Injector and method of injecting a solution into a subject using the injector

Abstract

The present application has an object to provide an injector that injects at least a fragile tissue. The object is achieved by an injector that injects a solution containing a substance functioning in a living body to a subject, the injector comprising: a housing that houses the solution; a nozzle portion that communicates with the housing and has a discharge port for discharging the solution to the subject; and a pressurizing portion that discharges the solution from the discharge port to the subject by pressurizing the solution housed in the housing at the time of operation, wherein a value obtained by dividing kinetic energy of the discharged solution by an area of the discharge port is 40 mJ / mm 2 or more and 1500 mJ / mm 2 or less.

Description

Technical Field

[0001] This disclosure relates to an injector and a method for injecting a solution into an object using the injector. Background Technology

[0002] As injectors for delivering medication to a target, there are needle-type injectors that inject via a needle and needle-free injectors that inject without a needle. In addition, catheters equipped with a needle and a drive source, and multi-hole needles are also used to deliver medication to a target.

[0003] In needle-free injectors, a configuration is sometimes employed that uses pressurized gas, a spring, or electromagnetic force to apply pressure to a chamber containing the injection solution, thereby ejecting the injection component. For example, a configuration is used where multiple nozzle holes are formed inside the injector body, and a piston is positioned corresponding to each nozzle hole and driven during ejection (Patent Document 1). This configuration aims to achieve uniform injection of the injection solution to the target by simultaneously spraying the injection solution from multiple nozzle holes. Then, by injecting a plasmid containing the luciferase gene into rats, efficient cell transduction was achieved.

[0004] Furthermore, pressurized gas can be used as the power source for ejecting the injection liquid in a needle-free injector. For example, a pressurization method is illustrated in which a large pressure is applied momentarily at the initial stage of ejection, and then the pressure is gradually reduced over 40 to 50 minutes (Patent Document 2).

[0005] In the above-described injection method, the subcutaneous and intradermal areas were mainly studied as the injection targets (Patent Document 1).

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 2004-358234

[0009] Patent Document 2: U.S. Patent Application Publication No. 2005 / 0010168 Summary of the Invention

[0010] The problem that the invention aims to solve

[0011] The inventors studied jet injection using fragile tissues such as the liver and spleen as injection targets, and found that when the needle-free injector was pressed against the target to inject the solution, it sometimes penetrated the target.

[0012] The technical problem addressed in this disclosure is at least as follows: to provide an injector for use with fragile tissue as the target. Furthermore, to provide a method for injecting a solution into the target using the injector.

[0013] Solution for solving the problem

[0014] In order to solve the above-mentioned technical problems, the inventors have repeatedly conducted in-depth research and found that the above-mentioned technical problems can be solved by using a specified injector.

[0015] That is, the main point of this disclosure is as follows.

[0016] [1] An injector for injecting a solution containing a functional substance from a living organism into a target, the injector comprising: a receiving portion for receiving the solution; a nozzle portion communicating with the receiving portion and having an ejection port for ejecting the solution toward the target; and a pressurizing portion for pressurizing the solution received in the receiving portion during operation 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 / mm². 2 Above and 1500mJ / mm 2 the following.

[0017] [2] According to the injector described in [1], the volume of the solution is 0.3 μL or more and 4.0 μL or less.

[0018] [3] According to the injector described in [1] or [2], the area of ​​the injection port is 0.001 mm. 2 Above and 1.25mm 2 the following.

[0019] [4] The injector according to any one of [1] to [3], wherein the area of ​​the injection port is 0.001 mm. 2 Above and 0.02mm 2 the following.

[0020] [5] The injector according to any one of [1] to [4], wherein the functional substance in the organism is one or more selected from the group consisting of nucleic acids, peptides, proteins, carbohydrates and low molecular weight compounds and complexes thereof.

[0021] [6] The injector according to any one of [1] to [5], wherein the object is selected from one or more of the following: fat, skeletal muscle, ligament, aorta, superior vena cava, brain, eyeball, eardrum, inner ear, nerve, trachea, bronchus, lung, esophagus, stomach, liver, kidney, adrenal gland, spleen, gallbladder, pancreas, large intestine, small intestine, duodenum, cecum, appendix, rectum, greater omentum, ureter, bone marrow, lymph node, lymphatic reticulum, thyroid gland, 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 attached to any of them, and tumors arising from any of them.

[0022] [7] An injection method, wherein the injection method is a method of injecting the solution containing a functional substance in vivo into the object using an injector according to any one of [1] to [6].

[0023] Invention Effects

[0024] This disclosure provides an injector for injecting at least fragile tissue. Furthermore, it provides a method for injecting a solution into the target using the injector. Attached Figure Description

[0025] Figure 1 This is an overall diagram of an injector according to one embodiment of the present disclosure.

[0026] Figure 2 It means Figure 1 A cross-sectional view near the tip of the injector shown.

[0027] Figure 3 This is an overall diagram of an injector according to one embodiment of the present disclosure.

[0028] Figure 4 This is a graph showing the luminescence intensity (RFU / μL) when different volumes of pLuc were introduced into the liver or spleen of mice. n=4, mean ± SD. Detailed Implementation

[0029] The various components and combinations thereof in each embodiment are merely examples, and appropriate additions, omissions, substitutions, and other modifications may be made to the components without departing from the spirit of this disclosure. This disclosure is not limited to the embodiments but only to the claims. Furthermore, the various solutions disclosed in this specification can also be combined with any other features disclosed in this specification.

[0030] In addition, the numerical range indicated by “~” refers to the range of values ​​recorded before and after “~” as the lower and upper limits. “A~B” means above A and below B.

[0031] One embodiment of this disclosure is an injector that injects a solution containing a functional substance from a biological organism into a target. The injector includes: a receiving portion for receiving the solution; a nozzle portion communicating with the receiving portion and having an outlet for ejecting the solution toward the target; and a pressurizing portion that pressurizes the solution received in the receiving portion during operation, ejecting the solution from the outlet toward the target, wherein the kinetic energy of the ejected solution divided by the area of ​​the outlet is 40 mJ / mm². 2 Above and 1500mJ / mm 2 the following.

[0032] [A solution containing functional substances found in living organisms]

[0033] The injector of this embodiment can inject a solution containing a functional substance found in vivo. There are no particular limitations as long as the functional substance exhibits physiological activity in the injected target. The functional substance can be one or more substances. The functional substance can be a natural product or a synthetically produced substance.

[0034] The functional substances in the organism are preferably selected from one or more of the group consisting of nucleic acids, peptides, proteins, carbohydrates, low molecular weight compounds, and their complexes.

[0035] Examples of nucleic acids include DNA, RNA, and PNA. Furthermore, the nucleic acid can be a nucleic acid containing a protein-coding portion or a nucleic acid that does not contain a protein-coding portion (non-coding nucleic acid).

[0036] Examples of peptides and proteins include: antigens (substances that produce antibodies against a peptide or protein), antibodies, peptide vaccines, protein vaccines, peptide hormones, protein hormones, growth factors, cytokines, coagulation factors, serum albumin, digestive enzymes, anti-inflammatory peptides, and anti-inflammatory proteins.

[0037] Low molecular weight compounds are generally defined as compounds with a molecular weight of 2000 or less, but are not limited to this, including compounds that can be treated as low molecular weight compounds in this art. Preferred molecular weight ranges for low molecular weight compounds include, for example, 50 or more and 100 or more. Furthermore, ranges include 2000 or less and 1000 or less. That is, ranges of 50 to 2000, 50 to 1000, and 100 to 2000 can be listed.

[0038] A complex is a substance that consists of two or more substances that are equivalent to any one of nucleic acids, peptides, proteins, carbohydrates, or low molecular weight compounds, and are integrated through covalent bonds, ionic bonds, hydrogen bonds, hydrophobic interactions, etc.

[0039] In this disclosure, physiological activity refers to the effect on specific physiological regulatory functions of an organism. Evaluation indicators of physiological activity can be appropriately set according to the purpose, and can be any type of qualitative or quantitative indicator, but quantitative indicators are preferred. For example, specific mRNA levels, protein levels, cytokine levels, antibody titers, and the number of cells of a specific cell type can be used as indicators. These quantitative indicators can be quantified using methods known in the art.

[0040] Especially when the functional substance in an organism is a nucleic acid containing a portion encoding a protein, the amount of protein encoded by the nucleic acid can be quantified and used as an indicator of physiological activity. Furthermore, the activity of the protein can also be quantitatively evaluated. For example, when the protein is a luciferase, physiological activity can be evaluated by measuring the intensity of bioluminescence.

[0041] When the functional substance in a living organism is nucleic acid, the nucleic acid can be integrated into a viral vector or loaded onto lipid nanoparticles and contained in the solution, or it can be contained without a viral vector or lipid nanoparticles. By not using a viral vector or lipid nanoparticles, the possibility of inducing side effects such as allergic reactions in the subject can be reduced.

[0042] The concentration of the functional substance in the organism relative to the total amount of the solution can be appropriately set based on the type of functional substance, the target organism, and the physiological activity exerted by the functional substance in the target organism in which it has been injected. For example, concentrations of 0.0001 mg / mL or higher, 0.001 mg / mL or higher, and 0.01 mg / mL or higher can be listed. Furthermore, concentrations of 1000 mg / mL or lower, and 100 mg / mL or lower can be listed. That is, concentrations of 0.0001–1000 mg / mL, 0.001–100 mg / mL, and 0.01–100 mg / mL can be listed.

[0043] In addition to the functional substances in the organism, the solution may also contain commonly used additives such as buffers, isotonic agents, pH adjusters, antioxidants, thickeners, stabilizers, wetting agents, emulsifiers, and binders, as needed.

[0044] As buffers, for example, phosphate-based buffers (e.g., phosphate buffer, phosphate-buffered saline (PBS) (which can be PBS(+) or PBS(-)), Dulbecco phosphate-buffered saline (D-PBS), citrate / phosphate buffer, citrate / phosphate buffer, etc.), citrate buffer, tris(hydroxymethyl)aminomethane-HCl buffer (Tris-hydrochloric acid buffer), acetate buffer, GOOD buffer (e.g., HEPES-NaOH buffer), amino acid-based buffers (e.g., glycine-hydrochloric acid buffer, glycine-NaOH buffer, glycylglycine-NaOH buffer, glycylglycine-KOH buffer, etc.), imidazole buffer, etc.

[0045] From a generality perspective, a buffer solution using phosphate is preferred.

[0046] Examples of isotonic agents include ionic isotonic agents and nonionic isotonic agents.

[0047] Examples of ionic isotonic agents include salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

[0048] Examples of nonionic isotonic agents include: glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, and sucrose.

[0049] From a general perspective, sodium chloride is preferred.

[0050] Examples of pH adjusters include: hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0051] Antioxidants include: ascorbic acid, sodium sulfite, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and tocopherol.

[0052] Examples of thickeners include: alginate, polyethylene glycol, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose.

[0053] Regarding the pH of the solution, there are no particular limitations as long as the functional substances in the organism exert physiological activity and remain stable in the object when the solution is injected into the object, and there are no adverse effects such as damage to the object.

[0054] [Object]

[0055] The object in this embodiment can be one or more selected from the group consisting of cells, cell sheets, cell clusters, tissues, organs (skin, organs, etc.), organ systems, and individuals (organisms). Furthermore, it can be one or more selected from the group consisting of tissues, organs (skin, organs, etc.), organ systems, and individuals (organisms). It can be any type represented by in vitro systems, in vivo systems, and ex vivo systems. The cell cluster can be a cell cluster obtained through three-dimensional culture, and the organ (skin, organs, etc.) can be an organoid.

[0056] Furthermore, when injecting into the object, it is also possible to inject into the lower levels contained within the object. That is, for example, when the object is an individual (organism), it can be injected into the tissue contained in that individual (organism), or into the cells contained in that individual (organism), or into both. Furthermore, when the object is a tissue, it can be injected into the cells contained in that tissue, or into the extracellular matrix contained in that tissue, or into both. Furthermore, when the object is a cell, it can be injected into the cytoplasm of that cell, or into the nucleus of that cell, or into both the cytoplasm and the nucleus of that cell.

[0057] Furthermore, in this embodiment, when the object is selected from one or more of the group consisting of cells, cell sheets, cell clusters, tissues, organs (skin, organs, etc.), and organ systems, it can be in a state existing in an individual (organism) and selected from one or more of the group consisting of cells, cell sheets, cell clusters, tissues, organs (skin, organs, etc.), or it can be in a state not existing in an individual (organism) (e.g., a state removed or separated from an individual (organism), or a state made outside an individual (organism)) and selected from one or more of the group consisting of cells, cell sheets, cell clusters, tissues, organs (skin, organs, etc.), and organ systems.

[0058] In addition, the object in this embodiment may be one or more of the following groups: cells, cell sheets, cell clusters, tissues, organs (skin, organs, etc.) and organ systems derived from stem cells such as iPS cells (artificial pluripotent stem cells). They may be in a state existing in an individual (organism) or in a state not existing in an individual (organism) (e.g., a state of being removed or separated from an individual (organism), or a state of being made outside an individual (organism)).

[0059] The individual (organism) is preferably a mammal. There are no particular limitations on the mammal; humans and other mammals besides humans can be listed. Examples of mammals other than humans include: mice, rats, guinea pigs, hamsters, cattle, goats, sheep, pigs, monkeys, dogs, cats, etc.

[0060] The organs may be selected from one or more of the following: fat, skeletal muscle, ligaments, aorta, superior vena cava, brain, eyeball, eardrum, inner ear, nerve, trachea, bronchus, lung, esophagus, stomach, liver, kidney, adrenal gland, spleen, gallbladder, pancreas, large intestine, small intestine, duodenum, cecum, appendix, rectum, greater omentum, ureter, bone marrow, lymph nodes, lymphatic reticulum, thyroid gland, sebaceous gland, sweat gland, salivary gland, thymus, mammary gland, prostate, fallopian tube, ovary, uterus, cervix, testis, vas deferens, seminal vesicle, and mucous membranes and connective tissues attached to any of them, and tumors arising from any of them.

[0061] These organs are more fragile than tissues like skin.

[0062] [Injector]

[0063] As described above, the injector of this embodiment includes: a receiving portion for receiving the solution; a nozzle portion communicating with the receiving portion and having an ejection port for ejecting the solution toward the object; and a pressurizing portion for pressurizing the solution received in the receiving portion during operation and ejecting the solution from the ejection port toward the object, wherein the injector injects the solution into the object by ejecting the solution from the ejection port of the nozzle portion.

[0064] The injector of this embodiment, for example, when the distance from the injector body to the object is large, may include a prescribed structure such as a conduit or similar object that guides the solution from the injector body to the object. Therefore, the injector of this embodiment may or may not include such a prescribed structure.

[0065] In the injector of this embodiment, the energy imparted by the pressurizing section for pressurizing the solution can be applied using known pressurization techniques. An example of the imparted energy is chemically generated energy, such as combustion energy generated through the oxidation reaction of gunpowder, explosives, etc. Alternatively, the energy for pressurization can be electrically generated; examples include energy from a piezoelectric element or an electromagnetic actuator driven by an applied power source. Another method is physical generation of the energy for pressurization. Examples include elastic energy from an elastic body and the internal energy of a compressed object such as compressed gas. In short, the energy for pressurization can be any energy that allows the solution to be ejected from the injector. Furthermore, the energy for pressurization can also be a composite energy that appropriately combines combustion energy, electrical energy, elastic energy, and other internal energies.

[0066] Based on the above, the pressurizing section can be, for example, a pressurizing section that uses the pressure generated by the combustion of gunpowder ignited by the ignition device, or a pressurizing section that uses the pressure generated when compressed gas is released. Furthermore, the pressurizing section can be a pressurizing section that uses the force applied by a compression spring, or a pressurizing section that uses electromagnetic force, such as a pressurizing section that uses a linear electromagnetic actuator. Preferably, the pressurizing section utilizes at least the pressure generated by the combustion of gunpowder ignited by the ignition device; furthermore, it can be used in conjunction with any of the other pressurizing methods described above.

[0067] Hereinafter, referring to the accompanying drawings, an example of the injector in this embodiment will be described. Figures 1-3 The syringe 100 shown will be described below. It should be noted that the configuration of the following embodiment is illustrative, and the technology disclosed herein is not limited to the configuration of this embodiment. It should be noted that in the following description, "tip side" and "base side" are used as terms indicating the relative positional relationship in the longitudinal direction of the syringe 100. "Tip side" refers to the side of the syringe 100 located in the longitudinal direction... Figure 1 The "base end side" refers to the side opposite to the outlet hole 4b side in the longitudinal direction of the syringe 100.

[0068] Figure 1 This is an overall view of the syringe 100 according to this embodiment. Figure 1 The figure shows a cross-section along the longitudinal direction of the syringe 100. Furthermore, Figure 2 This is a cross-sectional view showing the area near the tip of the syringe 100. (Example) Figure 1As shown, the syringe 100 includes: a jet syringe 1 as the injector body, a housing 2 that detachably houses the jet syringe 1, an injection needle 4 as the ejection part, and a fixing clamp 5 for fixing the injection needle 4 to the jet syringe 1.

[0069] [Jet Injector]

[0070] like Figure 1 As shown, the jet injector 1 includes a container 11, a container support 12, a driver 13, and a housing 14, which are integrally assembled. An ejection port, indicated by reference numeral 11c, is formed at the top of the jet injector 1. The jet injector 1 uses the combustion energy of gunpowder to pressurize a solution (hereinafter sometimes simply referred to as "solution") containing functional substances from a living organism, thereby ejecting the solution from the ejection port 11c. The jet injector 1 of this embodiment is configured as a needle-free injector capable of injection without a needle. A needle-free injector is a syringe that injects the solution into the object without inserting the injector body into the object via a predetermined structure. Specifically, Figure 3 The syringe 100 shown is referred to as a needle-free syringe. However, the jet syringe 1 may not be a needle-free syringe. Furthermore, as follows... Figure 1 As shown, a syringe 100 equipped with an injection needle 4 and a fixing clamp 5 is sometimes referred to as a needle-equipped syringe.

[0071] [case]

[0072] like Figure 1 As shown, the housing 14 is a cylindrical component that houses the actuator 13. An ignition device 131 (described later) for the actuator 13 is embedded at the base end of the housing 14, and a container support 12 is embedded at the top end of the housing 14. Furthermore, as... Figure 2 As shown, a threaded portion 14a for engaging the housing 14 with the container support 12 is formed on the inner circumferential surface of the top end side of the housing 14. The container support 12 and the actuator 13 are connected via the housing 14.

[0073] [container]

[0074] like Figure 2As shown, the container 11 has a main body 111 and a nozzle 112 with a diameter smaller than that of the main body 111, and is formed in a cylindrical shape. Furthermore, inside the container 11, there is a containment space 11a, which serves as a space for containing a solution containing functional substances from a living organism, and a flow path 11b communicating with the containment space 11a and opening at its top. More specifically, the containment space 11a is formed inside the main body 111, and the flow path 11b is formed inside the nozzle 112. The containment space 11a is an example of the containment portion of this disclosure. An opening of the flow path 11b is formed on the top surface of the nozzle 112, and this opening becomes the ejection hole 11c of the injection syringe 1. That is, the injection syringe 1 ejects the solution from the ejection hole 11c formed on the top surface of the nozzle 112. Figure 2 As shown, the inner diameter of the flow path 11b of the container 11 is smaller than the inner diameter of the containing space 11a. With this configuration, the solution pressurized to high pressure is ejected to the outside from the ejection hole 11c of the flow path 11b. Furthermore, a threaded portion 111a for connecting the container 11 to the container support 12 is formed on the outer peripheral surface of the main body 111.

[0075] The material of container 11 is not particularly limited; for example, container 11 can be formed from a resin material. As a resin material for forming container 11, for example, known materials such as nylon 6-12, polyarylate, polycarbonate, polybutylene terephthalate, polyphenylene sulfide, or liquid crystal polymer can be used.

[0076] [Container support]

[0077] like Figure 2 As shown, the container support 12 is cylindrical, holding the container 11 embedded within it. A threaded portion 12a is formed on the inner circumferential surface of the container support 12 at its base end. The container 11 is joined to the container support 12 by screwing the threaded portion 11a of the container 11 into the threaded portion 12a of the container support 12. Furthermore, a threaded portion 12b is formed on the outer circumferential surface of the container support 12 at its base end. The container support 12 is joined to the housing 14 by screwing the threaded portion 12b of the container support 12 into the threaded portion 14a of the housing 14. Additionally, a threaded portion 12c is formed on the outer circumferential surface of the container support 12 at its top end for joining the container support 12 to the fixing clamp 5.

[0078] The material of the container support 12 is not particularly limited; for example, the container support 12 can be formed of a metal material. Examples of metal materials that can be used to form the container support 12 include stainless steel, copper, aluminum, iron, titanium, and titanium alloys.

[0079] [Driver]

[0080] Figure 1The actuator 13 shown is configured to pressurize the solution during operation. Actuator 13 is an example of the "pressurization section" of this disclosure. Figure 1 As shown, the driver 13 includes an ignition device 131, a piston 132, and a plunger 133 housed in the housing 14.

[0081] An ignition device 131 is disposed at the base end of the housing 14, a plunger 133 is disposed at the top end of the housing 14, and a piston 132 is adjacent to the plunger 133 and disposed between the ignition device 131 and the plunger 133. A combustion chamber 15 is formed in the internal space of the housing 14 between the ignition device 131 and the piston 132.

[0082] [Ignition device]

[0083] The ignition device 131 includes an igniter 1311 and a retaining member 1312. The igniter 1311 acts as a driving source for the actuator 13, generating energy to pressurize and eject the solution from the syringe 100. The igniter 1311 is configured as an electric igniter that releases combustion products by igniting the initiating explosive contained therein. The retaining member 1312 is formed by resin injection molding. The injection molding can be performed using known methods. Furthermore, the retaining member 1312 can use the same resin material as the container 11. The ignition device 131 is configured as an igniter assembly in which the igniter 1311 is fixed to the base end of the housing 14 via the retaining member 1312, and is embedded in the housing 14 in a manner that blocks the base end of the housing 14. Furthermore, the ignition device 131 is disposed in the housing 14 with the igniter 1311 and the base end face of the piston 132 facing each other, so as to transfer the combustion energy of the initiating explosive of the igniter 1311 and the combustion energy of the gas generator 10 (described later) to the base end face (the end face on the base end side) of the piston 132.

[0084] [Detonating charge]

[0085] Here, examples of initiating propellants used in igniter 1311 include zirconium and potassium perchlorate propellants (ZPP), titanium hydride and potassium perchlorate propellants (THPP), titanium and potassium perchlorate propellants (TiPP), aluminum and potassium perchlorate propellants (APP), aluminum and bismuth oxide propellants (ABO), aluminum and molybdenum oxide propellants (AMO), aluminum and copper oxide propellants (ACO), aluminum and iron oxide propellants (AFO), or combinations thereof. These propellants generate high-temperature, high-pressure plasma upon immediate combustion after ignition, but if the combustion products condense at room temperature, they contain no gaseous components, thus exhibiting a characteristic of a rapid pressure drop. It should be noted that other propellants can also be used as initiating propellants, provided a suitable solution can be ejected.

[0086] [Gas Generator]

[0087] Furthermore, in the injection injector 1, a gas generating agent 10 is disposed in the combustion chamber 15 to adjust the pressure change applied to the solution via the piston 132. This gas generating agent 10 generates gas by burning the combustion products of the initiating charge released from the igniter 1311. That is, the injection injector 1 is configured to pressurize the solution using the combustion energy of the initiating charge in the igniter 1311, in addition to the combustion energy of the gas generating agent 10. The gas generating agent 10 is disposed in a position where it can be exposed to the combustion products from the igniter 1311. Alternatively, as another method, the gas generating agent 10 can be disposed within the igniter 1311 as disclosed in International Publication No. 01-031282 and Japanese Patent Application Publication No. 2003-25950. As an example of a gas generating agent, a single-base smokeless gunpowder (GG) composed of 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate can be cited. In addition, various gas generating agents used in airbag gas generators and seatbelt pretensioner gas generators can be used. By adjusting the size, shape, and especially the surface shape of the gas generating agent disposed in the combustion chamber 15, the combustion end time of the gas generating agent can be changed, thereby adjusting the pressure shift applied to the solution and causing the injection pressure to shift as desired. It should be noted that the injection injector 1 may also pressurize the solution using only the combustion energy of the initiating explosive of the igniter 1311 without containing the gas generating agent 10. In this disclosure, the pressurization section also includes a gas generating agent or the like, which may be used as needed.

[0088] [piston]

[0089] The piston 132 is disposed on the top side of the housing 14 such that it can slide inside the housing 14 by being pressurized by the operation of the igniter 1311. The piston 132 is made of metal, and to improve the sealing with the sliding surface (i.e., the inner circumferential surface of the housing 14) on which the piston 132 slides, an O-ring or the like may be provided on a part of the piston 132. Alternatively, the piston 132 may be made of resin, in which case metal may be used in parts requiring heat resistance and pressure resistance.

[0090] [Plunger]

[0091] The plunger 133 is a component that pressurizes the solution contained in the containment space 11a by receiving the combustion energy of the initiating propellant of the igniter 1311 and the combustion energy of the gas generating agent via the piston 132. The plunger 133 is housed in the housing 14 and disposed between the piston 132 and the nozzle portion 112 of the container 11. The plunger 133 is formed in the shape of a rod, with its base end engaging with the tip portion of the piston 132. Furthermore, the tip portion of the plunger 133 is inserted into the body portion 111 of the container 11, and the containment space 11a is defined by the plunger 133 and the body portion 111. The plunger 133 is slidable inside the body portion 111. By sliding the plunger 133, the solution contained in the containment space 11a is pressurized and ejected through the flow path 11b from the ejection port 11c. Therefore, the plunger 133 is formed of a material that slides smoothly relative to the body portion 111 of the container 11 and prevents the solution from leaking out from the plunger 133 side.

[0092] For example, butyl rubber or silicone rubber can be used as the material for the plunger 133. In addition, in order to ensure / adjust the sliding properties between the plunger 133 and the main body 111 of the container 11, the outer peripheral surface of the plunger 133 and the inner peripheral surface of the main body 111 can be coated / surface-processed with various substances.

[0093] Here, the outline of the tip of the plunger 133 is roughly the same as the outline of the tip of the receiving space 11a. As a result, when the solution is ejected, when the plunger 133 slides to the deepest position in the main body 111, the receiving space 11a formed between the plunger 133 and the nozzle 112 can be minimized as much as possible, thereby preventing solution from being wasted due to remaining in the receiving space 11a.

[0094] [shell]

[0095] Figure 1 The housing 2 shown is a component that houses the injection syringe 1 and functions as a handle for the user to grip when using the syringe 100. Figure 1 As shown, a battery 3 is provided inside the housing 2 for supplying drive current to the driver 13 (more specifically, igniter 1311) of the injection injector 1. Furthermore, as... Figure 1As shown, multiple switches 21 for operating the injection injector 1 to eject the solution are provided on the outer surface of the housing 2. Furthermore, a socket (not shown) for connecting to the igniter 1311 of the injection injector 1 is provided on the inner surface of the housing 2. Power is supplied to the injection injector 1 from the battery 3 via wiring between the electrodes on the housing 2 side and the electrodes on the igniter 1311 side of the injection injector 1, operated by the user pressing the button 21. Additionally, a control unit (not shown), such as a microcomputer, is located inside the housing 2. The control unit controls the supply of ignition current to the igniter 1311 of the injection injector 1 based on signals from each switch, thereby controlling the operation of the injection injector 1.

[0096] It should be noted that, as described above, in this embodiment, the power for activating the igniter 1311 is supplied by a battery built into the housing 2, but alternatively, power can be supplied from the outside via a power cable.

[0097] [Injection needle]

[0098] like Figure 1 As shown, the injection needle 4 is mounted on the nozzle portion 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 the "ejection portion" of this disclosure, which is configured to allow the flow of a solution pressurized by the driver 13 of the jet injector 1 and to eject the inflowing solution toward a target.

[0099] The solution, pressurized by the actuator 13, flows into the base 41. For example... Figure 1 As shown, the base 41 is formed into a cylindrical shape. More specifically, as... Figure 2 As shown, 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 extending radially outward. The nozzle portion 112 of the injection syringe 1 is pressed into the opening at the base end side of the base body 411. Therefore, the opening at the base end side of the base body 411 is configured as an inlet hole 4a, which allows a solution containing functional substances from the organism to flow from the receiving space 11a of the container 11 into the injection needle 4.

[0100] The base 41 can be formed of a resin material, for example. Commonly known synthetic resins such as polycarbonate, polypropylene, and polyethylene can be used as the resin material for forming the base 41. Alternatively, the base 41 can also be made of metal. Examples of metal materials for forming 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, a material with high rigidity, such as stainless steel, is preferably used in the base 41.

[0101] The needle 42 is inserted into the target body to inject a solution containing functional substances from the body. The base of the needle 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 42. Therefore, the opening at the tip of the needle 42 is configured as an outlet hole 4b, which allows the solution containing functional substances from the body that flows into the injection needle 4 from the inlet hole 4a to be ejected towards the target body. Furthermore, in order to insert the needle 42 into the target body, a sharp needle tip for piercing the skin is formed at the tip of the needle 42.

[0102] From the perspective of suppressing tissue damage to the target, it is preferable that the injection needle 4 (more specifically, the needle 42 inserted into the target) is thinner. For example... Figure 2 As shown in the enlarged view A1, the inner diameter of the needle tube 42 is set as d1, and the outer diameter of the needle tube 42 is set as d2. In this case, the inner diameter d1 is preferably 1.5 mm or less, more preferably 0.41 mm or less. The outer diameter d2 is preferably 1.7 mm or less, more preferably 0.72 mm or less. However, the range of the inner and outer diameters of the needle tube 42 is not limited to the above ranges. Furthermore, the length of the needle tube 42 can be appropriately set according to the object, for example, a value selected from the range of 1 mm or more and 180 mm or less can be used.

[0103] The material of the syringe 42 is not particularly limited; for example, stainless steel can be used. Other metals besides stainless steel include aluminum, aluminum alloys, titanium, and titanium alloys. Additionally, the syringe 42 can also be made of resin.

[0104] As described above, since the internal space of the base 41 is connected to the internal space of the needle tube 42, a flow path 4c is formed in the injection needle 4, from the inlet hole 4a to the outlet hole 4b, through the internal space of the base 41 and the internal space of the needle tube 42. The solution flowing into the injection needle 4 from the inlet hole 4a flows through the flow path 4c to the outlet hole 4b, and is ejected from the outlet hole 4b toward the target.

[0105] A sealant can also be used between the nozzle portion 112 of the container 11 and the base 41 of the injection needle 4 to improve liquid tightness. Examples of sealants include O-rings, seals, sealing strips, and liquid sealants.

[0106] [Fixed clamp]

[0107] The retaining clamp 5 is a component used to fix the injection needle 4 to the nozzle portion 112 of the jet injector 1. The retaining clamp 5 includes a cylindrical peripheral wall portion 51 and a capping wall portion 52 that blocks the top end of the peripheral wall portion 51. A container support 12 is embedded in the peripheral wall portion 51. Furthermore, a threaded portion 51a is formed on the inner peripheral surface of the peripheral wall portion 51. The container support 12 is engaged with the retaining clamp 5 by screwing the threaded portion 12c of the container support 12 into the threaded portion 51a of the retaining clamp 5. A through hole 52a is formed in the capping wall portion 52, extending from the base end side to the top end side. The base body 411 of the injection needle 4 is embedded in the through hole 52a. At this time, the capping wall portion 52 presses the flange portion 412 of the injection needle 4 from the top end side, thereby preventing the injection needle 4 from falling out of the nozzle portion 112 of the jet injector 1. In this way, the injection needle 4 is fixed to the nozzle portion 112 by the retaining clamp 5.

[0108] The material of the fixing clamp 5 is not particularly limited. Similar to the container retainer 12, the fixing clamp 5 can be formed from metal materials such as stainless steel, copper, aluminum, iron, titanium, and titanium alloys. Alternatively, the fixing clamp 5 can also be formed from resin materials such as polycarbonate, polypropylene, and polyethylene.

[0109] [Action of the injector]

[0110] use Figure 1 The syringe 100 injects a solution into the object by operating the syringe 100 while the syringe needle 42 is inserted into the object. Furthermore, as... Figure 3 As shown, when the syringe 100 is used as a needle-free syringe, it is operated by having the syringe 100 in contact with the object. The operation of the syringe 100 will be explained below. It should be noted that the solution containing functional substances from the body can be initially contained in the containing space 11a of the container 11, or it can be contained in the containing space 11a by drawing the solution from outside the syringe 100 through the outlet hole 4b or the ejection hole 11c of the injection needle 4. When the containing part and the ejection part are integrally formed, by initially containing the solution containing functional substances from the body in the containing space 11a of the container 11, drug leakage and dead volume can be reduced.

[0111] In addition to solutions containing functional substances from the organism, the containment chamber can also hold gases. In this case, the solution is injected into the object while pressurizing and dissolving the gas in it. It is presumed that after injection into the object, depressurization and the restoration of some of the dissolved gas to gas can generate numerous microbubbles, thereby forming multiple pores in the object through the shearing action of these bubbles. These pores typically have a maximum diameter of about 10 μm to about 1000 μm, but sometimes larger pores can be formed by multiple pores connecting together. The formation of pores can be confirmed using a stereomicroscope or similar instruments.

[0112] The gap can be used, for example, as a flow path or storage container for any liquid or gas.

[0113] There is no particular limitation on the gas that the containment section can hold; air can be cited as an example. The ratio of the gas volume 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%. Furthermore, it is preferably less than 100%, more preferably 80% or less. That is, preferred ranges for the gas volume ratio include: 30% or more and less than 100%, 30% or more and less than 80%, and more than 60% and less than 80%.

[0114] When the driver 13 of the injection injector 1 is activated by supplying a driving current to the driver 13 (more specifically, the igniter 1311) via the user's operation of the switch 21, the combustion products of the initiating explosive are released from the igniter 1311 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 initiating explosive, generating gas in the combustion chamber 15. As described above, the base end face of the piston 132 is exposed in the combustion chamber 15. Therefore, when the driver 13 is activated, the piston 132, which bears the combustion energy (pressure) of the initiating explosive and the gas generating agent at its base end face, slides towards the top end of the housing 14. As a result, the plunger 133 is pressed into the top end of the receiving space 11a by the piston 132, pressurizing the solution in the receiving space 11a. As a result, the solution is ejected from the receiving space 11a through the flow path 11b and from the ejection orifice 11c formed in the nozzle portion 112. In use... Figure 3 In the case of the needleless injector shown, the solution can be injected into the object.

[0115] like Figure 1 , Figure 2 As shown, when using the injection needle 4 and the fixing clamp 5, the solution ejected from the ejection port 11c of the nozzle 112 flows into the injection needle 4 through the inlet port 4a of the injection needle 4 mounted on the nozzle 112. The solution flows through the flow path 4c and is ejected towards the target from the outlet port 4b. As described above, the operation of the syringe 100 is completed.

[0116] In this embodiment, injecting the solution into the object via an injector can be a jet injection into the object.

[0117] In this disclosure, "jet injection" refers to an injection characterized by the ejection of a solution from an ejector port toward an object, thereby forming a through-hole penetrating the inner and outer boundaries of the object, and generating a high-pressure ultrafine liquid flow capable of penetrating the through-hole and injecting the solution into the object. For example, in the case where the object is an individual mammal (organism), it refers to an injection characterized by the generation of a high-pressure ultrafine liquid flow capable of penetrating the skin or the like of the individual mammal (organism).

[0118] In this embodiment, the kinetic energy of the ejected solution divided by the area of ​​the ejection port yields a value of 40 mJ / mm². 2 Above and 1500mJ / mm 2 The following value represents the pressure applied to the object during injection. The value obtained by dividing the kinetic energy of the ejected solution by the area of ​​the injection port is preferably 40 mJ / mm². 2 Above and 1000mJ / mm 2 The preferred value is 40 mJ / mm. 2 Above and 300mJ / mm 2 The following is particularly preferred: 40 mJ / mm 2 Above and 100mJ / mm 2 The following applies. When the value obtained by dividing the kinetic energy of the ejected solution by the area of ​​the ejection port is within the aforementioned range, it is possible to inject the solution into the target while preventing the ejected solution from penetrating the target.

[0119] When the mass of the solution is set as m (kg) and the ejection velocity is set as v (m / s), the kinetic energy of the solution is 1 / 2 × m × v 2 express.

[0120] In this disclosure, the ejection velocity is the velocity of the solution as it exits the ejection port. The ejection velocity can be calculated, for example, by capturing images of the solution being ejected from the ejection port using a high-speed camera or similar imaging device at 20,000 fps, and dividing the distance the tip of the ejected solution moves between two consecutive images by the shooting interval, i.e., 50 μs.

[0121] The injection speed can be set to the above range by adjusting the injection energy according to the shape and material of the nozzle, as well as the volume and viscosity of the solution.

[0122] In this disclosure, the ejection port refers to the opening from which a solution is ejected from an injector assembled integrally. In the syringe 100 described above, when the syringe 100 is used as a needleless syringe, the ejection port is an ejection hole 11c, and when the syringe 100 is used as a needle syringe, the ejection port is an outlet hole 4b.

[0123] The area of ​​the injection port is preferably 0.001 mm. 2 Above and 1.25mm 2 Hereinafter, 0.001 mm is preferred. 2 Above and 0.1mm 2 Hereinafter, 0.001 mm is particularly preferred. 2 Above and 0.02mm 2 The following applies. If the area of ​​the injection port is within the above range, it is easy to inject the material into the target.

[0124] The injector of this embodiment can eject the solution at an ejection rate typically exceeding 83.3 μL / s. The lower limit of the ejection rate is preferably 200 μL / s or more, more preferably 250 μL / s or more, further preferably 300 μL / s or more, even more preferably 350 μL / s or more, and most preferably 400 μL / s or more. Furthermore, the upper limit of the ejection rate 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 for ejection rates include: exceeding 83.3 μL / s and 5000 μL / s or less, 200 μL / s or more and 1000 μL / s or less, 250 μL / s or more and 700 μL / s or less, 300 μL / s or more and 700 μL / s or less, and 350 μL / s or more and 700 μL / s or less.

[0125] If the ejection velocity is within the above range, it is easy to inject the material into the target.

[0126] Furthermore, the lower limit of the injection velocity of the injector in this embodiment is preferably 40 m / s or more, more preferably 45 m / s or more. Furthermore, the upper limit of the injection velocity is preferably 100 m / s or less, more preferably 90 m / s or less. That is, preferred ranges for the injection velocity include: 40 m / s or more and 100 m / s or less, and 45 m / s or more and 90 m / s or less.

[0127] The volume of the solution is preferably 0.3 μL or more and 4.0 μL or less. More preferably, it is 0.3 μL or more and 1.5 μL or less, and even more preferably, it is 0.3 μL or more and 1.0 μL or less. If the volume of the solution is within the above range, it is easy to prevent the ejected solution from penetrating the object.

[0128] The time required for the solution to be injected into the target is not particularly limited as long as it is the time required to eject the injected amount of solution at the ejection rate. Examples include: 0.001 seconds or more, 0.005 seconds or more, or 0.01 seconds or more. Furthermore, examples include: 100 seconds or less, 50 seconds or less, or 10 seconds or less. That is, examples include: 0.001 to 100 seconds, 0.005 to 50 seconds, and 0.01 to 10 seconds.

[0129] By using the injector of this embodiment, a solution containing functional substances from within a living organism can be injected into a subject. Specifically, one embodiment of this disclosure is an injection method that uses the injector to inject the solution containing functional substances from within a living organism into the subject.

[0130] The above method may include the following steps: a step of containing the solution in the containing portion; a step of pressurizing the solution contained in the containing portion; and a step of injecting the solution into the object.

[0131] For details regarding the injection target, the method of containing the solution in the container, the method of pressurizing the solution contained in the container, and the method of injecting the solution into the target, please refer to the description of the injector.

[0132] Example

[0133] The present disclosure will now be described in detail with reference to embodiments. However, the present disclosure is not limited to the embodiments described below.

[0134] [Experiment 1: Study on Ejection Conditions]

[0135] The ejection assay used Actranza (registered trademark) Lab (for intradermal administration in mice) equipped with a 20 μL container, equivalent to... Figure 3 The needle-free injector shown is used. The Actranza Lab is filled with 1% (w / v) malachite green (specific gravity: 1.0018) of the volume specified in Table 1 to operate, thereby injecting the solution into a transparent plastic tube with 1mm interval graduations. In the Actranza Lab, ZPP is used as the initiator, and GG (containing 98% wt nitrocellulose, 0.8% wt diphenylamine, and 1.2% wt potassium sulfate) is used as the gas generator to inject the solution. The injection process is filmed using a high-speed camera at 20,000 fps. The injection velocity is calculated by dividing the distance the tip of the solution travels between the first and second frames confirming the injection from the nozzle by the filming interval of 50 μs. Furthermore, the kinetic energy is calculated by setting the specific gravity of the solution to 1.

[0136] Next, the kinetic energy is divided by the opening area of ​​the Actranza Lab's injection port, which is 7.85 × 10⁻⁶. -3 mm 2 This allows us to calculate the energy applied to the object.

[0137] Table 1 shows the liquid volume, ejection velocity, kinetic energy, and kinetic energy / opening area.

[0138] [Table 1]

[0139]

[0140] [Experiment 2: Study on tissue penetration of mouse liver or spleen]

[0141] Eight-week-old male ICR mice (SLC Corporation, Japan) were intraperitoneally administered three mixed anesthesias (volume per unit mouse body weight: metoprimidine: 0.3 mg / kg, midazolam: 4 mg / kg, butorphanol: 5 mg / kg). After confirming no avoidance response when the hind limbs were grasped with forceps, the mice were abdominally opened to expose the liver or spleen. Using ActranzaLab, 1% (w / v) malachite green was injected into the exposed liver or spleen at the volumes described in Table 2. The detonator and gas generator were the same as in Experiment 1. If pigment diffusion was confirmed immediately after injection, tissue penetration was considered achieved through injection. In three administrations, cases where no tissue penetration was confirmed in any of them were designated as "A", cases where no tissue penetration was confirmed in at least one administration were designated as "B", and cases where tissue penetration was confirmed in all three administrations were designated as "C". The results are shown in Table 2.

[0142] [Table 2]

[0143]

[0144] As shown in Table 2, the kinetic energy / opening area ratio is 40 mJ / mm². 2 Above and 1500mJ / mm 2 The following conditions can inhibit tissue penetration.

[0145] [Gene expression in the liver or spleen of mice in Experiment 3]

[0146] Fill the Actranza Lab container with 0.3 μL, 1.3 μL, or 5.3 μL of the luciferase (Luc) expression plasmid pGL4 (hereinafter, sometimes referred to as pLuc). Pre-dilute pGL4 to 1 μg / μL with PBS. The initiator and gas generator are the same as in Experiment 1.

[0147] Three types of combined anesthesia were administered intraperitoneally to the mice. After confirming that there was no avoidance response when the hind limbs were grasped with forceps, the mice were abdominally opened to expose the liver or spleen. pLuc was administered by pressing the tip of Actranza Lab onto the organ and activating it. The muscles and skin at the surgical site were then ligated and sutured to close the abdomen.

[0148] Twenty-four hours later, the mice were anesthetized and their cervical spine was dislocated. After confirming that the mice died from bloodletting through the carotid artery, the organs were removed.

[0149] Luc activity was determined using the Luc-assay kit (Promega). 0.5–1 mL of the accompanying Passive Lysis buffer was added, and the tissue was pulverized with scissors for approximately 2–3 minutes. The tissue was then frozen in a freezer, thawed at room temperature, and centrifuged at 10000×g for 10 minutes at 16°C. Following the procedure, 20 μL of the supernatant and 100 μL of the substrate were mixed in a Lumitube (Kikkoman), and the relative fluorescence units (RFU) were rapidly measured using a Lumiester C-110 (Kikkoman). The RFU value was multiplied by a correction value to calculate the total RFU per unit of passive lysis buffer added, which was then used as the total RFU per unit of tissue sample.

[0150] Figure 4 The values ​​obtained by dividing the total RFU by the volume of liquid supplied are shown.

[0151] like Figure 4 As shown, in Experiment 2, the gene expression efficiency was significantly higher under the feeding conditions rated A compared to those rated C.

[0152] Explanation of reference numerals in the attached figures

[0153] 100: Syringe;

[0154] 1: Jet injector;

[0155] 10: Gas generating agent;

[0156] 11: Container;

[0157] 11a: Accommodation space;

[0158] 11b: Flow path;

[0159] 11c: Injection port;

[0160] 111: Main body;

[0161] 111a: Threaded portion;

[0162] 112: Nozzle section;

[0163] 12: Container support;

[0164] 12a: Threaded portion;

[0165] 12b: Threaded portion;

[0166] 12c: Threaded section;

[0167] 13: Driver;

[0168] 131: Ignition device;

[0169] 1311: Ignition device;

[0170] 1312: Holding component;

[0171] 132: Piston;

[0172] 133: Plunger;

[0173] 14: Shell;

[0174] 14a: Threaded portion;

[0175] 15: Combustion chamber;

[0176] 2: Outer shell;

[0177] 21: Switch;

[0178] 3: Battery;

[0179] 4: Injection needle;

[0180] 4a: Inlet hole;

[0181] 4b: Outlet hole;

[0182] 4c: flow path;

[0183] 41: Base;

[0184] 411: Base body;

[0185] 412: Flange portion;

[0186] 42: Syringe;

[0187] 5: Fixture;

[0188] 51: Peripheral wall section;

[0189] 51a: Threaded portion;

[0190] 52: Cover wall portion;

[0191] 52a: Through hole.

Claims

1. An injector for injecting a solution containing a functional substance from a living organism into a subject, the injector comprising: The container holds the solution; A nozzle portion, communicating with the receiving portion, has an ejection port for ejecting the solution toward the object; and The pressurizing unit pressurizes the solution contained within the container during operation, and ejects the solution from the injection port toward the target, wherein... The kinetic energy of the ejected solution divided by the area of ​​the ejection port yields a value of 40 mJ / mm². 2 Above and 1500mJ / mm 2 the following.

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

3. The injector according to claim 1, wherein, The area of ​​the injection port is 0.001 mm. 2 Above and 1.25mm 2 the following.

4. The injector according to claim 1, wherein, The area of ​​the injection port is 0.001 mm. 2 Above and 0.02mm 2 the following.

5. The injector according to claim 1, wherein, The functional substances in the organism are selected from one or more of the group consisting of nucleic acids, peptides, proteins, carbohydrates, low molecular weight compounds, and their complexes.

6. The injector according to claim 1, wherein, The subject is selected from one or more of the following: fat, skeletal muscle, ligaments, aorta, superior vena cava, brain, eyeball, eardrum, inner ear, nerve, trachea, bronchus, lung, esophagus, stomach, liver, kidney, adrenal gland, spleen, gallbladder, pancreas, large intestine, small intestine, duodenum, cecum, appendix, rectum, greater omentum, ureter, bone marrow, lymph nodes, lymphatic reticulum, thyroid gland, sebaceous gland, sweat gland, salivary gland, thymus, mammary gland, prostate, fallopian tube, ovary, uterus, cervix, testis, vas deferens, seminal vesicle, and mucous membranes and connective tissues attached to any of them, and tumors arising from any of them.

7. An injection method, wherein the injection method is a method of injecting the solution containing a functional substance in vivo into the object using an injector according to any one of claims 1 to 6.

Images