer is preferably 80°C or higher, more preferably 110°C or higher, even more preferably 140°C or higher, and even more preferably 200°C or higher. The glass transition temperature of the heat-resistant organic polymer is the temperature at the intersection of the tangents before and after the inflection point of the chart obtained by performing TMA (thermal mechanical analysis) on a sample of the heat-resistant organic polymer at a heating rate of 5°C / min. By having the substrate 11 have a layer containing a heat-resistant resin, deformation and deterioration of the substrate 11 can be suppressed even if the substrate 11 is heated simultaneously when the needle-shaped portion 12 is manufactured in the manufacturing process by melting a composition containing a high-melting point resin at a temperature above its melting point to bond the substrate 11, or when the needle-shaped portion 12 is formed by melting a composition containing a high-melting point resin at a temperature above its melting point. Since the melting point of the high-melting point resin is 130°C or higher, the possibility of obtaining such an effect can be further increased if the glass transition temperature of the heat-resistant organic polymer is 140°C or higher.

[0051] Furthermore, the phrase "liquid permeable in the thickness direction" means that the substrate 11 itself is not made of a liquid-permeable material, but is preferably made of a liquid-impermeable material and configured to allow liquid to pass through the substrate 11 in the thickness direction via the through-holes 15 formed in the substrate 11. The liquid-impermeable nature of the substrate 11 can suppress liquid absorption by the substrate 11, so that liquid can pass only through the through-holes 15 in the substrate 11. Therefore, the body fluid obtained from the needle-shaped portion 12 or the drug solution transported to the needle-shaped portion 12 does not seep into the substrate 11, and the entire amount can circulate through the through-holes 15. As a result, when the microneedle structure 10 is used as a test patch, the body fluid can quickly pass through the substrate 11, enabling rapid analysis. Furthermore, even when the microneedle structure 10 is used as a drug administration patch, the drug solution does not seep out, and the entire amount of drug solution can be quickly delivered to the skin.

[0052] The layer containing a heat-resistant resin of the substrate 11 is preferably formed from a flexible material that conforms well to the skin. The layer containing a heat-resistant resin is preferably a resin film containing a heat-resistant resin, from the viewpoint of imparting liquid impermeability to the substrate 11. Examples of heat-resistant resins include heat-resistant organic polymers and silicone resins, as described above. The heat-resistant organic polymer is preferably at least one selected from polymethyl methacrylate, polystyrene, polyacrylonitrile, polyphenylene oxide, polyethylene naphthalate, polyphenylene sulfide, polytetrafluoroethylene, polycarbonate, allyl resin, polyether ether ketone, acetyl cellulose resin, polysulfone, polyethersulfone, polyimide, and polyamideimide. Among heat-resistant organic polymers, at least one selected from polyethylene naphthalate, polyphenylene sulfide, polytetrafluoroethylene, polycarbonate, allyl resin, polyether ether ketone, acetyl cellulose resin, polysulfone, polyether sulfone, polyimide, and polyamide imide is more preferred, and at least one selected from polycarbonate, allyl resin, polyether ether ketone, acetyl cellulose resin, polysulfone, polyether sulfone, polyimide, and polyamide imide is even more preferred, and at least one selected from polyether sulfone, polyimide, and polyamide imide is even more preferred. Furthermore, as the heat-resistant organic polymer, a copolymer obtained by copolymerizing the monomers that are the raw materials for these heat-resistant organic polymers with any other monomer may be used. Examples of such heat-resistant organic polymers include acrylonitrile-butadiene-styrene copolymers. Generally, the higher the glass transition temperature of the heat-resistant organic polymer, the higher the heat resistance of the heat-resistant organic polymer. For example, the typical glass transition temperature of polyimide is 300°C or higher.

[0053] In the case of the second embodiment described above, that is, when a low-melting-point resin having a melting point of 130° C. or less is used as the resin forming the needle-shaped portion 12, the composition containing the low-melting-point resin can be processed at low temperatures, thereby avoiding exposure of the substrate 11 to high temperatures. Therefore, instead of a resin film containing a heat-resistant resin as the layer containing a heat-resistant resin, a resin film using a resin such as polybutylene terephthalate, polyethylene terephthalate, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, vinyl chloride, acrylic resin, polyurethane, or polylactic acid may be used as the layer constituting the substrate, and even resin films using these resins are less likely to cause problems such as deformation of the substrate.

[0054] The substrate 11 may be a single layer or may have a multi-layer laminate configuration. The thickness of the substrate 11 is preferably 3 to 200 μm, more preferably 10 to 140 μm, and even more preferably 30 to 115 μm. A thickness of 3 μm or more makes it easier to maintain the strength of the substrate 11, while a thickness of 200 μm or less improves conformability to the skin and shortens the liquid transport time.

[0055] The substrate 11 may also be provided with an adhesive layer 16. In this embodiment, an adhesive layer 161 is provided on the surface of the substrate 11 opposite to the surface (one side) on which the needle-shaped portion 12 is formed. The provision of this adhesive layer 161 has the advantage of facilitating adhesion of the tape to the substrate 11 or improving adhesion between the tape and the substrate 11 when a tape is laminated on the surface opposite to the one side of the substrate 11 so as to cover an analysis sheet or the like, as will be described later. The adhesive constituting such adhesive layer 161 is preferably a pressure-sensitive adhesive, and examples thereof include an acrylic adhesive, a silicone adhesive, a rubber adhesive, etc., and more preferably an acrylic adhesive.

[0056] Furthermore, by providing an adhesive layer 162 on the surface of the substrate 11 on which the needle-shaped portion 12 is formed, in the manufacturing method of the microneedle structure described below, a solid composition 31 (not shown in FIG. 1 ; described below) is preliminarily adhered to the substrate 11, and the substrate 11 and the solid composition 31 are placed in a mold and heated and pressed in the forming process, thereby easily obtaining the microneedle structure 10. When the adhesive layer 162 is provided on the substrate 11, there is a concern that a gap may be formed between the substrate 11 and the needle-shaped portion 12, causing liquid leakage, or that the adhesive layer may prevent liquid from passing between the substrate 11 and the needle-shaped portion 12. Therefore, it is preferable to provide the adhesive layer 162 so as to surround the region of the substrate 11 through which the liquid must pass, while providing a region in the center where the adhesive layer 162 is not formed. Although the microneedle structure 10 cannot be obtained in this simple manner, for example, a first primer layer (not shown) may be provided instead of the adhesive layer 162 in order to improve adhesion between the needle-shaped portion 12 and the substrate 11. Furthermore, even when the substrate 11 has the adhesive layer 162, a first primer layer may be provided as an intermediate layer between the substrate 11 and the adhesive layer 162. Examples of the primer layer include an acrylic primer layer and a polyester primer layer.

[0057] The acrylic adhesive may contain an acrylic polymer obtained by polymerizing a monomer mainly composed of an acrylic acid alkyl ester. The acrylic polymer may be a copolymer of an acrylic acid alkyl ester and another monomer. Examples of the other monomer include acrylic acid esters other than acrylic acid alkyl esters, such as acrylic acid esters having a hydroxyl group, acrylic acid esters having a carboxyl group, and acrylic acid esters having an ether group, as well as monomers other than acrylic acid esters, such as vinyl acetate and styrene.

[0058] The acrylic polymer may be one which has been crosslinked by a reaction between a crosslinking agent and a functional group derived from the above-mentioned acrylic acid ester having a hydroxyl group or acrylic acid ester having a carboxyl group.

[0059] In addition to the above components, the acrylic pressure-sensitive adhesive may contain a tackifier, a plasticizer, an antistatic agent, a filler, a curable component, etc. Furthermore, either a solvent-based or emulsion-based coating liquid can be used to obtain the acrylic pressure-sensitive adhesive.

[0060] A plurality of through holes 15 are provided in the substrate 11. In this embodiment, since the needle-shaped portion 12 and the base portion 14 have a porous structure, there is no need to align the through holes 15 with the needle-shaped portion 12. By appropriately forming the through holes 15, liquid can flow through, and the microneedle structure 10 can be easily formed. In this embodiment, the shape of the through holes 15 provided in the substrate 11 is circular when viewed from above, but this is not limited thereto and may be rectangular or the like. The through holes 15 preferably have an opening diameter sufficient to cause capillary action and are provided in plurality in the substrate 11 from the viewpoint of ensuring a sufficient amount of liquid flow. For example, when the opening shape of the through holes 15 is circular, the diameter is 2 mm or less, preferably 0.05 to 1 mm, and more preferably 0.1 to 0.8 mm. In this embodiment, when transporting liquid from the needle-shaped portion 12, the substrate 11 is liquid-impermeable, so the liquid does not seep into the substrate 11, and the liquid circulates in the thickness direction of the substrate 11 through the through holes 15. Therefore, the transport distance is short, and when configured as a detection patch, detection can be performed at a high analysis speed, and when configured as a drug administration patch, drug liquid can be administered early.

[0061] The sum of the areas of the through holes 15 (total area) is preferably 0.05 to 15% in total of the area of ​​the region on the substrate 11 where the through holes 15 are provided, more preferably 0.75 to 10%, and even more preferably 1 to 5%. When the total area of ​​the through holes 15 is 15% or less of the area of ​​the region on the substrate 11, the rigidity of the substrate 11 is easily ensured. Furthermore, when the total area of ​​the through holes 15 is 0.05% or more of the area of ​​the region on the substrate 11, body fluid can be more efficiently acquired through the substrate 11.

[0062] When the microneedle structure 10 has a base 14, the base 14 is directly bonded to one side of the substrate 11 and is integrally formed with the needle-shaped portion 12. This allows the needle-shaped portion 12 to be provided on the substrate 11 without the use of adhesive, resulting in good communication between the holes 13 and easy passage of liquid. A microneedle structure 10 having such a configuration can be obtained by adhering the solid composition 31 to the substrate 11 by heating during the formation step of the microneedle structure manufacturing method described below, or by a similar heating method, even if the substrate 11 does not have an adhesive layer 16. In this case, the composition containing the high-melting-point resin must be heated to a temperature at which it can be adhered to the substrate 11. However, in the present invention, the substrate 11 has a layer made of a heat-resistant resin, which prevents deformation or deterioration of the substrate 11 due to heating. In this embodiment, the base 14 is provided over the entire surface of the substrate 11, but this is not limited thereto. It is preferable that the base 12 be formed at least in the region where the needle-shaped portion 12 is formed. Even when the base 14 is directly adhered to one side of the substrate 11, as described above, the substrate 11 may be provided with a first primer layer instead of the adhesive layer 16, and the base 14 may be adhered to the substrate 11 via the first primer layer, or via another layer other than the adhesive layer 16 and the first primer layer.

[0063] The microneedle structure 10 formed in this manner can be used as a test patch or a drug administration patch. For example, in the test patch 2 shown in FIG. 2 , an analysis sheet 17 is placed facing the needle-shaped portion 12 at a position covering the region of the substrate 11 of the obtained microneedle structure 10 where the through-hole 15 is formed, and tape 18 is laminated to cover the analysis sheet 17. In the case of a drug administration patch, a drug administration member is placed in place of the analysis sheet 17 at the region of the substrate 11 of the obtained microneedle structure 10 where the through-hole 15 is formed, facing the needle-shaped portion 12, and tape 18 is laminated to cover the drug administration member. Even in such test patch 2 or drug administration patch, the needle-shaped portion 12 has high strength, so it can be inserted into the skin without damaging the needle-shaped portion 12, and the constituent material of the needle-shaped portion 12 can be prevented from remaining in the body, which is preferable. Note that the tape 18 that fixes the analysis sheet 17 or drug administration member to the substrate 11 may be an adhesive tape provided with an adhesive layer.

[0064] [Method for manufacturing microneedle structure]

[0065] 3 and 4 show a method for manufacturing a microneedle patch 1 according to an embodiment of the present invention. In this embodiment, a mixture 33 containing a high-melting-point resin and a water-soluble material is adhered to a substrate 11 to obtain a substrate-attached solid composition 31 (adhesion step), and then the solid composition is heated and pressurized to form protrusions 32 (formation step). Thereafter, the water-soluble material is removed from the protrusions 32 (removal step), converting the protrusions 32 into needle-like portions 12. This will be described in detail below.

[0066] (Bonding Process) The preparation of the substrate 11 and the solid composition 31 will be described first. First, a high-melting-point resin and a water-soluble material are heated, melted, and mixed to prepare a mixture 33, which is a composition containing a high-melting-point resin. In this embodiment, the high-melting-point resin is water-insoluble. When preparing the mixture 33, the mixture is preferably heated at a temperature 5°C higher than the melting point of the high-melting-point resin but not higher than 80°C, more preferably at a temperature 10°C higher than the melting point of the high-melting-point resin but not higher than 70°C, and even more preferably at a temperature 15°C higher than the melting point of the high-melting-point resin but not higher than 60°C. For example, when polylactic acid with a melting point of 170°C is used as the high-melting-point resin, the mixture is preferably heated at 175 to 250°C, more preferably at 180 to 240°C, and even more preferably at 185 to 230°C. It is preferable that the mixture 33 is in a molten state. When it is important to heat at a lower temperature, the mixture 33 may be softened to the extent that it adheres to the substrate 11. However, in consideration of shortening the manufacturing time, it is preferable to heat the mixture 33 at a temperature equal to or higher than the melting point of the high-melting-point resin at which the water-insoluble material starts to melt, as described above.

[0067] The water-soluble material is preferably one having a melting point higher than room temperature. The water-soluble material may be organic or inorganic, and examples include sodium chloride, potassium chloride, sodium sulfate, sodium carbonate, potassium nitrate, alum, sugar, and water-soluble resins. The water-soluble resin is preferably a water-soluble thermoplastic resin, preferably one having a melting point higher than room temperature. Examples of water-soluble thermoplastic resins include the biodegradable resins described below, as well as hydroxypropyl cellulose and polyvinylpyrrolidone. Taking into consideration the effects on the human body, the water-soluble thermoplastic resin is more preferably a biodegradable resin. Examples of such biodegradable resins include at least one selected from the group consisting of polyalkylene glycols such as polyethylene glycol and polypropylene glycol, polyvinyl alcohol, collagen, and mixtures thereof, with polyalkylene glycols being particularly preferred. The molecular weight of the polyalkylene glycol is preferably 200 to 4,000,000, more preferably 600 to 500,000, and particularly preferably 1,000 to 100,000. Among the polyalkylene glycols, polyethylene glycol is preferably used.

[0068] The water-soluble resin preferably has a melting point of 200°C or less, more preferably 30 to 180°C, and even more preferably 35 to 150°C. A melting point of 150°C or less has the effect of allowing the resin to be easily melted at the heating temperature used to melt the high-melting-point resin. Furthermore, in order to facilitate melting both the high-melting-point resin and the water-soluble material at the same heating temperature when preparing mixture 33, the difference between the melting points of the high-melting-point resin and the water-soluble material is preferably 40°C or less, and more preferably 30°C or less.

[0069] The water-insoluble high-melting-point resin and the water-soluble material are preferably mixed in a mass ratio of 9:1 to 1:9, more preferably 8:2 to 2:8, and particularly preferably 7:3 to 3:7. By forming the mixture 33 in this ratio, it is possible to form the needle-shaped portions 12 with the desired porosity, and it is easy to achieve both liquid permeability and strength for the needle-shaped portions 12.

[0070] The mixture 33 may contain not only the water-insoluble material and the water-soluble material as non-volatile solid components, but also other materials. For example, to further increase the strength of the needle-shaped portion, a water-insoluble material other than resin, such as silica filler, may be included.

[0071] 3(a), the mixture 33 is poured into a recess 42 for a solid composition formed in a mold (die) 41 for a solid composition (filling step). The recess 42 for a solid composition may be formed in any shape and with any volume that can store a desired amount of the mixture 33.

[0072] The material of the mold 41 for the solid composition is not particularly limited, but it is preferable that it be made of a silicone compound or the like, which makes it easy to make an accurate mold and makes it easy to peel off the solidified solid composition 31, and in this embodiment it is made of polydimethylsiloxane.

[0073] With the mixture 33 stored in the recess 42 for solid composition, a sheet 43 for solid composition made of, for example, polydimethylsiloxane (PDMS) is placed as a lid on the upper surface of the recess 42 for solid composition to flatten the surface of the resulting solid composition 31. By holding the mold 41 for solid composition at -10 to 3°C for 1 to 60 minutes, the molten mixture 33 solidifies and becomes solid. The sheet 43 for solid composition is then peeled off from the mold 41 for solid composition, and the sheet 43 for solid composition is then peeled off. This yields the solid composition 31 shown in Figure 3(b).

[0074] Next, a substrate 11 is prepared. In this embodiment, the substrate 11 has an adhesive layer 162 on the surface of the substrate 11 on which the needle-shaped portion 12 is formed. Although the adhesive layer 162 may be formed by coating or application, in this embodiment, an adhesive tape having the adhesive layer 162 in a predetermined region is used as the substrate 11. Then, a through hole 15 is formed in the substrate 11. The method for forming the through hole 15 is not particularly limited, and the through hole 15 can be formed by punching or laser drilling, for example.

[0075] 3(c), the solid composition 31 is attached to the adhesive layer 162 of the substrate 11 to integrate the substrate 11 and the solid composition 31. In this way, by having the adhesive layer 162, the solid composition 31 is adhered to the substrate 11 in advance, and the substrate 11 and the solid composition 31 are placed in a mold and heated and pressed in the forming step described below, where heating and pressing are performed, thereby easily obtaining the microneedle structure 10. Furthermore, by integrating the substrate 11 and the solid composition 31, handling, such as transportation, becomes easier.

[0076] Next, as shown in FIG. 4( a), the solid composition 31 provided with the substrate 11 is placed in the recess 51 of a mold 52 having a recess 51. A protrusion-forming recess 53 is also provided in the center of the bottom surface of the recess 51. The solid composition 31 is placed on the protrusion-forming recess 53. The protrusion-forming recess 53 is for forming the needle-like portions 12, and is formed with a shape and size corresponding to the needle-like portions 12. Then, a lid 54 of the mold 52 is placed on the other surface side (back side) of the substrate 11. This lid 54 is also made of polydimethylsiloxane.

[0077] 4(b) is performed. The forming step is for forming protrusions 32 and the like having a desired shape, and while heating and pressurizing may be performed all at once, as in the present embodiment, it is preferable that the forming step comprises a preliminary step of starting melting of the solid composition 31 provided with the substrate 11, and a main step of sufficiently filling the recesses 51 and the like with the molten solid composition 31, in order to sufficiently fill the recesses 51 and the like with the solid composition 31.

[0078] 4(b), in the preliminary step and the main step, the substrate 11 and the solid composition 31 are sandwiched between a mold 52 and a lid 54 with the solid composition 31 placed in the recess 51. Then, in this state, the mold 52 and the lid 54 are placed on a lower stage 56, and an upper stage 57 is installed on the mold 52 and the lid 54.

[0079] The heating conditions in the preliminary step and this step are preferably at a temperature 10°C higher than the melting point of the high-melting-point resin but not higher than 110°C, more preferably at a temperature 17°C higher than the melting point of the high-melting-point resin but not higher than 95°C, and even more preferably at a temperature 25°C higher than the melting point of the high-melting-point resin but not higher than 80°C. For example, when polylactic acid with a melting point of 170°C is used as the high-melting-point resin, heating is preferably carried out at 180 to 280°C, more preferably at 187 to 265°C, and even more preferably at 195 to 250°C. In this embodiment, heating is carried out at a temperature at which the solid composition 31 can melt. Note that, to heat the solid composition 31, at least one of the lower stage 56 and the upper stage 57 may be heated, or both may be heated. In this step, heating may be maintained after the preliminary step, and the temperature may be changed as appropriate.

[0080] In this state, the mold 52 is pressed (pressurized) between the upper stage 57 and the lower stage 56. The pressure in this preliminary step is preferably 0.1 to 5.0 MPa. By using a pressure in this range, the solid composition 31 can be melted in a short time, and the molten solid composition 31 can be quickly filled into the recesses 51, etc. Then, by holding the pressure for 10 seconds to 10 minutes, the solid composition 31 is in a molten state. Note that the pressurizing conditions may be different between the preliminary step and the main step. For example, in the main step, pressurization can be performed under conditions of higher pressure or for a longer time than in the preliminary step.

[0081] By carrying out the preliminary step and the main step as in this embodiment, the solid composition 31 is sufficiently melted and filled into the recesses 51 and the protrusion-forming recesses 53. Furthermore, if the resulting needle-like portion 12 or base 14 has a porous structure, the adhesion area of ​​the needle-like portion 12 or base 14 to the substrate 11 will be small, which will be detrimental to the adhesion between them. However, by undergoing heating in the formation step in a state in which the substrate 11 and the solid composition 31 are adhered, the adhesion between the needle-like portion 12 or base 14 and the substrate 11 can be improved.

[0082] Thereafter, the mold 52 is removed from the lower stage 37, and the molten solid composition 31 is refrigerated and solidified by being held at −10 to 3° C. for 1 to 60 minutes (refrigerated solidification step). As a result, protrusions 32 and the like having a highly transferable shape corresponding to the protrusion-forming recesses 53 are formed.

[0083] (Removal process) After the adhesion process is completed, the solidified protrusion 32 and the substrate 11 are separated from the mold 52 and left to stand in a liquid to remove the water-soluble material and form the needle-shaped portion 12, in a removal process.

[0084] The cleaning solution used in this removal step contains water. As shown in FIG. 4( c), in this embodiment, the removal step is performed by placing the protrusions 32 and the substrate 11 bonded together in a cleaning solution 58. By placing the protrusions 32 and the like in a cleaning solution containing water, the water-soluble material contained in the protrusions 32 and the like that is exposed to the outside or that is connected to the exposed portions dissolves and flows into the water, resulting in removal. The cleaning solution 58 may contain water, and may be, for example, a mixed solvent of water and alcohol. This removal process forms holes 13 in the protrusions 32 and the like, forming needle-shaped portions 12 composed of a water-insoluble component containing a high-melting-point resin. In addition to the needle-shaped portions 12, the water-soluble material is also removed from the molten solid composition 31 that was adhering to one side of the substrate 11 by filling the recesses 51, thereby forming the base 14 with the same porous structure. This results in the microneedle structure 10 of this embodiment. In this embodiment, the microneedle structure 10 of the first embodiment described above can be obtained.

[0085] (Method of manufacturing test patches, etc.) Although not shown, a test patch can be manufactured by placing an analysis sheet 17 at a predetermined position on the back side of the substrate 11 of the obtained microneedle structure 10 and laminating tape 18 so as to cover the analysis sheet 17 (installation step). A conventionally known lamination method can be used for the lamination method. For example, a test patch can be manufactured by placing the analysis sheet 17 on the back side of the substrate 11, and then laminating adhesive tape 18 formed on a tape substrate with a commonly used adhesive layer of a rubber-based adhesive, acrylic-based adhesive, silicone-based adhesive, or the like. Drug administration patches can also be manufactured by a similar method.

[0086] (Modification) In this embodiment, the solid composition 31 contains a water-soluble material and a high-melting-point resin. However, the solid composition 31 is not particularly limited and may contain a low-melting-point resin or a filler. In this case, the microneedle structure 10 of the second embodiment described above can be obtained. Using the solid composition 31 as in this embodiment is preferable because the composition does not contain a solvent, thereby suppressing discoloration and deformation of the substrate 11. Furthermore, in this embodiment, the bonding step may be performed immediately after the filling step and before the mixture 33 is maintained at a low temperature. That is, after filling the recess 42 with the mixture 33, the substrate and the mixture 33 may be brought into contact with each other, the mixture 33 may be solidified to form the solid composition 31, and the substrate and the solid composition 31 may be bonded together. In this case, the heat resistance of the substrate 11 is maintained even against residual heat from the filling step.

[0087] In this embodiment, the needle-shaped portion 12 is formed using a water-insoluble high-melting-point resin to easily form the hole 13 by removing the water-soluble material, but the method for producing the hole 13 is not particularly limited. For example, in the forming step, the mold 52 may be filled with a particulate high-melting-point resin or the like and sintered at a temperature equal to or higher than the melting point of the high-melting-point resin to obtain a microneedle structure having a porous structure composed of sintered particles and numerous voids formed between the particles. Even in this case, when the forming step and the bonding step are performed simultaneously, deformation and deterioration of the substrate 11 can be suppressed by providing the substrate 11 with a layer made of a heat-resistant resin.

[0088] Furthermore, in this embodiment, the solid composition 31 is formed by filling the recess 1 with the mixture 33, but this is not limiting. For example, the forming step may be a method in which a liquid composition containing a water-soluble material and a high-melting-point resin is prepared on the substrate 11 so that the viscosity is 0.1 to 1000 mPa·s, and the liquid composition is dripped onto the substrate 11 using a dispenser or the like to form the protrusions 32. The liquid composition 31 containing the high-melting-point resin is melted at a high temperature to form the protrusions 32, and even if the substrate is indirectly heated, the heat-resistant substrate 11 does not deform or soften, resulting in good workability.

[0089] Furthermore, the bonding step may be performed after the forming step. In this case, even if heating is involved when bonding the protrusions 32 etc. before the removing step or the needle-like portions 12 etc. after the removing step to the substrate 11, the substrate 11, which has heat resistance, is not deformed or softened, and workability is good.

[0090] The present invention will be described in more detail below with reference to examples.

[0091] [Examples] (Example 1-1) 3 g of polyethylene glycol (PEG) (weight average molecular weight 4,000, melting point 40°C) and 7 g of polycaprolactone (PCL) (weight average molecular weight 10,000) as water-soluble materials were heated to 110°C and stirred with a stirrer. Furthermore, 0.5 g of ARBOCEL Natural Cellulose Fibers (average fiber length: 45 μm, manufactured by Rettenmeyer Japan, containing 10% by mass of ignition residue at 850°C for 4 hours other than cellulose fibers) was added and stirred again. This resulted in preparation of mixture 33. A mold 42 for a solid composition made of polydimethylsiloxane was prepared, and a recess 42 with a square opening measuring 15 mm x 15 mm and a depth of 1.5 mm was formed in this mold 41 for a solid composition. The mixture 33 was poured into the recess 42 of the mold 41 for the solid composition so as to fill it.

[0092] A polydimethylsiloxane solid composition sheet 43 was used as a lid and placed on a solid composition mold 41 into which the mixture 33 had been poured, flattening the surface of the solid composition 31. This state was maintained at 3°C ​​for 5 minutes, during which the molten mixture 33 solidified and became solid. The mold was then separated from the solid composition mold 41, yielding a solid composition 31. Next, the adhesive layer 16 of the substrate 11, which was an adhesive tape (a polyethylene terephthalate (PET) substrate (100 μm thick) with an acrylic adhesive layer (25 μm thick) formed on it), was attached to one side of the solid composition 31, resulting in a solid composition 31 provided with the substrate 11.

[0093] To carry out the forming step, a mold 52 having protrusion-forming recesses 53 was prepared. The mold 52 was made of polydimethylsiloxane, and the protrusion-forming recesses 53 were formed on its surface having recesses 51 as detailed below. - Shape of the protrusion-forming recesses: quadrangular pyramid shape with a square cross section - Length of one side of the largest cross section of the protrusion-forming recesses: 500 μm - Height of the protrusion-forming recesses: 900 μm - Pitch of the protrusion-forming recesses: 1000 μm - Number of protrusion-forming recesses: 13 columns x 13 rows, totaling 169 - Size of the area where the protrusion-forming recesses were formed: 15 mm square - Arrangement of the protrusion-forming recesses: square lattice

[0094] The mold 52 was placed on the lower stage 56 of a heating press (manufactured by AS ONE Corporation, AH-1T), and the solid composition 31 with the substrate 11 was placed on the mold 52 so that it faced the recess 51. A 30 mm square polydimethylsiloxane sheet (lid 54) was then placed on top of the mold 52. The heating press was set at a lower stage temperature of 100 ° C. and an upper stage temperature of 90 ° C., and the preparatory step was performed by pressing at 2 MPa for 1 minute and 30 seconds. Thereafter, the temperature of the heating press was maintained and the heated state was maintained, and the main step was performed by pressing at 4 MPa for 30 seconds. The substrate 11 and the molten composition contained in the lid 54 and mold 52 were then stored in a refrigerator at 3 ° C. for 5 minutes to solidify the composition, and protrusions 32 and the like were formed. Thereafter, the substrate 11 was peeled from the mold 52, and the substrate 11 and the formed protrusions 32 and the like were immersed in purified water at 23 ° C. for 24 hours to dissolve and remove the water-soluble material. Thereafter, the substrate 11 and the molded solid composition 31 were left to stand in a drying oven (30° C.) for 5 hours to evaporate the water and dry, thereby obtaining a microneedle structure 10 .

[0095] Example 1-2 A microneedle structure 10 was obtained in the same manner as in Example 1, except that 2.0 g of ARBOCEL Natural Cellulose Fibers was added as a filler.

[0096] (Example 1-3) A microneedle structure 10 was obtained in the same manner as in Example 1, except that 0.5 g of ARBOCEL Ultrafine Cellulose (average particle size: 6-12 μm, manufactured by Rettenmeyer Japan Co., Ltd.) was added as a filler instead of ARBOCEL Natural Cellulose Fibers.

[0097] (Example 1-4) A microneedle structure 10 was obtained in the same manner as in Example 1, except that 2.0 g of ARBOCEL Ultrafine Cellulose (average particle size: 6-12 μm, manufactured by Rettenmeyer Japan Co., Ltd.) was added as a filler instead of ARBOCEL Natural Cellulose Fibers.

[0098] (Example 1-5) A microneedle structure 10 was obtained in the same manner as in Example 1, except that 0.5 g of lactic acid polymer (PLA) particles (glass transition temperature: 60 ° C., irregular shape, average particle size: 53.4 μm) was added instead of ARBOCEL Natural Cellulose Fibers as a filler.

[0099] (Example 1-6) A microneedle structure 10 was obtained in the same manner as in Example 1, except that 0.5 g of Techpolymer SSX (manufactured by Sekisui Chemical Co., Ltd., spherical cross-linked polymethyl methacrylate (PMMA) microparticles, glass transition temperature of PMMA: 100 ° C., particle diameter: 1.5 μm) was added instead of ARBOCEL Natural Cellulose Fibers as a filler.

[0100] Comparative Example 1-1 A microneedle structure was obtained in the same manner as in Example 1, except that ARBOCEL Natural Cellulose Fibers was not added as a filler.

[0101] The microneedle structures obtained in Examples 1-1 to 1-6 and Comparative Example 1-1 were subjected to the following evaluation of microneedle array transferability and microneedle tip strength.

[0102] (Microneedle array transferability evaluation) In each example and comparative example, protrusions were formed by cooling the composition, and after peeling from the mold, the protrusions were observed under an optical microscope (magnification: 50x and 100x) before being immersed in purified water, and the number of protrusions remaining on the substrate was counted. The ratio of this remaining number to the total number of protrusions in the design was calculated to obtain the transfer rate. When the transfer rate was 50% or more and 100% or less, it was evaluated as "A", and when it was 0% or more and less than 50%, it was evaluated as "B".

[0103] (Microneedle Tip Strength Evaluation) The microneedle structures obtained in the examples and comparative examples were placed on a stage with the needle-shaped portion facing upward, observed under a microscope, and one needle-shaped body with a sharp tip shape was selected. The attachment (made of iron, 2 mmφ) of the measuring instrument (digital force gauge (manufactured by Imada Co., Ltd.)) was brought close to the needle-shaped portion, taking care not to let the attachment come into contact with the adjacent needle-shaped portion. The attachment was moved up and down to a position where it contacted the tip of the needle-shaped portion but no force was applied to the needle-shaped portion, and then raised 0.1 mm from there. The attachment was lowered at a descent rate of 5 mm / min to start measuring the force applied to the attachment (measurement range: 1 to 5000 mN). At this time, the measurement temperature was 23 ° C. and the relative humidity was 50%. On the graph outputting the measured force, when a decrease in force was first observed, the maximum force value shown at the position before the decrease in force was read, or if no decrease in force was observed before the attachment's descent distance reached 100 μm, the force value at the time the attachment's descent distance reached 100 μm was read, and this value was taken as the tip strength of the needle-like portion. If the tip strength was 60 mN or greater, it was evaluated as "A." If the tip strength was less than 60 mN and 40 mN or greater, it was evaluated as "B." If the tip strength was less than 40 mN, it was evaluated as "C." In the transferability evaluation, for examples or comparative examples in which the transfer rate was less than 100%, one needle-like portion that remained on the substrate without falling off was selected and evaluated. In Examples 1-1 to 1-6 and Comparative Example 1-1, a decrease in force was observed before the attachment's descent distance reached 100 μm.

[0104] The evaluation results are shown in Table 1. (Table 1)

[0105] As shown in Table 1, in Comparative Example 1-1, the microneedle tip strength was evaluated as less than 40 mN, resulting in a rating of C, but in Examples 1-1 to 1-6, the rating was A or B, and the strength was further increased by the inclusion of filler. In Examples 1-1 to 1-6, the microneedle array transferability rating was A or B, but in Examples 1-1 to 1-5, the adhesiveness at the interface between the resin and filler constituting the needle-shaped portion 12 was high, and the resin and filler were well compatible, resulting in high transferability.

[0106] In Examples 2-1, 2-2, and Comparative Example 2-1, the weight-average molecular weight (Mw) was measured using gel permeation chromatography (GPC) under the following conditions (GPC measurement) and was calculated using a polystyrene standard. Samples for GPC measurement were prepared as follows: First, 1 g of the polycaprolactone (PCL) used in the Examples and Comparative Examples and 9 g of tetrahydrofuran (THF, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a screw tube, shaken, and completely dissolved to prepare a 10% PCL solution. Furthermore, 1 ml of the resulting solution and 9 ml of THF were added dropwise to a separately prepared screw tube to prepare a 1% PCL solution. This 1% PCL solution was filtered through a GD / X syringe filter (manufactured by Whatman) and added dropwise to the GPC apparatus. (Measurement conditions) Measurement device: HLC-8320, manufactured by Tosoh Corporation GPC columns (passed in the following order): TSK gel super H-H, TSK gel super HM-H, TSK gel super H2000, manufactured by Tosoh Corporation Measurement solvent: tetrahydrofuran Measurement temperature: 40°C

[0107] Example 2-1: 3 g of polyethylene glycol (PEG) (weight average molecular weight: 4,000) and 7 g of pelletized polycaprolactone (weight average molecular weight: 80,000) as water-soluble materials were heated and kneaded at 170°C in a Laboplastomill 4C150 (Toyo Seiki Seisakusho, Ltd.). Thus, a mixture 33 was prepared. A mold 42 for a solid composition made of polydimethylsiloxane was prepared, and a recess 42 with a square opening measuring 15 mm x 15 mm and a depth of 1.5 mm was formed in the mold 41 for a solid composition. The mixture 33 was poured into the mold 41 for a solid composition so as to fill the recess 42.

[0108] A solid composition mold lid (a sheet made of polydimethylsiloxane) 43 was placed on the solid composition mold 41, and the surface of the solid composition 31 was flattened. This state was maintained at 3°C ​​for 5 minutes, and the molten mixture 33 solidified into a solid form. The solid composition 31 was then separated from the solid composition mold 41, yielding a solid composition 31. Next, the adhesive layer of the substrate 11, which was adhesive tape (a PET substrate (100 μm thick) with an acrylic adhesive layer (25 μm thick) formed on it), was adhered to the solid composition 31. This yielded a solid composition 31 equipped with the substrate 11.

[0109] To carry out the forming step, a mold 52 having protrusion-forming recesses 53 was prepared. The mold 52 was made of polydimethylsiloxane, and the protrusion-forming recesses 53 were formed on its surface having recesses 51 as detailed below. - Shape of the protrusion-forming recesses: quadrangular pyramid shape with a square cross section - Length of one side of the largest cross section of the protrusion-forming recesses: 500 μm - Height of the protrusion-forming recesses: 900 μm - Pitch of the protrusion-forming recesses: 1000 μm - Number of protrusion-forming recesses: 13 columns x 13 rows, totaling 169 - Size of the area where the protrusion-forming recesses were formed: 15 mm square - Arrangement of the protrusion-forming recesses: square lattice

[0110] The mold 52 was placed on the lower stage 56 of a heating press (manufactured by AS ONE Corporation, AH-1T), and the solid composition 31 with the substrate 11 was placed on the mold 52 so that it faced the recess 51. A 30 mm square polydimethylsiloxane sheet (lid 54) was then placed on top of the mold 52. The heating press was set at a lower stage temperature of 140 ° C. and an upper stage temperature of 140 ° C., and the preparatory step was performed by pressing at 2 MPa for 3 minutes. Thereafter, the temperature of the heating press was maintained, and the heated state was pressed at 4 MPa for 30 seconds to perform the main step. The substrate 11 and the molten composition contained in the lid 54 and mold 52 were then stored in a refrigerator at 3 ° C. for 5 minutes to solidify the composition, and protrusions 32 and the like were formed. Thereafter, the substrate 11 was peeled from the mold 52, and the substrate 11 and the formed protrusions 32 and the like were immersed in purified water at 23 ° C. for 24 hours to dissolve and remove the water-soluble material. Thereafter, the substrate 11 and the molded solid composition 31 were left to stand in a drying oven (30° C.) for 5 hours to evaporate the water and dry, thereby obtaining a microneedle structure 10 .

[0111] (Example 2-2) As the resin constituting the needle-shaped portion 12, 7 g of pellet-shaped polycaprolactone (weight average molecular weight 40,000) having a different molecular weight from that of Example 1 was used, and the temperature of the heating process in the formation process was set to 110°C in both cases, but the microneedle structure 10 was obtained in the same manner as Example 1.

[0112] (Comparative Example 2-1) A microneedle structure was obtained in the same manner as in Example 1, except that 7 g of pellet-shaped polycaprolactone (weight average molecular weight 10,000) with a different molecular weight from that in Example 1 was used as the resin constituting the needle-shaped portion, the temperature of the heating step in the forming process was 110°C in all cases, and the pressurization time in the preliminary step was 1 minute 30 seconds.

[0113] The microneedle structures obtained in Examples 2-1 and 2-2 and Comparative Example 2-1 were subjected to the following evaluation of microneedle array transferability and microneedle tip strength.

[0114] (Microneedle array transferability evaluation) In each example and comparative example, protrusions were formed by cooling the composition, and after peeling from the mold, the protrusions were observed under an optical microscope (magnification: 50x and 100x) before being immersed in purified water, and the number of protrusions remaining on the substrate was counted. The ratio of this remaining number to the total number of protrusions in the design was calculated to obtain the transfer rate. When the transfer rate was 50% or more and 100% or less, it was evaluated as "A", and when it was 0% or more and less than 50%, it was evaluated as "B".

[0115] (Microneedle Tip Strength Evaluation) The microneedle structures obtained in the examples and comparative examples were placed on a stage with the needle-shaped portion facing upward, observed under a microscope, and one needle-shaped body with a sharp tip shape was selected. The attachment (made of iron, 2 mmφ) of the measuring instrument (digital force gauge (manufactured by Imada Co., Ltd.)) was brought close to the needle-shaped portion, taking care not to let the attachment come into contact with the adjacent needle-shaped portion. The attachment was moved up and down to a position where it contacted the tip of the needle-shaped portion but no force was applied to the needle-shaped portion, and then raised 0.1 mm from there. The attachment was lowered at a descent rate of 5 mm / min to start measuring the force applied to the attachment (measurement range: 1 to 5000 mN). At this time, the measurement temperature was 23 ° C. and the relative humidity was 50%. On the graph outputting the measured force, when a decrease in force was first observed, the maximum force value indicated at the position before the decrease in force was read. Alternatively, if no decrease in force was observed before the attachment's descent distance reached 100 μm, the force value at the time the attachment's descent distance reached 100 μm was read, and this value was taken as the tip strength of the needle-like portion. If the tip strength exceeded 200 mN, it was evaluated as "A," if the tip strength was 100 to 200 mN, it was evaluated as "B," and if the tip strength was less than 100 mN, it was evaluated as "C." In the transferability evaluation, for Examples or Comparative Examples in which the transfer rate was less than 100%, one needle-like portion that remained on the substrate without falling off was selected and evaluated. In Examples 2-1 and 2-2, no decrease in force was observed until the attachment's descent distance reached 100 μm. On the other hand, in Comparative Example 2-1, a decrease in force was observed before the attachment's descent distance reached 100 μm.

[0116] The evaluation results are shown in Table 2. (Table 2)

[0117] As shown in Table 2, in Examples 2-1 and 2-2 and Comparative Example 2-1, the microneedle array transferability evaluation was A. On the other hand, as shown in Table 2, in Comparative Example 2-1, the microneedle tip strength evaluation was C, as the microneedle tip strength was less than 40 mN. This shows that the strength of the needle-shaped portion 12 was greatest when a low-melting point resin with a high molecular weight (weight average molecular weight of 40,000 or more) was used.

[0118] Example 3-1 A mixture was prepared by heating 100 parts by weight of polyethylene glycol (molecular weight 4,000, melting point 40°C) as a water-soluble material and 100 parts by weight of polylactic acid (melting point 170°C) as a high-melting point material to 190°C while stirring with a stirrer to melt and mix them. A mold 42 for a solid composition made of polydimethylsiloxane was prepared, and this mold 41 for a solid composition had a recess 42 with a square opening measuring 15 mm x 15 mm on each side and a depth of 1.5 mm formed in it. A mixture 33 was poured into this mold 41 for a solid composition so as to fill the recess 42.

[0119] Next, a solid composition sheet 43 made of polydimethylsiloxane was used as a lid and placed on the mold 41 for solid composition into which the mixture 33 had been poured, to flatten the surface of the solid composition 31. This state was maintained at 3°C ​​for 5 minutes, and the molten mixture 33 solidified into a solid form, and then the mold 41 for solid composition was removed to obtain the solid composition 31.

[0120] Next, the adhesive layer 162 of the substrate 11, which was an adhesive sheet having a 25 μm thick adhesive layer 162 made of an acrylic adhesive on a polyimide film (PI, manufactured by DuPont-Toray Co., Ltd., product name: Kapton, thickness: 25 μm), was attached to one side of the solid composition 31. In this way, a solid composition 31 equipped with the substrate 11 was obtained.

[0121] To carry out the forming step, a mold 52 having protrusion-forming recesses 53 was prepared. The mold 52 was made of polydimethylsiloxane, and the protrusion-forming recesses 53 were formed on its surface having recesses 51 as detailed below. - Shape of the protrusion-forming recesses: quadrangular pyramid shape with a square cross section - Length of one side of the largest cross section of the protrusion-forming recesses: 500 μm - Height of the protrusion-forming recesses: 900 μm - Pitch of the protrusion-forming recesses: 1000 μm - Number of protrusion-forming recesses: 13 columns x 13 rows, totaling 169 - Size of the area where the protrusion-forming recesses were formed: 15 mm square - Arrangement of the protrusion-forming recesses: square lattice

[0122] The mold 52 was placed on the lower stage 56 of a heating press (AH-1T, manufactured by AS ONE Corporation), and the substrate-attached solid composition 31 was placed on the mold 52 so that it faced the recess 51. A 30 mm square polydimethylsiloxane sheet (lid 54) was then placed on top of the mold 52. A preliminary step was performed in which only the lower stage of the heating press was heated at a set heating temperature of 230°C and pressed at 2 MPa for 3 minutes. Thereafter, the main step was performed in which only the lower stage of the heating press was heated at 230°C and pressed at 4 MPa for 30 seconds. Furthermore, the substrate 11 and the molten composition contained in the lid 54 and mold 52 were stored in a refrigerator at 3°C ​​for 5 minutes to solidify the composition, and protrusions 32 and the like were formed. Thereafter, the substrate 11 was peeled from the mold 52, and the substrate 11 and composition were immersed in purified water at 23°C for 24 hours to dissolve and remove the water-soluble material. Thereafter, the substrate 11 and the molded solid composition 31 were left to stand for 24 hours in an environment of 23° C. and 50% relative humidity to evaporate the water and dry, thereby obtaining a microneedle structure 10 .

[0123] (Reference Example 3-1) A microneedle structure was prepared in the same manner as in Example 1, except that instead of the adhesive sheet of Example 1, an adhesive sheet having an adhesive layer made of a 25 μm thick acrylic adhesive on a polyethylene terephthalate (PET) film was used.

[0124] (Comparative Example 3-1) In this comparative example, instead of the high-melting-point resin polylactic acid used in Example 1, a needle-shaped portion was formed using a low-melting-point resin polycaprolactone (melting point 60°C), and instead of the adhesive sheet used in Example 1, an adhesive sheet was used in which an adhesive layer made of a 25 μm thick acrylic adhesive was provided on a polyethylene terephthalate (PET) film. Furthermore, a microneedle structure was produced in the same manner as in Example 1, except that the heating temperatures in the adhesion step and the formation step were changed as follows: Heating temperature when preparing the mixture in the adhesion step: 100°C Lower stage temperature, pressure and time in the preliminary step in the formation step: 110°C, 2 MPa, 3 minutes Lower stage temperature, pressure and time in the main step in the formation step: 110°C, 4 MPa, 30 seconds

[0125] The microneedle structures obtained in Example 1 and Comparative Examples 1 and 2 were subjected to the following evaluation of microneedle array transferability, microneedle tip strength, and substrate deformation.

[0126] (Microneedle array transferability evaluation) In each example and comparative example, protrusions were formed by cooling the composition, and after peeling from the mold, the protrusions were observed under an optical microscope (magnification: 50x and 100x) before being immersed in purified water, and the number of protrusions remaining on the substrate was counted. The ratio of this remaining number to the total number of protrusions in the design was calculated to obtain the transfer rate. When the transfer rate was 50% or more and 100% or less, it was evaluated as "A", and when it was 0% or more and less than 50%, it was evaluated as "B".

[0127] (Microneedle Tip Strength Evaluation) The microneedle structures of the Examples and Comparative Examples were placed on a stage with the needle-shaped portion facing upward, observed under a microscope, and one needle-shaped body with a sharp tip shape was selected. The attachment (made of iron, 2 mmφ) of the measuring instrument (digital force gauge (manufactured by Imada Co., Ltd.)) was brought close to the needle-shaped portion, taking care not to let the attachment come into contact with the adjacent needle-shaped portion. The attachment was moved up and down to a position where it contacted the tip of the needle-shaped portion but no force was applied to the needle-shaped portion, and then raised 0.1 mm from there. The attachment was lowered at a descent rate of 5 mm / min to start measuring the force applied to the attachment (measurement range: 1 to 5000 mN). At this time, the measurement temperature was 23 ° C. and the relative humidity was 50%. On the graph outputting the measured force, when a decrease in force was first observed, the maximum force value shown at the position before the decrease in force was read, or if no decrease in force was observed before the attachment had fallen to a distance of 100 μm, the force value at the time the attachment had fallen to a distance of 100 μm was read, and this value was taken as the tip strength of the needle-like portion. When this tip strength was 40 mN or more, it was evaluated as "A," and when it was less than 40 mN, it was evaluated as "B." In the transferability evaluation, for Examples or Comparative Examples in which the transfer rate was less than 100%, one needle-like portion that had not fallen off the substrate was selected and evaluated.

[0128] (Evaluation of deformation of substrate) The shape of the substrate of the obtained microneedle structure was visually observed. If the substrate did not shrink, melt, bend, or discolor, it was rated as "A", and if at least one of shrinkage, melting, bending, and discoloration of the substrate was observed, it was rated as "B".

[0129] The evaluation results are shown in Table 3. (Table 3)

[0130] As shown in Table 3, in Example 3-1, the tip strength of the needle-shaped portion was 40 mN or more, and the deformation of the substrate was also evaluated as A, whereas in Reference Example 3-1, the deformation of the substrate was evaluated as B, and the microneedle structure of Comparative Example 3-1 was unable to achieve a tip strength of the needle-shaped portion of 40 mN or more.

[0131] The microneedle structure of the present invention can be used as a test patch, for example, by placing an analysis sheet on the back side and laminating it with tape.

[0132] REFERENCE SIGNS LIST 10 Microneedle structure 11 Substrate 12 Needle-shaped portion 13 Hole portion 14 Base portion 15 Through-hole 16 Adhesive layer 31 Solid composition 32 Projection portion 33 Mixture

Claims

1. A microneedle structure comprising a needle-shaped portion having a hole formed therein and a substrate having the needle-shaped portion on one side thereof, wherein a porous structure is formed in the needle-shaped portion, and the needle-shaped portion has a tip strength of 40 mN or more as measured by the following evaluation method. Evaluation method: The microneedle structure was placed on a stage with the needle-shaped part facing upward and observed under a microscope. One needle-shaped body with a sharp tip was selected and aligned with the position of the needle-shaped part. The attachment of the digital force gauge (made of iron, 2 mm diameter) was lowered at a rate of 5 mm / min to measure the force applied to the attachment (measurement environment temperature: 23°C, measurement environment relative humidity: 50%). On the graph outputting the measured forces, when a decrease in force was first observed, the maximum force value indicated at the position before the decrease in force was read, or if no decrease in force was observed before the attachment had been lowered 100 μm, the force value at the time the attachment had been lowered 100 μm was read, and this value was taken as the tip strength of the needle-shaped part.

2. The microneedle structure according to claim 1, wherein the hole opens on the side surface of the needle-shaped portion.

3. The microneedle structure according to claim 1, characterized in that the needle-shaped portion contains a high-melting-point resin having a melting point exceeding 130°C, and the base material includes a layer containing a heat-resistant resin and is capable of passing a liquid in the thickness direction.

4. The microneedle structure according to claim 3, wherein the high-melting-point resin is a water-insoluble resin.

5. The microneedle structure according to claim 3, wherein the high-melting-point resin is a biodegradable resin.

6. The microneedle structure according to claim 3, wherein the high-melting-point resin is a copolymer of at least one monomer selected from polylactic acid and polyglycolic acid with another monomer.

7. The microneedle structure described in claim 3, characterized in that the layer containing the heat-resistant resin contains at least one heat-resistant organic polymer selected from polymethyl methacrylate, polystyrene, polyacrylonitrile, polyphenylene oxide, polyethylene naphthalate, polyphenylene sulfide, polytetrafluoroethylene, polycarbonate, allyl resin, polyether ether ketone, acetyl cellulose resin, polysulfone, polyethersulfone, polyimide, and polyamideimide, a copolymer obtained by copolymerizing a monomer that is a raw material for the heat-resistant organic polymer with any other monomer, or a silicone resin.

8. The microneedle structure according to claim 3, wherein the substrate and the needle-shaped portion are directly bonded via a base portion made of the same material as the needle-shaped portion.

9. The microneedle structure according to claim 1, wherein the needle-shaped portion contains a low-melting-point resin having a melting point of 130°C or less.

10. The microneedle structure according to claim 1, wherein the needle-shaped portion contains a high-melting point resin and a low-melting point resin having a melting point of 130°C or less.

11. A method for manufacturing a microneedle structure comprising a needle-shaped portion having a hole formed therein and a substrate having the needle-shaped portion on one side thereof, the method comprising a forming step of heating a composition containing a high-melting point resin having a melting point exceeding 130°C and forming protrusions on the substrate using the composition.

12. A method for manufacturing a microneedle structure as described in claim 11, characterized in that the high-melting point resin is a water-insoluble resin, the composition is a mixture containing the water-insoluble resin and a water-soluble material, and after the formation process, a removal process is performed in which the water-soluble material in the formed protrusions is removed with a solution containing water to form holes in the protrusions.

13. A method for manufacturing a microneedle structure comprising a needle-shaped portion having a hole formed therein and a substrate having the needle-shaped portion on one side thereof, the method comprising a bonding step of heating a composition containing a high-melting point resin having a melting point of more than 130°C and bonding the heated composition to the substrate.

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