Microneedle, microneedle array, and method for manufacturing a microneedle

Abstract

To provide a porous microneedle capable of getting pinpoint access to a target part on a surface of the skin or under the skin, a microneedle array, and a method of manufacturing the microneedle.SOLUTION: A surface of a porous needle body 11 is partially coated with a coating material 12. The needle body 11 can also be provided with a channel that is internally extended in a net-like pattern. Additionally, the needle body 11, which is made of a porous body, can also be provided with a channel that is formed of a void part of the porous body.SELECTED DRAWING: Figure 1

Description

[[TECHNICAL FIELD]]

[0001] The present invention relates to microneedles, microneedle arrays, and methods for producing microneedles. [[BACKGROUND ART]]

[0002] Microneedles are micro-needles with a length of about several hundred micrometers. Since they can access the interior of the skin in a minimally invasive manner while minimizing pain, their application as tools for transdermal drug delivery, intradermal substance sensing and the like by breaking through the barrier of the skin surface layer is progressing (see, for example, Non-Patent Document 1 or 2).

[0003] Conventionally, as a basic microneedle, there is a hollow microneedle 51 shown in Fig. 9(a) (see, for example, Non-Patent Document 3). The hollow microneedle 51 has a structure obtained by miniaturizing a conventional injection needle having a through-hole inside the needle, and allows the opening of the hole to access a subcutaneous target site in a pinpoint manner. However, considering the influence on the sharpness and strength of the needle, it is difficult to form an opening at the apex of the needle, and there has been a problem that the sharpness of the needle tip is also lost due to the opening. In addition, relatively complicated processing technology is required to form the hollow shape, and there has also been a problem that biological tissue fragments and the like enter the hole and cause blockage during use.

[0004] Therefore, a porous microneedle 52, shown in Figure 9(b), has been developed to solve these problems (see, for example, Patent Document 1 or Non-Patent Document 4). This porous microneedle 52 has various forms, such as a needle body made of a porous material in which interconnected voids form channels, connecting to the entire surface including the apex of the needle body, or a needle body made of a hydrogel with a fine polymer network structure, or a xerogel obtained by drying the hydrogel, where the network acts as a channel, connecting to the entire surface of the needle body. Compared to a hollow microneedle 51, the porous microneedle 52 has a simpler shape, can be easily processed using methods such as mold molding, and has low resistance to fluid delivery (flows smoothly), so it is expected to have applications as a tool for transdermal drug delivery and diagnosis (see, for example, Patent Document 2, Non-Patent Document 5 or 6).

[0005] Furthermore, with advances in microfabrication technology, microneedle arrays have been developed in which multiple microneedles are arranged and integrated on a single substrate (see, for example, Patent Documents 3 and 4). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Liu, G.-S. et al., “Microneedles for transdermal diagnostics: Recent advances and new horizons”, Biomaterials, 2020, 232, 119740 [Non-Patent Document 2] Chang, H., Zheng, M., Chew, SWT and Xu, C., “Advances in the Formulations of Microneedles for Manifold Biomedical Applications”, Adv. Mater. Technol., 2020, 5, p.1-19 [Non-licensed document 3] Lhernould, MS, “Optimizing hollow microneedles arrays aimed at transdermal drug delivery”, Microsyst. Technol., 2013, 19, p.1-8

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

[0007]

Patent Document 1

Patent document 2

Patent document 3

[0008] The porous microneedles described in Patent Documents 1 and 2, and Non-Patent Documents 4 to 6, have low resistance to fluid delivery and flow smoothly, making them suitable for use as drug delivery and diagnostic tools. However, because the entire surface of the needle body has openings for the flow channels, there is a problem in that it is not possible to access the target area on the skin surface or subcutaneously with pinpoint accuracy. For example, when used for drug delivery, there was a possibility of drug loss.

[0009] This invention addresses these challenges and aims to provide porous microneedles, microneedle arrays, and methods for manufacturing microneedles that can precisely access target areas on the skin surface or subcutaneously. [Means for solving the problem]

[0010] To achieve the above objective, the microneedle according to the present invention is characterized in that a portion of the surface of the porous needle body is covered with a coating material.

[0011] The microneedle according to the present invention allows for pinpoint access to the skin surface or subcutaneous target area by covering the surface of the porous needle body with a coating material, except for the desired portion, and utilizing the opening of the pores in the desired portion. For example, when used for subcutaneous drug delivery using the channel formed by the opened pores, efficient drug delivery to the target area becomes possible, improving the drug administration effect and reducing drug loss. Furthermore, when used as a diagnostic tool for sensing intradermal information, information can be efficiently acquired at the desired location. The skin is a collection of various tissues, and the boundary between the outermost epidermal tissue and the dermal tissue below it is located at a depth of approximately 0.1 mm from the skin surface. For example, by making an opening in a range that spans both tissues, it is possible to collect interstitial fluid from the target area or measure electrical potential, which is an indicator of skin health.

[0012] In the microneedle according to the present invention, the needle body may have a network of channels extending inside. Alternatively, the needle body may be made of a porous material and have channels formed by the voids in the porous material. In these cases, for example, the needle body can be made of a hydrogel having a fine polymer network structure, a xerogel obtained by drying the hydrogel, a hydrogel material, a resin, an oxide, a metal, a biodegradable material, and the like.

[0013] In the microneedle according to the present invention, the needle body preferably has a plurality of openings on its surface that communicate with the flow channels, and the coating material is provided so as to cover some of the multiple openings. In this case, it is preferable that the flow channels consist of a plurality of channels, and each opening communicates with at least one flow channel. In these cases, the openings not covered by the coating material can be used to access the target area on the surface of the skin or in the subcutaneous tissue.

[0014] In the microneedle according to the present invention, the coating material may cover any portion of the surface of the needle body. For example, the coating material may cover the surface of the needle body excluding the tip, leaving the tip open; or it may cover only the surface of the flange portion around the rear end of the needle body, leaving the area from the rear end to the tip open; or it may cover both the rear and tip of the needle body, leaving the middle portion open. Regardless of which portion the coating material covers, the microneedle according to the present invention can prevent a decrease in the sharpness of the tip of the needle body.

[0015] The coating material may consist of any material that can close the openings of the holes on the surface of the needle body, for example, a protective film made of a resist material. The coating material is preferably selected according to the application, for example, when used for electrical measurement, it is preferable to use an insulating material that does not conduct electricity, such as parylene. Furthermore, the coating material is not limited to a solid, but may also be a liquid or gel.

[0016] The microneedle array according to the present invention is characterized by having a plurality of microneedles according to the present invention, and each microneedle being arranged in a row.

[0017] The microneedle array according to the present invention has multiple microneedles arranged in a row, so it can efficiently perform, for example, edema measurement by measuring the resistance of the skin epithelium, or linear or planar drug administration. The microneedle array according to the present invention may be arranged in any configuration, for example, the microneedles may be arranged in a row on the surface of a rigid substrate or a flexible substrate, or the microneedles may be connected and arranged.

[0018] The microneedle and microneedle array according to the present invention may be manufactured by any method. The method for manufacturing a microneedle according to the present invention for manufacturing the microneedle and microneedle array according to the present invention comprises, for example: a needle forming step of manufacturing the needle body in a state where the flow path is blocked with a soluble material that is soluble in a predetermined solution; a coating step of applying the coating material to the surface of the needle body in a state where a part of the surface of the needle body is covered with a protective material; and a flow path forming step of dissolving the soluble material with the predetermined solution after removing the protective material.

[0019] When this protective material is used, the needle forming step may be any method as long as it can manufacture the needle body in a state where the flow path is blocked with a soluble material, and for example, known methods described in Non-Patent Documents 4 to 6 and Patent Documents 1 to 4 may be used. When using a known method, the needle forming step may block the flow path with a soluble material after manufacturing a porous microneedle by a known method, or may use the needle body in a state where the flow path is blocked with a soluble material, which is obtained during the process of manufacturing a porous microneedle by a known method. Further, in the needle forming step, the entire flow path may be blocked with the soluble material, but only the opening portion of the flow path on the surface of the needle body may be blocked.

[0020] Further, when this protective material is used, the soluble material may be made of any material as long as it is different from the material of the needle body. The predetermined solution capable of dissolving the soluble material preferably dissolves only the soluble material without dissolving the needle body, and may be made of any material as long as it satisfies this requirement.

[0021] Furthermore, as another method of manufacturing the microneedle according to the present invention, for example, without using a soluble material, a needle body in a state where the flow path is not blocked, i.e., a needle body in which a flow path has been formed, may be coated with a protective material on a part of its surface, and then the protective material may be removed. Alternatively, without using a protective material or a soluble material, a needle body in a state where the flow path is not blocked, i.e., a needle body in which a flow path has been formed, may be coated with a protective material on a part of its surface, without blocking the openings in other parts. Alternatively, a needle body in a state where all the openings of the flow path are blocked with a soluble coating material may be manufactured, and only the soluble coating material blocking the openings at desired positions may be dissolved when using or during use. [Effects of the Invention]

[0022] According to the present invention, it is possible to provide porous microneedles, microneedle arrays, and methods for manufacturing microneedles that can precisely access target areas on the surface or subcutaneous tissue of the skin. [Brief explanation of the drawing]

[0023] [Figure 1] This is a cross-sectional view showing a microneedle according to an embodiment of the present invention, in which (a) the needle body is open from the rear end to the tip, (b) as shown, the needle body is open only at the tip, (c) the needle body is widely open at the tip, and (d) the middle part of the needle body is open. [Figure 2] This is a cross-sectional view showing the needle formation steps (a) to (d) of the method for manufacturing microneedles according to an embodiment of the present invention. [Figure 3] This is a cross-sectional view showing (a) and (b) coating steps and (c) and (d) channel formation steps of a method for manufacturing microneedles according to an embodiment of the present invention. [Figure 4]This is a perspective view showing (a) a method for masking a microneedle array in which three or more microneedles are integrated, and (b) a method for masking when there is only one microneedle on a single substrate, in the coating process of a method for manufacturing microneedles according to an embodiment of the present invention. [Figure 5] (a) A scanning electron microscope (SEM) image showing the position of the line scan near the tip of the needle body by EDX, and (b) A graph of the Cl signal intensity showing the line scan results of the microneedle according to an embodiment of the present invention. [Figure 6] The images show (a) a cross-sectional view of the filling of a microneedle according to an embodiment of the present invention, illustrating the method of testing the diffusion of the dye, (b) a cross-sectional view of the diffusion of the dye, (c) a micrograph of an uncoated microneedle (comparative example) showing the results of the dye diffusion test, and (d) a micrograph of a microneedle coated except for the tip. [Figure 7] The images show (a) a cross-sectional view of the filling of an electrolyte solution to measure the DC resistance of a microneedle according to an embodiment of the present invention, and (b) a cross-sectional view of the application of a DC current to determine the resistance value, and (c) a graph showing the resistance values ​​of an uncoated microneedle (comparative example), a microneedle coated except for the tip, and a microneedle coated entirely (comparative example) as a result of the DC resistance measurement test. [Figure 8] The images show (a) a cross-sectional view illustrating a method for measuring epidermal potential of a microneedle according to an embodiment of the present invention, (b) a magnified cross-sectional view of a single inserted microneedle, and (c) graphs showing the measurement results of epidermal potential, including a microneedle coated except for the tip, an uncoated microneedle (comparative example), and epidermal potential measured using a conventional method. [Figure 9] This is a cross-sectional view showing (a) a conventional hollow microneedle and (b) a porous microneedle. [Modes for carrying out the invention]

[0024] Embodiments of the present invention will be described below with reference to the drawings. Figures 1 to 8 show a microneedle, a microneedle array, and a method for manufacturing a microneedle according to an embodiment of the present invention. As shown in Figures 1(a) to 1(d), the microneedle 10 of the embodiment of the present invention has a needle body 11 and a coating material 12. In addition, the microneedle array of the embodiment of the present invention has multiple microneedles 10 arranged side by side.

[0025] The needle body 11 is porous, conical in shape, and has a flange portion 21 around the rear end on the base side of the cone. The needle body 11 has a flow channel inside and a plurality of openings on its surface that communicate with the flow channel. The flow channel may extend in a network-like manner inside the needle body 11, or it may be formed by the void portion of the porous needle body 11. Preferably, the flow channel consists of multiple channels, and each opening communicates with at least one flow channel. In a specific example, the needle body 11 is made of a hydrogel having a fine polymer network structure, a xerogel obtained by drying the hydrogel, a hydrogel material, a resin, an oxide, a metal, a biodegradable material, etc.

[0026] Here, a hydrogel material refers to a material that forms a hydrogel when dispersed in water (dispersion medium). Examples of hydrogel materials include natural polymers such as agar, gelatin, agarose, xanthan gum, gellan gum, sclerotium gum, arabic gum, tragacanth gum, karaya gum, cellulose gum, tamarind gum, guar gum, locust bean gum, glucomannan, chitosan, carrageenan, quince seed, galactan, mannan, starch, dextrin, curdlan, casein, pectin, collagen, fibrin, peptides, chondroitin sulfates such as sodium chondroitin sulfate, hyaluronic acid (mucopolysaccharide) and hyaluronic acid sodium, alginates such as alginic acid, sodium alginate, and calcium alginate, and derivatives thereof; cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof; polyacrylic acid, polymethacrylic acid, Examples include poly(meth)acrylic acids such as sodium methacrylate and acrylic acid-alkyl methacrylate copolymers, and their salts; polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylamide, poly(N-isopropylacrylamide), polyvinylpyrrolidone, polystyrene sulfonic acid, polyethylene glycol, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, maleic anhydride copolymer, polyalkylene oxide resins, crosslinked products of poly(methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol, polyethylene glycol crosslinked products, N-vinylacetamide crosslinked products, acrylamide crosslinked products, starch-acrylate graft copolymer crosslinked products, and other synthetic polymers; silicones; interpenetrating network hydrogels and semi-interpenetrating network hydrogels; poly-2-hydroxyethyl methacrylic acid, poly-2-acrylamide-2-methylpropanesulfonic acid; and mixtures of two or more of these.Among these, collagen, glucomannan, carboxymethylcellulose, sodium carboxymethylcellulose, polyacrylic acid, sodium polyacrylate, interpenetrating network hydrogels, and semi-interpenetrating network hydrogels are preferred as materials constituting hydrogels from the viewpoint of load-bearing capacity and biocompatibility. Furthermore, crosslinked poly(methyl vinyl ether-alt-maleic anhydride) and polyethylene glycol are preferred from the viewpoint of obtaining excellent mechanical strength and excellent biocompatibility. Moreover, crosslinked polyethylene glycol is preferred from the viewpoint of ensuring the electrical neutrality of the hydrogel.

[0027] Examples of resins include polycarbonate, acrylonitrile-butadiene-styrene (ABS) resin, phenolic resin, acrylic resin, and methacrylic resin (such as polyglycidyl methacrylate resin). Examples of oxides include inorganic oxides and their derivatives, where examples of inorganic oxides include silicon dioxide, tin oxide, zirconia oxide, titanium dioxide, niobium oxide, tantalum oxide, aluminum oxide, tungsten oxide, hafnium oxide, and zinc oxide. Examples of metals include nickel, iron, and alloys thereof. Examples of biodegradable materials include polylactic acid-glycolic acid copolymer (PLGA) and mixed materials mainly composed of PLGA, tricalcium β-phosphate, calcium carbonate, polycaprolactone, polydioxanone, hydroxyapatite, polyethylene glycol, and magnesium alloy. The needle body 11 may consist of a combination of two or more of the substances listed here.

[0028] The coating material 12 is provided to cover a portion of the surface of the needle body 11. The coating material 12 is provided to cover a portion of the multiple openings on the surface of the needle body 11. The coating material 12 may cover any portion of the surface of the needle body 11. For example, as shown in Figure 1(a), the microneedle 10 may have the coating material 12 covering only the surface of the flange portion 21 around the rear end of the needle body 11, leaving the area from the rear end to the tip open. Alternatively, as shown in Figure 1(b), the coating material 12 may cover the surface of the needle body 11 excluding the tip, leaving only the tip open. Furthermore, as shown in Figure 1(c), the coating material 12 may cover the surface of the needle body 11 excluding a wide area of ​​the tip, leaving the tip of the needle body 11 wide open. Furthermore, as shown in Figure 1(d), the coating material 12 may cover the rear end and tip of the needle body 11, and the middle part of the needle body 11 may be open. These microneedles 10 can carry fluids, electrical signals, etc., through the flow path as indicated by the arrows in the figure.

[0029] The coating material 12 may be made of any material that can close the opening on the surface of the needle body 11, for example, it may be made of a protective film made of a resist material. The coating material 12 is preferably selected according to the application, for example, when used for electrical measurement, it is preferably made of an electrically insulating material such as parylene. Furthermore, the coating material 12 is not limited to a solid, but may also be a liquid or a gel.

[0030] The microneedle 10 and microneedle array according to the embodiment of the present invention can be manufactured by the microneedle manufacturing method according to the embodiment of the present invention shown below. That is, in the microneedle manufacturing method according to the embodiment of the present invention, first, a needle body 11 is manufactured in a state in which the flow path is blocked with a soluble material that can be dissolved in a predetermined solution by a needle formation step. In the needle formation step, a known microneedle manufacturing method may be used. For example, the microneedle may be manufactured by a known method and then the flow path may be blocked with a soluble material, or a needle body in a state in which the flow path is blocked with a soluble material obtained during the manufacturing of the microneedle by a known method may be used. Furthermore, the soluble material may consist of any material different from the needle body 11. The predetermined solution capable of dissolving the soluble material may consist of any solution that dissolves the soluble material without dissolving the needle body 11.

[0031] After the needle formation process, a portion of the surface of the needle body 11 is covered with a protective material, and a coating material 12 is applied to the surface of the needle body 11 (coating process). Then, the protective material is removed, and the soluble material is dissolved with a predetermined solution (channel formation process). In this way, a microneedle 10 or a microneedle array according to an embodiment of the present invention can be manufactured.

[0032] The microneedle 10 allows for pinpoint access to the skin surface or subcutaneous target area by covering the surface of the porous needle body 11 with a coating material 12, except for the desired portion. This enables efficient drug delivery to the target area, improving drug efficacy and reducing drug loss, for example, when used for subcutaneous drug delivery. Furthermore, when used as a diagnostic tool for sensing intradermal information, it allows for efficient acquisition of information at a desired location. For example, by creating an opening that spans both epidermal and dermal tissue, interstitial fluid can be collected from the target area, or electrical potential measurements, which are indicators of skin health, can be performed.

[0033] The microneedle 10 can prevent a decrease in the sharpness of the tip of the needle body 11, regardless of which part is covered by the coating material 12. Furthermore, because the microneedle array has multiple microneedles 10 arranged side by side, it can efficiently perform tasks such as measuring edema by measuring the resistance of the skin epithelium, or administering drugs in a linear or planar manner.

[0034] In the embodiment of the present invention, as an alternative manufacturing method, for example, a needle body 11 in a state where the flow path is not blocked, i.e., a needle body 11 in which a flow path has been formed, may be manufactured without using a soluble material, with a portion of the surface covered with a protective material, a coating material 12 applied to the surface of the needle body 11, and then the protective material removed. Alternatively, a needle body 11 in a state where the flow path is not blocked, i.e., a needle body 11 in which a flow path has been formed, may be manufactured without using a protective material or a soluble material, with the coating material 12 applied to a portion of the surface, without blocking the openings in other parts. Alternatively, a needle body 11 in which all the openings of the flow path are blocked with a soluble coating material 12 may be manufactured, and only the soluble coating material 12 blocking the openings at desired positions may be dissolved when using or during use. [Examples]

[0035] Microneedles 10 were manufactured using the manufacturing method of the microneedles according to an embodiment of the present invention, and various evaluation experiments were conducted. The reagents, materials, and equipment used for manufacturing and experiments are as follows.

[0036] • Glycidyl methacrylate (GMA, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Trimethylolpropane trimethacrylate (TRIM, manufactured by Sigma-Aldrich) • Polyethylene glycol (PEG 10 kDa, manufactured by Sigma-Aldrich) • Diethylene glycol (DEG, manufactured by Tokyo Chemical Industry Co., Ltd.) • Irgacure 184 (manufactured by BASF SE) • Parylene C (manufactured by Dai-San Kasei Co., Ltd.) • Polydimethylsiloxane (PDMS, SILPOT 184, manufactured by DuPont-Toray Specialty Materials Co., Ltd.) • Methanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Rhodamine B (manufactured by Fujifilm Wako Pure Chemical Corporation) • Gellan gum (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Ethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Ringer's solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) • Acrylic sheet (manufactured by AcrySunday Co., Ltd.) • Cutting machine (manufactured by Modia Systems Co., Ltd.) • Scanning electron microscope (SEM; VE-9800, manufactured by Keyence Corporation) ·Energy dispersive X-ray spectrometer (SEM EDX; JSM-7400F, manufactured by JEOL Ltd.) • Electrochemical analyzer (ALS 7082E, manufactured by BAS Corporation)

[0037] The microneedles 10 were manufactured using the methods described in Non-Patent Documents 4 to 6. In this process, a microneedle array consisting of three microneedles 10 arranged in a row was manufactured. First, the needle formation process shown in Figure 2 was performed. Specifically, a female mold in the shape of a microneedle was created by drilling holes in an acrylic plate using a cutting machine. This was then transferred in two steps using PDMS to produce the female mold 31 made of PDMS shown in Figure 2(a).

[0038] Next, a precursor solution for forming the porous needle body 11 was prepared. The precursor solution was prepared by mixing solutions A and B with a photopolymerization initiator. Solution A was prepared by mixing the soluble material PEG (4 g) and the solvent DEG (20 mL) at 60°C. Since DEG has a molecular structure closer to that of the solute PEG, it can prevent the precipitation of the solute during the preparation process. Alternatively, 2-methoxyethanol may be used instead of DEG. Solution B was prepared by mixing the monomer GMA (10 mL) with the crosslinking agents Trim (5.23 mL) and TEGDMA (15.7 mL). Solution A (450 μL), solution B (550 μL), and the photopolymerization initiator Irgacure 184 (1.8 mg) were mixed at 40°C to obtain the precursor solution. As shown in Figure 2(b), the precursor solution 32 was poured into a PDMS female mold 31, and degassing was performed at 25°C for 80 minutes under reduced pressure of -0.096 MPa. This degassing process prevents defects in the needle body shape due to air bubble contamination.

[0039] After degassing, as shown in Figure 2(c), ultraviolet light with a wavelength of 365 nm was irradiated at 25°C for 1 hour to polymerize the monomer and crosslinking agent, causing solidification. Then, as shown in Figure 2(d), the solidified molded body 33 was removed from the female mold 31. The resulting molded body 33 is needle-shaped, with the voids of the porous needle body 11 sealed with porogenized PEG.

[0040] Next, the coating process shown in Figures 3(a) and (b), and the channel formation process shown in Figures 3(c) and (d) were performed. First, as shown in Figure 3(a), the molded body 33 was placed on the PDMS plate 34 with the needle tips facing downwards, and a weight 35 was placed on the molded body 33 to apply a constant load, thereby inserting the needle tips into the PDMS plate 34 and masking it. The PDMS plate 34 acts as a protective material. Here, using a microneedle array with three microneedles integrated, the change in the masking state depending on the magnitude of the load was confirmed, and it was confirmed that as the load increased, the PDMS plate 34 sank deeper and the masking area also increased. As shown in Figure 4(a), in the case of a microneedle array with three or more microneedles 10 of the same length integrated, it can be made to stand stably even when placed facing downwards. As shown in Figure 4(b), when there is only one microneedle 10 on a single substrate, multiple microneedles can be placed facing downwards on the same plate and fixed to stabilize them. In the example shown in Figure 3(a), a 10 g weight 35 is used to ensure stable and reliable masking. To enlarge the masking area at the tip and create a wider opening at the tip, a heavier weight 35 (for example, 30 g or 50 g) can be used.

[0041] As shown in Figure 3(a), with the tip of the needle of the molded body 33 inserted into a PDMS plate 34 and masked, Parylene C was deposited using a parylene deposition apparatus until the film thickness reached 2 μm, forming the coating material 12. After deposition, as shown in Figure 3(b), the coating material 12 on the substrate opposite the needle of the molded body 33 was removed using a cutting tool. As shown in Figure 3(c), the molded body 33 with the coating material 12 formed on it was immersed overnight in a mixed solution of distilled water and methanol (volume ratio 1:1) 36 to dissolve the PEG. In this way, as shown in Figure 3(d), a microneedle 10 was manufactured in which a portion of the surface of the porous needle body 11 was covered with the parylene coating material 12. Each microneedle 10 is arranged integrally on the surface of the substrate, and the substrate forms the flange portion 21 of each needle body and is made of the same material as each needle body 11.

[0042] [Evaluation of manufactured microneedles] A line scan was performed on the tip of the needle body 11 of the manufactured microneedle 10 using EDX. The results are shown in Figure 5. As shown in Figure 5, it was confirmed that the intensity of the parylene-derived Cl signal decreased near the tip of the needle body 11. Furthermore, when the porosity of the manufactured microneedle 10 and an uncoated microneedle (comparative example) was calculated by gravimetry from the water absorption amount, the results were 40.7±1.3% (n=7) and 40.2±1.6% (n=8), respectively, confirming that the presence or absence of coating does not affect PEG elution.

[0043] Next, a diffusion test of the dye was performed on the manufactured microneedles. As shown in Figure 6(a), a dye consisting of ethanol (rhodamine B concentration: 10 mM) 41 in which rhodamine B was dissolved was dropped onto the manufactured microneedle 10 and an uncoated microneedle (comparative example) from the substrate side opposite the needle body 11 for 30 minutes to allow for sufficient absorption. Then, as shown in Figure 6(b), each needle body 11 was inserted into a 2 wt% gellan gum hydrogel 42, and the diffusion of the dye was observed. The results are shown in Figures 6(c) and (d). As shown in Figure 6(c), in the uncoated microneedle, the dye leaked out from the entire needle, whereas as shown in Figure 6(d), in the manufactured microneedle 10, it was confirmed that the dye diffused only from the tip of the needle body 11.

[0044] Next, a test was conducted to measure the DC resistance of the manufactured microneedles. As shown in Figure 7(a), the manufactured microneedle 10 (invention), an uncoated microneedle (comparative example 1), and a fully coated microneedle (comparative example 2) were filled with an electrolyte solution (Ringer's solution) 43 into their pores. As shown in Figure 7(b), a DC current was applied using an electrochemical analyzer (constant current application mode), and the DC resistance value was calculated from Ohm's law. The results are shown in Figure 7(c). As shown in Figure 7(c), the larger the coating area, the higher the resistance value, confirming that the insulating coating can limit the path of current.

[0045] [Epidermal potential measurement test] Epidermal potential was measured using a microneedle 10 (invention of the present invention) in which the tip of the needle body 11 is slightly exposed and the rest of the body is covered with a coating material 12. Since epidermal potential is generated in the thickness direction of the epidermal tissue covering the skin surface, an uncoated microneedle with the entire body exposed cannot measure the potential difference between the inside and outside of the epidermis due to a short circuit. On the other hand, with the microneedle 10, which allows for pinpoint connection at the tip, the tip of the needle body 11 can be connected only to the dermis beneath the epidermal tissue, making it possible to measure the potential difference between the inside and outside of the epidermis.

[0046] As shown in Figures 8(a) and (b), the potential difference between the surface of the pig skin sample 44 and the tip of the needle body 11, which was inserted to reach the dermis, was measured. For comparison, measurements were also performed using an uncoated microneedle (Comparative Example 1) and a conventional method (a method of making a wound that reaches the dermis to allow conductivity to the area beneath the epidermal tissue). To ensure ion-mediated conductivity between the microneedle and the skin tissue, an electrolyte solution (Ringer's solution) was impregnated into the microneedle or hydrogel and used as a salt bridge. An electrochemical analyzer (voltmeter mode) was used to measure the potential difference. The measurement results are shown in Figure 8(c).

[0047] As shown in Figure 8(c), the measured values ​​were almost identical between the microneedle 10 with a conductive tip and the conventional method, and a larger potential difference was obtained than when using an uncoated microneedle. From these results, it was confirmed that in the microneedle 10 with a conductive tip, only the tip of the needle body 11 is responsible for conductivity, and that it makes a pinpoint connection to the dermis. [Explanation of Symbols]

[0048] 10 microneedles 11 Needle body 21 Flange section 12 Coating materials 31 Female type 32 Precursor Solution 33 Molded body 34 PDMS flat plate 35 weights 36 Mixed solution 41. Ethanol in which rhodamine B has been dissolved. 42 2 wt% gellan gum hydrogel 43. Electrolyte solution (Ringer's solution) 44 Pig skin samples

Claims

1. The rear and front ends of the porous needle body are covered with a coating material, and the middle section is open. The needle body has a network of flow channels extending inside, or it is made of a porous material and has flow channels formed by the voids in the porous material. The needle body has a plurality of openings on its surface that communicate with the flow path, The coating material is made of an insulating material and is provided to cover some of the multiple openings. The characteristic feature is the microneedle.

2. The microneedle according to claim 1, characterized in that when inserted into the skin, it is configured to allow access to the surface of the skin or a target area in the subcutaneous tissue by using openings other than the opening covered with the coating material.

3. The aforementioned flow path consists of multiple parts, Each opening is connected to at least one flow path. A microneedle characterized by the features of claim 1 or 2.

4. A plurality of microneedles according to any one of claims 1 to 3, Each microneedle is arranged in a line. A distinctive feature is the microneedle array.

5. A method for manufacturing a microneedle according to any one of claims 1 to 3 or a microneedle array according to claim 4, A needle forming step for manufacturing the needle body in a state in which the flow path is blocked with a soluble material that can be dissolved in a predetermined solution, A coating step in which the coating material is applied to the surface of the needle body while the middle part of the surface of the needle body is covered with a protective material, The process includes a channel formation step in which, after removing the protective material, the soluble material is dissolved with the predetermined solution, To manufacture a microneedle in which the rear end and tip of the surface of the needle body are covered with the coating material and the middle part is open. A method for manufacturing microneedles that are a key feature.

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