Microneedle structure, microneedle patch, and method for manufacturing microneedle structure

Abstract

[Problem] To provide a microneedle structure capable of analyzing body fluids by using a means other than a functional member. [Solution] A microneedle structure 10 comprises: a liquid storage layer 20 for absorbing and storing a liquid derived from a living body; and a needle-shaped portion 11 in which a flow path 13 is formed, wherein the flow path 13 in the needle-shaped portion 11 is in contact with the liquid storage layer 20.

Description

Microneedle structure, microneedle patch, and method for manufacturing a microneedle structure

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

[0002] In recent years, microneedle patches have been proposed that use microneedle structures that supply drugs to the body or collect body fluids from the body through through-holes formed in micro-sized needle-shaped portions. Examples of microneedle patches include a liquid-impermeable substrate having through-holes, a liquid-absorbing absorbent material filled in the through-holes, a needle-shaped portion provided on one side of the substrate and having a flow path formed therein, and a functional member provided on the other side of the substrate, where the needle-shaped portion and the absorbent material are connected to each other, and the absorbent material and the functional member are connected to each other (Patent Document 1).

[0003] International Publication No. 2023 / 042525

[0004] Currently, there is a demand for analytical methods for collecting and analyzing body fluids that are less painful and less stressful on the human body, and the use of microneedle patches as analytical means is being considered. Microneedle patches are preferable for testing because they cause less pain and stress on the human body. However, the microneedle patch described in Patent Document 1 is configured to deliver interstitial fluid from the needle-shaped portion to the functional member through through-holes in the substrate, and although it can be used as a test patch as a functional member to perform simple tests, it is not suitable for, for example, performing precise analysis using a dedicated device or absorbing the amount required for analysis by means other than the functional member.

[0005] The present invention has been made in view of the above circumstances, and has an object to provide a microneedle structure that can analyze body fluids by means other than a functional member.

[0006] In order to achieve the above-mentioned object, first, the present invention provides a microneedle structure comprising a liquid storage layer that absorbs and stores biological liquid, and a needle-shaped portion having a flow path formed therein, wherein the flow path of the needle-shaped portion is in contact with the liquid storage layer (Invention 1).

[0007] The above invention (Invention 1) is configured to have a liquid storage layer that absorbs and stores liquid derived from a living body, so that the liquid can be stored and the configuration is suitable for a variety of analyses.

[0008] In the above invention (Invention 1), it is preferable that the liquid storage layer and the needle-shaped portion are each made of a porous material (Invention 2).

[0009] In the above invention (Invention 1), it is preferable that the liquid storage layer contains a nonwoven fabric formed from rayon (Invention 3).

[0010] In the above invention (Invention 2), it is preferable that the liquid storage layer and the needle-shaped portion are made of the porous materials different from each other in structure or composition (Invention 4).

[0011] In the above invention (Invention 2), the porous material of the liquid storage layer contains a resin, and the resin contains carbon atoms and oxygen atoms in its molecular structure, and the ratio of the number of oxygen atoms to the number of carbon atoms may be 1 / 2 or more (Invention 5).

[0012] In the above invention (Invention 2), the porous material of the liquid storage layer may contain a resin, and the resin may have hydroxyl groups in a portion other than the molecular terminals and be insoluble in water (Invention 6).

[0013] In the above invention (Invention 1), it is preferable that, in a top view of the microneedle structure, the area in which the needle-shaped portion exists is entirely included in the area of ​​the liquid storage layer (Invention 7).

[0014] In the above invention (Invention 1), it is preferable that the liquid storage layer is a hard porous material and has a thickness of 300 μm or more (Invention 8). A liquid storage layer thickness of 300 μm or more allows for sufficient storage of liquid even when an analysis requires a larger amount of liquid, and can also improve the strength of the microneedle structure.

[0015] In the above invention (Invention 1), it is preferable that the needle-shaped portion is formed on one surface of a sheet-like base, the liquid storage layer is directly laminated on the other surface of the base, and the flow path of the needle-shaped portion is connected to the liquid storage layer via a flow path formed in the base (Invention 9). By forming the needle-shaped portion on the sheet-like base, the needle-shaped portion can be stably held. Furthermore, by directly laminating the liquid storage layer on the other surface of the base and connecting the flow path of the needle-shaped portion to the liquid storage layer via a flow path formed in the base, the needle-shaped portion and the liquid storage layer are in communication, allowing the liquid storage layer to sufficiently absorb and store liquid.

[0016] In the above invention (Invention 8), it is preferable that the liquid storage layer is directly fixed to the base (Invention 10). By directly fixing the liquid storage layer, the strength of the base and the needle-shaped part is improved, and breakage can be suppressed.

[0017] Secondly, the present invention provides a microneedle patch (Invention 11) characterized by comprising the microneedle structure of any of the above inventions (Inventions 1 to 10).

[0018] Thirdly, the present invention provides a method for manufacturing a microneedle structure, the microneedle structure comprising a needle-shaped portion formed on one side of a sheet-like base and having a flow path formed therein, and a liquid storage layer arranged on the other side of the sheet-like base and absorbing and storing a liquid derived from a living body, the base and the liquid storage layer being made of a porous material, the method comprising an impregnation step of impregnating at least one of the base and the liquid storage layer with a resin solution, and a drying step of volatilizing the solvent from the resin solution and drying the base and the liquid storage layer in a stacked state after the impregnation step (Invention 12). By having an impregnation process in which a resin solution is impregnated into at least one of the base and the liquid storage layer, and a drying process in which the solvent is evaporated from the resin solution and dried while the base and the liquid storage layer are stacked after the impregnation process, the liquid storage layer and the base are bonded to each other with good interfacial permeability by the resin, allowing liquid to be stored in the liquid storage layer, and it is possible to easily manufacture microneedle structures with configurations suitable for a variety of analyses.

[0019] In the above invention (Invention 12), after the impregnation step, it is preferable to stack one of the base or the liquid storage layer impregnated with the resin solution on the other of the base or the liquid storage layer that has not been impregnated, and place the stacked state in a reduced pressure environment (Invention 13). By placing the stacked state in a reduced pressure environment, the liquid storage layer and the base can be easily bonded with good interfacial permeability.

[0020] In the above invention (Invention 12), it is preferable that the resin is a hydrophilic resin (Invention 14). When the resin is a hydrophilic resin, it is easy to impregnate the inside of the porous material of the base and the liquid storage layer with a resin solution and allow the resin to adhere by drying.

[0021] Fourth, the present invention provides a microneedle structure comprising a needle-shaped portion formed on one surface of a sheet-like base and having a flow path formed therein, and a liquid storage layer disposed on the other surface of the sheet-like base and configured to absorb and store a biologically derived liquid, the base and the liquid storage layer being made of a porous material, and a resin being attached to the interior of the porous material of the base and the liquid storage layer (Invention 15). The resin being attached to the interior of the porous material of the base and the liquid storage layer allows for high liquid flow and allows the liquid to be stored in the liquid storage layer, making the structure suitable for a variety of analyses.

[0022] In the above invention (Invention 15), it is preferable that the resin adhering to the inside of the porous material of the base and the resin adhering to the inside of the porous material of the liquid storage layer are the same resin (Invention 16). By using the same resin, the manufacturing process can be simplified.

[0023] In the above invention (Invention 15), it is preferable that the base and the liquid storage layer are bonded by the attached resin (Invention 17). By bonding the base and the liquid storage layer by the attached resin, liquid can be stored in an interface liquid storage layer between the base and the liquid storage layer, making the configuration suitable for various analyses.

[0024] (a) is a schematic cross-sectional view of a microneedle structure of the present invention, and (b) is a schematic plan view of a microneedle structure of the present invention. It is an enlarged partial cross-sectional view of a needle-shaped portion of a microneedle structure of the present invention. (a) to (c) are explanatory views showing the steps of a method for manufacturing a microneedle structure according to an embodiment. (a) to (c) are explanatory views showing the steps of a method for manufacturing a microneedle structure according to an embodiment. (a) to (b) are explanatory views showing the steps of a method for manufacturing a microneedle structure according to an embodiment. It is a schematic cross-sectional view of a microneedle structure according to a second embodiment of the present invention.

[0025] (Embodiment 1) A microneedle patch 1 according to one embodiment of the present invention comprises a microneedle structure 10 including a needle-shaped portion 11 and a liquid storage layer 20, and a tape 30.

[0026] 1 and 2 show a microneedle structure 10 according to one embodiment of the present invention. The microneedle structure 10 comprises a plurality of needle-shaped portions 11. Each of the needle-shaped portions 11 has a plurality of holes 12 formed therein, and the holes 12 open on the surface of the needle-shaped portion 11. The microneedle structure 10 is capable of absorbing body fluids from within the skin through the holes 12 of the needle-shaped portions 11. In the present invention, body fluids include blood, lymph, interstitial fluid, etc.

[0027] The shape of the needle-like portion 11 may be cylindrical, prismatic, conical, pyramidal, or the like, and in this embodiment, it is conical. The maximum diameter or maximum cross-sectional dimension of the needle-like portion 11 may be, for example, 25 to 1000 μm, the tip diameter or cross-sectional dimension of the tip may be, for example, 1 to 100 μm, the height of the needle-like portion 11 may be, for example, 50 to 2000 μm, and the spacing between the needle-like portions 11 (the distance from the center of the maximum cross-section) may be, for example, 200 to 3000 μm, preferably 400 to 2000 μm. When the region where the needle-like portion 11 is present is rectangular, the distance between the tip of the needle located at one end of the needle-like portion 11 and the tip of the needle located at the other end is preferably 3 to 20 mm, more preferably 5 to 10 mm. Furthermore, the area of ​​the region where the needle-like portion 11 is present may be, for example, 9 to 400 mm. ２ It is preferable that the thickness is 25 to 100 mm. ２ In addition, it is preferable that the number of needles of the needle-shaped portion 11 in the region where the needle-shaped portion 11 exists is about 10 to 100, and more preferably about 25 to 75.

[0028] One or more holes 12 are formed in one needle-shaped portion 11, and one or more holes 12 open on the surface of the needle-shaped portion 11. Multiple holes 12 are formed in the needle-shaped portion 11. In this embodiment, the needle-shaped portion 11 is made of a porous material. By using a porous material, it is not necessary to mechanically form fine flow paths, which is preferable. Furthermore, since bodily fluids can flow through multiple flow paths formed in the needle-shaped portion 11, the flow rate can be increased compared to when a single, simple, communicating hole is formed. Furthermore, since the needle-shaped portion 11 is made of a porous material, multiple holes 12 open on the side surface of the needle-shaped portion 11, which increases the rate at which fluids are absorbed or released from the needle-shaped portion 11 compared to a structure in which holes open only at the top of the needle-shaped portion.

[0029] Porous materials that can be used for the needle-shaped portion 11 include foamed molding materials formed by foaming a resin, sintered porous bodies formed by sintering resin particles, and porous materials with a porous structure formed by removing a pore-forming material. In this embodiment, the needle-shaped portion 11 is formed by a so-called salt leaching method, in which a protrusion is made from a composition obtained by mixing a pore-forming material with a material constituting the needle-shaped portion, and the pore-forming material is removed in a removal step to form the pores 12, while the material constituting the needle-shaped portion 11 remains, forming the needle-shaped portion 11 with a porous structure (details will be described later). Forming the needle-shaped portion 11 by such a salt leaching method is preferable because it allows the pore diameter of the pores 12 to be increased, thereby improving the absorbency of body fluids.

[0030] The needle-shaped portion 11 can be made of a water-insoluble material. Considering ease of handling during the manufacturing process, the water-insoluble material is preferably a water-insoluble resin. Examples of the water-insoluble resin 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.

[0031] Furthermore, such a water-insoluble resin is preferably a water-insoluble biodegradable resin that is less likely to affect the human body. As the biodegradable resin, aliphatic polyesters and their derivatives are preferably used, and at least one selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, and copolymers obtained by copolymerizing the monomers constituting these resins may also be used. A mixture of two or more of these biodegradable resins may also be used. For example, a copolymer of polycaprolactone or caprolactone with a monomer constituting another biodegradable resin may be used.

[0032] From the viewpoint of ease of heat processing, the water-insoluble resin is preferably a water-insoluble resin having a melting point of 130° C. or lower. Examples of water-insoluble resins having a melting point of 130° C. or lower include polycaprolactone, which is a biodegradable resin, and copolymers of caprolactone and other monomers constituting biodegradable resins, and a homopolymer of polycaprolactone is preferred.

[0033] The needle-shaped portion 11 may further contain a filler. By containing a filler in the needle-shaped portion 11, the mechanical strength of the needle-shaped portion 11 can be improved. The filler is preferably contained so as to be in a dispersed state in the resin of the needle-shaped portion 11. The filler is preferably made of a resin, and is preferably made of one type selected from the group consisting of natural organic polymers or modified products thereof, and biodegradable resins. An example of a natural organic polymer is cellulose, and examples of fillers made of natural organic polymers or modified products thereof include cellulose fiber and spherical cellulose acetate microparticles.

[0034] In this embodiment, as described above, the hole 12 is a void formed by removing the pore-forming material from a protrusion made of the material constituting the needle-shaped portion 11 and the pore-forming material. Body fluid passes through the flow path 13 formed by these hole 12 communicating with each other. As shown in the cross section of the needle-shaped portion 11, the flow path is formed by the removal of the pore-forming material, forming multiple voids that communicate with each other. The size of the opening of the hole 12 is determined depending on the analysis method using the microneedle structure 10, but from the perspective of facilitating the passage of liquid, 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.

[0035] The needle-like portions 11 are provided at predetermined intervals on the sheet-like base 21. In this embodiment, the needle-like portions 11 are provided in a plurality of rows in one direction, and a plurality of needle-like portions 11 are formed in each row and arranged in a matrix on the base 21.

[0036] The base 21 is formed simultaneously with the needle-shaped portion 11 during the manufacturing process. Therefore, the base 21 is formed with the same structure and composition as the needle-shaped portion 11. That is, like the needle-shaped portion 11, the base 21 is also made of a porous material, and the base 21 also has holes 12 and flow channels 13 formed therein. Therefore, although the base 21 can also absorb liquid, it is sheet-shaped and thin, typically having a thickness of 150 μm or more and less than 300 μm, and therefore cannot function as the liquid storage layer 20. The base 21 can fix the needle-shaped portion 11 to prevent it from falling off, and the flow channel 13 of the base 21 can communicate between the flow channel of the needle-shaped portion 11 and the liquid storage layer 20. Furthermore, such a thin base can shorten the flow channel 13 through which liquid reaches the liquid storage layer 20, allowing the liquid storage layer 20 to absorb biological liquid more quickly.

[0037] (Liquid storage layer) In the microneedle structure 10 of this embodiment, the needle-shaped portion 11 is provided on one surface of the base 21, and the liquid storage layer 20 is directly laminated on the other surface. The liquid storage layer 20 has a circular shape that is smaller than the base 21 when viewed from above.

[0038] The liquid storage layer 20 is configured to be able to store liquid (body fluid), and is preferably made of a porous material.

[0039] Furthermore, in the microneedle structure 10 of this embodiment, when viewed from above, the region where the needle-shaped portions 11 are present is entirely included in the region of the liquid storage layer 20. As shown in Fig. 1(b) , the region where the needle-shaped portions 11 are present refers to region A1, which is the region where all of the needle-shaped portions 11 are formed, and the region of the liquid storage layer 20 refers to region A2, which is the region where the liquid storage layer 20 is provided, when viewed from above. By configuring the microneedle structure 10 in this way, the area of ​​the liquid storage layer 20 is larger than the area of ​​the region where the needle-shaped portions 11 are present, making it easier to store biological liquid absorbed from the needle-shaped portions 11 in sufficient amounts for various analyses.

[0040] Porous materials that can be used for the liquid storage layer 20 include porous materials obtained by the aforementioned salt leaching method, as well as hard porous materials such as sintered porous bodies obtained by sintering resin particles. The thickness of the hard porous liquid storage layer 20 is preferably 300 μm or more, and preferably approximately 300 to 1000 μm. By adopting such a thick, hard porous liquid storage layer 20, the amount of liquid that the liquid storage layer 20 can absorb can be increased, and the strength of the microneedle structure can be easily improved. Porous materials that can be used for the liquid storage layer 20 include paper, nonwoven fabric, woven fabric, knitted fabric, and the like. In this case, the thickness of the liquid storage layer 20 is preferably approximately 30 to 150 μm. When the liquid storage layer 20 is made of a material other than a porous material, for example, a polymeric water-absorbing material such as polyacrylate particles can be used. However, from the perspective of facilitating separation of the stored biological liquid, it is preferable to form the liquid storage layer 20 from a porous material.

[0041] Furthermore, the liquid storage layer 20 preferably includes a resin whose molecular structure includes carbon atoms and oxygen atoms, with the ratio of the number of oxygen atoms to carbon atoms being 1 / 2 or greater. Even if such a resin does not itself have pores, it can be made porous by the salt leaching method described above. The hydrophilicity of the liquid storage layer 20 can be enhanced by using a resin whose molecular structure includes carbon atoms and oxygen atoms, with the ratio of the number of oxygen atoms to carbon atoms being 1 / 2 or greater, as the liquid storage layer 20. When the resin is a biodegradable resin, examples of such hydrophilic resins include polylactic acid, whose molecular structure includes a ratio of the number of oxygen atoms to carbon atoms of 2 / 3, polyglycolic acid, whose molecular structure includes a ratio of 1 / 1, and copolymers of lactic acid and glycolic acid.

[0042] The liquid storage layer 20 may also contain a water-insoluble resin that has hydroxyl groups except for the molecular ends. The inclusion of such a resin can enhance the hydrophilicity of the liquid storage layer 20. Furthermore, the water-insolubility of the resin can prevent elution of the resin when storing biologically derived liquids. Examples of such resins include fully saponified polyvinyl alcohol and polysaccharides. Examples of polysaccharides include cellulose, calcium alginate, chitin, cross-linked hyaluronic acid, and derivatives thereof. Cellulose or its derivatives are preferred as polysaccharides, with cellulose being even more preferred, from the perspective of keeping raw material costs low. The water-insoluble resin that has hydroxyl groups except for the molecular ends may be cellulose, as described above, which may be mixed in particulate form as a filler into the base resin of the porous material. For example, a porous material may be formed using a composition based on polycaprolactone and mixed with cellulose fiber as a filler.

[0043] The porous material constituting the liquid storage layer 20 may be paper, nonwoven fabric, woven fabric, or knit fabric formed from cellulose fibers. Examples of cellulose fibers include natural cellulose fibers such as cotton, and regenerated cellulose fibers such as viscose rayon and cuprammonium rayon (cupra).

[0044] The liquid storage layer 20 is preferably made of rayon. That is, the nonwoven fabric constituting the liquid storage layer 20 is preferably a nonwoven fabric containing rayon or a nonwoven fabric made of rayon. Such nonwoven fabrics are compressible and absorbent, and rayon is a resin containing hydroxyl groups and insoluble in water, which can advantageously store sufficient amounts of biological fluid absorbed by the needle-shaped portion 11 for various analyses. Furthermore, rayon has long fibers, high water absorption, and high strength. Therefore, in addition to being suitable as a material for the liquid storage layer 20, rayon is not easily broken during liquid extraction. Furthermore, rayon does not easily lose short fibers, which does not interfere with the analysis of components in the liquid. Furthermore, because rayon fibers are self-adhesive and can be formed into a sheet, the liquid storage layer 20 can be manufactured without containing unnecessary additives (impurities), which eliminates the need to consider impurities in analyses.

[0045] In this embodiment, the base 21 and the liquid storage layer 20 are made of materials with different compositions. The base 21 is made of the same biodegradable resin as the needle-shaped portion 11, and the liquid storage layer 20 is made of a nonwoven fabric formed from cellulose fibers. By making the needle-shaped portion 11 and the liquid storage layer 20 out of materials with different compositions in this manner, it is possible to use a material for the liquid storage layer 20 that is more liquid absorbent than the needle-shaped portion 11, thereby increasing the amount of liquid that can be stored in the liquid storage layer 20. For example, it is possible to use a material for the needle-shaped portion 11 that has a high acid dissociation constant, is less irritating to the living body, such as polycaprolactone, but has poor liquid absorption properties, while using a material with high liquid absorption properties for the liquid storage layer 20. In this way, it is possible to use a material for the needle-shaped portion 11 that has a different liquid absorption function from that of the liquid storage layer 20. Furthermore, as in this embodiment, it is also possible to use a material in a form that cannot be used for the needle-shaped portion 11, such as a nonwoven fabric, for the liquid storage layer 20.

[0046] Furthermore, the needle-shaped portion 11 and the liquid storage layer 20 may be made of porous materials of the same composition but with different pore structures. For example, it is possible to increase the strength of the needle-shaped portion 11 by making the volume of the pores 12 in the total volume relatively small, and to obtain a microneedle structure 10 that can hold more liquid by making the volume of the pores 12 in the liquid storage layer 20 large. Furthermore, although only one layer of the liquid storage layer 20 is provided in this embodiment, it may also be configured to consist of multiple layers. For example, it may be configured by laminating multiple different nonwoven fabrics, or by laminating materials with different pore structures.

[0047] (Tape) In this embodiment, the tape 30 has a rectangular shape larger than the base 21 when viewed from above. Therefore, the tape 30 covers the microneedle structure (the liquid storage layer 20 and the base 21), and the portion of the tape 30 outside the base 21 is directly attached to the skin. The tape 30 is preferably liquid-impermeable. A liquid-impermeable tape 30 prevents liquid from spreading from the liquid storage layer 20 toward the tape 30, allowing the liquid storage layer 20 to efficiently absorb the liquid. Examples of liquid-impermeable tapes 30 include those with a resin film as a base material. Examples of resins used for the resin film include polyester resins such as polyethylene terephthalate, polyolefin resins such as polyethylene, and polyurethane resins. Furthermore, the base material of the tape 30 may be, for example, a stretchable nonwoven fabric, woven fabric, or knit fabric, taking into consideration the conformability when applied to a living body. Conventionally known materials can be used. To impart liquid-impermeability to nonwoven fabrics, woven fabrics, or knit fabrics, these may be impregnated with a resin.

[0048] An adhesive layer (not shown) is provided on the tape 30. This adhesive layer is preferably a biologically safe adhesive because it is attached to the skin, and examples of such adhesive include acrylic adhesives, rubber adhesives, etc. The adhesive layer is configured to have a weak adhesive strength that allows the microneedle structure 10 to be removably attached after being attached to the microneedle structure 10.

[0049] A film 31 is provided between the liquid storage layer 20 and the tape 30 to prevent the adhesive layer of the tape 30 from coming into direct contact with the liquid storage layer 20. The film 31 may be provided on the tape 30 in advance. In this case, the film 31 may be a release sheet of the tape 30.

[0050] A liquid-impermeable film is preferable as the film 31. The same material as the base material of the liquid-impermeable tape 30 described above can be used.

[0051] Furthermore, a plurality of through holes 32 are formed at intervals around the periphery of the liquid storage layer 20 of the tape 30, so that air can be pushed out through the through holes 32 when the tape 30 is applied. Note that, in the manufacturing process, it is preferable that the through holes 32 are formed before application.

[0052] 3 to 5 show a method for manufacturing the microneedle patch 1 according to an embodiment of the present invention. In this embodiment, as shown in Fig. 3(a), a mixture 41 containing a needle-shaped portion material and a pore-forming material is prepared (preparation step), and as shown in Fig. 3(b) and (c), a predetermined process is carried out to give the mixture 41 a desired shape, thereby obtaining a solid composition 42 (composition formation step).

[0053] Thereafter, as shown in Figures 4(a) and (b), the solid composition 42 is heated and pressurized to form protrusions 43 (protrusion formation process), and then, as shown in Figure 4(c), the pore-forming material is dissolved and removed from the protrusions 43 to form needle-shaped portions 11 (removal process).

[0054] Through these steps, the protrusions 43 become needle-shaped portions 11 as shown in Fig. 5(a). Thereafter, as shown in Fig. 5(b), a tape 30, which is a removable adhesive sheet in which the adhesive layer is sealed with a polyethylene terephthalate film, and a liquid storage layer 20 are provided to obtain the microneedle structure 10 and the microneedle patch 1.

[0055] (Preparation step) First, a mixture 41 of the material constituting the needle-shaped portion 11 and the pore-forming material is prepared. The above-mentioned materials can be used as the material constituting the needle-shaped portion 11. In order to make it easier for the pore-forming material to diffuse into the material constituting the needle-shaped portion 11, the material constituting the needle-shaped portion 11 may be heated and melted before use.

[0056] Examples of pore-forming materials include water-soluble materials with melting points 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 thermoplastic water-soluble resin, preferably one with a melting point higher than room temperature. Examples of thermoplastic water-soluble resins include the biodegradable resins described below, as well as hydroxypropyl cellulose and polyvinylpyrrolidone. Furthermore, considering the effects on the human body, it is more preferable that the thermoplastic water-soluble resin be biodegradable. Examples of such biodegradable and thermoplastic water-soluble 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 glycol being particularly preferred.

[0057] The pore-forming material is preferably water-soluble particles made of the water-soluble material described above. The particulate shape makes it possible to preferably form the flow paths 13 and the holes 12 in the needle-shaped portion 11 and the base portion 21.

[0058] The material constituting the needle-shaped portions 11 and the pore-forming material are preferably mixed at a mass ratio of 8:2 to 2:8, and more preferably 7:3 to 3:7. By forming the mixture 41 at this ratio, needle-shaped portions 11 with the desired porosity can be formed, and it becomes easier to achieve both liquid permeability and strength for the needle-shaped portions 11.

[0059] The pore-forming material may be mixed with a solvent, such as isopropyl alcohol, ethyl acetate, ethanol, dichloromethane, dimethylformamide, or toluene.

[0060] The mixture 41 may contain not only the material constituting the needle-shaped portion 11 and the pore-forming material, but also other materials, such as a filler.

[0061] (Composition Forming Step) The mixture 41 is poured into a recess 45 for a solid composition formed in a mold (die) 44 for a solid composition. The recess 45 for a solid composition may be formed with a shape and volume that allows a desired amount of the mixture 41 to be stored therein.

[0062] The material of the mold 44 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 mixture 41, and in this embodiment it is made of polydimethylsiloxane.

[0063] With the mixture 41 stored in the recess 45 for the solid composition, unnecessary mixture 41 is removed with a spatula or the like, and the surface of the resulting solid composition 42 is flattened. In this case, heating may be performed to partially remove the solvent contained in the mixture 41. The solid composition mold 44 is then pressurized at 2 to 20 MPa, and after the pressure is released, the mixture is held at −10 to 15°C for 1 to 60 minutes, whereby the molten mixture 41 solidifies and becomes solid. When the mixture is held in a cooled state, it may be sandwiched between, for example, cooled SUS plates. The mixture is then heated at 35 to 70°C to evaporate the remaining solvent from the solid mixture 41, thereby drying the mixture, and the solid composition 42 is obtained.

[0064] 4( a), the solid composition 42 is placed in a recess 51 of a mold 52 having a recess 51. As with the mold 44 for the solid composition, the material of the mold 52 is not particularly limited, but it is preferable that the mold 52 be made of a silicone compound or the like that makes it easy to form an accurate mold and to peel off the solid composition 42, and in this embodiment, it is made of polydimethylsiloxane.

[0065] A protrusion-forming recess 53 is formed in the center of the bottom surface of the recess 51. The protrusion-forming recess 53 is for forming the needle-like portion 11 and is formed in a shape and size corresponding to the needle-like portion 11. A lid 54 of the mold 52 is then placed on the other surface side (rear side). This lid 54 is also made of polydimethylsiloxane. The solid composition 42 is placed on the protrusion-forming recess 53.

[0066] Next, a heating and pressurizing treatment is carried out to form the desired shapes of protrusions 43, etc. In this case, the heating and pressurizing treatment may be carried out all at once, but as in the present embodiment, it is preferable to carry out the heating and pressurizing treatment in two steps: a preliminary step of starting to melt the solid composition 42 so that the solid composition 42 is sufficiently filled into the recesses 51 and the protrusion-forming recesses 53 of the mold 52; and a main step of sufficiently filling the recesses 51 and the protrusion-forming recesses 53 of the mold 52 with the molten solid composition 42.

[0067] 4(b), in the preliminary step and the main step, the solid composition 42 is placed in the recess 51 and sandwiched between the mold 52 and the lid 54. Then, in this state, the mold 52 and the lid 54 are placed on the lower stage 56, and the upper stage 57 is placed on the mold 52 and the lid 54.

[0068] The heating conditions in the preliminary step and this step may be any temperature higher than the melting point of the material constituting the needle-shaped portion 11, and in this embodiment, heating is performed at a temperature at which the solid composition 42 can melt. Note that, to heat the solid composition 42, 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.

[0069] 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 42 can be melted in a short time, and the molten solid composition 42 can be quickly filled into the recesses 51, etc. Then, by maintaining this state for 10 seconds to 10 minutes, the solid composition 42 becomes molten. 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.

[0070] By carrying out the preliminary step and the main step as in this embodiment, the solid composition 42 is sufficiently melted and filled into the recesses 51 and the protrusion-forming recesses 53 .

[0071] Thereafter, the mold 52 is removed from the lower stage 56, and the molten solid composition 42 is refrigerated and solidified by being held at −10 to 15° C. for 1 to 60 minutes, thereby forming the protrusions 43 and the like having a shape corresponding to the protrusion-forming recesses 53 and having high transferability.

[0072] (Removal Step) Then, the solid composition 42 on which the solidified protrusions 43 have been formed is separated from the mold 52 and left to stand in a cleaning solution to remove the pore-forming material, thereby performing a removal step to form the needle-shaped portions 11.

[0073] The cleaning solution used in this removal step contains water, and the removal step is performed by placing the solid composition 42 on which the protrusions 43 have been formed in a cleaning solution 58, as shown in FIG. 4(c). By placing the solid composition 42 in a cleaning solution containing water, the pore-forming material contained in the protrusions 43, etc., that is exposed to the outside or that is connected to the exposed portions dissolves and flows into the water, where it is removed. The cleaning solution 58 may contain water, and may be, for example, a mixed solvent of water and alcohol. This removal forms holes 12 in the protrusions 43, etc., and forms needle-shaped portions 11 made of a water-insoluble component, as shown in FIG. 5(a). In addition to the needle-shaped portions 11, the pore-forming material is also removed from the molten solid composition 42 that had adhered to the recesses 51 by filling them, and the base 21 is also formed with the same porous structure.

[0074] 5(b), the liquid storage layer 20 is placed at a predetermined position on the back side of the obtained base 21. Thereafter, a tape 30 having a film 31 as a release layer is laminated so as to cover the liquid storage layer 20, thereby manufacturing a microneedle patch 1 having the microneedle structure 10 of this embodiment that is capable of extracting a desired amount of liquid.

[0075] The method for fixing the liquid storage layer 20 to the back surface of the base 21 is not limited to this, and the base 21 may also be bonded by heating and melting it, followed by cooling. In this case, the liquid storage layer 20 and the base 21 may be bonded to each other at the stage of the solid composition 42 for forming the base 21, before the removal step. When the liquid storage layer 20 and the base 21 are both sintered porous bodies, the resin particles for forming the liquid storage layer 20 and the resin particles for forming the base 21 may be sintered simultaneously to form the liquid storage layer 20 and the base 21 integrally.

[0076] Second Embodiment A second embodiment of the present invention will be described below. In this embodiment, the same components as those in the first embodiment are denoted by the same reference numerals, and the description thereof will be omitted.

[0077] In the microneedle structure 10 of the first embodiment described above, the base 21 and the liquid storage layer 20 are fixed with tape 30, or the base 21 and the liquid storage layer 20 are fixed by heating. In contrast, the microneedle structure 60 of the microneedle patch of the present embodiment shown in Fig. 6 differs from the microneedle structure 10 of the first embodiment in that the base 21 made of a porous material and the liquid storage layer 20 made of a porous material are bonded with a resin with good interfacial permeability, rather than using tape 30 as in the microneedle structure 10 of the first embodiment, and that a resin (not shown) is attached to the interiors (pores) of the base 21 made of a porous material and the liquid storage layer 20 made of a porous material. Due to the good interfacial permeability between the base 21 made of a porous material and the liquid storage layer 20 made of a porous material, a larger amount of biological liquid can be absorbed and stored in the liquid storage layer 20 even if the puncture time of the microneedle structure 10 is the same.

[0078] The porous materials that can be used for the base 21 and the liquid storage layer 20 of the microneedle structure 60 can be those described in embodiment 1. In this embodiment, the base 21 is made of a water-insoluble resin from which the pore-forming material has been removed by a salt leaching method, and the liquid storage layer 20 is a nonwoven fabric made of cellulose fibers. Even if the base 21 and the liquid storage layer 20 are formed from different materials in this way, in this embodiment, as described below, resin is attached to the opposing surfaces of the base 21 and the liquid storage layer 20, and the resin bonds them with good interfacial permeability.

[0079] In the microneedle patch of this embodiment, the base 21 and the liquid storage layer 20 are bonded via resin, so there is no need to fix the liquid storage layer 20 to the base 21 with tape 30. Unlike the microneedle patch 1 of embodiment 1, since there is no need to fix them with tape 30, in the microneedle patch of this embodiment, the areas of the base 21 and the liquid storage layer 20 in top view can be made the same, which makes it possible to reduce the material of the base 21 and to increase the area of ​​the liquid storage layer 20.

[0080] Specifically, the resin is adhered to the outer surfaces of the porous material constituting the base 21 and the liquid storage layer 20, and to the interior, i.e., the inner surfaces of the pores formed in the porous material. Different resins may be adhered to the porous material constituting the base 21 and the porous material constituting the liquid storage layer 20. However, from the viewpoint of ease of manufacturing the microneedle structure 60 and the expected improvement in adhesiveness, it is preferable that a common resin be adhered. When different resins are used, it is preferable to select resins that are easily miscible with each other. Depending on the amount and concentration of the resin in the resin solution described below, the resin may be adhered to the porous material in a dotted pattern, a patchy pattern, or a continuous pattern along the porous material, forming a film inside the pores 12 of the base 21 and the flow channel 11. In this embodiment, the resin is adhered continuously along the porous material, i.e., in a film-like pattern, to the areas on the outer surfaces of the base 21 and the liquid storage layer 20 where the porous material is present (areas where the pores are not exposed) and to the inner surfaces of the pores. Since the resin is continuously attached along the porous material in this manner, it is believed that the resin can bond the base 21 and the liquid storage layer 20 with better interfacial permeability. Note that the resin does not need to be in the form of a film, as long as it is attached to the porous material.

[0081] In this way, in the microneedle patch of this embodiment, the base 21 and the liquid storage layer 20 are bonded together with resin, so that liquid is less likely to stagnate between the base 21 and the liquid storage layer 20, and the liquid storage layer 20 can absorb and store liquid more efficiently. Furthermore, if the resin is a hydrophilic resin, the adhesion of the hydrophilic resin makes it easier for liquid to penetrate and be absorbed into the porous material, and the liquid absorbency of the microneedle structure 60 can be further improved.

[0082] Such a microneedle structure 60 may be manufactured by any method as long as the base 21 and the liquid storage layer 20 made of a porous material are bonded with a resin with good interfacial permeability, but the present embodiment applies a manufacturing method in which some of the manufacturing steps are different from those of Embodiment 1. That is, the manufacturing method of the microneedle patch according to the present embodiment, in addition to the manufacturing method of Embodiment 1, includes an impregnation step in which at least one of the base 21 and the liquid storage layer 20 is impregnated with a resin solution, and a drying step in which, after the impregnation step, the solvent is volatilized from the resin solution and the resin is dried in a state in which the base 21 and the liquid storage layer 20 are stacked together, thereby bonding the base 21 and the liquid storage layer 20 with the resin.

[0083] That is, in the manufacturing method of the microneedle patch, the preparation process through the removal process are performed in the same manner as in the first embodiment. Then, the impregnation process described above is performed, in which at least one of the base 21 and the liquid storage layer 20 is impregnated with a resin solution. Next, the base 21 and the liquid storage layer 20 are stacked together. During this process, the resin solution impregnated into the base 21 and / or the liquid storage layer 20, which are made of a porous material, permeates from one of the components impregnated with the solution to the other, or permeates between the components impregnated with the solution. Then, in a drying process, the solvent is volatilized from the resin solution in the stacked state of the base 21 and the liquid storage layer 20, and the resulting layers are dried, causing the remaining resin to adhere to the base 21 and the liquid storage layer 20, thereby obtaining the microneedle structure 60 described above. Details are described below.

[0084] (Impregnation Step) As described above, in the impregnation step, the resin solution is impregnated into at least one of the base 21 and the liquid storage layer 20. Specifically, the base 21 etc. after the removal step (the base 21 and the needle-like portion 11 formed from the solid composition 42) or the liquid storage layer 20 can be immersed directly in the resin solution, or the solution can be applied to the base 21 etc., thereby impregnating the base 21 etc.

[0085] When the base 21 is impregnated with a resin solution, the resin solution impregnated into the base 21 permeates into the liquid storage layer 20 when the base 21 is laminated with the liquid storage layer 20. Furthermore, when the liquid storage layer 20 is impregnated with a resin solution, the base 21 and the liquid storage layer 20 are subsequently laminated, and the resin solution contained in the liquid storage layer 20 permeates into the base 21, thereby impregnating the base 21 with the resin solution. In this way, by impregnating one of the base 21 and the liquid storage layer 20 with the resin solution, the resin solution can also permeate and impregnate the other of the base 21 and the liquid storage layer 20 when they are laminated. Furthermore, the base 21 and the liquid storage layer 20 may each be immersed in the resin solution to be impregnated. Furthermore, in order to promote penetration into the porous material, an impregnated base 21 and an unimpregnated liquid storage layer 20 may be stacked together, or an impregnated liquid storage layer 20 and an unimpregnated base 21 may be stacked together, and then these may be placed in a reduced pressure environment.

[0086] It is preferable that the solvent contained in the resin solution used in the impregnation process is a solvent in which the material constituting the base 21 or the needle-shaped portion 11 does not dissolve. For example, if the needle-shaped portion 11 is formed from a polyester resin such as polycaprolactone, it is preferable that the solvent be water, an alcohol with a small number of carbon atoms such as ethanol, or the like.

[0087] The resin contained in the resin solution is not particularly limited as long as it can bond the base 21 and the liquid storage layer 20, but a hydrophilic resin is preferred. Examples of hydrophilic resins include starch, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl ether, and polyacrylates. A resin that is soluble in water or warm water is preferred, as this facilitates adhesion of the resin to the interior of the porous material of the base 21 and the liquid storage layer 20 by impregnating the solution and drying.

[0088] The solution preferably has a resin concentration of 1 to 20%, more preferably 1 to 10%, and most preferably 1 to 5%. A concentration of 1% or more tends to increase the adhesiveness of the resin between the base 21 and the liquid storage layer 20, while a concentration of 20% or less allows the amount of resin to be adjusted to an appropriate level, which is thought to prevent the flow of liquid through the holes from being hindered.

[0089] Furthermore, before the impregnation step, plasma irradiation may be performed as a pretreatment on the base 21 and the needle-shaped portion 11. In particular, when a hydrophilic resin is used as the resin in the impregnation step, plasma treatment can make the adhered resin less likely to peel off.

[0090] (Drying Process) As described above, the base 21 and the liquid storage layer 20 are laminated together and the moisture is evaporated to dry them. At this time, the resin adheres to the inside of the holes 12 of the base 21 and the inside of the liquid storage layer 20, bonding the base 21 and the liquid storage layer 20 together. Furthermore, this method does not prevent the flow of liquid at the interface between the base 21 made of a porous material and the liquid storage layer 2 made of a porous material.

[0091] When the base 21 and the liquid storage layer 20 including paper, nonwoven fabric, woven fabric, or knit are bonded together by, for example, heating and melting the resin that constitutes the base 21, the resin that constitutes the base 21 and the needle-like portions 11 may penetrate into the paper, nonwoven fabric, woven fabric, or knit, which may result in an unintended shape of the base 21 or the needle-like portions 11. Furthermore, when the base 21 is formed by the salt leaching method, if a removal step is performed after bonding the base 21 and the liquid storage layer 20, the paper, nonwoven fabric, woven fabric, or knit of the liquid storage layer 20 may absorb the cleaning solution, causing the liquid storage layer 20 to warp, which may result in an unintended shape of the microneedle structure. In contrast, in the method for manufacturing a microneedle patch according to this embodiment, the base 21 and the liquid storage layer 20 including the nonwoven fabric can be bonded without heat melting, and the base 21 and the liquid storage layer 20 can be bonded after the removal step, which prevents problems such as defective shapes of the base 21 or the needle-like portions 11 and warping of the liquid storage layer 20. Furthermore, the base 12 and the liquid storage layer 20 can be bonded easily without significantly increasing the number of manufacturing steps.

[0092] The drying temperature in the drying step is about 28 to 120°C, and is preferably lower than the temperatures at which deformation of the water-insoluble resin is likely to occur, such as the melting point, softening point, and glass transition temperature. For example, when the water-insoluble resin is polycaprolactone, which has a melting point of 60°C, the drying temperature is preferably 50°C or lower. The drying time is not particularly limited as long as drying is possible, but is, for example, about 10 minutes to 72 hours.

[0093] To specifically explain one example of a method for manufacturing such a microneedle patch, first, after the removal step, the base 21 and the like are immersed in an aqueous solution of polyvinyl alcohol as a resin solution, and the base 21 is impregnated with the aqueous solution. Then, a nonwoven fabric made of cupric ammonium rayon as the liquid storage layer 20 is overlaid on the base 21 and placed in a reduced pressure environment (low vacuum environment) of about 0.01 to 0.3 MPa, allowing the nonwoven fabric to absorb the aqueous solution. Then, the base 21 and the nonwoven fabric are dried by volatilizing the water in the aqueous solution. This results in the microneedle structure 60 of this embodiment, in which the back side of the base 21 and the liquid storage layer 20 made of nonwoven fabric are bonded with the resin.

[0094] In this embodiment, the liquid storage layer 20 is adhered to the base 21 and does not need to be fixed to the back surface of the base 21 with the tape 30, but for example, a microneedle patch may be formed by providing the tape 30 to fix the microneedle structure 60 to the surface of a living body. After the drying step, the tape 30 is laminated to cover the liquid storage layer 20 in the patch formation step, thereby making it possible to manufacture a microneedle patch having the microneedle structure 60 of this embodiment that is capable of extracting a desired amount of liquid as shown in Figure 6.

[0095] The present invention will be described in detail below using examples. Microneedle patches were manufactured according to Examples 1-1 to 1-3 and a reference example, and the liquid absorption rate of the liquid storage layer of each microneedle patch was evaluated by weight measurement. Furthermore, microneedle patches were manufactured according to Examples 2-1 to 2-15 and a comparative example, and the adhesive state of the nonwoven fabric and the liquid absorption evaluation were performed.

[0096] (Example 1-1) Sodium chloride (Nakuru UM-05, manufactured by Naikai Salt Industry Co., Ltd.) with an average particle size of 5 μm was used as the pore-forming material. In order to break up the aggregation of the pore-forming material particles, the pore-forming material was ground in a mortar beforehand. 7 g of the pore-forming material was transferred to a 100 mL beaker. 5 g each of isopropyl alcohol and ethyl acetate were poured into the beaker as solvents, and the mixture was dispersed using an ultrasonic device.

[0097] Thereafter, 3 g of pellet-shaped polycaprolactone (weight average molecular weight 40,000, melting point 60°C) was placed in a beaker, and the beaker was placed on a hot plate heated to 65°C and left to stand for 1 hour to melt the polycaprolactone. Next, the mixture was stirred using a pencil mixer (manufactured by AS ONE Corporation) to obtain a mixture 41 of the pore-forming material and the material constituting the needle-shaped portion 11.

[0098] Then, a mold 44 for a solid composition made of polydimethylsiloxane was prepared. The recess 45 for a solid composition of the mold 44 for a solid composition had an opening in the shape of a square measuring 20 mm x 20 mm on each side and a depth of 0.25 mm. The prepared mixture 41 was poured into the recess 45 for a solid composition of the mold 44 for a solid composition. Next, the amount of the mixture 41 poured into the recess 45 for a solid composition that did not fit into the recess was scraped off with a spatula. The mixture was then left to stand on a hot plate heated to 120°C for 10 minutes to partially remove the solvent. Furthermore, in order to flatten the mixture, a jig was prepared in which a release film was attached to one side of a stainless steel plate (2 mm thick, rectangular in shape with short sides of 80 mm and long sides of 100 mm when viewed from above) with double-sided tape so that the release-treated surface faced outward. This jig was placed on the mixture 41 poured into the mold for solid composition 44 so that the release-treated surface was adhered, and a pressure of 10 MPa was applied for 3 minutes using a heated press (AH-1T, manufactured by AS ONE Corporation) with no temperature setting. After the pressure was released, the mold for solid composition 44 into which the jig and the mixture 41 had been poured were sandwiched from above and below between two SUS plates (2 mm thick, rectangular in shape with short sides of 80 mm and long sides of 100 mm when viewed from above) that had been cooled to 3°C in advance, and the four corners of the two SUS plates were fixed with clips. The mixture was cooled and solidified for 10 minutes, and the solidified mixture 41 was removed from the mold for solid composition 44.

[0099] The mixture 41 was then left to stand in a drying oven (40° C.) for 24 hours, and the remaining solvent was evaporated again to dry the mixture 41. As a result, a solid composition 42 was obtained.

[0100] Next, a mold 52 was prepared. The mold 52 was made of polydimethylsiloxane and had a plurality of protrusion-forming recesses 53 for forming the needle-like portions 11. The protrusion-forming recesses 53 had the following characteristics: Shape of the protrusion-forming recesses 53: conical with a circular cross section Diameter of the largest cross section of the protrusion-forming recesses 53: 300 μm Height of the protrusion-forming recesses 53: 600 μm Pitch of the protrusion-forming recesses 53: 1000 μm Number of the protrusion-forming recesses 53: 7 vertical columns and 7 horizontal columns, totaling 49 Size of the area where the protrusion-forming recesses 53 were formed: 6.3 mm square Arrangement of the protrusion-forming recesses 53: square lattice

[0101] Next, the mold was placed on the lower stage of a heating press (AH-1T, manufactured by AS ONE Corporation), and the solid composition 42 was placed on the protrusion-forming recesses 53. Furthermore, a 30 mm square lid 54 (a polydimethylsiloxane sheet) was placed on top of the solid composition 42.

[0102] As a preliminary step, the solid composition 42 was pressed at 2 MPa for 1 minute and 30 seconds while the lower stage 56 was heated to a set heating temperature of 115°C and the upper stage 57 was heated to a set heating temperature of 105°C. Thereafter, as a main step, the solid composition 42 was pressed at 3 MPa for 30 seconds while the lower stage 56 and the upper stage 57 were heated to the same temperatures as in the preliminary step. Thereafter, the solid composition 42 molten between the lid 54 and the mold 52 was refrigerated at 3°C ​​for 5 minutes to solidify the solid composition 42. As a result, a sample having protrusions 43 and the like formed thereon was obtained.

[0103] Next, the sample was peeled from the mold 52 and immersed in purified water at room temperature for 1 hour and stirred with a stirrer bar. The sample was fixed to the wall of the container with double-sided tape to avoid contact with the stirrer bar. The purified water was then replaced, and the sample was immersed in purified water at room temperature for another 1 hour and stirred with a stirrer bar to dissolve and remove the pore-forming material. The sample was then placed in a drying oven (40°C) for 24 hours, allowing the water and solvent to completely evaporate and dry. This resulted in the formation of holes 11 and flow paths 13 in the needle-shaped portion 12 and base 21.

[0104] In the center of the surface where the needle-shaped portions 11 were not formed, a circular, 10 mm diameter nonwoven fabric made of cupra (cupra continuous fiber nonwoven fabric, Bemliese, SN-140, manufactured by Asahi Kasei Corporation, thickness: 70 μm) was placed as the liquid storage layer 20. In addition, a removable adhesive sheet with an adhesive layer partially sealed with a polyethylene terephthalate film was prepared as the tape 30. This adhesive sheet was a square with four 20 mm sides, similar to the shape of the outer edge of the microneedle structure, and a polyethylene terephthalate film (thickness: 50 μm) of the same shape as the liquid storage layer 20 was attached to the center of the adhesive layer, thereby functioning as the film 31.

[0105] Eight through-holes 32 were also drilled at equal intervals in the tape 30 along the outer edge of the film 31. The tape 30 was attached to the surface of the microneedle structure 10 on which the liquid storage layer 20 was placed, thereby obtaining a microneedle patch 1. The removable adhesive sheet can be peeled off from the surface of the microneedle structure, and the liquid storage layer 20 does not adhere to the adhesive layer of the tape 30. Therefore, after storing a biologically derived liquid in the liquid storage layer 20 using the microneedle patch 1, the tape 30 can be peeled off to safely remove the liquid storage layer 20.

[0106] (Example 1-2) A microneedle patch 1 was produced in the same manner as in Example 1, except that a sintered porous body formed from polylactic acid particles described below was used as the liquid storage layer 20 instead of a nonwoven fabric made of cupra, and the liquid storage layer 20 was directly fixed to the base 21.

[0107] Specifically, polylactic acid particles with a particle size of 20 μm were prepared, sealed in a 20 mm square polydimethylsiloxane mold, and heated to 120°C and held at a pressure of 1 mPa for 60 minutes to sinter the polylactic acid particles together, resulting in a sintered porous body with a thickness of 200 μm and a size of 20 mm × 20 mm. A solid composition 42 was then placed in a mold 52, and the sintered porous body was placed on top of the solid composition 42, followed by a heating treatment similar to that in Example 1. This resulted in a microneedle structure 10 in which the base 21 and the liquid storage layer 20 made of the sintered porous body were bonded together.

[0108] (Examples 1-3) A microneedle patch was prepared in the same manner as in Example 1, except that the liquid storage layer 20 was formed using the following porous material instead of a nonwoven fabric made of cupra, and the liquid storage layer 20 was directly fixed to the base 21. 3.5 g of sodium chloride having an average particle size of 5 μm and 3.5 g of sodium chloride (Nakuru UM, manufactured by Naikai Salt Industry Co., Ltd.) having an average particle size of 45 μm were blended as a pore-forming material, and a solid composition for the liquid storage layer was prepared in the same manner as in Example 1. Then, in the step of placing the solid composition 42 on the mold 52 in Example 1, this solid composition for the liquid storage layer was placed on the solid composition 42, and simultaneously subjected to heating and pressure treatment. As a result, the liquid storage layer 20 was adhered and laminated on the base 21. In this case, the thickness of the liquid storage layer 20 was 200 μm or more. In this manner, a microneedle structure 10 was obtained, in which a liquid storage layer 20 having the same composition as the needle-shaped portion 11 but a different structure was formed.

[0109] (Examples 1-4) A microneedle patch was prepared in the same manner as in Example 1, except that the liquid storage layer 20 was formed using the following porous material instead of a nonwoven fabric made of cupra, and the liquid storage layer 20 was directly fixed to the base 21. The amount of sodium chloride (a pore-forming agent) with an average particle size of 5 μm was changed to 7 g, and a solid composition for the liquid storage layer was prepared similarly to the solid composition 42 in Example 1. Then, instead of placing the solid composition 42 on the mold 52 in Example 1, this solid composition for the liquid storage layer was placed on top of the solid composition 42, and simultaneously subjected to heating and pressure treatment. As a result, the liquid storage layer 20 was adhered and laminated on the base 21. In this case, the thickness of the liquid storage layer 20 was 500 μm or more. In this manner, a microneedle structure 10 was obtained, in which a liquid storage layer 20 having the same composition and structure as the needle-shaped portion 11 was formed.

[0110] Comparative Example 1-1 A microneedle patch was produced in the same manner as in Example 1, except that the microneedle structure was used as a microneedle patch without being provided with the liquid storage layer 20 .

[0111] (Evaluation Method) The liquid absorption rate of the microneedle patches 1 obtained in Examples 1-1 to 1-4 was measured and evaluated.

[0112] First, 300 mg of agarose gel (NE-AG01, manufactured by Fast Gene) was placed in a petri dish, and 27 ml of purified water and 3 ml of phosphate-buffered saline (PBS) (Nacalai Tesque, Inc., Dulbecco's phosphate-buffered saline (10-fold concentrated): D-PBS(-) (10x)) were mixed using a measuring cylinder to prepare a 10-fold diluted solution, which was then poured into the petri dish containing the agarose gel. The petri dish containing this mixture was placed on a hot plate heated to 120°C, and the agarose gel was dissolved while stirring with a spoon. The mixture was then allowed to cool to room temperature, yielding a 1% agarose gel containing PBS.

[0113] The needle-shaped portion 11 of the microneedle patch 1 was punctured into this agarose gel, and the microneedle patch 1 was lightly pressed with a finger five times, and the finger was left there and held for one minute. This operation was repeated five times. Thereafter, the microneedle patch 1 was removed from the agarose gel, and water droplets on the needle-shaped portion 11 were removed by blowing them off with an air blow gun. The weight of the microneedle patch 1 after liquid absorption was then measured. The liquid absorption rate (the ratio of the absorbed PBS to the weight of the microneedle patch 1) was then calculated using the following formula. Note that for the microneedle patch 1 of Example 1, the microneedle structure and the liquid storage layer 20, excluding the tape 30, were used as a sample, and the total weight of these was measured. Liquid absorption rate (%) = (weight of sample after liquid absorption - weight of sample before liquid absorption) ÷ weight of sample before liquid absorption × 100

[0114] The liquid absorption rate of the microneedle patch obtained in Comparative Example 1-1 was also examined in the same manner. Three microneedle patches were prepared for each example and comparative example, and the liquid absorption rate of each was examined, and the average liquid absorption rate of each of the three microneedle patches was calculated. The results are shown in Table 1.

[0115]

[0116] As shown in Table 1, compared with the comparative examples, all of the examples showed high absorption rates and were able to sufficiently absorb body fluids. In particular, Example 1 had the highest absorption rate.

[0117] Example 2-1: 3.0 g of pelletized polycaprolactone (weight-average molecular weight 50,000, melting point 60°C) was prepared as the needle-shaped portion-forming resin. This was placed in a 100 ml beaker, followed by the addition of 6.0 g of ethyl acetate as a solvent. The beaker was placed on a hot plate heated to 65°C and stirred with a stir bar at 300 rpm for 60 minutes. To this was added 6.3 g of sodium chloride (Nacul UM-10, manufactured by Naikai Salt Industry Co., Ltd.) with an average particle size of 10 μm and 0.7 g of polyethylene glycol (weight-average molecular weight 4,000, melting point 40°C) as a pore-forming agent (water-soluble particles). Next, 2.0 g of ethyl acetate was separately prepared and added dropwise along the edge of the beaker. While maintaining the temperature at 65°C, the magnetic stirrer's rotation speed was increased to 500 rpm, and stirring was continued for an additional 10 minutes to obtain mixture 41.

[0118] Next, a polydimethylsiloxane mold 44 for a solid composition was prepared. The opening of the solid composition recess 45 in the mold 44 for a solid composition was a square with sides of 20 mm x 20 mm and a depth of 0.25 mm. The prepared mixture 41 was dropped into the solid composition recess 45 in the mold 44 for a solid composition using a dropper with its tip cut off. Next, the amount of mixture 41 that had been poured into the solid composition recess 45 and did not fit into the recess was scraped off with a spatula.

[0119] The mold 44 for the solid composition was then placed on a hot plate heated to 120°C for 10 minutes to remove the solvent. Furthermore, the surface of this mixture was flattened. Specifically, a stainless steel plate (a rectangle with a thickness of 2 mm, a short side of 80 mm, and a long side of 100 mm) was first prepared, and a release film was attached to one side of this stainless steel plate with double-sided tape so that the release-treated surface faced outward, creating a jig. This jig was placed on the mixture 41 poured into the mold 44 for the solid composition so that the release-treated surface was adhered. The mixture was then pressurized at 10 MPa or more for 10 minutes using a heated press (AH-1T, manufactured by AS ONE Corporation) with no temperature setting. After the pressure was released, the mold 44 for the solid composition into which the jig and the mixture 41 had been poured were placed between two SUS plates (a rectangle with a thickness of 2 mm, a short side of 80 mm, and a long side of 100 mm) that had been cooled to 3°C in advance, the four corners were fixed with clips, and the mixture 41 was cooled for 10 minutes to solidify.

[0120] Next, the solidified mixture 41 was removed from the solid composition mold 44. Then, the mixture 41 was left to stand in a drying oven (30°C) for 24 hours to dry, thereby obtaining a solid composition 42 in which the water-soluble particles were present in a dispersed state.

[0121] Next, a mold 52 was prepared. The mold 52 was made of polydimethylsiloxane and had a plurality of protrusion-forming recesses 53 for forming the needle-like portions 11. The protrusion-forming recesses 53 had the following characteristics: Shape of the protrusion-forming recesses 53: conical with a circular cross section Diameter of the largest cross section of the protrusion-forming recesses 53: 300 μm Height of the protrusion-forming recesses 53: 600 μm Pitch of the protrusion-forming recesses 53: 1000 μm Number of protrusion-forming recesses 53: 3 in the first and seventh rows, 5 in the second and sixth rows, and 7 in the third, fourth, and fifth rows, for a total of 37 Size of the area in which the protrusion-forming recesses 53 were formed: 6.3 mm square Arrangement of the protrusion-forming recesses 53: regular octagonal

[0122] The mold 52 was placed on the lower stage 56 of a heat press (AH-1T, manufactured by AS ONE Corporation). Furthermore, the solid composition 42 was placed on the protrusion-forming recesses 53. Furthermore, a 30 mm square polydimethylsiloxane sheet (lid 54) was placed on top of the solid composition 42.

[0123] As a preliminary step, the solid composition 42 was pressed at 2 MPa for 1 minute and 30 seconds while the lower stage 56 was heated to a set heating temperature of 120°C and the upper stage 57 was heated to a set heating temperature of 110°C. Thereafter, as a main step, the solid composition 42 was pressed at 3 MPa for 30 seconds while the lower stage 56 and the upper stage 57 were heated to the same temperatures as in the preliminary step. Furthermore, the solid composition 42 melted by the lid 54 and mold 52 was refrigerated at 3°C ​​for 5 minutes to solidify the solid composition 42. As a result, a sample on which protrusions 43 and the like were formed was obtained.

[0124] The sample was then peeled off from the mold 52. The sample was then immersed in purified water at room temperature for 1 hour and stirred with a stirrer bar. During this process, the sample was fixed to the wall of the container with double-sided tape to avoid contact with the stirrer bar. The sample was then immersed in a new container of purified water and stirred with a stirrer bar at 200 rpm for 30 minutes. The sample was then immersed in a new container of purified water and stirred again with a stirrer bar at 200 rpm for 30 minutes to dissolve and remove the pore-forming agent, thereby obtaining a base 21 and the like. The sample was then left to stand in a drying oven (30°C) for 24 hours to evaporate the water and dry it.

[0125] Next, as a pretreatment for the impregnation process, plasma irradiation was performed for 30 seconds each on the side of the dried base 21 etc. on which the needle-shaped portion 12 was formed and on the opposite side (back side) from where the needle-shaped portion 12 was formed, using a tabletop vacuum plasma device (YHS-R, manufactured by Sakigake Semiconductor Co., Ltd.).

[0126] Next, polyvinyl alcohol (manufactured by ALDRICH, weight average molecular weight: 31,000 to 50,000) was sealed in a centrifuge tube and diluted with purified water heated to 100° C. to obtain a 1.0% aqueous solution of polyvinyl alcohol.

[0127] The plasma-irradiated base 21 and the like were immersed in a 1.0 wt % polyvinyl alcohol (PVA) aqueous solution and placed in a reduced pressure environment of 0.09 MPa at 25°C for 1 hour, so that the 1.0 wt % PVA aqueous solution penetrated into the interior of the porous material of the base 21 and the like (impregnation process).

[0128] Next, a nonwoven fabric made of cupra (copper ammonium rayon) (Cupra continuous long fiber nonwoven fabric Bemliese, TA-50G, manufactured by Asahi Kasei Corporation, thickness: 310 μm) was cut to the same shape as the base 21 and prepared. The back surface of the base 21 (the surface without the needle-shaped portion 12) was faced to the nonwoven fabric, and the base 21 and the like were placed on top of the nonwoven fabric placed on a horizontal surface and stacked. In this state, the base 21 and the nonwoven fabric were left to stand in a drying oven (30°C) for 24 hours to evaporate the water and dry. Thereafter, the base 21 and the nonwoven fabric were cut into a circle with a diameter of 12 mm so that the region where the needle-shaped portion was formed was located in the center, and the microneedle structure 60 according to Example 2-1 was obtained. In the microneedle structure 60, the base 21 and the nonwoven fabric were adhered without easily peeling off, which was the same in all other Examples.

[0129] Examples 2-2 and 2-3 The microneedle structures 60 were obtained under the same conditions as in Example 2-1, except that the concentration of the aqueous polyvinyl alcohol solution used in the impregnation step was changed to the value shown in Table 2.

[0130] (Example 2-4) The nonwoven fabric was also immersed in the same 1.0 wt% polyvinyl alcohol aqueous solution as that used to immerse the microneedle structure 60 in Example 2-1, and the nonwoven fabric was impregnated with the aqueous solution. As shown in Table 2, the microneedle structure 60 was obtained under the same conditions as in Example 2-1 except for this point.

[0131] Examples 2-5 to 2-12 Microneedle structures 60 were obtained under the same conditions as in Example 2-4, except that the concentration of the aqueous polyvinyl alcohol solution used for immersing the nonwoven fabric or the base 21 was changed to the value shown in Table 2.

[0132] (Example 2-13) The impregnation step for the base 21, etc. was not performed, and instead of placing the base 21, etc. on a nonwoven fabric placed on a horizontal surface, a nonwoven fabric was placed on the back of the base 21, etc. placed on a horizontal surface with the needle-shaped portion 11 facing the horizontal surface, and the nonwoven fabric was layered on the base 21, etc., and then placed in a reduced pressure environment similar to the impregnation step for the base 21, etc., to obtain a microneedle structure 60 under the same conditions as in Example 2-4, except that

[0133] Examples 2-14 and 2-15 Microneedle structures 60 were obtained under the same conditions as in Example 2-13, except that the concentration of the aqueous polyvinyl alcohol solution used for immersing the nonwoven fabric was changed to the value shown in Table 2.

[0134] (Comparative Example 2-1) A base, etc., was obtained in the same manner as in Example 2-1, except that after the impregnation step, the base, etc., was left in a drying oven (30°C) for 24 hours to evaporate the water and dry before being placed on the nonwoven fabric. The obtained base, etc., was cut into a circle with a diameter of 12 mm so that the region where the needle-shaped portions were formed was located in the center, and a nonwoven fabric was placed in the center of the back side of the base, etc., (the surface of the base opposite the surface where the needle-shaped portions were formed). The nonwoven fabric was made of the same material as in Example 2-1, and was a circle with a diameter of 12 mm. It was placed so that its outer periphery overlapped with the base, and this was used as the sample of this example.

[0135] Comparative Examples 2-2 and 2-3 Samples were obtained under the same conditions as in Comparative Example 2-1, except that the concentration of the aqueous polyvinyl alcohol solution used for immersing the base and the like was changed to the value shown in Table 2.

[0136] (Comparative Example 2-4) Instead of adhering a nonwoven fabric after forming the base 21, etc., a solid composition 42 was placed on the protrusion-forming recess 53, and then the same nonwoven fabric as in Example 2-1 was placed on the solid composition 42, and then a 30 mm square polydimethylsiloxane sheet (lid) was placed on top of it. A microneedle structure was obtained in the same manner as in Example 2-1. For the obtained Examples 2-1 to 2-15 and Comparative Examples 2-1 to 2-4, evaluation of the nonwoven fabric adhesion state and liquid absorption evaluation were performed under the following conditions. The results are shown in Table 2.

[0137] (Evaluation of nonwoven fabric adhesion state) When the microneedle structure 60 was bent by hand, the interface between the base and the nonwoven fabric was visually observed. The presence or absence of peeling was evaluated according to the following criteria. Note that in the samples of Comparative Examples 2-1 to 2-3, the base and the nonwoven fabric were not adhered, so this evaluation was not performed. ○: No partial peeling occurred. △: Slight partial peeling occurred. ×: Not slight partial peeling occurred.

[0138] (Liquid absorption evaluation) 300 mg of agarose gel (NE-AG01 manufactured by Fast Gene) was placed in a petri dish. Furthermore, 27 ml of purified water and 3 ml of phosphate-buffered saline (PBS) (Nacalai Tesque, Inc., Dulbecco's phosphate-buffered saline (10-fold concentrated): D-PBS(-) (10x)) were mixed in a measuring cylinder to prepare a 10-fold diluted solution, which was poured into the petri dish containing the agarose gel. The petri dish containing this mixture was placed on a hot plate heated to 120°C, and the agarose gel was dissolved while stirring with a spoon. The mixture was then allowed to cool at room temperature to obtain a 1% agarose gel containing PBS. This agarose gel was used to absorb the microneedle structure 60. That is, the microneedle structure 60 was punctured into the agarose gel and left to stand for 5 minutes. Thereafter, the microneedle structure 60 was removed from the agarose gel, and droplets adhering to the needle-shaped portion 11 were blown off and removed with an air blow gun. Then, the mass of the microneedle structure 60 after liquid absorption was measured. The mass before liquid absorption was also measured in advance before the liquid absorption test. For the samples of Comparative Examples 2-1 to 2-3, the masses of the microneedle structure and the nonwoven fabric were measured after liquid absorption, and the total weight was taken as the weight of the microneedle structure 60, and the mass before liquid absorption was also measured in advance. Then, the liquid absorption rate was calculated according to the following formula 1. (Formula 1) Liquid absorption rate (%) = (mass of microneedle structure after liquid absorption - mass of microneedle structure before liquid absorption) ÷ mass of microneedle structure before liquid absorption × 100

[0139] (Table 2)

[0140] When the Examples and Comparative Examples were examined, the microneedle structures 60 obtained in Comparative Examples 2-1 to 2-3 all had low liquid absorption. This is thought to be because the base and liquid storage layer were not bonded by resin in the microneedle structures 60 obtained in the Comparative Examples compared to the Examples, resulting in inferior liquid absorption. Furthermore, although the base 21 and nonwoven fabric were firmly bonded in the microneedle structure 60 obtained in Comparative Example 2-4, a phenomenon thought to be warping due to the removal process occurred. Furthermore, because no resin was attached to the inside of the porous material of the liquid storage layer, the liquid absorption rate was also low. On the other hand, all of the microneedle structures 60 produced in the Examples had high liquid absorbency.

[0141] REFERENCE SIGNS LIST 1 Microneedle patch 10, 60 Microneedle structure 11 Needle-shaped portion 12 Hole portion 13 Flow path 20 Liquid storage layer 21 Base portion 30 Tape 31 Film 32 Through-hole 41 Mixture 42 Solid composition 43 Protrusion portion 44 Mold for solid composition 45 Recess for solid composition 51 Recess 52 Mold 53 Recess for forming protrusion portion 54 Lid 56 Lower stage 57 Upper stage 58 Cleaning liquid

Claims

1. A microneedle structure comprising a liquid storage layer that absorbs and stores liquid derived from a living body, and a needle-shaped part having a flow path formed therein, the flow path of the needle-shaped part being connected to the liquid storage layer.

2. The microneedle structure according to claim 1, wherein the liquid storage layer and the needle-shaped portion are each made of a porous material.

3. The microneedle structure according to claim 1, wherein the liquid storage layer comprises a nonwoven fabric made of rayon.

4. The microneedle structure according to claim 2, wherein the liquid storage layer and the needle-shaped portion are made of porous materials different from each other in structure or composition.

5. The microneedle structure described in claim 2, characterized in that the porous material of the liquid storage layer contains a resin, the resin contains carbon atoms and oxygen atoms in its molecular structure, and the ratio of the number of oxygen atoms to the number of carbon atoms is 1 / 2 or more.

6. The microneedle structure according to claim 2, characterized in that the porous material of the liquid storage layer contains a resin, the resin having hydroxyl groups in parts other than the molecular ends and being insoluble in water.

7. The microneedle structure according to claim 1, wherein the liquid storage layer is made of a hard porous material and has a thickness of 300 μm or more.

8. The microneedle structure according to claim 1, characterized in that, when viewed from above, the area in which the needle-shaped portion exists is entirely included in the area of ​​the liquid storage layer.

9. A microneedle structure as described in claim 1, characterized in that the needle-shaped portion is formed on one side of a sheet-like base, the liquid storage layer is directly laminated on the other side of the base, and the flow path of the needle-shaped portion is connected to the liquid storage layer via a flow path formed in the base.

10. The microneedle structure according to claim 9, wherein the liquid storage layer is directly fixed to the base.

11. A microneedle patch comprising the microneedle structure according to any one of claims 1 to 10.

12. A method for manufacturing a microneedle structure, the microneedle structure comprising a needle-shaped portion formed on one surface of a sheet-like base and having a flow path formed therein, and a liquid storage layer disposed on the other surface of the sheet-like base for absorbing and storing liquid derived from a living body, the base and the liquid storage layer being made of a porous material, the method comprising: an impregnation step of impregnating at least one of the base and the liquid storage layer with a resin solution; and a drying step of volatilizing the solvent from the resin solution and drying the base and the liquid storage layer in a laminated state after the impregnation step.

13. A method for manufacturing a microneedle structure as described in claim 12, characterized in that after the impregnation process, one of the base or the liquid storage layer impregnated with the resin solution is stacked on the other of the base or the liquid storage layer which has not been impregnated, and the stacked state is placed in a reduced pressure environment.

14. The method for producing a microneedle structure according to claim 12, wherein the resin is a hydrophilic resin.

15. A microneedle structure comprising a needle-shaped portion formed on one surface of a sheet-like base and having a flow path formed therein, and a liquid storage layer disposed on the other surface of the sheet-like base and absorbing and storing liquid derived from a living body, wherein the base and the liquid storage layer are made of a porous material, and a resin is attached to the inside of the porous material of the base and the liquid storage layer.

16. The microneedle structure described in claim 15, characterized in that the resin adhered to the inside of the porous material of the base and the resin adhered to the inside of the porous material of the liquid storage layer are a common resin.

17. The microneedle structure according to claim 15, wherein the base and the liquid storage layer are bonded together by the applied resin.

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