Injector and method for injecting solution into intended site using injector

Abstract

The present invention addresses the problem of providing at least an injector for injection into fragile tissue. The problem is solved by an injector for injecting a solution containing a biologically active substance into an intended site, the injector comprising: a container part for containing the solution; a nozzle part in communication with the container part, the nozzle part having an injection port for injecting the solution toward the site; and a pressurization part for pressurizing the solution contained in the container part, and thus injecting the solution toward the site from the injection port during operation. A value obtained by dividing the kinetic energy of the injected solution by the area of the injection port is 40 mJ / mm2 or more and 1500 mJ / mm2 or less.

Description

Injector and method for injecting a solution into a subject using said injector

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

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

[0003] Among these, needle-free syringes mainly employ a configuration in which pressure is applied to a chamber containing the injection solution using pressurized gas, a spring, or electromagnetic force to eject the injection component. For example, a configuration has been adopted in which multiple nozzle holes are formed inside the syringe body, and pistons that are driven during ejection are positioned corresponding to each nozzle hole (Patent Document 1). This configuration aims to simultaneously eject the injection solution from multiple nozzle holes, thereby achieving uniform injection into the subject. Furthermore, a plasmid containing a luciferase gene was injected into rats, achieving highly efficient cell transfer. Another type of needle-free syringe uses pressurized gas as the injection power source for the injection solution. For example, a pressurization configuration has been exemplified in which a large amount of pressure is applied instantaneously at the beginning of injection, followed by a gradual reduction in the pressure over 40 to 50 msec (Patent Document 2).

[0004] In the above-described jet injection method, subcutaneous and intradermal injections are mainly being considered (Patent Document 1).

[0005] Patent Document 1: Japanese Patent Application Publication No. 2004-358234 Patent Document 2: U.S. Patent Application Publication No. 2005 / 0010168

[0006] The present inventors have investigated jet injection into fragile tissues such as the liver and spleen, and have found that when a needleless syringe is pressed against a target to inject a solution, the target may be penetrated. The present disclosure addresses at least the following: to provide an injector for injecting fragile tissues; and to provide a method for injecting a solution into a target using the injector.

[0007] The present inventors have conducted extensive research to solve the above problems and have found that the above problems can be solved by using a specific injector.

[0008] That is, the gist of the present disclosure is as follows: [1] An injector for injecting a solution containing a biofunctional substance into a target, comprising: a storage section for storing the solution; a nozzle section communicating with the storage section and having an ejection port for ejecting the solution toward the target; and a pressurizing section that, when activated, pressurizes the solution stored in the storage section to eject the solution from the ejection port toward the target, wherein the kinetic energy of the ejected solution divided by the area of ​​the ejection port is 40 mJ / mm ２ 1500mJ / mm or more ２ [2] The injector according to [1], wherein the volume of the solution is 0.3 μL or more and 4.0 μL or less. [3] The area of ​​the injection port is 0.001 mm ２ 1.25mm or more ２ [4] The syringe according to [1] or [2], wherein the area of ​​the injection port is 0.001 mm or less. ２ More than 0.02 mm ２ The injector according to any one of [1] to [3], wherein the biofunctional substance is one or more selected from the group consisting of nucleic acids, peptides, proteins, sugars, and low-molecular-weight compounds, as well as complexes thereof. [6] The injector according to any one of [1] to [5], wherein the target is one or more selected from the group consisting of fat, skeletal muscle, ligament, aorta, superior vena cava, brain, eyeball, tympanic membrane, inner ear, nerve, trachea, bronchi, lung, esophagus, stomach, liver, kidney, adrenal gland, spleen, gallbladder, pancreas, large intestine, small intestine, duodenum, cecum, appendix, rectum, omentum, ureter, bone marrow, lymph nodes, lymphatic network, thyroid, sebaceous gland, sweat gland, salivary gland, thymus, mammary gland, prostate, fallopian tube, ovary, uterus, cervix, testis, vas deferens, seminal vesicle, mucosa and connective tissue associated with any one of these, and tumors occurring in any one of these. [7] A method for injecting a solution containing the biofunctional substance into the subject using the injector according to any one of [1] to [6].

[0009] The present disclosure may provide at least an injector for injecting fragile tissue as a target, and may also provide a method for injecting a solution into a target using the injector.

[0010] 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 an embodiment of the present disclosure. Fig. 4 is a graph showing the luminescence (RFU / μL) when various liquid volumes of pLuc were introduced into mouse liver or spleen. n=4, means±SD.

[0011] 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.

[0012] One embodiment of the present disclosure is an injector for injecting a solution containing a biofunctional substance into a target, the injector comprising: a storage section for storing the solution; a nozzle section communicating with the storage section and having an ejection port for ejecting the solution toward the target; and a pressurizing section that, when activated, pressurizes the solution stored in the storage section to eject the solution from the ejection port toward the target, wherein the kinetic energy of the ejected solution divided by the area of ​​the ejection port is 40 mJ / mm ２ 1500mJ / mm or more ２ Below is the injector.

[0013] [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.

[0014] The biofunctional substance is preferably one or more selected from the group consisting of nucleic acids, peptides, proteins, sugars, low molecular weight compounds, and complexes thereof.

[0015] 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).

[0016] 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.

[0017] 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.

[0018] A complex refers to two or more substances that fall into the category of nucleic acids, peptides, proteins, sugars, or low molecular weight compounds, which are bound together by covalent bonds, ionic bonds, hydrogen bonds, hydrophobic interactions, or the like.

[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, when the protein is luciferase, the 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 viral vectors or lipid nanoparticles may not be used. When viral vectors or lipid nanoparticles are not used, the possibility of inducing side reactions such as anaphylaxis in the 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, the physiological activity exhibited by the biofunctional substance in the subject into which the biofunctional substance is injected, etc. Examples include 0.0001 mg / mL or more, 0.001 mg / mL or more, and 0.01 mg / mL or more. Also included are 1000 mg / mL or less and 100 mg / mL or less. That is, examples include 0.0001 to 1000 mg / mL, 0.001 to 100 mg / mL, and 0.01 to 100 mg / mL.

[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 pH of the solution is not particularly limited as long as, when the solution is injected into a subject, the biofunctional substance exhibits physiological activity in the subject, is present stably, and does not have any adverse effects such as destroying the subject.

[0030] [Subject] The subject in this embodiment may be, for example, one or more selected from the group consisting of cells, cell sheets, cell masses, tissues, organs (skin, organs, etc.), organ systems, individuals (living organisms), etc. Furthermore, it may be one or more selected from the group consisting of tissues, organs (skin, organs, etc.), organ systems, individuals (living organisms), etc. It may be any system, including in vitro systems, in vivo systems, and ex vivo systems. The cell mass may be a cell mass obtained by three-dimensional culture, and the organ (skin, organ, etc.) may be an organoid.

[0031] Furthermore, when injected into the subject, it may be injected into a lower layer contained therein. That is, for example, when an individual (living body) is the subject, it may be injected into a tissue contained in the individual (living body), or into a cell contained in the individual (living body), or into both. Furthermore, when a tissue is the subject, it may be injected into a cell contained in the tissue, or into the extracellular matrix contained in the tissue, or into both. Furthermore, when a cell is the subject, it may be injected into the cytoplasm of the cell, or into the cell nucleus of the cell, or into both the cytoplasm and the cell nucleus of the cell.

[0032] Furthermore, when the subject in this embodiment is one or more selected from the group consisting of cells, cell sheets, cell clumps, tissues, organs (skin, organs, etc.), and organ systems, it may be one or more selected from the group consisting of cells, cell sheets, cell clumps, tissues, organs (skin, organs, etc.), and organ systems in a state where they are present in an individual (living organism), or it may be one or more selected from the group consisting of cells, cell sheets, cell clumps, tissues, organs (skin, organs, etc.), and organ systems in a state where they are not present in an individual (living organism) (for example, a state where they have been extracted or separated from an individual (living organism) or a state where they have been produced outside an individual (living organism)).

[0033] Furthermore, the subject in this embodiment may be one or more selected from the group consisting of cells, cell sheets, cell masses, tissues, organs (skin, internal organs, etc.), and organ systems derived from stem cells such as iPS cells (induced pluripotent stem cells), and these may be in a state that exists in an individual (living organism) or in a state that does not exist in an individual (living organism) (for example, in a state that has been extracted or separated from an individual (living organism), or in a state that has been produced outside an individual (living organism)).

[0034] The individual (living body) is preferably a mammalian individual (living body). The mammal is not particularly limited, but includes humans and non-human mammals. Non-human mammals include mice, rats, guinea pigs, hamsters, cows, goats, sheep, pigs, monkeys, dogs, cats, etc.

[0035] The organ may be one or more selected from the group consisting of fat, skeletal muscle, ligament, aorta, superior vena cava, brain, eyeball, tympanic membrane, inner ear, nerve, trachea, bronchi, lung, esophagus, stomach, liver, kidney, adrenal gland, spleen, gallbladder, pancreas, large intestine, small intestine, duodenum, cecum, appendix, rectum, omentum, ureter, bone marrow, lymph node, lymphatic network, thyroid, sebaceous gland, sweat gland, salivary gland, thymus, mammary gland, prostate, fallopian tube, ovary, uterus, cervix, testis, vas deferens, seminal vesicle, mucosa and connective tissue associated with any one of these, and tumor occurring in any one of these. These organs are tissues that are more fragile than skin etc.

[0036] [Injector] As described above, the injector of this embodiment includes a storage section that stores the solution, a nozzle section that communicates with the storage section and has an ejection outlet for ejecting the solution toward the target, and a pressure section that, when activated, pressurizes the solution stored in the storage section, causing the solution to be ejected from the ejection outlet toward the target; and the solution is injected into the target by ejecting it from the ejection outlet of the nozzle section.

[0037] The injector according to this embodiment may include a predetermined structure, such as a catheter, for guiding the solution from the injector body to the target, for example, when the distance from the injector body to the target is large. Therefore, the injector according to this embodiment may or may not include such a predetermined structure.

[0038] In the injector according to this embodiment, the energy applied by the pressurizing unit to pressurize the solution can be applied in the form of energy application 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, explosives, or the like. Alternatively, the energy for pressurization may be generated electrically, such as energy generated by a piezoelectric element or an electromagnetic actuator driven by input power. Still another example is physical generation of the energy for pressurization. Examples include elastic energy generated by an elastic body and internal energy possessed by 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. The energy for pressurization may also be a composite energy that appropriately combines internal energies such as combustion energy, electrical energy, and elastic energy.

[0039] 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.

[0040] Hereinafter, with reference to the drawings, a syringe 100 shown in FIGS. 1 to 3 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 "distal side" and "base end side" are used to describe the relative positional relationship in the longitudinal direction of the syringe 100. The "distal 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 end side" refers to the side of the syringe 100 opposite the outlet hole 4b in the longitudinal direction.

[0041] 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 detachably 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.

[0042] [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 uses the combustion energy of explosives to pressurize a solution containing a biofunctional substance (hereinafter, sometimes simply referred to as the "solution"), thereby injecting the solution from the injection hole 11c. The jet injector 1 according to this embodiment is configured as a needleless syringe that can perform injections independently without using a syringe needle. A needleless syringe injects the solution into a target from the syringe body without performing injection through a predetermined structure inserted into the target. Specifically, the syringe 100 shown in FIG. 3 is referred to as a needleless syringe. However, the jet injector 1 does not necessarily have to be a needleless syringe. In the following description, the syringe 100 including the injection needle 4 and the fixing jig 5 as shown in FIG. 1 may be referred to as a needle syringe.

[0043] [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.

[0044] [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.

[0045] 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.

[0046] [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.

[0047] 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 for the container holder 12 include stainless steel, copper, aluminum, iron, titanium, and titanium alloys.

[0048] 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.

[0049] 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.

[0050] [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.

[0051] [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.

[0052] [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.

[0053] [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.

[0054] [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.

[0055] 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.

[0056] 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.

[0057] [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.

[0058] 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.

[0059] 1, the injection needle 4 is attached to the nozzle portion 112 of the jet injector 1, and is configured to include a base portion 41 and a needle tube 42. The injection needle 4 is an example of an "ejection portion" 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 a target.

[0060] 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.

[0061] 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.

[0062] The needle tube 42 is inserted into an injection target and injects a solution containing a biofunctional substance into the 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 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 target.

[0063] From the viewpoint of suppressing tissue damage to the target, it is preferable that the injection needle 4 (more specifically, the needle tube 42 inserted into the 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. In this case, the inner diameter d1 is preferably 1.5 mm or less, and more preferably 0.41 mm or less. The outer diameter d2 is preferably 1.7 mm or less, and more 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 the above. Furthermore, the length of the needle tube 42 can be appropriately set depending on the target, and can be, for example, a value selected from the range of 1 mm to 180 mm.

[0064] The material of the needle tube 42 is not particularly limited, but may be, for example, stainless steel. Metal materials other than stainless steel may also be used, such as aluminum, aluminum alloys, titanium, and titanium alloys. The needle tube 42 may also be made of a resin material.

[0065] As described above, the internal space of the base 41 and the internal space of the needle tube 42 are connected to 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 toward the subject.

[0066] 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.

[0067] [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 .

[0068] 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.

[0069] [Operation of the Injector] Injection of a solution into a target using the syringe 100 shown in FIG. 1 is performed by operating the syringe 100 with the needle tube 42 of the injection needle 4 inserted into the target. Furthermore, as shown in FIG. 3 , when the syringe 100 is used as a needleless syringe, the injection is performed by operating the syringe 100 with the ejection hole 11c abutting against the 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 drawing the solution from outside the syringe 100 through the exit hole 4b or the ejection hole 11c of the injection needle 4. When the storage portion and the ejection 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.

[0070] The storage section may contain a gas in addition to the solution containing the biofunctional substance. In this case, the solution is injected into the subject while the gas dissolves in the solution as the pressure is increased. After injection into the subject, a portion of the gas dissolved in the solution returns to a gas state as the pressure is reduced, generating countless microbubbles, and it is presumed that the shearing action of the bubbles can form multiple voids in the subject. The voids typically have a maximum diameter of approximately 10 μm to approximately 1000 μm, but larger voids may also form when multiple voids are connected. The formation of voids can be confirmed using a stereomicroscope or the like. The voids can be used, for example, as flow paths or reservoirs for any liquid or gas.

[0071] The gas that can be contained in the container is not particularly limited, but air can be exemplified. The ratio of the volume of the gas to the total volume of the solution and the gas is not particularly limited, but is preferably 30% or more, more preferably more than 60%. Also, it is preferably less than 100%, more preferably 80% or less. That is, preferred ranges for the volume ratio of the gas include 30% or more and less than 100%, 30% or more and 80% or less, and more than 60% and 80% or less.

[0072] 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. When using the needleless syringe shown in FIG. 3, the solution can be injected into the subject.

[0073] 1 and 2, when the injection needle 4 and fixing jig 5 are used, the solution injected from the injection 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 injected into the target from the outlet hole 4b. In this manner, the operation of the syringe 100 is completed.

[0074] In this embodiment, injecting a solution into a target using an injector may be referred to as jet injection into the target. In this disclosure, "jet injection" refers to an injection in which a solution is ejected from an injection port toward a target, thereby forming a through-hole that penetrates the boundary between the inside and outside of the target, and generating a high-pressure ultra-microfluidic stream capable of injecting the solution into the target through the through-hole. For example, if the target is a mammalian individual (living body), this refers to an injection in which a high-pressure ultra-microfluidic stream is generated that can penetrate the outer skin, etc., of the mammalian individual (living body).

[0075] In this embodiment, the value obtained by dividing the kinetic energy of the ejected solution by the area of ​​the ejection port is 40 mJ / mm ２1500mJ / mm or more ２ This value represents the pressure exerted on the target at the time of ejection. The value obtained by dividing the kinetic energy of the ejected solution by the area of ​​the ejection port is 40 mJ / mm ２ More than 1000mJ / mm ２ Preferably, 40 mJ / mm or less ２ 300mJ / mm or more ２ More preferably, 40 mJ / mm or less ２ 100mJ / mm or more ２ The following is particularly preferable: When the value obtained by dividing the kinetic energy of the ejected solution by the area of ​​the ejection port is within the above range, the ejected solution can be jet injected into the target while preventing the ejected solution from penetrating the target.

[0076] The kinetic energy of the solution is 1 / 2 x m x v, where m (kg) is the mass of the solution and v (m / s) is the injection speed. ２ In the present disclosure, the injection speed is the speed of the solution when it is ejected from the ejection port. The injection speed can be calculated by, for example, capturing images of the solution being ejected from the ejection port using an imaging device such as a high-speed camera at 20,000 fps, and dividing the distance traveled by the tip of the ejected solution between two consecutive images by the imaging interval of 50 μs. The injection speed can be set within the above range by adjusting the injection energy depending on the shape and material of the nozzle portion, the volume and viscosity of the solution, etc.

[0077] In this disclosure, the term "ejection port" refers to the opening through which the solution is ejected from the integrally assembled syringe. In the syringe 100, when the syringe 100 is used as a needleless syringe, the ejection port is the ejection hole 11c, and when the syringe 100 is used as a needle syringe, the ejection port is the exit hole 4b.

[0078] The area of ​​the injection port is 0.001 mm ２ 1.25mm or more ２ Preferably, 0.001 mm or less ２ More than 0.1 mm ２ More preferably, 0.001 mm or less ２ More than 0.02 mm ２The following is particularly preferable: When the area of ​​the injection port is within the above range, jet injection into the target is easy.

[0079] The syringe according to this embodiment can typically inject the solution at an injection speed exceeding 83.3 μL / s. The lower limit of the injection speed is preferably 200 μL / s or more, more preferably 250 μL / s or more, even more preferably 300 μL / s or more, even more preferably 350 μL / s or more, and most preferably 400 μL / s or more. The upper limit of the injection speed is preferably 5000 μL / s or less, more preferably 1000 μL / s or less, and even more preferably 700 μL / s or less. That is, preferred ranges of the injection speed include greater than 83.3 μL / s and 5000 μL / s or less, 200 μL / s or more to 1000 μL / s or less, 250 μL / s or more to 700 μL / s or less, 300 μL / s or more to 700 μL / s or less, and 350 μL / s or more to 700 μL / s or less. When the injection speed is within the above range, jet injection into the target is easy.

[0080] The lower limit of the injection speed of the syringe according to this embodiment is preferably 40 m / s or more, more preferably 45 m / s or more. The upper limit of the injection speed is preferably 100 m / s or less, more preferably 90 m / s or less. That is, preferred ranges of the injection speed include 40 m / s or more and 100 m / s or less, and 45 m / s or more and 90 m / s or less.

[0081] The volume of the solution is preferably 0.3 μL to 4.0 μL, more preferably 0.3 μL to 1.5 μL, and even more preferably 0.3 μL to 1.0 μL. When the volume of the solution is within the above range, it is easy to prevent the injected solution from penetrating the target.

[0082] The time required to inject the solution into the subject is not particularly limited as long as it is a time that allows the injection of the injection amount of solution at the injection speed, and examples thereof include 0.001 seconds or more, 0.005 seconds or more, or 0.01 seconds or more. Also examples thereof include 100 seconds or less, 50 seconds or less, and 10 seconds or less. That is, examples thereof include 0.001 to 100 seconds, 0.005 to 50 seconds, and 0.01 to 10 seconds.

[0083] By using the injector according to this embodiment, a solution containing a biofunctional substance can be injected into a target. That is, one embodiment of the present disclosure is a method for injecting a solution containing the biofunctional substance into the target using the injector.

[0084] The above method may include the steps of: storing the solution in the storage unit; pressurizing the solution stored in the storage unit; and injecting the solution into the target. For details of the injection target, the method of storing the solution in the storage unit, the method of pressurizing the solution stored in the storage unit, and the method of injecting the solution into the target, please refer to the description of the injector.

[0085] 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.

[0086] [Experiment 1: Investigation of Injection Conditions] For the injection experiment, an Actranza® Lab (for intradermal administration to mice, corresponding to the needleless syringe shown in Figure 3) equipped with a rated 20 μL container was used. The Actranza Lab was filled with 1% (w / v) malachite green (specific gravity: 1.0018) at the volume shown in Table 1, and the solution was injected into a transparent plastic tube marked with 1 mm intervals by operating the syringe. The Actranza Lab 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 generant. The injection was recorded using a high-speed camera at 20,000 fps. The injection speed was calculated by dividing the distance traveled by the tip of the injected solution between the first and second frames, in which the solution was observed ejecting from the nozzle tip, by the 50 μs imaging interval. Furthermore, the kinetic energy was calculated assuming the specific gravity of the solution to be 1. Next, the kinetic energy was multiplied by the opening area of ​​the injection port of Actranza Lab, which is 7.85 × 10 －３ mm ２ The energy given to the target was calculated by dividing by . Table 1 shows the liquid volume, injection speed, kinetic energy, and kinetic energy / opening area.

[0087]

[0088] Experiment 2: Investigation of mouse liver or spleen tissue penetration. Eight-week-old ICR mice (Japan SLC Co., Ltd., male) were intraperitoneally administered a triple anesthesia mixture (medetomidine: 0.3 mg / kg, midazolam: 4 mg / kg, butorphanol: 5 mg / kg, dose per mouse body weight). After confirming that the mice showed no avoidance reaction when their lower limbs were pinched with tweezers, the mice were abdominally opened to expose the liver or spleen. 1% (w / v) malachite green was administered to the exposed liver or spleen using Actranza Lab in the volume shown in Table 2. The ignition charge and gas generant were the same as in Experiment 1. If dye diffusion was confirmed immediately after administration, it was determined that the injection had penetrated the tissue. The results are shown in Table 2. Out of three administrations, no tissue penetration was observed in any of the cases (A), no tissue penetration was observed at least once (B), and tissue penetration was observed all three times (C).

[0089]

[0090] As shown in Table 2, the value of kinetic energy / opening area is 40 mJ / mm ２ 1500mJ / mm or more ２ If the following conditions are met, tissue penetration can be suppressed.

[0091] [Experiment 3: Gene Expression in Mouse Liver or Spleen] The container of the Actranza Lab was filled with 0.3 μL, 1.3 μL, or 5.3 μL of luciferase (Luc) expression plasmid pGL4 (hereinafter sometimes referred to as pLuc). pGL4 was pre-diluted to 1 μg / μL with PBS. The ignition charge and gas generant were the same as those in Experiment 1. A triple-anesthesia mixture was administered intraperitoneally to the mice. After confirming that there was no avoidance reaction when the lower limbs were pinched with tweezers, the mice were abdominally opened and the liver or spleen was exposed. pLuc was administered by pressing the tip of the Actranza Lab against the target organ and operating it. The abdomen was then closed by ligating and suturing the muscles and skin at the incision site.

[0092] After 24 hours, mice were anesthetized and cervically dislocated. After confirming death by exsanguination of the carotid artery, the target organs were removed. Luc activity was measured using a Luc-assay kit (Promega). 0.5-1 mL of the included passive lysis buffer was added, and the tissue was crushed with scissors for approximately 2-3 minutes. The tissue was then frozen in a freezer, left at room temperature to thaw, and centrifuged at 10,000 x g for 10 minutes at 16°C. Following the protocol, 20 μL of the supernatant and 100 μL of substrate solution were mixed in a Lumitester (Kikkoman), and the relative fluorescence units (RFU) were immediately measured using a Lumitester C-110 (Kikkoman). The RFU measurement value was multiplied by the correction value to calculate the RFU per total amount of passive lysis buffer added, which was taken as the total RFU per tissue specimen. Figure 4 shows the values ​​obtained by dividing the total RFU by the amount of solution administered.

[0093] As shown in FIG. 4, the administration conditions rated A in Experiment 2 had significantly higher gene expression efficiency than the conditions rated C.

[0094] REFERENCE SIGNS LIST 100 Syringe 1 Jet injector 10 Gas generating agent 11 Container 11a Storage space 11b Flow path 11c Injection hole 111 Main body 111a Threaded portion 112 Nozzle portion 12 Container holder 12a Threaded portion 12b Threaded portion 12c Threaded portion 13 Actuator 131 Ignition device 1311 Initiator 1312 Holding member 132 Piston 133 Plunger 14 Casing 14a Threaded portion 15 Combustion chamber 2 Housing 21 Switch 3 Battery 4 Syringe needle 4a Inlet hole 4b Outlet hole 4c Flow path 41 Base 411 Base main body 412 Flange portion 42 Needle tube 5 Fixing jig 51 Peripheral wall portion 51a Threaded portion 52 Lid wall portion 52a through hole

Claims

1. An injector for injecting a solution containing a biofunctional substance into a target, comprising: a container for containing the solution; a nozzle communicating with the container and having an ejection port for ejecting the solution toward the target; and a pressurizing unit for pressurizing the solution contained in the container when actuated, thereby ejecting the solution from the ejection port toward the target; and a value obtained by dividing the kinetic energy of the ejected solution by the area of ​​the ejection port is 40 mJ / mm. ２ 1500mJ / mm or more ２ Below is the injector.

2. The injector according to claim 1, wherein the volume of the solution is between 0.3 μL and 4.0 μL.

3. The area of ​​the injection port is 0.001 mm ２ 1.25mm or more ２ 2. The injector of claim 1, wherein:

4. The area of ​​the injection port is 0.001 mm ２ More than 0.02 mm ２ 2. The injector of claim 1, wherein:

5. The injector according to claim 1, wherein the biofunctional substance is one or more selected from the group consisting of nucleic acids, peptides, proteins, sugars, and low molecular weight compounds, as well as complexes thereof.

6. The injector of claim 1, wherein the target is one or more selected from the group consisting of fat, skeletal muscle, ligament, aorta, superior vena cava, brain, eye, tympanic membrane, inner ear, nerve, trachea, bronchi, lung, esophagus, stomach, liver, kidney, adrenal gland, spleen, gallbladder, pancreas, large intestine, small intestine, duodenum, cecum, appendix, rectum, omentum, ureter, bone marrow, lymph node, lymphatic network, thyroid, sebaceous gland, sweat gland, salivary gland, thymus, mammary gland, prostate, fallopian tube, ovary, uterus, cervix, testis, vas deferens, seminal vesicle, and mucosa and connective tissue associated with any one of these, and tumor occurring in any one of these.

7. A method for injecting a solution containing the biofunctional substance into the subject using the injector according to any one of claims 1 to 6.

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