Microneedle structure and method for producing same

Abstract

This microneedle structure comprises needle-shaped sections to be inserted into an object. The needle-shaped sections have a porous structure. The porous structure includes openings in the side surfaces of the needle-shaped sections, and holes through which a liquid to be injected into the object or a liquid received from the object flows. The side-surface opening count, which is the number of openings per 10,000 μm2 in the side surfaces of the needle-shaped sections, is 30 or greater.

Description

Microneedle structure and manufacturing method thereof

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

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

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

[0004] International Publication No. 2022 / 211059

[0005] It is desirable for a microneedle structure to be able to quickly collect or inject a liquid. Therefore, the microneedle structure is required to have high liquid absorption. Therefore, an object of the present invention is to provide a microneedle structure having high liquid absorption.

[0006] In one aspect, the present invention relates to a microneedle structure. The microneedle structure includes a needle-shaped portion to be inserted into a subject. The needle-shaped portion has a porous structure. The porous structure has an opening on the side surface of the needle-shaped portion and holes through which a liquid to be injected into the subject or a liquid received from the subject flows. ２ The number of apertures per aperture is 30 or more.

[0007] In one aspect, the present invention relates to a method for manufacturing a microneedle structure having a needle-shaped portion to be inserted into a subject. The method includes the steps of preparing a base material containing a water-insoluble needle-shaped resin and water-soluble particles, the water-soluble particles being present in a particulate state in the base material; filling the base material into a mold and molding it by heating, the mold having a recess corresponding to the shape of the needle-shaped portion; solidifying the molded base material to obtain a molded product; and treating the molded product with water to remove the water-soluble particles to obtain a microneedle structure. The needle-shaped resin includes a low-melting-point resin having a melting point of 130°C or less. The water-soluble particles include first particles having an average particle size of 17 μm or less.

[0008] According to the present invention, a microneedle structure having high liquid absorption properties is provided.

[0009] Fig. 1 is a schematic cross-sectional view showing a microneedle structure according to an embodiment. Fig. 2 is a schematic cross-sectional view showing an example of a microneedle patch. Fig. 3 is a schematic view showing a method for manufacturing a microneedle structure. Fig. 4 is a schematic cross-sectional view showing a microneedle patch produced in an example. Fig. 5 is a schematic cross-sectional view showing a method for measuring liquid absorption rate.

[0010] Hereinafter, an embodiment of the present invention will be described with reference to the drawings.

[0011] 1 is a schematic cross-sectional view showing a microneedle structure 1 according to this embodiment. This microneedle structure 1 is used to transfer a liquid to and from a target (for example, a living organism, a human body).

[0012] As shown in FIG. 1 , the microneedle structure 1 has a needle-shaped portion 2 and a base portion 3 .

[0013] The base 3 is a portion that supports the needle-like portion 2. There are no particular limitations on the shape of the base 3. In this embodiment, the base 3 is in the shape of a flat plate.

[0014] The needle-shaped portion 2 is the portion that is inserted into the target. Multiple needle-shaped portions 2 are provided. The multiple needle-shaped portions 2 extend upright from one surface of the base 3 (hereinafter, sometimes referred to as the needle-shaped portion forming surface). The needle-shaped portion 2 has a porous structure. Specifically, multiple holes are formed in the needle-shaped portion 2. The holes are open on the side surface of the needle-shaped portion 2. The holes function as flow paths. In other words, when the needle-shaped portion 2 is inserted into the target, a liquid to be injected into the target or a liquid received from the target flows through the holes.

[0015] In the example shown in FIG. 1 , the base 3 is integrated with the needle-shaped portion 2. That is, the base 3 also has a porous structure. As a result, the holes provided in the needle-shaped portion 2 are connected to the back surface of the base 3 (the surface opposite to the surface on which the needle-shaped portion is formed) via holes present in the base 3. That is, liquid can flow between the surface of the needle-shaped portion 2 and the back surface of the base 3. Therefore, although not shown, if a functional member (a member that stores liquid to be injected into the subject, or a member that passively acts on liquid from the subject) is placed on the back surface of the base 3, liquid can be exchanged between the functional member and the subject via the microneedle structure 1.

[0016] The base 3 and the needle-shaped portion 2 do not necessarily have to be integral, and may be formed of different materials. The base 3 only needs to have a structure that allows the needle-shaped portion 2 to communicate with the back surface of the base 3, and does not necessarily have to have a porous structure like the needle-shaped portion 2.

[0017] (Side aperture number of needle-shaped portion) In this embodiment, the needle-shaped portion is designed to have an improved liquid absorption rate. Specifically, the needle-shaped portion has a side aperture number of 30 or more. The "side aperture number" refers to the number of apertures per 10,000 μm on the side of the needle-shaped portion. ２ Specifically, it means the number of apertures in a square area with one side of 100 μm. ２This means openings having an area of ​​100 or more. If the needle-shaped portion has such a number of side openings, remarkably high liquid absorption can be achieved. The number of side openings is preferably 40 or more, more preferably 100 or more. There is no particular upper limit to the number of side openings, but from the viewpoint of improving the strength of the needle-shaped portion, it is, for example, 500 or less, preferably 300 or less, more preferably 200 or less.

[0018] The side aperture number can be determined by a method that will be explained in the examples below.

[0019] The total area of ​​the openings on the side surfaces determined by the method described in the examples below is preferably 300 to 1500 μm ２ , more preferably 400 to 1000 μm ２ is.

[0020] (Internal pore area in needle-shaped portion) The internal pore area in the needle-shaped portion is, for example, 200 μm ２ or more, preferably 330 μm ２ More preferably, 360 μm or more ２ Here, the "internal pore area" refers to the area of ​​the pores within 2500 μm ２ Specifically, it means the total area of ​​holes contained in a square area with one side of 50 μm. The "hole" here means the total area of ​​holes contained in a square area with one side of 50 μm in the cross section of the needle-shaped part. ２ The term "pores having an area of ​​at least 100 mm" means pores having an area of ​​at least 100 mm. If the pores have an internal pore area of ​​at least 100 mm, even higher liquid absorbency can be achieved.

[0021] The upper limit of the internal hole area is not particularly limited, but from the viewpoint of improving the strength of the needle-shaped portion, it is, for example, 1000 μm ２ Less than 700 μm, preferably ２ The following is the result.

[0022] The internal pore area can be determined by the method described in the examples below.

[0023] The number of holes inside the needle-like portion determined by the method explained in the examples below is preferably 20 to 150, and more preferably 30 to 100.

[0024] (Liquid absorption rate) According to the microneedle structure 1 of this embodiment, the needle-shaped portion has the specific configuration as described above, and as a result, high liquid absorption is achieved. Specifically, according to this embodiment, a microneedle structure having a liquid absorption rate of 5% or more can be realized, as measured by the method described in the examples below. In a preferred embodiment, the liquid absorption rate of the microneedle structure 1 is 20% or more, in a more preferred embodiment, 40% or more, and in an even more preferred embodiment, 50% or more.

[0025] (Material of the needle-shaped portion) The material of the needle-shaped portion is not particularly limited. Preferably, the needle-shaped portion contains a resin with a melting point of 130°C or less (hereinafter referred to as low-melting-point resin). If the needle-shaped portion contains a low-melting-point resin, it becomes easier to employ a method of heating and melting the material during the manufacture of the microneedle structure 1, or of heating the material and molding it in a mold. The melting point of the low-melting-point resin is preferably 100°C or less, more preferably 80°C or less.

[0026] The low-melting-point resin is preferably solid at room temperature (25°C). By using such a resin, the strength of the needle-shaped portion is easily maintained at room temperature. The melting point of the low-melting-point resin is preferably 40°C or higher, more preferably 45°C or higher.

[0027] The low-melting-point resin is preferably a water-insoluble resin. If a water-insoluble resin is used, the needle-shaped portion is less likely to dissolve in aqueous liquid present in the target when the needle-shaped portion is inserted into the target. In other words, the shape of the needle-shaped portion is more likely to be maintained during insertion. In addition, it becomes possible to adopt the manufacturing method described below.

[0028] Specific examples of low-melting-point resins include polyesters; polyolefin-based resins such as polyethylene and α-olefin copolymers; olefin copolymer-based resins such as ethylene-vinyl acetate copolymer resins and ethylene-ethyl acrylate copolymers; polyurethane-based elastomers; and derivatives thereof.

[0029] Furthermore, the low-melting-point resin is preferably a biodegradable resin. When a biodegradable resin is used, the impact of the needle-shaped portion on a living organism can be reduced. Examples of biodegradable resins include polyesters and their derivatives. Preferred examples of polyesters and their derivatives include aliphatic 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. Examples of biodegradable aliphatic polyesters include polybutylene succinate (melting point: 84-115°C) and aliphatic-aromatic copolyesters (melting point: 110-120°C). Examples of polybutylene succinate that can be used include BioPBS, available from Mitsubishi Chemical Corporation. Examples of aliphatic-aromatic copolyesters that can be used include Ecoflex, available from BASF.

[0030] The biodegradable resin is preferably a resin in which the acid dissociation constant of the monomer is 4 or more. By having the acid dissociation constant of the monomer be 4 or more, the impact on the living body when the microneedle structure is applied to the living body can be reduced. In addition, when the monomer is a cyclic ester, the acid dissociation constant of the monomer referred to here is the acid dissociation constant of the hydroxycarboxylic acid in which the cyclic ester is ring-opened. The acid dissociation constant of the monomer is preferably 4.0 or more, more preferably 4.5 or more. Furthermore, the acid dissociation constant of the monomer is preferably 25 or less, more preferably 15 or less. An example of a monomer constituting such a biodegradable resin and having an acid dissociation constant of 4 or more is caprolactone. In the biodegradable resin, the constituent units derived from a monomer having an acid dissociation constant of 4 or more preferably account for 70% by mass or more of all constituent units, more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0031] In a particularly preferred embodiment, the low melting point resin comprises a homopolymer or copolymer containing units derived from caprolactone. Most preferably, the low melting point resin comprises polycaprolactone.

[0032] 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. Within this range, the strength required for the needle-shaped portion is easily maintained. The weight-average molecular weight of the low-melting-point resin is a value determined by the method described in the Examples below.

[0033] 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. If it is within this range, the workability of the needle-shaped portion is further improved.

[0034] The needle-shaped portion may contain components other than the low-melting-point resin. However, it is preferable that the main component of the needle-shaped portion (a component accounting for 50% by mass or more) is a low-melting-point resin. The content of the low-melting-point resin in the needle-shaped portion is, for example, 50% by mass or more, preferably 65% ​​by mass or more, more preferably 70% by mass or more, and even more preferably 90% by mass or more. If the low-melting-point resin is contained in such an amount, it becomes easier to employ a method of heating and melting the material during the production of the microneedle structure 1, or heating the material and molding it in a mold.

[0035] (Other configurations of the needle-shaped portion) The shape, size, formation pitch, and number of needle-shaped portions are not particularly limited. For example, the shape of each needle-shaped portion can be cylindrical, prismatic, conical, or pyramidal. The maximum diameter or maximum dimension of the cross section at the base end of each needle-shaped portion is, for example, 25 to 1000 μm. The tip diameter or tip cross-sectional dimension of each needle-shaped portion is, for example, 1 to 100 μm. The height of each needle-shaped portion is, for example, 50 to 2000 μm. The multiple needle-shaped portions are arranged, for example, in a matrix. The number of needle-shaped portions included in the microneedle structure is, for example, 10 to 1000, preferably 20 to 100.

[0036] (Microneedle Patch) The microneedle structure 1 according to this embodiment can be used, for example, as a microneedle patch. Fig. 2 is a schematic cross-sectional view showing an example of a microneedle patch 8. This microneedle patch 8 has the microneedle structure 1, a support tape 9, and a functional member 10. The support tape 9 supports the functional member 10 and the microneedle structure 1.

[0037] The support tape 9 is realized by, for example, an adhesive tape. The microneedle structure 1 is supported on one surface of the support tape 9. An attachment area for attachment to a target is provided on the outer periphery of the support tape 9. When the support tape 9 is attached to the target with the microneedle structure 1 facing the target, the needle-shaped portions 2 of the microneedle structure 1 are inserted into the target.

[0038] The functional member 10 is a member that transfers liquid between the subject and the functional member 10 via the microneedle structure 1. The functional member 10 is sandwiched between the microneedle structure 1 and the support tape 9. When the needle-shaped portion 2 is inserted into the subject, the functional member 10 is connected to the subject via the microneedle structure 1. As a result, liquid is transferred between the functional member 10 and the subject, and a desired function is realized. For example, the functional member 10 may be a test sheet for collecting an aqueous liquid (such as a body fluid) from the subject and testing its components. Alternatively, the functional member 10 may be a storage member for storing a liquid (medicinal solution) to be injected into the subject. Furthermore, the functional member 10 may be an absorbent member for absorbing the aqueous liquid collected from the subject. Examples of the absorbent member include porous materials, such as nonwoven fabrics, that have a different structure from the microneedle structure 1.

[0039] (Uses of Microneedle Structure or Microneedle Patch) Preferably, the microneedle structure 1 or microneedle patch is used to absorb liquid from a living body. Examples of liquid include blood and interstitial fluid. For example, if the functional member 10 is a test sheet for testing interstitial fluid, the components of the interstitial fluid absorbed by the microneedle structure 1 or microneedle patch are tested using the test sheet. Furthermore, if the functional member 10 is an absorbent member for absorbing interstitial fluid, the interstitial fluid absorbed by the microneedle structure 1 or microneedle patch and further absorbed into the absorbent member can be extracted in a test liquid, and the components of the interstitial fluid can be analyzed.

[0040] (Method of manufacturing a microneedle structure) Next, an example of a method of manufacturing a microneedle structure according to this embodiment will be described. Figure 3 is a diagram schematically showing the manufacturing method according to this embodiment.

[0041] (1) Step S1: Preparation of base material (FIGS. 3(a) to 3(d)) First, a base material 14 for the microneedle structure is prepared. Specifically, as shown in FIG. 3(a), water-soluble particles are mixed with a solvent to prepare a dispersion liquid.

[0042] The water-soluble particles are substances that function as pore-forming agents to obtain a porous structure. A detailed description of the water-soluble particles will be given later.

[0043] The solvent used may be one that does not dissolve the water-soluble particles. For example, organic solvents such as IPA (isopropyl alcohol), ethyl acetate, ethanol, dichloromethane, dimethylformamide, and toluene may be used. The amount of solvent used is, for example, 50 to 150 parts by mass, preferably 80 to 120 parts by mass, based on 100 parts by mass of the total of the water-soluble particles and the needle-shaped portion-forming resin described below.

[0044] Next, as shown in Figure 3(b), needle-shaped portion-forming resin 12 is added to the dispersion, heated to melt, and stirred. This produces a mixture. At this time, the water-soluble particles are present in the mixture in a dispersed particulate state without dissolving. Therefore, the water-soluble particles are incompatible with both the solvent and the needle-shaped portion-forming resin, but are soluble in water.

[0045] Next, as shown in FIG. 3(c), the obtained mixture is poured into a base material forming mold 13. The base material forming mold 13 has a recessed portion with a size corresponding to the size of the microneedle structure. The mixture is poured into this recessed portion. The mixture is then heated so that the solvent is removed. The mixture is then compressed and molded by pressing or the like.

[0046] 3(d), the formed mixture is cooled and solidified, and then the solidified mixture is taken out as a base material 14. In the obtained base material 14, the water-soluble particles are present in a particulate state (dispersed state).

[0047] (2) Step S2: Molding (FIG. 3(e)) Next, as shown in FIG. 3(e), the base material 14 is filled into a mold 15. A mold having a recess having a shape corresponding to the needle-shaped portion is used. Then, a heat press is performed. By heating, the base material becomes fluid and is molded into a shape corresponding to the mold. In other words, the base material is molded into a shape corresponding to the microneedle structure.

[0048] (3) Step S3: Solidification (FIG. 3(f)) The molded base material is then cooled and solidified. Then, as shown in FIG. 3(f), the molded base material is removed from the mold as a molded product 16.

[0049] (4) Step S4: Treatment with Water (FIGS. 3(g) to 3(h)) Subsequently, as shown in FIG. 3(g), the molded product 16 is treated with water. This dissolves and removes the water-soluble particles present in the molded product 16. As a result, a porous structure is formed in the molded product 16. After the water-soluble particles are removed, the molded product is dried as shown in FIG. 3(h). This results in a microneedle structure 1 including a needle-shaped portion with a porous structure.

[0050] The above is an outline of the method for manufacturing the microneedle structure. In the above example, the mixture was obtained by mixing the water-soluble particles with a solvent to prepare a dispersion liquid and then adding the needle-shaped portion-forming resin 12 to the dispersion liquid, but the mixture may also be obtained by adding the water-soluble particles to the needle-shaped portion-forming resin 12 that has been heated and melted without using a solvent.

[0051] According to the inventors' findings, the water-soluble particles used as the pore-forming agent and the melting point of the needle-shaped portion-forming resin affect the porous structure of the needle-shaped portion. Therefore, by controlling these factors, needle-shaped portions having the desired porous structure can be achieved. These points are described in detail below.

[0052] (Water-soluble particles) In this embodiment, the water-soluble particles include first particles having an average particle size of 17 μm or less. The average particle size here refers to the 50% particle size diameter measured by laser diffraction particle size measurement. Laser diffraction particle size measurement is performed by wet measurement using absolute ethanol. An example of an apparatus for performing laser diffraction particle size measurement is the "MacroTrack Particle Size Analyzer MT3300" manufactured by Nikkiso Co., Ltd. Using first particles of this size facilitates the formation of numerous openings on the side surfaces of the needle-shaped portions.

[0053] Preferably, the water-soluble particles include second particles in addition to the first particles. The second particles are water-soluble particles having an average particle size of more than 17 μm. When the second particles are used in addition to the first particles, the pores inside the needle-shaped portion tend to be connected to each other. As a result, the internal pore area of ​​the needle-shaped portion tends to be larger. This makes it possible to further improve the liquid absorption.

[0054] The amount of water-soluble particles used (the total amount of first particles and second particles when used) is, for example, 50 to 90 parts by mass, preferably 60 to 80 parts by mass, where the total amount of the water-soluble particles and the needle-shaped portion-forming resin is 100 parts by mass.

[0055] The amount of the first particles used is, for example, 20 to 90 parts by mass, preferably 30 to 70 parts by mass, when the total amount of the water-soluble particles and the needle-shaped portion-forming resin is 100 parts by mass.

[0056] The amount of the second particles used is, for example, 1 to 40 parts by mass, preferably 3 to 30 parts by mass, when the total amount of the water-soluble particles and the needle-shaped portion-forming resin is 100 parts by mass.

[0057] The first particles and the second particles may be made of the same material or different materials.

[0058] The type of water-soluble particles can also affect the porous structure. As water-soluble particles, inorganic salts and sugars can be used, for example, from the viewpoint of being incompatible with both the solvent and the needle-shaped portion-forming resin. Among these, inorganic salts are preferred from the viewpoint of easily controlling the side aperture number of the needle-shaped portion.

[0059] As inorganic salts, for example, Na ＋ , Mg ２＋ , Ca ２＋ , Al ３＋ , and H ＋ Cations such as Cl － ,Br － , S.O. ４ ２－ , S.O. ３ ２－ , NO ２ － , NO ３ － , P.O. ４ ３－ , CO ３ ２－ , O.H. － Specific examples of inorganic salts include compounds that dissociate into anions such as NaCl, KCl, Na ２ SO ４ , CaCl ２ , AlCl ３ , Al ２ (SO ４ ) ３ etc. can be used.

[0060] Examples of sugars include maltodextrin, D-mannitol, D-sorbitol, erythritol, xylitol, deoxylitol, sucralose, sucrose, maltitol, lactose, and lactitol.

[0061] When the above-mentioned water-soluble particles are used, the side aperture number increases. The reason for this is thought to be related to the state of the water-soluble particles in the base material. That is, when inorganic salts, sugars, etc. are used as water-soluble particles, a solid base material in which the water-soluble particles exist in a dispersed state is obtained, unlike when PEG (polyethylene glycol) or the like is used. Then, during molding (step S2), such a base material is heated and becomes fluid. When inorganic salts, sugars, etc. are used, it is thought that even when the base material becomes fluid, the first particles with small particle sizes are more likely to exist in particle form on the surface of the base material. As a result, it is thought that the side aperture number increases.

[0062] Furthermore, the use of water-soluble particles results in a needle-shaped portion with superior toughness compared to the use of other pore-forming agents such as PEG, which makes the needle-shaped portion less likely to collapse upon insertion and reduces the possibility of the needle-shaped portion remaining in the subject.

[0063] (Melting Point of Needle-Shaped Portion-Forming Resin) The melting point of the needle-shaped portion-forming resin can also affect the porous structure of the resulting needle-shaped portion. In the manufacturing method according to this embodiment, the needle-shaped portion-forming resin contains a low-melting-point resin having a melting point of 130°C or less. This facilitates increasing the number of side openings in the needle-shaped portion. Using a low-melting-point resin allows the base material to be molded at a relatively low temperature in step S2. It is believed that the flow state of the base material during molding differs between when molding is performed at a relatively low temperature using a low-melting-point resin and when molding is performed at a high temperature using a high-melting-point resin. Therefore, the presence state of water-soluble particles in the base material during molding also differs. Although the detailed mechanism is unknown, first particles having an average particle size of 17 μm or less are more likely to be present on the surface of the needle-shaped portion than second particles having a larger particle size. This is thought to affect the porous structure, such as the number of side openings.

[0064] The molding temperature of the base material (temperature of the base material) during molding (step S2) is, for example, 150°C or lower, and preferably 130°C or lower.

[0065] Next, examples carried out by the present inventors will be described in order to explain the present invention in more detail, but the present invention should not be construed as being limited to the following examples.

[0066] Example 1 Sodium chloride (manufactured by Naikai Salt Industry Co., Ltd., Nakuru UM-05, corresponding to first particles) with an average particle size of 5 μm was prepared as a pore-forming agent (water-soluble particles). In order to prevent aggregation of the pore-forming agent particles, the pore-forming agent was ground in advance in a mortar. Then, as shown in FIG. 3( a), 7 g of the pore-forming agent was transferred to a beaker with a volume of 100 mL. Next, 5 g each of isopropyl alcohol and ethyl acetate were poured as a solvent. Next, an ultrasonic device was used to disperse the water-soluble particles in the solvent to obtain a dispersion.

[0067] Next, 3 g of pelletized polycaprolactone (weight-average molecular weight 40,000, melting point 60°C) was prepared as the needle-shaped portion-forming resin (the weight-average molecular weight of polycaprolactone was measured using the method described below). Next, as shown in Figure 3(b), 3 g of polycaprolactone was poured into a beaker to obtain a mixture. The beaker was placed on a hot plate heated to 65°C and left to stand for 1 hour to melt the polycaprolactone. The mixture was then stirred using a pencil mixer (manufactured by AS ONE Corporation).

[0068] Next, as shown in FIG. 3(c), a base material molding mold made of polydimethylsiloxane was prepared. The base material molding mold had a recess (a square opening measuring 20 mm x 20 mm on each side and 0.25 mm deep). The prepared mixture was poured into the recess of this base material molding mold. The excess mixture was then scraped off with a spatula. The base material molding mold was then placed on a hot plate heated to 120°C for 10 minutes to remove the solvent. The surface of the mixture was then flattened. Specifically, a stainless steel plate (a rectangle with a thickness of 2 mm, short sides of 80 mm, and long sides of 100 mm) was prepared, and a release film was attached to one side of the SUS plate with double-sided tape, with the release-treated surface facing outward, to create a jig. This jig was then placed on the mixture poured into the base material molding mold so that the release-treated surface adhered to it. The mixture was then pressurized at 10 MPa for 3 minutes using a heated press (AH-1T, manufactured by AS ONE Corporation) with no temperature setting. After the pressure was released, the jig and the base material mold into which the mixture had been injected were placed between two SUS plates (2 mm thick, rectangular with short sides of 80 mm and long sides of 100 mm) that had been cooled to 3°C in advance, and the four corners were fixed with alligator clips. The mixture was cooled for 10 minutes to solidify.

[0069] Next, as shown in Figure 3(d), the solidified mixture was removed from the base material mold. The base material was then placed in a drying oven (40°C) for 24 hours, and the remaining solvent that had not been completely removed by heating on the hot plate was evaporated and dried. This resulted in a base material containing dispersed water-soluble particles.

[0070] Next, as shown in Figure 3(e), a mold (casting die) for hot pressing was prepared. The mold used was made of polydimethylsiloxane and had a plurality of recesses for forming needle-shaped portions. The recesses for forming needle-shaped portions had the following characteristics: Shape of recesses for forming needle-shaped portions: circular cone shape with a circular cross section Diameter of maximum cross section of recesses for forming needle-shaped portions: 300 µm Height of recesses for forming needle-shaped portions: 600 µm Pitch of recesses for forming needle-shaped portions: 1000 µm Number of recesses for forming needle-shaped portions: 7 in vertical rows and 7 in horizontal rows, a total of 49 Size of area where recesses for forming needle-shaped portions were formed: 15 mm square Arrangement of recesses for forming needle-shaped portions: square lattice

[0071] Next, the mold was placed on the lower stage of a heating press (AH-1T, manufactured by AS ONE Corporation). Furthermore, the base material was placed on the recess for forming the needle-shaped portion. Furthermore, a 30 mm square polydimethylsiloxane sheet (lid) was placed on top of it. Then, as a preliminary step, the base material was pressed at 2 MPa for 1 minute 30 seconds while being heated at a lower stage setting temperature of 115°C and an upper stage setting temperature of 105°C. Thereafter, as the main step, the base material was pressed at 3 MPa for 30 seconds while the lower and upper stages were heated to the same temperature as in the preliminary step. Furthermore, the molten base material contained in the lid and mold was refrigerated at 3°C ​​for 5 minutes to solidify the base material. This resulted in a sample (molded product) having a needle-shaped portion and a base.

[0072] Thereafter, as shown in FIG. 3(f), the sample was peeled off from the mold. Then, as shown in FIG. 3(g), the sample was immersed in purified water at room temperature for 1 hour and stirred with a stirrer bar. Next, the purified water was replaced, and the sample was immersed in purified water at room temperature for another 1 hour, and the purified water was stirred with a stirrer bar to dissolve and remove the pore-forming agent. Thereafter, the sample was left to stand in a drying oven (40°C) for 24 hours, and the water was evaporated and dried. This resulted in a microneedle structure according to Example 1.

[0073] Example 2 The pore-forming agent was changed to sodium chloride having an average particle size of 10 μm (Nakuru UM-10, manufactured by Naikai Salt Industry Co., Ltd.). A microneedle structure according to Example 2 was fabricated in the same manner as in Example 1 except for the above.

[0074] Comparative Example 1 The pore-forming agent was changed to sodium chloride having an average particle size of 20 μm (Nakuru UM-20, manufactured by Naikai Salt Industry Co., Ltd.) and the other points were the same as in Example 1 to prepare a microneedle structure according to Comparative Example 1.

[0075] Comparative Example 2 The pore-forming agent was changed to sodium chloride having an average particle size of 45 μm (Nakuru UM-45, manufactured by Naikai Salt Industry Co., Ltd.) and the other points were the same as in Example 1 to prepare a microneedle structure according to Comparative Example 2.

[0076] (Example 3) As the pore-forming agent, 6.3 g of sodium chloride (first particles) having an average particle size of 5 μm and 0.7 g of sodium chloride (second particles) having an average particle size of 45 μm used in Comparative Example 2 were used. In other respects, a microneedle structure according to Example 3 was produced in the same manner as in Example 1.

[0077] Example 4 A microneedle structure according to Example 4 was fabricated in the same manner as in Example 3 except that 4.9 g of sodium chloride (first particles) having an average particle size of 5 μm and 2.1 g of sodium chloride (second particles) having an average particle size of 45 μm were used as pore-forming agents.

[0078] (Example 5) As the pore-forming agent, sodium chloride having an average particle size of 10 μm was used instead of the sodium chloride having an average particle size of 5 μm used in Example 2. A microneedle structure according to Example 5 was produced in the same manner as in Example 3 in other respects.

[0079] Example 6 A microneedle structure according to Example 6 was fabricated in the same manner as in Example 5 except that 4.9 g of sodium chloride having an average particle size of 10 μm and 2.1 g of sodium chloride having an average particle size of 45 μm were used as pore-forming agents.

[0080] Comparative Example 3: 3 g of polyethylene glycol (PEG) (weight average molecular weight 4,000) was used as the pore-forming agent. 7 g of polycaprolactone was used as the needle-shaped portion-forming resin. These were then placed in a 100 mL beaker. The beaker was placed on a hot plate heated to 120°C for 1 hour. The mixture was then stirred using a pencil mixer (manufactured by AS ONE Corporation). A base material molding mold made of polydimethylsiloxane was then prepared. The base material molding mold had recesses (each opening was a square 15 mm x 15 mm, with a depth of 1.5 mm). The prepared mixture was poured into the recesses of this base material molding mold. The same jig as in Example 1 was prepared. This jig was placed on the mixture poured into the base material mold so that the release-treated surface was adhered to it, and then sandwiched between two SUS plates (2 mm thick, 80 mm long, 100 mm long rectangles) that had been cooled to 3°C in advance. The four corners were secured with alligator clips, and the mixture was cooled and solidified for 10 minutes. This yielded a base material. The resulting base material was then removed from the base material mold.

[0081] Next, the same hot press mold as used in the examples was prepared. Next, the mold was placed on the lower stage of a hot press (AH-1T, manufactured by AS ONE Corporation). Furthermore, a base material was placed on the recess for forming the needle-shaped portion. Furthermore, a 30 mm square polydimethylsiloxane sheet (lid) was placed on top of it. Then, as a preliminary step, the base material was pressed at 2 MPa for 1 minute 30 seconds while being heated at a lower stage setting temperature of 100°C and an upper stage setting temperature of 90°C. Thereafter, as the main step, the base material was pressed at 3 MPa for 30 seconds while the lower and upper stages were heated to the same temperature as in the preliminary step. Furthermore, the molten base material contained in the lid and mold was refrigerated at 3°C ​​for 5 minutes to solidify the base material. This resulted in a sample having a needle-shaped portion and a base. The sample was then peeled off from the mold and immersed in purified water heated to 40°C for 24 hours, stirred with a stirrer bar, and the pore-forming agent was dissolved and removed. The sample was then left to stand in a drying oven (40°C) for 24 hours to evaporate the water and dry. This resulted in a microneedle structure according to Comparative Example 3.

[0082] [Measurement method] The microneedle structures obtained in the examples and comparative examples were evaluated for the number of side openings, the internal pore area in the needle-shaped portion, the liquid absorption rate, and the breakage rate. The measurement methods for each physical property are explained below. The measurement method for the weight-average molecular weight of polycaprolactone used as the needle-shaped portion-forming resin is also explained.

[0083] (Side Numerical Aperture) The microneedle structure was photographed using a scanning electron microscope (SEM). Using the image analysis software "Image J" (open source software developed by the National Institutes of Health, USA), square areas with sides of 100 μm were randomly cut out from the image of the microneedle structure on the side of the needle-shaped portion. The cut-out image was binarized by setting the contrast to the maximum value in "Brightness / Contrast". Dark areas in the binarization process were identified as openings. The image after binarization was processed using "Analyze Particles" to identify 1 μm square areas. ２ The number of openings having an area of ​​at least this value was calculated and used as the result. The total area of ​​the openings was also calculated. The conditions for "Analyze Particles" were left as the initial settings, except that the size item was changed from "0-Infinity" to "1-Infinity."

[0084] (Internal pore area) The microneedle was cooled with liquid nitrogen. Then, using an ultramicrotome, the needle-shaped portion was processed so that the cross section was exposed. Then, as in the measurement of "side numerical aperture", a cross-sectional image of the needle-shaped portion was taken using an SEM. Then, a square area with a side length of 50 μm was cut out from the SEM image. The cut-out image was subjected to image processing under the same conditions as in the measurement of "side numerical aperture", and a 1 μm ２ The number of pores having an area equal to or greater than this was determined. Furthermore, the total area of ​​the pores was calculated as the internal pore area.

[0085] (Liquid Absorption Rate) A sample microneedle structure and a nonwoven fabric (Bemliese SN140, 10 mmφ, manufactured by Asahi Kasei Corporation) to be placed on the back of the microneedle structure were prepared. The initial weights of the microneedle structure and the nonwoven fabric were measured, and the total weight was used as the sample weight before liquid absorption. Next, a microneedle patch was prepared as shown in FIG. 4. Specifically, a nonwoven fabric 4 was placed on the back of the microneedle structure 1 (the side opposite to the side on which the needle-shaped portion was provided). Furthermore, a removable adhesive tape 6 (Adwill C-902, 20 × 20 mm, manufactured by Lintec Corporation) was prepared, on which a PET film 5 (thickness 50 μm, 10 mmφ) of the same size as the nonwoven fabric 4 was provided. Eight ventilation holes were opened at equal intervals in the adhesive tape along the outer edge of this PET film 5 using thumbtacks. The size of the removable adhesive tape 6 is not particularly limited as long as it can cover and seal the nonwoven fabric. The prepared removable adhesive tape 6 was attached to the back surface of the microneedle structure 1 so that the PET film 5 was placed on the nonwoven fabric 4 .

[0086] Next, agarose gel (NE-AG01, manufactured by Fast Gene) was prepared. 300 mg of the prepared agarose gel was placed in a petri dish. Next, 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 then poured into the petri dish containing the agarose gel. Next, the petri dish was placed on a hot plate heated to 120°C, and the agarose gel was dissolved by stirring with a spoon. The mixture was then allowed to cool to room temperature, yielding a 1% agarose gel containing PBS.

[0087] Next, as shown in FIG. 5( a), the needle-shaped portion of the sample was punctured into the prepared agarose gel 7. Then, as shown in FIG. 5( b), the sample was lightly pressed with a finger five times, and the finger was left in place for one minute. After one minute, the sample was pressed with a finger five times again and held for one minute. This procedure was repeated five times to puncture the sample into the agarose gel. Then, as shown in FIG. 5( c), the sample was removed from the agarose gel 7, and water droplets on the surface where the needle-shaped portion was provided were blown off with an air blow gun. Then, as shown in FIG. 5( d), the re-peelable adhesive tape 6 was peeled off. Next, as shown in FIG. 5( e), the microneedle structure 1 and the nonwoven fabric 4 were separated, and their respective weights were determined. The total weight of the microneedle structure 1 and the nonwoven fabric 4 was calculated as the weight of the sample after liquid absorption. The liquid absorption rate was then calculated using the following formula 1. (Formula 1) Absorption rate (%) = (Sample weight after absorption - Sample weight before absorption) ÷ Sample weight before absorption × 100

[0088] (Breakage rate) A compressive load was applied to the microneedle structures obtained in the examples and comparative examples by lowering a 2 mmφ iron attachment at a rate of 5 mm / min using a force gauge (digital force gauge manufactured by Imada Co., Ltd.). The breakage rate was calculated as the percentage of the number of needle-like parts that were broken and separated from the main body (excluding needle-like parts that were simply deformed by bending, crushing, etc. and had no separated parts from the main body) out of the total number of needle-like parts.

[0089] (Weight-Average Molecular Weight of Polycaprolactone) The weight-average molecular weight (Mw) of the polycaprolactone (PCL) used in the examples was measured using gel permeation chromatography (GPC) under the following conditions (GPC measurement), and is a value converted to a standard polystyrene standard. Samples for GPC measurement were prepared as follows. 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 resulting solution and 9 ml of THF were added dropwise to a separately prepared screw tube to prepare a 1% PCL solution. This 1% PCL solution was filtered through a GD / X syringe filter (manufactured by Whatman) and added dropwise to a GPC apparatus. (Measurement conditions) Measurement device: HLC-8320, manufactured by Tosoh Corporation GPC columns (passed in the following order): TSK gel super H-H, TSK gel super HM-H, TSK gel super H2000, manufactured by Tosoh Corporation Measurement solvent: tetrahydrofuran Measurement temperature: 40°C

[0090] [Results and Discussion] The results are shown in Table 1. In Examples 1 to 6, the number of side openings was 30 or more. Also, a liquid absorption rate of 5% or more was obtained. In contrast, the number of side openings in Comparative Examples 1 to 3 was less than 30. And the liquid absorption rate was less than 5%, which was extremely low compared to Examples 1 to 6. From these comparison results, it can be seen that the liquid absorption rate is significantly improved by having the number of side openings be 30 or more.

[0091] In Examples 1 to 6, in which sodium chloride was used as the pore-forming agent, the breakage rate was 0%. In contrast, in Comparative Example 1, in which PEG was used as the pore-forming agent, the breakage rate was 90%. From these results, it can be seen that the strength of the needle-shaped portion is significantly improved by using sodium chloride, a type of water-soluble particle, as the pore-forming agent.

[0092] In Example 1, in which only the first particles were used as the pore-forming agent, the internal pore area of ​​the needle-shaped portion was 200 μm ２ Although it was more than 330 μm ２On the other hand, in Examples 3 to 6, in which second particles were used as the pore-forming agent in addition to the first particles, the internal pore area was 330 μm ２ That was the result. Example 1 had a better liquid absorption rate than the comparative example, but Examples 3 to 6 had even better liquid absorption rates than Example 1. This confirmed that the combined use of the first particles and the second particles increases the internal pore area of ​​the needle-like portion, thereby further improving the liquid absorption rate.

[0093]

[0094] (Additional Notes) The contents described in the above-described embodiments and examples can also be understood as aspects described in the following additional notes.

[0095] (Supplementary Note 1) A needle-shaped portion to be inserted into a target is provided, the needle-shaped portion having a porous structure, the porous structure having an opening on a side surface of the needle-shaped portion and holes through which a liquid to be injected into the target or a liquid received from the target flows, and a 10000 μm ２ The microneedle structure according to claim 1, wherein the number of side openings per 2500 μm 2 is 30 or more. (Supplementary Note 2) The microneedle structure according to claim 1, wherein the needle-shaped portion contains a low-melting-point resin having a melting point of 130° C. or less. (Supplementary Note 3) The microneedle structure according to claim 1, wherein the number of side openings per 2500 μm 2 is 30 or more. ２ The total area of ​​the holes per ２The microneedle structure according to any one of Supplementary Notes 1 to 2, wherein the number of side openings is 100 or more. (Supplementary Note 4) The microneedle structure according to any one of Supplementary Notes 1 to 3, wherein the number of side openings is 100 or more. (Supplementary Note 5) The microneedle structure according to any one of Supplementary Notes 1 to 4, wherein the liquid absorption rate is 5% or more. (Appendix 6) A method for manufacturing a microneedle structure having a needle-shaped portion to be inserted into a target, comprising the steps of: preparing a base material containing a water-insoluble needle-shaped portion-forming resin and water-soluble particles, wherein the water-soluble particles are present in a particulate state in the base material; filling the base material into a mold and shaping it by heating, wherein the mold has a recessed portion having a shape corresponding to the needle-shaped portion; solidifying the shaped base material to obtain a molded product; and treating the molded product with water to remove the water-soluble particles to obtain the microneedle structure, wherein the needle-shaped portion-forming resin comprises a low-melting point resin having a melting point of 130°C or less, and the water-soluble particles comprise first particles having an average particle size of 17 μm or less. (Appendix 7) The manufacturing method described in Appendix 6, wherein the water-soluble particles further comprise second particles having an average particle size of more than 17 μm. (Supplementary Note 8) A needle-shaped portion to be inserted into a subject is provided, the needle-shaped portion having a porous structure, the porous structure having an opening on a side surface of the needle-shaped portion and holes through which a liquid to be injected into the subject or a liquid received from the subject flows, and a diameter of 2500 μm in a cross section of the needle-shaped portion is 2500 μm ２ The total area of ​​the holes per ２a microneedle structure having a needle-shaped portion to be inserted into a target, the microneedle structure comprising: a step of preparing a base material containing a needle-shaped portion-forming resin that is insoluble in water and water-soluble particles, the water-soluble particles being present in a particulate state in the base material; a step of filling a mold with the base material and molding the base material, the mold having a recessed portion having a shape corresponding to the needle-shaped portion; a step of solidifying the molded base material to obtain a molded product; and a step of treating the molded product with water to remove the water-soluble particles to obtain the microneedle structure, the water-soluble particles comprising second particles having an average particle size of more than 17 μm.

[0096] (Citation by Reference) This application claims priority based on Japanese Patent Application No. 2023-193715 (filing date: November 14, 2023) and Japanese Patent Application No. 2023-193717 (filing date: November 14, 2023), the contents of which are incorporated herein by reference.

[0097] DESCRIPTION OF SYMBOLS 1 Microneedle structure 2 Needle part 3 Base part 4 Nonwoven fabric 5 PET film 6 Removable adhesive tape 7 Agarose gel 8 Microneedle patch 9 Tape 10 Functional member

Claims

1. A needle-shaped part to be inserted into a target is provided, the needle-shaped part has a porous structure, the porous structure has an opening on a side surface of the needle-shaped part and a hole through which a liquid to be injected into the target or a liquid received from the target flows, and ２ The number of side openings per microneedle structure is 30 or more.

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

3. 2500 μm in the cross section of the needle-shaped portion ２ The total area of ​​the holes per ２ The microneedle structure according to claim 1 .

4. The microneedle structure according to claim 1, wherein the number of side openings is 100 or more.

5. The microneedle structure according to claim 1, having a liquid absorption rate of 5% or more.

6. A method for manufacturing a microneedle structure having a needle-shaped portion to be inserted into a target, comprising the steps of: preparing a base material containing a needle-shaped portion-forming resin that is insoluble in water and water-soluble particles, wherein the water-soluble particles are present in a particulate state in the base material; filling the base material into a mold and shaping it by heating, wherein the mold has a recess of a shape corresponding to the needle-shaped portion; solidifying the shaped base material to obtain a molded product; and treating the molded product with water to remove the water-soluble particles to obtain the microneedle structure, wherein the needle-shaped portion-forming resin comprises a low-melting point resin having a melting point of 130°C or less, and the water-soluble particles include first particles having an average particle size of 17 μm or less.

7. The method according to claim 6, wherein the water-soluble particles further comprise second particles having an average particle size of more than 17 μm.