Microneedle structure

Abstract

The microneedle structure 10 of the present invention is provided with a needle-shaped part 12 having a pore portion 13 formed therein, wherein the needle-shaped part 12 contains a low melting point resin having a weight-average molecular weight of 25,000 or more and a melting point of 130°C or less. Such a microneedle structure can be configured to have a needle-shaped part having high strength.

Description

Microneedle structure

[0001] The present invention relates to 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 upon 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 is not strong enough and breaks. Furthermore, if the needle-shaped portion of the microneedle has low strength, it may break when puncturing the skin, which may reduce the efficiency of drug delivery, etc.

[0005] The present invention has been made in view of the above circumstances, and has an object to provide a microneedle structure having a needle-like portion with high strength.

[0006] In order to achieve the above-mentioned object, first, the present invention provides a microneedle structure having a needle-shaped portion with a hole formed therein, characterized in that the needle-shaped portion contains a low-melting point resin having a weight-average molecular weight of 25,000 or more and a melting point of 130°C or less (Invention 1).

[0007] In the above invention (Invention 1), the needle-shaped portion contains a low-melting-point resin having a weight-average molecular weight of 25,000 or more and a melting point of 130°C or less, thereby maintaining sufficient strength. That is, if the needle-shaped portion has a structure in which multiple holes are opened on its side, it is possible to increase the rate at which fluid is absorbed or released from the needle-shaped portion compared to a structure in which holes are opened only at the top of the needle-shaped portion, but the needle-shaped portion may become brittle and lack sufficient strength. However, in the present invention, the needle-shaped portion contains a low-melting-point resin having a weight-average molecular weight of 25,000 or more and a melting point of 130°C or less, thereby increasing strength and preventing breakage of the needle-shaped portion, for example, when piercing the skin.

[0008] In the above invention (Invention 1), the needle-shaped portion preferably contains a water-insoluble hydrophilic resin (Invention 2).

[0009] In the above invention (Invention 1), the water-insoluble hydrophilic resin is preferably a water-insoluble polysaccharide (Invention 3).

[0010] In the above inventions (Inventions 1 to 3), it is preferable that the needle-shaped portion has a porous structure (Invention 4).

[0011] In the above invention (Invention 4), it is preferable that the needle-shaped portion has a base and the water absorption rate of the needle-shaped portion, measured by the following test method when the needle-shaped portion is composed only of the porous structure, is 8.5% or more (Invention 5). (Test Method) The needle-shaped portion is immersed in 10 ml of purified water at 25°C. The immersed needle-shaped portion is placed in a reduced pressure environment of 0.09 MPa for 1 hour to allow water to penetrate into the porous structure. The needle-shaped portion is then removed from the water bath and water droplets adhering to the surface are removed. Water droplets on the surface of the needle-shaped portion where the needle-shaped portion is formed are removed by blowing them off with an air blow gun. Water droplets on the surface of the needle-shaped portion near the base are removed by placing the base on a glass plate and allowing the weight of the needle-shaped portion to push the water droplets around the base. After leaving it to stand for 5 seconds, the needle-shaped portion is removed from the glass plate. The weight of the sample after water absorption is then measured. Then, the water absorption rate (the ratio of absorbed water to the sample's own weight) is calculated using the following formula: Water absorption rate (%) = (sample weight after water absorption - sample weight before water absorption) / sample weight before water absorption x 100

[0012] In the above invention (Invention 1), the needle-shaped portion preferably contains a filler (Invention 6).

[0013] 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;

[0014] Hereinafter, embodiments of the present invention will be described. [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 predetermined intervals on one side of a substrate 11. Each of the needle-shaped portions 12 has a plurality of holes 13 formed therein. The substrate 11 has through-holes 15 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 of 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 of the substrate 11 and the needle-shaped portions 12. In the present invention, body fluid includes blood, lymph, interstitial fluid, etc.

[0015] (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.

[0016] The needle-shaped portion 12 is made of resin. In this embodiment, the resin constituting the needle-shaped portion 12 is a low-melting-point resin having a weight-average molecular weight of 25,000 or more, i.e., a high-molecular-weight low-melting-point resin. The low-melting-point resin is a thermoplastic resin that is solid at room temperature and has a melting point of 130°C or less. As a low-melting-point resin, a material with a melting point of 40 to 120°C is particularly preferred, and a material with a melting point of 45 to 100°C is most preferred. 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 heating at high temperatures, resulting in low cost and good workability. Furthermore, even if the resin is adhered to the substrate 11 in a molten state or the resin is heated while the resin and the substrate are adhered, the substrate 11 will not soften, deform, or burn, allowing for 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.

[0017] The weight-average molecular weight of the low-melting-point resin is 25,000 or more, preferably 40,000 to 200,000, and more preferably 60,000 to 150,000. This range allows the needle-shaped portion 12 to maintain the necessary strength. Furthermore, a weight-average molecular weight of 25,000 or more of the low-melting-point resin improves the water absorption of the needle-shaped portion 12. While the reason for this is not entirely clear, it is presumed that the use of a high-molecular-weight low-melting-point resin results in a different structure of the pores 13 of the needle-shaped portion 12 than when a low-molecular-weight low-melting-point resin is used. Furthermore, when the low-melting-point resin has a weight-average molecular weight of 60,000 or more, the water absorption of the needle-shaped portion 12 can be further improved when the needle-shaped portion 12 contains a water-insoluble hydrophilic resin, as described below.

[0018] The tip strength of the needle-shaped portion 12 obtained by containing a high molecular weight, low-melting point resin in this way is usually 100 mN or more, preferably 150 mN or more, and more preferably 200 mN or more. Having a tip strength of 100 mN or more highly prevents the needle-shaped portion 12 from chipping even when puncturing the skin, and the microneedle structure 10 can be used, for example, as a test patch. The tip strength of the needle-shaped portion 12 is a value measured by the procedure described in the Examples below.

[0019] As will be described later, 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, but the needle-shaped portion 12 becomes brittle and is prone to losing strength. However, in this embodiment, the needle-shaped portion 12 is formed using a low-melting-point resin whose weight-average molecular weight is 25,000 or more, which increases the strength of the needle-shaped portion 12, particularly the strength of the tip of the needle-shaped portion 12, and can prevent the needle-shaped portion 12 from breaking when, for example, the needle-shaped portion 12 is pierced into the skin.

[0020] The high-molecular-weight, low-melting-point resin constituting the needle-shaped portion 12 may further be a water-insoluble resin. Being water-insoluble prevents dissolution in water-containing fluids, such as body fluids, when applied to a living body, allowing the microneedle structure 10 to maintain its shape for the desired application time. Furthermore, as described below, it is possible to easily form minute holes 13. Examples of water-insoluble resins include polyolefin resins such as polyethylene and α-olefin copolymers, olefin copolymer resins such as ethylene-vinyl acetate copolymer resins, polyurethane elastomers, and acrylic copolymer resins such as ethylene-ethyl acrylate copolymers. In order to reduce solubility in water, it is preferable that the water-insoluble, low-melting-point resin does not have hydrophilic functional groups, such as hydroxyl groups, carboxyl groups, sulfonic acid groups, amine groups, or acetamide groups, except at the ends.

[0021] Furthermore, the high-molecular-weight, low-melting-point resin that constitutes the needle-shaped portion 12 may be a biodegradable resin. Here, biodegradable resins are those that are eventually decomposed into CO2 by the action of microorganisms present in nature after use. ２It is a plastic that completely decomposes into carbon and water, and by being a biodegradable resin, its impact on living organisms can be reduced. 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 composed of two or more monomers. Furthermore, polybutylene succinate (melting point: 84-115°C) and aliphatic aromatic copolyesters (melting point: 110-120°C) can also be used as low-melting 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.

[0022] 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.

[0023] From the viewpoint of efficiently obtaining the effect of enabling resin processing at low temperatures, 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% by mass or more, more preferably 65% ​​by mass or more, and even more preferably 80% by mass or more. The needle-shaped portion 12 may further contain a high-melting-point resin having a melting point higher than 130°C, as long as it does not impair the effect of enabling resin processing at low temperatures. Examples of high-melting-point resins include biodegradable resins such as polyglycolic acid (melting point: 218°C), polylactic acid (melting point: 170°C), and polyhydroxybutyric acid (melting point: 175°C).

[0024] Most preferably, the resin constituting the needle-shaped portion 12 is a water-insoluble, high-molecular-weight, low-melting-point resin that is also biodegradable, and includes polycaprolactone or a copolymer of caprolactone and another polymer, in which the acid dissociation constant of the monomer is 4 or greater.

[0025] The needle-shaped portion 12 preferably contains a water-insoluble hydrophilic resin from the viewpoint of improving the water absorption of the needle-shaped portion 12. The water-insoluble hydrophilic resin is a polymeric substance that is insoluble in water and has hydrophilic functional groups. Because the water-insoluble hydrophilic resin is insoluble in water, it is not dissolved by water-containing fluids such as body fluids when applied to a living body, and is able to maintain the shape of the microneedle structure 10 for the desired application time. Furthermore, by containing a water-insoluble hydrophilic resin, it is possible to easily form minute holes 13 in the needle-shaped portion 12, as described below. Examples of hydrophilic functional groups include hydroxyl groups, carboxyl groups, sulfonic acid groups, amine groups, acetamide groups, etc., with hydroxyl groups and carboxyl groups being preferred. The water-insoluble hydrophilic resin preferably has a hydrophilic functional group in the main chain or side chain. Note that the carboxyl group may be in the form of a carboxylate in the presence of a counterion such as a metal ion.

[0026] The water-insoluble hydrophilic resin may be a resin having both a repeating unit having a hydrophilic functional group and a repeating unit not having a hydrophilic functional group. In this case, however, it is preferable that the mass of the repeating unit having the hydrophilic functional group accounts for more than half of the mass of the resin. More preferably, the water-insoluble hydrophilic resin includes a resin in which all repeating units have a hydrophilic functional group.

[0027] The equivalent weight of the hydrophilic functional group in the water-insoluble hydrophilic resin is, for example, 1500 or less, preferably 1100 or less, more preferably 900 or less, and even more preferably 500 or less.

[0028] Examples of the water-insoluble hydrophilic resin include fully saponified polyvinyl alcohol, water-insoluble polysaccharides such as cellulose, calcium alginate, chitin, cross-linked hyaluronic acid, etc. Among these, water-insoluble polysaccharides, which are biologically derived substances, are preferred from the viewpoint of affinity with living bodies, and cellulose is preferred from the viewpoint of keeping raw material costs low.

[0029] The amount of water-insoluble hydrophilic resin contained in the needle-shaped portion 12 is preferably 4 to 50 parts by mass, more preferably 5 to 45 parts by mass, and even more preferably 15 to 40 parts by mass, per 100 parts by mass of the high-molecular-weight low-melting-point resin, from the viewpoints of further improving the water absorption of the needle-shaped portion 12 and facilitating the preparation of the composition for forming the needle-shaped portion 12. The water-insoluble hydrophilic resin is usually not miscible with the low-melting-point resin and exists in the needle-shaped portion 12 in a state separated from the low-melting-point resin.

[0030] The needle-shaped portion 12 may contain 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 in the resin of the needle-shaped portion 12 so as to be in a dispersed state.

[0031] The filler is preferably made of a resin, preferably one selected from the group consisting of natural organic polymers or their modifications, and biodegradable resins. Resin fillers can also contain inorganic components, such as organic-inorganic hybrid fillers in which inorganic materials are attached to the surfaces of resin particles. However, in consideration of their effects on living organisms, they are preferably made of only resin and organic components, and more preferably made of only resin. Examples of natural organic polymers include polysaccharides such as cellulose. Examples of fillers made of natural organic polymers or their modifications include cellulose fiber and spherical cellulose acetate microparticles. The above-mentioned water-insoluble polysaccharides may be incorporated into the needle-shaped structures 12 in the form of particles to function as fillers.

[0032] The biodegradable resin may be any of those listed above. However, when a biodegradable resin is used as a high-molecular-weight, low-melting-point resin, 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 butyrate diacetate also qualify as modified natural organic polymers.

[0033] 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).

[0034] The filler is preferably 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 resin that constitutes the needle-shaped portion 12, even when the filler is melted at a low temperature relative to the resin that constitutes the needle-shaped portion 12. 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 80° C. or lower. Examples of resins with a glass transition temperature of 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). Among these, biodegradable resins are preferred, as described above. Polylactic acid, polyglycolic acid, polyhydroxybutyric acid, or copolymers of these polymer monomers are preferred. From the perspective of further improving the mechanical strength of the needle-shaped portion 12, the filler is also preferably made of a resin with a glass transition temperature of -10°C or higher. The filler is more preferably made of a resin with a glass transition temperature of 10 to 80°C, and even more preferably of a resin with a glass transition temperature of 30 to 75°C.

[0035] 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. Furthermore, when the filler is a water-insoluble polysaccharide, the content of the water-insoluble polysaccharide filler relative to 100 parts by mass of the high-molecular-weight low-melting-point resin is preferably 4 parts by mass or more and 50 parts by mass or less, more preferably 5 parts by mass or more and 45 parts by mass or less, and even more preferably 15 parts by mass or more and 40 parts by mass or less.

[0036] 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 resin that constitutes the needle-shaped portion 12 in a molten state, thereby improving 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 improves compatibility 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.

[0037] 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 are opened on the surface of the needle-shaped portion 12. The holes 13 may be formed in any manner, for example, by mechanically providing a single communicating hole. However, as in this embodiment, a porous structure is preferably formed in the needle-shaped portion 12. Forming at least a portion of the needle-shaped portion 12 to have a porous structure allows body fluids or medicinal liquids to pass through the porous hole 13, which is preferable because it eliminates the need to mechanically form nano-order flow paths. Furthermore, since the body fluids or medicinal liquids can flow through all flow paths in the porous portion of the needle-shaped portion 12, the flow rate can be increased compared to when a single communicating hole is simply formed. When the needle-shaped portion 12 has a porous structure, the surface area of ​​the holes 13 with which water-containing fluids such as body fluids or medicinal liquids come into contact inside the needle-shaped portion 12 is large. Therefore, by including a water-insoluble hydrophilic resin in the needle-shaped portion 12, the hydrophilicity of the surface of the hole 13 is increased, which makes it easier to obtain the effect of improving the water absorption of the needle-shaped portion 12. Furthermore, when the needle-shaped portion 12 is formed so that at least a portion thereof has a porous structure, if the porous structure is not covered on part or all of the side surface of the needle-shaped portion, the hole 13 will also open on the side surface of the needle-shaped portion 12. In this case, the amount of liquid that flows through can be increased compared to when the hole 13 is open only at the tip of the needle-shaped portion 12.

[0038] However, in such a case, it is conceivable that the needle-shaped portion 12 would become brittle. In this embodiment, however, the needle-shaped portion 12 is formed using a low-melting point resin having a weight-average molecular weight of 25,000 or more and a melting point of 130°C or less, so that the needle-shaped portion 12 can be formed with high strength without becoming brittle.

[0039] As a method for forming the porous structure, which will be described in detail later, from the viewpoint of forming the pores 13 into 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 protrusions 32 (not shown in FIG. 1 , described later) without a porous structure and then form the porous structure in the protrusions 32. In the latter case, for example, the protrusions 32 may be formed by mixing two or more different materials, and then at least one material may be removed to form the pores 13, thereby obtaining the needle-shaped portion 12 with a porous structure. When the needle-shaped portion 12 contains a filler, according to such a method for forming a porous structure, the filler is contained in a dispersed state in the resin of the needle-shaped portion 12. In this embodiment, the needle-shaped portion 12 is made of high-molecular-weight polycaprolactone, and as described below, the protrusion portion 32 is made from polycaprolactone, which is a water-insoluble resin, and a water-soluble material. In a removal process, the water-soluble material is removed to form the hole portion 13, while the water-insoluble resin, which is insoluble in water, remains, thereby forming the needle-shaped portion 12 with a porous structure.

[0040] Thus, the pores 13 are voids formed by removing the water-soluble material from the protrusions 32, which are made of a water-insoluble, high-molecular-weight, 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.

[0041] In this embodiment, the needle-like portion 12 is formed by removing the water-soluble material from the protrusion 32 made of a water-insoluble, high-molecular-weight, low-melting-point resin and a water-soluble material, but this is not limitative and the needle-like portion 12 can also be formed using a porous, high-molecular-weight, low-melting-point resin. Alternatively, a porous structure may be formed simultaneously with the formation of the needle-like portion 12 using a foaming material or the like, or the porous structure may be formed by sintering a particulate composition containing a low-melting-point resin.

[0042] 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.

[0043] The base 14 also preferably has a porous structure similar to the needle-shaped portion 12, and it is more preferable to use the same resin to form 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-molecular-weight, low-melting-point resin as 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.

[0044] When the needle-shaped portion 12 has a porous structure and a base 14, the water absorption rate of the needle-shaped portion 12, when composed solely of a porous structure, as measured by the following test method is preferably 8.5% or more. (Test Method) The needle-shaped portion is immersed in 10 ml of purified water at 25°C. The immersed needle-shaped portion is placed in a reduced pressure environment of 0.09 MPa for one hour to allow water to penetrate into the porous structure. The needle-shaped portion is then removed from the water bath and water droplets adhering to the surface are removed. Water droplets on the surface of the needle-shaped portion where the needles are formed are removed by blowing them off with an air blow gun. Water droplets on the surface of the needle-shaped portion's base are removed by placing the base on a glass plate and allowing the weight of the needle-shaped portion to push the water droplets around the base. After leaving it to stand for 5 seconds, the needle-shaped portion is removed from the glass plate. The weight of the sample after water absorption is then measured. Then, the water absorption rate (the ratio of absorbed water to the weight of the sample) is calculated using the following formula: Water absorption rate (%) = (weight of sample after absorbing water - weight of sample before absorbing water) / weight of sample before absorbing water x 100

[0045] Specifically, the water absorption rate can be measured by the method described in the Examples below. When the microneedle structure 10 includes a substrate 11 described below, the substrate 11 can be removed to leave a needle-shaped portion consisting only of a porous structure, and the water absorption rate can be measured in the same manner. Such a water absorption rate is more preferably 13% or more, even more preferably 20% or more, and even more preferably 28% or more. The upper limit of the water absorption rate is not particularly limited, but is usually about 50% or less.

[0046] (2) Substrate The needle-shaped portion 12 has holes 13 formed therein as flow paths through which a liquid flows, but this reduces the strength of the needle-shaped portion 12 compared to a needle-shaped portion that does not have holes 13. If a porous structure is formed in the needle-shaped portion 12, the strength of the needle-shaped portion 12 tends to be further reduced. Therefore, in this embodiment, in order to support the needle-shaped portion 12 from the base side of the needle-shaped portion 12 and improve the strength of the microneedle structure 10, the microneedle structure 10 includes a substrate 11 having the needle-shaped portion 12 on one side.

[0047] The substrate 11 is preferably configured to allow liquid to pass through in its thickness direction. The phrase "allowing liquid to pass through in the thickness direction of the substrate 11" means that the substrate 11 itself may be made of a liquid-permeable material, or the substrate 11 may be made of a liquid-impermeable material but may be configured to allow liquid to pass through in the thickness direction of the substrate 11 via the through-holes 15 formed in the substrate 11.

[0048] Examples of the substrate 11 made of a liquid-permeable material include a porous substrate in which a plurality of voids are interconnected, forming minute substrate pores that penetrate from one side (the side on which the needle-shaped portion 12 is provided) to its back side (the side opposite the side on which the needle-shaped portion 12 is provided). When a low-melting-point resin 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, various substrates can be selected as the substrate 11 depending on the application. The substrate 11 made of such a liquid-permeable material may be in the form of a plate, but preferably in the form of a sheet that has good skin conformability. The substrate 11 is preferably made of a fibrous material that is easy to handle. Here, the fibrous material in this invention refers to fibers such as natural fibers and chemical fibers. Examples of substrates made of a fibrous material include nonwoven fabrics, woven fabrics, knitted fabrics, and paper made of these fibers.

[0049] If the substrate 11 is made of a liquid-impermeable material but allows liquid to pass through it in its thickness direction via the through-holes 15, liquid absorption by the substrate 11 can be suppressed, allowing the liquid to 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, allowing the entire amount of drug solution to be quickly delivered to the skin. When the substrate 11 has through-holes 15, the microneedle structure 10 may be configured such that the through-holes are filled with an absorbent material capable of absorbing liquid, as described in International Publication WO 2023 / 042525, or the absorbent material may be a porous material. The microneedle structure 10 having such a configuration makes it possible to more quickly pass the analysis sheet 17 (described below) provided on the back side of the substrate 11, and liquids such as body fluids between the drug storage section and the living body.

[0050] Examples of such liquid-impermeable materials include resin films, metal-containing sheets, and glass films. Metal-containing sheets include metal foils. Resin films with low water resistance may be coated with a metal layer by vapor deposition or other methods to improve their water resistance, and these may be used as metal-containing sheets. Materials that are not liquid-impermeable, such as nonwoven fabrics or paper, may also be used as laminated resin films, which are formed by laminating a water-insoluble resin onto these to make them liquid-impermeable as a whole.

[0051] In this embodiment, the substrate 11 is made of a liquid-impermeable resin film. Resins used for such resin films include relatively low-heat-resistant resins selected from the group consisting of polybutylene terephthalate, polyethylene terephthalate, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, vinyl chloride, acrylic resin, polyurethane, and polylactic acid, as well as heat-resistant resins such as polyimide, polyamideimide, and polyethersulfone. In this embodiment, a low-melting-point resin is used as the resin for forming the needle-shaped portion 12. Since compositions containing low-melting-point resins can be processed at low temperatures, the substrate 11 can be prevented from being exposed to high temperatures. Therefore, even resin films made of resins with low heat resistance are less likely to cause problems such as deformation of the substrate.

[0052] The substrate 11 may be a single layer or may be a laminate of multiple layers. The substrate 11 may be a laminate of a porous substrate 11 such as a nonwoven fabric and a liquid-impermeable substrate 11 having through-holes formed therein. The resin film may also be a composite film obtained by impregnating a nonwoven fabric or cloth with a resin. 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.

[0053] An adhesive layer 16 is provided on one side of the substrate 11 on which the needle-shaped portion 12 is formed. This improves the adhesion between the needle-shaped portion 12 and the substrate 14 and the substrate 11. Such an adhesive layer is preferably a pressure-sensitive adhesive, and examples thereof include acrylic adhesives, silicone adhesives, and rubber adhesives. More preferably, an acrylic adhesive can be used. Furthermore, by providing the adhesive layer 16 on the substrate 11, in the method for manufacturing a microneedle structure described below, a 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 a heating and pressing process, thereby easily obtaining the microneedle structure 10. When the adhesive layer 16 is provided on the substrate 11, there is a concern that voids 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 16 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 16 is not formed. Note that, although such an effect cannot be obtained, a first primer layer (not shown) may be provided instead of the adhesive layer 16 in order to improve the adhesion between the needle-shaped portion 12 and the substrate 11. Furthermore, even when the substrate 11 has the adhesive layer 16, the first primer layer may be provided as an intermediate layer between the substrate 11 and the adhesive layer 16. Examples of the primer layer include an acrylic primer layer and a polyester primer layer.

[0054] 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.

[0055] 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.

[0056] In addition to the above components, the acrylic adhesive may contain a tackifier, a plasticizer, an antistatic agent, a filler, a curable component, and the like.

[0057] As a coating liquid for obtaining an acrylic pressure-sensitive adhesive, either a solvent-based or emulsion-based liquid can be used.

[0058] The shape of the through-holes 15 formed in the substrate 11 is not particularly limited, but a structure having multiple narrow through-holes is preferred from the viewpoint of ensuring sufficient flow while generating capillary action. The diameter of the through-holes 15 is, for example, 2 mm or less, preferably 0.05 to 1 mm, and more preferably 0.1 to 0.8 mm. The method for forming the through-holes 15 is not particularly limited, and they can be formed by, for example, punching or laser drilling. 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 flows in the thickness direction of the substrate 11 through the through-holes 15. This shortens the transport distance, allowing detection at a high analysis speed when configured as a detection patch, and allowing early administration of a drug solution when configured as a drug administration patch.

[0059] 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.

[0060] 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 an 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 in the formation step of the microneedle structure manufacturing method described below, or by a similar heating adhesion method, even if the substrate 11 does not have an adhesive layer 16. In this embodiment, the base 14 is provided over the entire surface of the substrate 11, but this is not limiting. 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.

[0061] The microneedle structure 10 thus formed can be used as a test patch or a drug administration patch. For example, as shown in FIG. 2 , a test patch 2 includes an analysis sheet 17 disposed in the region of the substrate 11 of the microneedle structure 10 where the through-hole 15 is formed, facing the needle-shaped portion 12, and a tape 18 laminated to cover the analysis sheet 17. In the case of a drug administration patch, a drug administration member is disposed in place of the analysis sheet 17 in a region covering the region of the substrate 11 of the microneedle structure 10 where the through-hole 15 is formed, facing the needle-shaped portion 12, and the tape 18 is laminated to cover the drug administration member. Even in such test patches or drug administration patches, the needle-shaped portion 12 has high strength, allowing it to be inserted into the skin without being damaged, and preventing the constituent material of the needle-shaped portion 12 from remaining in the body, which is preferable. The tape 18 used to fix the analysis sheet 17 or drug administration member to the substrate 11 may be an adhesive tape provided with an adhesive layer.

[0062] [Method for manufacturing microneedle structure]

[0063] 3 and 4 show a method for manufacturing a microneedle structure and a test patch 2 according to an embodiment of the present invention. In this embodiment, a water-insoluble, high-molecular-weight, low-melting-point resin and a water-soluble material for forming the holes 13 are melted and filled into a mold (filling step), the filled mixture is solidified to obtain a solid composition 31, which is then adhered to the substrate 11 (adhesion step), and the solid composition 31 is then heated and pressurized to form protrusions 32 (forming step). The water-soluble material is then removed from the protrusions 32 (removal step), converting the protrusions 32 into needle-like portions 12. This will be described in detail below.

[0064] (Filling Step) First, a description will be given of the preparation of the substrate 11 and the solid composition 31. First, a composition containing a water-insoluble polymeric low-melting-point resin, a water-soluble material, and optional components (e.g., a water-insoluble hydrophilic resin and a filler) is heated to melt and mixed to prepare a mixture 33.

[0065] In this embodiment, the shape of the high molecular weight low melting point resin is not particularly limited, but a commonly used pellet-shaped resin can be used.

[0066] When preparing the mixture 33, heating is preferably performed at 40°C or higher and 180°C or lower, more preferably at 55 to 180°C, and even more preferably at 70 to 170°C, so as to reduce the viscosity of the resin when melted. In this embodiment, a water-insoluble, high-molecular-weight, low-melting-point resin is used as the resin constituting the needle-shaped portion 12, allowing the heating temperature to be set relatively low. Therefore, even if the substrate 11 is heated together with the solid composition 31 to form the protrusions 32 in the subsequent forming process, the heating temperature is low. This results in low cost and ease of work, and the substrate 11 does not soften, deform, or burn, allowing for greater freedom in selecting the substrate 11. When using a pellet-like high-molecular-weight, low-melting-point resin, the high-molecular-weight, low-melting-point resin and the water-soluble material can be thoroughly mixed by kneading using a kneader. It is preferable that the mixture 33 be in a molten state. If heating at a lower temperature is important, the mixture 33 may be softened to the extent that it adheres to the substrate 11, but considering the reduction of manufacturing time, it is preferable to heat the mixture 33 at a temperature equal to or higher than the melting point of the low-melting-point resin at which the water-insoluble material begins 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] Furthermore, in order to make it easy to melt both the high molecular weight, low melting point resin and the water-soluble material at the same heating temperature when preparing mixture 33, it is preferable that the difference in melting point between the high molecular weight, low melting point resin and the water-soluble material be 40°C or less, and more preferably 30°C or less.

[0069] The water-insoluble material and the water-soluble material are preferably mixed at a mass ratio of 9:1 to 1:9, more preferably 8.5:1.5 to 3:7, and particularly preferably 8:2 to 5:5. By forming the mixture 33 at these ratios, 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] 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. The recess 42 for a solid composition may be formed in any shape and with a volume that allows a desired amount of the mixture 33 to be stored therein.

[0071] 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.

[0072] 3(b), 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, and the sheet 43 for solid composition is peeled off from the mold 41 for solid composition, and then the sheet 43 for solid composition is peeled off. In this way, the solid composition 31 is obtained.

[0073] A substrate 11 is prepared. In this embodiment, the substrate 11 has an adhesive layer 16. Although the adhesive layer 16 may be formed by coating or application, in this embodiment, an adhesive tape having the adhesive layer 16 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.

[0074] 3(c), the solid composition 31 is attached to the adhesive layer 16 of the substrate 11 to integrate the substrate 11 and the solid composition 31. In this way, by having the first adhesive layer 16, 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 heating and pressing step described below, thereby easily obtaining the microneedle structure 10. Furthermore, by integrating the substrate 11 and the solid composition 31, handling such as transportation becomes easier.

[0075] (Forming Step) 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 bottom surface of the recess 51, i.e., 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, for example, polydimethylsiloxane.

[0076] 4(b) is carried out. The heating step is for forming protrusions 32 and the like of a desired shape, and although heating and pressurization may be carried out all at once, as in the present embodiment, in order to sufficiently fill the recesses 51 of the mold 52 with the solid composition 31, it is preferable to carry out the heating step by including a preliminary step for starting melting of the solid composition 31 provided with the substrate 11 and a main step for sufficiently filling the recesses 51 and the like with the molten solid composition 31.

[0077] 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.

[0078] The heating conditions in the preliminary step and this step are 40°C or higher and 180°C or lower, which has minimal effect on the substrate 11. Preferably, heating is performed at 55 to 180°C, and more preferably at 70 to 170°C. In this embodiment, heating is performed at a temperature at which the solid composition 31 can melt. 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. However, heating both is preferred. In order to quickly fill the recesses 51 and the like with the solid composition 31 containing a high-molecular-weight, low-melting-point resin, it is preferable to heat the lower stage 56 at a high temperature. For example, the lower stage may be heated to a temperature in the range of 120 to 180°C. The temperature of the upper stage 57 is preferably set to a temperature in the range of 70 to 110°C, from the viewpoint of suppressing deformation of the substrate due to heat while improving the adhesion between the needle-shaped portion 12 or the base 14 and the substrate 11, as described below. In this step, heating after the preliminary step may be maintained, and the temperature may be changed as appropriate.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] (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.

[0083] 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 made of the remaining high-molecular-weight, low-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.

[0084] (Method for manufacturing test patch, etc.) The test patch 2 can be manufactured by placing the 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, the test patch 2 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.

[0085] (Variations) In this embodiment, the solid composition 31 contains a water-soluble material and a water-insoluble, high-molecular-weight, low-melting-point resin. However, the solid composition 31 is not particularly limited as long as it contains at least a resin. 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 order of the bonding step and the forming step may be reversed, and the bonding step may be performed in parallel with the forming step. That is, the recess 42 may be filled with the mixture 33, and before solidification, the substrate 11 may be placed on the mixture 33 and the bonding step may be performed to obtain the solid composition 31 with the substrate.

[0086] In this embodiment, the needle-shaped portion 12 is formed using a water-insoluble, high-molecular-weight, low-melting-point resin to easily form the hole 13 by removing the water-soluble material. However, the method for producing the hole 13 is not particularly limited as long as the aforementioned high-molecular-weight, low-melting-point resin is used. For example, in the forming process, a microneedle structure having a porous structure formed by numerous voids between the particles may be obtained by filling the mold 2 with a particulate high-molecular-weight, low-melting-point resin or the like and sintering at a temperature above the melting point of the low-melting-point resin. Even in this case, if the forming process and the bonding process are performed simultaneously, deformation and deterioration of the substrate 11 can be suppressed by having the substrate 11 have a layer made of a heat-resistant resin. In either case, using a high-molecular-weight, low-melting-point resin to form the needle-shaped portion 12 eliminates the need for high-temperature heating, resulting in low cost and good workability, and the substrate 11 does not deform or soften, allowing for greater freedom in selecting the substrate 11.

[0087] In this embodiment, the needle-shaped portion 12 is formed using a water-insoluble material so that the hole 13 can be easily formed by removing the water-soluble material, but the method for producing the needle-shaped portion 12 is not particularly limited. For example, the formation step may be a method in which a liquid composition containing a water-soluble material, a water-insoluble material, and a solvent is formed, the solvent is evaporated, and the composition other than the solvent is filled into the protrusion-forming recess, and then dried to form the protrusion. Alternatively, for example, the formation step may be a method in which a liquid composition containing the water-soluble material and the water-insoluble material is prepared so that the viscosity is 0.1 to 1000 mP·s, and the liquid composition is dripped onto the substrate 11 using a dispenser or the like, thereby forming the needle-shaped portion 12.

[0088] Examples The present invention will be described in more detail below with reference to the following examples. In the examples and comparative examples, the weight-average molecular weight (Mw) is measured using gel permeation chromatography (GPC) under the following conditions (GPC measurement) and is the weight-average molecular weight converted to a standard 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 a 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

[0089] Example 1: 3 g of polyethylene glycol (PEG) (weight average molecular weight 4,000, melting point 40°C) as a water-soluble material and 7 g of pellet-form polycaprolactone (weight average molecular weight 80,000) 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.

[0090] 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 an 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.

[0091] 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

[0092] 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 .

[0093] (Example 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 microneedle structure 10 was obtained in the same manner as Example 1, except that the temperature of the heating process in the formation process was 110°C in both cases.

[0094] (Comparative Example 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 pressure application time in the preliminary step was 1 minute 30 seconds.

[0095] The microneedle structures obtained in Examples 1 and 2 and Comparative Example 1 were subjected to the following evaluation of microneedle array transferability and microneedle tip strength.

[0096] (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".

[0097] (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 drop in force was first observed, the maximum force value indicated at the position before the drop in force was read, or if no drop in force was observed before the attachment had dropped 100 μm, the force value at the time the attachment had dropped 100 μm was read, and this value was taken as the tip strength of the needle-like portion. When the tip strength exceeded 200 mN, it was rated as "A," when the tip strength was 100 to 200 mN, it was rated as "B," and when the tip strength was less than 100 mN, it was rated 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.

[0098] The evaluation results of Examples 1 and 2 and Comparative Example 1 are shown in Table 1. (Table 1)

[0099] As shown in Table 1, in Examples 1 and 2 and Comparative Example 1, the microneedle array transferability evaluation was A. On the other hand, as shown in Table 1, in Comparative Example 1, the microneedle tip strength evaluation was C, as the microneedle tip strength was less than 100 mN. As a result, the strength of the needle-shaped portion 12 was increased by using a low-melting point resin with a high molecular weight (weight-average molecular weight of 25,000 or more).

[0100] Example 3 A microneedle structure 10 was obtained in the same manner as in Example 1, except for the following changes. The microneedle structure 10 obtained in this example did not have a substrate 11. The substrate 11 was not adhered to the solid composition 31, and the lid 54 was placed directly on the solid composition 31. Regarding the temperature and time of the heating step in the forming step, the heating temperature of the lower stage of the heat press was set to 115°C, the heating temperature of the upper stage was set to 105°C, and the time of the preliminary step was changed to 1 minute 30 seconds (the time of the main step was unchanged). The conditions for immersing the molded solid composition 31 in purified water were changed to 24 hours in purified water at 40°C, and the conditions for drying the molded solid composition 31 were changed to 24 hours at 40°C.

[0101] (Example 4) A microneedle structure 10 was obtained in the same manner as in Example 3, except that 7 g of pellet-shaped polycaprolactone (weight average molecular weight 40,000) having a different molecular weight from that in Example 3 was used as the resin constituting the needle-shaped portion 12.

[0102] (Comparative Example 2) A microneedle structure was obtained in the same manner as in Example 3, except that 7 g of pellet-shaped polycaprolactone (weight average molecular weight 10,000) having a different molecular weight from that in Example 3 was used as the resin constituting the needle-shaped portion.

[0103] (Example 5) A microneedle structure 10 was obtained in the same manner as in Example 3, except that when preparing the mixture 33, 0.5 g of ARBOCEL Ultrafine Cellulose (average particle size: 6-12 μm, manufactured by Rettenmeyer Japan Co., Ltd.) was further added as a filler made of cellulose (a water-insoluble hydrophilic resin).

[0104] Example 6 A microneedle structure 10 was obtained in the same manner as in Example 5, except that the amount of filler added was changed to 2.0 g.

[0105] (Example 7) A microneedle structure 10 was obtained in the same manner as in Example 4, except that when preparing the mixture 33, 0.5 g of ARBOCEL Ultrafine Cellulose (average particle size: 6-12 μm, manufactured by Rettenmeyer Japan Co., Ltd.) was further added as a filler made of cellulose.

[0106] Example 8 A microneedle structure 10 was obtained in the same manner as in Example 7, except that the amount of filler added was changed to 2.0 g.

[0107] (Reference Example 1) When preparing the mixture 33, 0.5 g of ARBOCEL Ultrafine Cellulose (average particle size: 6-12 μm, manufactured by Rettenmeyer Japan Co., Ltd.) was further added as a filler made of cellulose. A microneedle structure 10 was obtained in the same manner as in Comparative Example 2.

[0108] Reference Example 2 A microneedle structure 10 was obtained in the same manner as in Reference Example 1, except that the amount of filler added was changed to 2.0 g.

[0109] The microneedle structures (needle-shaped portions having no substrate) obtained in Examples 3 to 8, Comparative Example 2, and Reference Examples 1 and 2 were subjected to the following evaluation of water absorbency.

[0110] (Water Absorption Evaluation) The weight of the needle-shaped sample before water absorption was measured. Next, the sample was placed in a tray (non-charged balance dish, manufactured by AS ONE Corporation) in an environment of 25°C, and 10 ml of purified water was poured into the sample to immerse it. The tray was then placed in a reduced-pressure environment of 0.09 MPa for 1 hour to allow water to penetrate into the porous structure of the sample. Next, the sample was removed from the tray, and water droplets adhering to the surface were removed. Specifically, water droplets on the surface of the needle-shaped portion where the needles were formed were removed by blowing them off with an air blow gun. Water droplets on the surface of the base of the needle-shaped portion were removed by placing the base on a glass plate and allowing the weight of the needle-shaped portion to push the water droplets around the base. After leaving it for 5 seconds, the needle-shaped portion was removed from the glass plate. The weight of the sample after water absorption was then measured. The water absorption rate (the ratio of absorbed water to the weight of the sample) was calculated using the following formula. Water absorption rate (%) = (weight of sample after water absorption - weight of sample before water absorption) ÷ weight of sample before water absorption × 100

[0111] The evaluation results are shown in Table 2. In Table 2, the "addition amount" of the water-insoluble hydrophilic resin is the ratio of the mass of the water-insoluble hydrophilic resin to the total mass of the low-melting-point resin and the water-soluble resin, expressed as a percentage (Table 2). The water absorption rates of Examples 3 and 2 were higher than those of Comparative Example 2, and it was confirmed that the water absorption rate increased as the molecular weight of the low-melting-point resin increased. Furthermore, in Examples 5, 6, and 7, 8, the water absorption rate increased significantly compared to Examples 3 and 4, which had the same molecular weight of the low-melting-point resin, by containing cellulose, a water-insoluble hydrophilic resin. Even in these cases, Examples 5 and 6, in which the weight-average molecular weight of the low-melting-point resin was 80,000, tended to have a higher water absorption rate than Examples 7 and 8 and Reference Examples 1 and 2, which contained the same amount of cellulose.

[0112] 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.

[0113] 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 having a needle-shaped portion in which a hole is formed inside, The needle-shaped portion is characterized by containing a low-melting-point resin having a weight-average molecular weight of 25,000 or more and a melting point of 130°C or less.

2. The microneedle structure according to claim 1, characterized in that the needle-shaped portion contains a water-insoluble hydrophilic resin.

3. The microneedle structure according to claim 2, characterized in that the water-insoluble hydrophilic resin is a water-insoluble polysaccharide.

4. The microneedle structure according to any one of claims 1 to 3, characterized in that a porous structure is formed in the needle-shaped portion.

5. The microneedle structure according to claim 4, characterized in that the needle-shaped portion has a base and the needle-shaped portion is composed solely of the porous structure, and the water absorption rate of the needle-shaped portion, as measured by the following test method, is 8.5% or more. (Test method) Under conditions of 25°C, the needle-shaped portion is immersed in 10 ml of purified water. The immersed needle-shaped portion is then placed under reduced pressure of 0.09 MPa for 1 hour to allow water to penetrate the porous structure. Next, the needle-shaped portion is removed from the purified water, and any water droplets adhering to its surface are removed. Water droplets on the surface of the needle-shaped portion on the side where the needle is formed are removed by blowing them off with an air blow gun, and water droplets on the surface of the base-side portion are removed by placing the base on a glass plate and allowing the water droplets to be pushed out around the base by the weight of the needle-shaped portion. After standing for 5 seconds, the needle-shaped portion is removed from the glass plate. The weight of the sample after water absorption is then measured. The water absorption rate (the ratio of absorbed water to the weight of the sample) is then calculated using the following formula. Water absorption rate (%) = (Weight of sample after water absorption - Weight of sample before water absorption) ÷ Weight of sample before water absorption × 100

6. The microneedle structure according to claim 1, characterized in that the needle-shaped portion contains a filler.