Method for producing microneedle structure, and microneedle structure

Abstract

This method for producing a microneedle structure comprises: a step for preparing a needle-shaped section-forming resin composition containing a pore-forming agent and a water-insoluble resin; a step for producing a microneedle intermediate that has a needle-shaped section formed from the needle-shaped section-forming resin composition; and a water treatment step for treating the microneedle intermediate with water so as to remove the pore-forming agent and forming a porous structure in the needle-shaped section. The pore-forming agent contains water-soluble inorganic particles and a water-soluble resin.

Description

Method for manufacturing a microneedle structure and a microneedle structure

[0001] This invention relates to a method for manufacturing a microneedle structure.

[0002] A microneedle structure is a structure having a fine needle-like structure (hereinafter sometimes referred to as the needle portion). Microneedle structures are used, for example, to collect liquid (such as body fluid) from a target (such as a living organism or the human body) or to inject liquid into a target. In such a microneedle structure, a channel is formed in the needle portion. The needle portion is inserted into the target, and liquid is collected from the target through the channel, or liquid is injected into the target.

[0003] In relation to the above, Patent Document 1 (International Publication No. 2022 / 211059) discloses a microneedle structure having a needle-shaped portion on one side of a specific substrate, wherein the needle-shaped portion is made of a composition containing a low-melting-point resin having a melting point of 150°C or less, and pores are formed on the surface and inside of the needle-shaped portion.

[0004] For microneedle structures, it is desirable that liquids can be rapidly collected or injected. Therefore, high liquid absorption capacity is required for microneedle structures. Accordingly, the object of the present invention is to provide a manufacturing method that can obtain a microneedle structure having high liquid absorption capacity.

[0005] The inventors have discovered that high liquid absorption can be achieved by using a specific combination of pore-forming agents when forming a porous structure in the needle-shaped portion.

[0006] In other words, in one embodiment, a method for manufacturing a microneedle structure according to the present invention comprises the steps of: preparing a needle-shaped portion forming resin composition containing a pore-forming agent and a water-insoluble resin; producing a microneedle intermediate having needle-shaped portions formed by the needle-shaped portion forming resin composition; and a water treatment step of treating the microneedle intermediate with water so as to remove the pore-forming agent and to form a porous structure in the needle-shaped portions. The pore-forming agent contains water-soluble inorganic particles and a water-soluble resin.

[0007] According to the present invention, a method for manufacturing a microneedle structure having high liquid absorption properties is provided.

[0008] Figure 1 is a schematic cross-sectional view showing a microneedle structure according to the embodiment. Figure 2 is a schematic diagram showing an example of a manufacturing method according to the embodiment. Figure 3 is a schematic cross-sectional view showing an example of a microneedle patch. Figure 4 is a schematic cross-sectional view showing a microneedle patch manufactured in the example. Figure 5 is a schematic diagram showing the procedure for the puncture test performed in the example.

[0009] The embodiments of the present invention will be described below with reference to the drawings.

[0010] (Microneedle Structure) First, the configuration of the microneedle structure manufactured by the manufacturing method according to this embodiment will be described. Figure 1 is a schematic cross-sectional view showing the microneedle structure 1 according to this embodiment. This microneedle structure 1 is used to exchange liquid with an object (for example, a living organism, the human body).

[0011] As shown in Figure 1, the microneedle structure 1 has a needle-shaped portion 2 and a base portion 3. In the example shown in Figure 1, the needle-shaped portion 2 and the base portion 3 are integral. However, the needle-shaped portion 2 and the base portion 3 may be formed from separate components.

[0012] The base portion 3 is the part that supports the needle-shaped portion 2. The shape of the base portion 3 is not particularly limited. In this embodiment, the base portion 3 is flat.

[0013] The needle-shaped portion 2 is the part that is inserted into the target. Multiple needle-shaped portions 2 are provided. Each needle-shaped portion 2 extends upward from one surface of the base portion 3 (hereinafter sometimes referred to as the needle-shaped portion forming surface). The needle-shaped portions 2 are made of a water-insoluble resin.

[0014] A flow channel is formed inside the base portion 3 and the needle-shaped portion 2. In this embodiment, the base portion 3 and the needle-shaped portion 2 have a porous structure. The pores contained in this porous structure function as a flow channel. In the needle-shaped portion 2, the flow channel opens on the surface of the needle-shaped portion 2. Therefore, when the needle-shaped portion 2 is inserted into an object, the liquid injected into the object, or the liquid received from the object, flows through the flow channel. The opening on the surface of the needle-shaped portion 2 is connected to the back surface of the base portion 3 (the surface opposite to the surface on which the needle-shaped portion 2 is formed) via a flow channel provided inside the needle-shaped portion 2 and the base portion 3. Therefore, although not shown in Figure 1, if a functional member (a member that stores the liquid injected into the object, or a member that acts passively on the liquid absorbed from the object) is placed on the back surface of the base portion 3, it becomes possible to exchange liquid between the functional member and the object via the microneedle structure 1.

[0015] (Method for manufacturing a microneedle structure) Next, the method for manufacturing the microneedle structure described above will be explained. The method for manufacturing a microneedle structure according to this embodiment comprises the steps of: preparing a needle-shaped portion forming resin composition containing a pore-forming agent and a water-insoluble resin (step S1); producing a microneedle intermediate having needle-shaped portions formed from the needle-shaped portion forming resin composition (step S2); and a water treatment step (step S3) in which the microneedle intermediate is treated with water to remove the pore-forming agent and form a porous structure in the needle-shaped portions. Here, the pore-forming agent contains water-soluble inorganic particles and a water-soluble resin.

[0016] According to the method described above, a combination of water-soluble inorganic particles and a water-soluble resin is used as the pore-forming agent, and as can be seen in the examples described later, a microneedle structure with high liquid absorption is realized. Specifically, by using water-soluble inorganic particles, the formation of pores on the surface and inside the needle-shaped portion is promoted, and the surface openings and internal pores are more easily connected. Furthermore, by using a water-soluble resin in combination, the formation of channels inside the needle-shaped portion is promoted. As a result, it is believed that high liquid absorption is achieved.

[0017] Figure 2 is a schematic diagram showing an example of the manufacturing method according to this embodiment. The steps in the manufacturing method according to this embodiment will be described in detail below with reference to Figure 2. Note that Figure 2 shows an example of a manufacturing method in which the needle-shaped portion 2 and the base portion 3 are integrated.

[0018] (1) Step S1: Preparation of needle-shaped resin composition (Figure 2(a)) First, as shown in Figure 2(a), a needle-shaped resin composition 6, which will be the raw material for the needle-shaped parts, is prepared. Specifically, a water-insoluble resin, a pore-forming agent (water-soluble inorganic particles and water-soluble resin), and a solvent are mixed to prepare a dispersion. These may be mixed by melt mixing as needed.

[0019] As a solvent, one that does not dissolve water-soluble inorganic particles can be used. For example, organic solvents such as IPA (isopropyl alcohol), ethyl acetate, ethanol, dichloromethane, dimethylformamide, and toluene can be used. The amount of solvent used is, for example, 50 to 150 parts by mass, preferably 80 to 120 parts by mass, when the total amount of the pore-forming agent and the water-insoluble resin is 100 parts by mass.

[0020] (2) Step S2: Preparation of microneedle intermediate (Figures 2(b) to 2(e)) Next, as shown in Figure 2(b), the obtained needle-shaped resin composition 6 is injected into the mold 7 for base material molding. The mold 7 for base material molding is provided with recesses of a size corresponding to the size of the microneedle structure. The mixture is injected into these recesses. The mixture is then heated so that the solvent is removed. The mixture is also compressed and molded by pressing or other means.

[0021] Next, as shown in Figure 2(c), the molded mixture is cooled and solidified. Then, the solidified mixture is removed as the base material 8.

[0022] Subsequently, as shown in FIG. 2(d), the base material 8 is filled into the mold 9. As the mold 9, one having a concave portion with a shape corresponding to the needle-shaped portion is used. Then, hot pressing is performed. By heating, the base material 8 becomes a fluid state and is formed into a shape corresponding to the mold 9. That is, the base material 8 is formed into a shape corresponding to the micro-needle structure. Note that the molding temperature (temperature of the base material) of the base material 8 during molding is, for example, 150° C. or lower, preferably 130° C. or lower.

[0023] Subsequently, the molded base material 8 is cooled and solidified. Then, as shown in FIG. 2(e), the molded base material is removed from the mold 9 as the micro-needle intermediate 10.

[0024] (3) Step S3: Water treatment process (FIGS. 2(f) to 2(g)) Subsequently, as shown in FIG. 2(f), the micro-needle intermediate 10 is treated with water. Thereby, the pore-forming agent present in the micro-needle intermediate 10 is dissolved and removed. As a result, a porous structure is formed in the micro-needle intermediate 10 including the needle-shaped portion. After removing the pore-forming agent, as shown in FIG. 2(g), the molded product is dried. Thereby, the micro-needle structure 1 according to the present embodiment is obtained.

[0025] By the method described above, the micro-needle structure 1 including the needle-shaped portion having a specific porous structure is obtained. As described above, according to the method according to the present embodiment, since a combination of water-soluble inorganic particles and water-soluble resin is employed as the pore-forming agent, a micro-needle structure having high liquid absorption property can be obtained.

[0026] Note that the above example is merely an example. For example, in the above example, the case where a solvent is used when mixing the pore-forming agent and the water-insoluble resin is described. However, the solvent may be omitted. For example, the needle-shaped portion forming resin composition 6 may be obtained by introducing the pore-forming agent into the heat-melted water-insoluble resin without using a solvent.

[0027] (Pore-forming agent) Subsequently, the water-soluble inorganic particles and water-soluble resin used as the pore-forming agent will be described.

[0028] (Water-soluble inorganic particles) The water-soluble inorganic particles may be in particulate form and formed of an inorganic compound. Examples of the inorganic compound include inorganic salts. Examples of the inorganic salts include cations such as Na ＋ , Mg ２＋ , Ca ２＋ , Al ３＋ , and H ＋ etc., or compounds that generate anions such as Cl － , Br － , SO ４ ２－ , SO ３ ２－ , NO ２ － , NO ３ － , PO ４ ３－ , CO ３ ２－ , and OH － etc. Specific examples of the inorganic salts include NaCl, KCl, Na ２ SO ４ , CaCl ２ , AlCl ３ , Al ２ (SO ４ ) ３ etc. can be used.

[0029] The amount of the water-soluble inorganic particles used is, based on the mass of the acicular part-forming resin composition excluding the solvent (i.e., on a solid basis), for example, 20 to 90% by mass, preferably 40 to 80% by mass.

[0030] (Small-diameter particles) Preferably, the water-soluble inorganic particles contain particles having an average particle diameter of 17 μm or less. Hereinafter, particles having an average particle diameter of 17 μm or less may be referred to as "small-diameter particles". By using small-diameter particles, the strength of the acicular parts is likely to increase.

[0031] In this specification, the "average particle diameter" means the particle size 50% diameter measured by laser diffraction particle size measurement. The laser diffraction particle size measurement is performed by wet measurement using absolute ethanol. Examples of the apparatus for performing the laser diffraction particle size measurement include the "Macro Track Particle Size Analyzer MT3300" manufactured by Nikkiso Co., Ltd.

[0032] In the needle-like part forming resin composition, the content of the small-diameter particles is, on a solid basis, for example, 20 to 90% by mass, preferably 40 to 80% by mass.

[0033] (Large-diameter particles) The water-soluble inorganic particles may contain large-diameter particles in addition to the small-diameter particles. The large-diameter particles are particles having an average particle diameter of more than 17 μm. By using the large-diameter particles, the pores formed in the needle-like part are likely to be connected to each other, and a flow path is likely to be formed. As a result, the liquid absorption property is likely to be enhanced.

[0034] On the other hand, when the amount of the large-diameter particles used is increased, the strength of the needle-like part is likely to decrease. Therefore, the content of the large-diameter particles in the needle-like part forming resin composition is preferably 12.5% by mass or less on a solid basis. If the content of the large-diameter particles is within such a range, the strength of the needle-like part is unlikely to decrease. Also, the large-diameter particles may not be used, and only the small-diameter particles may be used.

[0035] As confirmed in the examples described later, by adopting the manufacturing method according to the present embodiment, it is also possible to obtain a micro needle structure in which the strength of the needle-like part is 75 mN or more by controlling the amount of the large-diameter particles used. The "strength of the needle-like part" referred to here is a parameter measured by the method described in the examples described later.

[0036] The large-diameter particles and the small-diameter particles may be the same substance or different substances.

[0037] (Water-soluble resin) The water-soluble resin that functions as a pore-forming agent is not particularly limited. For example, a thermoplastic resin is used as the water-soluble resin. Also, the water-soluble resin is preferably a biodegradable resin.

[0038] Also, the water-soluble resin is preferably a resin in a solid state at room temperature (25°C). Specifically, it is preferably a resin having a melting point exceeding 25°C. The melting point of the water-soluble resin is preferably 30 to 130°C, and more preferably 35 to 100°C.

[0039] Specific examples of water-soluble resins include at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, and collagen. A preferred water-soluble resin is polyalkylene glycol.

[0040] Examples of polyalkylene glycols include polyethylene glycol and polypropylene glycol, with polyethylene glycol being preferred.

[0041] The polyethylene glycol preferably has a molecular weight such that it is solid at room temperature. The molecular weight of the polyethylene glycol is, for example, 200 to 4,000,000, preferably 600 to 500,000, and more preferably 1,000 to 100,000.

[0042] (Water-Insoluble Resin) Next, we will explain water-insoluble resins. Unlike pore-forming agents, water-insoluble resins are substances that ultimately remain as at least a needle-shaped portion. In this specification, a water-insoluble resin is a resin that is insoluble in water at room temperature (25°C). When a water-insoluble resin is used, when the needle-shaped portion is inserted into a target, it becomes difficult for the needle-shaped portion to dissolve due to the aqueous liquid present in the target. In other words, the shape of the needle-shaped portion is more easily maintained when inserted.

[0043] The water-insoluble resin is not particularly limited. Preferably, the water-insoluble resin includes a resin having a melting point of 130°C or lower (hereinafter referred to as a low-melting-point resin). Including a low-melting-point resin makes it easier to employ methods such as heating and melting the material or heating the material and molding it in a mold during the manufacture of the microneedle structure 1. In other words, it makes it easier to employ the manufacturing method described above. The melting point of the low-melting-point resin is preferably 100°C or lower, and more preferably 80°C or lower.

[0044] The low-melting-point resin is preferably solid at room temperature (25°C). Using such a resin makes it easier to maintain the strength of the needle-shaped portion at room temperature. The melting point of the low-melting-point resin is preferably 40°C or higher, more preferably 45°C or higher.

[0045] Specific examples of low-melting-point resins include, for example, polyester; polyolefin resins such as polyethylene and α-olefin copolymers; olefin copolymer resins such as ethylene-vinyl acetate copolymers and ethylene-ethyl acrylate copolymers; polyurethane elastomers; and derivatives thereof.

[0046] Furthermore, the low-melting-point resin is preferably a biodegradable resin. Using a biodegradable resin can reduce the impact of the needle-like structure on living organisms when the target is a living organism. Examples of biodegradable resins include polyester and its derivatives. Aliphatic polyesters and their derivatives are preferably used as polyesters and their derivatives. Examples of aliphatic polyesters and their derivatives include homopolymers or copolymers containing units derived from at least one selected from the group consisting of glycolic acid, lactic acid, and caprolactone. In addition, polybutylene succinate (melting point: 84 to 115°C) and aliphatic aromatic copolyester (melting point: 110 to 120°C) can also be cited as aliphatic polyesters that are biodegradable resins. As a polybutylene succinate, for example, BioPBS provided by Mitsubishi Chemical Corporation can be used. As an aliphatic aromatic copolyester, Ecoflex manufactured by BASF can be used.

[0047] The biodegradable resin is preferably a resin in which the acid dissociation constant of its monomer is 4 or higher. Having an acid dissociation constant of 4 or higher reduces the impact on the body when the microneedle structure is applied to a living organism. The acid dissociation constant of the monomer referred to here is the acid dissociation constant of the hydroxycarboxylic acid formed when the monomer is a cyclic ester. The acid dissociation constant of the monomer is preferably 4.0 or higher, and more preferably 4.5 or higher. Furthermore, the acid dissociation constant of the monomer is preferably 25 or less, and more preferably 15 or less. An example of a monomer constituting such a biodegradable resin with an acid dissociation constant of 4 or higher is caprolactone. In the biodegradable resin, it is preferable that the constituent units derived from monomers with an acid dissociation constant of 4 or higher constitute 70% by mass or more of the total constituent units, more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0048] In a particularly preferred embodiment, the low-melting-point resin comprises a homopolymer or copolymer containing caprolactone-derived units. Most preferably, the low-melting-point resin comprises polycaprolactone.

[0049] The weight-average molecular weight of the low-melting-point resin is not particularly limited, but is, for example, 5,000 or more, preferably 15,000 or more, and more preferably 40,000 or more. Within this range, the necessary strength for the needle-shaped portion is easily maintained. The weight-average molecular weight of the low-melting-point resin is the value obtained by the method described in the examples below.

[0050] The upper limit of the weight-average molecular weight of the low-melting-point resin is not particularly limited, but is, for example, 200,000 or less, preferably 150,000 or less. Within this range, the processability of the needle-shaped portion is further improved.

[0051] The water-insoluble resin may contain components other than the low-melting-point resin. However, it is preferable that the main component of the needle-shaped portion (i.e., the component accounting for 50% or more by mass of the total components of the needle-shaped portion forming resin composition 6, excluding the pore-forming agent removed in the water treatment step) is the low-melting-point resin described above. The content of the low-melting-point resin in the needle-shaped portion is, for example, 50% or more by mass, preferably 65% ​​or more by mass, more preferably 70% or more by mass, and even more preferably 90% or more by mass. If the low-melting-point resin is included in such an amount, it becomes easier to employ methods such as heating and melting the material or heating the material and molding it in a mold during the manufacture of the microneedle structure 1.

[0052] (Liquid absorption rate of microneedle structure) According to this embodiment, high liquid absorption is achieved as a result of adopting the above-described manufacturing method. Specifically, according to this embodiment, a microneedle structure having a liquid absorption rate of 5% or more can be realized by measuring it using the method described in the examples below. The liquid absorption rate of the microneedle structure 1 is 15% or more in a preferred embodiment, 25% or more in a more preferred embodiment, and 45% or more in an even more preferred embodiment.

[0053] (Other configurations of the needle-like portion) The shape, size, formation pitch, and number of needle-like portions are not particularly limited. For example, the shape of each needle-like portion may be cylindrical, prismatic, conical, or pyramidal. The maximum diameter or dimension of the cross-section at the base end of each needle-like portion is, for example, 25 to 1000 μm. The tip diameter or tip cross-sectional dimension of each needle-like portion is, for example, 1 to 100 μm. The height of each needle-like portion is, for example, 50 to 2000 μm. Multiple needle-like portions are arranged, for example, in a matrix. The number of needle-like portions included in the microneedle structure is, for example, 10 to 1000, preferably 20 to 100.

[0054] (Microneedle Patch) The microneedle structure 1 according to this embodiment can be used, for example, as a microneedle patch. Figure 3 is a schematic cross-sectional view showing an example of a microneedle patch 20. This microneedle patch 20 includes the microneedle structure 1, a support tape 15, and a functional member 14. The support tape 15 supports the functional member 14 and the microneedle structure 1.

[0055] The support tape 15 is made of, for example, adhesive tape. The microneedle structure 1 is supported on one surface of the support tape 15. An attachment area is provided on the outer circumference of the support tape 15 to be attached to the target. When the support tape 15 is attached to the target with the microneedle structure 1 facing the target, the needle-shaped portion 2 of the microneedle structure 1 is inserted into the target.

[0056] The functional member 14 is a component that exchanges liquid with the target via the microneedle structure 1. The functional member 14 is sandwiched between the microneedle structure 1 and the support tape 15. When the needle-shaped portion 2 is inserted into the target, the functional member 14 is connected to the target via the microneedle structure 1. As a result, liquid is exchanged between the functional member 14 and the target, and the desired function is realized. For example, the functional member 14 may be an inspection sheet for collecting aqueous liquid (such as body fluid) from the target and examining its components. Alternatively, the functional member 14 may be a storage component for storing liquid (medicinal solution) to be injected into the target.

[0057] (Uses of Microneedle Structures or Microneedle Patches) Preferably, the microneedle structure 1 or microneedle patch is used to absorb fluid from a living body. Examples of fluids include blood and interstitial fluid. For example, if the functional member 14 is an inspection sheet for examining interstitial fluid, the components of the interstitial fluid absorbed by the microneedle structure 1 or microneedle patch 20 are examined by the inspection sheet. Alternatively, if the functional member 14 is an absorbent member that absorbs interstitial fluid, the microneedle structure 1 or microneedle patch 20 absorbs the interstitial fluid, and the interstitial fluid absorbed by the absorbent member can be extracted in a test solution to analyze the components of the interstitial fluid.

[0058] Next, in order to explain the present invention in more detail, examples made by the inventors will be described. However, the present invention should not be interpreted as being limited to the following examples.

[0059] Table 1 shows the composition and physical properties of the materials used in the examples and comparative examples.

[0060] (Example 1) As a water-insoluble resin, 3.0 g of pelletized PCL (polycaprolactone, weight-average molecular weight 50,000, melting point 60°C; the method for measuring weight-average molecular weight will be described later) was prepared. This was placed in a 100 ml beaker. Next, 6.0 g of ethyl acetate was added as a solvent. The beaker was placed on a hot plate heated to 65°C and stirred with a stirrer bar at a rotation speed of 300 rpm for 60 minutes. Next, 6.3 g of NaCl (corresponding to small-diameter particles: manufactured by Naikai Salt Industry Co., Ltd., Nacle UM-10) with an average particle size of 10 μm and 0.7 g of PEG (polyethylene glycol, weight-average molecular weight 4,000, melting point 40°C) were added as pore-forming agents. Next, 2.0 g of ethyl acetate, prepared separately, was added dropwise along the edge of the beaker. While maintaining a temperature of 65°C, the rotation speed of the magnetic stirrer was increased to 500 rpm, and the mixture was stirred for a further 10 minutes to obtain a mixture for base material formation (resin composition for forming needle-shaped parts).

[0061] Next, a mold made of polydimethylsiloxane was prepared for forming the base material. The mold used for forming the base material had a recess (with an opening that was square in shape, with sides of 20 mm x 20 mm, and a depth of 0.25 mm). The base material forming mixture, which had been returned to room temperature, was dropped into the recess of this base material forming mold using a dropper with a cut tip. Any portion of the dropped mixture that did not fit into the recess was scraped off with a spatula. The base material forming mold was left to stand on a hot plate heated to 120°C for 10 minutes to remove the solvent.

[0062] Furthermore, the surface of the mixture for base material formation was flattened. Specifically, a SUS plate (2 mm thick, 80 mm short side, 100 mm long side, rectangular) was prepared, and a release film was attached to one side of this SUS plate with double-sided tape so that the release treatment surface faced outwards, creating a jig. Immediately after the heating of the mold for base material formation was completed, this jig was positioned so that the release treatment surface was in contact with the mixture injected into the mold for base material formation. Then, using a heating press machine (AH-1T, manufactured by AS ONE Corporation) without a temperature setting, the mixture was pressurized at 10 MPa for 10 minutes. After the pressure was released, the mold for base material formation with the jig and mixture injected was placed between two SUS plates (2 mm thick, 80 mm short side, 100 mm long side, rectangular) that had been cooled to 3°C beforehand, the four corners were fixed with alligator clips, and the mixture was cooled for 10 minutes to solidify.

[0063] Next, the solidified mixture was removed from the mold used for forming the base material. The base material was then left to dry in a drying oven (30°C) for 24 hours. This obtained the base material.

[0064] A mold for heat pressing was prepared. The mold used was made of polydimethylsiloxane and had multiple recesses for forming needle-like structures. The recesses used for forming needle-like structures had the following characteristics: • Recess shape: Conical shape with a circular cross-section • Maximum cross-sectional diameter of the recess: 300 μm • Height of the recess: 600 μm • Pitch of the recesses: 1000 μm • Number of recesses: 3 in rows 1 and 7, 5 in rows 2 and 6, and 7 in rows 3, 4 and 5, for a total of 37 • Size of the area where the recesses are formed: 6.3 mm square • Arrangement of the recesses: Regular octagonal shape

[0065] A mold was placed on the lower stage of a heating press machine (AH-1T, manufactured by AS ONE Corporation). The base material was then placed on the recess for needle-shaped portion formation. A 30 mm square sheet (lid) made of polydimethylsiloxane was then placed on top. As a preliminary step, the base material was pressed at 2 MPa for 1 minute and 30 seconds while heating the lower stage at a set heating temperature of 120°C and the upper stage at a set heating temperature of 110°C. Then, as the main step, the base material was pressed at 3 MPa for 30 seconds with the lower and upper stages heated to the same temperatures as the preliminary step. The molten base material contained in the lid and mold was then refrigerated at 3°C ​​for 5 minutes to solidify. This yielded a sample (microneedle intermediate) with needle-shaped portions and a base. The sample was then removed from the mold. Finally, the sample was immersed in purified water at room temperature for 1 hour and stirred with a stirrer bar. At this point, the sample was secured to the beaker wall with double-sided tape to prevent contact with the stirrer bar. Next, the sample was immersed in purified water and stirred with the stirrer bar at 200 rpm for 30 minutes. Then, it was immersed again in purified water and stirred once more with the stirrer bar at 200 rpm for 30 minutes to dissolve and remove the pore-forming agent. After that, the sample was left to stand in a drying oven (30°C) for 24 hours to evaporate the moisture and dry it. This resulted in obtaining a microneedle structure.

[0066] (Examples 2-10) Compared to Example 1, the composition of the pore-forming agent was changed as shown in Table 1. Microneedle structures according to Examples 2-10 were obtained under the same conditions as in Example 1.

[0067] [Evaluation of Liquid Absorption Rate] (Weighing of Sample) A microneedle structure, which is the sample, and a nonwoven fabric (Cupro (copper ammonia rayon), manufactured by Asahi Kasei Corporation, Benliese SN140, 10 mmφ) of a size corresponding to the area where the needle-shaped portion is provided were prepared. The initial weight of the prepared microneedle structure and nonwoven fabric was measured. The total weight of the microneedle structure and nonwoven fabric was then used as the sample weight before liquid absorption.

[0068] (Fabrication of Microneedle Patch) A microneedle patch having the configuration shown in Figure 4 was fabricated. Specifically, a nonwoven fabric 16 was placed on the back surface of the microneedle structure 1 (the surface opposite to the surface on which the needle-like portion is provided). Furthermore, a liquid-impermeable, repositionable adhesive tape 12 (Lintec Corporation, Adwill C-902, 20 x 20 mm) was prepared, with a PET film 11 (thickness 50 μm, PET50, 10 mmφ, liquid-impermeable resin film) of the same size (diameter 1 cm) as the nonwoven fabric 16 provided on the adhesive surface. The prepared repositionable adhesive tape 12 was attached to the back surface of the microneedle structure 1 so that the PET film 11 was positioned on the nonwoven fabric 16.

[0069] (Preparation of Agarose Gel) Next, a 1% agarose gel (NE-AG01, manufactured by Fast Gene) was prepared. 300 mg of the prepared agarose gel was placed in a petri dish. 27 ml of purified water and 3 ml of phosphate-buffered saline (PBS) (Dulbecc's phosphate-buffered saline (10x concentrate): D-PBS(-)(10x), manufactured by Nacalai Tesque Co., Ltd.) were prepared in a graduated cylinder and poured into the petri dish containing the agarose gel. Then, the petri dish was placed on a hot plate heated to 120°C, and the agarose gel was dissolved while stirring with a spoon. It was then allowed to cool to room temperature to obtain a 1% agarose gel containing PBS.

[0070] (Puncture Test) Next, as shown in Figure 5, a puncture test was performed. Specifically, the needle-shaped portion of the sample was punctured into the prepared agarose gel 13, the sample was lightly pressed with a finger, and then released and left to stand for 5 minutes. After that, the sample was removed from the agarose gel 13, and any water droplets on the surface where the needle-shaped portion was located were removed by blowing them off with an air blow gun. Then, the re-peelable adhesive tape 12 was peeled off.

[0071] (Re-weighing of the sample and calculation of the absorption rate) Next, the total weight of the microneedle structure 1 and the nonwoven fabric 4 was measured as the sample weight after absorption. Then, the PBS absorption rate was calculated using the following formula 1. (Formula 1) PBS absorption rate (%) = (Sample weight after absorption - Sample weight before absorption) ÷ Sample weight before absorption × 100

[0072] [Strength Evaluation of Microneedle Structures] Using a force gauge (manufactured by IMADA), the stress was measured by crushing each needle-shaped portion individually. Specifically, each microneedle structure was placed on a stage with the needle-shaped portion facing upwards, observed with a microscope, and one needle-shaped portion with a sharp tip was selected. The attachment was then brought close to the microneedle, aligning it with the position of the selected needle-shaped portion. Care was taken to ensure that the attachment did not come into contact with adjacent microneedles. The vertical position of the attachment was moved to a position where it contacted the tip of the needle-shaped portion but no force was applied to the needle-shaped portion. From there, it was raised by 0.1 mm, and then the attachment was lowered at a descent rate of 5 mm / min to begin measuring the force applied to the attachment. Ten needle-shaped portions were measured, and the stress at the tip of the needle-shaped portion was set to 0.0 mm. Stresses for every 0.02 mm displacement were extracted up to 0.3 mm. Of these, the stress at the 0.2 mm displacement point was calculated and defined as the microneedle strength. Of the results of measuring the microneedle strength of the 10 needle-shaped parts, the lowest value was used as the final result.

[0073] (Weight-average molecular weight of polycaprolactone) The weight-average molecular weight (Mw) of polycaprolactone (PCL) was measured using gel permeation chromatography (GPC) under the following conditions (GPC measurement), and is the value converted to a standard polystyrene. The sample for GPC measurement was prepared in the following procedure. First, 1 g of polycaprolactone (PCL) 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. 1 ml of the obtained solution and 9 ml of THF were added dropwise to a separately prepared screw tube to prepare a 1% PCL solution. This 1% PCL solution was filtered through a GD / X syringe filter (manufactured by Whatman) and added dropwise to the GPC instrument. (Measurement conditions) • Measuring device: Tosoh Corporation, HLC-8320 • GPC column (passed in the following order): Tosoh Corporation TSK gel superH-H, TSK gel superHM-H, TSK gel superH2000 • Solvent: Tetrahydrofuran • Measurement temperature: 40°C

[0074] [Results and Discussion] The results are shown in Table 1.

[0075] Comparing Examples 1 to 4, which used 6.3 g of small-diameter particles, Examples 1, 3, and 4, which combined water-soluble inorganic particles and water-soluble resin (PEG), had higher liquid absorption rates than Example 2, which lacked PEG. Similarly, comparing Examples 5 to 7, which used 5.6 g of small-diameter particles, Examples 6 and 7, which combined water-soluble inorganic particles and PEG, had higher liquid absorption rates than Example 5, which lacked PEG. Furthermore, comparing Examples 8 to 10, which used 4.9 g of small-diameter particles, Examples 9 and 10, which combined water-soluble inorganic particles and PEG, had significantly higher liquid absorption rates than Example 8, which lacked PEG. Therefore, it was found that combining water-soluble inorganic particles and PEG as a pore-forming agent increases liquid absorption rates. More specifically, in Examples 1, 3-4, 6-7, and 9-10, which combined water-soluble inorganic particles and water-soluble resin (PEG), liquid absorption rates of 20% or more were obtained.

[0076] Furthermore, in Examples 1-4 and 6-7, where the content of large-diameter particles in the needle-forming resin (total of water-insoluble resin and pore-forming agent) was 12.5% ​​by mass or less based on solid matter, the needle-shaped portion exhibited a high strength of 75 mN or more.

[0077]

[0078] (Note) The main embodiments included in the present invention are summarized below as notes. (Note 1) A method for producing a microneedle structure, comprising the steps of: preparing a needle-shaped portion forming resin composition comprising a pore-forming agent and a water-insoluble resin; producing a microneedle intermediate having a needle-shaped portion formed by the needle-shaped portion forming resin composition; and a water treatment step of treating the microneedle intermediate with water so as to remove the pore-forming agent and to form a porous structure in the needle-shaped portion, wherein the pore-forming agent comprises water-soluble inorganic particles and a water-soluble resin.

[0079] (Note 2) A manufacturing method as described in Note 1, wherein the water-soluble inorganic particles include small-diameter particles having an average particle size of 17 μm or less.

[0080] (Note 3) A manufacturing method as described in Note 2, wherein the water-soluble inorganic particles further include large-diameter particles having an average particle size of more than 17 μm.

[0081] (Note 4) A manufacturing method as described in Note 3, wherein the content of the large-diameter particles is 12.5% ​​by mass or less on a solid basis with respect to the needle-shaped resin composition.

[0082] (Note 5) A manufacturing method described in Note 2, wherein the pore-forming agent does not contain large-diameter particles having an average particle size of more than 17 μm.

[0083] (Appendix 6) A manufacturing method according to any one of Appendix 1 to 5, wherein the water-soluble inorganic particles contain an inorganic salt.

[0084] (Note 7) The manufacturing method described in Note 6, wherein the inorganic salt is NaCl, KCl, Na ２ SO ４ CaCl ２ AlCl ３ , and Al２ (SO ４ ) ３ A manufacturing method comprising at least one selected from the group consisting of the following.

[0085] (Note 8) A manufacturing method according to any one of Notes 1 to 7, wherein the water-soluble resin comprises at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, and collagen.

[0086] (Note 9) A manufacturing method according to any one of Notes 1 to 8, wherein the water-soluble resin contains a resin that is solid at room temperature (25°C).

[0087] (Note 10) A manufacturing method according to any one of Notes 1 to 9, wherein the water-insoluble resin contains a low-melting-point resin having a melting point of 130°C or less.

[0088] (Note 11) A microneedle structure having a needle-shaped portion that is inserted into a target, wherein a channel is provided inside the needle-shaped portion for the liquid injected into the target or the liquid received from the target to flow, and the liquid absorption rate of the needle-shaped portion, as measured by the following test method, is 20% or more. (Test method) Prepare a 10 mmφ copper ammonia rayon nonwoven fabric and determine its mass. Determine the mass of the microneedle structure. The total mass of the nonwoven fabric and the microneedle structure shall be the sample mass before liquid absorption. Prepare a liquid-impermeable, repositionable adhesive tape and attach a liquid-impermeable resin film cut into a circle with a diameter of 1 cm to the adhesive surface of the repositionable adhesive tape. Place the nonwoven fabric in the center of the surface of the microneedle structure where the needle-shaped portion is not formed. Obtain the sample by attaching the repositionable adhesive tape so that the positions of the nonwoven fabric and the circular resin film coincide. The needle portion of the sample is punctured into a 1% agarose gel containing phosphate-buffered saline, and after standing for 5 minutes, the sample is removed from the agarose gel, and any water droplets on the surface where the needle portion was located are removed. Then, the removable adhesive tape is peeled off from the microneedle structure. The mass of the microneedle structure and nonwoven fabric is taken as the mass of the sample after absorption. The absorption rate is calculated from the sample mass before absorption and the sample mass after absorption using the following formula 1. (Formula 1) Absorption rate (%) = (Sample weight after absorption - Sample weight before absorption) ÷ Sample weight before absorption × 100

[0089] (Note 12) A microneedle structure as described in Note 11, wherein the strength of the needle-shaped portion measured by the following test method is 75 mN or more. (Test method) Prepare a force gauge. Place the microneedle structure on the force gauge stage with the needle-shaped portion facing upward. Observe the needle-shaped portion with a microscope, select one needle-shaped body with a sharp tip, and bring the force gauge attachment close to the microneedle structure, aligning it with the position of that needle-shaped body. Move the vertical position of the attachment to a position where it contacts the tip of the needle-shaped body but no force is applied to the needle-shaped body, raise it by 0.1 mm from there, and then lower the attachment at a descent rate of 5 mm / min to start measuring the force applied to the attachment. Measure for 10 needle-shaped portions, and extract the stress for every 0.02 mm displacement down to 0.3 mm, with the tip of the needle-shaped portion set to 0.0 mm. Of these, the stress at the 0.2 mm displacement point is calculated and defined as the microneedle strength. The microneedle strength of 10 needle-shaped sections is measured, and the lowest value is taken as the result.

[0090] (Incorporation by Reference) This application claims priority under Japanese Patent Application No. 2024-171020, filed September 30, 2024 and Japanese Patent Application No. 2025-57881, filed March 31, 2025, the disclosures of these applications are incorporated herein by reference.

[0091] 1... Microneedle structure, 2... Needle-shaped portion, 3... Base portion, 6... Resin composition for forming the needle-shaped portion, 7... Microneedle patch, 8... Support tape, 9... Functional component, 10... Nonwoven fabric, 11... PET film, 12... Removable adhesive tape, 13... Agarose gel

Claims

A method for producing a microneedle structure, comprising:

1. the step of preparing a needle-shaped portion forming resin composition comprising a pore-forming agent and a water-insoluble resin; 2. the step of producing a microneedle intermediate having a needle-shaped portion formed by the needle-shaped portion forming resin composition; and 3. the step of treating the microneedle intermediate with water so as to remove the pore-forming agent and to form a porous structure in the needle-shaped portion, wherein the pore-forming agent comprises water-soluble inorganic particles and a water-soluble resin.

2. A manufacturing method according to claim 1, wherein the water-soluble inorganic particles include small-diameter particles having an average particle size of 17 μm or less.

3. A manufacturing method according to claim 2, wherein the water-soluble inorganic particles further include large-diameter particles having an average particle size of more than 17 μm.

4. A manufacturing method according to claim 3, wherein the content of the large-diameter particles is 12.5% ​​by mass or less on a solid basis with respect to the needle-shaped resin composition.

5. A manufacturing method according to claim 2, wherein the pore-forming agent does not contain large-diameter particles having an average particle size of more than 17 μm.

6. A method for producing according to claim 1 or 2, wherein the water-soluble inorganic particles contain an inorganic salt.

7. The manufacturing method according to claim 6, wherein the inorganic salt is NaCl, KCl, Na ２ SO ４ CaCl ２ AlCl ３ , and Al ２ (SO ４ ) ３ A manufacturing method comprising at least one selected from the group consisting of the following.

8. A method for producing according to claim 1 or 2, wherein the water-soluble resin comprises at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, and collagen.

9. A manufacturing method according to claim 1 or 2, wherein the water-soluble resin comprises a resin that is solid at room temperature (25°C).

10. A manufacturing method according to claim 1 or 2, wherein the water-insoluble resin comprises a low-melting-point resin having a melting point of 130°C or less.

11. A microneedle structure having a needle-like portion that is inserted into a target, wherein a channel is provided inside the needle-like portion for the liquid injected into the target or the liquid received from the target to flow, and the liquid absorption rate measured by the following test method is 20% or more. (Test method) Prepare a 10 mmφ copper ammonia rayon nonwoven fabric and determine its mass. Determine the mass of the microneedle structure. The total mass of the nonwoven fabric and the microneedle structure shall be the sample mass before liquid absorption. Prepare a liquid-impermeable, repositionable adhesive tape and attach a liquid-impermeable resin film cut into a circle with a diameter of 1 cm to the adhesive surface of the repositionable adhesive tape. Place the nonwoven fabric in the center of the surface of the microneedle structure where the needle-like portion is not formed. Obtain the sample by attaching the repositionable adhesive tape so that the positions of the nonwoven fabric and the circular resin film coincide. The needle portion of the sample is punctured into a 1% agarose gel containing phosphate-buffered saline, and after standing for 5 minutes, the sample is removed from the agarose gel, and any water droplets on the surface where the needle portion was located are removed. Then, the removable adhesive tape is peeled off from the microneedle structure. The mass of the microneedle structure and nonwoven fabric is taken as the mass of the sample after absorption. The absorption rate is calculated from the sample mass before absorption and the sample mass after absorption using the following formula 1. (Formula 1) Absorption rate (%) = (Sample weight after absorption - Sample weight before absorption) ÷ Sample weight before absorption × 100 12. A microneedle structure according to claim 11, wherein the strength of the needle-shaped portion measured by the following test method is 75 mN or more. (Test method) Prepare a force gauge. Place the microneedle structure on the force gauge stage with the needle-shaped portion facing upward. Observe the needle-shaped portion with a microscope, select one needle-shaped body with a sharp tip, and bring the force gauge attachment close to the microneedle structure, aligning it with the position of that needle-shaped body. Move the vertical position of the attachment to a position where it contacts the tip of the needle-shaped body but no force is applied to the needle-shaped body, raise it by 0.1 mm from there, and then lower the attachment at a descent rate of 5 mm / min to start measuring the force applied to the attachment. Measure for 10 needle-shaped portions, and extract the stress at every 0.02 mm displacement up to 0.3 mm, with the tip of the needle-shaped portion set to 0.0 mm. Calculate the stress at the 0.2 mm displacement point and define it as the microneedle strength. The microneedle strength of the 10 needle-shaped parts is measured, and the lowest value is taken as the result.

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