WO2023100732A1 - Injection needle, needle assembly, administration device, and intradermal administration method - Google Patents

Abstract

Provided are an injection needle, a needle assembly, an administration device, and an intradermal administration method, enabling intradermal administration to a non-human small animal through perpendicular puncture to be smoothly carried out in a more reliable manner. An injection needle (110) comprises a needle tube (111) with a blade face (113) formed on a needle tip (112) of the needle tube (111). The outer diameter D1 of the needle tube (111) is 0.1-0.2 mm. The protrusion length L1 of the needle tube (111) is 0.1-0.6 mm. The length L2 of the blade face (113) along the extending direction of the needle tube (111) is less than 0.3 mm. The injection needle (110) is used to intradermically administer a drug to a non-human small animal through perpendicular puncture.

Description

Injection needle, needle assembly, administration device, and intradermal administration method

The present invention relates to injection needles, needle assemblies, administration devices, and intradermal administration methods.

Conventionally, as a method of administering drugs such as vaccines to humans, so-called "intradermal administration", which targets the upper layer of the skin where many immunocompetent cells are present, has been known. It is being investigated to reduce the dose of the drug by performing intradermal administration. When the subject of administration is a human, the intradermal administration described above includes a 50 μm to 200 μm thick “epidermal layer” from the skin surface, a 0.5 to 3.5 mm thick “dermis layer” continuing from the epidermal layer, and a deeper layer than the dermal layer. Among the skin composed of the "subcutaneous tissue layer", it is common to aim for administration to the dermis layer.

The following points are considered to be issues in implementing intradermal administration. In general, the human epidermis layer is thin, and the thickness of the human epidermis layer depends on the age difference, gender difference, individual difference, variation in medical history and treatment history, etc. of the administration subject. Therefore, when intradermal administration is attempted using a conventional drug administration device equipped with an injection needle used for subcutaneous administration, the depth of the administration site closer to the epidermis in the dermis layer cannot be uniquely determined, It is not easy to properly position the tip of the injection needle within the dermis layer.

In addition, the upper layers of the skin, including the epidermis and dermis layers, contain a large amount of elastic fibrous tissue such as elastin and collagen, so they are harder than the subcutaneous tissue. Therefore, administration to the upper layer of the skin requires a higher injection pressure than administration to the subcutaneous tissue because high back pressure is generated in the upper layer of the skin when the drug is injected. As described above, various problems are known to exist in order to realize intradermal administration to humans. In addition, animals other than humans, particularly small animals, have thinner skin than humans, making the technique of intradermal administration even more difficult.

Therefore, as described in Patent Document 1 below, there has been proposed a drug administration device for vertical puncture that can solve the above problems.

WO2016/117164

A drug administration device described in Patent Document 1 includes a needle hub to which an injection needle is connected. The needle hub includes an adjusting portion that adjusts the projection length (exposure length) of the injection needle from the needle hub, and a stabilizing portion that surrounds the adjusting portion. When the injection needle is vertically punctured into the epidermis layer, the adjusting portion contacts the epidermis layer and spreads the epidermis layer around the injection needle. At this time, the skin layer is flattened in the space provided between the adjusting portion and the stabilizing portion. With the epidermis layer spread out in this way, by inserting the injection needle arranged to maintain a predetermined protrusion length from the epidermis layer side, the epidermis layer is not dependent on variations in the state of the epidermis layer for each patient. , the tip of the injection needle can be properly guided into the dermis layer.

In addition, in the injection needle of Patent Document 1, the dimensions of each part such as the outer diameter and projection length of the injection needle are designed so that the injection pressure of the drug does not become excessively large. Therefore, intradermal administration can be performed reliably and smoothly by advancing the plunger of the drug administration device with the needle tip of the injection needle described in Patent Document 1 placed in the dermis layer.

As mentioned above, many studies have been conducted on devices and methods for realizing intradermal administration to humans. However, sufficient studies have not been made on intradermal administration to non-human animals other than humans, especially to small non-human animals that are often used in animal experiments.

When intradermally administering to small non-human animals, it is conceivable to adopt the Mantoux method, etc., in which the injection needle is inserted obliquely. However, a typical injection needle used for administration to small non-human animals is configured with an outer diameter of about 0.4 mm (27G), which is larger than a typical injection needle for humans. Also, small non-human animals have thinner epidermal and dermal layers than humans. Therefore, when the Mantoux method is used for intradermal administration in small non-human animals, it is difficult to accurately place the injection needle in the dermis layer, and the tip of the needle may penetrate the dermis layer and penetrate the subcutaneous tissue layer. have a nature.

For example, if the administration device for vertical puncture described in Patent Document 1 is used for intradermal administration to small non-human animals, intradermal administration can be easily and smoothly performed in the same way as for humans. Conceivable.

However, as mentioned above, non-human small animals have thinner epidermal and dermal layers than humans. Therefore, when a vertical puncture injection needle or drug administration device developed for humans is used, there is a high possibility that the tip of the needle penetrates the dermis layer and reaches the subcutaneous tissue. In addition, when the blade surface length of the needle tip of the injection needle is simply configured to be short in order to prevent the needle tip from penetrating the dermis layer as described above, when the needle tip is pressed vertically against the skin surface, , it becomes difficult to smoothly insert the needle tip into the epidermis layer.

The inventors of the present invention found a unique problem for realizing intradermal administration by vertical puncture of non-human small animals as described above, and as a result of intensive studies, an injection needle that can solve the problem, I have invented a needle assembly, an administration device, and an intradermal administration method.

An object of the present invention is to provide an injection needle, a needle assembly, an administration device, and an intradermal administration method that enable smooth and more reliable intradermal administration of non-human small animals by vertical puncture. do.

An injection needle according to one aspect of the present invention is an injection needle provided with a needle tube having a blade surface formed on the needle tip, the outer diameter of the needle tube being 0.1 mm or more and 0.2 mm or less, and the needle tube The protruding length is 0.1 mm or more and 0.6 mm or less, the length of the blade surface along the extending direction of the needle tube is less than 0.3 mm, and vertical puncture is used for intradermal administration to non-human small animals. Used.

In addition, a method for intradermal administration according to another aspect of the present invention is a method for intradermally administering a drug to a small non-human animal, comprising a vertical puncture under the site of the small non-human animal where the drug is to be administered. A support member for stabilizing the is placed, the administration site is prepared by stretching the site to be administered so as to be flat, and the guide portion provided in the needle hub holding the injection needle is pressed against the administration site, The drug is administered intradermally to the administration site by vertical puncture through the injection needle in a state in which the guide section is separated from the administration site by a predetermined distance.

According to the injection needle, needle assembly, administration device, and administration method of the present invention, intradermal administration to small non-human animals can be performed smoothly and more reliably by vertical puncture.

1 is a perspective view of an embodiment delivery device; FIG. FIG. 2 is an exploded view of an embodiment needle hub; FIG. 10 is a partial cross-sectional view of an embodiment needle hub and syringe; FIG. 2 is a perspective view of an embodiment needle hub; [0013] Fig. 4 is an enlarged cross-sectional view of an embodiment needle hub; It is an enlarged plan view of the blade surface of the injection needle according to the embodiment. It is an expansion perspective view of the blade surface of the injection needle which concerns on embodiment. 8A is a side view of the blade surface of the injection needle as seen from the direction of arrow 8A shown in FIG. 6, and FIG. 8B is a perspective view of the blade surface of the injection needle as seen from the direction of arrow 8B shown in FIG. It is a side view. 9A is a side view of the blade surface of the injection needle as seen from the direction of arrow 9A shown in FIG. 6, and FIG. 9B is a perspective view of the blade surface of the injection needle as seen from the direction of arrow 9B shown in FIG. It is a side view. FIG. 4 is a cross-sectional view schematically showing an example of use of the administration device; FIG. 11 is a cross-sectional view showing an enlarged dashed line portion 11A shown in FIG. 10;

The injection needle 110, the needle assembly 100, the administration device 10, and the intradermal administration method according to the embodiments of the present invention will be described below with reference to the drawings. In addition, the same code|symbol is attached|subjected to the member which is common in each figure.

[Administration device]
FIG. 1 is a perspective view schematically showing the overall configuration of the administration device 10. FIG.

The administration device 10, as shown in FIGS. 10 and 11, can be used to administer a drug to the dermal layer s2 of small non-human animals.

10 and 11 show schematic cross-sectional views of the epidermal layer s1, dermal layer s2, and subcutaneous tissue layer s3 of the non-human small animal to which the drug is administered. In this specification, the epidermis layer s1 and the dermis layer s2 are combined to form an upper skin layer s4.

As shown in FIG. 1, the administration device 10 includes a needle assembly 100 having a needle hub 120 holding an injection needle 110, and a syringe 200 connectable to the needle assembly 100.

As shown in FIG. 3, inside the syringe 200, a liquid chamber 240 capable of accommodating a medicine (medicine solution) is provided. A plunger (not shown) is inserted into the liquid chamber 240 of the syringe 200 to feed the medicine from the liquid chamber 240 to the lumen 111 a of the needle tube 111 of the injection needle 110 .

In this embodiment, the extending direction of the injection needle 110 and the extending direction of the syringe 200 are also referred to as "axial directions". The needle tip 112 side of the injection needle 110 is defined as the "distal side", and the end side opposite to the distal side is defined as the "base end side".

A medical worker (hereinafter referred to as a "user") including an operator etc. moves the pusher toward the tip side of the syringe 200 with the needle tip 112 of the injection needle 110 placed in the dermis layer s2. As a result, the drug can be intradermally administered to the small non-human animal through the tip opening 112a formed on the needle tip 112 (see FIG. 11).

The administration device 10 can be configured, for example, as a disposable device that fills the liquid chamber 240 with a drug for intradermal administration and discards the filled drug solution each time it is administered. The administration device 10 can also be configured as a pre-filled device in which the liquid chamber 240 is pre-filled with a drug prior to intradermal administration. Further, there is no particular limitation on the specific type of drug (medicine administered intradermally) contained in the liquid chamber 240 .

As shown in FIG. 1, the syringe 200 includes a first cylindrical portion 210 having a locking mechanism 205 (see FIG. 3) connectable to the needle hub 120 disposed on the distal end side, and a proximal end side of the first cylindrical portion 210. and a second tubular portion 220 arranged in the .

The first cylindrical portion 210 and the second cylindrical portion 220 have substantially cylindrical outer shapes. The second tubular portion 220 arranged on the base end side of the first tubular portion 210 has an outer diameter larger than that of the first tubular portion 210 .

When performing intradermal administration using the administration device 10, the user can hold the second tubular portion 220 located on the proximal side of the syringe 200. Since the second tubular portion 220 has a larger diameter than the first tubular portion 210, the user can easily grip the second tubular portion 220, and the grip force when gripping the second tubular portion 220 is enhanced. Therefore, when the user performs intradermal administration using the administration device 10, the needle tip 112 of the injection needle 110 projecting toward the distal end of the administration device 10 can be firmly inserted into the epidermal layer s1. be possible.

The lock mechanism 205 shown in FIG. 3 can be composed of, for example, a member provided with thread grooves on its inner surface. In this embodiment, a connecting portion 128 that can be screwed into the thread groove of the locking mechanism 205 is provided at the proximal end portion of the second member 127 of the needle hub 120 . The user detachably connects needle hub 120 to syringe 200 by rotating and screwing needle hub 120 while inserting the base end of needle hub 120 inside locking mechanism 205 . be able to.

For example, the thread groove provided in the lock mechanism 205 can be configured with a female thread, and the connecting portion 128 provided in the needle hub 120 can be configured with a male thread. However, the screw groove on the lock mechanism 205 side may be formed by a male screw, and the screw groove on the connection portion 128 side may be formed by a female screw. There is no particular limitation on the specific mechanism for connecting needle hub 120 and syringe 200. For example, the distal end of syringe 200 may be inserted into the proximal end of needle hub 120 to fit them together. It is also possible to employ such a mechanism. Needle hub 120 may also be permanently fixed to syringe 200 using an adhesive or the like.

As shown in FIG. 3, the liquid chamber 240 of the syringe 200 communicates with the lumen 111a (see FIG. 6) of the injection needle 110 when the needle hub 120 and the syringe 200 are connected. Needle 110 is secured within needle hub 120 by adhesive 126, as described below.

[Needle assembly]
As shown in FIGS. 1, 2, and 3, needle assembly 100 has injection needle 110 and needle hub 120 in which injection needle 110 is held.

An exploded view of the needle assembly 100 is shown in FIG.

The needle hub 120 has a first member 121 arranged on the distal side of the needle hub 120 and a second member 127 arranged on the proximal side of the first member 121, as shown in FIG.

The injection needle 110 is fixed to the first member 121 with an adhesive 126 filled inside the first member 121 . An elastic member 125 is arranged between the proximal end of the first member 121 and the distal end of the second member 127 . Needle 110 is positioned within needle hub 120 with proximal end 115 of needle 110 aligned with the distal end of fluid chamber 240 .

As shown in FIGS. 3, 4, and 5, the first member 121 of the needle hub 120 exposes a certain range from the needle tip 112 of the needle tube 111 of the injection needle 110 toward the proximal side, thereby The adjustment part 122 for adjusting the protrusion length L1 of the adjustment part 122 and the needle tube 111 surrounds the part exposed from the adjustment part 122, and is arranged with a space 122a between the adjustment part 122 and the needle tube 111. and a guide portion 123 .

The adjusting portion 122 is provided at a substantially center position of the needle hub 120 in the surface direction. The adjustment portion 122 is configured by a hollow portion that exposes a portion of the injection needle 110 on the needle tip 112 side. As shown in FIG. 5, the injection needle 110 is attached to the needle hub 120 with the adhesive 126 described above in a state in which a portion of the needle tip 112 side is exposed from the adjustment portion 122 toward the distal end side by a predetermined length L1. is fixed. Therefore, the needle hub 120 is configured so that the needle tip 112 of the injection needle 110 is pressed against the epidermal layer s1 of the small non-human animal when intradermal administration is performed using the administration device 10, and the proximal end of the injection needle 110 is pushed. It is possible to prevent the projection length L1 from changing due to the movement to the side.

The guide portion 123 is arranged concentrically with the adjustment portion 122 . Therefore, as shown in FIG. 4, a circular space 122a is formed around the adjusting portion 122 with the adjusting portion 122 at the center.

As shown in FIGS. 3 and 4, a planarly extending flange portion 124 is arranged at a position on the further outer peripheral side of the guide portion 123 . The flange portion 124 is arranged concentrically with the adjustment portion 122 in the same manner as the guide portion 123 . The flange portion 124 extends in the outer peripheral direction from near the base end of the guide portion 123 .

The elastic member 125 arranged near the proximal end 115 of the injection needle 110 enhances the liquid tightness at the connection between the liquid chamber 240 of the syringe 200 and the needle hub 120 . This can prevent the drug from leaking near the proximal end of the injection needle 110 when the drug is delivered from the liquid chamber 240 to the lumen 111 a of the injection needle 110 .

The administration device 10 may have a cap member 130 shown in FIG. Cap member 130 is configured to be connectable to first member 121 of needle hub 120 . Cap member 130 is arranged to cover needle tip 112 of injection needle 110 from the distal end side of needle hub 120 when connected to needle hub 120 . By attaching the cap member 130 to the needle hub 120, the user can prevent the needle tip 112 of the injection needle 110 from being erroneously punctured.

Each part of the needle hub 120 shown in FIG. 5 can be formed, for example, with the following example dimensions. However, it is not limited to the dimension examples shown below.

A distance T1 (corresponding to the width of the space 122a in the horizontal direction) from the outer peripheral edge of the adjusting portion 122 to the inner peripheral edge of the guide portion 123 can be set to, for example, 4.9 mm or more and 5.3 mm or less.

A distance T2 from the outer peripheral edge of the guide portion 123 to the outer peripheral edge of the flange portion 124 can be set to, for example, 2.9 mm or more and 3.1 mm or less.

A dimensional difference Hg between the adjustment portion 122 and the guide portion 123 in the projecting direction of the injection needle 110 can be set to, for example, 0.2 mm or more and 0.4 mm or less.

Each part of the needle hub 120 and the syringe 200 can be made of, for example, a known resin material or a known metal material. As an example, synthetic resins such as polycarbonate, polypropylene, and polyethylene, and metals such as stainless steel and aluminum can be used.

10 and 11 show schematic cross-sectional views when performing intradermal administration to non-human small animals with the injection needle 110. FIG.

As shown in FIG. 10, when the injection needle 110 vertically punctures the epidermis layer s1, the adjustment part 122 contacts the epidermis layer s1 and spreads the epidermis layer s1 around the injection needle 110. At this time, the skin layer s1 is flattened in a space 122a provided between the adjustment portion 122 and the guide portion 123. As shown in FIG. By pressing the adjusting portion 122 until the flange portion 124 comes into contact with the skin layer s1, the user can secure the force of the adjusting portion 122 and the needle tube 111 pressing the skin layer s1 to a predetermined value or more. With the adjustment portion 122 and the flange portion 124 pressed against the skin layer s1, the user inserts the injection needle 110 arranged to maintain a predetermined protrusion length L1 from the skin layer s1 side, thereby The needle tip 112 of the injection needle 110 can be appropriately guided into the dermis layer s2 without depending on variations in the state of the epidermis layer s1 of small animals.

A specific procedure of the intradermal administration method using the administration device 10 and the injection needle 110 according to this embodiment will be described in more detail through examples described later.

[Needle]
6 to 9 show enlarged portions of the tip side (blade surface 113 side) of the injection needle 110 according to this embodiment.

6 is a plan view of the front end opening 112a of the injection needle 110, and FIG. 7 is a perspective view of the injection needle 110. FIG. 8A is a side view (left side view) of the injection needle from the direction of arrow 8A shown in FIG. 6, and FIG. 8B is a perspective side view of injection needle 110 viewed from the direction of arrow 8B shown in FIG. is. 9A is a side view (right side view) of the injection needle from the direction of arrow 9A shown in FIG. 6, and FIG. 9B is a perspective side view of injection needle 110 viewed from the direction of arrow 9B shown in FIG. is.

As shown in FIG. 6, the injection needle 110 according to this embodiment includes a needle tube 111 having a needle tip 112 with a blade surface 113 formed thereon.

A straight line O1 shown in FIGS. 6 to 9 indicates the central axis along the extending direction of the injection needle 110 (needle tube 111).

Inside the needle tube 111, a lumen 111a is formed through which an intradermally administered drug can flow. A tip opening 112a communicating with the lumen 111a is formed at the tip of the needle tip 112 .

In the administration device 10 described above, the injection needle 110 is arranged in a state where a certain range on the proximal side of the injection needle 110 is housed inside the needle hub 120 (inside the first member 121 and the second member 127). be. A part of the tip side of the injection needle 110 is arranged to protrude further to the tip side than the adjusting portion 122 of the needle hub 120 .

A portion of the injection needle 110 that is closer to the proximal end of the needle tube 111 than the portion where the blade surface 113 is formed and that is exposed from the adjusting portion 122 constitutes a needle barrel portion 114 .

The injection needle 110 can be composed of, for example, a "lancet needle" or a "semi-lancet needle" which will be described in the examples below. However, the specific shape and structure of injection needle 110 are not particularly limited. For example, the injection needle 110 may be not only a straight needle but also a tapered needle at least partially tapered, or the cross-sectional shape of the needle tube 111 in the radial direction may be a polygon such as a triangle. good.

The injection needle 110 can be composed of, for example, a metal needle whose constituent material is metal. As the metal forming the injection needle 110, for example, stainless steel, aluminum, aluminum alloys, titanium, titanium alloys, and other metals can be used.

As shown in FIGS. 6 and 7, the blade surface 113 includes a first blade surface 113a positioned on the proximal side of the needle tube 111 and a boundary positioned on the needle tip 112 side (front end side) of the first blade surface 113a. It has a second blade surface 113b and a third blade surface 113c forming a ridgeline at 116 .

The second blade surface 113b and the third blade surface 113c are formed symmetrically with respect to the boundary line 116 in the plan view shown in FIG. Therefore, the second blade surface angle θ2 and the third blade surface angle θ3, which will be described later, are substantially the same, and the blade surface length L22 of the second blade surface 113b and the blade surface length L23 of the third blade surface 113c are also substantially the same. The second blade surface 113b and the third blade surface 113c have different shapes (for example, the second blade surface angle θ2 and the third blade surface angle θ3 and/or the blade surface length L22 of the second blade surface 113b and the third blade surface The blade surface length L23 of the surface 113c may be formed in a different shape).

The first blade surface angle θ1 shown in FIGS. 8(A) and 9(A) is the angle formed by the central axis O1 of the needle tube 111 and the first blade surface 113a. A straight line H1 shown in FIGS. 8A and 8B is an imaginary straight line along the first blade surface 113a. That is, the first blade face angle θ1 is the angle formed by the central axis O1 and the straight line H1.

The second blade surface angle θ2 shown in FIG. 9(B) is the angle formed by the central axis O1 of the needle tube 111 and the second blade surface 113b. A straight line H2 shown in FIG. 9B is a virtual straight line along the second blade surface 113b. That is, the second blade face angle θ2 is the angle formed by the central axis O1 and the straight line H2.

A third blade surface angle θ3 shown in FIG. 8(B) is an angle formed by the central axis O1 of the needle tube 111 and the third blade surface 113c. A straight line H3 shown in FIG. 8B is a virtual straight line along the third blade surface 113c. That is, the third blade face angle θ3 is the angle formed by the central axis O1 and the straight line H3.

A ridge line angle α1 shown in FIGS. 8(A) and 9(A) is an angle formed between the central axis line O1 and the ridge line formed at the boundary 116 . A straight line B1 shown in FIGS. 8A and 8B is an imaginary straight line along the ridgeline. That is, the edge line angle α1 is the angle formed by the central axis O1 and the straight line B1.

The first blade face angle θ1 and the ridge line angle α1 can be formed, for example, at acute angles. Also, the first blade face angle θ1 can be formed so as to be sharper than the edge line angle α1. In addition, "the degree of acute angle is large" means that the angle is smaller within the range of the acute angle.

The second blade face angle θ2 and the third blade face angle θ3 can be formed, for example, at acute angles. Also, the first blade surface angle θ1 can be formed to be sharper than each of the second blade surface angle θ2 and the third blade surface angle θ3.

Injection needle 110 has the relationship between blade surface angles θ1, θ2, θ3 and edge line angle α1 as described above. Penetrability into the epidermis layer s1 is improved.

Next, preferred dimension examples of each part of the injection needle 110 according to the present embodiment will be described with reference to FIGS. 6 to 9. FIG. The effects and the like when each dimension example illustrated below is employed will be described in detail through examples described later.

The outer diameter D1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.1 mm or more and 0.2 mm or less. In addition, the outer diameter D1 of the needle tube 111 is more preferably 0.130 mm or more and 0.1845 mm or less from the viewpoint of enabling more reliable and simple intradermal administration to small non-human animals.

The inner diameter Φ1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.07 mm or more and 0.1 mm or less.

A projection length L1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.1 mm or more and 0.6 mm or less. Moreover, the protrusion length L1 of the needle tube 111 is more preferably 0.45 mm or more and 0.5 mm or less from the viewpoint of enabling more reliable and simple intradermal administration to small non-human animals.

The length (blade surface length) L2 of the blade surface 113 along the extending direction (direction parallel to the central axis O1) of the needle tube 111 shown in FIG. 6 can be formed to be less than 0.3 mm. In addition, the length L2 of the blade surface 113 is more preferably 0.15 mm or more and 0.2 mm or less from the viewpoint of enhancing the penetration of the epidermal layer s1 of small non-human animals.

The blade face length L2 is the sum of the blade face length L21 of the first blade face 113a and the blade face length L22 of the second blade face 113b, or the blade face length L21 of the first blade face 113a and the third blade face 113c. is the total value of the blade face length L23.

The needle barrel length L3 shown in FIG. 6 can be formed to be 0.05 mm or more and 0.5 mm or less. The needle barrel length L3 is more preferably 0.3 mm or more and 0.35 mm or less from the viewpoint of enabling more reliable and simple intradermal administration to small non-human animals.

The thickness t1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.01 mm or more and 0.06 mm or less. The wall thickness t1 of the needle tube 111 is 0.0215 mm or more and 0.0505 mm or less from the viewpoint of making the injection pressure of the drug by the injection needle 110 an appropriate value in consideration of the outer diameter D1 of the needle tube 111 and the inner diameter Φ1 of the needle tube 111. It is more preferable to have

The ratio of the blade surface length L22 of the second blade surface 113b and the blade surface length L23 of the third blade surface 113c to the total length L2 of the blade surface 113 shown in FIG. 6 (L2/L22 and L2/L23) is 40% or more. It can be formed to 60% or less. From the viewpoint of enhancing the puncture property of the epidermal layer s1 of small non-human animals, the ratio is more preferably 47% or more and 56% or less.

In addition, when the blade surface length L2 is formed to be 0.15 mm or more and 0.2 mm or less, when the above ratio is 47% or more and 56% or less, the blade surface length L22 of the second blade surface 113b and the third blade surface 113c The blade face length L23 of can be formed to be 0.05 mm or more and 0.09 mm or less, for example. In this case, the blade surface length L21 of the first blade surface 113a can be formed to be, for example, 0.09 mm or more and 0.17 mm or less.

The first blade surface angle θ1 shown in FIGS. 8(A) and 9(A) can be formed to be 10° or more and 65° or less. From the viewpoint of enhancing the penetrability of the needle tip 112 into the skin layer s1, the first blade surface angle θ1 is more preferably 23° or more and 40° or less.

The second blade surface angle θ2 and the third blade surface angle θ3 shown in FIGS. 9(A) and 9(B) can be formed to be 20° or more and 85° or less. From the viewpoint of enhancing the penetrability of the needle tip 112 into the skin layer s1, the second blade surface angle θ2 and the third blade surface angle θ3 are more preferably 21° or more and 45° or less.

A ridge line angle α1 shown in FIGS. 8(A) and 9(A) can be formed to be 15° or more and 70° or less. The ridge line angle α1 is more preferably 28° or more and 44° or less from the viewpoint of enhancing the penetrability of the needle tip 112 into the skin layer s1.

[Intradermal administration method]
Next, an intradermal administration method according to this embodiment will be described. In addition, the present invention is not limited only to the following embodiments.

As described above, the injection needle 110 and the administration device 10 according to this embodiment have configurations suitable for intradermal administration to small non-human animals.

Accordingly, this embodiment provides a method for intradermal administration of a drug to a small non-human animal, comprising a support member for stabilizing a vertical puncture under the site of the small non-human animal to be administered the drug. The site to be administered is flattened to form an administration site, and the guide portion of the needle hub that holds the injection needle is pressed against the administration site. A method of intradermal administration to small non-human animals is provided, comprising intradermally administering said drug to said administration site through said injection needle with a vertical puncture separated by a distance.

As used herein, the term "small animal" means an animal with thin skin. Specifically, the thickness of the drug-administering site of the non-human small animal in the non-stretched state is 1.0 mm or less.

In one embodiment of the present invention, the administration site is the upper skin layer s4 having a dermis layer s2 with a thickness of 1.0 mm or less. Also, in this embodiment, the thickness of the administration site is measured by an ultrasound diagnostic imaging device.

In addition, the projection length L1 of the injection needle 110 used for intradermal administration is such that the ratio of the projection length L1 of the injection needle 110 to the thickness of the upper skin layer s4 of the non-human small animal is 1.25 or less. is preferred, less than 1.00 is more preferred, and less than 0.90 is particularly preferred. As a result, the needle tube 111 can be more reliably placed in the upper layer s4 of the skin, and the success rate of intradermal administration can be further improved.

Instead of or in addition to the above, when performing intradermal injection, it is preferable that the entire blade surface 113 of the injection needle 110 is buried in the upper skin layer s4 of the non-human small animal. Thereby, leakage of the medicine from the needle tube 111 can be suppressed.

Specifically, the blade face length L2 is smaller than the thickness of the skin upper layer s4 of the non-human small animal, and the blade face length L2 of the injection needle 110 with respect to the thickness of the skin upper layer s4 of the non-human small animal The ratio is preferably less than 0.60, more preferably less than 0.56, even more preferably less than 0.50, particularly preferably less than 0.35. As a result, the entire amount of the drug can be more reliably injected into the upper layer s4 of the skin, and the success rate of intradermal administration can be further improved.

Non-human small animals (in particular, non-human small experimental animals) that can be used in the administration method according to this embodiment are preferably warm-blooded animals. Warm-blooded animals that can be used include, for example, mammals (eg, rats, mice, muskrats, gerbils, rabbits, pikas, guinea pigs, hamsters) and birds (eg, chickens, pigeons, quail, etc.). Among them, mammals are more preferred, rodents (rat, mouse, rabbit, guinea pig, hamster, etc.) are more preferred, rats, mice and rabbits are particularly preferred, and rats are most preferred. Genetically modified animals such as transgenic animals and disease model animals may also be used as small non-human animals.

In the intradermal administration method, first, a supporting member (hereinafter referred to as a (also simply referred to as a “support member”). Here, the support member is preferably made of silicone resin or the like. Since such a support member has appropriate hardness, the administration site can be stably fixed. The upper skin layer s4 of non-human small animals is very thin. Therefore, even if an attempt is made to vertically puncture the needle tip 112 without using a support member, there is concern that it may be difficult or impossible to puncture the administration site with the needle tube 111 appropriately. In other words, there is a possibility that the success rate of intradermal administration will greatly decrease.

Next, an administration site is prepared by flattening any part of the upper skin layer s4 of the non-human small animal. At this time, after the guide portion 123 of the needle hub 120 is pressed against the administration site, the guide portion 123 is separated from the administration site by a predetermined distance (moved in the direction of lifting from the epidermis layer s1). As a result, the injection pressure of the medicine (medicine solution) is lowered, and intradermal administration can be performed satisfactorily.

In addition, if the guide part 123 and the administration site are not separated from each other and the administration site is intradermally administered by vertical puncture, the injection pressure of the drug solution becomes too high, making it difficult to appropriately inject the drug into the administration site through the needle tube 111. may become. The reason for this is presumed as follows. It should be noted that the following is a guess, and the present invention is not limited by the above guess.

Non-human small animals (especially rodents such as rats) have a tissue called "cutaneous muscle". The cutaneous muscle is a membrane-like tissue that exists between the subcutaneous tissue and the intracutaneous tissue, and is absent in humans. If the guide portion is kept pressed against the rat without being separated, the skin muscle blocks the tip opening 112a (see FIG. 6) of the needle tube 111, which may increase the injection pressure of the drug. .

Here, it is preferable that the separation distance between the guide portions 123 is such that the injection pressure of the medicine is sufficiently lowered. Specifically, the distance is preferably such that the injection pressure at the time of administration is 5 to 20N, and more preferably the distance is such that the injection pressure at the time of administration is 10 to 15N. Thus, in a preferred form of the invention, the drug is administered intradermally to the administration site with a pressure of 5-20N.

In this specification, the injection pressure is measured by the following method. In other words, the injection pressure is determined by measuring the pressure when the digital force gauge is pressed with a similar force based on the feeling of the hand when administering to a small non-human animal, and using this pressure as the injection pressure. , is measured.

Also, from the viewpoint of the procedure, it is preferable that the injection needle 110 has a low puncture resistance. Specifically, the injection needle preferably has a puncture resistance of 0.15 N or less at the maximum value of the load variation curve when puncturing a 0.5 mm silicone rubber sheet at 10 mm/min. In order to achieve the puncture resistance described above, the outer periphery of the injection needle may be coated with an oil lubricant such as silicone oil. Silicone oils that can be used in this case include, for example, silicone oils conforming to JIS T3209, more specifically, cross-linking silicone oils such as condensed cross-linking silicone oils and added cross-linking silicone oils. be done.

That is, in a preferred embodiment of the present invention, the drug is delivered through the injection needle 110 having a maximum value of 0.15 N or less in the load variation curve when puncturing a 0.5 mm silicone rubber sheet at 10 mm/min. is administered intradermally at the administration site.

In a more preferred embodiment of the present invention, the drug is administered intradermally to the site of administration. Furthermore, the injection needle has a puncture resistance of 0.15 N or less at the maximum value of the load fluctuation curve when puncturing a 0.5 mm silicone rubber sheet at 10 mm/min with the guide portion 123 separated from the administration site. Via 110, the drug is administered intradermally to the site of administration by vertical puncture.

Due to the intradermal administration method and the puncture resistance of the injection needle, the drug can be reliably and accurately delivered intradermally (upper layer s4 of the skin) of non-human small animals.

Conventionally, the Mantoux method is well known as a method of administering drugs into the dermal layer s2 of small non-human animals. The Mantoux method is a method in which an injection needle 110 obliquely punctures an upper skin layer s4 having a dermis layer s2.

As described above, the skin is composed of the upper skin layer s4 consisting of the epidermis layer s1 and the dermis layer s2, and the subcutaneous tissue layer s3. The thickness of the upper skin layer of the human deltoid muscle is generally about 2 mm, whereas the thickness of the upper skin layer s4 of the back of rats and mice is less than 1 mm. thin. Therefore, intradermal administration to the upper skin layer s4 is difficult, and the drug may leak into the subcutaneous tissue layer s3 or to the skin surface depending on the technique used and the diameter of the injection needle used. Moreover, whether or not intradermal administration is successful may vary depending on the skill of the operator who performs the injection. On the other hand, according to the intradermal administration method according to the present embodiment, vertical puncture is used, so the procedure is easy and variation among operators can be suppressed. In addition, leakage of medicine can be suppressed. Therefore, according to the intradermal administration method of the present embodiment, a predetermined amount of drug can be delivered intradermally to a small non-human animal reliably and accurately. In addition, even if the amount of the drug is smaller than that in the past, the effect of the administered drug can be exhibited. Therefore, the intradermal administration method according to this embodiment is particularly effective for small non-human experimental animals, which require a large number of individuals to examine drug efficacy.

The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In the following examples, unless otherwise specified, operations were performed at room temperature (25°C).

<Examples 1-3, Comparative Examples 1-2>
A needle assembly 100 (outer diameter of guide portion 123=13.1 mm) shown in FIG. 3 and injection device 10 shown in FIG. A syringe 200 was connected to the needle assembly 100 . Physiological saline (pH 4.5 to 8.0) was injected into the syringe 200 through the needle tube 111 .

49 female rats (slc: Wistar, 8-9 weeks old, purchased from Japan SLC) were subjected to a 5-7 day quarantine and acclimatization period, and all rats were healthy and had no weight loss. was confirmed and submitted for testing. The rats were given food and water ad libitum in a breeding environment of 12 hours of lighting, temperature of 20-26°C and humidity of 30-70%. The following experiments were conducted in accordance with Terumo Corporation's guidelines for animal experiments.

The thickness of the upper skin layer s4 of each rat was measured and the average was calculated. The results are shown as skin thickness in Table 1 below. Further, the ratio of the projection length L1 of the injection needle 110 to the thickness of the upper skin layer s4 and the ratio of the blade surface length L2 of the injection needle 110 to the thickness of the upper skin layer s4 are respectively defined as "protrusion length / skin thickness" and It was written together as "blade face length/skin thickness".

Next, as shown in Table 1 below, the rats were divided into the following five groups: Group 1; Needle 1 (10 animals) (Example 1), Group 2; Needle 2 (9 animals) ( Example 2), Group 3; Needle 3 (10 animals) (Example 3), Group 4; Needle 4 (10 animals) (Comparative Example 1), and Group 5; Needle 5 (10 animals) ) (Comparative Example 2). In Comparative Examples 1 and 2, the blade face length L2 is 0.3 mm.

Next, after the rats in each group were shaved from their backs, they were laid down and placed on a silicone plate (size: 10 cm x 6 cm, thickness: 0.5 cm) as a support member. The hair-plucked part was flattened to form an administration site. After the guide part 123 is pressed against the administration site, the guide part 123 is separated from the administration site by about 1 mm so that the guide part 123 can move. 50 μL was intradermally administered by vertical puncture, and each injection needle 1 to 5 could be easily punctured without resistance.

When the injection pressure at this time was measured, it was 10 to 15 N, and the physiological saline could be injected smoothly. In addition, when intradermally administered by vertical puncture without separating the guide part 123 and the administration site, the injection pressure was too high, and the physiological saline could not be administered intradermally. From these results, it is considered that physiological saline can be reliably and easily administered intradermally by arranging the silicone plate under the administration site and separating the guide part 123 from the administration site.

The wheal formed at the administration site of each rat intradermally administered was visually confirmed, and the wheal diameter (diameter) of 3 mm or more and the color of the wheal was whiter than the surrounding skin was judged as "successful intradermal administration". Then, the intradermal administration success rate (%) was calculated. Regarding the wheal diameter (diameter), according to the US CDC (Centers for Disease Control and Prevention) guidelines, in the case of humans, a wheal with a diameter of 6 mm or more is formed when 100 μL of the drug solution is administered. Intradermal administration was judged to be successful when the wheal diameter was 3 mm or more, because the volume of the administered liquid was 50 μL, which was half of the volume in the case of rats in this example. The color of wheals was added to the criteria to distinguish from subcutaneous administration, since the skin of rats is softer than that of humans, and wheals may be observed even in the case of subcutaneous administration. The results are shown in Table 1 below.

From the results in Table 1, it can be seen that the success rate of intradermal administration can be significantly improved by setting the blade surface length L2 of the injection needle 110 to less than 0.3 mm.

<Example 4>
500 μg of ovalbumin (manufactured by Sigma Adrich) and 2.5 μg of alum adjuvant (aluminum hydroxide) (manufactured by Thermo Scientific) were added to 50 μL of phosphate buffered saline (D-PBS(−)) and mixed. to prepare the doses.

An 18G injection needle (manufactured by Terumo Corporation) (aspiration needle) was connected to the syringe 200, and the administration material prepared above was aspirated into the syringe. Next, after removing the 18G injection needle (suction needle), the needle assembly 100 having the injection needle 110 of Example 2 is connected to the syringe 200 in the same manner as in Examples 1 to 3 described above, and the administration device 10 was made. The administration prepared above was injected into the syringe 200 through the injection needle 110 .

Five female rats (slc: Wistar, 9 weeks old, purchased from Japan SLC) were subjected to a 6-day quarantine and acclimatization period, and it was confirmed that there was no abnormality in the health condition of all rats and no weight loss was observed. , was tested. The rats were given food and water ad libitum in a breeding environment of 12 hours of lighting, temperature of 20-26°C and humidity of 30-70%. The following experiments were conducted in accordance with Terumo Corporation's guidelines for animal experiments.

Next, after the back of each rat was shaved, it was placed on its side and placed on a silicone plate (size: 10 cm x 6 cm, thickness: 0.5 cm) as a support member. The hair-plucked part was flattened to form an administration site.

After the guide part 123 is pressed against the administration site, the guide part 123 is separated from the administration site by about 1 mm so that the guide part 123 can move. Administered intradermally (Day 0; initial intradermal administration). On the 22nd day after the first intradermal administration, the administered substance was intradermally administered again to rats in the same manner as above (22nd intradermal administration; second intradermal administration). Thirty-five days after the first intradermal administration, the rats were bled and plasma was separated.

The resulting plasma IgG concentration (U/mL) was measured by the following ELISA method.

First, Rat IgG (H+L) Cross-Adsorbed Secondary Antibody (manufactured by Bethyl Laboratories, trade name: Rat IgG Heavy and Light Chain Cross-Adsorbed Antibody, A1 10-322A) 50 μL each in a 96-well plate It was added to the wells and allowed to stand overnight at 4° C. to solidify. Each well was washed four times with PBS Tween 20 buffer and blocked with Blocking One (manufactured by Nacalai Tesque). Next, 50 μL of the 100-fold diluted plasma separated above was added to each well, reacted with the antibody at 37° C. for 1 hour, and then washed four times with PBS Tween 20 buffer. 50 μL of biotinylated ovalbumin (manufactured by NANOCS) adjusted to 2.5 μg/mL was added to each well and incubated at 37° C. for 1 hour to allow biotinylated ovalbumin to bind. Washed 4 times with 20 buffer. Furthermore, 50 μL of streptavidin-HRP (manufactured by BD Pharmingen) diluted 1000-fold was added to each well and incubated at 37° C. for 1 hour to allow streptavidin-HRP to bind. Washed 6 times with Tween 20 buffer. Furthermore, TMB (3,3',5,5'-tetramethylbenzidine) peroxidase substrate (manufactured by SeraCare Life Sciences) was added to each well by 50 µL, and allowed to stand at room temperature in a dark room for 25 minutes for color development. 50 μL of 2N (1 mol/L) sulfuric acid was added to each well to stop the reaction, absorbance at 450 nm and 550 nm was measured, and the difference between these absorbances [=(absorbance at 450 nm)-(absorbance at 550 nm )] was calculated. A standard curve was prepared using the plasma of individuals intraperitoneally administered with a known amount of administration, and the blood IgG concentration was quantified based on this standard curve, resulting in an average of 7466.2 (U/mL). rice field. For samples with a blood IgG concentration below the detection limit, the blood IgG concentration was set to 1371.7 (U/mL), which is the lowest value of the standard curve for antibody concentration.

<Comparative Example 3>
500 µg of ovalbumin (manufactured by Sigma Adrich) and 2.5 µg of alum adjuvant (aluminum hydroxide) (manufactured by Thermo Scientific) were added to 250 µL of phosphate buffered saline (D-PBS(-)) and mixed. to prepare the doses.

A 26G injection needle (manufactured by Terumo Corporation, trade name: Terumo injection needle, needle tube outer diameter = 0.45 mm, needle tube protrusion length = 13 mm) was prepared for intramuscular injection. A 1 mL syringe was attached to this injection needle, and the administration material prepared above was injected into the syringe through the injection needle. This was used as an administration device for comparison.

For 4 female rats (slc: Wistar, 9 weeks old, purchased from Japan SLC), a 6-day quarantine/acclimation period was established, and it was confirmed that there was no abnormality in the health condition of all individuals and no weight loss was observed. , was tested. The rats were given food and water ad libitum in a breeding environment of 12 hours of lighting, temperature of 20-26°C and humidity of 30-70%. The following experiments were conducted in accordance with Terumo Corporation's guidelines for animal experiments.

Next, the back of each rat was shaved and laid down to prepare the administration site. A control dosing device was used to administer 250 μL of dosing intramuscularly at the dosing site (day 0; first intramuscular dose). On the 22nd day after the first intramuscular administration, the doses were administered intramuscularly to the rats again in the same manner as above (day 22; second intramuscular administration). Thirty-five days after the first intramuscular administration, the rats were bled and plasma was separated.

The IgG concentration in the obtained plasma was measured in the same manner as described in Example 4, and the average was 2825.2 (U/mL). For samples with a blood IgG concentration below the detection limit, the blood IgG concentration was set to 1371.7 (U/mL), which is the lowest value of the standard curve for antibody concentration.

From the results of Example 4 and Comparative Example 3, it can be seen that intradermal administration using the injection needle according to the present invention increases the blood IgG concentration by about 2.6 times compared to intramuscular administration. . From this result, it can be expected that the injection needle according to the present invention can induce immunity with a smaller dose.

As described above, the present invention has been described based on the embodiments and examples, but the present invention is not limited to the contents described in this specification, and can be appropriately modified based on the description of the claims. It is possible.

This application is based on Japanese Patent Application No. 2021-195928 filed on December 2, 2021, the disclosure of which is incorporated by reference in its entirety.

10 Administration device 100 Needle assembly 110 Injection needle 111 Needle tube 111a Needle tube lumen 112 Needle point 112a Tip opening 113 Blade surface 113a First blade surface 113b Second blade surface 113c Third blade surface 114 Needle body 115 Base end 116 Border 120 Needle hub 121 First member 122 Adjusting portion 122a Space 123 Guide portion 124 Flange portion 127 Second member 130 Cap member 200 Syringe 210 First cylindrical portion 220 Second cylindrical portion 240 Liquid chamber D1 Outer diameter Hg of needle tube Adjusting portion Dimensional difference in the projection direction of the guide part L1 Projection length of the needle tube L2 Total length of the blade surface L21 Blade surface length of the first blade surface L22 Blade surface length of the second blade surface L23 Blade surface length of the third blade surface L3 Needle barrel length O1 Needle tube central axis T1 Distance between adjustment part and guide part T2 Distance between guide part and flange part s1 Epidermis layer s2 Dermis layer s3 Subcutaneous tissue layer s4 Upper skin layer t1 Needle thickness Φ1 Needle inner diameter α1 Edge line angle θ1 1st blade flank angle θ2 2nd blade flank angle θ3 3rd blade flank angle

Claims (13)

1. An injection needle comprising a needle tube having a blade surface formed on the tip of the needle,
   The outer diameter of the needle tube is 0.1 mm or more and 0.2 mm or less,
   The protruding length of the needle tube is 0.1 mm or more and 0.6 mm or less,
   The length of the blade surface along the extending direction of the needle tube is less than 0.3 mm,
   An injection needle used for intradermal administration to non-human small animals by vertical puncture.
2. The injection needle according to claim 1, wherein the needle barrel length is 0.05 mm or more and 0.5 mm or less.
3. The injection needle according to claim 1 or 2, wherein the needle tube has a wall thickness of 0.01 mm or more and 0.06 mm or less.
4. The blade surface includes a first blade surface located on the proximal end side of the needle tube, and a second blade surface and a third blade surface forming a ridgeline at a boundary located on the needle tip side of the first blade surface. have
   Any one of claims 1 to 3, wherein the ratio of the blade surface length of the second blade surface and the blade surface length of the third blade surface to the total length of the blade surface is 40% or more and 60% or less. The injection needle described in .
5. A first blade surface angle formed by the central axis of the needle tube and the first blade surface is 10° or more and 65° or less,
   The second blade surface angle and the third blade surface angle formed by the center axis and the second blade surface and the third blade surface are 20 ° or more and 85 ° or less,
   5. The injection needle according to claim 4, wherein a ridge angle between the central axis and the ridge is 15[deg.] or more and 70[deg.] or less.
6. the injection needle according to any one of claims 1 to 5;
   a needle hub that holds the injection needle,
   The needle hub is
   an adjustment unit that adjusts the projection length of the needle tube by exposing a certain range from the tip of the needle tube toward the proximal end;
   a guide portion surrounding a portion of the adjusting portion and the needle tube exposed from the adjusting portion and arranged with a space between the adjusting portion and the needle tube.
7. a needle assembly according to claim 6;
   a syringe connected to the needle hub, comprising:
   The syringe includes a first tubular portion arranged on the proximal side of the needle hub and a second tubular portion arranged on the proximal side of the first tubular portion and having an outer diameter larger than that of the first tubular portion. and a dosing device.
8. A method for intradermally administering a drug to a small non-human animal, comprising: placing a support member for stabilizing vertical puncture under the site of the small non-human animal to which the drug is to be administered; is flattened to prepare an administration site, the guide part of the needle hub that holds the injection needle is pressed against the administration site, and then the guide part is separated from the administration site by a predetermined distance. A method of intradermal administration, comprising intradermally administering the drug to the administration site by vertical puncture through the injection needle.
9. The drug is intradermally administered to the administration site through the injection needle having a maximum puncture resistance of 0.15 N or less in the load variation curve when a 0.5 mm silicone rubber sheet is punctured at 10 mm/min. The intradermal administration method according to claim 8.
10. The intradermal administration method according to claim 8 or 9, wherein the drug is intradermally administered to the administration site at a pressure of 5 to 20 N.
11. The intradermal administration method according to claim 8 or claim 9, wherein the site to which the drug is to be administered is an upper skin layer having a dermis layer with a thickness of 1.0 mm or less in a non-stretched state.
12. The intradermal administration method according to claim 11, wherein the ratio of the projection length of the injection needle to the thickness of the upper layer of the skin of the non-human small animal is 1.25 or less.
13. The intradermal administration method according to claim 11 or 12, wherein the ratio of the cutting edge length of the injection needle to the thickness of the upper layer of the skin of the non-human small animal is less than 0.60.

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