Injector, and method for injecting solution using said injector

Abstract

At least the following is provided. Namely, provided is technology by which it is possible to obtain high physiological activity when injecting, into an injection target, a solution containing an in-vivo functional material exhibiting physiological activity in the injection target. This injector for injecting, into an injection target, an in-vivo functional material-containing solution comprises: a storage part that stores the in-vivo functional material-containing solution; a pressurization part that pressurizes the in-vivo functional material-containing solution during actuation; and an ejection unit that can be inserted into the injection target, the ejection unit having an inlet hole into which the in-vivo functional material-containing solution can flow in from the storage part when the in-vivo functional material-containing solution is pressurized by the pressurization part, and an outlet hole which can eject, to the injection target, the in-vivo functional material-containing solution that has flowed in, wherein the ejection speed of the in-vivo functional material-containing solution exceeds 83.3 μL / s.

Description

Injector and method for injecting a solution using the injector

[0001] The present disclosure relates to an injector and a method for injecting a solution using the injector.

[0002] Injectors for injecting a medicinal liquid into an injection target include needle-equipped syringes that inject using a syringe needle, needleless syringes that inject without using a syringe needle, etc. In addition, catheters equipped with a syringe needle and a driving source, multi-hole syringes, etc. are also used to transport a medicinal liquid to an injection target.

[0003] Among these, needle syringes involve inserting a needle into the target and slowly injecting the medicinal solution by pushing the plunger, allowing the medicinal solution to diffuse throughout the target and ensure the medicinal effect is properly achieved. In particular, when administering medicinal solutions without relying on blood flow, extremely small amounts are administered slowly (e.g., approximately 0.0033 μL / s). Furthermore, in many cases, the "slow" administration is based on the subjective judgment of the administering individual. Meanwhile, needleless syringes use compressed gas or spring force as a driving force to instantly push the medicinal solution from the nozzle tip and administer the medicinal solution into the body through the skin surface (Non-Patent Document 1). Furthermore, needleless syringes have been developed that utilize the combustion energy of an ignition charge as the driving force (Patent Document 1).

[0004] Needle-free syringes, which utilize the combustion energy of an ignition charge as the ejection energy, instantly expel and administer a drug solution, enabling delivery of the drug solution to the cell nucleus or cytosol. Because needle-free syringes can deliver active ingredients to injection targets without necessarily requiring viral vectors or lipid carriers, their usefulness has been attracting attention from the perspective of drug delivery systems (DDS), and their use in delivering various anti-cancer drugs, such as small molecules, peptides, proteins, and antibodies, has been considered. In particular, in the fields of vaccines and immunization, needle-free syringes have been reported to increase antibody titers and induce cellular immunity (Non-Patent Document 2). Furthermore, it has been reported that intradermal administration of plasmid DNA into experimental animals using a needle-free syringe significantly enhanced gene expression compared to administration using a conventional needle syringe (Non-Patent Document 3). Drug solutions administered via the skin surface using a needle-free syringe form a jet stream that penetrates the stratum corneum and is delivered intradermally (Non-Patent Document 1). By adjusting the output, it is also possible to deliver drug solutions subcutaneously or intramuscularly (Non-Patent Document 4).

[0005] JP 2012-61269 A

[0006] Clin. Cosmet. Investig. Dermatol., 2018 May 1,11:231-238AAPS PharmSciTech., 2019 Dec 9,21(1):19Journal of Pharmaceutical Sciences, 2019, 108: 2415-2420.Gene, 2021, 788: 145664

[0007] When the inside of a living body is the target of injection, a classic needle syringe is generally used as an injector for injecting a medicinal solution, but there is room for improvement in terms of medicinal efficacy. The object of the present disclosure is at least as follows: to provide a technology that, when the inside of a living body is the target of injection, can obtain high physiological activity when a solution containing a biofunctional substance that exerts physiological activity in the target of injection is injected into the target of injection.

[0008] As a result of extensive research into solving the above problems, the inventors have discovered that the above problems can be solved by an injector that has an injection part that can be inserted into the injection target and is capable of injecting a solution at a predetermined high injection speed.

[0009] That is, the gist of the present disclosure is as follows. [1] An injector for injecting a solution containing a biofunctional substance into an injection target, comprising: a storage section for storing the solution containing the biofunctional substance; a pressurizing section for pressurizing the solution containing the biofunctional substance when activated; and an injection section insertable into the injection target, the injection section having an inlet hole through which the solution containing the biofunctional substance can flow from the storage section when pressurized by the pressurizing section, and an outlet hole through which the solution containing the biofunctional substance can be injected into the injection target, wherein the injection speed of the solution containing the biofunctional substance exceeds 83.3 μL / s. [2] The injector according to [1], wherein the injection speed of the solution containing the biofunctional substance is 200 μL / s or more. [3] The injector according to [1] or [2], wherein the inner diameter of the injection section is 0.41 mm or less. [4] The injector according to any one of [1] to [3], wherein the outer diameter of the injection part is 0.72 mm or less. [5] The injector according to any one of [1] to [4], wherein the injection part is a syringe needle. [6] The injector according to any one of [1] to [5], wherein the biofunctional substance is one or more selected from the group consisting of nucleic acids, peptides, proteins, and low-molecular-weight compounds. [7] The injector according to any one of [1] to [6], wherein the injection target is one or more selected from the group consisting of joint cavities, spleens, eyeballs, skin, muscles, bones, cartilage, bone marrow, ligaments, brains, spinal cords, lungs, livers, hearts, kidneys, pancreases, gallbladder, digestive tracts, bladder, reproductive organs, lymph nodes, lymphatic networks, and blood vessels, tumors occurring in any one of these, and mucous membranes and connective tissues associated with any one of these. [8] A method for injecting a solution containing the biofunctional substance into the injection target using the injector according to any one of [1] to [7].

[0010] The present disclosure can achieve at least the following effect: That is, when the interior of a living body is the injection target, it can provide a technology that can obtain high physiological activity when a solution containing an in vivo functional substance that exhibits physiological activity in the injection target is injected into the injection target.

[0011] FIG. 1 is an overall view of an injector according to an embodiment of the present disclosure. FIG. 2 is a cross-sectional view showing the vicinity of the tip of the injector shown in FIG. 1. FIG. 3 is an overall view of an injector according to a modified example. FIG. 4 is a cross-sectional view of the injector shown in FIG. 3. FIG. 5 is a graph showing Luc activity (total RFU) in the joints of the 2.5 mL Hamilton syringe with 30 G needle (Syr) group (n=4), the 30 G-pNFI-25 / 40 (25 / 40 Device) group (n=4), and the 30 G-pNFI-35 / 40 (35 / 40 Device) group (n=4). Mean value + SD.

[0033] Figure 1 shows the intra-articular Luc activity (total RFU) of the 30G needle-equipped 25mL Hamilton syringe administered at a rate of 0.25μL / s (administration rate 0.25μL / s) group (n = 4), the 30G needle-equipped 25mL Hamilton syringe administered at a rate of 83.3μL / s (administration rate 83.3μL / s) group (n = 8), and the 30G-pNFI-35 / 40 group (n = 8). Mean value + SD, Student t-test, *: P < 0.05.

[0034] Figure 1 shows the intra-articular Luc activity (total RFU) of the 30G-pNFI-35 / 40 (35 / 40) group, the 30G-pNFI-55 / 40 (55 / 40) group, and the 30G-pNFI-75 / 40 (75 / 40) group. Mean value + SD. Graph showing the injection rate of the solution when using 30G-pNFI-25 / 40, 30G-pNFI-35 / 40, 30G-pNFI-55 / 40, 30G-pNFI-75 / 40, or pNFI-35 / 40. Graph showing Luc activity (total RFU) in the spleen when administered using 30G-pNFI-35 / 40 and an insulin syringe with a 30G needle (30G-Syr). Mean value + SD. Graph showing Luc activity (total RFU) in the spleen when administered using 30G-pNFI-35 / 40 and a Hamilton syringe with a 30G needle (30G-Syr / pump). Mean value + SD. Graph showing Luc activity (total RFU) in the spleen when administered using 30G-pNFI-25 / 40, 30G-pNFI-35 / 40, and a 30G Hamilton syringe with a needle (30G-Syr / pump). Mean value + SD. Graph showing Luc activity (total RFU) in the testis when administered using 30G-pNFI-25 / 40, 30G-pNFI-35 / 40, and a 30G Hamilton syringe with a needle (30G-Syr / pump). Mean value + SD.Graph showing Luc activity (total RFU) in the caput epididymis when administered using 30G-pNFI-25 / 40, 30G-pNFI-35 / 40, and a 30G Hamilton syringe with a needle (30G-Syr / pump). Mean value + SD. Graph showing Luc activity (total RFU) in the cauda epididymis when administered using 30G-pNFI-25 / 40, 30G-pNFI-35 / 40, and a 30G Hamilton syringe with a needle (30G-Syr / pump). Mean value + SD. Graph showing Luc activity (total RFU) in the liver when administered using 30G-pNFI-25 / 40 and a 30G insulin syringe with a needle (30G-Syr). Mean value + SD.

[0012] Each configuration and combination thereof in each embodiment is merely an example, and additions, omissions, substitutions, and other modifications of configurations are possible as appropriate within the scope of the present disclosure. The present disclosure is not limited by the embodiments, but only by the scope of the claims. Furthermore, each aspect disclosed in this specification can be combined with any other feature disclosed in this specification. Furthermore, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits, and "A to B" means greater than or equal to A and less than or equal to B.

[0013] One embodiment of the present disclosure is an injector for injecting a solution containing a biofunctional substance into an injection target, comprising: a storage section for storing the solution containing the biofunctional substance; a pressurizing section for pressurizing the solution containing the biofunctional substance when activated; and an injection section insertable into the injection target, the injection section having an inlet hole through which the solution containing the biofunctional substance can flow from the storage section when pressurized by the pressurizing section, and an outlet hole through which the solution containing the biofunctional substance that has flowed in can be injected into the injection target, wherein the injection speed of the solution containing the biofunctional substance exceeds 83.3 μL / s. With the injector of this embodiment, high physiological activity can be obtained when a solution containing a biofunctional substance that exhibits physiological activity in the injection target is injected into the injection target.

[0014] <Solution containing a biofunctional substance> The solution that can be injected by the injector according to this embodiment contains a biofunctional substance. The biofunctional substance is not particularly limited as long as it exerts physiological activity in the injection target. The biofunctional substance may be one type or multiple types. The biofunctional substance may be a natural product or may be artificially synthesized.

[0015] The biofunctional substance is preferably one or more selected from the group consisting of nucleic acids, peptides, proteins, and low molecular weight compounds.

[0016] Examples of nucleic acids include DNA, RNA, and PNA. The nucleic acid may be a nucleic acid containing a portion that encodes a protein, or a nucleic acid that does not contain a portion that encodes a protein (non-coding nucleic acid).

[0017] Examples of peptides and proteins include antigens (i.e., substances that induce the production of antibodies against the peptide or protein), antibodies, peptide vaccines, protein vaccines, peptide hormones, protein hormones, growth factors, cytokines, blood coagulation factors, serum albumin, digestive enzymes, anti-inflammatory peptides, and anti-inflammatory proteins.

[0018] A low molecular weight compound generally refers to a compound having a molecular weight of 2000 or less, but is not limited to this and includes compounds that are considered to be low molecular weight compounds in the art. Preferred ranges for the molecular weight of low molecular weight compounds include, for example, 50 or more and 100 or more. Other preferred ranges include 2000 or less and 1000 or less. That is, examples include 50 to 2000, 50 to 1000, and 100 to 2000.

[0019] In the present disclosure, physiological activity refers to an effect on a specific physiological regulatory function of a living organism. Evaluation indicators for physiological activity can be appropriately set depending on the purpose and may be either qualitative or quantitative, with quantitative indicators being preferred. For example, specific mRNA levels, protein levels, cytokine levels, antibody titers, cell counts of specific cell types, etc. can be used as indicators. These quantitative indicators can be quantified by methods known in the art.

[0020] In particular, when the biologically functional substance is a nucleic acid containing a portion encoding a protein, the amount of the protein encoded by the nucleic acid can be quantified and used as an evaluation index for physiological activity. Alternatively, the activity of the protein may be quantitatively evaluated. For example, as shown in the Examples below, when the protein is luciferase, physiological activity can be evaluated by measuring the intensity of bioluminescence.

[0021] When the biofunctional substance is a nucleic acid, the nucleic acid may be incorporated into a viral vector or supported on lipid nanoparticles and then contained in the solution, but the injector according to this embodiment can achieve high physiological activity even without using a viral vector or lipid nanoparticles. When a viral vector or lipid nanoparticles is not used, the possibility of inducing side reactions such as anaphylaxis in the injected subject can be reduced.

[0022] The content of the biofunctional substance relative to the total volume of the solution can be appropriately set based on the type of the biofunctional substance, the subject to be injected, the physiological activity exhibited by the biofunctional substance in the subject to which the biofunctional substance is injected, etc.

[0023] The solution may contain, in addition to the biofunctional substance, conventional additives such as a buffer, an isotonicity agent, a pH adjuster, an antioxidant, a thickener, a stabilizer, a wetting agent, an emulsifier, and a binder, as needed.

[0024] Examples of buffers that can be used include buffers using phosphate (e.g., phosphate buffer, phosphate buffered saline (PBS) (which may be PBS(+) or PBS(-)), Dulbecco's phosphate buffered saline (D-PBS), citrate-phosphate buffer, citrate-phosphate buffered saline, etc.), citrate buffer, trishydroxymethylaminomethane-HCl buffer (tris-hydrochloric acid buffer), acetate buffer, GOOD buffer (e.g., HEPES-NaOH buffer, etc.), amino acid buffer (e.g., glycine-hydrochloric acid buffer, glycine-NaOH buffer, glycylglycine-KOH buffer, etc.), imidazole buffer, etc. Among these, buffers using phosphate are preferred from the viewpoint of versatility.

[0025] Examples of the isotonicity agent include ionic isotonicity agents and nonionic isotonicity agents. Examples of the ionic isotonicity agents include salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Examples of the nonionic isotonicity agents include glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, and sucrose. Among these, sodium chloride is preferred from the viewpoint of versatility.

[0026] Examples of pH adjusters include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.

[0027] Examples of antioxidants include ascorbic acid, sodium sulfite, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, and tocopherol.

[0028] Thickeners include alginic acid, polyethylene glycol, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and the like.

[0029] The content of the biofunctional substance in the solution is not particularly limited and can be appropriately adjusted by a person skilled in the art within a range in which the biofunctional substance can exert its physiological activity. Examples include 0.0001 mg / mL or more, 0.001 mg / mL or more, 0.01 mg / mL or more, etc. Also included are 1000 mg / mL or less, 100 mg / mL or less, etc. That is, examples include 0.0001 to 1000 mg / mL, 0.001 to 100 mg / mL, 0.01 to 100 mg / mL, etc.

[0030] The pH of the solution is not particularly limited as long as, when the solution is injected into an injection target, the biologically active substance in the injection target is present stably and does not have any adverse effects such as destroying the injection target.

[0031] <Injector> As described above, the injector of this embodiment comprises a storage section that stores a solution containing a biologically functional substance, a pressurizing section that pressurizes the solution, and an injection section that can be inserted into the target of injection of the solution, and injects the solution into the target of injection by injecting the solution from the outlet hole of the injection section.

[0032] In the injector according to this embodiment, the energy applied by the pressurizing unit to pressurize the solution containing the biofunctional substance can be applied using known pressurizing techniques. One example of the applied energy may be chemically generated energy, such as combustion energy generated by the oxidation reaction of gunpowder or explosives. Alternatively, the energy for pressurization may be electrically generated, such as energy generated by a piezoelectric element or an electromagnetic actuator driven by input power. Still another example of the energy for pressurization may be physically generated, such as elastic energy generated by an elastic body or internal energy of a compressed object such as compressed gas. In other words, the energy for pressurization may be any energy that enables the injection of the solution from the injector. Furthermore, the energy for pressurization may be a composite energy that appropriately combines internal energies such as combustion energy, electrical energy, and elastic energy.

[0033] In view of the above, the pressurizing unit may apply pressure by utilizing the pressure generated by the combustion of explosives ignited by an ignition device, or by utilizing the pressure generated when compressed gas is released. Furthermore, the pressurizing unit may apply pressure by utilizing the biasing force of a compression spring, or by utilizing electromagnetic force, for example, by utilizing a linear electromagnetic actuator. The pressurizing unit is preferably one that at least utilizes the pressure generated by the combustion of explosives ignited by an ignition device, and may also be used in combination with any of the other pressurizing modes described above.

[0034] When the pressurizing unit utilizes the pressure generated by the combustion of explosives, the explosives may be, for example, any one of the following explosives: zirconium and potassium perchlorate (ZPP), titanium hydride and potassium perchlorate (THPP), titanium and potassium perchlorate (TiPP), aluminum and potassium perchlorate (APP), aluminum and bismuth oxide (ABO), aluminum and molybdenum oxide (AMO), aluminum and copper oxide (ACO), and aluminum and iron oxide (AFO), or a combination of these explosives. A feature of these explosives is that their combustion products are gaseous at high temperatures but do not contain gaseous components at room temperature, so the combustion products condense immediately after ignition.

[0035] Furthermore, when the pressurizing section utilizes the energy generated by the combustion of a gas generating agent as ejection energy, it is also possible to use, as the gas generating agent, single-base smokeless powder (GG) or various gas generating agents used in gas generators for airbags and gas generators for seatbelt pretensioners.

[0036] The injector according to the present embodiment may be configured as, for example, a needle-type syringe including an injector body having a storage portion and a pressurizing portion, and an injection needle attached to the injector body as an injection portion. The injector according to the present embodiment may also be configured such that the storage portion and injection portion of the injector body are integrally molded. The injector body may also be configured as, for example, a needleless syringe capable of performing injection independently without a needle. However, the injector body according to the present disclosure is not limited to a needleless syringe. The injector body may also be, for example, a syringe pump. The injection portion according to the present disclosure is not limited to an injection needle. For example, when the distance from the injector body to the injection target is large, a catheter or a multi-hole injection needle may be used as the injection portion to guide the solution containing the biofunctional substance from the storage portion of the injector body to the injection target.

[0037] Here, from the viewpoint of suppressing tissue damage to the injection target, it is preferable that the injection portion inserted into the injection target be thin. Specifically, the inner diameter of the injection portion is preferably 0.41 mm or less, and the outer diameter of the injection portion is preferably 0.72 mm or less. However, the ranges of the inner and outer diameters of the injection portion according to the present disclosure are not limited to those described above. Furthermore, the length of the injection portion can be appropriately set depending on the injection target. For example, when the injection portion is configured as an injection needle, the length of the injection needle can be selected from the range of 1 mm to 180 mm. If the injection needle length is 1 mm or more, the injection needle can reach the intradermal area when inserted perpendicularly to the skin. Furthermore, even when the injection target is assumed to be deep inside a human internal organ, a length of 180 mm can ensure that the injection needle can reach the deep inside the organ sufficiently. Furthermore, the material of the injection portion is not particularly limited, but metal materials or resin materials can be used.

[0038] Furthermore, in the injector according to this embodiment, the solution containing the biologically functional substance may be contained in the storage section from the beginning, or may be contained in the storage section by sucking the solution from outside the injector through the outlet hole of the injection section.

[0039] [Syringe] Hereinafter, with reference to the drawings, a syringe 100 shown in FIGS. 1 and 2 will be described as an example of a syringe according to this embodiment. Note that the configuration of the following embodiment is an example, and the technology of the present disclosure is not limited to the configuration of this embodiment. Note that in the following description, the terms "tip side" and "base side" are used to describe the relative positional relationship in the longitudinal direction of the syringe 100. The "tip side" refers to the side of the syringe 100 that faces the outlet hole 4b shown in FIG. 1 and the like in the longitudinal direction, and the "base side" refers to the side of the syringe 100 opposite the outlet hole 4b in the longitudinal direction.

[0040] Fig. 1 is an overall view of a syringe 100 according to this embodiment. Fig. 1 shows a cross section along the longitudinal direction of the syringe 100. Fig. 2 is a cross section showing the vicinity of the tip of the syringe 100. As shown in Fig. 1, the syringe 100 includes a jet injector 1 as an injector main body, a housing 2 that accommodates the jet injector 1, an injection needle 4 as an injection part, and a fixing jig 5 for fixing the injection needle 4 to the jet injector 1.

[0041] [Jet Injector] As shown in FIG. 1 , the jet injector 1 is an assembly that includes a container 11, a container holder 12, an actuator 13, and a casing 14, all assembled together. An injection hole, designated by the reference symbol 11c, is formed at the tip of the jet injector 1. The jet injector 1 injects a solution containing a biofunctional substance (hereinafter sometimes simply referred to as "solution") from the injection hole 11c by pressurizing the solution using the combustion energy of explosives. The jet injector 1 according to this embodiment is configured as a needleless syringe that can perform injections independently without the use of a syringe needle. However, the jet injector 1 does not have to be a needleless syringe.

[0042] [Casing] As shown in Fig. 1, the casing 14 is a cylindrical member that houses the actuator 13. An ignition device 131 (described later) of the actuator 13 is fitted into the base end side of the casing 14, and the container holder 12 is fitted into the tip end side of the casing 14. In addition, as shown in Fig. 2, a threaded portion 14a is formed on the inner peripheral surface of the tip end side of the casing 14 to connect the casing 14 and the container holder 12. The container holder 12 and the actuator 13 are connected via the casing 14.

[0043] [Container] As shown in FIG. 2 , the container 11 is cylindrical and includes a main body 111 and a nozzle 112 having a smaller diameter than the main body 111. The container 11 includes a storage space 11a capable of storing a solution containing a biofunctional substance, and a flow path 11b communicating with the storage space 11a and opening at the distal end. More specifically, the storage space 11a is formed within the main body 111, and the flow path 11b is formed within the nozzle 112. The storage space 11a is an example of a storage portion according to the present disclosure. An opening of the flow path 11b is formed in the distal end surface of the nozzle 112, which serves as the injection hole 11c of the jet injector 1. The jet injector 1 injects the solution from the injection hole 11c formed in the distal end surface of the nozzle 112. As shown in FIG. 2 , the inner diameter of the flow path 11b of the container 11 is smaller than the inner diameter of the storage space 11a. With this configuration, the highly pressurized solution is injected to the outside through the injection hole 11c of the flow path 11b. In addition, a threaded portion 111a is formed on the outer circumferential surface of the main body 111 for connecting the container 11 and the container holder 12.

[0044] The material of the container 11 is not particularly limited, but the container 11 can be made of, for example, a resin material. Examples of resin materials that can be used to make the container 11 include known nylon 6-12, polyarylate, polycarbonate, polybutylene terephthalate, polyphenylene sulfide, and liquid crystal polymers.

[0045] [Container Holder] As shown in Fig. 2, the container holder 12 is formed in a cylindrical shape and holds the container 11 fitted into the container holder 12. A threaded portion 12a is formed on the inner peripheral surface of the base end side of the container holder 12. The container 11 and the container holder 12 are joined together by threading the threaded portion 111a of the container 11 into the threaded portion 12a of the container holder 12. A threaded portion 12b is formed on the outer peripheral surface of the base end side of the container holder 12. The container holder 12 and the casing 14 are joined together by threading the threaded portion 12b of the container holder 12 into the threaded portion 14a of the casing 14. A threaded portion 12c is formed on the outer peripheral surface of the tip end side of the container holder 12 to join the container holder 12 to the fixing jig 5.

[0046] The material of the container holder 12 is not particularly limited, but the container holder 12 may be made of, for example, a metal material. Examples of the metal material that can be used to form the container holder 12 include stainless steel, copper, aluminum, iron, titanium, and titanium alloys.

[0047] 1 is configured to pressurize a solution when activated. The actuator 13 is an example of a "pressurizing unit" according to the present disclosure. As shown in FIG. 1, the actuator 13 includes an ignition device 131 and a piston 132 housed in a casing 14, and a plunger 133.

[0048] The ignition device 131 is disposed on the base end side of the casing 14, the plunger 133 is disposed on the tip end side of the casing 14, and the piston 132 is disposed adjacent to the plunger 133 and between the ignition device 131 and the plunger 133. A combustion chamber 15 is formed in the internal space of the casing 14 between the ignition device 131 and the piston 132.

[0049] [Ignition Device] The ignition device 131 includes an initiator 1311 and a holding member 1312. The initiator 1311 serves as a driving source for the actuator 13, generating energy for the syringe 100 to pressurize and inject the solution. The initiator 1311 is configured as an electric igniter that releases combustion products by burning an ignition charge contained therein. The holding member 1312 is formed by injection molding of a resin. A known method can be used for the injection molding. The holding member 1312 can be made of the same resin material as the container 11. The ignition device 131 is configured as an igniter assembly in which the initiator 1311 is fixed to the base end of the casing 14 via the holding member 1312, and is fitted into the casing 14 so as to close the base end of the casing 14. In addition, the ignition device 131 is arranged in the casing 14 so that the initiator 1311 faces the base end face (end face on the base end side) of the piston 132 so that the combustion energy of the ignition charge by the initiator 1311 and the combustion energy of the gas generating agent 10 described later can be transmitted to the base end face.

[0050] [Ignition Charge] Examples of ignition charges used in the initiator 1311 include explosives containing zirconium and potassium perchlorate (ZPP), explosives containing titanium hydride and potassium perchlorate (THPP), explosives containing titanium and potassium perchlorate (TiPP), explosives containing aluminum and potassium perchlorate (APP), explosives containing aluminum and bismuth oxide (ABO), explosives containing aluminum and molybdenum oxide (AMO), explosives containing aluminum and copper oxide (ACO), explosives containing aluminum and iron oxide (AFO), and explosives consisting of a combination of these explosives. These explosives generate high-temperature, high-pressure plasma during combustion immediately after ignition, but when the temperature returns to room temperature and the combustion products condense, the generated pressure drops rapidly because they do not contain gas components. However, other explosives may be used as long as they are capable of properly ejecting the solution.

[0051] [Gas Generating Agent] In the jet injector 1, a gas generating agent 10 is disposed in the combustion chamber 15. The gas generating agent 10 generates gas by combustion using combustion products of an ignition charge released from an initiator 1311, in order to adjust the transition of pressure applied to the solution via the piston 132. In other words, the jet injector 1 is configured to pressurize the solution by utilizing the combustion energy of the gas generating agent 10 in addition to the combustion energy of the ignition charge generated by the initiator 1311. The gas generating agent 10 is disposed in a location where it can be exposed to the combustion products from the initiator 1311. Alternatively, the gas generating agent 10 may be disposed within the initiator 1311, as disclosed in International Publication No. 01-031282 and Japanese Patent Application Laid-Open No. 2003-25950. One example of a gas generating agent is a single-base smokeless powder (GG) composed of 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate. It is also possible to use various gas generating agents used in gas generators for airbags and gas generators for seatbelt pretensioners. By adjusting the dimensions, size, shape, and particularly the surface shape, of the gas generating agent when placed in the combustion chamber 15, it is possible to change the time until combustion of the gas generating agent is completed, thereby adjusting the change in pressure applied to the solution and achieving the desired change in injection pressure. Note that the jet injector 1 may not include a gas generating agent 10 and instead pressurize the solution using only the combustion energy of the ignition charge generated by the initiator 1311. In the present disclosure, the pressurizing section also includes a gas generating agent or the like that is used as needed.

[0052] [Piston] The piston 132 is disposed at the tip side of the casing 14 so that it can be pressurized by the operation of the initiator 1311 and slide inside the casing 14. The piston 132 is made of metal, and an O-ring or the like may be disposed on a part of the piston 132 to improve adhesion with the sliding surface on which the piston 132 slides (i.e., the inner peripheral surface of the casing 14). Alternatively, the piston 132 may be made of resin, in which case metal may be used in combination in parts that require heat resistance or pressure resistance.

[0053] [Plunger] The plunger 133 is a member that pressurizes the solution contained in the storage space 11a by receiving, via the piston 132, the combustion energy of the ignition charge produced by the initiator 1311 and the combustion energy of the gas generating agent. The plunger 133 is housed in the casing 14 and disposed between the piston 132 and the nozzle portion 112 of the container 11. The plunger 133 is formed in a rod shape, and its base end engages with the tip end of the piston 132. The tip end of the plunger 133 is inserted into the main body portion 111 of the container 11, and the storage space 11a is defined by the plunger 133 and the main body portion 111. The plunger 133 is slidable inside the main body portion 111, and as the plunger 133 slides, the solution contained in the storage space 11a is pressurized and ejected from the ejection hole 11c through the flow path 11b. Therefore, the plunger 133 is formed from a material that allows smooth sliding relative to the main body 111 of the container 11 and prevents the solution from leaking from the plunger 133 side.

[0054] Specific examples of the material that can be used for the plunger 133 include butyl rubber and silicone rubber. In order to ensure and adjust the slidability between the plunger 133 and the main body 111 of the container 11, the outer circumferential surface of the plunger 133 and the inner circumferential surface of the main body 111 may be coated or surface-treated with various substances.

[0055] Here, the contour of the tip of the plunger 133 is shaped to roughly match the contour of the tip of the storage space 11 a, so that when the plunger 133 slides during injection of the solution and reaches the innermost position in the main body 111, the storage space 11 a formed between the plunger 133 and the nozzle 112 can be made as small as possible, and the solution remaining in the storage space 11 a and being wasted can be prevented.

[0056] [Housing] The housing 2 shown in FIG. 1 is a component that houses the jet injector 1 and functions as a grip that the user grasps to use the syringe 100. As shown in FIG. 1, a battery 3 is provided inside the housing 2 to supply a driving current to the actuator 13 (more specifically, the initiator 1311) of the jet injector 1. Also shown in FIG. 1, a plurality of switches 21 for operating the jet injector 1 to inject a solution are provided on the outer surface of the housing 2. A socket (not shown) that connects to the initiator 1311 of the jet injector 1 is provided on the inner surface of the housing 2. Power is supplied from the battery 3 to the jet injector 1 between an electrode on the housing 2 side and an electrode on the initiator 1311 side of the jet injector 1 via wiring when the user presses the switch 21. A control unit (not shown), such as a microcomputer, is also provided inside the housing 2. The control unit controls the supply of ignition current to the initiator 1311 of the jet injector 1 based on signals from each switch, thereby controlling the operation of the jet injector 1.

[0057] As described above, in this embodiment, the power for operating the initiator 1311 is supplied from a battery built into the housing 2, but instead, power may be supplied from the outside via a power cable.

[0058] 1, the injection needle 4 is attached to the nozzle 112 of the jet injector 1, and is configured to include a base 41 and a needle tube 42. The injection needle 4 is an example of an "ejection unit" according to the present disclosure, and is configured so that a solution pressurized by the actuator 13 of the jet injector 1 flows into the injection needle 4, and the flowed-in solution can be injected into an injection target.

[0059] A solution pressurized by the actuator 13 flows into the base 41. As shown in FIG. 1 , the base 41 is formed in a cylindrical shape. More specifically, as shown in FIG. 2 , the base 41 includes a cylindrical base body 411 and a flange portion 412 formed at the base end of the base body 411 and projecting radially outward. The nozzle portion 112 of the jet injector 1 is press-fitted into the opening on the base end side of the base body 411. Therefore, the opening on the base end side of the base body 411 is configured as an inlet hole 4a through which the solution containing the biofunctional substance can flow from the storage space 11a of the container 11 into the injection needle 4.

[0060] The base 41 can be made of, for example, a resin material. Examples of resin materials that can be used to form the base 41 include known synthetic resins such as polycarbonate, polypropylene, and polyethylene. The base 41 may also be made of metal. Examples of metal materials that can form the base 41 include stainless steel, aluminum, aluminum alloys, titanium, and titanium alloys. The material of the base 41 is not particularly limited, but considering the need to suppress pressure loss of the solution flowing into the injection needle 4, it is preferable to use a relatively rigid material such as stainless steel for the base 41.

[0061] The needle tube 42 is inserted into an injection target and injects a solution containing a biofunctional substance into the injection target. The base end of the needle tube 42 is connected to the tip of the base 41, and the internal space of the base 41 communicates with the internal space of the needle tube 42. Therefore, the opening on the tip side of the needle tube 42 is configured as an outlet hole 4b through which the solution containing a biofunctional substance that has flowed into the injection needle 4 from the inlet hole 4a can be injected into the injection target. In addition, a sharp needle tip for puncturing the skin is formed at the tip of the needle tube 42 so that the needle tube 42 can be inserted into the injection target.

[0062] Here, from the viewpoint of suppressing tissue damage to the injection target, it is preferable that the injection needle 4 (more specifically, the needle tube 42 inserted into the injection target) be thin. As shown in the enlarged view A1 of FIG. 2 , the inner diameter of the needle tube 42 is d1, and the outer diameter of the needle tube 42 is d2. Here, the inner diameter d1 is preferably 0.41 mm or less, and the outer diameter d2 is preferably 0.72 mm or less. However, the ranges of the inner diameter and outer diameter of the needle tube 42 are not limited to those described above. Furthermore, the length of the needle tube 42 can be appropriately set depending on the injection target, and can be, for example, a value selected from the range of 1 mm to 180 mm.

[0063] The material of the needle tube 42 is not particularly limited, but may be, for example, stainless steel. Metal materials other than stainless steel include aluminum, aluminum alloys, titanium, and titanium alloys. The needle tube 42 may also be made of a resin material.

[0064] As described above, the internal space of the base 41 and the internal space of the needle tube 42 are in communication with each other, and therefore a flow path 4c extending from the inlet hole 4a to the outlet hole 4b is formed in the injection needle 4 by the internal spaces of the base 41 and the needle tube 42. The solution that flows into the injection needle 4 from the inlet hole 4a flows through the flow path 4c to the outlet hole 4b, and is injected from the outlet hole 4b into the injection target.

[0065] A sealant may be used between the nozzle portion 112 of the container 11 and the base portion 41 of the injection needle 4 to improve liquid-tightness. Examples of the sealant include an O-ring, a packing, a sealing tape, and a liquid sealant.

[0066] [Fixing Jig] The fixing jig 5 is a member for fixing the injection needle 4 to the nozzle 112 of the jet injector 1. The fixing jig 5 includes a cylindrical peripheral wall 51 and a cover wall 52 that closes the tip of the peripheral wall 51. The container holder 12 is fitted into the peripheral wall 51. A threaded portion 51a is formed on the inner peripheral surface of the peripheral wall 51, and the container holder 12 and the fixing jig 5 are joined together by threading the threaded portion 12c of the container holder 12 into the threaded portion 51a of the fixing jig 5. The cover wall 52 has a through-hole 52a that penetrates the cover wall 52 from the base end to the tip end. The base body 411 of the injection needle 4 is fitted into the through-hole 52a. At this time, the cover wall 52 presses the flange 412 of the injection needle 4 from the tip end, thereby preventing the injection needle 4 from falling off the nozzle 112 of the jet injector 1. In this way, the injection needle 4 is fixed to the nozzle portion 112 by the fixing jig 5 .

[0067] The material of the fixing jig 5 is not particularly limited, but like the container holder 12, the fixing jig 5 can be made of a metal material such as stainless steel, copper, aluminum, iron, titanium, or a titanium alloy. Alternatively, the fixing jig 5 can be made of a resin material such as polycarbonate, polypropylene, or polyethylene.

[0068] [Operation of Injector] Injection of a solution into an injection target using the syringe 100 is performed by operating the syringe 100 with the needle tube 42 of the injection needle 4 inserted into the injection target. The operation of the syringe 100 will be described below. The solution containing the biofunctional substance may be initially contained in the storage space 11a of the container 11, or may be contained in the storage space 11a by sucking the solution from outside the syringe 100 through the outlet hole 4b of the injection needle 4. When the storage portion and the injection portion are integrally molded, the solution containing the biofunctional substance is initially contained in the storage space 11a of the container 11, thereby reducing drug leakage and dead volume.

[0069] When a user operates the switch 21, a drive current is supplied to the actuator 13 (more specifically, the initiator 1311) of the jet injector 1. When the actuator 13 is activated, the initiator 1311 releases combustion products of the ignition charge into the combustion chamber 15. As a result, the gas generating agent 10 disposed in the combustion chamber 15 is combusted by the combustion products of the ignition charge, generating gas in the combustion chamber 15. As described above, the base end surface of the piston 132 is exposed to the combustion chamber 15. Therefore, when the actuator 13 is activated, the piston 132 receives the combustion energy (pressure) of the ignition charge and gas generating agent at its base end surface and slides toward the tip end of the casing 14. As a result, the plunger 133 is pushed toward the tip end of the accommodation space 11a by the piston 132, and the solution in the accommodation space 11a is pressurized. As a result, the solution is ejected from the accommodation space 11a through the flow path 11b and from the ejection hole 11c formed in the nozzle portion 112.

[0070] The solution ejected from the ejection hole 11c of the nozzle portion 112 flows into the injection needle 4 via the inlet hole 4a of the injection needle 4 attached to the nozzle portion 112. The solution flows through the flow path 4c and is ejected from the outlet hole 4b into the injection target. In this way, the operation of the syringe 100 is completed.

[0071] [Modification] FIG. 3 is an overall view of a syringe 100A according to a modification of the present embodiment. FIG. 3 illustrates the external appearance of the syringe 100A. FIG. 4 is a cross-sectional view of the syringe 100A. As shown in FIG. 3, a power cable 6 for supplying a driving current to the actuator 13 of the jet injector 1 is provided in the housing 2 of the syringe 100A. As shown in FIG. 4, the actuator 13 of the jet injector 1 according to the modification has a cylindrical body 134 that houses an ignition device 131 and a piston 132. The ignition device 131 is disposed on the base end side of the body 134, and the piston 132 is disposed on the tip end side. A combustion chamber 15 is formed in the internal space of the body 134 between the ignition device 131 and the piston 132. The syringe according to the present disclosure can also be implemented with a configuration similar to that of the syringe 100A.

[0072] [Injection Speed ​​of Solution] The injector according to this embodiment can inject the solution containing the biofunctional substance at an injection speed exceeding 83.3 μL / s. The injection speed is preferably 200 μL / s or higher, more preferably 250 μL / s or higher, even more preferably 300 μL / s or higher, even more preferably 350 μL / s or higher, even more preferably 400 μL / s or higher, and most preferably 500 μL / s or higher. There is no particular upper limit, but an example is 5000 μL / s or lower. That is, preferred ranges of injection rate include more than 83.3 μL / s and less than 5000 μL / s, 200 μL / s or more and less than 5000 μL / s, 250 μL / s or more and less than 5000 μL / s, 300 μL / s or more and less than 5000 μL / s, 350 μL / s or more and less than 5000 μL / s, 400 μL / s or more and less than 5000 μL / s, and 500 μL / s or more and less than 5000 μL / s. When the injection rate exceeds 83.3 μL / s, high physiological activity is obtained when the solution is injected into the injection target. While the detailed mechanism is unclear, it is presumed that applying shear stress to the tissues and cells surrounding the injection site enhances endocytosis and improves the delivery of biofunctional substances into cells. Based on the above mechanism, it is considered that the higher the injection rate within the above range, the more preferable it is. When the injection rate is below the above upper limit, damage to cells and tissues can be suppressed.

[0073] In the present disclosure, the injection speed refers to the speed of the solution as it is ejected from the injection hole, and can be calculated, for example, by dividing the ejected volume by the time required from the start to the end of injection. The time required from the start to the end of injection can be measured, for example, by capturing images of the solution being ejected from the injection hole using an imaging device such as a high-speed camera. The injection speed can be adjusted to fall within the above range by adjusting the injection energy depending on the shape and material of the injection part, as well as the volume and viscosity of the solution.

[0074] <Injection Target> The biological species of the injection target that can be injected with the injector according to this embodiment are not particularly limited, but include mammals, such as humans, mice, rats, guinea pigs, hamsters, cows, goats, sheep, pigs, monkeys, dogs, and cats. Mammals other than humans are also possible. The injection target can be, but is not limited to, the interior of a living body. The term "interior of a living body" refers to a part of the living body that is not the outer surface, and may be the surface of an organ inside the living body, the interior of an organ, or a space such as a body cavity. Specifically, the injection target is preferably one or more selected from the group consisting of a joint cavity, a spleen, an eyeball, skin, muscle, bone, cartilage, bone marrow, ligament, brain, spinal cord, lung, liver, heart, kidney, pancreas, gallbladder, digestive tract, bladder, reproductive organs, lymph nodes, lymphatic network, and blood vessels, tumors occurring in any one of these, and mucosa and connective tissue associated with any one of these. Reproductive organs include testes and ovaries. Among these, one or more selected from the group consisting of articular cavity, spleen, testis, and liver are preferred.

[0075] When the injection target is one or more selected from the group consisting of the spleen, the testis, and the liver, the lower limit of the injection speed of the injector according to this embodiment may be 1 μL / s or more, or may be 10 μL / s or more. By injecting the solution into the injection target at an injection speed within this range, sufficient physiological activity can be obtained.

[0076] The amount of the solution to be injected into the injection subject can be appropriately set based on the content and type of the biofunctional substance, the injection subject, the physiological activity of the biofunctional substance in the injection subject into which the biofunctional substance has been injected, etc. Examples of the amount of the solution to be injected into the injection subject include 10 μL or more, 50 μL or more, or 100 μL or more. Examples of other amounts include 50 mL or less, 10 mL or less, and 5 mL or less. Examples of such amounts include 10 μL to 50 mL, 50 μL to 10 mL, and 100 μL to 5 mL.

[0077] The time required to inject the solution into the injection target is not particularly limited as long as it is a time that allows the injection amount of solution to be injected at the injection speed, and examples thereof include 0.005 seconds or more, 0.01 seconds or more, or 0.1 seconds or more. Other examples include 500 seconds or less, 100 seconds or less, and 10 seconds or less. That is, examples include 0.005 to 500 seconds, 0.01 to 100 seconds, and 0.1 to 10 seconds.

[0078] The present disclosure will be specifically described below with reference to examples, but the present disclosure is not limited to the aspects of the following examples.

[0079] (Animals) SD rats (8 weeks old, male, SLC) or ICR mice (8 weeks old, male, SLC) were used. All surgical procedures and syringe or device administration were performed under isoflurane (Pfizer) maintenance anesthesia or triple-dose anesthesia using a gas anesthesia device (Nacrobit-E, Natsume Seisakusho). All animal experiments were approved by the Animal Experiment Review Committee of the Natural Materials Research Institute Co., Ltd. (Kawasaki City) or the Animal Reproduction Research Institute (Kasumigaura City), where the experiments were conducted.

[0080] (Injection of Solution) For administration to the knee joints of rats, the hair of both left and right knee joints was shaved, and under isoflurane anesthesia, the needle tip was inserted 5 mm below the midline patella and 5 mm deep, aiming at the upper tibia epiphysis, to administer the luciferase (Luc) expression plasmid pGL4 (hereinafter sometimes referred to as pLuc). pGL4 was pre-diluted to 1 mg / mL with PBS. For administration to the spleen, testis, or liver of mice, the hair of the left ventral region, the scrotal area, or the central abdominal region was shaved under triple anesthesia, and the organs to be administered were exposed by laparotomy under anesthesia, and pLuc was injected. After confirming that there was no bleeding from the administration site, the muscle and skin at the incision site were each ligated and sutured to close the abdomen.

[0081] (Injector) The injectors used were an insulin syringe with a 30G needle (BD), a Hamilton syringe (Luer lock type, syringe capacity 50-50,000 μL, Hamilton) equipped with a 30G needle (disposable needle, No. 30 Dentronics needle, 0.3 x 12 mm, Dentronics), or a jet injector (pNFI, see Figure 1) equipped with or without a 30G needle. For manual administration with the 30G Hamilton syringe, the plunger was slowly depressed over approximately 1 second (approximately 30 μL / s) to administer the drug. For syringe pump administration with the 30G Hamilton syringe, the syringe pump's administration rate program (0.25-83.3 μL / s) was used. Meanwhile, the jet injector used ZPP as the ignition charge and GG (containing 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate) as the gas generating agent, and the solution was administered using these. The injection speed of the jet injector was measured by the test described below. As shown in FIG. 2 , the injection needle 4 was fixed to the tip of the nozzle portion 112 of the jet injector with a metal fixing jig 5. Hereinafter, for example, a jet injector equipped with 35 mg of ZPP and 40 mg of GG will be referred to as "pNFI-35 / 40," and a jet injector equipped with a 30G injection needle will be referred to as "30G-pNFI-35 / 40."

[0082] (Organ Sample Collection) Dissection and organ sample collection were performed after cervical dislocation of animals under isoflurane anesthesia and confirming death by carotid artery exsanguination. Furthermore, if necessary, a triple-anesthesia mixture (medetomidine: 0.3 mg / kg, midazolam: 4 mg / kg, butorphanol: 5 mg / kg per mouse body weight) was intraperitoneally administered, and the same procedures as those under isoflurane anesthesia were performed. For samples administered to the knee joint, skin and excess muscle were removed with scissors, and the lower limbs were detached from the hip joint. The samples were collected individually in 15 mL tubes and frozen. On the day of Luc activity measurement, the frozen samples were thawed, and the knee joint, skin, knee ligament, and synovium were collected. The collection site for the joint samples was previously identified by histological analysis of the rat joint to identify appropriate collection sites for Luc activity measurement. Specifically, excess muscle was removed from the lower limbs, and the areas near the lower end of the femur and the upper end of the tibia were physically crushed with forceps to remove bone marrow components, which served as the collection site. The collection site included at least cartilage, synovium, cruciate ligaments, and joint capsules. For samples administered to the spleen or testis, the entire organ was collected as a single specimen and frozen at -80°C. The head and tail of the epididymis, which are attached to the testis, were carefully separated from the testis and frozen. For the liver, a 1 cm square (approximately 3 mm thick) was collected from the center of the administration site and frozen at -80°C.

[0083] (Luc activity measurement) A Luc-assay kit (Promega) was used to measure Luc activity. 1 mL of the included passive lysis buffer was added to rat knee joint specimens, 1 mL to mouse spleen specimens and mouse testis specimens, 0.3 mL each to mouse epididymal caput and tail specimens, and 0.5 mL to mouse liver specimens, and the specimens were finely cut with scissors. The specimens were then frozen in a freezer, left to thaw at room temperature, and centrifuged at 10,000 x g for 10 minutes at 16°C. According to the protocol, 20 μL of the supernatant and 100 μL of substrate solution were mixed in a Lumitube (Kikkoman Corporation), and the relative fluorescence units (RFU) were quickly measured using a Lumitester C-110 (Kikkoman Corporation). The RFU measurement value was multiplied by the correction value to calculate the RFU per total amount of passive lysis buffer added, and this was taken as the total RFU per tissue specimen.

[0084] Test Example 1 Using a 2.5 mL Hamilton syringe with a 30G needle (administration rate 15 μL / s or 0.5 μL / s, n=2 for each), 30G-pNFI-25 / 40 (n=4), or 30G-pNFI-35 / 40 (n=4), 30 μL of pLuc at a concentration of 1 mg / mL was administered into the knee joint of rats. Hereinafter, these groups are referred to as the Syr group, 25 / 40 Device group, and 35 / 40 Device group, respectively. 24 hours (Day 1) and 10 days (Day 10) after administration, the lower limbs were collected, and Luc activity in the knee joint was measured. The results, which compare the mean value + SD, are shown in Figure 5. Within the Syr group, Luc activity (total RFU) was 14,150 and 34,350 on Day 1 at 15 μL / s, 11,550 and 11,800 on Day 1 at 0.5 μL / s, 400 and 400 on Day 10 at 15 μL / s, and 1,450 and 400 on Day 10 at 0.5 μL / s, which were similar, so the samples from each collection time point were combined to form the Syr group (n=4).

[0085] On Day 1, the Luc activity of the 25 / 40 Device group was 31.1 times higher than that of the Syr group, and that of the 35 / 40 Device group was 42.3 times higher (Figure 5). On Day 10, the Luc activity of the 25 / 40 Device group was 32.8 times higher than that of the Syr group, and that of the 35 / 40 Device group was 184.3 times higher (Figure 5). In both groups, a decrease in Luc activity was observed on Day 10 compared to Day 1, but the decrease in the 35 / 40 Device group was less than that of the Syr and 25 / 40 Device groups. On Day 1 and Day 10, no significant difference was observed between the 25 / 40 Device group and the 35 / 40 Device group, but a tendency for the Luc activity to be higher in the 35 / 40 Device group was observed.

[0086] [Test Example 2] 30 μL of pLuc at a concentration of 1 mg / mL was administered into the knee joint of rats using a 25 mL Hamilton syringe with a 30G needle (administration rate 0.25 μL / s, n = 4 or 83.3 μL / s, n = 8), or 30G-pNFI-35 / 40 (n = 8). Hereinafter, these groups are referred to as the 0.25 μL / s administration rate group, the 83.3 μL / s administration rate group, and the 30G-pNFI-35 / 40 group, respectively. The injection rate of the 30G-pNFI-35 / 40 group is 692.8 μL / s, as shown in Test Example 4 below. 24 hours after administration, the lower limbs were collected, and Luc activity in the knee joint was measured. The results of comparing the mean value + SD are shown in Figure 6.

[0087] Compared to the 0.25 μL / s administration rate group, the Luc activity was 3.9 times higher in the 83.3 μL / s administration rate group and 105 times higher in the 30G-pNFI-35 / 40 group. The Luc activity of the 30G-pNFI-35 / 40 group was significantly higher than that of the 0.25 μL / s group and the 83.3 μL / s group.

[0088] Test Example 3: 30 μL of pLuc at a concentration of 1 mg / mL was administered into the knee joint of rats using 30G-pNFI-35 / 40 (n = 6), 30G-pNFI-55 / 40 (n = 6), or 30G-pNFI-75 / 40 (n = 6). Hereinafter, these groups are referred to as the 35 / 40 group, 55 / 40 group, and 75 / 40 group, respectively. 24 hours after administration, the lower limbs were harvested and Luc activity in the knee joint was measured. The results of a comparison of the mean value + SD are shown in Figure 7. No significant differences were observed between the 35 / 40 group, 55 / 40 group, and 75 / 40 group in intra-articular Luc activity.

[0089] Test Example 4: The injection rate was measured using 30G-pNFI-25 / 40, 30G-pNFI-35 / 40, 30G-pNFI-55 / 40, 30G-pNFI-75 / 40, or pNFI-35 / 40. The tip of the syringe was immersed in PBS, and 30 μL of a 1% aqueous malachite green solution was injected. The time required from the start to the end of injection was measured using high-speed camera analysis, and the injection rate was calculated by dividing 30 μL by that time. The results are shown in FIG.

[0090] The injection rate of the needled 30G-pNFI was significantly higher than the maximum syringe pump speed of 83.3 μL / s under all conditions, reaching 398.4 μL / s or higher. The injection rate also increased in a dose-dependent manner with ZPP.

[0091] Test Example 5 pLuc was administered to the spleen of mice at a concentration of 1 mg / mL using an insulin syringe with a 30G needle (dosage volume 30 μL, administration rate approximately 30 μL / s, n=4) or 30G-pNFI-35 / 40 (dosage volume 3 μL: n=4, 10 μL: n=4, 30 μL: n=3). 24 hours after administration, the spleen was collected and Luc activity was measured. The results, which compare the mean value + SD, are shown in Figure 9.

[0092] When 30G-pNFI-35 / 40 was used, Luc activity increased in a dose-dependent manner. Furthermore, when the same amount of pLuc was administered using 30G-pNFI-35 / 40, Luc activity increased approximately three-fold compared to when an insulin syringe with a 30G needle was used.

[0093] Test Example 6 Using a Hamilton syringe with a 30G needle (administration rate 0.25 μL / s, n=4) or 30G-pNFI-35 / 40 (n=4), 30 μL of pLuc at a concentration of 0.3, 1, or 3 mg / mL was administered to the spleen of a mouse. 24 hours after administration, the spleen was collected and Luc activity was measured. The results of comparing the mean value + SD are shown in FIG. 10.

[0094] When 30G-pNFI-35 / 40 was used, the Luc activity of the 1 mg / mL administration group was 3.6 times that of the 0.3 mg / mL administration group, and the Luc activity of the 3 mg / mL administration group was similar to that of the 1 mg / mL administration group. A similar trend was also observed when a 30G needle-equipped Hamilton syringe (30G-Syr / pump) was used. When comparing 30G-pNFI-35 / 40 and a 30G needle-equipped Hamilton syringe with the same pLuc concentration, 30G-pNFI-35 / 40 showed approximately 50 times the Luc activity of a 30G needle-equipped Hamilton syringe at any pLuc concentration.

[0095] Test Example 7 Using a Hamilton syringe with a 30G needle (administration rate of 1 μL / s or 10 μL / s, n=4 for each), 30G-pNFI-25 / 40 (n=4), or 30G-pNFI-35 / 40 (n=4), 40 μL of pLuc at a concentration of 1 mg / mL was administered to the spleen of a mouse. 24 hours after administration, the spleen was collected and Luc activity was measured. The results of comparing the mean value + SD are shown in FIG. 11.

[0096] When 30G-pNFI was used, Luc activity increased in an administration rate (amount of ZPP explosive) dependent manner. Furthermore, when a Hamilton syringe with a 30G needle (30G-Syr / pump) was used, Luc activity increased in an administration rate dependent manner.

[0097] Test Example 8: 30 μL of pLuc at a concentration of 1 mg / mL was administered to the testes of mice using a Hamilton syringe with a 30G needle (administration rate of 1 μL / s or 10 μL / s, n=4 for each), 30G-pNFI-25 / 40 (n=4), or 30G-pNFI-35 / 40 (n=4). 24 hours after administration, the testes, caput epididymis, and cauda epididymis were collected, and Luc activity was measured. The results of comparing the mean value + SD for Luc activity in the testes, caput epididymis, and cauda epididymis are shown in Figures 12, 13, and 14, respectively.

[0098] The drug was administered at an administration rate of 1 μL / s or 10 μL / s using a Hamilton syringe with a 30G needle, resulting in an RFU value of 3.0 ± 1.2 × 10 in the testes. ５ , 8.2±1.9×10 ５ When 30G-pNFI-25 / 40 and 30G-pNFI-35 / 40 were used, the RFU values ​​in the testis were 6.1±3.7×10 ７ , 7.3±3.6×10 ７ and were of the same order of magnitude.

[0099] Test Example 9: 10 μL of pLuc at a concentration of 1 mg / mL was administered into the left lateral lobe of the liver of a mouse using a Hamilton syringe with a 30G needle (administration rate of 1 μL / s or 10 μL / s) or 30G-pNFI-25 / 40. 24 hours after administration, the liver was harvested and Luc activity was measured. The results of comparing the mean value + SD (n=4) are shown in Figure 15.

[0100] Luc activity increased in the following order: administration at an administration rate of 1 μL / s using a Hamilton syringe with a 30G needle, administration at an administration rate of 10 μL / s using a Hamilton syringe with a 30G needle, and administration using 30G-pNFI-25 / 40. These results suggest that Luc activity increased in an administration rate-dependent manner.

Claims

1. An injector for injecting a solution containing a bioactive substance into a target, A container for containing a solution containing the aforementioned bioactive substance, A pressurizing unit that pressurizes the solution containing the bioactive substance during operation, An injection unit that can be inserted into the injection target, having an inlet hole through which the solution containing the bioactive functional substance can flow in from the containment unit when the solution containing the bioactive functional substance is pressurized by the pressurization unit, and an outlet hole through which the flowed-in solution containing the bioactive functional substance can be injected into the injection target, Equipped with, The injection rate of the solution containing the aforementioned bioactive substance exceeds 83.3 μL / s. syringe.

2. The injector according to claim 1, wherein the injection rate of the solution containing the bioactive substance is 200 μL / s or more.

3. The injector according to claim 1, wherein the inner diameter of the injection section is 0.41 mm or less.

4. The injector according to claim 1, wherein the outer diameter of the injection section is 0.72 mm or less.

5. The injector according to claim 1, wherein the injection part is a hypodermic needle.

6. The injector according to claim 1, wherein the in vivo functional substance is one or more selected from the group consisting of nucleic acids, peptides, proteins, and low molecular weight compounds.

7. The injector according to any one of claims 1 to 6, wherein the target of injection is one or more selected from the group consisting of joint cavities, spleen, eyeballs, skin, muscles, bones, cartilage, bone marrow, ligaments, brain, spinal cord, lungs, liver, heart, kidneys, pancreas, gallbladder, digestive tract, bladder, reproductive organs, lymph nodes, lymphatic network, and blood vessels, tumors occurring in any one of these, and mucous membranes and connective tissue associated with any one of these.

8. A method of injecting a solution containing the bioactive substance into the target of injection using the injector described in claim 1.