WO2022149550A1 - 注入器 - Google Patents
注入器 Download PDFInfo
- Publication number
- WO2022149550A1 WO2022149550A1 PCT/JP2021/048866 JP2021048866W WO2022149550A1 WO 2022149550 A1 WO2022149550 A1 WO 2022149550A1 JP 2021048866 W JP2021048866 W JP 2021048866W WO 2022149550 A1 WO2022149550 A1 WO 2022149550A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gas
- biomolecule
- injection
- solution containing
- injector
- Prior art date
Links
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Images
Classifications
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- A61M5/2053—Media being expelled from injector by pressurised fluid or vacuum
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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- A61M5/2448—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic comprising means for injection of two or more media, e.g. by mixing
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- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0016—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the nucleic acid is delivered as a 'naked' nucleic acid, i.e. not combined with an entity such as a cationic lipid
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- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/89—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microinjection
Definitions
- This disclosure relates to an injector.
- a needled syringe that injects through an injection needle
- a needleless syringe that injects without an injection needle
- an injection needle for transporting the drug solution to an injection target.
- catheters equipped with a drive source and the like.
- the needleless syringe may be configured to inject the injection component by applying pressure to the storage chamber in which the injection liquid is stored by a pressurized gas, a spring, or an electromagnetic force.
- a configuration is adopted in which a plurality of nozzle holes are formed inside the syringe body and a piston driven at the time of injection is arranged corresponding to each nozzle hole (Patent Document 1).
- Patent Document 3 A technique for injecting a drug solution after providing a gas pocket on the outlet side in the drug solution chamber has been disclosed because it is significantly attenuated by the length of time sensed between the drug solution and the patient's skin.
- Patent Document 4 an in vitro test has been reported in which DNA can be efficiently introduced into the cells of an adherent cell line by containing air in the containment chamber of a needleless syringe (in vitro test).
- An object of the present disclosure is to provide an injector in which, at least, when a solution containing a biomolecule is injected into an injection target, the proportion of the biomolecule that functions in the injection target is large.
- One embodiment of the present disclosure is An injector that injects a solution containing biomolecules and a predetermined gas into an injection target without using an injection needle.
- An accommodating portion accommodating the solution containing the biomolecule and the gas,
- a nozzle portion that communicates with the accommodating portion and has an ejection port for ejecting the solution containing the biomolecule and the gas toward the injection target.
- the solution containing the biomolecule and the gas are ejected from the injection port toward the injection target.
- Department and It is an injector equipped with.
- the injector preferably has a volume of the gas housed in the housing section of 20% or more and 60% or less of the volume of the housing section.
- the injector also preferably has the gas being air.
- the injector also preferably has the biomolecule DNA containing a gene.
- the present disclosure can also provide a method of injecting a solution containing a biomolecule and a predetermined gas into an injection target by using the injector.
- the present disclosure can at least have the effect that when a solution containing a biomolecule is injected into the injection target, the proportion of the biomolecule that functions in the injection target is large.
- One embodiment of the present disclosure is An injector that injects a solution containing biomolecules and a predetermined gas into an injection target without using an injection needle.
- An accommodating portion accommodating the solution containing the biomolecule and the gas,
- a nozzle portion that communicates with the accommodating portion and has an ejection port for ejecting the solution containing the biomolecule and the gas toward the injection target.
- the solution containing the biomolecule and the gas are ejected from the injection port toward the injection target.
- Department and It is an injector equipped with.
- the biomolecule injected into the injection target is not particularly limited as long as it functions in the injection target when injected into the injection target.
- the biomolecule may be a natural product or an artificially synthesized one.
- nucleic acids or derivatives thereof nucleosides, nucleotides or derivatives thereof; amino acids, peptides, proteins or derivatives thereof; lipids or derivatives thereof; metal ions; low molecular weight compounds or derivatives thereof; antibiotics; vitamins or derivatives thereof.
- it may be DNA or RNA, and they may contain a gene.
- a free plasmid DNA containing a luciferase gene is used as a biomolecule, and the luciferase gene is used as a reporter gene.
- the biomolecule injected into the injection target functions in the injection target when injected into the injection target, the biomolecule is stably present, and there is no adverse effect such as destroying the injection target.
- a free form, a form fixed to a carrier such as nanoparticles, or a modified form, including a solvent is not particularly limited.
- the DNA contains a gene, it may be designed in a form in which the gene is contained in an expression cassette or an expression vector.
- the gene may be arranged under the control of a promoter suitable for the injection target and the injection site into which the DNA is injected. That is, known genetic engineering techniques can be used in any of the embodiments.
- a mammalian expression vector pGL4.13 [luc2 / SV40] Vector (manufactured by Promega), is used as the expression vector.
- the plasmid vector is known and can be obtained by those skilled in the art. Subcloning of expression vectors and recombinant vectors can be performed according to known methods.
- the injector of this embodiment contains a predetermined gas in a housing portion thereof.
- a predetermined gas when the solution containing the biomolecule is injected into the injection target, the biomolecule functions in the injection target, the biomolecule exists stably, and the injection target is destroyed.
- air can be exemplified.
- the air may be generally used air, and its composition is not particularly limited.
- a mixed gas of about 80% nitrogen and about 20% oxygen can be mentioned.
- examples of the gas include nitrogen, oxygen, ozone, carbon dioxide, hydrogen, and carbon monoxide, and a mixed gas of two or more of these can be exemplified.
- the gas is a gas that does not contain microorganisms or the like, or a gas that is dead even if it contains microorganisms or the like.
- the injection of the solution containing the biomolecule into the injection target is started while the gas is dissolved in the solution containing the biomolecule with pressurization, and the solution with the biomolecule is reduced.
- the solution containing the biomolecule can be injected into the injection target while giving a large shear stress to the injection target, and as a result, the injection is performed. It is presumed that the proportion of biomolecules that function in the subject will increase.
- such a mechanism when the solution containing the biomolecule is injected into the cell, such a mechanism preferably increases the solution containing the biomolecule that passes through the cell membrane and is injected into the cell, resulting in an increase. It is presumed that the proportion of biomolecules that function in the injection target will increase.
- the volume of the gas contained in the housing is too large with respect to the volume of the housing, the amount of the solution containing the biomolecule in the housing is small, so that all of the gas is described. It is presumed that the injection of the solution containing the biomolecule is completed before it dissolves in the solution containing the biomolecule, and sufficient share stress is not given to the injection target. That is, it is presumed that the large volume of the gas contained in the housing does not necessarily mean that the proportion of biomolecules that function in the injection target is large with respect to the volume of the housing. On the other hand, if the volume of the gas contained in the housing is too small with respect to the volume of the housing, the gas is to be injected while being pressurized and dissolved in the solution containing the biomolecule.
- the volume of the gas contained in the housing is preferably 20% or more, more preferably 30% or more, and more preferably 60% or less, more than the volume of the housing. It is preferably 50% or less.
- Examples of cases where the proportion of biomolecules that function in the injection target are large include the following when DNA as a biomolecule contains a gene.
- a solution containing DNA is injected into the injection target (this is referred to as aspect C). )
- the expression level of the gene per unit DNA amount injected into the injection target is defined as "expression level C”.
- the storage unit contains the DNA and the gas so that the total volume of the solution containing the DNA and the gas is the same as the volume of the solution containing the DNA contained in the storage unit in the embodiment C.
- Expression level of the gene per unit DNA amount injected into the injection target is defined as "expression level A" when the gas is injected into the injection target.
- Expression level C ⁇ Expression level A This is the case.
- a tissue is collected in a cylindrical shape having an arbitrary radius around the injection port after injection, a sample is prepared by a known biological method, and the sample is prepared. It can be confirmed by the gene expression assay.
- a known method can be appropriately used depending on the type of the gene and the like, and for example, when the gene is a luciferase gene, assaying the amount of luminescence using luciferin as a substrate can be mentioned.
- the injection target in this embodiment is, 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 bodies), and the like, and is often limited. There is no. It may be any of in vitro system, in vivo system, ex vivo system and the like.
- the cell mass may be a cell mass obtained by three-dimensional culture, and the organ (skin, organ, etc.) may be an organoid.
- the injection when the injection is performed to the injection target, the injection may be performed in the lower layer included in the injection target. That is, for example, when an individual (living body) is to be injected, it may be injected into a tissue contained in the individual (living body) or a cell contained in the individual (living body), both of which may be injected. May be injected into. Further, when a tissue is targeted for injection, the tissue may be injected into the cells contained in the tissue, the extracellular matrix contained in the tissue may be injected, or both may be injected.
- the injection target in this embodiment is one or more selected from the group consisting of cells, cell sheets, cell masses, tissues, organs (skin, organs, etc.), and organ systems
- the injection target in this embodiment is selected from a group consisting of 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). These may be one or more, and these may be in a state of being present in an individual (living body) or in a state of not being present in an individual (living body) (for example, a state of being removed or separated from the individual (living body)). Or, it may be a state produced outside an individual (living body).
- the cell mass may be a cell mass obtained by three-dimensional culture, and the organ (skin, organ, etc.) may be an organoid.
- the individual (living body) is preferably a mammalian individual (living body).
- the mammal is not particularly limited, and examples thereof include humans and mammals other than humans. Examples of mammals other than humans include mice, rats, guinea pigs, hamsters, cows, goats, sheep, pigs, monkeys, dogs, cats and the like.
- the injection when the injection is performed into a cell, the injection may be made into the cytoplasm of the cell or the cell nucleus of the cell. , Both in the cytoplasm and nucleus of the cell may be injected.
- the injection target in the present embodiment is not particularly limited, but is preferably one or more selected from the group consisting of the intradermal, subcutaneous, and muscular layers in the skin of an individual (living body) of a mammal. ..
- the solution containing the biomolecule and the gas are injected from the injector toward the skin surface and injected into the skin, and the group is selected from the group consisting of the intradermal, subcutaneous and lower muscle layers in the skin. It is possible to adopt a method of injecting more than one.
- the "tip side” means the side on which the injection port from which the solution containing the biomolecule and the predetermined gas are ejected from the injector is arranged, and is referred to as the "base end side”. Means the side of the injector opposite to the tip side, and these terms do not specifically refer to a particular location or location.
- the driving unit applies injection energy in order to inject the solution containing the biomolecule and the gas into the injection target.
- the injection energy from the driving unit is used to pressurize the solution containing the biomolecule and the gas contained in the accommodating portion by the pressurizing unit. By doing so, the solution containing the biomolecule and the gas flow through the flow path of the accommodating portion.
- the injection energy may be the injection energy used in a conventional injector, for example, combustion energy such as explosives, generated energy such as a gas generating agent, electrical energy such as a piezoelectric element, mechanical energy such as a spring, and the like. And energy in which these forms of energy are appropriately combined can be used.
- the explosives include, for example, explosives containing zirconium and potassium perchlorate (ZPP), explosives containing titanium hydride and potassium perchlorate (THPP), titanium and perchlorine.
- ZPP zirconium and potassium perchlorate
- THPP titanium hydride and potassium perchlorate
- APP gunpowder containing aluminum and potassium perchlorate
- ABO gunpowder containing aluminum and bismuth oxide
- AMO molybdenum oxide
- An explosive (ACO) an explosive containing aluminum and iron oxide (AFO), or an explosive containing a plurality of combinations thereof can be mentioned.
- the characteristic of these explosives is that even if the combustion product is gas at high temperature, it does not contain a gas component at room temperature, so that the combustion product immediately condenses after ignition.
- the temperature of the combustion product at the time of pressurization is adjusted to the solution containing the biomolecule and the gas by burning the igniter.
- the pressure applied to the gas can be changed to near room temperature in a short time after reaching the first peak emission output.
- the gas generating agent is a single-based smokeless powder (for example, 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, 1.2% by mass of potassium sulfate). Included is single-based smokeless powder), and various gas generators used in gas generators for airbags and gas generators for seatbelt pretensioners can also be used.
- the pressurizing portion pressurizes the solution containing the biomolecule and the gas contained in the accommodating portion during operation to pressurize the solution containing the biomolecule and the biomolecule from the ejection port.
- the gas is injected toward the injection target.
- the pressurization by the pressurizing portion is not particularly limited as long as the system is not destroyed, for example, by destroying the accommodating portion, and pressurization conditions in a normal injector can be adopted.
- the pressure is the pressure inside the accommodating portion.
- the measuring method is not particularly limited, but for example, in the case of measuring using the injector described in the examples described later, the measuring method may be performed by the method described in the "Measuring method of pressure in the accommodating portion" column described later. can.
- the injection energy from the drive unit is transmitted to the plunger via the piston, and the plunger slides in the accommodating portion to form a solution containing the biomolecule and the gas contained in the accommodating portion in the nozzle portion. It is extruded along the flow path and finally ejected from the ejection port toward the injection target.
- the storage portion may or may not contain the solution containing the biomolecule and the gas from the beginning, and if not contained, the solution containing the biomolecule via a nozzle having an ejection port. It can be accommodated by sucking the gas into the accommodating portion. As described above, by adopting a configuration that requires a storage operation in the storage portion, it is possible to inject a solution and a gas containing any required biomolecule into the injection target. Therefore, in the injector of the present embodiment, the syringe portion and the injector main body may be detachably configured. Further, although the accommodating portion accommodates the solution containing the biomolecule and the gas, it is preferable that the accommodating portion accommodates the solution containing the biomolecule on the distal end side.
- the gas is accommodated on the proximal end side in the accommodating portion. From this, it can be said that it is preferable that the gas is not accommodated on the tip side in the accommodating portion.
- the solution containing the biomolecule is first sucked into the accommodating portion through a nozzle having an injection port, then the gas is sucked into the accommodating portion, and then the injector is lightly shaken in the accommodating portion. It can be prepared so that the solution containing the biomolecule is accommodated on the tip side. Further, the gas is first sucked into the accommodating portion through a nozzle having an injection port, and then the position of the gas is maintained so that the accommodating gas exists on the proximal end side in the accommodating portion. , The solution containing the biomolecule can be sucked into the accommodating portion to prepare.
- the injector of the present embodiment is a conventional injector that can be used to inject an injection solution into an injection target without using an injection needle, and the container contains the solution containing the biomolecule and the gas. You can get it.
- Such conventional injectors include, for example, the injector described in International Publication No. 2019/156238, the injector described in International Publication No. 2019/156239, and the injector described in International Publication No. 2019/156237. , The injector described in Japanese Patent No. 5989039 and the like.
- the syringe 1 (needleless syringe) will be described as an example of the injector of the present embodiment with reference to the drawings.
- the configuration of the following embodiment is an example, and is not limited to the configuration of the present embodiment.
- the terms “tip side” and “base end side” are used to indicate the relative positional relationship of the syringe 1 in the longitudinal direction.
- the "tip side” represents a position closer to the tip of the syringe 1, which will be described later, that is, a position closer to the ejection port 31a
- the "base end side” is a direction opposite to the "tip side” in the longitudinal direction of the syringe 1. That is, it represents the direction on the drive unit 7 side.
- this example is an example in which the combustion energy of the explosive ignited by the ignition device is used for pressurization as injection energy, but the present embodiment is not limited to this.
- FIG. 1 is a diagram showing a schematic configuration of a syringe 1, and is also a cross-sectional view of the syringe 1 along its longitudinal direction.
- the syringe 1 is a syringe assembly 10 in which a sub-assembly composed of a syringe unit 3 and a plunger 4 and a sub-assembly composed of a syringe body 6, a piston 5, and a drive unit 7 are integrally assembled. , It is configured to be attached to the housing (syringe housing) 2.
- the syringe assembly 10 is configured to be removable with respect to the housing 2.
- the accommodating portion 32 formed between the syringe portion 3 and the plunger 4 included in the syringe assembly 10 is filled with a solution containing a biomolecule and a predetermined gas, and the syringe assembly 10 is the living body. It is a unit that is thrown away every time a solution containing molecules and the gas are injected.
- the housing 2 side includes a battery 9 that supplies electric power to the igniter 71 included in the drive unit 7 of the syringe assembly 10.
- Power is supplied from the battery 9 to the electrode on the housing 2 side and the electrode on the drive unit 7 side of the syringe assembly 10 via wiring by the user pressing a button 8 provided on the housing 2. Will be done between.
- the shapes and positions of both electrodes are designed so that the electrodes on the housing 2 side and the electrodes on the drive unit 7 side of the syringe assembly 10 automatically contact each other when the syringe assembly 10 is attached to the housing 2.
- the housing 2 is a unit that can be used repeatedly as long as the electric power that can be supplied to the drive unit 7 remains in the battery 9. In the housing 2, when the power of the battery 9 is exhausted, only the battery 9 may be replaced and the housing 2 may be used continuously.
- the syringe portion 3 is formed with an accommodating portion 32 which is a space capable of accommodating the solution containing the biomolecule and the gas. More specifically, as shown in FIG. 1, the plunger 4 is slidably arranged along the inner wall surface extending in the axial direction of the syringe portion 3, and the inner wall surface of the syringe portion 3 and the plunger 4 cause the accommodating portion 32 to be slidably arranged. It is defined.
- the syringe portion 3 has a nozzle portion 31 communicating with the accommodating portion 32, and an injection port 31a is formed on the tip end side of the nozzle portion 31.
- the cross-sectional area of the flow path of the nozzle portion 31 gradually decreases from the accommodating portion 32 side toward the injection port 31a side, and the solution containing biomolecules and a predetermined gas filled in the accommodating portion 32 are injected into the nozzle portion 31. It is a flow path for leading to 31a.
- the shape of the tip side of the plunger 4 substantially matches the shape of the nozzle portion 31.
- the piston 5 is made of metal, for example, and is pressurized by a combustion product (combustion gas) generated by the igniter 71 of the drive unit 7 to slide through a through hole formed inside the syringe body 6. It is configured as follows.
- the syringe body 6 is a substantially cylindrical member, and the piston 5 is slidably housed along an inner wall surface extending in the axial direction thereof.
- the piston 5 may be made of resin, and in that case, a metal may be used in combination with a portion where heat resistance and pressure resistance are required. Further, as shown in FIG. 1, the piston 5 is integrally connected to the plunger 4.
- the drive unit 7 As shown in FIG. 1, the drive unit 7 is fixed to the proximal end side with reference to the through hole in the syringe body 6.
- the drive unit 7 has an igniter 71, which is an electric igniter.
- the igniter 71 is arranged so as to face the inside of the through hole in the syringe body 6, and the igniter is housed in the igniter 71.
- the igniting agent various explosives can be adopted as described above. Further, the igniter can be housed in, for example, an explosive cup made of an appropriate thin-walled metal.
- the syringe 1 configured as described above is adjusted so that the volume of the gas contained in the storage unit 32 is, for example, 20% or more and 60% or less of the volume of the storage unit 32.
- the operation contents of the syringe 1 having the above configuration will be described.
- a solution containing biomolecules and a predetermined gas are sucked from the ejection port 31a of the nozzle portion 31.
- the solution containing the biomolecule and the predetermined gas can be filled in the accommodating portion 32.
- the operation is driven from the battery 9 using this as a trigger. Operating power is supplied to the igniter 71 of the unit 7, and the igniter 71 operates.
- the igniter 71 When the igniter 71 is activated, the igniter is ignited and burned to generate a combustion product (flame, combustion gas, etc.). As a result, for example, the explosive cup of the igniter 71 is cleaved, and the combustion gas of the igniter is discharged into the through hole in the syringe body 6. As a result, the pressure in the through hole of the syringe body 6 rapidly increases, and the piston 5 is pressed toward the tip side of the syringe body 6, and as a result, the piston 5 is directed toward the tip side along the inner wall surface of the through hole in the syringe body 6. And the piston 5 slides.
- a combustion product flame, combustion gas, etc.
- the plunger 4 since the plunger 4 is integrally connected to the piston 5, the plunger 4 also slides along the inner wall surface of the syringe portion 3 in conjunction with the piston 5. That is, when the plunger 4 is pushed toward the nozzle portion 31 located on the distal end side of the syringe portion 3, the volume of the accommodating portion 32 in which the solution containing the biomolecule and the predetermined gas are contained decreases, and the volume suddenly decreases. It will be pressurized. As a result, the solution containing the biomolecules and the predetermined gas filled in the accommodating portion 32 are pushed into the nozzle portion 31, and are ejected from the ejection port 31a at high pressure. This makes it possible to inject a solution containing biomolecules and a predetermined gas into the injection target.
- a gas generator or the like that burns with a combustion product generated by combustion of explosives in the igniter 71 to generate gas can also be arranged in the igniter 71 or in the through hole of the syringe body 6.
- the configuration for arranging the gas generating agent in the igniter 71 is a technique already known as disclosed in International Publication No. 01-031282, Japanese Patent Application Laid-Open No. 2003-25950, and the like.
- the gas generating agent a single-based smokeless powder containing 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate can be mentioned. It is also possible to use various gas generators used in gas generators for airbags and gas generators for seatbelt pretensioners. By adjusting the size, size, and shape of the gas generating agent when it is placed in the through hole, particularly the surface shape, it is possible to change the combustion completion time of the gas generating agent.
- the pressure transition applied to the solution containing the biomolecule and the gas can be a desired transition, that is, a transition in which the solution containing the biomolecule and the gas can appropriately reach the injection target.
- the drive unit 7 also includes a gas generating agent or the like used as needed.
- the "pressurizing portion" is configured including the plunger 4 and the piston 5.
- Another embodiment of the present disclosure is a method of injecting a solution containing a biomolecule and a predetermined gas into an injection target by using the injector of the above embodiment.
- the solution containing the injector, the injection target, and the biomolecule in this embodiment the above description of the embodiment is incorporated.
- Example 1 As a plasmid, pGL4.13 [luc2 / SV40] Vector (promega) was prepared, and the required amount was amplified to prepare a plasmid having a concentration of 1 ⁇ g / ⁇ L. The plasmid solution was sucked up into the syringe container (volume: 100 ⁇ L) from the nozzle of the syringe by 100 ⁇ L, 80 ⁇ L, 70 ⁇ L, 50 ⁇ L, 40 ⁇ L, or 30 ⁇ L.
- the plunger was pulled up to the scale of 100 ⁇ L without sucking up the plasmid solution, and filled with air in a normal laboratory. That is, they have a volume of air contained in the accommodating portion of 0%, 20%, 30%, 50%, 60%, and 70%, respectively, of the volume of the accommodating portion (hereinafter, said accommodating portion).
- the volume of air contained in the container with respect to the volume of the above is sometimes referred to as "air abundance"), and the amount of plasmid to be injected is 100 ⁇ g, 80 ⁇ g, 70 ⁇ g, 50 ⁇ g, 40 ⁇ g, and 30 ⁇ g, respectively. ..
- the air in the storage portion at the time of injection was stored in the proximal end side, and the plasmid solution was accommodated in the distal end side.
- the injector is used as a device for injecting the injection into the abdomen of a test animal, which will be described later, and is the injector shown in FIG.
- 35 mg of ZPP is used as an igniter
- 40 mg of a single-based smokeless powder (containing 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate) is used as a gas generating agent. did.
- the conventional technique was used to measure the time from the start of pressurization until the pressure reaches the maximum pressure and the maximum pressure.
- the injection force is distributed and applied to the diaphragm of the load cell arranged downstream of the nozzle, and the output from the load cell is the detection amplifier. It was measured by a method in which it was collected by a data collection device and stored as an hourly emission output (N).
- the injection pressure was calculated by dividing the injection pressure measured in this way by the area of the injection port 31a of the injector.
- the measured value by the internal pressure measurement of the accommodating portion is equivalent to the injection pressure, and the injection pressure can be used as the pressure inside the accommodating portion.
- the maximum pressure was 10.3 MPa.
- a domestic pig (Specific Pathogen Free, SPF) was used as a test animal, anesthetized in advance, and after shaving, the injection in the injector was injected into the abdomen. After the injection, the animals were kept for about 24 hours and euthanized by blood removal under anesthesia.
- the injection site is hollowed out with a biopsy trepan ⁇ 8.0 mm (shell mark), collected in a 2.0 mL tube, and 1 mL each of Passive Lysis 5 ⁇ Buffer (Promega) diluted 5 times with Milli-Q water is added to about 1 mm. Mince with scissors until it becomes a piece of skin.
- the Luciferase Assay System (Promega) was used for luciferase measurement. That is, 20 ⁇ L of the protein extract was added to 100 ⁇ L of the substrate solution, mixed, and the luminescence amount (RLU) was measured with Lumitester C (Kikkoman).
- Example 1 Separately, the following comparative experiment was conducted. That is, the same operation as in Example 1 was performed except that the same amount of TE buffer (Nacalai Tesque) was filled in place of the air. As a result, it was confirmed that the plasmid concentration did not affect the expression efficiency per 1 ⁇ g of the plasmid.
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Abstract
Description
このうち無針注射器では、加圧ガスやバネ、電磁力により注射液が収容された収容室に対して圧力を加えることで注射成分を射出する構成が採られることがある。例えば、注射器本体の内部に複数のノズル孔が形成されるとともに、各ノズル孔に対応して射出時に駆動されるピストンを配置させる構成が採用されている(特許文献1)。この構成により、複数のノズル孔から注射液を同時に噴射させて対象への均一な注射を実現しようとしている。そして、ルシフェラーゼ遺伝子を含むプラスミドをラットに注射し、高効率に細胞移入できている。
また、無針注射器での注射液の射出動力源として、加圧ガスを利用する形態がある。例えば、射出初期に瞬間的に大きな加圧を行った後、40~50msecかけて加圧力を徐々に低減させていく加圧形態が例示されている(特許文献2)。
また、無針注射器を用いた注入の際、薬液チャンバの射出口で薬液と患者の皮膚とが予め接触している状態で注入をすると、駆動バーが薬液に衝突して発生する衝撃力が、薬液と患者の皮膚との間で感知される時間長によって大幅に減衰されてしまうため、薬液チャンバ内の射出口側にガス・ポケットを設けた上で薬液を注入する技術が開示されている(特許文献3)。
さらに、生体を対象にした試験ではないが、無針注射器の収容室が空気を含むことによって、DNAを接着系株化細胞の細胞内へ効率よく導入できるというin vitro試験が報告されている(特許文献4)。
注射針を介することなく生体分子を含む溶液と所定の気体とを注入対象に注入する注入器であって、
前記生体分子を含む溶液と前記気体とを収容した収容部と、
前記収容部と連通するノズル部であって、前記生体分子を含む溶液と前記気体とを前記注入対象に向けて射出するための射出口を有するノズル部と、
作動時に前記収容部に収容されている前記生体分子を含む溶液と前記気体とを加圧することで前記射出口から前記生体分子を含む溶液と前記気体とを前記注入対象に向けて射出する加圧部と、
を備える、注入器である。
前記注入器はまた、前記気体が空気であることを好ましい態様としている。
前記注入器はまた、前記生体分子が遺伝子を含むDNAであることを好ましい態様としている。
注射針を介することなく生体分子を含む溶液と所定の気体とを注入対象に注入する注入器であって、
前記生体分子を含む溶液と前記気体とを収容した収容部と、
前記収容部と連通するノズル部であって、前記生体分子を含む溶液と前記気体とを前記注入対象に向けて射出するための射出口を有するノズル部と、
作動時に前記収容部に収容されている前記生体分子を含む溶液と前記気体とを加圧することで前記射出口から前記生体分子を含む溶液と前記気体とを前記注入対象に向けて射出する加圧部と、
を備える、注入器である。
本態様における、注入対象に注入される生体分子とは、注入対象に注入された際に該注入対象において機能するものであれば特に制限されない。また、該生体分子は天然物であってもよいし、人工的に合成されたものであってもよい。例えば、核酸又はその誘導体;ヌクレオシド、ヌクレオチド、又はそれらの誘導体;アミノ酸、ペプチド、タンパク質、又はそれらの誘導体;脂質又はその誘導体;金属イオン;低分子化合物、又はその誘導体;抗生物質;ビタミン又はその誘導体等が挙げられる。核酸であれば、DNAでもRNAでもよく、それらは遺伝子を含んでもよい。後述の実施例では、生体分子として、ルシフェラーゼ遺伝子を含む遊離のプラスミドDNAを用い、該ルシフェラーゼ遺伝子をレポーター遺伝子として用いている。
注入対象に注入される生体分子は、注入対象に注入された際に該注入対象において機能し、また、生体分子が安定して存在し、また、該注入対象を破壊するなどの悪影響がなければ、遊離の形態でもナノ粒子等の担体に固定されている形態でもよく、修飾されていてもよく、溶媒を含め、その態様は特に限定されない。
前記DNAが遺伝子を含む場合には、発現カセットや発現ベクターに該遺伝子が含まれた形態で設計されること等が挙げられる。さらに、例えば、前記DNAが注入される注入対象および注入部位に適したプロモーターの制御下に遺伝子が配置されていてもよい。すなわち、いずれの態様においても公知の遺伝子工学的手法を用いることができる。後述の実施例では、発現ベクターとして、哺乳類発現ベクターであるpGL4.13[luc2/SV40]Vector(プロメガ社製)を用いている。当該プラスミドベクターは公知であり、当業者であれば入手可能である。発現ベクター及び組換えベクターのサブクローニングは公知の方法に従って行うことができる。
本実施態様の注入器は、その収容部が所定の気体を含む。
前記気体としては、注入対象に前記生体分子を含む溶液が注入された際に該生体分子が該注入対象において機能し、また、前記生体分子が安定して存在し、また、該注入対象を破壊するなどの悪影響がなければ特に制限されないが、空気が例示できる。前記空気は、一般的に用いられる空気であってよく、その組成は特段限定されない。例えば、約8割の窒素と約2割の酸素の混合気体が挙げられる。また、前記気体としては、窒素、酸素、オゾン、二酸化炭素、水素、一酸化炭素が例示でき、これらのうちのいずれか二種以上の混合気体が例示できる。また、好ましい一態様では、前記気体は、微生物等を含まない気体や、微生物等を含む場合でもそれが死滅した気体である。
一方で、前記収容部の容積に対して、前記収容部に収容された前記気体の体積が小さすぎると、上記と同様に、加圧とともに前記生体分子を含む溶液に前記気体が溶け込みながら注入対象への前記生体分子を含む溶液の注入が始まり、減圧とともに前記生体分子を含む溶液に溶け込んでいた前記気体の一部が気体に戻るが、前記生体分子を含む溶液に溶け込む前記気体の量が少ないために注入対象に与えるシェアストレスが小さくなると推測される。その結果、注入対象において機能する生体分子の割合が小さくなると推測される。
それらの観点から、前記収容部に収容された前記気体の体積は、前記収容部の容積の、好ましくは20%以上、より好ましくは30%以上であり、一方で、好ましくは60%以下、より好ましくは50%以下である。
前記注入対象において機能する生体分子の割合が大きいことの例としては、生体分子としてのDNAが遺伝子を含む場合としては下記が挙げられる。
前記収容部が前記気体を収容しないで(すなわち、前記収容部が前記生体分子を含む溶液で満たされている場合で)DNAを含む溶液を注入対象に注入したとき(これを態様Cとする。)の、前記注入対象へ注入された単位DNA量あたりの該遺伝子の発現量を「発現量C」とし、
DNAを含む溶液と前記気体との総体積が、前記態様Cにおいて前記収容部に収容した前記DNAを含む溶液の体積と同一となるように、前記収容部が前記DNAを含む溶液と前記気体とを収容して、前記注入対象に注入したときの、前記注入対象へ注入された単位DNA量あたりの該遺伝子の発現量を「発現量A」としたとき、
発現量C < 発現量A
の場合である。
本実施態様における注入対象は、例えば、細胞、細胞シート、細胞塊、組織、器官(皮膚や臓器等)、器官系、個体(生体)等からなる群から選択される一以上であってよく制限はない。in vitro系、in vivo系、ex vivo系をはじめ、いずれであってよい。前記細胞塊は3次元培養で得られた細胞塊であってよく、前記器官(皮膚や臓器等)はオルガノイドであってよい。
本実施態様の注入器において、「先端側」とは、注入器から生体分子を含む溶液と所定の気体とが射出される射出口が配置されている側を意味し、「基端側」とは、注入器において先端側とは反対の側を意味するものであり、これらの文言は、特定の箇所や位置を限定的に指すものではない。
火薬の燃焼エネルギーを射出エネルギーとして利用する場合、火薬としては、例えば、ジルコニウムと過塩素酸カリウムを含む火薬(ZPP)、水素化チタンと過塩素酸カリウムを含む火薬(THPP)、チタンと過塩素酸カリウムを含む火薬(TiPP)、アルミニウムと過塩素酸カリウムを含む火薬(APP)、アルミニウムと酸化ビスマスを含む火薬(ABO)、アルミニウムと酸化モリブデンを含む火薬(AMO)、アルミニウムと酸化銅を含む火薬(ACO)、アルミニウムと酸化鉄を含む火薬(AFO)のうち何れか一つの火薬、又はこれらのうち複数の組み合わせを含む火薬が挙げられる。これらの火薬の特徴としては、その燃焼生成物が高温状態では気体であっても常温では気体成分を含まないため、点火後燃焼生成物が直ちに凝縮を行う。それにより、前記生体分子を含む溶液と前記気体の射出のための加圧過程において、該加圧時の燃焼生成物の温度を、点火薬の燃焼により、前記生体分子を含む溶液と前記気体とに掛かる圧力が最初のピーク射出力を迎えてから短時間に常温近傍まで推移させることができる。
また、ガス発生剤の発生エネルギーを射出エネルギーとして利用する場合、ガス発生剤としては、シングルベース無煙火薬(例えば、ニトロセルロース98質量%、ジフェニルアミン0.8質量%、硫酸カリウム1.2質量%を含むシングルベース無煙火薬が挙げられる。)や、エアバッグ用ガス発生器やシートベルトプリテンショナ用ガス発生器に使用されている各種ガス発生剤を用いることも可能である。
前記加圧部による加圧は、例えば、前記収容部を破壊するなど、系を破壊することがない限り特に制限されず、通常の注入器における加圧条件を採用することができる。
ここで、前記圧力とは収容部内の圧力のことである。その測定方法は特に制限されないが、例えば、後述の実施例に記載した注入器を用いて測定する場合には、後述の「収容部内の圧力の計測方法」欄に記載した方法で測定することができる。
また、前記収容部は、前記生体分子を含む溶液と前記気体とを収容しているが、前記収容部内において先端側に前記生体分子を含む溶液を収容していることが好ましい。換言すれば、前記収容部内において基端側に前記気体を収容していることが好ましい。このことは、前記収容部内において先端側には前記気体を収容していないことが好ましいとも言える。
例えば、射出口を有するノズルを介して、先に前記生体分子を含む溶液を収容部内に吸引し、次いで前記気体を収容部内に吸引し、次いで、注入器を軽く振るなどして、収容部内において先端側に前記生体分子を含む溶液が収容されるようにして調製することができる。また、射出口を有するノズルを介して、先に前記気体を収容部内に吸引し、次いで、収容された前記気体が前記収容部内において基端側に存在するように前記気体の位置を維持しながら、前記生体分子を含む溶液を収容部内に吸引して調製することができる。
図1は、注射器1の概略構成を示す図であり、注射器1のその長手方向に沿った断面図でもある。注射器1は、シリンジ部3とプランジャ4とで構成されるサブ組立体と、注射器本体6とピストン5と駆動部7とで構成されるサブ組立体とが一体に組み立てられた注射器組立体10が、ハウジング(注射器ハウジング)2に取り付けられることで構成される。
本実施態様における注入器、注入対象、生体分子を含む溶液については、上記した前記実施態様の説明を援用する。
プラスミドとしてはpGL4.13[luc2/SV40]Vector(プロメガ)を準備し、必要量を増幅して1μg/μLの濃度に調製したものを使用した。
前記プラスミド溶液を、注入器の収容部(容積:100μL)に、該注入器のノズルから100μL、80μL、70μL、50μL、40μL、又は30μL吸い上げた。その後、100μLの前記プラスミド溶液を吸い上げた場合以外は、いずれも前記プラスミド溶液を吸い上げることなく100μLの目盛りまでプランジャを引き上げて、通常の実験室内の空気を充填した。すなわち、それらは、収容部に収容された空気の体積が、前記収容部の容積の、それぞれ、0%、20%、30%、50%、60%、70%であり(以下、前記収容部の容積に対する収容部に収容された空気の体積を「空気存在率」と称することがある。)、且つ、注入されるプラスミド量は、それぞれ、100μg、80μg、70μg、50μg、40μg、30μgである。また、注入時の前記収容部内の空気は基端側に収容されるようにし、前記プラスミド溶液は先端側に収容されるようにした。
尚、加圧開始から圧力が最大圧力に到達するまでの時間と該最大圧力の測定には従来技術を利用した。すなわち、特開2005-21640号公報に記載の測定方法のように、射出の力を、ノズルの下流に配置されたロードセルのダイアフラムに分散して与えるようにし、ロードセルからの出力は、検出増幅器を介してデータ採取装置にて採取されて、時間ごとの射出力(N)として記憶されるという方法によって測定した。このように測定された射出圧を、注入器の射出口31aの面積によって除することで、射出圧を算出した。収容部の内圧測定による測定値は射出圧と同等であり、射出圧をもって収容部内の圧力とすることができる。その結果、例えば、収容部に収容された空気の体積が、前記収容部の容積の0%である場合では、加圧開始から圧力が最大圧力に到達するまでの時間は0.55ミリ秒であり、該最大圧力は10.3MPaであった。
なお別途、次の比較実験を行った。すなわち、前記空気の代わりに同量のTE緩衝液(ナカライテスク)を充填すること以外は実施例1と同様の操作を行った。その結果、プラスミド濃度は、プラスミド1μgあたりの発現効率に影響を与えないことを確認した。
2・・・・ハウジング
3・・・・シリンジ部
4・・・・プランジャ
5・・・・ピストン
6・・・・注射器本体
7・・・・駆動部
8・・・・ボタン
9・・・・バッテリ
10・・・・注射器組立体
31・・・・ノズル部
31a・・・射出口
32・・・・収容部
71・・・・点火器
Claims (5)
- 注射針を介することなく生体分子を含む溶液と所定の気体とを注入対象に注入する注入器であって、
前記生体分子を含む溶液と前記気体とを収容した収容部と、
前記収容部と連通するノズル部であって、前記生体分子を含む溶液と前記気体とを前記注入対象に向けて射出するための射出口を有するノズル部と、
作動時に前記収容部に収容されている前記生体分子を含む溶液と前記気体とを加圧することで前記射出口から前記生体分子を含む溶液と前記気体とを前記注入対象に向けて射出する加圧部と、
を備える、注入器。 - 前記収容部に収容された前記気体の体積は、前記収容部の容積の20%以上60%以下である、請求項1に記載の注入器。
- 前記気体が空気である、請求項1又は2に記載の注入器。
- 前記生体分子が遺伝子を含むDNAである、請求項1~3のいずれか一項に記載の注入器。
- 請求項1~4のいずれか一項に記載の注入器を用いて、注入対象に生体分子を含む溶液と所定の気体とを注入する方法。
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