Injection device and injection kit

Abstract

An injection device (1) according to the present invention comprises an injection needle (10) and a drug solution supply barrel (20) containing a drug solution (L). The injection needle (10) has conical protrusions (11) each protruding from a base surface (2) and having an opening (11a) in a side surface thereof. The openings (11a) have a horizontal dimension of 25 μm - 60 μm and a vertical dimension of 25 μm -130 μm. The openings have an area (X) of 500 μm2 - 6100 μm2. The drug solution has a viscosity (Y) at 20°C of 1.00 mPa·s -10 mPa·s. Depending on the categorized type of the drug solution, any one of predetermined relationships (Q), (R), and (S) is further satisfied.

Description

Injection equipment and injection kits

[0001] The present invention relates to an injection device and an injection kit.

[0002] In recent years, in the fields of medicine and cosmetics, intradermal administration of liquids such as medicinal solutions using injection needles equipped with fine needle-like protrusions, also known as microneedles, has attracted attention. This injection needle allows the microneedle to be inserted into a relatively shallow layer of the skin, such as the stratum corneum, to inject liquid into the body, significantly reducing the pain felt by the subject compared to conventional syringes. Therefore, it has attracted attention as a minimally invasive means of administering liquids. For example, Patent Document 1 proposes a microneedle designed to deliver medicinal solutions intradermally.

[0003] US2002 / 0198509A1

[0004] The present invention relates to an injection device comprising an injection needle and a drug solution feeder containing a drug solution. In one embodiment, the injection needle preferably has a cone-shaped protrusion protruding from a base surface and having an opening on a side surface. In one embodiment, the opening preferably has a horizontal width of 25 μm or more and 60 μm or less and a vertical width of 25 μm or more and 130 μm or less. In one embodiment, the area X of the opening calculated from the horizontal width and the vertical width of the opening is 500 μm or less. 2 6100 μm or more 2 In one embodiment, the viscosity Y of the medicinal solution at 20°C is preferably 1.00 mPa·s or more and 10 mPa·s or less. In one embodiment, the injection device preferably satisfies any one of the following relationships (Q), (R), and (S): (Q) The medicinal solution contains an organic compound A2 having a weight-average molecular weight of 1000 or more as an active ingredient, and the viscosity Y (mPa·s) of the medicinal solution and the area X (μm ２) satisfy the relational expression Y≦0.00018×X+2.2. (R) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle diameter of 20 nm or more and 1200 nm or less, the fine particles being formed by aggregation, bonding or compounding of an inorganic compound and the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relational expression Y≦0.0015×X+3.0. (S) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles with a particle diameter of 20 nm or more and 1200 nm or less, the fine particles including fine particles formed by aggregation, bonding, or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relation Y≦0.00044×X+1.4.

[0005] The present invention also relates to a method for providing an injection device according to claim 1 or 2. In the method, it is preferable to provide the injection needle and the drug solution feeder containing the drug solution, in a state where they are separated from each other, together with an explanation of how they are used in combination. The present invention also relates to an injection kit including the injection device according to claim 1 or 2 and a holder that moves the injection device, with the injection needle attached to the drug solution feeder, toward the skin and punctures the skin with the protrusion of the injection needle.

[0006] The present invention also relates to an injection kit including an injection needle, an injection device including a drug solution supplying device capable of storing a drug solution, and the drug solution. In one embodiment, the injection needle preferably has a cone-shaped protrusion protruding from a base surface and having an opening on a side surface. In one embodiment, the opening preferably has a horizontal width of 25 μm or more and 60 μm or less, and a vertical width of 25 μm or more and 130 μm or less. In one embodiment, the area X of the opening calculated from the horizontal width and the vertical width of the opening is 500 μm or less. ２ 6100 μm or more ２In one embodiment, the viscosity Y of the medicinal solution at 20°C is preferably 1.00 mPa·s or more and 10 mPa·s or less. In one embodiment, the injection kit preferably satisfies any one of the following relationships (Q), (R), and (S): (Q) The medicinal solution contains an organic compound A2 having a weight-average molecular weight of 1000 or more as an active ingredient, and the viscosity Y (mPa·s) of the medicinal solution and the area X (μm ２ ) satisfy the relational expression Y≦0.00018×X+2.2. (R) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle diameter of 20 nm or more and 1200 nm or less, the fine particles being formed by aggregation, bonding or compounding of an inorganic compound and the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relational expression Y≦0.0015×X+3.0. (S) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles with a particle diameter of 20 nm or more and 1200 nm or less, the fine particles including fine particles formed by aggregation, bonding or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relation Y≦0.00044×X+1.4.

[0007] FIG. 1 is a schematic perspective view showing a syringe according to a preferred embodiment of the present invention, with the syringe needle and the drug solution supplier connected. FIG. 2 is a schematic perspective view of the drug solution supplier in the syringe shown in FIG. 1. FIG. 3 is an enlarged cross-sectional view of the connection portion of the drug solution supplier shown in FIG. 2. FIG. 4 is a schematic perspective view of the syringe needle shown in FIG. 1. FIG. 5 is a schematic perspective view of the fine protrusion device shown in FIG. 4. FIG. 6 is a schematic plan view of the fine protrusion device shown in FIG. 5. FIG. 7(a) is a cross-sectional view taken along line A-A in FIG. 6. FIG. 7(b) is a cross-sectional view taken along line B-B in FIG. 6. FIG. 7(c) is a cross-sectional view taken along line C-C in FIG. 6. FIG. 8 is a schematic view showing the syringe shown in FIG. 1 in use. FIGS. 9(a) to 9(d) are schematic plan views showing another preferred embodiment of the present invention. FIG. 10 is a schematic cross-sectional view showing a second protrusion according to another preferred embodiment of the present invention. FIG. 11 is a cross-sectional view taken along line D-D in FIG. 4. FIG. 12 is a plan view schematically showing the major and minor axes of a wheal measured in an evaluation of the relationship between fluid volume and wheal radius. FIG. 13 is an enlarged view of a hollow protrusion viewed from the side where the apertures are formed. FIGS. 14(a) to 14(c) are graphs showing evaluation results in Examples. FIG. 15 is a perspective view of a holder according to a preferred embodiment of the present invention. FIG. 16 is a cross-sectional view taken along line II-II in FIG. 15. FIG. 17 is a schematic cross-sectional view for explaining a method for measuring the puncture speed. FIG. 18 is a view showing a state in which the injection needle has punctured the skin, and is a cross-sectional view schematically showing a cross section along the thickness direction of the skin. FIG. 19 is a perspective view schematically showing a holder according to another preferred embodiment of the present invention. FIG. 20 is a perspective view showing the main body of the holder shown in FIG. 19 with the slider advanced. FIG. 21 is a perspective view showing the main body of the holder shown in FIG. 19 with the slider retracted. FIG. 22 is a cross-sectional view taken along CC in FIG. 20. FIG. 23 is a cross-sectional view taken along D-D in FIG. 20. Fig. 24 is an explanatory diagram of a holding state by the holding mechanism, and Fig. 25 is a perspective view showing a state in which the slider of the holder shown in Fig. 19 is retracted. Detailed Description of the Invention

[0008] However, the present inventors have found that when designing an injection needle with minimally invasive microprotrusions, conventional injection needles have problems in terms of ensuring sufficient ejection and administration of medicinal solutions. Administration efficiency, for example, means the ability to efficiently inject medicinal solutions into the skin. While the microneedles described in Patent Document 1 above provide a certain level of ejection and administration efficiency, there is a demand for injection devices and injection kits with even higher ejection and administration efficiency. Therefore, the present invention relates to injection devices and injection kits with excellent ejection and administration efficiency. After extensive research to solve the above-mentioned problems, the present inventors have found that ejection and administration efficiency can be dramatically improved by combining protrusions having openings of a predetermined size on their sides with a medicinal solution of a specific concentration.

[0009] The present invention will be described below with reference to preferred embodiments. A preferred embodiment of the injection device of the present invention, an injection device 1, includes an injection needle 10 and a drug solution supplier 20 containing a drug solution L. The injection needle 10 and the drug solution supplier 20 may be separate from each other, or may be connected in a detachable or non-detachable manner. FIG. 1 shows the injection device 1 in a state in which the injection needle 10 and the drug solution supplier 20 are connected. As shown in FIG. 2, the drug solution supplier 20 in the injection device 1 of this embodiment includes a syringe body 21. The syringe body 21 includes a drug solution container 22 capable of containing the drug solution L therein, and includes, at one longitudinal end thereof, a liquid injection port 23 for supplying the drug solution L to the injection needle 10 and a connection portion 24 for the injection needle 10. The drug solution supplier 20 may be something other than a syringe; for example, a tube, an electric injector, or the like may be used.

[0010] In this embodiment, the drug solution feeder 20 includes a cylindrical syringe body 21, a tip portion 25 integrally provided at one end of the syringe body 21, and a finger hook 26 integrally provided at the other end of the syringe body 21. As shown in FIG. 3 , the tip portion 25 includes a liquid inlet 23 and a connection portion 24 of the injection needle 10. The liquid inlet 23 is cylindrical with a diameter smaller than that of the syringe body 21 and has an open tip. The connection portion 24 of the injection needle 10 has a female thread ridge 24a formed on its inner circumferential surface and is capable of threadably engaging with a protruding portion 49 of the injection needle 10, which will be described later. The finger hook 26 is formed at the other end of the syringe body 21 and has a flange-like shape that protrudes outward in the radial direction from the periphery of the opening 27.

[0011] Syringe body 21 is made of, for example, glass or synthetic resin, but is not limited thereto. Finger hook 26 may be formed separately from syringe body 21 and attached to syringe body 21. Injection port 23 may be shaped like a square tube instead of a cylinder.

[0012] The syringe body 21 may also be configured such that a rubber stopper (not shown) that closes the liquid inlet 23 is detachably attached to the tip 25. The rubber stopper fits onto the outer peripheral surface of the liquid inlet 23 and is removed by pulling it out from the liquid inlet 23 before it is threaded onto the protruding portion 49 of the injection needle 10.

[0013] The drug solution feeder 20 includes a plunger member 28. The plunger member 28 includes an operating rod 29 and a gasket 30 that is provided at the tip of the operating rod 29 and disposed inside the syringe body 21, and is capable of being pushed into the syringe body 21.

[0014] In this embodiment, operating rod 29 is made of synthetic resin and is formed in a rod shape. Operating rod 29 is thinner than the inner diameter of syringe body 21 and can be inserted into syringe body 21 through opening 27. The length of operating rod 29 is set to a length that allows it to protrude outward from opening 27 of syringe body 21 even when gasket 30 reaches the tip of syringe body 21 and moves to the stroke end position where it abuts against the rear end of tip portion 25.

[0015] Gasket 30 is formed in a cylindrical shape with a triangular pyramidal tip made of an elastic material such as synthetic rubber, and is capable of sliding on the inner circumferential surface of syringe body 21. Gasket 30 is fixed to operating rod 29, for example, by fitting a convex portion (not shown) provided at the tip of operating rod 29 into a concave portion (not shown) provided in gasket 30.

[0016] The gasket 30 forms a medicinal solution storage section 22 in which the medicinal solution L is filled inside the syringe body 21. The medicinal solution L is supplied to the injection needle 10 from the liquid injection port 23 provided at the tip 25 by pushing the gasket 30 together with the operating rod 29 toward the inside of the syringe body 21.

[0017] The plunger member 28 may also be configured to include a pressing portion 31 that is circular in plan view and is integral with the rear end of the operating rod 29. By providing the pressing portion 31, the plunger member 28 can be pressed in by placing the index finger and middle finger on the finger hook portion 26 and pressing the pressing portion 31 with the thumb, thereby facilitating the operation of pressing the operating rod 29.

[0018] The injection needle 10 in this embodiment is configured to include a fine protrusion device 3 and a base component 4 (see FIG. 4 ). More specifically, the injection needle 10 is formed by liquid-tightly joining the fine protrusion device 3, which is manufactured by processing a sheet material, to the base component 4 by any joining means. The fine protrusion device 3 is configured to include a base surface 2 that is circular in a plan view and a plurality of protrusions protruding from one surface (upper surface) of the base surface 2. The fine protrusion device 3 typically has a protrusion arrangement region in which the protrusions are arranged in a dispersed state in the planar direction. The protrusion arrangement region typically preferably includes a first region R1 and a second region R2, which will be described later.

[0019] The protrusions of the micro-protrusion device 3 preferably include first protrusions 11 having a conical shape and openings 11a on their side surfaces. The openings 11a preferably have a circular shape, such as a circular or elliptical shape. In the example shown in FIG. 5 , the first protrusions 11 are micro-protrusions. From the viewpoint of minimal invasiveness, the protrusion height from the base surface from which the protrusions protrude is preferably 2500 μm or less, more preferably 2050 μm or less. From the viewpoint of puncture performance, the protrusion height is preferably 500 μm or more, more preferably 1250 μm or more. The conical shape of the first protrusions 11 is typically a circular cone shape, but may also be a polygonal pyramid such as a square pyramid. The conical shape includes, in addition to a circular cone shape, an eccentric cone in which the center and tip of the protrusion are at different positions. The first protrusions 11 are preferably micro-protrusions having a hollow portion 11b, so-called hollow microneedles (see FIG. 7( a)).

[0020] The micro-projection device 3 preferably has a first region R1 including one or more first projections 11 in plan view. The first region R1 is preferably located in the central region of the base surface 2 in plan view. The central region is, for example, a circular region with a diameter that is one-third, preferably one-half, of the diameter of the base surface 2. In the illustrated example, the center of the base surface 2 and the center of the first region R1 coincide, but the centers may be offset from each other.

[0021] As shown in FIG. 11 , the base component 4 is cylindrical and has a connecting portion 45 and a protrusion support portion 46 that supports the micro-protrusion 3, with a hollow portion 47 defined inside these portions 45, 46. The micro-protrusion 3 and the base component 4 are joined at the upper end of the protrusion support portion 46 to form a joint portion 5. The joining method is not particularly limited, and known joining means such as heat sealing, ultrasonic waves, lasers, and adhesives can be used. An opening 48 is formed in the center of the connecting portion 45, and the hollow portion 47 communicates with the outside through the opening 48. The opening 48 functions, for example, as a supply port when supplying the chemical solution L to the hollow portion 47 using the chemical solution supply device 20. A protruding portion 49 that threads onto the female thread ridge 24a of the chemical solution supply device 20 is formed at the lower end of the connecting portion 45.

[0022] The injection needle 10 has an opening 11a in the first projection 11, making it suitable for intradermal administration of a liquid such as a medicinal solution. Here, intradermal administration refers to administering a medicinal solution into the epidermis or dermis. In the present invention, administering a medicinal solution into the epidermis is preferable. Specifically, an opening 11a is formed in the side surface of the first projection 11, and the hollow portion 11b of the first projection 11 communicates with the outside via the opening 11a (see FIG. 7(a)). The opening 11a is a through-hole that penetrates the first projection 11 in the thickness direction, and is preferably located on the side surface of the conical first projection 11. The hollow portion 11b of the first projection 11 functions as a passage for the liquid to be discharged from the opening 11a to the outside.

[0023] When using the injection device 1 of this embodiment, first, the syringe body 21 of the drug solution feeder 20 is filled with the drug solution L. Specifically, with the inlet 23 of the syringe body 21 immersed in the drug solution L, the plunger member 28 inserted into the syringe body 21 is pulled up, and the drug solution L is drawn into the syringe body 21. The injection needle 10 is attached to the syringe body 21 filled with the drug solution L to form the injection device 1. Alternatively, in the case of a prefilled syringe, the drug solution L is filled through the opening 27 with a rubber stopper attached to the inlet 23, and the plunger member 28 is inserted into the syringe body 21. Then, the rubber stopper connected to the inlet 23 may be removed, and the injection needle 10 may be attached to the syringe body 21 filled with the drug solution L to form the injection device 1. The plunger member 28 of the drug solution feeder 20 is pressed down, and the drug solution L is filled into the first protrusion 11 of the injection needle 10. Then, when the tip of the first protrusion is inserted substantially perpendicularly into the skin S, the index finger and middle finger are placed on the finger hook portion 26, and the pressing portion 31 of the plunger member 28 is pressed with the thumb, the volume of the medicinal solution storage portion 22 decreases, and the medicinal solution L stored in the medicinal solution storage portion 22 is forced out through the opening 11a of the first protrusion 11, allowing the medicinal solution L to be injected into the skin. When the medicinal solution L is injected into the skin S, the injected medicinal solution L causes the skin to swell, forming a wheal (see FIG. 8 ). Note that if the first protrusion 11 is unable to puncture the skin and the medicinal solution leaks, or if the first protrusion is inserted too deeply and the medicinal solution cannot be injected to the required depth, no wheal will be formed.

[0024] In the injection device 1, the horizontal width L2 of the opening 11a of the first projection 11 is 25 μm or more and 60 μm or less, and the vertical width L1 is 25 μm or more and 130 μm or less (see FIG. 13 ). The viscosity of the drug solution L at 20°C is 1.00 mPa·s or more and 10 mPa·s or less. This allows the user to eject the drug solution L from the injection needle 10 with little force, minimizing residual drug solution L, and therefore the injection device 1 has excellent ejection properties. Furthermore, the injection device 1 of the present invention has openings 11a on the side surfaces of the first projections 11, so that the ejection direction of the drug solution L is approximately parallel to the skin S, facilitating the entry of liquid such as the drug solution L into the skin S and allowing the drug solution to be efficiently injected without leakage. In other words, the injection device 1 has excellent administration properties. As such, the injection device 1 of the present invention has excellent ejection properties and administration properties, such as the ability to efficiently inject the drug solution into the skin.

[0025] From the viewpoint of facilitating the discharge of the liquid medicine L contained in the liquid medicine container 22 from the opening 11a, the area X of the opening 11a of the first projection 11 calculated from the horizontal width L2 and the vertical width L1 (hereinafter also referred to as the hole area X) is preferably 500 μm ２ More preferably, 1250 μm or more ２ From the viewpoint of preventing leakage of liquid onto the skin surface after puncturing, it is preferable that the thickness is 6100 μm or more. ２ Less than or equal to 4800 μm, more preferably ２ From the viewpoint of achieving both, it is preferably 500 μm or less. ２ 6100 μm or more ２ Less than or equal to 1250 μm, more preferably ２ 4800 μm or more ２ Here, the horizontal width L2 and vertical width L1 for calculating the area X of the aperture are calculated based on the minimum length of the cross section of the aperture 11a in the axial direction.

[0026] From the viewpoint of making it easier to eject the medicinal liquid L contained in the medicinal liquid storage section 22 from the opening 11a, the width L2 of the opening 11a of the first protrusion 11 is preferably 25 μm or more, more preferably 40 μm or more, and from the viewpoint of preventing leakage of the liquid onto the skin surface after puncture, it is preferably 100 μm or less, more preferably 60 μm or less, and from the viewpoint of achieving both, it is preferably 25 μm or more and 100 μm or less, more preferably 40 μm or more and 60 μm or less.

[0027] From the viewpoint of making it easier to eject the medicinal solution L contained in the medicinal solution storage section 22 from the opening 11a, the vertical width L1 of the opening 11a of the first protrusion 11 is preferably 25 μm or more, more preferably 40 μm or more, and even more preferably 80 μm or more. From the viewpoint of preventing leakage of the liquid onto the skin surface after puncturing, it is preferably 200 μm or less, more preferably 130 μm or less, and even more preferably 100 μm or less. From the viewpoint of achieving both of these, it is preferably 25 μm or more and 200 μm or less, more preferably 40 μm or more and 200 μm or less, even more preferably 25 μm or more and 130 μm or less, still more preferably 40 μm or more and 130 μm or less, particularly preferably 80 μm or more and 130 μm or less, even more particularly preferably 40 μm or more and 100 μm or less, and even more particularly preferably 80 μm or more and 100 μm or less.

[0028] From the viewpoint of further ensuring the strength of the primary projections, the ratio (L1 / L2) of the vertical width L1 to the horizontal width L2 of the opening 11a of the primary projections 11 is preferably 1.0 or more, more preferably 1.6 or more; from the viewpoint of further improving administration ease, it is preferably 5.2 or less, more preferably 3.25 or less; and from the viewpoint of achieving both, it is preferably 1.0 or more and 5.2 or less, more preferably 1.6 or more and 3.25 or less. The horizontal width L2 and vertical width L1 of the opening 11a are measured as follows. The hole area X is calculated as follows.

[0029] <Method for measuring the width and length of the opening 11a> All injection devices 1 to be manufactured are inspected with a camera during production, and the dimensions of the opening 11a (dimensions along the opening surface) on the outer surface of the first protrusion 11 are measured from the inspection image.

[0030] <Method of calculating hole area X> The hole 11a is considered to be an ellipse (including a perfect circle), and the hole area X (μm 2 )=π×(L2 / 2)×(L1 / 2) (1) It is preferable that the shape of the opening 11a in front view is circular or elliptical.

[0031] From the viewpoint of facilitating the discharge of the chemical liquid L from the opening 11 a, the viscosity of the chemical liquid L at 20° C. is preferably 1.00 mPa·s or more, more preferably 1.05 mPa·s or more, and preferably 10 mPa·s or less, more preferably 5.26 mPa·s or less, also preferably 1.00 mPa·s or more and 10 mPa·s or less, more preferably 1.00 mPa·s or more and 7.10 mPa·s or less, and even more preferably 1.05 mPa·s or more and 5.26 mPa·s or less. The viscosity of the chemical liquid L is measured as follows.

[0032] <Method for Measuring Viscosity of Chemical Solution L> The viscosity of chemical solution L can be measured using a general viscosity measuring device such as a rheometer. Specifically, a cone plate is pressed against chemical solution L, and the shear rate is increased in the shear direction under measurement conditions of 20°C, and the value at which the viscosity (mPa s) becomes constant is defined as the viscosity of chemical solution L.

[0033] The medicinal solution L to be injected into the skin is not particularly limited as long as it can be injected into the skin using the injection device 1 of the present invention, and can include, for example, one or more active ingredients selected from vaccines for preventing infectious diseases such as hepatitis A, hepatitis B, hepatitis C, influenza, COVID-19, respiratory syncytial virus, tuberculosis, rabies, polio, chickenpox, rubella, measles, tetanus, shingles, and malaria; vaccines for treating chronic hepatitis B, tuberculosis, rabies, malignant neoplasms, shingles, and malaria; analgesics for cancer patients; insulin; biological products; gene therapy drugs; injectable preparations and skin-applied preparations used in medical settings, etc. Since the first protrusion 11 of the injection needle 10 punctures the skin, the injection needle 10 can be used not only for pharmacologically active substances used for conventional transdermal administration, but also for pharmacologically active substances that require subcutaneous injection, intramuscular injection, intravenous injection, etc. The skin S into which the medicinal liquid L is injected by the injection needle 10 may be human skin or may be the skin of an animal other than a human.

[0034] When the drug solution L contains a low molecular weight compound, the concentration of the drug solution L is preferably 300 mg / mL or less, from the viewpoint of making it easier to eject the drug solution L from the opening 11a. The low molecular weight compound used in the present invention indicates a compound having a weight average molecular weight of preferably 10,000 or less, more preferably 2,000 or less, and even more preferably 1,000 or less. Furthermore, when the drug solution L contains a protein, the concentration of the drug solution L is preferably 100 mg / mL or less, from the viewpoint of making it easier to eject the drug solution L from the opening 11a. The concentration of the drug solution L is measured as follows.

[0035] <Method for Measuring the Concentration of Drug Solution L> When preparing drug solution L, if a solid drug, such as a powder, is dissolved in a liquid to form the drug solution, the solid drug is weighed and dissolved and diluted with a solvent. The unit of display depends on the preparation method, but it is preferable to display it in weight / volume. Solid drugs include those containing the aforementioned various vaccines, painkillers, insulin, biological products, gene therapy drugs, etc. as active ingredients. The concentration of drug solution L can be measured using high-performance liquid chromatography (HPLC), chromatography, mass spectrometry, etc. For example, when drug solution L contains a protein and is measured using HPLC, a uniformly dissolved drug solution L is prepared, and an Agilent Technologies HPLC is used, with an appropriate column selected for protein separation. A reverse column (C18 column) or the like is typically used. An appropriate organic solvent can be selected as the solvent. As an example, when acetonitrile is used as the organic solvent, the target protein is separated by varying the acetonitrile / water ratio between 5% and 70%. An appropriate flow rate is selected within the range of 1 mL / min to 2 mL / min. The UV detector wavelength is selected appropriately depending on the type of protein, but can generally be measured at 280 nm. If the drug solution L contains protein, measurement can also be performed using the BCA method or the like.

[0036] From the viewpoint of pharmacokinetics or immune induction, it is also preferable to use a medicinal solution L containing an organic compound with a weight-average molecular weight of 1000 or more as an active ingredient. The organic compound contained as an active ingredient is also referred to as organic compound A2. The organic compound A2 contained in medicinal solution L may be one or more types, or may be a complex of one or more types. The medicinal solution of the injection device of the present invention preferably contains, as organic compound A2, one or more types selected from peptides, proteins, nucleic acids, carbohydrates, glycolipids, and glycopeptides. These organic compounds A2 preferably have functions such as pharmacological activity and immunogenicity. More specifically, the organic compound A2 is preferably one or more types selected from peptides, proteins, nucleic acids, carbohydrates, glycolipids, and glycopeptides with pharmacological activity. Specific examples include functional proteins such as antibodies, immunogenic antigen proteins or peptide fragments, and some or all of the components of virus particles. The medicinal solution of the injection device of the present invention preferably contains, as organic compound A2, one or more compounds selected from peptides, proteins, and nucleic acids, and may contain other components such as lipids, carbohydrates, etc. The medicinal solution of the injection device of the present invention may contain lipids and nucleic acids in addition to peptides such as peptide fragments with pharmacological effects, proteins such as antibodies and immunogenic antigen proteins, virus particles, carbohydrates, etc.

[0037] In the case of (Q) where a drug solution containing organic compound A2 is used as the drug solution L, from the viewpoint of making it easier to discharge the drug solution L from the opening 11a and from the viewpoint of properly administering the drug solution intradermally and penetrating the drug solution, the viscosity Y (mPa s) of the drug solution and the area X (μm ２ ) preferably satisfy the relational formula Y≦0.00018×X+2.2, and more preferably Y≦0.00018×X+2.05. In the present invention, (Q) may contain an organic compound having a weight-average molecular weight of less than 1,000 (hereinafter also referred to as "organic compound A1"), although this does not include the cases of (R) and (S) described below.

[0038] Examples of organic compound A1 include ascorbic acid, which is a vitamin C derivative, opioid analgesics (e.g., morphine, hydrocodone, oxycodone, fentanyl, etc.), α2 adrenergic receptor agonists, anesthetics (e.g., profopol, sevoflurane, isoflurane, etc.), analgesics (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs (aspirin, ibuprofen, naproxen, diclofenac, indomethacin, etc.))), acetaminophen, angiotensin convertase inhibitors (e.g., enalapril, ramipril, etc.), and orexin receptor antagonists (e.g., lemborexant, etc.), and these can be used alone or in combination of two or more.

[0039] When a drug solution containing organic compound A2 is used as drug solution L, from the viewpoint of making it easier to eject drug solution L from opening 11a and from the viewpoint of properly administering intradermally and allowing the drug solution to penetrate, the concentration of drug solution L is preferably 0.01 mg / mL or more, more preferably 0.1 mg / mL or more, and preferably 100 mg / mL or less, more preferably 25 mg / mL or less, and preferably 0.01 mg / mL or more and 100 mg / mL or less, more preferably 0.1 mg / mL or more and 25 mg / mL or less.

[0040] The drug solution L containing the organic compound A2 is preferably at least one selected from the group consisting of a GLP-1 receptor agonist, an insulin analogue, a small molecular weight biopharmaceutical, a viral protein, a nucleic acid sequence encoding a viral protein, a protozoan protein, a nucleic acid sequence encoding a protozoan protein, a bacterial protein, and a nucleic acid sequence encoding a bacterial protein.

[0041] Examples of the medicinal solution L containing the organic compound A2 include peptide drugs (GLP-1 receptor agonists), insulin analogs (gylargine, deglidex, etc.), small molecule biopharmaceuticals (insulin, human growth hormone, epoetin, interferon, etc.), hepatitis A virus proteins, hepatitis B virus proteins, hepatitis C virus proteins, influenza virus proteins, SARS-CoV-2 virus proteins, respiratory syncytial virus proteins, Mycobacterium tuberculosis-derived proteins, rabies virus proteins, poliovirus proteins, varicella-zoster virus (VZV) (human herpesvirus type 3) proteins, rubella virus proteins, and measles virus proteins, and Clostridium tetani proteins such as Examples of the antigenic antigen include viruses, bacteria, and protozoa that cause infectious diseases, such as tetanus (Clostridium tetani) bacteria-derived proteins and malaria parasite-derived proteins, ovalbumin, peptide fragments of the above proteins, nucleic acids encoding the genetic information of the above proteins, antigenic peptide fragments that become neoantigens of malignant neoplasms, nucleic acids encoding the genetic information of neoantigens, and proteins and peptide fragments that become allergens, and nucleic acids encoding the genetic information of allergens.

[0042] From the viewpoint of enhancing the effects of the drug solution L, it is preferable that the drug solution L contain fine particles. The fine particles may be lipid aggregates in which the active ingredient of the drug solution L binds and aggregates with metal ions or the like, particles such as lipid micelles, emulsion particles, liposomes, and lipid nanoparticles, nanogel transporters made of carbohydrates, dendrimers, or cellular components. The fine particles exist as fine particles by containing one or more active ingredients of the drug solution L and forming particles made of metal ions, carbohydrates, lipids, or nucleic acids. The fine particles may be a single particle or a mixture of two or more types of particles. From the viewpoint of enhancing the effects of the drug solution L, the average particle size of the fine particles used in the present invention is preferably 20 nm or more, more preferably 80 nm or more. Furthermore, from the viewpoint of facilitating the discharge of the drug solution L through the opening 11a, the average particle size is preferably 8,000 nm or less, more preferably 3,000 nm or less. Considering the above, the average particle size of the fine particles is preferably 20 nm or more and 8,000 nm or less, more preferably 80 nm or more and 3,000 nm or less. The average particle size of the fine particles is measured as follows.

[0043] <Method for Measuring the Average Particle Size of Fine Particles> The average particle size of fine particles can be determined using various known methods, including, for example, a general particle size distribution analyzer. Specific examples include, but are not limited to, instruments that measure using laser diffraction / scattering, centrifugal sedimentation, particle tracking, and dynamic light scattering. All of the above methods enable the measurement of particle size distribution in a short period of time. A diluted solution of the drug solution L is primarily used to measure particle size. In addition to the solvent used in the drug solution L, a phosphate buffer solution or the like may also be used as the dilution solvent. Furthermore, when the drug solution L has a single particle size or multiple particle sizes are expected, measurement can be easily performed by switching the measurement mode. For example, when measuring using dynamic light scattering, the drug solution L is appropriately diluted approximately 100 to 20,000 times with the solvent used, depending on the concentration of the drug solution L. Confirm that the autocorrelation function forms a clean sigmoid curve, and check the peak consisting of the detected particle size and its frequency. If a single peak is detected (peak area ratio is 100%), the average particle size can be calculated and used as the average particle size of the object being measured. When multiple peaks are observed, the average particle size and the peak area ratio can be calculated for each peak to determine the average particle size and abundance ratio of the multiple particle sizes possessed by the measurement target. When multiple peaks are obtained, the average value of the peak with the largest peak area ratio is taken as the average particle size of the main peak, and it is preferable that the average particle size of the main peak is within the range of the average particle size of the above-mentioned preferred medicinal liquid L. Furthermore, when measuring the particle size of a precipitated vaccine or the like, since there is a possibility that large protein aggregates are formed, it is desirable to perform the measurement using a noise removal mode or the like installed in the measuring device as appropriate, and to use the detected particle size as the particle size of the medicinal liquid L.

[0044] When the medicinal solution contains microparticles, from the viewpoint of making it easier to eject the medicinal solution L from the opening 11a and from the viewpoint of properly administering the medicinal solution intradermally and allowing the medicinal solution to penetrate, the concentration of the medicinal solution L is preferably 0.01 mg / mL or more, more preferably 0.1 mg / mL or more, and preferably 25 mg / mL or less, more preferably 5 mg / mL or less, and preferably 0.01 mg / mL or more and 25 mg / mL or less, more preferably 0.1 mg / mL or more and 5 mg / mL or less.

[0045] Examples of microparticles contained in the drug solution include aggregates of metal ions and proteins, liposomes, complexes of loaded particles and compounds, lipid nanoparticles (LNPs), etc. These may be used alone or in combination of two or more. Among these, from the viewpoint of enhancing the intradermal localization of the drug solution L, it is preferable to use aggregates of metal ions and proteins, from the viewpoint of enhancing the transfer of the drug solution L to immune tissues, it is preferable to use liposomes, and from the viewpoint of enhancing the delivery performance of mRNA or nucleic acids, it is preferable to use LNPs.

[0046] It is also preferable that the chemical solution L contains an organic compound A2 having a weight-average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle size of 20 nm or more and 1200 nm or less, the fine particles being fine particles formed by aggregation, bonding, or compounding of an inorganic compound and the organic compound A2 (case (R)).It is also preferable that the chemical solution L contains an organic compound A2 having a weight-average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle size of 20 nm or more and 1200 nm or less, the fine particles being fine particles formed by aggregation, bonding, or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2 (case (S)). Examples of the drug solution in the case of (R) or (S) include a drug solution containing an organic compound A2, such as a protein or nucleic acid, encapsulated in a fine particle selected from liposomes, oil emulsion particles (preferably oil-in-water), and lipid nanoparticles (LNPs) (in this drug solution, the encapsulated protein or nucleic acid corresponds to the organic compound A2); a protein preparation that forms a fine particle state by interacting with liposomes or oil emulsions; a protein preparation that forms a fine particle state by interacting with a state in which an adjuvant component, such as squalene, an animal-extracted oil, or an amphiphilic glycoside extracted from a plant, such as QS-21, is contained in the lipid membrane of liposomes or oil emulsions; and a protein preparation that forms an aggregate state by interacting with an aluminum adjuvant.

[0047] In the case of using the drug solution L containing organic compound A2 and particles formed by aggregation, bonding, or compounding of an inorganic compound with a part or all of organic compound A2 or another organic compound (R), preferably in the case of a drug solution containing an aluminum adjuvant and particles containing aggregates, from the viewpoint of making it easier to discharge the drug solution L from the opening 11a and from the viewpoint of properly administering the drug solution intradermally and penetrating the drug solution, the viscosity Y (mPa s) of the drug solution and the area X (μm ２ ) preferably satisfies the relationship Y≦0.0015×X+3.0, and more preferably Y≦0.0015×X+0.65. In the present invention, the (R) case does not include the (S) case, but may contain organic compound A1. The inorganic compound is contained in an adjuvant and formulated into an injection device. From the viewpoint of forming a complex or aggregate with organic compound A2, the inorganic compound is preferably a polyvalent metal compound, such as a hydroxide, phosphate compound, sulfate, chloride, amine salt, or carbonate of a polyvalent metal. Preferred examples include polyvalent metal hydroxides and polyvalent metal phosphate compounds, and preferred examples of polyvalent metals include aluminum. Furthermore, fine particles formed by an inorganic compound and organic compound A2 include particles in which the inorganic compound and organic compound A2 are bonded together by adsorption of organic compound A2 to polyvalent metal ions in the polyvalent metal compound. Here, the term "bonded particles" also includes composite and aggregate forms. From the viewpoint of forming fine particles by aggregation, bonding or compounding with an inorganic compound, the organic compound A2 is preferably one or more selected from proteins and nucleic acids.

[0048] In the case of using a drug solution L containing fine particles formed by aggregation, bonding, or compounding of organic compound A2 and a part or all of organic compound A2 with an organic compound B other than organic compound A2 (case (S)), preferably in the case of using a drug solution in the form of liposomes, oil emulsion particles, or LNPs as fine particles, from the viewpoint of making it easier to discharge drug solution L from opening 11a and from the viewpoint of properly administering intradermally and penetrating the drug solution, the viscosity Y (mPa s) of the drug solution and the area X (μm ２) preferably satisfy the relational formula Y≦0.00044×X+1.4, and more preferably Y≦0.00044×X+1.0. In the present invention, the case of (S) does not include the cases of (Q) and (R), but may contain organic compound A1.

[0049] The microparticles formed by aggregation, binding, or conjugation of organic compound A2 and organic compound B preferably contain one or more selected from liposomes, oil emulsion particles (preferably oil-in-water particles), and lipid nanoparticles (LNPs). Examples of pharmaceutical solutions containing these microparticles include pharmaceutical solutions containing proteins or nucleic acids encapsulated in lipid nanoparticles (LNPs) (in these pharmaceutical solutions, the encapsulated proteins or nucleic acids correspond to organic compound A2), protein preparations that form a microparticle state by interacting with liposomes or oil emulsions, protein preparations that form a microparticle state by interacting with a state in which an adjuvant component such as squalene or QS-21 is contained in the lipid membrane of liposomes or oil emulsions, and protein preparations that form an aggregated state by interacting with an aluminum adjuvant.

[0050] The organic compound B is contained in an adjuvant and incorporated into a syringe. From the viewpoints of usability as a syringe and the ability to form fine particles having a lipid membrane such as liposomes or oil emulsions, it is preferably an oil or fat that constitutes a lipid membrane, or a glycoside in which multiple sugars are bound to a carbon skeleton that has high lipid membrane formability due to its amphiphilicity. From the viewpoint of high lipid membrane formability, examples of the organic compound B include animal-extracted oils such as squalene, amphiphilic glycosides such as saponins typified by QS-21, bacterial-derived lipid components (glycolipids) typified by lipid A and modified forms thereof, amphiphilic oils such as phospholipids and cholesterol, and polyvalent metal-chelating lipids such as nickel-chelating lipids. Preferably, the organic compound B is one or more selected from animal-extracted oils, amphiphilic glycosides of plant extracts, glycolipids or modified forms thereof, phospholipids, cholesterol, or other amphiphilic oils. From the viewpoints of stability and effect, more preferably, the organic compound B is one or more selected from squalene, saponins, lipid A, phospholipids, and cholesterol. From the viewpoint of the ability to form fine particles such as liposomes and oil emulsions, the organic compound A2 is preferably one or more selected from proteins and nucleic acids.

[0051] From the viewpoint of pharmacokinetics or immune induction, it is preferable to use a vaccine or the like formulated with an aluminum adjuvant as the medicinal liquid containing microparticles. When using a vaccine or the like formulated with an aluminum adjuvant as the medicinal liquid, from the viewpoint of facilitating ejection of the medicinal liquid L from the opening 11a and from the viewpoint of appropriate intradermal administration and penetration of the medicinal liquid, the concentration of the medicinal liquid L is preferably 0.01 mg / mL or more, more preferably 0.1 mg / mL or more, and preferably 25 mg / mL or less, more preferably 5 mg / mL or less, and preferably 0.01 mg / mL to 25 mg / mL or less, more preferably 0.1 mg / mL to 5 mg / mL. Examples of vaccines formulated with an aluminum adjuvant include protein preparations bound with an aluminum adjuvant (e.g., aluminum adjuvant Alhydrogel, manufactured by Croda, or aluminum adjuvant Immuject, manufactured by Thermo Scientific, mixed 1:1 with a protein).

[0052] From the viewpoint of pharmacokinetics or immune induction, it is also preferable to use, as the medicinal liquid containing microparticles, a vaccine formulated by mixing with a lipid or glycoside adjuvant such as squalene or QS-21, etc. When using, as the medicinal liquid, a vaccine formulated by mixing with a lipid or glycoside adjuvant such as squalene or QS-21, etc. When using, from the viewpoint of making it easier to expel the medicinal liquid L from the opening 11a and from the viewpoint of properly administering the medicinal liquid intradermally and penetrating the medicinal liquid, the concentration of the medicinal liquid L is preferably 0.01 mg / mL or more, more preferably 0.1 mg / mL or more, and is preferably 25 mg / mL or less, more preferably 5 mg / mL or less, and is preferably 0.01 mg / mL or more and 25 mg / mL or less, more preferably 0.1 mg / mL or more and 5 mg / mL or less. Examples of vaccines formulated by mixing with a lipid or glycoside adjuvant such as squalene or QS-21 include protein preparations formulated by mixing with squalene (Addavax or MF59, manufactured by GSK, mixed with protein at a 1:1 ratio). When a lipid adjuvant is used, a bacterially derived physiologically active lipid, typified by lipid A, or a modified lipid obtained by modifying lipid A with an acyl group or the like may be further added.

[0053] From the viewpoint of pharmacokinetics or immune induction, it is also preferable to use a drug solution containing a protein or nucleic acid encapsulated in liposomes or lipid nanoparticles (LNP) as a drug solution containing fine particles. When using a drug solution containing a protein or nucleic acid encapsulated in liposomes or lipid nanoparticles (LNP) as a drug solution, from the viewpoint of making it easier to eject the drug solution L from the opening 11a and from the viewpoint of properly administering the drug intradermally and penetrating the drug solution, the concentration of the drug solution L is preferably 0.001 mg / mL or more, more preferably 0.01 mg / mL or more, and preferably 5.0 mg / mL or less, more preferably 1.0 mg / mL or less, and preferably 0.001 mg / mL or more and 5.0 mg / mL or less, more preferably 0.01 mg / mL or more and 1.0 mg / mL or less. Examples of proteins or nucleic acids encapsulated in liposomes or LNP include mRNA-LNP formulations.

[0054] The injection device preferably satisfies any one or more of the relationships (Q) to (S). In this case, the organic compound A2 contained in the medicinal solution is preferably one or more selected from the group consisting of peptide pharmaceuticals, insulin analogs, small molecule biopharmaceuticals, proteins derived from viruses, bacteria, or protozoa that cause infectious diseases, such as peptide pharmaceuticals, insulin analogs, small molecule biopharmaceuticals, hepatitis A virus proteins, hepatitis B virus proteins, hepatitis C virus proteins, influenza virus proteins, SARS-CoV-2 virus proteins, respiratory syncytial virus proteins, proteins derived from Mycobacterium tuberculosis, rabies virus proteins, poliovirus proteins, varicella-zoster virus, rubella virus proteins, measles virus proteins, proteins derived from Clostridium tetani bacteria, and proteins derived from malaria parasites, ovalbumin, peptide fragments of the above proteins, nucleic acids encoding the genetic information of the above proteins, peptide fragments having antigenicity that serve as neoantigens of malignant neoplasms or nucleic acids encoding the genetic information of neoantigens, and allergenic proteins, peptide fragments, and nucleic acids encoding the genetic information of allergens. Peptide drugs and small molecule biopharmaceuticals include organic compounds with a weight-average molecular weight of 1000 or more that have pharmacological effects, immunogenicity, and other functions.

[0055] From the viewpoint of improving administration, such as enabling efficient injection of the medicinal solution L into the skin, it is preferable that the openings 11a are located on the side surfaces of the first projections 11, and that the height position of the apexes of the first projections 11 is spaced apart from the height position of the centers of the openings 11a in the height direction of the first projections 11. More specifically, when the height of the first projections 11 is divided into an upper half and a lower half by dividing the height into two equal halves, it is preferable that the centers of the openings 11a be located in the upper half, and it is preferable that the centers of the openings 11a be located at a position spaced apart from 200 μm to 1000 μm downward from the tips of the first projections 11. That is, the distance H4 from the tips of the first projections 11 to the center positions of the openings 11a [see FIG. 7(a)] (hereinafter also referred to as the "center position of the openings") is preferably 1000 μm or less, and more preferably 500 μm or less. From the same viewpoint, distance H4 is preferably 100 μm or more, and preferably 200 μm or more, and also preferably 100 μm or more and 1000 μm or less, and more preferably 200 μm or more and 500 μm or less. Here, the center position of aperture 11a refers to the position that divides the distance between distal end 11x and proximal end 11y of aperture 11a into two equal halves in the height direction. Furthermore, distal end 11x of aperture 11a refers to the end of the opening of aperture 11a that opens onto the outer surface of first protrusion 11 in the height direction that is farther from the tip of first protrusion 11, and proximal end 11y of aperture 11a refers to the end of the opening of aperture 11a that opens onto the outer surface of first protrusion 11 in the protruding direction that is closer to the tip of first protrusion 11.

[0056] The protrusions of the micro-protrusion device 3 preferably include, in addition to the first protrusions 11, second protrusions 12 without apertures. The second protrusions 12 are also fine protrusions, preferably with a protrusion height of 2000 μm or less. The second protrusions 12 may be hollow or solid. In the injection needle 10 of this embodiment, the second protrusions 12 are solid (see FIGS. 7(b) and 7(c)). The solid second protrusions 12 can reduce the amount of medicinal solution remaining in the injection needle 10 when injecting the medicinal solution L from the injection needle 10. As shown in FIG. 5, the second protrusions 12 preferably have a cone-shaped stimulation protrusion 32 and a puncture depth control protrusion (hereinafter also referred to as the "control protrusion") 33, the tip surface of which functions as a puncture depth control unit 40 that controls the puncture depth of the first protrusion. The tip surface of the control protrusion 33 is preferably flat, i.e., linear and extending horizontally, or curved and convex toward the protruding direction of the control protrusion 33. Although the conical shape of the stimulation protrusion 32 is illustrated as a columnar shape in Fig. 5, it may be an approximately conical shape or a polygonal pyramid, similar to the first protrusion 11. Furthermore, the columnar shape of the control protrusion 33 may be a circular cylinder or a polygonal cylinder such as a square cylinder. It is preferable that the fine protrusion device 3 includes, as the second protrusion 12, a stimulation protrusion 32 that is conical in shape or a control protrusion 33 that is columnar in shape, and more preferably includes both.

[0057] The first region R1 may include one or more first protrusions 11. The multiple first protrusions 11 are preferably arranged to form any shape as a whole. The multiple first protrusions 11 are preferably arranged, for example, in a triangular shape (see FIG. 6), a circular shape (see FIG. 9(a)), or a linear shape (see FIG. 9(d)). The multiple first protrusions 11 are preferably arranged so that an imaginary line C1 connecting the centers of the first protrusions 11 forms a ring in a plan view (see FIGS. 6, 9(a), and 9(c)). Here, "ring" refers to a closed shape and includes not only a circular shape but also a polygonal shape. When the first protrusions 11 are arranged so that an imaginary line C1 connecting the centers of the first protrusions 11 forms a ring, it is preferable that no first protrusions 11 are arranged entirely within the region surrounded by the imaginary line C1. In the micro-projection device 3 shown in FIG. 6, the centers of the multiple first protrusions 11 are located on the same circle.

[0058] The micro-projection device 3 preferably has a second region R2 including two or more second projections 12. The second region preferably sandwiches or surrounds the first region R1. In the example shown in FIG. 6, the second region R2 surrounds the first region R1. The second projections 12 included in the second region R2 are preferably arranged so that an imaginary line connecting the centers of each second projection 12 forms a ring in a plan view. For example, the imaginary line C2 connecting the centers of the second projections 12 may be a circular ring (see FIGS. 6 and 9(a)), a quadrangular ring (see FIG. 9(b)), or a triangular ring (see FIG. 9(c)). In the micro-projection device 3 shown in FIG. 6, the centers of the multiple second projections 12 are located on the same circle. FIG. 9(d) shows an example in which the second region R2 sandwiches the first region R1. When the second region R2 sandwiches the first region R1, it is preferable that the first region R1 does not extend beyond the second region R2.

[0059] Next, the first region R1 and the second region R2 will be described in detail. As shown in Figures 6 and 9(a), when a plurality of first protrusions 11 are present collectively in the central region of the base surface 2 in a plan view, the region inside the smallest circle that surrounds the plurality of first protrusions 11 is the first region R1. As shown in Figures 6 and 9(a), when a plurality of second protrusions 12 are arranged so as to surround the first region R1, the region between the smallest circle that surrounds the plurality of second protrusions 12 and the largest circle inscribed in the plurality of second protrusions 12 is the second region R2. When a single first protrusion 11, instead of a plurality of first protrusions 11, is present in the central region of the base surface 2 in a plan view, the region inside the smallest circle that surrounds the first protrusion 11 is the first region R1.

[0060] When the multiple second protrusions 12 are arranged in a polygonal shape so as to surround the multiple first protrusions 11 present collectively in the central region, or when the multiple second protrusions 12 are arranged in a polygonal shape so as to surround a single first protrusion 11 present in the central region, the first region R1 may be defined as the region inside the smallest shape that is similar to the polygonal shape and surrounds the multiple first protrusions 11 (see FIGS. 9(b) and 9(c)). When the multiple second protrusions 12 are arranged in a polygonal shape, the second region R2 may be defined as the region between the smallest line that is similar to the polygonal shape and surrounds the multiple second protrusions 12, and the largest line that is similar to the polygonal shape and inscribes the multiple second protrusions 12 in a plan view (see FIGS. 9(b) and 9(c)).

[0061] When a plurality of first protrusions 11 are arranged in one direction, the first region R1 is the area inside the smallest rectangle that surrounds the plurality of first protrusions 11 (see FIG. 9(d)). When a plurality of second protrusions 12 are arranged to sandwich the first region R1 (see FIG. 9(d)), the second region R2 is the area inside the smallest rectangle that surrounds the second protrusions 12 arranged on both sides of the first region R1.

[0062] In the micro-projection device 3, the second projection 12 preferably has a stimulating projection 32 and a control projection 33. Since the second projection 12 has the stimulating projection 32, when the injection needle 10 is pressed against the skin and the first projection 11 is inserted into the skin from the tip side, the stimulating projection 32 also penetrates the skin. Penetration of the stimulating projection 32 into the skin prevents the skin from stretching, improving puncture ease. Furthermore, when the stimulating projection 32 penetrates the skin, it stimulates the skin and promotes blood flow, thereby promoting the immune induction effect. Additionally, the stimulating projection 32 causes microscopic damage to the skin, thereby promoting the immune induction effect. Therefore, with the injection needle 10 having this configuration, the first projection 11 can easily inject liquid into the skin, and the stimulating projection 32 can promote blood flow and promote the immune induction effect. The presence or absence of a blood flow promotion effect can be determined by various known methods, such as by determining whether a flare reaction occurs in the skin or by visualizing the blood flow distribution using a laser blood flowmeter. The presence or absence of an immune-stimulating effect due to micro-damage can be easily evaluated by comparing the efficacy of an injection device 1 that does not have a stimulating protrusion 32 as the second protrusion 12 with that of an injection device 1 that has a stimulating protrusion 32 on the second protrusion 12.

[0063] Because the second protrusion 12 has the control protrusion 33, when the first protrusion 11 and the stimulation protrusion 32 are inserted into the skin from the tip side, the puncture depth control unit 40 of the control protrusion 33 comes into contact with the surface of the skin. This stops the first protrusion 11 and the stimulation protrusion 32 from penetrating deeper into the skin. In other words, the puncture depth control unit 40 functions as a stopper that limits the penetration depth of the first protrusion 11 and the stimulation protrusion 32. That is, because the injection needle 10 is capable of controlling the penetration depth of the first protrusion 11 and the stimulation protrusion 32 into the skin, it is possible to intradermally administer a medicinal solution to any depth in the skin and effectively promote blood flow. Therefore, by adjusting the penetration depth of the first protrusion 11 depending on the type of medicinal solution, etc., it is possible to maximize the effect of the medicinal solution. Furthermore, by adjusting the penetration depth of the stimulation protrusion 32 depending on the desired level of blood flow promotion, it is possible to effectively promote blood flow.

[0064] In the fine-projection device 3, the first projections 11 are preferably taller than the second projections 12. By doing so, the second projections 12 come into contact with the skin after the first projections 11 have pierced the skin. This allows the first projections to be pierced efficiently and prevents the second projections 12 from stretching the skin. Thereafter, the first projections 11 can be smoothly pierced to any desired depth. Typically, the second projections 12 have stimulation projections 32 and control projections 33, and it is preferable that the first projections 11 be taller than the stimulation projections 32 and the control projections 33. From the viewpoint of significantly reducing pain associated with intradermal administration or reliably injecting the medicinal solution into the skin S from the first projections 11, the difference H1-H3 between the protrusion height H1 of the first projections 11 and the protrusion height H3 of the control projections 33 is preferably 300 μm or more, more preferably 400 μm or more. Moreover, the difference H1-H3 is preferably 2000 μm or less, more preferably 1200 μm or less, from the viewpoint of not damaging the skin more than necessary.

[0065] From the viewpoint of significantly reducing the pain associated with the blood flow promoting effect of the stimulation protrusions 32 and enabling the stimulation protrusions to be sufficiently inserted into elastic skin, it is preferable that the protrusion height H2 of the stimulation protrusions 32 be equal to or greater than the protrusion height H3 of the control protrusions 33, i.e., H2≧H3, and more preferably H2>H3. From the same viewpoint, the difference H2-H3 between the protrusion height H2 of the stimulation protrusions 32 and the protrusion height H3 of the control protrusions 33 is preferably 0 μm or greater, more preferably 100 μm or greater, and more preferably 200 μm or greater. Furthermore, from the viewpoint of not damaging the skin more than necessary, the difference H2-H3 is preferably 1000 μm or less, and even more preferably 700 μm or less.

[0066] From the viewpoint of ensuring a more reliable blood flow promoting effect, ensuring reliable puncturing by the first protrusions 11, and efficient injection, it is preferable that the first protrusions 11 be taller than the stimulating protrusions 32. More specifically, the difference H1-H2 between the protruding height H1 of the first protrusions 11 and the protruding height H2 of the stimulating protrusions 32 is preferably 100 μm or more, more preferably 200 μm or more. Furthermore, from the viewpoint of easily achieving both ease of injection of the liquid and the blood flow promoting effect, the difference H1-H2 is preferably 1000 μm or less, more preferably 700 μm or less.

[0067] The protrusion height H2 of the stimulation protrusions 32 is preferably 1000 μm or more, more preferably 1350 μm or more, from the viewpoint of stimulating the skin by pressing it against the skin and promoting blood flow. Furthermore, the protrusion height H2 of the stimulation protrusions 32 is preferably 2000 μm or less, more preferably 1800 μm or less, and even more preferably 1450 μm or less, from the viewpoint of minimal invasiveness. The protrusion height H3 of the control protrusions 33 is preferably 600 μm or more, more preferably 750 μm or more, from the viewpoint of making the skin as non-invasive as possible and increasing the distance between the base material and the skin to improve puncture performance. Furthermore, the protrusion height H3 of the control protrusions is preferably 1200 μm or less, more preferably 1050 μm or less, and even more preferably 950 μm or less, from the viewpoint of improving the puncture performance of the first protrusions 11.

[0068] In the fine protrusion device 3, from the viewpoint of balancing the ease of puncturing and liquid injection with the blood flow promoting effect, the ratio of the number of second protrusions 12 to the number of first protrusions 11 (number of second protrusions 12 / number of first protrusions 11) is preferably 2.4 or more, more preferably 3.0 or more, and even more preferably 3.5 or more. Furthermore, from the viewpoint of minimal invasiveness, it is preferably 10 or less, more preferably 8 or less, and even more preferably 6 or less.

[0069] In the fine-projection device 3, from the viewpoint of enabling efficient injection of liquid through the injection needle 10, the first region R1 preferably includes two or more, and more preferably three or more, first projections 11. Furthermore, from the viewpoint of enabling satisfactory injection of liquid through all of the first projections 11, the first region R1 preferably includes 20 or less, more preferably 15 or less, and even more preferably 10 or less.

[0070] In the micro-projection device 3, the second region R2 may include the first projections 11, but preferably does not include the first projections 11 (see FIG. 9). By not including the first projections 11 in the second region R2, only the first region R1 in the micro-projection device 3 is a region into which liquid can be injected, so the location of the wheal can be limited to the first region, and it is possible to prevent the formation of the wheal from being inhibited in other locations.

[0071] The micro-projection device 3 may include, as the second projection 12, a composite second projection 52 having a puncture depth control unit 40 integrally formed around the periphery of the stimulation projection 32. An example of this is shown in FIG. 10 . In the example shown in FIG. 10 , the puncture depth control unit 40 is integrally molded around the outer periphery of the base-side portion of the stimulation projection 32, thereby forming the composite second projection 52. More specifically, an enlarged diameter portion 41 is formed in the base-side portion, and a step that protrudes outward in the radial direction of the stimulation projection 32 is formed at the upper end of the enlarged diameter portion 41. This step serves as the puncture depth control unit 40. When the first projection 11 and the composite second projection 52 are inserted into the skin from the tip side, the puncture depth control unit 40 comes into contact with the surface of the skin, stopping the first projection 11 and the composite second projection 52 from penetrating deeper into the skin. In the composite second protrusion 52, the puncture depth control unit 40 is integrally formed around the stimulation protrusion 32, so that the composite second protrusion 52 can be more reliably prevented from penetrating deeper into the skin.

[0072] Next, the constituent materials of the injection device 1 will be described. The fine protrusion device 3 of the injection needle 10 preferably contains a thermoplastic resin from the viewpoints of material handling, strength and processability of the injection needle, ensuring hardness of the first protrusions 11 and the second protrusions 12, facilitating liquid injection, and improving the blood flow promoting effect. More preferably, the fine protrusion device is formed from a base sheet containing a thermoplastic resin. Examples of the thermoplastic resin include one or more selected from polyolefin, polyester, polyamide, polyamideimide, polyetheretherketone, polyetherimide, polyvinyl chloride, acrylic resin, polystyrene resin, etc. Examples of the polyolefin include one or more selected from polypropylene, polyethylene, etc. Examples of the polyester include one or more selected from polyethylene terephthalate, polyfatty acid ester, polylactic acid, polycaprolactone, polybutylene succinate, etc. Examples of the polyamide include one or more selected from nylon, etc. From the viewpoint of biodegradability, it is preferable to contain a polyfatty acid ester. Specifically, examples of the polyfatty acid ester include one or more selected from polylactic acid and polyglycolic acid.

[0073] When the joint is formed by fusion, the base component 4 of the injection needle 10 is preferably formed containing the same type of thermoplastic resin as the fine protrusion device 3, from the viewpoint of ease of forming the joint. When the joint is formed using an adhesive, the base component 4 may be formed from a material different from that of the fine protrusion device 3, for example, may be made of metal.

[0074] Examples of materials for the syringe body 21 in the drug solution feeder 20 include various resins such as polyvinyl chloride, polyethylene, polypropylene, cyclic polyolefin, polystyrene, poly-(4-methylpentene-1), polycarbonate, acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyester such as polyethylene terephthalate, butadiene-styrene copolymer, polyamide (e.g., nylon 6, nylon 6.6, nylon 6.10, nylon 12), glass, ceramics, metal, etc. Note that the material for the syringe body 21 is preferably substantially transparent to ensure visibility of the interior.

[0075] The material of the gasket 30 is not particularly limited as long as it is a material that can exhibit liquid-tightness with the syringe body 21 and does not have an adverse effect on the medicinal liquid L to be contained therein. Examples of the material include various rubber materials such as natural rubber, butyl rubber, isoprene rubber, butadiene rubber, and silicone rubber, various elastomers such as polyurethane-based, polyester-based, polyamide-based, polyolefin-based, and polystyrene-based elastomers, and mixtures thereof.

[0076] The mass ratio of the thermoplastic resin contained in the micro-projection device 3 to the total mass of the micro-projection device 3 is preferably 50% or more, more preferably 70% or more, and even more preferably 90% or more, from the viewpoint of improving the moldability and dimensional stability of the micro-projection device 3. Furthermore, the mass ratio of the thermoplastic resin is preferably 100% or less, more preferably 98% or less, and even more preferably 96% or less, from the viewpoint of imparting various effects to the injection needle by adding, for example, a functional agent. Here, various functional agents that can be used include antibacterial agents, disinfectants, moisturizers, flow improvers, antistatic agents, colorants, etc.

[0077] The medicinal liquid to be injected into the skin by the injection device 1 can be selected appropriately depending on the intended use of the injection device 1. In addition to intradermal administration of medicinal liquid, the injection device 1 can also be used for subcutaneous administration, intratissue administration, etc. The medicinal liquid to be injected into the skin by the injection device 1 may be an intradermal administration drug, a subcutaneous administration drug, an intramuscular administration drug, an intravenous administration drug, or an intratissue administration drug. An intradermal administration drug refers to a drug whose recommended administration method is intradermal administration. A subcutaneous administration drug refers to a drug whose recommended administration method is subcutaneous administration. An intramuscular administration drug, an intravenous administration drug, or an intratissue administration drug refers to a drug whose recommended administration method is intramuscular, intravenous, or intratissue administration, respectively. Although a recommended administration route is set for each drug, any drug may be used. Because the injection device 1 allows for easy intradermal administration of medicinal liquid, the medicinal liquid to be injected into the skin by the injection device 1 is preferably an intradermal administration drug, and more preferably an intradermal administration vaccine drug. In particular, when an intradermal vaccine drug is used, not only can the drug be reliably administered intradermally, but antigen recognition by the immune system can be more efficiently strengthened than with subcutaneous administration, which is expected to enhance the effectiveness of the vaccine. The skin comprises, in order from the body surface side, the epidermis, dermis, and subcutaneous tissue, and the dermis contains a relatively large number of immune cells. Therefore, when an intradermal vaccine drug is administered intradermally using the injection device 1, it is preferable to administer it into the dermis from the perspective of enhancing the effectiveness of the vaccine.

[0078] The present invention encompasses a kit including an injection device and a holder that moves the injection device, with the injection needle attached to a drug solution feeder, toward the skin and punctures the skin S with the first protrusion 11 of the injection needle 10. The injection device included in the injection kit of the present invention can be the injection device 1 of the present invention described above. The holder is a tool used to puncture the skin S with the injection needle, and has a spring or the like as a structure for imparting a speed at which the injection needle punctures the skin. The "speed" refers to the speed at which the first protrusion 11 of the injection needle 10 punctures the skin. The kit of the present invention includes a protrusion having an opening of a predetermined size on its side and a drug solution of a specific concentration, and therefore has excellent administration properties, such as ejection properties and the ability to efficiently inject the drug solution into the skin.

[0079] Figures 15 and 16 show a holder 100 according to a preferred embodiment of the present invention. The holder 100 has, for example, a guide mechanism that regulates the movement direction of the injection needle 10 so that the first protrusion 11 of the injection needle 10 pierces the skin approximately perpendicularly, and a drive mechanism that moves the injection needle 10 along the guide mechanism. The drive mechanism preferably includes a drive means such as a spring that moves the injection needle 10 while controlling the puncture speed of the first protrusion 11 of the injection needle 10 to a predetermined speed. The drive mechanism is preferably configured so that the drive means can be operated manually.

[0080] The guide mechanism includes, for example, a guide hole 61 provided in the side wall of a cylindrical main body 70 that forms the main body of the holder 100, and an injection device holder 60 having a guide protrusion 62 inserted into the guide hole 61. The guide hole 61 has an opening shape extending along the axial direction of the main body 70. The injection device holder 60 holds the injection device 1 formed by connecting the injection needle 10 and the drug solution feeder 20. By inserting the guide protrusion 62 of the injection device holder 60 into the guide hole 61, the movement direction of the injection device holder 60 is restricted to the axial direction of the main body 70. The injection device holder 60 is disposed inside the main body 70. It is preferable that the biasing member 65 of the drive mechanism is configured to move the injection device holder 60. Furthermore, if the drive means is a spring, it is preferable that the holder 100 has a stopper mechanism for maintaining the spring in a contracted state. It is preferable that the stopper mechanism fixes the position of the guide projection, thereby maintaining the spring in a contracted state.

[0081] A method for injecting a medicinal solution into the skin using the holder 100 will be described. First, the syringe body 21 of the medicinal solution feeder 20 is filled with the medicinal solution. Specifically, with the inlet 23 of the syringe body 21 immersed in the medicinal solution L, the plunger member 28 inserted into the syringe body 21 is pulled up, and the medicinal solution L is drawn into the syringe body 21. The injection needle 10 is attached to the syringe body 21 filled with the medicinal solution L, to form the injection device 1. The plunger member 28 of the medicinal solution feeder 20 is pressed down, and the first protrusion 11 of the injection needle 10 is filled with the medicinal solution L. The injection device 1 is held by the injection device holder 60, and the injection device 1 is attached to the holder 100. The guide protrusion 62 of the injection device holder 60 is pushed up along the guide hole 61, and the spring of the drive mechanism that biases the injection device holder 60 is contracted. The guide protrusion is fixed by a stopper mechanism, and the spring is maintained in a contracted state (hereinafter, this state is also referred to as the "standby state"). The first protrusion 11 of the injection needle 10 in the holder 100 in the standby state is brought close to the skin to which the medicinal solution is to be administered. At this time, it is preferable that the axial direction of the main body 70 of the holder 100 is perpendicular to the skin. Then, the fixation of the guide protrusion is released. Then, the injection needle 10 is urged toward the skin, and the first protrusion 11 punctures the skin. Thereafter, the plunger member 28 of the medicinal solution feeder 20 is pressed down to inject the medicinal solution into the skin.

[0082] To efficiently perform intradermal administration using the holder 100, it is necessary not only to simply puncture the skin with the first projection 11 of the injection device 1, but also to puncture the first projection 11 to an appropriate depth that enables intradermal administration. Specifically, when the first projection 11 punctures the skin, it is preferable that the opening 11a of the first projection 11 reaches a layer S12 in the epidermis S1 that is deeper than the stratum corneum S11 (see FIG. 18 ). Note that the opening 11a of the first projection 11 may extend beyond the epidermis S1 and reach the dermis S2. Even when the opening 11a of the first projection 11 reaches the dermis S2, the drug solution ejected from the opening 11a penetrates not only the dermis S2 but also the epidermis S1, allowing the drug solution to be injected into the epidermis S1. When the opening 11a of the first protrusion 11 reaches the dermis S2, it is preferable that the opening 11a be located at a position in the dermis S2 closer to the epidermis S1, in order to ensure that the medicinal solution ejected from the opening 11a penetrates into the epidermis S1.

[0083] As a result of thorough research by the inventors into puncturing using the holder 100, it was found that if the kinetic energy when the first protrusion 11 is punctured (hereinafter also referred to as "kinetic energy at puncture") and the mass of the injection device 1 satisfy a certain relationship, the first protrusion 11 can be punctured to an appropriate depth, and intradermal administration can be carried out efficiently.

[0084] Specifically, it is preferable that the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy the following formula (1): E≧0.0077ln(x)+0.0057 (1) (where E represents the kinetic energy, and x represents the mass of the injection device).

[0085] If the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy the above-mentioned formula (1), when the first protrusions 11 of the injection device 1 are punctured into the skin by the holder 100, the first protrusions 11 are more likely to penetrate the stratum corneum of the skin and reach the epidermis. Therefore, the first protrusions 11 are more likely to be punctured to an appropriate depth, and intradermal administration can be performed efficiently.

[0086] Furthermore, from the viewpoint of making it easier for the first projections 11 to reach the epidermis and enabling more efficient intradermal administration, it is preferable that the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy the following formula (2): E≧0.0077ln(x)+0.01 (2) (where E represents the kinetic energy at the time of puncturing, and x represents the mass of the injection device).

[0087] Furthermore, it is preferable that the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy the following formula (3): E≦0.05ln(x)+0.075 (3) (where E represents the kinetic energy at the time of puncturing, and x represents the mass of the injection device.) When the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy formula (3), the injection device 1 is biased by the holder 100, and excessive pain when the injection needle 10 hits the skin can be prevented.

[0088] From the viewpoint of further reducing the pain when the injection needle 10 hits the skin, it is preferable that the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy the following formula (4): E≦0.05ln(x)+0.055 (4) (where E represents the kinetic energy at the time of puncturing, and x represents the mass of the injection device.)

[0089] Furthermore, from the viewpoint of further reducing the pain when the injection needle 10 hits the skin, it is preferable that the kinetic energy at the time of puncturing and the mass of the injection device 1 satisfy the following formula (5): E≦0.05ln(x)+0.015 (5) (where E represents the kinetic energy at the time of puncturing, and x represents the mass of the injection device).

[0090] The mass of the injection device 1 is preferably 1.9 g or more, more preferably 2.5 g or more, and even more preferably 3.0 g or more, from the viewpoint of providing sufficient kinetic energy during puncturing to puncture the first protrusion 11 to an appropriate depth and ensuring reliable puncturing. Furthermore, the mass of the injection device 1 is preferably 40.0 g or less, more preferably 30.0 g or less, and even more preferably 21.0 g or less, from the viewpoint of ensuring that the biasing member 65 of the holder 100 operates appropriately and provides a constant speed. Furthermore, from the viewpoint of achieving both of these, the mass of the injection device 1 is preferably 1.9 g or more and 40.0 g or less, more preferably 2.5 g or more and 30.0 g or less, and even more preferably 3.0 g or more and 21.0 g or less.

[0091] Here, the mass of the syringe 1 includes not only the mass of the drug solution supplier 20 and the injection needle 10, but also the mass of the drug solution filled in the drug solution supplier 20. When the drug solution supplier 20 is not filled with the drug solution, the mass of the drug solution filled in the drug solution supplier 20 is 0. The mass of the syringe 1 can be measured, for example, by the following method. <Method for Measuring the Mass of the Syringe> First, the drug solution supplier 20 is filled with the drug solution. Then, the injection needle 10 is attached to the drug solution supplier 20 filled with the drug solution, thereby forming the syringe 1. Thereafter, the plunger member 28 is pressed down to remove air from the drug solution supplier 20. Specifically, the plunger member 28 is pressed down until the amount of drug solution filled in the drug solution supplier 20 reaches a predetermined amount (e.g., 100 μL). Then, excess drug solution adhering to the tip of the first protrusion 11 of the injection needle 10 is removed by absorbing it with a Kimwipe. Then, the mass of the syringe 1 after the air removal is measured using an electronic balance (AG135, Mettler Trade Co., Ltd.). The mass is measured five times, and the average value is taken as the mass of the syringe.

[0092] The kinetic energy during puncturing is preferably 0.014 J or more, and more preferably 0.018 J or more, from the viewpoint of making it easier for the primary projections 11 to reach into the epidermis.

[0093] If the kinetic energy during puncturing is excessively high, there is a risk that the first protrusion 11 will puncture too deeply. If the first protrusion 11 punctures too deeply, the medicinal solution ejected from the opening 11a will penetrate subcutaneously without penetrating the epidermis, making it impossible to administer the medicinal solution intradermally. Furthermore, if the kinetic energy during puncturing is excessively high, the injection needle 10 biased by the holder 100 may collide strongly with the skin, causing pain during puncturing. From the viewpoint of preventing the first protrusion 11 from puncturing too deeply and preventing pain during puncturing, the kinetic energy during puncturing is preferably 0.23 J or less, more preferably 0.21 J or less, and even more preferably 0.17 J or less.

[0094] The kinetic energy at the time of puncturing is preferably 0.014 J or more and 0.23 J or less, more preferably 0.018 J or more and 0.21 J or less, and even more preferably 0.018 J or more and 0.17 J or less, from the viewpoint of simultaneously making it easier for the first protrusions 11 to reach into the epidermis, preventing the first protrusions 11 from puncturing too deeply, and preventing pain during puncturing.

[0095] The puncture speed when the protrusion of the injection device biased by the biasing member 65 punctures the skin is preferably 1700 mm / s or more, more preferably 1800 mm / s or more, from the viewpoint of making it easier for the first protrusion 11 to reach into the epidermis.

[0096] If the puncture speed is excessively high, the first protrusion 11 may puncture too deeply, which may prevent the medicinal solution from being administered intradermally or cause pain during puncture. From the viewpoint of preventing the first protrusion 11 from puncturing too deeply and causing pain during puncture, the puncture speed is preferably 9300 mm / s or less, more preferably 8600 mm / s or less, and even more preferably 7000 mm / s or less.

[0097] The puncture speed is preferably 1700 mm / s or more and 9300 mm / s or less, more preferably 1800 mm / s or more and 8600 mm / s or less, and even more preferably 1800 mm / s or more and 7000 mm / s or less, from the viewpoint of simultaneously making it easier for the first protrusions 11 to reach into the epidermis, preventing the first protrusions 11 from puncturing too deeply, and preventing pain during puncture.

[0098] The puncture speed can be measured, for example, by the following method. <Method for measuring puncture speed> First, the drug solution supplier 20 is filled with the drug solution. Then, the injection needle 10 is attached to the drug solution supplier 20 filled with the drug solution, thereby forming the syringe 1. Thereafter, the plunger member 28 is pressed down to remove air from inside the drug solution supplier 20. Specifically, the plunger member 28 is pressed down until the amount of drug solution filled in the drug solution supplier 20 reaches a predetermined amount (for example, 100 μL). Then, excess drug solution adhering to the tip of the first protrusion 11 of the injection needle 10 is removed by absorbing it with a Kimwipe.

[0099] Next, the syringe 1 after air removal is attached to the holder 100. Then, a sponge 7 (chloroprene rubber sponge, thickness: 5 mm, hardness: Asker C25) is attached to the tip of the holder 100 with the syringe 1 attached. The sponge 7 is attached so that the first protrusion 11 of the syringe needle will puncture the sponge 7 when the holder 100 is released from the standby state.

[0100] Then, after the holder 100 with the sponge 7 attached is placed in a standby state, the syringe holder is released and the puncturing operation is performed. At this time, the movement amount and movement time of the pressing portion 31, which is the end of the plunger member 28 opposite the injection needle 10, are measured using a laser displacement meter (manufactured by Keyence Corporation, model number LK-H080) and a controller (manufactured by Keyence Corporation, model number LK-HD500). Specifically, the movement amount and movement time of the position of the pressing portion 31 are measured from the standby state until the syringe holder is released and the first protrusion 11 punctures the sponge 7. The sampling period of the laser displacement meter is, for example, 20 μs.

[0101] The speed is then calculated from the measured movement amount and movement time. Specifically, the position of the pressing portion 31 when the first projection 11 punctures the sponge 7 is set to a reference position K (see FIG. 17), and the speed is calculated when the distance D (see FIG. 17) between the pressing portion 31 and the reference position changes from 2 mm to 1 mm. The movement amount and movement time are measured and the speed is calculated three times, and the average of the calculated speeds is used as the puncture speed.

[0102] It is preferable that the holder stores energy for moving the injection device 1 in the biasing member 65 by, for example, contracting a spring, and holds the injection device 1 at a retracted position retracted away from the skin from the advanced position by a stopper mechanism or a holding mechanism, and then releases the held state by any operation such as pressing it against the skin or releasing the engagement state of the engaging protrusion, thereby obtaining the required kinetic energy when the first protrusion 11 punctures the skin. It is preferable to design the amount of energy applied to the injection device 1 by the biasing member so that the required kinetic energy can be obtained, taking into consideration the mass of the injection device including the mass of the medicinal solution and the distance from the retracted position to the advanced position where the first protrusion 11 punctures.

[0103] A wide variety of holders equipped with a biasing member can be used as the holder for obtaining the required kinetic energy, and for example, holder 100a shown in FIGS. 19 to 25 can be used. Holder 100a preferably includes a slider 120 and a main body 130. Slider 120 is preferably capable of detachably fixing syringe 1. Slider 120 is preferably disposed inside main body 130. Main body 130 preferably supports slider 120 so that it can move back and forth in one direction X. One direction X in which slider 120 moves back and forth is also simply referred to as the slider's moving back and forth direction X. Furthermore, the same direction as slider's moving back and forth direction X in main body 130 is also referred to as the axial direction X of the main body.

[0104] The slider 120 typically has an elongated shape extending in the advancing / retreating direction X, with the length in the axial direction X being longer than the length in the width direction Y perpendicular to the axial direction. The slider 120 preferably has an arc-shaped cross section in which a circumferential portion of the peripheral wall of the cylinder is continuously missing along the axial direction of the cylinder. The missing portion of the cylinder preferably forms a side opening 123 extending along the advancing / retreating direction X of the slider 120. The slider 120 preferably has a drug solution feeder housing 121. The drug solution feeder housing 121 typically houses the drug solution feeder 20. A syringe holder 122 that restrains a portion of the base component 4 of the syringe 1 is preferably provided on the skin side of the drug solution feeder housing 121. It is preferable that the length of the drug solution feeder housing 121 along the circumferential direction of the syringe 1 be equal to or shorter than half the circumference of the syringe 1, from the viewpoint of facilitating attachment of the syringe 1. The syringe holder 122 preferably has an arc shape in a cross section perpendicular to the one direction. The syringe holder 122 preferably has a smaller radius of curvature than the drug solution feeder housing portion 121. The syringe holder 122 preferably includes a pair of gripping protrusions 122a at both circumferential ends. The length of the syringe holder 122 along the circumferential direction of the syringe 1, including the pair of gripping protrusions 122a, is preferably longer than half the length of the restrained portion of the syringe 1.

[0105] In the injection device 1, the connection portion 45 between the protrusion support portion 46 of the base component 4 and the tip portion 25 of the syringe body 21 preferably has a constricted portion 50. This constricted portion 50 preferably serves as an engagement groove that engages with the injection device holder 122 and / or the pair of gripping protrusions 122a. This constricted portion 50 is smaller than the outer dimensions of the protrusion support portion 46 and the tip portion 25. The constricted portion 50 preferably serves as a restrained portion that is restrained by the injection device holder 122. In this case, simply by pushing the constricted portion 50 of the injection needle 10 into the injection device holder 122 from the side where the side opening 123 is open, the constricted portion is restrained by the injection device holder 122. Therefore, rattle is less likely to occur between the injection needle 10 and the injection device holder 122. The engagement groove that engages with the injection device holder 122 and / or the pair of gripping protrusions 122a is hereinafter also referred to as a restraining engagement groove. The restraining engagement groove is preferably disposed between the micro-projection tool 3 and the drug solution supplier 20. The restraining engagement groove is, for example, a constricted portion 50 formed around the female connector by connecting the male and female connectors of a small-diameter connector for liquids and gases (ISO 80369-7:2021), but may also be formed by other methods. For example, a ring-shaped groove may be formed around the protrusion tool support portion 46 and used as the engagement groove. When connecting the base component 4 and the drug solution supplier 20 with a luer connector, the male and female connectors are preferably luer lock connectors. Luer lock connectors are preferred because they are difficult to disconnect and the state in which the syringe 1 is held by the slider 120 is difficult to release. The restraining engagement groove is not limited to a length corresponding to the entire circumference of the syringe 1, and may be a length that does not correspond to the entire circumference of the syringe 1, for example, a length corresponding to half the circumference.

[0106] The syringe holder 122 preferably engages with an engagement groove located between the fine protrusion device 3 and the drug solution supplier 20, for example, the constricted portion 50 described above. With such a syringe holder 122, the portion located near the skin is restrained when the syringe 1 is punctured into the skin. This makes it less likely that the syringe 1 will be affected even if it is tilted slightly within the slider 120. Therefore, individual differences in puncture conditions, such as the puncture angle, are less likely to occur. Furthermore, the syringe 1 can also be used with a different drug solution supplier 20 having a smaller outer diameter.

[0107] The slider 120 preferably includes a rear fixing portion 124 that fits around the injection device 1 on the non-skin side of the drug solution feeder housing 121. The rear fixing portion 124 preferably has an arc-shaped cross section with a smaller radius of curvature than the drug solution feeder housing 121, and includes a pair of gripping protrusions 124a at both circumferential ends. The length of the rear fixing portion 124 along the circumferential direction of the injection device 1, including the pair of gripping protrusions 124a, is preferably longer than half the circumference of the syringe barrel 151a, which is the restrained portion of the injection device 1. Therefore, by simply pushing a part of the injection device 1 into the rear fixing portion 124 from the side where the side opening 123 is open, the part can be fixed without any rattle between the rear fixing portion 124 and the syringe barrel 151a.

[0108] The main body 130 preferably has an internal space and an internal space surrounding portion 131. The slider 120 is accommodated in the internal space. In a cross section perpendicular to the slider advance / retract direction X, the internal space surrounding portion 131 surrounds the periphery of the internal space except for a portion that forms a side opening 133. The internal space surrounding portion 131 has an inner wall 134 facing the internal space and an outer wall 135 that forms the outer surface of the main body 130. Furthermore, the side opening 123 of the slider 120 and the side opening 133 of the main body 130 typically open in the same direction in a cross section perpendicular to the slider advance / retract direction X. Furthermore, both sides of the side opening 133 in the main body 130 typically form connecting walls that connect the inner wall 134 and the outer wall 135, and the gap between these connecting walls forms the side opening 133. The side openings 123, 133 preferably have a width sufficient to allow passage of the injection device 1. In a cross section of the main body 130 perpendicular to the advancing / retracting direction X of the slider 120, the side having the side opening 133 is also referred to as the front side, and the side not having the side opening 133 is also referred to as the back side.

[0109] The holder 100a typically allows the injection device 1 to be attached to the slider 120 from the side of the main body 130 via the side openings 123, 133, facilitating the attachment operation of the injection device 1. The possibility of contact between the first protrusion 11 and the holder 100a can be reduced when attaching the injection device 1 to the slider 120 or when removing the injection device 1 after an injection. This prevents the first protrusion 11 from being damaged, rendering the injection device 1 or injection needle 10 unusable or reducing the effectiveness of the injection. Furthermore, when attaching the injection device 1 to the slider 120, it is not necessary to remove the injection needle 10 from the syringe body 21. Therefore, the injection needle 10 can be attached to the syringe body 21, and the amount of medicinal solution contained in the medicinal solution storage portion 22 can be optimized before being attached to the slider. When removing the injection device 1 from the slider 120 after an injection, it is also not necessary to remove the injection needle 10 from the syringe body 21. This also reduces the possibility that the medicinal liquid leaking from the injection device 1 will adhere to the holder 100a. Therefore, after the injection device 1 is attached to the holder 100a and an injection operation is performed, the holder 100a can be reused by replacing only the injection device 1.

[0110] The holder 100a preferably has a guide mechanism that restricts the advancement / retraction direction X of the slider 120 to one direction X. The guide mechanism preferably includes a groove formed in the inner wall 134 of the internal space surrounding portion 131 and a guide protrusion 121a provided on the slider 120. The guide protrusion 121a preferably slidably engages with the groove in the one direction X to constitute the guide mechanism. The groove typically has an opening shape that extends along the advancement / retraction direction X of the slider 120. The guide protrusion 121a inserted into the groove moves along the guide hole, thereby restricting the advancement / retraction direction X of the slider 120 to the specific one direction X. The guide protrusions 121a are provided, for example, at both ends of a peripheral wall portion of the drug solution supply device accommodating portion 121 of the slider 120 that has an arc-shaped cross section, so as to protrude outward in the width direction Y. Two or more guide protrusions 121a may be provided at intervals along the longitudinal direction of the slider 120. From the viewpoint of more accurately regulating the forward and backward movement of the slider 120, it is preferable that the gap between the groove and the guide protrusions 121a be greater than 0 mm and less than 1 mm when they are engaged. From the same viewpoint, it is preferable that the grooves and guide protrusions 121a constituting the guide mechanism are each provided at two or more locations in the circumferential direction of the holder 100a. The guide may be formed by providing the guide protrusions 121a on the inner wall 134 of the internal space surrounding portion 131 and a groove into which the guide protrusions 121a are inserted on the slider 120. The presence of a guide suppresses slider wobble during puncture and / or drug solution injection. Furthermore, it becomes easier to maintain the appropriate angle of inclination of the injection needle relative to the skin during puncture and / or drug solution injection.

[0111] Specifically, the main body 130 of the holder 100a preferably includes two biasing members that bias the slider 120 in the forward direction A. In this embodiment, the biasing members are coil springs. The coil spring 161 is typically disposed in a slightly compressed state between the rear wall 136 of the main body 130 and a spring receiving portion 125 formed on the slider 120 so as to protrude outward from the side wall portion. The forward position of the slider 120 is typically a position where the slider 120 has advanced due to the repulsive force of the coil spring 161 until it abuts against a forward restriction portion 162 provided on the main body 130. An example of this is shown in FIG. 22 .

[0112] The main body 130 preferably includes a holding mechanism and a holding release mechanism. The holding mechanism holds the slider 120 in a retracted position, which is retracted away from the skin from the advanced position. The holding release mechanism releases the holding mechanism and advances the slider to the advanced position. The advanced position is the position where the injection needle penetrates the skin. The non-skin direction is the direction away from the skin, typically the same direction as the retracted direction B. The holding mechanism includes, for example, a holding protrusion 164 protruding from the slider 120 and a holding support 165 provided on the main body 130. The holding protrusion 164 and the holding support 165 are configured to engage with each other when the slider 120 is retracted beyond a predetermined position against the biasing force of the coil spring 161. Specifically, the holding protrusion 164 is preferably provided on the back surface of the slider 120. Preferably, the inner wall 134 of the main body 130 is provided with a guide hole 134a extending in the axial direction X of the main body 130 and allowing the inserted holding protrusion 164 to move in the forward / backward direction X. An example of this is shown in FIGS. 23 and 24 . The holding release mechanism preferably includes a rod-shaped release member 168 that physically interlocks with a skin holder 171 (described later). When the skin holder 171 is pressed against the skin, the release member 168 mechanically interlocks with the skin and presses a portion of the holding support 165. This preferably disengages the holding protrusion 164 from the holding support 165. Specifically, the holding support 165 preferably has a portion fixed to the outer wall 135 and an inclined portion that is inclined away from the outer wall 135 and approaches the slider 120. The inclined portion is pressed by the release member 168 and displaced in the direction D in the figure, thereby disengaging the engagement. When the engagement between the holding protrusion 164 and the holding support 165 is released, the slider 120 moves forward to the forward position due to the repulsive force of the highly compressed coil spring 161 generated by moving the slider 120 backward. In the drawing, symbol A indicates the forward direction, and symbol B indicates the backward direction.

[0113] The configurations of the holding mechanism and the holding release mechanism that hold the slider 120 in a retracted position that is retracted from the advanced position can be changed as desired. For example, a switch that activates the holding release mechanism may be provided on the side of the holder, and after pressing a part of the holder, such as a movable or non-movable skin presser, against the skin, the switch or the like may be operated to activate the holding release mechanism without interlocking with the skin presser.

[0114] The holder 100a has a drive mechanism that uses a biasing force to advance the slider 120 to an advanced position where the first protrusion 11 pierces the skin. The drive mechanism preferably includes two coil springs 161 that bias the slider 120 in the forward direction A. The two coil springs 161 are arranged so that the injection device 1 attached to the slider 120 is located between them. This makes it easier to form side openings 123, 133 in the main body 130 and the slider 120 compared to when the slider 120 is arranged at the center of the coil springs. Furthermore, the movement of the slider 120 in the one direction X is more stable compared to when a single coil spring 161 is arranged around the slider 120. Furthermore, this configuration makes it easier to install a guide that restricts the forward / backward movement of the slider 120 to the one direction X.

[0115] According to holder 100a, typically, after slider 120 is released from the retracted holding state, slider 120 automatically moves forward due to the repulsive force of compressed coil spring 161. This causes first protrusion 11 to puncture the skin, which makes it less likely that individual differences will occur in puncture conditions such as the puncture angle and puncture speed relative to the skin.

[0116] The holder 100a of this embodiment typically includes a retention mechanism that retains the slider 120 in a retracted position, retracted away from the skin side from the advanced position, by engaging the retention protrusion 164 with the retention support 165. The holder 100a also typically includes a retention release mechanism that disengages the retention protrusion 164 from the retention support 165 and advances the slider 120 to the advanced position using the repulsive force of the coil spring 161, rather than manually. This allows the holder 100a to be released from the retention state after being brought into an appropriate position close to the skin to which the medicinal solution is to be administered. This further ensures that the first protrusion 11 can be punctured using the holder 100a. The retention release mechanism is preferably a mechanism that releases the engagement between the retention protrusion 164 and the retention support 165 using a release member 168 that operates in conjunction with the skin presser 171. This mechanism is activated by pressing a portion of the holder 100a against the skin. Therefore, the first protrusions 11 can be punctured while maintaining an appropriate tension on the skin area that the first protrusions 11 come into contact with. Also, individual differences in the pressure applied to the skin can be reduced.

[0117] The retainer 100a preferably has a substantially annular skin presser 171 at its end in the skin direction, i.e., at the end closer to the skin in the advancing / retracting direction X of the slider 120. The substantially annular skin presser is preferably arranged on the circumferential outer side of the slider 120. "Arranged on the circumferential outer side of the slider" means that the skin presser is located around the slider 120 when the retainer 100a is viewed from the end side in the skin direction. More preferably, the retainer 100a of the present invention preferably has a substantially annular skin presser 171 that abuts against the periphery of the skin area with which the first protrusion 11 contacts. More specifically, the main body 130 preferably has, at its skin-side tip, a skin presser 171 that displaces along the advancing / retracting direction X. The displacing skin presser 171 is constantly biased in the advancing direction A by a biasing member such as a coil spring 161, and preferably retracts along the advancing / retracting direction X by pressing the skin presser 171 against the skin. The term "substantially annular" may refer to a continuous annular shape, i.e., a 360° continuous configuration, or may include a shape that is partially interrupted but can be considered annular as a whole. Annular skin presser 171 preferably has a surface that is parallel to a plane perpendicular to the advancing / retreating direction X of slider 120.

[0118] The holder 100a typically has a substantially annular skin presser 71 that abuts against the periphery of the skin area that is in contact with the first protrusions 11. This makes it possible to prevent height differences from occurring around the skin area that is in contact with the first protrusions 11. This prevents the skin from tilting when the first protrusions 11 are to be applied perpendicularly to the skin, making it easier to apply the first protrusions 11 perpendicularly.

[0119] To facilitate the operation of retracting the slider 120 equipped with the injection device 1, it is preferable to provide a knob 126 having an arc-shaped cross section at the end of the slider 120 on the retraction direction B side. The knob 126 makes it easy to pinch or grip the slider 120 with the fingers and move it in the retraction direction B. The shape and size of the knob 126 can be changed as desired. Note that a shape and size that do not interfere with the attachment of the injection device 1 to the slider 120 are preferred. It is also possible not to provide the knob 126.

[0120] The present invention encompasses a kit including an injection needle, a drug solution feeder capable of containing the drug solution, and the drug solution. The injection needle included in the injection kit of the present invention can be the same as the injection needle 10 described above. The drug solution feeder can be the same as the drug solution feeder 20 described above. The drug solution can be the same as the drug solution L described above. The injection kit of the present invention includes a protrusion having an opening of a predetermined size on its side and a drug solution of a specific concentration, and therefore has excellent ejection properties and administration properties, such as the ability to efficiently inject the drug solution into the skin.

[0121] One embodiment of the method for providing the injection device of the present invention includes, for example, providing the injection needle 10 and the drug solution feeder 20 containing the drug solution in the injection device 1 described above to a medical institution, wholesaler, or the like, together with an explanation of their combined use, both separately from each other. In this case, it is preferable to seal the injection port 23 with a rubber stopper member to prevent leakage of the drug solution from the drug solution feeder 20. The explanation of their combined use can be, for example, provided on the injection needle 10 or its individual packaging, and / or the drug solution feeder 20 or its individual packaging, with a product number, text, symbol, or the like that identifies the intended combination. The injection needle 10 and the drug solution feeder 20 may be provided separately in the same packaging box, and the packaging box may include a recommendation or warning that the injection needle 10 and the drug solution feeder 20 should be used in combination. By providing the injection device in this manner, it is possible to more easily and / or reliably demonstrate the performance of an injection device that exhibits excellent performance when combined with a specific injection needle having a specific aperture and a specific drug solution.

[0122] While the present invention has been described based on preferred embodiments, it is not limited to the above-described embodiments and can be modified as appropriate. For example, in the example shown in FIG. 7, the second protrusion 12 is solid, but the second protrusion 12 may be hollow. Furthermore, in the example shown in FIG. 10, the composite second protrusion 52 is solid, but the composite second protrusion 52 may be hollow. In the injection needle 10, it is preferable that the protrusions other than the first protrusion 11 are solid. This prevents the liquid to be ejected from the opening 11a of the first protrusion 11 from accumulating inside the other protrusions, thereby enabling efficient injection of the liquid. The injection device of the present invention may be all or part of a combination. The injection kit of the present invention may be all or part of a combination.

[0123] The following supplementary notes are further disclosed regarding the above-described embodiments of the present invention: <1> An injection device including an injection needle and a drug solution feeder containing a drug solution, wherein the injection needle has a cone-shaped protrusion protruding from a base surface and having an opening on a side surface, the opening has a width of 25 μm or more and 60 μm or less and a vertical width of 25 μm or more and 130 μm or less, and an area X of the opening calculated from the width and vertical width of the opening is 500 μm or less. ２ 6100 μm or more ２ The injection device has a viscosity Y of 1.00 mPa·s or more and 10 mPa·s or less at 20°C, and satisfies any one of the following relationships (Q), (R), and (S): (Q) The drug solution contains an organic compound A2 having a weight-average molecular weight of 1,000 or more as an active ingredient, and the viscosity Y (mPa·s) of the drug solution and the area X (μm ２ ) satisfy the relational expression Y≦0.00018×X+2.2. (R) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle diameter of 20 nm or more and 1200 nm or less, the fine particles being formed by aggregation, bonding or compounding of an inorganic compound and the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２) satisfy the relational expression Y≦0.0015×X+3.0. (S) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles with a particle diameter of 20 nm or more and 1200 nm or less, the fine particles including fine particles formed by aggregation, bonding or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relation Y≦0.00044×X+1.4.

[0124] <2> The injection device according to <1>, which is used for intradermal administration of the drug solution. <3> The injection device according to <1> or <2>, wherein the center of the opening is located 200 μm or more and 1000 μm or less below the tip of the protrusion in the height direction of the protrusion. <4> The injection device according to any one of <1> to <3>, wherein the injection needle has, in addition to the first protrusion that is the protrusion, a second protrusion that has no opening, and the second protrusion is a cone-shaped stimulation protrusion and / or a puncture depth control protrusion whose tip surface functions as a puncture depth control unit that controls the puncture depth of the first protrusion. <5> The injection device according to any one of <1> to <4>, which satisfies the relationship (R) or (S), and wherein the organic compound A2 is one selected from a peptide, a protein, a nucleic acid, a carbohydrate, a glycolipid, and a glycopeptide.

[0125] <6> The injection device according to any one of <1> to <5>, which satisfies the relationship (R) or (S), and wherein the organic compound A2 is at least one selected from the group consisting of a GLP-1 receptor agonist, an insulin analogue, a small molecule biopharmaceutical, a viral protein, a nucleic acid sequence encoding a viral protein, a protozoan protein, a nucleic acid sequence encoding a protozoan protein, a bacterial protein, and a nucleic acid sequence encoding a bacterial protein. <7> The injection device according to <6>, wherein the viral protein is at least one selected from the group consisting of a hepatitis A virus protein, a hepatitis B virus protein, a hepatitis C virus protein, an influenza virus protein, a SARS-CoV-2 virus protein, a respiratory syncytial virus protein, a rabies virus protein, a poliovirus protein, a varicella-zoster virus (Varicella-zoster virus, VZV) (human herpesvirus type 3) protein, a rubella virus protein, and a measles virus protein. <8> The injection device according to <6> above, wherein the nucleic acid sequence encoding the viral protein is a nucleic acid sequence encoding at least one selected from the group consisting of a hepatitis A virus protein, a hepatitis B virus protein, a hepatitis C virus protein, an influenza virus protein, a SARS-CoV-2 virus protein, a respiratory syncytial virus protein, a rabies virus protein, a poliovirus protein, a varicella-zoster virus (Varicella-zoster virus, VZV) (human herpesvirus type 3) protein, a rubella virus protein, and a measles virus protein. <9> The injection device according to <6> above, wherein the bacterial protein is at least one selected from the group consisting of a protein derived from Mycobacterium tuberculosis and a protein derived from Clostridium tetani (tetanus bacteria). <10> The injection device according to <6>, wherein the nucleic acid sequence encoding the bacterial protein is a nucleic acid sequence encoding at least one selected from the group consisting of a protein derived from Mycobacterium tuberculosis and a protein derived from Clostridium tetani (tetanus bacterium).

[0126] <11> The injection device according to any one of <1> to <4>, which satisfies the relationship (R), and wherein the inorganic compound constituting the microparticles is a polyvalent metal compound, and the organic compound A2 includes one or more selected from a protein, a peptide, a nucleic acid, a carbohydrate, a glycolipid, and a glycopeptide. <12> The injection device according to any one of <1> to <4>, which satisfies the relationship (S), and wherein the microparticles are one or more types of microparticles selected from a liposome, an emulsion particle, a lipid nanoparticle, and a virus particle, and the organic compound B constituting the microparticles includes one or more selected from an animal-extracted oil, a glycoside of a plant extract, a glycolipid and a modified glycolipid thereof, an amphipathic oil selected from a phospholipid and a cholesterol, and a polyvalent metal-chelating lipid. <13> The injection device according to any one of <1> to <12> above, wherein the concentration of the drug solution is preferably 0.01 mg / mL or more, more preferably 0.1 mg / mL or more, and preferably 25 mg / mL or less, more preferably 5 mg / mL or less, preferably 0.01 mg / mL to 25 mg / mL or less, more preferably 0.1 mg / mL to 5 mg / mL or less. <14> The injection device according to any one of <1> to <13> above, which satisfies the relationship (R) or (S), and wherein the average particle size of the microparticles is preferably 20 nm or more, preferably 80 nm or more, preferably 8000 nm or less, preferably 3000 nm or less, preferably 20 nm to 8000 nm or less, preferably 80 nm to 3000 nm or less. <15> An injection kit comprising the injection device according to any one of <1> to <14> above, and a holder that moves the injection device with the injection needle attached toward the skin and punctures the skin with the protrusion of the injection needle.

[0127] <16> The injection kit according to <15>, wherein the holder has a biasing member that biases the injection device in the puncture direction of the injection needle, and the mass of the injection device and the kinetic energy when the protrusion of the injection device biased by the biasing member punctures the skin satisfy the following formula (1): E≧0.0077ln(x)+0.0057 (1) (where E represents the kinetic energy, and x represents the mass of the injection device.) <17> The injection kit according to <16>, wherein the kinetic energy is preferably 0.014 J or more and 0.23 J or less, more preferably 0.018 J or more and 0.21 J or less, and even more preferably 0.018 J or more and 0.17 J or less. <18> The injection kit according to <16> or <17>, wherein the puncture speed when the protrusion of the injection device urged by the urging member punctures the skin is preferably 1700 mm / s or more and 9300 mm / s or less, more preferably 1800 mm / s or more and 8600 mm / s or less, and even more preferably 1800 mm / s or more and 7000 mm / s or less. <19> An injection kit comprising an injection needle, an injection device comprising a drug solution supplier capable of containing a drug solution, and a drug solution, wherein the injection needle has a cone-shaped protrusion protruding from a base surface and having an opening on a side surface, the opening has a width of 25 μm or more and 60 μm or less and a vertical width of 25 μm or more and 130 μm or less, and an area X of the opening calculated from the width and vertical width of the opening is 500 μm or less. ２ 6100 μm or more ２ and the viscosity Y of the medicinal solution at 20°C is 1.00 mPa·s or more and 10 mPa·s or less, and the injection kit satisfies any one of the following relationships (Q), (R), and (S): (Q) the medicinal solution contains an organic compound A2 having a weight-average molecular weight of 1,000 or more as an active ingredient, and the viscosity Y (mPa·s) of the medicinal solution and the area X (μm ２) satisfy the relational expression Y≦0.00018×X+2.2. (R) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle diameter of 20 nm or more and 1200 nm or less, the fine particles being formed by aggregation, bonding or compounding of an inorganic compound and the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relational expression Y≦0.0015×X+3.0. (S) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles with a particle diameter of 20 nm or more and 1200 nm or less, the fine particles including fine particles formed by aggregation, bonding or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relation Y≦0.00044×X+1.4.

[0128] <20> The injection kit according to <19>, further comprising: a holder that moves the injection device with the injection needle attached toward the skin and punctures the skin with the protrusion of the injection needle, the holder having a biasing member that biases the injection device in the puncture direction of the injection needle, and wherein the mass of the injection device and the kinetic energy when the protrusion of the injection device biased by the biasing member punctures the skin satisfy the following formula (1): E≧0.0077ln(x)+0.0057 (1) (where E represents the kinetic energy, and x represents the mass of the injection device.) <21> The injection kit according to <20>, further comprising: <22> The injection kit according to <20> or <21>, wherein the puncture speed when the protrusion of the injection device biased by the biasing member punctures the skin is preferably 1700 mm / s or more and 9300 mm / s or less, more preferably 1800 mm / s or more and 8600 mm / s or less, and even more preferably 1800 mm / s or more and 7000 mm / s or less.

[0129] <23> Use of the injection device according to any one of <1> to <14> above for intradermal administration of a medicinal solution. <24> A method for intradermal administration of a medicinal solution using the injection device according to <1> above. <25> A method for intradermal administration of a medicinal solution using the injection device according to <1> above and a holder that assists puncture with the protrusions, the method for intradermal administration of a medicinal solution according to <24> above, wherein the kinetic energy when the protrusions of the injection device puncture the skin satisfies the following formula (1): E≧0.0077ln(x)+0.0057 (1) (where E represents the kinetic energy, and x represents the mass of the injection device.) <26> The method according to <25> above, wherein the kinetic energy is preferably 0.014 J or more and 0.23 J or less, more preferably 0.018 J or more and 0.21 J or less, and even more preferably 0.018 J or more and 0.17 J or less. <27> The method according to <25> or <26>, wherein the holder has a biasing member that biases the injection device in the puncture direction of the injection needle, and the puncture speed when the protrusion of the injection device biased by the biasing member punctures the skin is preferably 1700 mm / s or more and 9300 mm / s or less, more preferably 1800 mm / s or more and 8600 mm / s or less, and even more preferably 1800 mm / s or more and 7000 mm / s or less.

[0130] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0131] [Injection Needle Sample 1] An injection needle with the same configuration as the injection needle 10 shown in Figure 1 was manufactured. This injection needle has the same projection arrangement as that shown in Figure 5. The dimensions of each projection of the injection needle, the horizontal and vertical widths of the openings of the primary projections, the central positions of the openings of the primary projections, and the ratio of the mass of the thermoplastic resin to the total mass of the fine projection device are as shown in Table 1. The injection needle was produced by subjecting a base sheet made of 100% polylactic acid, a thermoplastic resin, to a projection-forming process using a processing needle to which ultrasonic vibrations were applied, further subjecting the primary projections to hole processing to form the fine projection device, and then bonding the fine projection device to a base part.

[0132] [Injection needle samples 2 to 4] Except for varying the horizontal and vertical widths of the apertures, these were manufactured in the same manner as injection needle sample 1. Table 1 below shows the dimensions of each projection of the injection needle, the horizontal and vertical widths of the apertures, the center positions of the apertures, and the ratio of the mass of the thermoplastic resin to the total mass of the fine-projection device.

[0133]

[0134] [Drug Solution Samples 1 to 6] Powdered egg albumin (Fujifilm Wako Pure Chemicals, chemical grade, molecular weight: 45 kDa; hereinafter referred to as OVA) was adjusted to 100 mg / mL with phosphate buffer. This OVA corresponds to organic compound A2 with a weight-average molecular weight of 1,000 or more used in the cases of (Q), (R), and (S). The viscosity of Drug Solution Sample 1 at 20°C was as shown in Table 2 below. Drug Solution Samples 2 to 6 were prepared by appropriately diluting Drug Solution Sample 1 with phosphate buffer and adjusted to the concentrations shown in Table 2. Table 2 below shows the viscosity at 20°C, shear rate at the time of viscosity measurement, concentration, and average particle size of Drug Solution Samples 1 to 6. In the table, "-" indicates that evaluation was not performed.

[0135] [Drug Solution Samples 7 to 15] Drug Solution Sample 2 (OVA 50 mg / mL) and adjuvant (2% aluminum hydroxide Alhydrogel; manufactured by Croda; hereinafter referred to as OVA-Alhydrogel) were mixed at a 1:1 ratio (25 mg / mL OVA amount) to prepare a suspension designated Drug Solution Sample 7. The suspension was further adjusted with phosphate buffer to the concentrations of Drug Solution Samples 8 to 15 listed in Table 3. Table 3 below shows the viscosity at 20°C, shear rate at the time of viscosity measurement, concentration, and average particle size of Drug Solution Samples 7 to 15. The average particle size of Drug Solution Samples 7 to 15 was measured by dynamic light scattering after diluting Sample 7 1000-fold with phosphate buffer. The noise reduction mode was used for the measurement. The average value and area ratio of the peak obtained by dynamic light scattering were 1183 nm (100%) (the values ​​in parentheses indicate the peak area ratio). The arithmetic mean particle size was calculated using the following formula: Arithmetic mean particle size = Σ {frequency distribution value (%) × representative diameter of Jth particle size range (μm)} ÷ Σ {frequency distribution value (%)}, where J is the particle size division number (automatically applied from 1 to 64 at fixed intervals)

[0136] [Drug Solution Samples 16-23] Drug Solution Sample 2 (OVA 50 mg / mL) and adjuvant (aluminum hydroxide Imject™; manufactured by Thermo Scientific; hereinafter referred to as OVA-Imject) were mixed at a 1:1 ratio (OVA amount: 25 mg / mL) to prepare a suspension, designated Drug Solution Sample 16. The suspension was further adjusted with phosphate buffer to the concentrations of Drug Solution Samples 17-23 listed in Table 4. Table 4 below shows the viscosity at 20°C, shear rate at the time of viscosity measurement, concentration, and average particle size of Drug Solution Samples 16-23. The average particle size of Drug Solution Samples 16-23 was measured by dynamic light scattering after diluting Sample 16 200-fold with phosphate buffer. The noise reduction mode was used for the measurement. The average value and area ratio of the peak obtained by dynamic light scattering were 635 nm (100%) (the values ​​in parentheses indicate the peak area ratio). The arithmetic mean particle size was calculated using the following formula: Arithmetic mean particle size = Σ {frequency distribution value (%) × representative diameter of J-th particle size range (μm)} ÷ Σ {frequency distribution value (%)}, where J is the particle size division number (automatically applied from 1 to 64 at fixed intervals).

[0137] Drug Solution Samples 24 to 35: Drug Solution Sample 2 (OVA 50 mg / mL) and adjuvant (squalene; Addavax; manufactured by GSK) were mixed at a 1:1 ratio (OVA amount: 25 mg / mL) to prepare a suspension, which was designated Drug Solution Sample 24. The suspension was further adjusted with phosphate buffer to the concentrations of Drug Solution Samples 25 to 29 listed in Table 5. Drug Solution Sample 1 (OVA 100 mg / mL) and liposomes (DOPC:cholesterol = 4:1 (manufactured by Avanti) and liposomes were prepared using an Avanti Mini-extruder) at a 1:3 ratio (OVA amount: 25 mg / mL) to prepare a suspension, which was designated Drug Solution Sample 30. The suspension was further adjusted with phosphate buffer to the concentrations of Drug Solution Samples 31 to 32 listed in Table 5. These samples contained nucleic acid encoding firefly luciferase (Fluc) as mRNA, and were prepared according to Nat Protoc. 2023. A Flu-mRNA-LNP formulation prepared by the method disclosed in [Jan;18(1):265-291] was designated as drug solution sample 33, and further adjusted using phosphate buffer to the concentrations of drug solution samples 34 to 35 listed in Table 5.

[0138] Table 5 below shows the viscosity at 20°C, shear rate at the time of viscosity measurement, concentration, and average particle size of liquid samples 24 to 35. The average particle size of liquid samples 24 to 35 was measured by dynamic light scattering after diluting samples 24, 30, and 33 200 times with phosphate buffer. The noise reduction mode was used for the measurement. The average particle size and area ratio of the peaks obtained by dynamic light scattering were 142 nm, 180 nm, and 97 nm (100%), respectively (the values ​​in parentheses indicate the peak area ratio). The arithmetic mean particle size was calculated using the following formula: Arithmetic mean particle size = Σ {frequency distribution value (%) × representative diameter of Jth particle size range (μm)} ÷ Σ {frequency distribution value (%)}, where J is the particle size division number (automatically applied from 1 to 64 at fixed intervals).

[0139]

[0140]

[0141]

[0142]

[0143] [Evaluation] Using injection needle samples 1 to 4 and drug solution samples 1 to 35, ejection properties and administration properties were evaluated using the following evaluation methods. The results are shown in Tables 6 to 14. In the tables, "●" indicates samples for which ejection or administration was successful in the high concentration range of each drug solution sample, and therefore ejection or administration was clearly expected to be successful, so no evaluation was performed, or only viscosity measurements were performed. In the tables, " / " indicates that no evaluation was performed.

[0144] [Evaluation of ejection properties] A disposable syringe manufactured by Henke was used as the drug solution feeder. The drug solution was filled into a disposable syringe manufactured by Henke, injection needle samples 1 to 4 were attached, and air was removed. The amount of liquid in the disposable syringe manufactured by Henke (drug solution feeder) was set to 200 μL, and it was confirmed whether ejection was possible. [Evaluation criteria for ejection properties] ◯: The drug solution sample was ejected without resistance (the drug solution sample was ejected in a bubble-like form or while being clogged) from the start of ejection until 100 μL of the drug solution sample was ejected. △: There was resistance from the start of ejection until 100 μL of the drug solution sample was ejected, but 200 μL of the drug solution sample was ejected. ×: Ejection was not completed.

[0145] [Evaluation of Administration] Using injection needle samples 1 to 4 and drug solution samples 1 to 35, drug solutions were administered to the excised skin of a Göttingen miniature pig by the following method. The excised skin of a Göttingen miniature pig (male, 6 weeks old, ventral part; Oriental Yeast Co., Ltd.) stored at -20°C was transferred to a refrigerator (4°C) the day before the test and thawed. The excised skin was placed on 5 to 7 Kimtowels and used for administration. One drug solution sample selected from drug solution samples 1 to 35 was loaded into a glass manual syringe: a 100 μL PTFE needle-replaceable luer-lock syringe (Agilent, model number: 5190-1513) or a disposable syringe manufactured by Henke. The syringe was set in a holder and air was removed. The liquid volume in the drug solution supply device was set to 100 μL, and excess liquid adhering to the injection needle was removed by absorbing it with Kimwipes. The needle protrusion was inserted perpendicularly into the target, and 100 μL of the drug solution sample was injected. After administration, the needle was removed and the presence or absence of a wheal was immediately confirmed. Figure 12 shows a schematic plan view of a wheal. In Figure 12, reference numeral 91 indicates the outline of the wheal, and reference numeral 92 indicates the fluid within the wheal. Each dose was administered 1 to 5 times. [Criteria for evaluation of administration] ◯: Administration was successful (a wheal was formed) with the Henke disposable syringe. △: Administration was not possible with the Henke disposable syringe (clogging or leakage occurred), but administration was successful with the Agilent syringe. ×: Clogging occurred with both the Henke disposable syringe and the Agilent syringe, or a wheal was formed but the drug solution clearly leaked out.

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] Tables 6 to 14 show the results of tests 1 to 122 in which different combinations of injection needle samples and drug solution samples were used.

[0156] (1) For tests using drug solutions containing ovalbumin as organic compound A2 (drug solution samples 1 to 6), the results are shown in Tables 6 to 14. Figure 14(a) plots the administration evaluation results for multiple tests on a graph with hole area on the horizontal axis and viscosity on the vertical axis. As shown in Figure 14(a), it can be seen that excellent performance is obtained when the injection needle satisfies the above-mentioned relationship (Q), and even better performance is obtained when the relationship Y≦0.00018×X+2.05 is satisfied. In the figure, the solid line is the straight line expressed as Y=0.00018×X+2.2, and the dotted line is the straight line expressed as Y=0.00018×X+2.05.

[0157] (2) The results of tests using drug solutions (drug solution samples 7 to 23) containing ovalbumin as organic compound A2 and an adjuvant made of aluminum hydroxide are shown in Tables 6 to 14. Figure 14(b) shows the results of administerability evaluations for multiple tests plotted on a graph with hole area on the horizontal axis and viscosity on the vertical axis. As shown in Figure 14(b), it can be seen that excellent performance is obtained when the injection needle satisfies the relationship (R), and even better performance is obtained when the relationship 0.0015 × X + 0.65 is satisfied. In the figure, the solid line is the straight line expressed by Y = 0.0015 × X + 3.0, and the dotted line is the straight line expressed by Y = 0.0015 × X + 0.65.

[0158] (3) The results of tests using drug solutions (drug solution samples 24-35) containing ovalbumin as organic compound A2 and oil emulsion, liposome, or LNP are shown in Tables 6-14. Figure 14(c) plots the administration evaluation results for multiple tests on a graph with hole area on the horizontal axis and viscosity on the vertical axis. As shown in Figure 14(c), excellent performance is obtained when the injection needle satisfies relationship (S), and even better performance is obtained when the relationship Y≦0.00044×X+1.4 is satisfied. In the figure, the solid line is the straight line expressed by Y=0.00044×X+1.4, and the dotted line is the straight line expressed by Y=0.00044×X+1.0.

[0159] According to the present invention, there is provided an injection device with excellent ejection properties and administration properties. According to the present invention, there is provided a method for providing an injection device and an injection kit that can more easily and / or reliably exhibit the excellent performance of the injection device.

Claims

1. An injection device comprising an injection needle and a drug solution supply container containing a drug solution, wherein the injection needle has a cone-shaped protrusion protruding from a base surface and having an opening on the side, the width of the opening is 25 μm or more and 60 μm or less, and the vertical width is 25 μm or more and 130 μm or less, and the area X of the opening calculated from the width and vertical width of the opening is 500 μm or less. ２ 6100 μm or more ２ The injection device has a viscosity Y of 1.00 mPa·s or more and 10 mPa·s or less at 20°C, and satisfies any one of the following relationships (Q), (R), and (S): (Q) The drug solution contains an organic compound A2 having a weight-average molecular weight of 1,000 or more as an active ingredient, and the viscosity Y (mPa·s) of the drug solution and the area X (μm ２ ) satisfy the relational expression Y≦0.00018×X+2.

2. (R) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle diameter of 20 nm or more and 1200 nm or less, the fine particles being formed by aggregation, bonding or compounding of an inorganic compound and the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relational expression Y≦0.0015×X+3.

0. (S) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles with a particle diameter of 20 nm or more and 1200 nm or less, the fine particles including fine particles formed by aggregation, bonding or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relation Y≦0.00044×X+1.

4.

2. The injection device according to claim 1, which is used for intradermal administration of the drug solution.

3. An injection device as described in claim 1 or 2, wherein the center of the opening is located at a position 200 μm or more and 1000 μm or less below the tip of the protrusion in the height direction of the protrusion.

4. The injection device according to claim 1 or 2, wherein the injection needle has, in addition to the first protrusion, a second protrusion without an opening, and the second protrusion is a stimulation protrusion having a cone shape and / or a puncture depth control protrusion whose tip surface functions as a puncture depth control section that controls the puncture depth of the first protrusion.

5. The injection device according to claim 1 or 2, which satisfies the relationship (R), wherein the inorganic compound constituting the microparticles is a polyvalent metal compound, and the organic compound A2 includes one or more selected from proteins, peptides, nucleic acids, carbohydrates, glycolipids, and glycopeptides.

6. The injection device according to claim 1 or 2, which satisfies the relationship (S), wherein the microparticles are one or more types of microparticles selected from liposomes, emulsion particles, lipid nanoparticles, and virus particles, and wherein organic compound B constituting the microparticles includes one or more types selected from animal-extracted oils, glycosides of plant extracts, glycolipids and their modifications, amphipathic oils selected from phospholipids and cholesterol, and polyvalent metal chelating lipids.

7. An injection kit comprising the injection device according to claim 1 or 2 and a holder that moves the injection device with the injection needle attached toward the skin and punctures the skin with the protrusion of the injection needle.

8. An injection kit comprising an injection needle, an injection device having a drug solution supply device capable of storing a drug solution, and a drug solution, wherein the injection needle has a cone-shaped protrusion protruding from a base surface and having an opening on the side, the width of the opening is 25 μm or more and 60 μm or less, and the vertical width of the opening is 25 μm or more and 130 μm or less, and the area X of the opening calculated from the width and vertical width of the opening is 500 μm ２ 6100 μm or more ２ and the viscosity Y of the medicinal solution at 20°C is 1.00 mPa·s or more and 10 mPa·s or less, and the injection kit satisfies any one of the following relationships (Q), (R), and (S): (Q) the medicinal solution contains an organic compound A2 having a weight-average molecular weight of 1,000 or more as an active ingredient, and the viscosity Y (mPa·s) of the medicinal solution and the area X (μm ２ ) satisfy the relational expression Y≦0.00018×X+2.

2. (R) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles having a particle diameter of 20 nm or more and 1200 nm or less, the fine particles being formed by aggregation, bonding or compounding of an inorganic compound and the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relational expression Y≦0.0015×X+3.

0. (S) The chemical solution contains an organic compound A2 having a weight average molecular weight of 1000 or more as an active ingredient, and further contains fine particles with a particle diameter of 20 nm or more and 1200 nm or less, the fine particles including fine particles formed by aggregation, bonding or compounding of an organic compound B other than the organic compound A2 with all or a part of the organic compound A2, and the viscosity Y (mPa s) of the chemical solution and the area X (μm ２ ) satisfy the relation Y≦0.00044×X+1.4.

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