Fluid injection device

Abstract

Provided is a fluid injection device (10) capable of more effectively administering a drug. The first transport body (11) has a first transport flow path through which a first fluid (21) flows, and the second transport body (12) has a second transport flow path through which a second fluid (22) flows. A front-side microneedle (13) provided to a first transport body (11) has a first opening and a first flow path to which a positive charge is fixed. A negative-side microneedle (14) provided to the second transport body (12) has a second opening and a second flow path to which a negative charge is fixed. When a current / voltage application means (15) applies a current or a voltage between a first electrode (24) disposed in the first transport flow path and a second electrode (25) disposed in the second transport flow path, an ion current flows through the first fluid (21) and the second fluid (22), and by means of an electroosmotic flow, the first fluid (21) flows outward from the first opening, and the second fluid (22) flows outward from the second opening.

Description

Technical Field

[0001] This invention relates to a fluid injection device. Background Technology

[0002] Previously, iontophoresis was a method of drug delivery that promoted drug penetration by passing a tiny electric current through the body. Because iontophoresis can deliver drugs directly to blood vessels or affected areas, it can deliver drugs more effectively than conventional oral administration and has the advantage of minimizing drug side effects.

[0003] In particular, the efficacy of iontophoresis therapy in promoting drug penetration through the skin has been widely recognized (see, for example, Non-Patent Literature 1). Devices ranging from fixed devices requiring external power sources to portable, patch-type devices that adhere to the skin have been developed. Furthermore, in addition to the skin, iontophoresis therapy is considered effective for drug delivery to organs or tumors, with reports indicating that it can significantly improve the delivery efficiency of anticancer agents to cancerous tumors (see, for example, Non-Patent Literature 2).

[0004] It is believed that the penetration-enhancing effect of this iontophoresis therapy originates not only from the electrophoresis of the drug but also from the electroosmotic flow generated in the skin or tissue. Since drug molecules are present in smaller quantities compared to electrolyte ions, migration caused by electrophoresis is very small; it is thought that migration generated by electroosmotic flow is dominant. However, although skin or tissues within the body carry only a small amount of negative charge, electroosmotic flow is only generated along the migration direction of cations. Therefore, the effect of promoting penetration is limited to the positive electrode; at the negative electrode, flow occurs in the direction of absorbing body fluids, which may hinder drug penetration.

[0005] The inventors of this application have developed a porous microneedle with a negative charge fixed by chemical modification, which generates a large electroosmotic flow on the positive side (see, for example, Non-Patent Documents 3 and 4 or Patent Document 1). The report states that this microneedle allows pharmaceuticals to penetrate under the skin regardless of the charge of the pharmaceutical agent, i.e., regardless of the direction of electrophoresis.

[0006] In response, the inventors of this application have also developed an electroosmotic pump that uses a material that fixes a negative charge on the positive electrode side and a material that fixes a positive charge on the negative electrode side. It can supply a drug to the surface of the skin or tissue from both the positive and negative electrode sides by means of electroosmotic flow, without hindering the penetration of the drug on the negative electrode side (for example, see Patent Document 2).

[0007] Existing technical documents Non-patent literature Non-patent document 1: Kenji Sugibayashi, "New Method of Administering New Strains of Skin", Fructus Medical, 2001, Vol. 37, No. 5, p. 385-387 Non-patent literature 2: James D. Byrne et al., “Local iontophoretic administration of cytotoxic therapies to solid tumors”, Science Translational Medicine, 2015, 7, 273ra14 Non-patent document 3: Shinya Kusama et al., "Transdermal Electroosmotic FlowGenerated by a Porous Microneedle Array Patch", Nature Communications, 2021, 12, 658 Non-patent document 4: Hiroya Abe et al., "Porous Microneedle Patch for Electroosmosis-Promoted Transdermal Delivery of Drugs and Vaccines", AdvancedNanoBiomedical Research, 2022, 2, 2100066 Patent documents Patent Document 1: Japanese Patent Application Publication No. 2022-83780 Patent Document 2: Japanese Patent Application Publication No. 2023-69170 Summary of the Invention

[0008] (a) Technical problems to be solved The electroosmotic pump described in Patent Document 2 can deliver medication to the surface of skin or tissue from both the positive and negative electrode sides, thus increasing the dosage. Furthermore, it can simultaneously deliver two medications by supplying different medications from the positive and negative electrode sides. Therefore, compared to using only the positive electrode side for electroosmotic flow, the electroosmotic pump described in Patent Document 2 can deliver medication more effectively, but there is a need to develop a device that can deliver medication even more effectively.

[0009] This invention addresses this technical problem and aims to provide a fluid injection device that can deliver medication more effectively.

[0010] (II) Technical Solution To achieve the above objectives, the fluid injection device of the present invention is characterized by having: A first conveying body having a first conveying flow path for the flow of a first fluid; The second conveyor has a second conveying path for the flow of the second fluid; The positive-side microneedle has a first opening at the top end and a first flow path with a fixed positive charge and connected to the first opening. The positive-side microneedle is disposed on the first conveying body in such a way that the first flow path is connected to the first conveying flow path. A negative-side microneedle has a second opening at its tip and a second flow path fixed with a negative charge and communicating with the second opening. The negative-side microneedle is disposed on the second transport body such that the second flow path is connected to the second transport flow path. A current and voltage application mechanism has a first electrode disposed in the first delivery path and a second electrode disposed in the second delivery path, the current and voltage application mechanism being configured to apply current or voltage between the first electrode and the second electrode. The fluid injection device is configured such that when a current or voltage is applied between the first electrode and the second electrode through the current and voltage application mechanism, an ion current flows in the first fluid in the first flow path and the second fluid in the second flow path. Through electroosmotic flow, the first fluid flows outward from the first opening and the second fluid flows outward from the second opening.

[0011] The fluid injection device of the present invention is configured such that a positive microneedle is provided in a first delivery body and a negative microneedle is provided in a second delivery body. Through electroosmotic flow, a first fluid flows outward from a first opening of the positive microneedle, and a second fluid flows outward from a second opening of the negative microneedle, thereby enabling direct injection of the first and second fluids into the subcutaneous tissue or the inner side of the tissue. Therefore, by using fluids containing medication as the first and second fluids, medication can be delivered more effectively compared to conventional electroosmotic pumps without microneedles.

[0012] When the fluid injection device of the present invention uses a fluid containing a drug as both the first and second fluids, the drug can be supplied to the subcutaneous tissue or interior of the tissue through both the first opening of the positive microneedle and the second opening of the negative microneedle. Compared to supplying through either opening, the amount of drug administered can be increased by up to 2 times. Furthermore, by setting the drug contained in the first fluid and the drug contained in the second fluid to be different from each other, two drugs can be administered simultaneously.

[0013] The fluid injection device of the present invention utilizes a current and voltage application mechanism, with the first electrode as the negative electrode and the second electrode as the positive electrode. By applying current or voltage, an ion current flows through the first fluid in the first flow path and the second fluid in the second flow path. Through electroosmotic flow, the first fluid can flow outward from the first opening, and the second fluid can flow outward from the second opening. The fluid injection device of the present invention, by adjusting the applied current or voltage using the current and voltage application mechanism, can control the flow rate of the generated electroosmotic flow, resulting in excellent controllability of the discharge volume of the first and second fluids.

[0014] In the fluid injection device of the present invention, the positive and negative microneedles are composed of porous bodies, and the first and second flow paths can extend into a mesh-like structure in the gaps of the porous body. Furthermore, the positive and negative microneedles can each be configured as a single unit or multiple units. In the case of multiple units, microneedle arrays can be formed. Additionally, the positive and negative microneedles can each have a sharp tip to pierce the skin or tissue and directly inject the first and second fluids into the interior of the object; alternatively, their tips can be curved or flat to open the surface of the object and allow the first and second fluids to penetrate into the interior. Furthermore, the first and second openings can each be configured as a single unit or multiple units.

[0015] In the fluid injection device of the present invention, the positive-side microneedles can be made of any material as long as they can fix a positive charge in the first flow path, and the negative-side microneedles can be made of any material as long as they can fix a negative charge in the second flow path. In this case, the positive-side and negative-side microneedles are made of, for example, hydrogel materials, porous resins, oxides, metals, biodegradable materials, etc. More specifically, the positive-side microneedles only need to satisfy that the migration rate of anions is greater than that of cations when fluid is injected into the first flow path. For example, positive charges can be fixed on the wall of the first flow path, positive charges can be embedded in the surface layer, and they can also be made of hydrogels containing functional groups with positive charges. Furthermore, the negative-side microneedles only need to satisfy that the migration rate of cations is greater than that of anions when fluid is injected into the second flow path. For example, negative charges can be fixed on the wall of the second flow path, negative charges can be embedded in the surface layer, and they can also be made of hydrogels containing functional groups with negative charges.

[0016] In the fluid injection device of the present invention, the first fluid and the second fluid are preferably each a fluid containing a pharmaceutical agent, and can be composed of different fluids or the same fluid. In the fluid injection device of the present invention, preferably the first electrode is inserted into the first delivery path from the other end of the first delivery body, and the second electrode is inserted into the second delivery path from the other end of the second delivery body.

[0017] The fluid injection device of the present invention is preferably configured such that the positive-side microneedle and the negative-side microneedle are adjacent to each other. In this case, the device can be compactly constructed, achieving miniaturization. Furthermore, in this case, in order to facilitate the simultaneous insertion or pressing of the positive-side microneedle and the negative-side microneedle onto the object, it is preferable that their respective tip portions protrude on the same side.

[0018] In the fluid injection device of the present invention, the first delivery body is elongated, and the first delivery path extends from one end of the first delivery body to the other end. The second delivery body is also elongated, and the second delivery path extends from one end of the second delivery body to the other end. The positive-side microneedle can be disposed at one end of the first delivery body, and the negative-side microneedle can be disposed at one end of the second delivery body. In this case, the device as a whole can have an elongated shape, enabling miniaturization. Furthermore, in this case, it is preferable that the positive-side microneedle is disposed with its tip protruding from one end of the first delivery body along the extending direction of the first delivery body, and the negative-side microneedle is disposed with its tip protruding from one end of the second delivery body along the extending direction of the second delivery body. Thus, by moving one end of the first and second delivery bodies toward the object along their respective extending directions, the positive-side and negative-side microneedles can be easily inserted into or pressed against the object.

[0019] In the fluid injection device of the present invention, the first delivery body and the second delivery body can be configured separately or integrated as a single unit. When integrated as a single unit, the device can be compactly constructed, achieving miniaturization and facilitating operation.

[0020] The fluid injection device of the present invention has a rigid tube that integrates the first delivery body and the second delivery body. The tube is elongated and has two hollow portions extending from one end to the other. One of the hollow portions can form the first delivery flow path, and the other hollow portion can form the second delivery flow path. In this configuration, the tube can be held with one hand to insert or press the positive and negative microneedles into or against the target object, making it easy to operate.

[0021] Furthermore, in the fluid injection device of the present invention, the first delivery body and the second delivery body can each be constructed of flexible tubes. In this case, for example, by using a catheter as a tube, it is possible to easily intervene in tissues within a living organism, and to directly inject drugs or the like into the interior of that tissue. Thus, for example, it is possible to directly administer anticancer agents to tumors, enabling effective treatment.

[0022] (III) Beneficial Effects According to the present invention, a fluid injection device is provided that can deliver a drug more effectively. Attached Figure Description

[0023] Figure 1 This is a cross-sectional view illustrating a fluid injection device according to an embodiment of the present invention.

[0024] Figure 2 (a) is a perspective view showing the array of positive and negative microneedles of the fluid injection device according to an embodiment of the present invention. Figure 2 (b) is an enlarged side view of one negative-side microneedle of the fluid injection device according to an embodiment of the present invention.

[0025] Figure 3 The accompanying drawings illustrate an electroosmotic flow generation experiment using a Franz cell with horizontal capillary tubes on the positive and negative microneedles of the fluid injection device according to an embodiment of the present invention. Figure 3 (a) is a cross-sectional view representing the experimental method. Figure 3 (b) is a graph showing the relationship between current density and flow rate in the positive-side microneedle (“fixed positive charge” in the figure) and the negative-side microneedle (“fixed negative charge” in the figure), as a result of the experiment.

[0026] Figure 4 The accompanying drawings illustrate an experiment using a Franz diffusion cell to generate electroosmotic flow in the positive and negative microneedles of the fluid injection device according to an embodiment of the present invention. Figure 4 (a) is a cross-sectional view representing the experimental method. Figure 4 (b) indicates the position of the microneedle on the positive side (in the figure, "-0.5 mA / cm"). 2 ") and negative side microneedles (0.5 mA / cm in the figure) 2 A graph showing the time-varying molecular delivery of FITC-OVA (Transported OVA) in the figure.

[0027] Figure 5 The accompanying drawings illustrate an experiment using the fluid injection device according to an embodiment of the present invention to inject dextran into a slice of pig skin, wherein... Figure 5 (a) is a three-dimensional diagram representing the experimental method. Figure 5 (b) shows the application of 0.5 mA / cm to the negative microneedle. 2 Microscopic images of pig skin sections under bright field microscopy. Figure 5 (c) represents the application of 0.5 mA / cm to the negative microneedle. 2 Microscopic images of pig skin sections under fluorescence. Figure 5 (d) represents the application of -0.5 mA / cm to the anterolateral microneedles. 2 Microscopic images of pig skin sections under bright field microscopy. Figure 5(e) represents applying -0.5 mA / cm to the anterolateral microneedles. 2 Microscopic photograph of a section of pig skin under fluorescence.

[0028] Figure 6 The accompanying drawings illustrate an experiment using the fluid injection apparatus of an embodiment of the present invention to inject dextran into gellan gel, wherein... Figure 6 (a) is a side view of the fluorescence generated by dextran within the gel before the experiment. Figure 6 (b) shows a side view of the fluorescence generated by dextran within the gel after 20 minutes without current (0 mA). Figure 6 (c) represents a side view of the fluorescence generated by dextran within the gel when a 2.5 mA current is applied between the negative electrode (Anode) on the positive microneedle side and the positive electrode (Cathode) on the negative microneedle side for 20 minutes.

[0029] Figure 7 The accompanying drawings illustrate an embodiment of the stamp-type device of the fluid injection apparatus according to an embodiment of the present invention, wherein... Figure 7 (a) represents the exploded stereograph. Figure 7 (b) represents an enlarged three-dimensional view of one end of the tube. Figure 7 (c) represents a three-dimensional view of the usage state when held with one hand.

[0030] Figure 8 For use in Figure 7 The accompanying diagram shows an experiment in which a stamp-type device is used to inject Rhodamine B and methylene blue into gellan gel. Figure 8 (a) shows a side view of the permeation state of Rhodamine B and methylene blue in gellan gel before the experiment. Figure 8 (b) shows a side view of the permeation state of Rhodamine B and methylene blue in gellan gel when a current of 2.0 mA is passed between the first and second electrodes for 20 minutes.

[0031] Figure 9 For use in Figure 7 The attached diagram shows an experiment in which a stamp-type device was used to inoculate a mouse model of oral vaccine (OVA). Figure 9 (a) is a three-dimensional diagram showing the state before and during fluid injection. Figure 9 (b) is a graph showing the optical density of the positive and negative microneedles in each combination.

[0032] Figure 10 The accompanying drawings illustrate an embodiment of the fluid injection device of the present invention, specifically a conduit-type device. Figure 10 (a) is an enlarged three-dimensional view of one end of the tube. Figure 10 (b) represents the side view in the usage state. Detailed Implementation

[0033] The embodiments of the present invention will be described below with reference to the accompanying drawings and examples.

[0034] Figures 1 to 10 This describes a fluid injection device according to an embodiment of the present invention.

[0035] like Figure 1 As shown, the fluid injection device 10 has a first delivery body 11, a second delivery body 12, a positive microneedle 13, a negative microneedle 14, and a current and voltage application mechanism 15.

[0036] The first conveying body 11 is elongated and has a first conveying flow path (not shown) extending from one end of the first conveying body to the other end on its inner side. The first conveying body 11 is configured such that a first fluid 21 flows in the first conveying flow path. The second conveying body 12 is elongated and has a second conveying flow path (not shown) extending from one end of the second conveying body to the other end on its inner side. The second conveying body 12 is configured such that a second fluid 22 flows in the second conveying flow path. The first conveying body 11 and the second conveying body 12 can be configured separately or can be integrated as a single unit.

[0037] The first fluid 21 flowing in the first delivery path and the second fluid 22 flowing in the second delivery path can be any fluid as long as it is used for injecting into the target object. However, when the target object is skin or tissue inside a living organism, it is preferable that they are fluids containing a drug. The first fluid 21 and the second fluid 22 can be composed of different fluids or the same fluid.

[0038] like Figure 2 As shown, the positive-side microneedle 13 and the negative-side microneedle 14 are each composed of a porous body of porous material, and are conical in shape, with a flange 23 around the rear end portion on the base side of the cone. The positive-side microneedle 13 has at least a first opening (not shown) at its top end and a first flow path (not shown) with a fixed positive charge communicating with the first opening. The negative-side microneedle 14 has at least a second opening (not shown) at its top end and a second flow path (not shown) with a fixed negative charge communicating with the second opening. The first and second flow paths extend into a mesh-like structure through the void portions of the porous body. Figure 2 In a specific example shown, the height of the tip of the positive microneedle 13 and the negative microneedle 14 is 300 μm, and the height of the flange 23 is 300 μm.

[0039] like Figure 1As shown, a positive microneedle 13 is disposed at one end of the first conveyor 11 to connect the first flow path and the first transport flow path. Furthermore, the positive microneedle 13 is disposed such that its tip protrudes from one end of the first conveyor 11 along the extending direction of the first conveyor 11. A negative microneedle 14 is disposed at one end of the second conveyor 12 to connect the second flow path and the second transport flow path. Furthermore, the negative microneedle 14 is disposed such that its tip protrudes from one end of the second conveyor 12 along the extending direction of the second conveyor 12. Moreover, the positive microneedle 13 and the negative microneedle 14 are adjacent to each other, with their respective tip protruding on the same side.

[0040] The positive microneedle 13 and the negative microneedle 14 can be as follows Figure 2 The diagram shows a combination of multiple components, or each component can be a single component. In the case of multiple components, each can form a microneedle array. Furthermore, the positive-side microneedles 13 and the negative-side microneedles 14 can be arranged as follows... Figure 2 The device is designed with a sharp point to pierce the object, thereby directly injecting the first fluid 21 and the second fluid 22 into the interior of the object. Alternatively, the tip of each fluid can be curved or flat to open the surface of the object, allowing the first fluid 21 and the second fluid 22 to penetrate into the interior of the object. Furthermore, the first opening and the second opening can each be configured as one or multiple.

[0041] The positive-side microneedles 13 can be made of any material as long as they can fix a positive charge in the first flow path, and the negative-side microneedles 14 can be made of any material as long as they can fix a negative charge in the second flow path. For example, the positive-side microneedles 13 and 14 can be made of hydrogel materials, porous resins, oxides, metals, biodegradable materials, etc. More specifically, the positive-side microneedles 13 only need to have a higher migration rate of anions than cations when the fluid enters the first flow path. For example, positive charges can be fixed on the wall of the first flow path, positive charges can be embedded in the surface layer, and they can also be made of hydrogels containing functional groups with positive charges. Similarly, the negative-side microneedles 14 only need to have a higher migration rate of cations than anions when the fluid enters the second flow path. For example, negative charges can be fixed on the wall of the second flow path, negative charges can be embedded in the surface layer, and they can also be made of hydrogels containing functional groups with negative charges.

[0042] Hydrogel materials refer to materials that form hydrogels by dispersing them in water (dispersion medium). Examples of hydrogel materials include agar, gelatin, agarose, xanthan gum, gellan gum, sclerotium gum, gum arabic, tragacanth gum, ebony gum, cellulose gum, tamarind gum, guar gum, sophora bean gum, glucomannan, chitosan, carrageenan, quince seed, galactose, mannan, starch, dextrin, currant, casein, pectin, collagen, fibroin, peptides, chondroitin sulfate (sodium chondroitin sulfate), hyaluronic acid (a mucopolysaccharide) and sodium hyaluronate, alginate, sodium alginate and calcium alginate, and their derivatives; cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, and their salts; polyacrylic acid, polymethacrylic acid, sodium polymethacrylate, and propylene. Poly(meth)acrylic acids, such as alkyl methacrylate copolymers and their salts; polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylamide, poly(N-isopropylacrylamide), polyvinylpyrrolidone, polystyrene sulfonic acid, polyethylene glycol, carboxyvinyl polymers, alkyl-modified carboxyvinyl polymers, maleic anhydride copolymers, polyalkylene oxide resins, crosslinks of poly(methyl vinyl ether-alternating-maleic anhydride) and polyethylene glycol, polyethylene glycol crosslinks, N-vinyl acetamide crosslinks, acrylamide crosslinks, starch-acrylate graft copolymer crosslinks, etc.; organosilicon; interpenetrating network hydrogels and semi-interpenetrating network hydrogels; poly(2-hydroxyethyl methacrylate), poly(2-acrylamide-2-methylpropanesulfonic acid); and mixtures of two or more of the above substances. Among these components, the following materials are preferred as constituents of the hydrogel, considering their load-bearing capacity and biocompatibility: collagen, glucomannan; carboxymethyl cellulose, sodium carboxymethyl cellulose; polyacrylic acid, sodium polyacrylate; interpenetrating network hydrogels and semi-interpenetrating network hydrogels. Furthermore, considering their excellent physical strength and excellent biocompatibility, crosslinked products of poly(methyl vinyl ether-alternating-maleic anhydride) and polyethylene glycol are preferred. Moreover, considering their ability to ensure the electrical neutrality of the hydrogel, crosslinked polyethylene glycol is preferred.

[0043] Furthermore, examples of hydrogel materials with fixed charges (positive or negative charges) include gel materials incorporating functional groups with fixed charges into hydrogel materials without fixed charges, and gel materials containing monomer units with fixed charges. Among these, gel materials containing monomer units with fixed charges are preferred, and copolymers of non-charged monomers and monomers with fixed charges are more preferred.

[0044] In addition, 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; specifically, examples of inorganic oxides include silicon oxide, tin oxide, zirconium oxide, titanium dioxide, niobium oxide, tantalum oxide, aluminum oxide, tungsten oxide, hafnium oxide, and zinc oxide. Examples of metals include nickel, iron, and their alloys. Furthermore, examples of biodegradable materials include polylactic acid-glycolic acid copolymer (PLGA) and blends based on PLGA, tricalcium β-phosphate, calcium carbonate, polycaprolactone, polydioxanone, hydroxyapatite, polyethylene glycol, and magnesium alloys. The positive-side microneedles 13 and negative-side microneedles 14 can be composed of two or more of the substances listed above.

[0045] The current and voltage application mechanism 15 has a first electrode 24 disposed in a first delivery flow path and a second electrode 25 disposed in a second delivery flow path, configured to apply current or voltage between the first electrode 24 and the second electrode 25. The first electrode 24 is inserted into the first delivery flow path from the other end of the first delivery body 11, and the second electrode 25 is inserted into the second delivery flow path from the other end of the second delivery body 12. More specifically, the current and voltage application mechanism 15 is configured to apply current or voltage with the first electrode 24 as the negative electrode and the second electrode 25 as the positive electrode. Thus, when the fluid injection device 10 applies current or voltage between the first electrode 24 and the second electrode 25 through the current and voltage application mechanism 15, an ion current flows in the first fluid 21 in the first flow path and the second fluid 22 in the second flow path. Through electroosmotic flow, the first fluid 21 flows outward from the first opening, and the second fluid 22 flows outward from the second opening.

[0046] Next, the function will be explained.

[0047] The fluid injection device 10 is used as follows: First, a positive microneedle 13 located at one end of the first delivery body 11 and a negative microneedle 14 located at one end of the second delivery body 12 are inserted into or pressed against the skin or tissue inside a living organism. In this state, a current or voltage is applied between the first electrode 24 and the second electrode 25 by a current-voltage application mechanism 15. As a result, an ion current flows in the first fluid 21 in the first flow path and the second fluid 22 in the second flow path. Through electroosmotic flow, the first fluid 21 flows outward from the first opening of the positive microneedle 13, and the second fluid 22 flows outward from the second opening of the negative microneedle 14. Thus, the fluid injection device 10 can directly inject the first fluid 21 and the second fluid 22 into the subcutaneous tissue or the inner side of the tissue. Therefore, by using fluids containing medication as the first fluid 21 and the second fluid 22, medication can be delivered more effectively compared to conventional electroosmotic pumps without microneedles.

[0048] Furthermore, by using a fluid containing a drug as a first fluid 21 and a second fluid 22, the fluid injection device 10 can deliver a drug into the subcutaneous tissue or tissue through both the first opening of the positive microneedle 13 and the second opening of the negative microneedle 14, increasing the drug dosage by up to two times compared to delivery through either opening. Moreover, by using different drugs in the first fluid 21 and the second fluid 22, two drugs can be delivered simultaneously.

[0049] The fluid injection device 10 allows for control of the flow rate of the generated electroosmotic flow by adjusting the current or voltage applied by the current-voltage application mechanism 15, resulting in excellent control over the discharge volume of the first fluid 21 and the second fluid 22. Furthermore, since the positive-side microneedles 13 and negative-side microneedles 14 of the fluid injection device 10 are adjacent to each other and arranged with their respective tips protruding on the same side, the device can be compactly assembled, enabling miniaturization. Additionally, the positive-side microneedles 13 and negative-side microneedles 14 can be easily inserted into or pressed against the object simultaneously, facilitating operation.

[0050] Example Example 1 The positive microneedle 13 and negative microneedle 14 of the fluid injection device 10 were manufactured, and various tests were conducted on the fluid injection device 10. The reagents and materials used in the manufacturing and testing are shown below.

[0051] • Glycidyl Methacrylate (GMA, manufactured by FUJIFILM Wako PureChemical Corporation) • Trimethylolpropane trimethacrylate (TRIM, manufactured by Sigma-Aldrich Corporation) • Polyethylene glycol (PEG 10 kDa, manufactured by Sigma-Aldrich Corporation) • Diethylene glycol (DEG, manufactured by Tokyo Chemical Industry Co., Ltd.) • Irgacure (Irgacure 184, manufactured by BASF SE) • Polydimethylsiloxane (PDMS, SILPOT 184, manufactured by DuPont Toray Specialty Materials KK) Gellan gum (manufactured by FUJIFILM Wako Pure Chemical Corporation) • Triethylene glycol dimethacrylate (TEGDMA) ·(3-acrylamidopropyl)trimethylammonium (APTA) ·2-Acrylamide-2-methylpropanesulfonic acid (AMPS) ·2,2'-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044) ·N,N'-methylenebisacrylamide (MBAAmM) ·N,N,N',N'-tetramethylethylenediamine (TEMED) • Ammonium peroxodisulfate solution (APS, 10 w / v%) • Fluorescein isothiocyanate-dextran (FITC dextran, average mol wt 500,000, manufactured by Sigma-Aldrich Corporation) • Fluorescein isothiocyanate-ovalbumin (FITC-OVA, 4.4 kDa, 0.75 mg / mL, manufactured by Sigma-Aldrich Corporation) • 1xPBS(-) (Phosphate-buffered saline, FUJIFILM Wako Pure Chemical Corporation) Fabrication of microneedle arrays An array of positive-side microneedles 13 and negative-side microneedles 14 was fabricated. First, a negative mold for the protrusions of each microneedle was created by perforating an acrylic plate using a cutting machine. This negative mold was then transferred in two steps using PDMS to create a PDMS negative mold. Next, a precursor solution for forming the porous body was prepared. The precursor solution was prepared by mixing a photopolymerization initiator into solutions A and B, respectively, with the compositions shown below. Solution A was prepared by mixing PEG (4g), which, if dissolved, can form pores on the structure, with DEG (20mL) as a solvent at 60°C. Solution B was prepared by mixing GMA (10mL) as a monomer, Trim (5.23mL) as a crosslinking agent, and TEGDMA (15.7mL).

[0052] Next, solution A (450 μL), solution B (550 μL), and photopolymerization initiator Irgacure 184 (1.8 mg) were mixed at 40°C to obtain a precursor solution. This precursor solution was poured into a PDMS-based negative mold and degassed at 25°C and -0.096 MPa for 80 minutes. This degassed process prevents needle-shaped defects caused by air bubbles. After degassed, the substrate was irradiated with 365 nm ultraviolet light at 25°C for 1 hour to polymerize the monomer and crosslinking agent. The solidified protrusion array substrate was then removed from the negative mold. The protrusion array substrate was then immersed overnight in a mixture of distilled water and methanol (volume ratio 1:1) to dissolve the PEG. This method produces a porous structure. Figure 2 The microneedle array shown.

[0053] Next, the fabricated porous microneedle array was immersed in a silane coupling agent solution (2 mL; 0.6 mL TMSPMA, 1.4 mL ethanol) for 1 hour at room temperature to modify the surface containing the pores with the silane coupling agent. Then, the silane coupling agent-modified substrate was washed twice with distilled water using a shaker for 15 minutes each time to remove unreacted excess TMSPMA and ethanol. After thoroughly drying, the substrate was immersed in solution (1) at 4°C for 8 hours with a fixed negative charge, and in solution (2) at 4°C for 8 hours with a fixed positive charge.

[0054] (1) 0.05 M AMPS, 1v%APS and 0.1v%TEMED (2) 0.4 M APTAC containing 2v%VA-044 After impregnation in various solutions, polymerization was carried out in an oven at 80°C for 1 hour, thereby modifying the pore walls of the microneedle array with AMPS or PAPTAC through graft polymerization. In this way, an array of negatively charged microneedles 14 and an array of positively charged microneedles 13 were manufactured.

[0055] [Experiment on the generation of electroosmotic flow] An array of positive-side microneedles 13 and negative-side microneedles 14 was used to conduct an electroosmotic flow generation experiment. First, using... Figure 3 The Franz diffusion cell with horizontal capillary tubes shown in (a) was used in the experiment. In the experiment, positive microneedles 13 or negative microneedles 14 were clamped between the two chambers 31 of the Franz diffusion cell and fixed with clamps made of acrylic plates. The two chambers 31 of the Franz diffusion cell (with an opening diameter of 15 mm) were filled with PBS buffer at pH 7.0, and the injection ports of each chamber 31 were sealed using silicone rubber plugs 33 with Ag / Cl lines 32 inserted.

[0056] In this state, Ag / Cl line 32(AgCl+e) - ⇔Ag+Cl - Connected to source table 34, apply -1.0, -0.5, -0.25, 0, 0.25, 0.5, and 1.0 mA / cm every 15 minutes. 2 A direct current was applied, and a camera was used to measure the change in the water surface position within the horizontal capillary 35 (with a cross-sectional diameter of 1.6 mm) over time every 5 minutes. Furthermore, the experiment was conducted while confirming that no bubbles were generated from the Ag / Cl line 32 due to electrode reactions.

[0057] The test results are shown in Figure 3 (b). For example Figure 3As shown in (b), it was confirmed that both the positive-side microneedle 13 (“positive charge fixed” in the figure) and the negative-side microneedle 14 (“negative charge fixed” in the figure) generated flow through electroosmosis, and the flow rate increased with the increase of current density. Furthermore, it was confirmed that the flow directions were opposite in the positive-side microneedle 13 and the negative-side microneedle 14, and the slopes (electroosmotic efficiency) of each graph were essentially the same.

[0058] Next, use Figure 4 The Franz diffusion cell shown in (a) was used to determine the amount of molecular transport generated by electroosmosis by adding a mixture of FITC-OVA and PBS buffer to both chambers 31. In the experiment, -0.5 mA / cm² was applied between the cells from source table 34. 2 (At 13:00 on the front and side of the microneedle) or 0.5 mA / cm 2 (At 14 minutes on the negative side microneedle) a direct current is applied to sample a small amount of the solution in chamber 31 on the recipient side (chamber 31 on the left side of the figure) every 30 minutes. The solution is then quantitatively analyzed using an enzyme-linked immunosorbent assay (ELISA) reader to determine the amount of molecules delivered from chamber 31 on the supply side (chamber 31 on the right side of the figure) to chamber 31 on the recipient side.

[0059] The test results are shown in Figure 4 (b). For example Figure 4 As shown in (b), the positive and negative microneedles 13 ("-0.5mA / cm" in the figure) were confirmed. 2 ") and negative side microneedle 14 (0.5mA / cm in the figure) 2 The flow was due to electroosmotic flow, and the amount of FITC-OVA transported increased over time. Furthermore, nearly equal amounts of opposite transport were confirmed in the positive and negative microneedles 13 and 14. Measurements were also performed without current flow (0 mA / cm² in the figure). 2 "), confirming that no delivery occurred.

[0060] Next, as Figure 5 As shown in (a), using Figure 1 The fluid injection device 10 shown was used to conduct experiments injecting dextran into porcine skin slices 36. The fluid injection device 10 used fabricated positive and negative microneedles 13 and 14. In the experiment, FITC dextran was used as the first fluid 21 and the second fluid 22. Fluorescence microscopy was used to observe the effects of applying -0.5 mA / cm² to the positive and negative microneedles 13. 2 At that time, 0.5 mA / cm was applied to the negative microneedle 14. 2 The permeation state of FITC-glucan inside a 36-section pig skin.

[0061] The results of the experiment are shown in Figure 5 (b)~(e). For example... Figure 5 As shown in (b) to (e), fluorescence was observed inside the porcine skin slice 36 when current was applied to the positive microneedle 13 and the negative microneedle 14, indicating that FITC dextran had permeated.

[0062] Next, use Figure 1 The fluid injection device 10 shown was used to conduct an experiment injecting dextran into gellan gel 37. The fluid injection device 10 used the manufactured positive microneedles 13 and negative microneedles 14. In the experiment, an agarose gel containing FITC dextran was used as the first fluid 21 and the second fluid 22. The positive microneedles 13 and negative microneedles 14 were inserted into the gellan gel 37, and an electric current was applied with the negative microneedle 14 side as the positive electrode and the positive microneedle 13 side as the negative electrode.

[0063] The test results are shown in Figure 6 (a)~(c). For example... Figure 6 As shown in (b), no fluorescence was detected in gellan gel 37 after 20 minutes of no current flow (0 mA), confirming the lack of FITC-dextran permeation. In contrast, as... Figure 6 As shown in (c), fluorescence was confirmed in gellan gel 37 after energizing at 2.5 mA for 20 minutes, indicating that FITC dextran had undergone bipolar permeation.

[0064] Example 2 [Example of a fluid injection device: stamp-type device] like Figure 7 As shown, the fluid injection device 10 has a rigid tube 41 that integrates the first conveying body 11 and the second conveying body 12. The tube 41 is slender and has two hollow portions 42a and 42b extending from one end to the other inside. One hollow portion 42a can form the first conveying flow path and the other hollow portion 42b can form the second conveying flow path.

[0065] exist Figure 7 In one example shown, the fluid injection device 10 has the following structure: a semi-circular positive microneedle 13 and a negative microneedle 14 are embedded at one end of the tube body 41, thereby connecting the first flow path of the positive microneedle 13 with the first delivery flow path, and the second flow path of the negative microneedle 14 with the second delivery flow path. Furthermore, the tube body 41 is made of resin and can be manufactured using a 3D printer.

[0066] like Figure 7As shown in (c), the fluid injection device 10 is used by holding the tube body 41 with one hand and pressing one end of the tube body 41 against the object. Thus, the fluid injection device 10 can easily insert or press the positive microneedle 13 and negative microneedle 14 into or against the object. In addition to the body surface or scalp, the fluid injection device 10 can also be used on organs or tumors exposed by laparotomy. Furthermore, since the fluid injection device 10 is integrated into the tube body, it can be compactly constructed as a whole, enabling miniaturization.

[0067] use Figure 7 The fluid injection device 10 shown was used to conduct a fluid injection test. In the test, a solution of Rhodamine B (0.75 mg / mL, 479 Da) was used as the first fluid 21 on the positive side of the microneedle 13, and a solution of methylene blue (0.75 mg / mL, 320 Da) was used as the second fluid 22 on the negative side of the microneedle 14. Furthermore, as shown... Figure 8 As shown in (a), the positive microneedle 13 and the negative microneedle 14 were inserted into the gel chiller gel 38, and a current of 2.0 mA was applied between the first electrode 24 and the second electrode 25 for 20 minutes. The results are shown in... Figure 8 .like Figure 8 As shown in (b), it was confirmed that approximately the same amounts of Rhodamine B and methylene blue were infiltrated into the gellan gel 38 in both the positive microneedle 13 and the negative microneedle 14.

[0068] Next, use Figure 7 The fluid infusion device 10 shown is used to inoculate mice with an oral vegetative-agent (OVA) vaccine model. In the experiment, microneedles 13 (positive side) and 14 (negative side) were immersed in PBS buffer or an aqueous solution of 10 mg / mL OVA for 2 hours, respectively. Specifically, experiments were conducted using a combination of positive and negative microneedles 13 and 14, with three scenarios: PBS with PBS, OVA with PBS, and OVA with OVA. Furthermore, in the experiment, an aqueous solution of PBS was simultaneously used as the first fluid 21 on the positive microneedle 13 side and the second fluid 22 on the negative microneedle 14 side.

[0069] The experiment was conducted in the following manner. First, as... Figure 9 As shown in (a), with the positive microneedle 13 and negative microneedle 14 of the fluid injection device 10 pressed against the back of the hairless mouse 51, at an injection rate of 0.5 mA / cm 2A current density was applied between the first electrode 24 and the second electrode 25 for 1 minute. This was repeated under the same conditions 7 days later. After another 7 days (14 days after the initial application), 51 mice were euthanized, their blood was centrifuged, and serum was collected for analysis of IgG antibodies. To determine antibody titers, 10 μg / mL OVA was coated onto 96-well plates and incubated overnight at 4°C, followed by blocking with 3% BSA. 100 μL of serum diluted with 1% BSA was added, and after 2 hours of incubation, biotin-labeled anti-mouse IgG antibodies were added, followed by a further 2 hours of incubation. The absorbance at 450 nm was then measured using a microplate reader. The measured absorbance was proportional to the amount of IgG antibodies in the serum.

[0070] The measurement results are shown in Figure 9 (b) Additionally, four measurements were performed under each condition, and the error bars in the figure represent the standard deviation. Compared to when both positive and negative microneedles 13 and 14 were in PBS, a higher optical density was observed when one was in OVA, confirming a higher amount of IgG antibodies in the serum. Furthermore, when both were in OVA, a greater amount of IgG antibodies was confirmed to be produced. For comparison, measurements were also performed when both were in OVA and no current was applied (“no current” in the figure), confirming that almost no IgG antibody production occurred. These results confirm that OVA administration is achieved through electroosmotic flow generated by an electric current.

[0071] Example 3 [Example of a fluid injection device: conduit-type device] like Figure 10 As shown in (a), the first delivery body 11 and the second delivery body 12 of the fluid injection device 10 can each be composed of a flexible tube 43, such as a conduit, and are connected to each other on their outer surfaces along the length direction. Figure 10 In one example shown in (a), each of the positive-side microneedles 13 and the negative-side microneedles 14 consists of one. More specifically, the first delivery body 11 and the second delivery body 12 are each composed of an organosilicon tube with an outer diameter of 2 mm.

[0072] like Figure 10 As shown in (b), Figure 10 The fluid injection device 10 shown in (a) can easily intervene in the internal tissues of a living organism 1, allowing for the direct injection of drugs or the like into the tissue. Thus, for example, it is possible to directly administer anticancer agents to tumors for effective treatment. Previously, for example, in non-patent literature 2 demonstrating the effectiveness of iontophoresis on tumors, drug permeation from a positive electrode was utilized, with the negative electrode positioned at a considerable distance, creating a design that unnecessarily allows current to flow throughout the body. In contrast, as... Figure 10 As shown in (b), Figure 10 The fluid injection device 10 shown in (a) utilizes a catheter system to be inserted into the body of the organism 1 through a minimal incision, without allowing unnecessary current to flow through the whole body, and can directly deliver drugs to the tumor through both the positive and negative electrodes.

[0073] Explanation of reference numerals in the attached figures 10: Fluid injection device; 11: First delivery body; 21: First fluid; 12: Second delivery body; 22: Second fluid; 13: Positive microneedle; 14: Negative microneedle; 23: Flange; 15: Current and voltage application mechanism; 24: First electrode; 25: Second electrode; 31: Chamber; 32: Ag / Cl wire; 33: Silicone rubber plug; 34: Source surface; 35: Horizontal capillary; 36: Pig skin slice; 37, 38: Gel gel; 41: Tube body; 42a, 42b: Hollow part; 43: Tube; 51: Mouse.

Claims

1. A fluid injection device, characterized in that, It has the following characteristics: A first conveying body having a first conveying flow path for the flow of a first fluid; The second conveyor has a second conveying path for the flow of the second fluid; A positive-side microneedle has a first opening at its top end and a first flow path fixed with a positive charge and connected to the first opening. The positive-side microneedle is disposed on the first delivery body in such a way that the first flow path is connected to the first delivery flow path. The negative-side microneedle has a second opening at its top end and a second flow path fixed with a negative charge and connected to the second opening. The negative-side microneedle is disposed on the second delivery body in such a way that the second flow path is connected to the second delivery flow path. and A current and voltage application mechanism has a first electrode disposed in the first delivery path and a second electrode disposed in the second delivery path, the current and voltage application mechanism being configured to apply current or voltage between the first electrode and the second electrode. The fluid injection device is configured such that when a current or voltage is applied between the first electrode and the second electrode through the current and voltage application mechanism, an ion current flows in the first fluid in the first flow path and the second fluid in the second flow path. Through electroosmotic flow, the first fluid flows outward from the first opening and the second fluid flows outward from the second opening.

2. The fluid injection device according to claim 1, characterized in that, The fluid injection device is configured such that the positive microneedle and the negative microneedle are adjacent to each other.

3. The fluid injection device according to claim 1, characterized in that, The first conveyor body is elongated, and the first conveying flow path extends from one end of the first conveyor body to the other end. The second conveyor body is elongated, and the second conveying flow path extends from one end of the second conveyor body to the other end. The positive-side microneedle is disposed at one end of the first delivery body. The negative-side microneedle is disposed at one end of the second delivery body.

4. The fluid injection device according to claim 3, characterized in that, The microneedle on the front side is positioned such that its tip protrudes from one end of the first delivery body along the extending direction of the first delivery body. The negative-side microneedle is positioned such that its tip protrudes from one end of the second delivery body along the extension direction of the second delivery body.

5. The fluid injection device according to claim 1, characterized in that, The first conveyor and the second conveyor are configured as one unit.

6. The fluid injection device according to any one of claims 1 to 4, characterized in that, The fluid injection device has a rigid tube that integrates the first conveying body and the second conveying body into one unit. The tube is slender and has two hollow sections extending from one end to the other. One of the hollow sections forms the first conveying flow path, and the other hollow section forms the second conveying flow path.

7. The fluid injection device according to any one of claims 1 to 5, characterized in that, The first conveyor and the second conveyor are each made of flexible tubing.

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