Puncture needle

Abstract

[Problem] To reduce, at the time of administration, mechanical stress on a substance being administered containing a high-molecular-weight component (modality) such as a cell, antibody, nucleic acid, or protein. [Solution] A puncture needle 100 has a longitudinal shaft C, a base end part 102, and a leading end part 101, and comprises an inner cavity 110 that connects the base end part 102 and the leading end part 101 in the direction of the longitudinal shaft C; a puncture part 10 that is provided at the leading end part 101 and that can puncture a living body; and a leading end small-diameter part 20 connected to the puncture part 10 with a constant inner diameter. The cross-sectional area of the leading end small-diameter part 20 is at most 0.08 mm2. At least in the leading end small-diameter part 20, the arithmetic average roughness (Ra) of the inner surface is at most 0.11 μm, and the arithmetic average height (Sa) of the inner surface is at most 0.30 μm.

Description

puncture needle

[0001] This invention relates to a puncture needle.

[0002] Intravenous administration is the standard method for administering anticancer drugs used in chemotherapy for cancer treatment. However, intravenous administration of anticancer drugs has drawbacks, such as the limited amount of drug that can reach the tumor, which can reduce the therapeutic effect, and the potential for systemic side effects. Therefore, in recent years, attempts have been made to directly administer therapeutic substances such as drugs or cells to target sites within body cavities, such as inside organs (see, for example, Patent Document 1).

[0003] International Publication No. 2011 / 034627

[0004] Examples of drugs administered directly into organs (subjects) include biopharmaceuticals containing high molecular weight components (hereinafter also referred to as modalities) such as cells, antibodies, nucleic acids, and proteins. When biopharmaceuticals flow rapidly from a wide area to a narrow area within an administration device, such as from a syringe into a needle tube, they are affected by flow channel load (shear stress, etc.), which can lead to damage to modalities within the drug, as well as a decrease in their viability and function. Therefore, when administering subjects such as biopharmaceuticals, it is important to reduce the mechanical stress during administration. However, the invention described in Patent Document 1 does not take into consideration the reduction of mechanical stress on the drug being administered.

[0005] At least one embodiment of the present invention has been made in view of the above circumstances, and specifically aims to provide a puncture needle that can reduce mechanical stress during administration to a target substance (liposome, LNP preparation, etc.) containing high molecular weight modalities such as cells, viruses, antibodies, nucleic acids, and proteins.

[0006] The above objective of the present invention is achieved by any one of the following (1) to (26).

[0007] (1) A puncture needle having a longitudinal axis, a proximal end, and a tip, comprising: a lumen communicating from the proximal end to the tip in the direction of the longitudinal axis; a puncture portion provided at the tip that can penetrate a living body; and a narrow tip portion communicating with the puncture portion with a constant inner diameter, wherein the cross-sectional area of ​​the narrow tip portion is 0.08 mm ２ A puncture needle having the following characteristics, wherein at least in the tip-sized portion, the arithmetic mean roughness (Ra) of the inner surface is 0.11 μm or less, and the arithmetic mean height (Sa) of the inner surface is 0.30 μm or less.

[0008] (2) The puncture needle as described in (1) above, wherein the arithmetic mean roughness (Ra) is 0.09 μm or less.

[0009] (3) The puncture needle according to (1) or (2) above, wherein the arithmetic mean height (Sa) is 0.20 μm or less.

[0010] (4) The puncture needle according to any one of (1) to (3) above, wherein the inner diameter of the tip portion is 0.05 mm or more and 0.3 mm or less.

[0011] (5) The puncture needle according to any one of (1) to (4) above, wherein the length of the tip with a narrow diameter is 1 m or more.

[0012] (6) The puncture needle according to any one of (1) to (5) above, wherein the puncture needle has a large diameter portion at the base end, and between the large diameter portion at the base and the small diameter portion at the tip, it has an intermediate reduced diameter portion in which the inner diameter gradually decreases from the base to the tip.

[0013] (7) The puncture needle according to (6) above, wherein the intermediate diameter reduction portion has a relay portion, the relay portion has an inner diameter of 1.0 mm or more, or 10 / 3 or more of the inner diameter of the tip diameter reduction portion, and the first inclination angle of the straight line L1 connecting the inner surface of the relay portion and the inner surface of the base end of the tip diameter reduction portion with respect to the longitudinal axis is 25 degrees or less.

[0014] (8) The puncture needle as described in (7) above, wherein the second inclination angle of the straight line L2 connecting the intermediate portion and the inner surface of the tip of the large-diameter base portion with respect to the longitudinal axis is greater than the first inclination angle.

[0015] (9) The puncture needle according to any one of (6) to (8) above, wherein the intermediate diameter reduction portion has a continuously increasing inclination angle from the tip of the intermediate diameter reduction portion to the base of the intermediate diameter reduction portion.

[0016] (10) The puncture needle according to (7) or (8) above, wherein the first inclination angle is 6 degrees or more and 12 degrees or less.

[0017] (11) A puncture needle according to any one of (6) to (10) above, wherein, in a simulation by numerical fluid analysis, the maximum shear stress on the axis of the longitudinal axis within the lumen of the intermediate diameter reduction portion, calculated under a flow rate condition of 1 mL per minute, is 1.5 Pa or less.

[0018] (12) The puncture needle according to any one of (6) to (11) above, wherein the proximal diameter portion is configured to be connectable to an administration device at the proximal end.

[0019] (13) The puncture needle according to any one of (1) to (12) above, wherein the puncture portion has an opening on the side of the tip that communicates with the lumen.

[0020] (14) The puncture needle according to any one of (1) to (13) above, wherein the substance to be administered to the target of administration through the puncture site is a biopharmaceutical containing one or more high molecular weight components arbitrarily selected from cells, antibodies, nucleic acids, and proteins.

[0021] (15) A puncture needle having a longitudinal axis, a proximal end, and a tip, wherein the needle has a lumen that communicates from the proximal end to the tip in the direction of the longitudinal axis, a proximal large-diameter portion provided on the proximal end side, a puncture portion provided on the tip that can puncture a living body, a tip narrow-diameter portion that communicates with the puncture portion with a constant inner diameter, and an intermediate narrow-diameter portion disposed between the proximal large-diameter portion and the tip narrow-diameter portion, the intermediate narrow-diameter portion having an intermediate portion, the intermediate narrow-diameter portion having an inner diameter of 1 mm or more, or 10 / 3 or more of the inner diameter of the tip narrow-diameter portion, and the first inclination angle of the straight line L1 connecting the inner surface of the intermediate portion and the inner surface of the proximal end of the tip narrow-diameter portion with respect to the longitudinal axis is 25 degrees or less.

[0022] (16) The puncture needle as described in (15) above, wherein the second inclination angle of the straight line L2 connecting the intermediate portion and the inner surface of the tip of the large-diameter base portion with respect to the longitudinal axis is greater than the first inclination angle.

[0023] (17) The puncture needle according to (15) or (16) above, wherein the proximal diameter portion is configured to be connectable to an administration device at the proximal end.

[0024] (18) The puncture needle according to any one of (15) to (17) above, wherein the puncture portion has an opening on the side of the tip that communicates with the lumen.

[0025] (19) The puncture needle according to any one of (15) to (18) above, wherein the angle of inclination of the intermediate diameter reduction portion increases continuously from the tip of the intermediate diameter reduction portion to the base of the intermediate diameter reduction portion.

[0026] (20) A puncture needle according to any one of (15) to (19) above, wherein, in a simulation by numerical fluid analysis, the maximum shear stress on the axis of the longitudinal axis within the lumen of the intermediate diameter reduction portion, calculated under a flow rate condition of 1 mL per minute, is 1.6 Pa or less.

[0027] (21) The puncture needle according to any one of (15) to (20) above, wherein the inner diameter of the tip portion is 0.1 mm or more and 1.0 mm or less.

[0028] (22) The puncture needle according to any one of (15) to (21) above, wherein the first inclination angle is 6 degrees or more and 12 degrees or less.

[0029] (23) The puncture needle according to any one of (15) to (22) above, wherein the length of the tip with a small diameter is 1 m or more.

[0030] (24) The cross-sectional area of ​​the tip portion is 0.071 mm². ２ A puncture needle according to any one of (15) to (23) above, wherein, at least in the tip-sized portion, the arithmetic mean roughness (Ra) of the inner surface is 0.11 μm or less, and the arithmetic mean height (Sa) is 0.30 μm or less.

[0031] (25) The puncture needle according to (24) above, wherein the arithmetic mean roughness (Ra) is 0.09 μm or less.

[0032] (26) The puncture needle according to (24) or (25) above, wherein the arithmetic mean height (Sa) is 0.20 μm or less.

[0033] According to the present invention, mechanical stress applied during administration to an administration target containing high-molecular-weight components (modalities) such as cells, viruses, antibodies, nucleic acids, and proteins can be reduced.

[0034] FIG. 1 is a diagram showing the puncture needle according to the first embodiment. FIG. 2 is a schematic cross-sectional view of a puncture part and the periphery thereof. FIG. 3 is a schematic cross-sectional view of an intermediate reduced diameter part and the periphery thereof. FIG. 4 is a schematic cross-sectional view showing an example of the form of the intermediate reduced diameter part. FIGS. 5 to 9 are each schematic cross-sectional views showing another example of the form of the intermediate reduced diameter part. FIG. 10 is a diagram showing the puncture needle according to the second embodiment. FIG. 11 is a table showing specifications of samples used in Tests 1 to 5. FIGS. 12 and 13 are each graphs showing test results of Test 1. FIG. 14 is a photograph showing an inner surface of Sample 1 used in Test 2. FIG. 15 is a photograph showing an inner surface of Sample 3 used in Test 2. FIGS. 16 and 17 are each graphs showing test results of Test 2. FIG. 18: Panel (a) is a diagram showing a shear stress distribution of Sample 4-1 used in Test 3, and Panel (b) is a diagram showing a shear stress distribution of Sample D used in Test 3. FIG. 19: Panel (a) is a diagram showing a shear stress distribution of Sample 4-2 used in Test 3, Panel (b) is a diagram showing a shear stress distribution of Sample 5-1 used in Test 3, and Panel (c) is a diagram showing a shear stress distribution of Sample 5-2 used in Test 3. FIG. 20 is a table showing test results of Test 3. FIG. 21: Panel (a) is a diagram showing a shear stress distribution of Sample 5-1 used in Test 4, Panel (b) is a diagram showing a shear stress distribution of Sample 6 used in Test 4, and Panel (c) is a diagram showing a shear stress distribution of Sample D used in Test 4. FIG. 22 is a table showing test results of Test 4. FIGS. 23 and 24 are each graphs showing test results of Test 5. FIG. 25 is a graph of cytotoxic activity (AUC, %-ratio) for a control (no needle tube passage treatment) and Sample B.

[0035] Hereinafter, modes for carrying out the present invention will be described in detail with reference to the drawings. The embodiments shown herein are examples for embodying the technical idea of the present invention, and do not limit the present invention. In addition, all other practicable modes, examples, operation techniques, etc. that can be conceived by those skilled in the art without departing from the gist of the present invention are all included in the scope and gist of the present invention, and are also included in the scope of the invention described in the claims and the equivalent scope thereof.

[0036] Furthermore, for the convenience of illustration and ease of understanding, the drawings attached to the present specification may be appropriately converted from the actual product and schematically expressed in terms of scale, vertical / horizontal dimensional ratio, shape, etc., but this is merely an example and does not limit the interpretation of the present invention.

[0037] Expressions in the singular include expressions in the plural unless the context clearly indicates that it is explicitly singular. In addition, when a certain part "comprises", "includes", or "has" a certain component, this means that, unless there is a statement to the contrary, it does not exclude other components, and may further include other components.

[0038] In the following description, when ordinal numbers such as "first" and "second" are used for description, they are used for convenience unless otherwise specified, and do not define any order.

[0039] [First Embodiment] A puncture needle 100 according to the first embodiment will be described.

[0040] The puncture needle 100 is attached to the distal end side of an administration device 200, whereby an administration system for administering an administered substance to an administration target (such as an organ) in a living body can be configured.

[0041] As shown in FIG. 1, the puncture needle 100 is configured to include a puncture part 10, a distal small-diameter part 20, an intermediate reduced-diameter part 30, a proximal large-diameter part 40, and a hub part 50. The puncture needle 100 has a longitudinal axis C that coincides with the central axis in the longitudinal direction.

[0042] The puncture needle 100 has a tip portion 101 which is the end that punctures the target of the administered substance, and a base portion 102 which is the end opposite to the tip portion 101 and is the end that is attached to the administration device 200. The tip portion 101 includes a certain range in the longitudinal direction along the longitudinal axis C from the very tip of the puncture needle 100, and the base portion 102 includes a certain range in the longitudinal direction from the very base end of the puncture needle 100.

[0043] The puncture needle 100 is configured to be connectable to the tip portion 210 of an administration device 200, such as a syringe, via a connection portion 41 of the large-diameter base portion 40, as shown in Figure 1, for example. The administration device 200 is configured to have a tip portion 210 to which at least the puncture needle 100 can be attached, such as a syringe, and to have a configuration and function that allows for the storage and discharge of the substance to be administered. In this case, the inner surface of the large-diameter base portion 40 may be tapered to match the shape of the outer surface of the tip portion 210 of the administration device 200. Note that the administration device 200 is not limited to a syringe and may be composed of other devices.

[0044] The puncture needle 100 has a lumen 110 that extends along the longitudinal axis C from the tip 101 to the proximal end 102. The substance to be administered flows from the administration device 200 into the puncture needle 100 through the lumen 110 and is administered to the target through the opening 11 of the puncture portion 10.

[0045] The substance administered through the puncture needle 100 can consist of a fluid such as a biopharmaceutical (e.g., liposomes, LNP preparations) containing a modality that is a high molecular weight component such as cells, viruses, antibodies, nucleic acids, or proteins. The substance administered is not particularly limited as long as it is a fluid containing a high molecular weight component that can be administered into the body, in addition to a biopharmaceutical.

[0046] As shown in Figure 1, the puncture site 10 is located at the tip 101 of the puncture needle 100. The puncture site 10 is the site where the substance to be administered is punctured.

[0047] As shown in Figure 2, the puncture portion 10 has an opening 11 on its side facing the tip portion 101 that communicates with the lumen 110. The dotted line perpendicular to the longitudinal axis C shown in Figure 2 represents the boundary between the puncture portion 10 and the tip diameter portion 20, but the boundary does not necessarily represent a joint between different materials and can be defined arbitrarily.

[0048] The opening 11 allows for the discharge of the administered substance flowing through the lumen 110 while the puncture portion 10 is punctured into the target of administration. The opening 11 may be formed to open toward the longitudinal axis C of the puncture portion 10.

[0049] A marker portion 60 can be provided at the tip and / or proximal end of the opening 11, allowing the position of the opening 11 to be confirmed from outside the body. This allows the position of the opening 11 of the puncture needle 100 to be confirmed from outside the body, enabling the appropriate administration of the substance to the target.

[0050] As shown in Figure 2, if the puncture portion 10 has an opening 11 formed on the side of the tip portion 101, the tip shape can be a pencil point shape with a sharp tip, such as a cone or pyramidal shape. However, the puncture portion 10 may also have a blade surface formed by known processing steps such as lancet cut or back cut as the tip shape. In that case, the opening 11 is formed to open toward the longitudinal axis C. In this embodiment, there is one opening 11 formed on the side of the tip portion 101, but the number and position of the openings are not particularly limited, and multiple openings may be provided to improve the diffusion of the drug, or they may be provided on the inclined surface of the pencil point needle.

[0051] As shown in Figure 1, the narrow-diameter tip portion 20 is positioned between the puncture portion 10 and the intermediate reduced-diameter portion 30. The tip of the narrow-diameter tip portion 20 is connected to the base end of the puncture portion 10, and the base end is connected to the tip of the intermediate reduced-diameter portion 30. The narrow-diameter tip portion 20 communicates with the puncture portion 10 and the intermediate reduced-diameter portion 30 along its longitudinal axis C with a constant inner diameter. The base end of the narrow-diameter tip portion 20 is inserted into the hub portion 50 while connected in communication with the intermediate reduced-diameter portion 30. Alternatively, the base end of the narrow-diameter tip portion 20 is integrally attached to the outer surface of the hub portion 50 so as to be able to communicate with the intermediate reduced-diameter portion 30.

[0052] The inner surface of the lumen 110, which communicates from the narrow tip portion 20 to the puncture portion 10 of the tip portion 101, is smoothed overall by internal polishing to achieve the following linear roughness (Ra) and surface roughness (Sa). The inner surface of the narrow tip portion 20 may be smoothed using methods other than polishing.

[0053] The inner diameter of the narrow tip portion 20 is preferably 0.05 mm to 1.0 mm from the viewpoint of puncture performance to the target site. With this configuration, for example, in procedures using an endoscope, it can be used by passing it through the lumen through which forceps or the like are inserted, similar to endoscopic biopsy needles. Furthermore, from the viewpoint of compatibility with the outer diameter when considering injection resistance when manually administering drugs, bleeding during puncture, and the risk of drug leakage, it is more preferably 0.10 mm to 0.30 mm.

[0054] The cross-sectional area of ​​the narrow tip portion 20 is preferably as small as possible to reduce the risk of bleeding from the target site and leakage of the drug solution during puncture, specifically 0.08 mm. ２ The following is more preferable from the viewpoint of reducing mechanical stress on the drug: 0.071 mm ２ The details are as follows. Further information regarding the effect of needle tube shape on reducing mechanical stress on the drug will be provided later.

[0055] The inner surface of the lumen 110, which communicates from the tip-sized portion 20 to the puncture portion 10, has an arithmetic mean roughness (Ra), which is the linear roughness, of 0.11 μm or less, preferably 0.09 μm or less. The inner surface of the tip-sized portion 20 has an arithmetic mean height (Sa), which is the surface roughness, of 0.30 μm or less, preferably 0.20 μm or less from the viewpoint of reducing mechanical stress. The inner surface of the tip-sized portion 20 satisfies both the arithmetic mean roughness (Ra) and arithmetic mean height (Sa) described above. The arithmetic mean roughness (Ra) is measured in accordance with "ISO 25178", and the arithmetic mean height (Sa) is measured in accordance with "JIS B 0601-2001", and can be measured, for example, using a 3D measuring laser microscope (OLS-5100: manufactured by Olympus Corporation).

[0056] The lumen 110, which extends from the narrow-diameter tip 20 to the puncture site 10, has an inner surface that satisfies the aforementioned arithmetic mean roughness (Ra) and arithmetic mean height (Sa). This suppresses the generation of turbulence near the inner surface of the lumen 110 of the substance flowing in from the intermediate narrow-diameter section 30. Therefore, the puncture needle 100 can reduce mechanical stress on the modality of the substance being administered.

[0057] The length of the narrow tip portion 20 in the longitudinal axis C direction is not particularly limited, but if it is intended to be used in a procedure using an endoscope, for example, it is necessary to reach the target of administration through an endoscope placed in a biological lumen such as the digestive tract. For this reason, it is preferable that the narrow tip portion 20 be, for example, 1 m or more.

[0058] As shown in Figure 1, the intermediate diameter-reducing section 30 is positioned between the tip narrow-diameter section 20 and the base large-diameter section 40. The tip of the intermediate diameter-reducing section 30 is connected to the base end of the tip narrow-diameter section 20, and the base end is connected to the tip of the base large-diameter section 40. The inner diameter of the base end of the intermediate diameter-reducing section 30 matches that of the base large-diameter section 40, and the inner diameter of the tip matches that of the tip narrow-diameter section 20. The intermediate diameter-reducing section 30 communicates with the tip narrow-diameter section 20 and the base large-diameter section 40. The inner diameter of the intermediate diameter-reducing section 30 decreases from the base end to the tip. The intermediate diameter-reducing section 30 functions as a flow path load reduction section to reduce mechanical stress on the substance being administered as it flows from the base large-diameter section 40, which has a wide flow path cross-sectional area, to the tip narrow-diameter section 20, which has a narrow flow path cross-sectional area.

[0059] The intermediate diameter reduction section 30 has a tapered section 31 and a relay section 32.

[0060] As shown in Figure 3, the tapered portion 31 is continuous, connecting the narrow-diameter tip portion 20 and the large-diameter base portion 40. As shown in Figure 3, the tapered portion 31 can be formed in a multi-stage shape by combining straight lines with different inclination angles, separated by the intermediate portion 32, in the cross-sectional shape of the longitudinal axis C. As shown in Figure 3, the tapered portion 31 can be composed of a first tapered portion 31a extending from the tip to the intermediate portion 32, and a second tapered portion 31b extending from the intermediate portion 32 to the large-diameter base portion 40. As shown in Figure 3, the intermediate portion 32 can be located, for example, between the narrow-diameter tip portion 20 and the large-diameter base portion 40. Furthermore, the intermediate section 32 is not limited to the boundary of a shape change such as a change in the taper angle, but can be set at any position on a taper of a single angle. However, it is selected from any point on the intermediate reduced diameter section 30 that has an inner diameter of 1.0 mm or more, or an inner diameter of 1 / 3 or more of the inner diameter of the tip narrow diameter section 20, and is a point that intersects with a plane perpendicular to the longitudinal axis C.

[0061] In addition to the form shown in Figure 3, the tapered portion 31 can also be configured as shown in Figures 4A to 4E (Forms 1 to 5). The intermediate diameter reduction portion 30 may also be a shape other than Forms 1 to 5 shown in Figures 4A to 4E.

[0062] As shown in Figure 4A, the tapered portion 31 of Embodiment 1 can have a straight inner surface in the cross-sectional shape along the longitudinal axis C. As shown in Figure 4A, the tapered portion 31 of Embodiment 1 is composed of a first tapered portion 31a in which the inner diameter gradually decreases from the base end to the tip. The intermediate portion 32 of the tapered portion 31 of Embodiment 1 may be located at the base end, which is the connection point with the large-diameter base portion 40 shown in Figure 4A, or it may be located between the small-diameter tip portion 20 and the large-diameter base portion 40.

[0063] As shown in Figure 4B, the tapered portion 31 of Embodiment 2 can have a curved shape across its entire inner surface in the cross-sectional shape along the longitudinal axis C. As shown in Figure 4B, the tapered portion 31 of Embodiment 2 is composed of a first tapered portion 31a in which the inclination angle gradually increases from the tip (the side of the narrow-diameter tip portion 20) to the base (the side of the large-diameter base portion 40). The intermediate portion 32 of the tapered portion 31 of Embodiment 2 may be located at the base, which is the connection point with the large-diameter base portion 40 shown in Figure 4B, or it may be located between the narrow-diameter tip portion 20 and the large-diameter base portion 40. By making the tapered portion 31 of Embodiment 2 curved as shown in Figure 4B, the flow path load at the reduction in diameter can be reduced more effectively compared to the straight shape shown in Figure 4A.

[0064] As shown in Figure 4C, the tapered portion 31 of Embodiment 3 can have a multi-stage cross-sectional shape combining straight lines and curves with respect to the intermediate portion 32 in the longitudinal axis C. As shown in Figure 4C, the tapered portion 31 of Embodiment 3 can be composed of a first tapered portion 31a extending from the tip to the intermediate portion 32, and a second tapered portion 31b extending from the intermediate portion 32 to the large-diameter base portion 40. In the tapered portion 31 of Embodiment 3, the first tapered portion 31a is composed of a straight line, and the second tapered portion 31b is composed of a curve. As shown in Figure 4C, the intermediate portion 32 of the tapered portion 31 of Embodiment 3 is located between the narrow-diameter tip portion 20 and the large-diameter base portion 40.

[0065] As shown in Figure 4D, the tapered portion 31 of form 4 can have a multi-stage cross-sectional shape combining straight lines and curves with respect to the intermediate portion 32 in the longitudinal axis C. As shown in Figure 4D, the tapered portion 31 of form 4 can be composed of a first tapered portion 31a extending from the tip to the intermediate portion 32, and a second tapered portion 31b extending from the intermediate portion 32 to the large-diameter base portion 40. In the tapered portion 31 of form 4, the first tapered portion 31a is composed of a curve, and the second tapered portion 31b is composed of a straight line. As shown in Figure 4D, the intermediate portion 32 of the tapered portion 31 of form 4 is located between the small-diameter tip portion 20 and the large-diameter base portion 40.

[0066] As shown in Figure 4E, the tapered portion 31 of form 5 can be a multi-stepped staircase shape with a predetermined number of steps formed in the cross-sectional shape of the longitudinal axis C. The intermediate portion 32 of the tapered portion 31 of form 5 is located between the narrow-diameter tip portion 20 and the large-diameter base portion 40, as shown in Figure 4E. The number of steps and the height of the steps in the tapered portion 31 of form 5 are not particularly limited.

[0067] In the tapered portion 31 of form 6, the cross-sectional shape of the longitudinal axis C can be a multi-stage shape combining straight lines with different inclination angles separated by the intermediate portion 32. As shown in Figure 4F, the tapered portion 31 of form 6 can be composed of a first tapered portion 31a extending from the tip to the intermediate portion 32, and a second tapered portion 31b extending from the intermediate portion 32 to the base end large diameter portion 40. As shown in Figure 4F, in the tapered portion 31 of form 6, the second inclination angle θ2 of the straight line L2 connecting the inner surface of the intermediate portion 32 and the inner surface of the tip of the base end large diameter portion 40 with respect to the longitudinal axis C can be such that the first inclination angle θ1 of the straight line L1 connecting the inner surface of the intermediate portion 32 and the inner surface of the base end of the tip small diameter portion 20 is smaller than the first inclination angle θ1 (θ1 > θ2).

[0068] The tapered portion 31 decreases in diameter from the large-diameter base portion 40 towards the small-diameter tip portion 20. As shown in Figure 3, the tapered portion 31 has a first inclination angle θ1 of 25 degrees or less with respect to the longitudinal axis C of the straight line L1 connecting the inner surface of the intermediate portion 32 and the inner surface of the base end of the small-diameter tip portion 20. The first inclination angle θ1 is the angle between the straight line L1 and the longitudinal axis C. From the viewpoint of manufacturing the puncture needle 100, the first inclination angle θ1 is preferably 6 degrees or more and 12 degrees or less.

[0069] As shown in Figure 3, the tapered portion 31 has a second inclination angle θ2 with respect to the longitudinal axis C of the straight line L2 connecting the inner surface of the intermediate portion 32 and the inner surface of the tip of the large-diameter base portion 40, which is greater than the first inclination angle θ1 (θ1 < θ2). The second inclination angle θ2 is the angle between the straight line L2 and the longitudinal axis C. The inclination angle of the tapered portion 31 is not particularly limited as long as the first inclination angle θ1, which contributes greatly to the effect of reducing mechanical stress on the drug, is 25 degrees or less, preferably 6 degrees or more and 12 degrees or less, as mentioned above. For example, as shown in Figure 4F, the first inclination angle θ1 may be greater than the second inclination angle θ2 (θ2 < θ1).

[0070] The intermediate section 32 has an inner diameter of 1.0 mm or more, or an inner diameter of 1 / 3 or more of the inner diameter of the tip narrow section 20. Furthermore, the first inclination angle θ1 of the straight line L1 connecting the inner surface of the intermediate section 32 and the inner surface of the base end of the tip narrow section 20 with respect to the longitudinal axis C is 25 degrees or less. In other words, the puncture needle 100 of this embodiment has an intermediate section 32 that satisfies such conditions. Here, when a cell evaluation similar to the example was performed on a needle tube with an inner diameter of 4.5 mm at the base large-diameter section 40, an inner diameter of 0.3 mm at the tip narrow section 20, and no intermediate narrow-diameter section 30, a reduction in cytotoxic activity was observed in cells that passed through the needle tube. For this needle tube, computational fluid dynamics simulation was used to calculate the maximum shear stress along the longitudinal axis C within the lumen 110 under a flow rate of 1 mL per minute. When the calculation results were plotted with the maximum shear stress (Pa) on the vertical axis and the diameter of the proximal large-diameter section 40 (mm) on the horizontal axis, it was shown to be 2.9 Pa. In other words, under the given simulation conditions, if the maximum shear stress along the longitudinal axis C exceeds 2.9 Pa, it can be said that damage to cells passing through the needle tube occurs. Furthermore, the maximum shear stress along the longitudinal axis C within the lumen 110 was calculated when the inner diameter of the tip narrow-diameter section 20 was fixed at 0.3 mm and the inner diameter of the proximal large-diameter section 40 was varied from 0.5 mm to 4.5 mm. Under the condition where the inner diameter of the proximal large-diameter section 40 was 1.0 mm or more, the maximum shear stress was saturated and did not fluctuate much from around 2.9 Pa. On the other hand, it was shown that the maximum shear stress is significantly reduced when the inner diameter of the large-diameter base portion 40 is 1.0 mm or less. From these results, it is thought that when the ratio of the inner diameter of the large-diameter base portion 40 to the inner diameter of the small-diameter tip portion 20 is 10 / 3 or more, the flow path load due to the increase in maximum shear stress is maximized, and the intermediate reduced-diameter portion 30 equipped with the relay portion 32 in this embodiment can be expected to suppress the maximum shear stress. As a result, the puncture needle 100 can effectively reduce the flow path load on the administered substance flowing from the large-diameter base portion 40 through the intermediate reduced-diameter portion 30 to the small-diameter tip portion 20, and thus can also suppress damage to cells passing through the needle tube.

[0071] In a numerical fluid analysis simulation, the maximum shear stress on the axis of the longitudinal axis C within the lumen 110 of the intermediate diameter-reduced section 30, calculated under a flow rate of 1 mL per minute, is 1.6 Pa or less. This allows the puncture needle 100 to effectively reduce the flow path load on the administered substance as it flows from the large-diameter base section 40 through the intermediate diameter-reduced section 30 to the small-diameter tip section 20. Numerical fluid analysis simulations can be performed using known fluid analysis software such as scFLOW V2024.1 (manufactured by MSC Software, Inc.), by setting fluid conditions (flow rate, density, viscosity coefficient) and taper conditions of the intermediate diameter-reduced section 30 (taper length, inner diameter of the small-diameter tip section 20, inner diameter of the large-diameter base section 40) (details will be described later).

[0072] Here, examples of the taper length and first inclination angle θ1 configuration of the intermediate diameter reduction section 30 are given. In a configuration where the inner surface of the intermediate diameter reduction section 30 is straight as shown in Figure 4A, when the inner diameter of the tip narrow diameter section 20 is 0.30 mm and the inner diameter of the base large diameter section 40 is 4.5 mm, the following configurations are possible. When the taper length of the intermediate diameter reduction section 30 is 10.0 mm, the first inclination angle θ1 can be 11.86 degrees. When the taper length of the intermediate diameter reduction section 30 is 9.0 mm, the first inclination angle θ1 can be 13.13 degrees. When the taper length of the intermediate diameter reduction section 30 is 8.0 mm, the first inclination angle θ1 can be 14.71 degrees. When the taper length of the intermediate diameter reduction section 30 is 7.0 mm, the first inclination angle θ1 can be 16.70 degrees. When the taper length of the intermediate diameter reduction section 30 is 6.0 mm, the first inclination angle θ1 can be set to 19.29 degrees. When the taper length of the intermediate diameter reduction section 30 is 5.0 mm, the first inclination angle θ1 can be set to 22.78 degrees.

[0073] The large-diameter base portion 40 is located on the base end 102 side of the puncture needle 100 and is positioned at the base end of the intermediate-reduced-diameter portion 30. The tip of the large-diameter base portion 40 is connected to the base end of the intermediate-reduced-diameter portion 30. The large-diameter base portion 40 communicates with the intermediate-reduced-diameter portion 30 along the longitudinal axis C with a constant inner diameter.

[0074] The proximal diameter portion 40 has a connecting portion 41 on its proximal end side. The connecting portion 41 is configured to be connectable to the tip portion 210 of the administration device 200. For example, if the administration device 200 is a syringe and the tip portion 210 is of the Luer taper type or Luer lock type, the connecting portion 41 will be configured to match the shape of the tip portion 210. There are no particular restrictions on the shape of the connecting portion 41 as long as it is configured to be detachable from the administration device 200.

[0075] The hub portion 50 is positioned on the proximal end 102 side of the puncture needle 100 and is connected to the tip portion 210 of the administration device 200. The hub portion 50 has an intermediate diameter-reduced portion 30 and a proximal diameter-enlarged portion 40 formed inside, and the connection portion 41 of the proximal diameter-enlarged portion 40 is connected to the tip portion 210. The hub portion 50 allows the substance to be administered, which flows in from the administration device 200, to flow through the intermediate diameter-reduced portion 30 and the proximal diameter-enlarged portion 40 to the tip diameter-reduced portion 20.

[0076] [Second Embodiment] Next, a puncture needle 100A according to the second embodiment will be described. In the following description, the same configuration as the puncture needle 100 described above will be omitted, and only the differences will be described.

[0077] As shown in Figure 5, the puncture needle 100A of the second embodiment comprises a puncture portion 10, a thin tip portion 20, and a hub portion 50.

[0078] The narrow-diameter tip portion 20 has an opening 21 on its tip-side surface that communicates with the lumen 110. The opening 21 functions similarly to the opening 11 formed in the puncture portion 10 of the puncture needle 100 described above, and the administered substance flowing through the lumen 110 is discharged through it. The opening 21 is located on the proximal end side of the puncture portion 10. Therefore, when the puncture needle 100A is used to puncture a target, it is inserted until the opening 21 reaches the inside of the target.

[0079] A marker portion 60 can be provided at the tip and / or proximal end of the opening 21, similar to the opening 11 of the puncture needle 100, allowing the position of the opening 21 to be confirmed from outside the body. This allows the position of the opening 21 of the puncture needle 100A to be confirmed from outside the body, enabling the administration of the substance to the appropriate location on the target.

[0080] The narrow-diameter tip portion 20 can be reinforced with a reinforcing material 70, such as a heat-shrinkable tube, on its outer surface. This prevents the puncture needle 100A from bending or breaking during puncture, especially when the narrow-diameter tip portion 20 is long. In the configuration shown in Figure 5, the reinforcing material 70 is a continuous member extending from the base end of the narrow-diameter tip portion 20 to the front of the opening 21. However, since the reinforcing material 70 only needs to have the function of preventing the narrow-diameter tip portion 20 from bending during use, the number and position of the reinforcing material between the base end and the tip of the narrow-diameter tip portion 20 can be appropriately determined according to the specifications of the narrow-diameter tip portion 20.

[0081] The hub portion 50 is connected to the base end of the narrow-diameter tip portion 20 so as to be able to communicate with it. The hub portion 50 does not have an intermediate reduced-diameter portion 30 or a base-end large-diameter portion 40 formed inside, and is simply configured to be connectable to the tip portion 210 of the administration device 200. The substance to be administered flows from the administration device 200 to the narrow-diameter tip portion 20 via the hub portion 50. If the administration device 200 is a syringe and the tip portion 210 is a Luer taper type or Luer lock type, the hub portion 50 will be configured to match the shape of the tip portion 210. In this case, there are no particular restrictions on the shape of the hub portion 50 as long as it is configured to be detachable from the administration device 200, and as mentioned above, it does not form a tapered structure like the intermediate reduced-diameter portion 30 of the first embodiment for purposes other than connection to the administration device 200.

[0082] The puncture needle 100A of the second embodiment does not have an intermediate reduced diameter portion 30 and a base large diameter portion 40, and the substance to be administered that flows in from the hub portion 50 is discharged from the opening 21 through the tip narrow diameter portion 20. The tip narrow diameter portion 20 has an arithmetic mean roughness (Ra), which is the line roughness, of 0.11 μm or less, and an arithmetic mean height (Sa), which is the surface roughness, of 0.30 μm or less. As a result, the flow path load on the substance to be administered is reduced with the puncture needle 100A. Therefore, the decrease in drug efficacy due to damage to the modality contained in the substance administered with the puncture needle 100A is suppressed.

[0083] As described above, the puncture needle 100 according to this embodiment has a longitudinal axis C, a proximal end 102, and a tip 101, and comprises a lumen 110 that communicates from the proximal end 102 to the tip 101 in the direction of the longitudinal axis C, a puncture portion 10 provided on the tip 101 that can penetrate living tissue, and a narrow tip portion 20 that communicates with the puncture portion 10 with a constant inner diameter, the cross-sectional area of ​​the narrow tip portion 20 being 0.08 mm ２ The following conditions apply, and at least in the tip-sized portion 20, the arithmetic mean roughness (Ra) of the inner surface is 0.11 μm or less, and the arithmetic mean height (Sa) of the inner surface is 0.30 μm or less.

[0084] With this configuration, the puncture needle 100 can reduce mechanical stress on the administered substance flowing through the small-diameter tip portion 20, thereby suppressing a decrease in drug efficacy due to damage to modalities contained in the administered substance.

[0085] Furthermore, the following modifications can be adopted for the puncture needles 100 and 100A.

[0086] In the aforementioned lancet 100, the proximal large-diameter portion 40 is configured to be attached to the administration device 200 via the connecting portion 41. However, the lancet 100 may also be configured such that a plunger is directly inserted into the connecting portion 41, and the substance to be administered contained in the proximal large-diameter portion 40 is pushed out by the plunger. In other words, the lancet 100 can also be used to configure an administration system by combining the lancet 100 and a plunger without using the administration device 200.

[0087] Furthermore, the puncture needle 100 may be configured to be detachable from the administration device 200, or its proximal large-diameter portion 40 may be integrated with the tip portion 210 of the administration device 200.

[0088] 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 to the following examples.

[0089] The performance of the puncture needle according to the present invention was evaluated by conducting tests 1 to 5.

[0090] The sample conditions for the needle tubes used in Tests 1 to 5 are shown in Figure 6. Samples A to D are comparative examples, and Samples 1 to 6 are examples (including reference examples). The "internal surface roughness" shown in Figure 6 refers to the arithmetic mean roughness (so-called line roughness, Ra) and arithmetic mean height (so-called surface roughness, Sa) at the narrow tip. Samples with a taper condition of "no taper" are samples that do not have an intermediate narrowing section and consist only of a narrow tip and a large base. The inner diameter, internal surface roughness, and taper conditions (taper length, taper angle) of the needle tube differ for each sample, and one was selected and used according to the purpose of each test. In addition, each sample was processed and created using generally known techniques. Note that in Figure 6, "-" indicates that the conditions were not set using computer simulation.

[0091] Figure 15 shows graphs of cytotoxic activity (AUC, %-ratio) for the control (no needle tube passage treatment) and sample B. In sample B, where the inner diameter of the narrow section was set to 0.25 mm, cytotoxic activity was significantly reduced compared to the control. From these results, it was confirmed that, as described in Patent Document 1 above, reducing the diameter of the needle tube inhibits cytotoxic activity. The protocol and conditions for evaluating cytotoxic activity were carried out in the same manner as in the examples described later, so a detailed explanation is omitted here.

[0092] [Test 1] In Test 1, the number of dead cells (cells / mL) and the cytotoxicity rate (AUC, %-ratio) were measured after needle passage treatment using samples from the examples and comparative examples. The test conditions for Test 1 were as follows:

[0093] <Specifications of needle tube samples> For Test 1, Sample 1 and Sample A, as shown in Figure 6, were used.

[0094] <Measurement of inner surface roughness of the tip's narrow diameter section> The inner surface roughness of the tip's narrow diameter section was measured using a 3D measuring laser microscope (OLS-5100: manufactured by Olympus Corporation). The measurement range for the arithmetic mean height (Sa) was set to 30 μm × 30 μm, and the microscope was positioned so that the bottom (longitudinal axis) was in the center.

[0095] <Cell Types Used> The following two types of cells were used:・Primary NK cells (Effector cells used in the needle passage treatment) Cryopreserved Primary NK cells were thawed at 37°C, added to a medium (AB+) that had been returned to room temperature, and mixed. Thereafter, the mixture was centrifuged (300×g, 5 min, room temperature), the supernatant was discarded, a medium (IL-2+) was added, and the cells were thoroughly suspended by pipetting. The cell suspension was transferred to a culture flask for suspension cells (75.0 mL), and incubated at 37°C in an environment of 5% CO ２ concentration. Based on the measured number of viable cells, the concentration of the cell suspension was adjusted to 6.00×10 ５ cells / mL by appropriate dilution with medium (IL-2+), and the cells were maintained under this condition. Trypan blue dye exclusion method and Countess II were used for cell counting. ・Leukemia cell line (Target cells used when measuring cytotoxic activity) Cryopreserved leukemia cells were thawed at 37°C, added to a medium (FBS+) that had been returned to room temperature, and mixed. Thereafter, the mixture was centrifuged (300×g, 5 min, room temperature), the supernatant was discarded, a medium (FBS+) was added, and the cells were thoroughly suspended by pipetting. The cell suspension was transferred to a culture flask for suspension cells (75.0 mL), and incubated at 37°C in an environment of 5% CO ２ concentration. Based on the measured number of viable cells, the concentration of the cell suspension was adjusted to 1.00×10 5 cells / mL (not exceeding 3.00×10 ６ cells / mL) by appropriate dilution with medium (FBS+), and the cells were maintained under this condition. Trypan blue dye exclusion method and Countess II were used for cell counting.

[0096] <Implementation Conditions for Cell Passage Treatment Through a Needle> The cell passage treatment was carried out by passing cells through the needle under the following conditions:・Cell concentration: 1 to 3×10 ６ cells / mL ・Passage speed: 50 to 250 μL / sec ・Passage distance (needle length): 100 mm.

[0097] <Protocol and conditions for evaluating dead cell count> After suspending the cell suspension in a 1:1 ratio with trypan blue, the trypan blue dye exclusion method was performed using Countess II. Three measurements were taken per pass-through sample, and the average values ​​and percentages of live cells, dead cells, and total cells were calculated.

[0098] <Protocol and Conditions for Evaluation of Cytotoxic Activity> Leukemia cell lines were seeded on plates using a non-RI cytotoxicity assay kit (manufactured by Techno Suzuta Co., Ltd.). BM-HT Reagent was added to the leukemia cell lines, and a specified number of Primary NK cells (untreated, needle-pass treated) were added to the plates containing the leukemia cell lines. Eu Solution was added to the supernatant, and time-resolved fluorescence was measured using a plate reader.

[0099] <Calculation of Spontaneous Leakage Rate and Cytotoxic Activity Rate of Target Cells> The spontaneous leakage rate and cytotoxic activity rate of target cells were calculated using the following formulas 1 and 2: Spontaneous leakage rate (%) = (TubeB / average value of medium only (Negative Control) - TubeA / average value of medium only (Background)) / (TubeB / average value with Detergent added (Positive Control) - TubeA / average value of medium only (Background)) × 100 ... Formula 1 Cytotoxic activity rate (%) = A / B × 100 ... Formula 2 Here, A = (Sample average value - TubeA / medium only average value) - (TubeB / medium only average value - TubeA / medium only average value), and B = (TubeB / detergent added average value - TubeA / medium only average value) - (TubeB / medium only average value - TubeA / medium only average value). Also, TubeA is a leukemia cell line / DMSO added, and TubeB is a leukemia cell line / BM-HT Reagent added, A is the fluorescence intensity at a certain E / T ratio, and B is the fluorescence intensity at maximum leakage.

[0100] <Results> The results of Experiment 1 are shown in Figures 7A and 7B. Figure 7A shows graphs of dead cell counts (cells / mL) for the control (no needle tubular treatment), Sample 1, and Sample A. Figure 7B shows graphs of cytotoxic activity (AUC, %-ratio) for the control (no needle tubular treatment), Sample 1, and Sample A. As shown in Figure 7A, the dead cell count for the control (untreated without needle tubular treatment) was 2.8 × 10⁶. ５ In contrast to the cell count of ５ Cells / mL increased significantly. Furthermore, as shown in Figure 7B, the AUC, which indicates cytotoxic activity, was significantly lower in sample A (341.17) compared to the control (418.49). In this case, sample 1, which had a smoothed inner surface and a narrow tip, showed a dead cell count of 3.84 × 10⁶. ５ The cells / mL and AUC of cytotoxic activity were 422.31, which was comparable to the control that had not undergone needle passage treatment. From these results, it was found that cells may be affected by mechanical stress when passing through a small-diameter needle, which can impair their viability and cellular function (toxic activity). By smoothing the inner surface of the small-diameter tip of the puncture needle and reducing the arithmetic mean roughness and arithmetic mean height, mechanical stress on cells can be reduced.

[0101] [Test 2] In Test 2, samples from the examples and comparative examples were subjected to needle tubular passage treatment, and the number of dead cells (cells / mL) and cytotoxic activity (AUC, %-ratio) were measured. The test conditions in this test were the same as in Test 1.

[0102] <Sample Specifications> Test 2 used Sample 1, Sample 3, and Sample A as shown in Figure 6. Figure 8A is a photograph showing the inner surface of the narrow tip of Sample 1, and Figure 8B is a photograph showing the inner surface of the narrow tip of Sample 3.

[0103] <Results> The results of Experiment 2 are shown in Figures 9 and 10. Figure 9 is a graph of the number of dead cells (cells / mL) for the control (no needle passage treatment), sample 1, sample 3, and sample A. Figure 10 is a graph of the cytotoxic activity (AUC, %-ratio) for the control (no needle passage treatment), sample 1, sample 3, and sample A. As shown in Figure 9, in the comparison of the number of dead cells, sample 1 was 8.95 × 10⁶. ４ The result was cells / mL, and sample 3 was 8.37 × 10⁻⁶. ４ Compared to cells / mL, the control was 6.28 × 10 ４ The values ​​were close to cells / mL. As shown in Figure 10, when comparing the cytotoxic activity, Sample 1 was 321.461, which was slightly higher than Sample 3's 319.994 and close to the control's 357.179, but no significant difference was observed between the two examples. From these results, it was found that regarding the roughness of the inner surface in the narrow tip, a lower arithmetic mean roughness (Ra) is more effective in reducing mechanical stress on cells, and while a lower arithmetic mean height (Sa) is preferable, its influence is small.

[0104] [Test 3] In Test 3, in order to confirm the effect of the taper, a simulation was conducted using four types of samples that were reference examples that did not take into account the inner surface roughness, to examine the relationship between the taper length and the maximum shear stress along the longitudinal axis. The test conditions for Test 3 were as follows.

[0105] <Sample Specifications> Test 3 used samples 4-1, 4-2, 5-1, 5-2, and D.

[0106] The analysis software used was scFLOW V2024.1 (manufactured by MSC Software Co., Ltd.), and the fluid conditions and taper conditions were set as follows: <Fluid Conditions> - Flow rate: 1.0 mL / min - Density: 998.2 kg / m³ ３ Viscosity coefficient: 1.005 mPa·s.

[0107] <Results> The results of Test 3 are shown in Figures 11A and 11B. Figure 11A (a) shows the shear stress distribution of sample 4-1. Figure 11B (b) shows the shear stress distribution of sample D. Figure 11B (a) shows the shear stress distribution of sample 4-2. Figure 11B (b) shows the shear stress distribution of sample 5-1. Figure 11B (c) shows the shear stress distribution of sample 5-2. The maximum shear stress was obtained by analyzing the maximum shear stress along the central axis from the shear stress distribution in each figure. The value of the maximum shear stress on the central axis for each sample is shown in Figure 11C. At this time, as shown in Figure 11A, the maximum shear stress of sample D, which does not have a taper, was 2.9 Pa, while the maximum shear stress of sample 4-1, which has a taper, was 1.6 Pa. These results show that when reducing the diameter to a smaller size, having a tapered intermediate diameter reduction section reduces the maximum shear stress. Furthermore, as shown in Figure 11A (a), Figure 11B (b), and Figure 11C, when the inner diameter of the tip's smaller diameter section was 0.3 mm, the maximum shear stress (Pa) of sample 4-1 was 1.6 Pa, which was 1.4 times higher than the maximum shear stress (Pa) of sample 5-1 (1.1 Pa). Also, when the inner diameter of the tip's smaller diameter section was 0.1 mm, as shown in Figures 11B and 11C, the maximum shear stress (Pa) of sample 4-2 was 36.0 Pa, which was 1.4 times higher than the maximum shear stress (Pa) of sample 5-2 (25.7 Pa). From these results, it was confirmed that the rate of change of the maximum shear stress of the puncture needle did not vary significantly depending on the size of the inner diameter of the tip's smaller diameter section, but rather depended on the taper length. Furthermore, keeping the maximum shear stress below 1.6 Pa, which is the maximum shear stress of Sample 4-1, is thought to have the effect of suppressing the reduction of cell function as the maximum shear stress decreases. (The effect on cell function will be described in Test 5 below.) [Test 4] In Test 4, in order to confirm the effect of the taper, a simulation was conducted to examine the relationship between the taper shape and the maximum shear stress using samples that serve as reference examples and comparative examples when the inner surface roughness is ignored. The test conditions for Test 4 were the same as those for Test 3.

[0108] <Sample Specifications> Test 4 used samples 5-1, 6, and D shown in Figure 6.

[0109] <Results> The results of Test 4 are shown in Figures 12A and 12B. Figure 12A(a) shows the shear stress distribution of sample 5-1. Figure 12A(b) shows the shear stress distribution of sample 6. Figure 12A(c) shows the shear stress distribution of sample D. Figure 12B is a table showing the maximum shear stress values ​​on the central axis of each sample. The maximum shear stress of sample 5-1 was 1.1 Pa, the maximum shear stress of sample 6 was 0.3 Pa, and the maximum shear stress of sample D was 2.9 Pa. From these results, it was found that a curved taper shape is more effective than a straight taper shape in the tapered section of the puncture needle in reducing the maximum shear stress.

[0110] [Test 5] In Test 5, samples from the examples and comparative examples were subjected to needle tubular passage treatment, and the number of dead cells (cells / mL) and cytotoxic activity (AUC, %-ratio) were measured. Test 5 was conducted under the same test conditions as Test 1.

[0111] <Sample Specifications> Test 5 used Sample 2, Sample A, and Sample C shown in Figure 6.

[0112] <Results> The results of Test 5 are shown in Figures 13 and 14. Figure 13 is a graph of the number of dead cells (cells / mL) for the control (no needle tubular passage treatment), sample 2 (inner surface smoothing treatment, tapered), sample A (no smoothing treatment, no tapered), and sample C (no smoothing treatment, tapered). Figure 14 is a graph of the cytotoxic activity (AUC, %-ratio) for the control (no needle tubular passage treatment), sample 2 (inner surface smoothing treatment, tapered), sample A (no smoothing treatment, no tapered), and sample C (no smoothing treatment, tapered). In the results shown in Figure 13, the number of dead cells in the control (no needle tubular passage treatment) was 2.26 × 10⁻⁶. ５While the cell count is 4.51 × 10⁻¹⁰ cells / mL, sample A, which has no smoothing treatment on the inner surface of the narrow tip and does not have a tapered structure, has a cell count of 4.51 × 10⁻¹⁰ cells / mL. ５ Cells / mL and the number of dead cells increased significantly. In this case, sample C, which only had a tapered structure, showed a value of 3.97 × 10⁻⁶. ５ Sample 2, which has both a smoothed inner surface and a tapered structure, showed a slightly decreasing trend in the number of dead cells / mL compared to Sample A, and the cell count was 3.11 × 10⁶. ５ Cells / mL decreased significantly. Furthermore, as shown in Figure 14, the AUC of cytotoxic activity was 310.95 for the control, significantly decreased to 233.88 for sample A, and showed a decreasing trend to 281.62 for sample C. At this time, the cytotoxic activity of sample 2, an example, was 324.00, showing a significant recovery in activity to the same level as the control.

[0113] As shown in Figures 13 and 14, Sample C, which has a tapered intermediate diameter section, slightly increased cell viability compared to Comparative Example Sample A, which does not have a tapered intermediate diameter section, and was also confirmed to suppress the reduction in cytotoxic activity. Furthermore, Sample 2, which has a smoothed inner surface of the tip diameter section and a tapered intermediate diameter section, also increased cell viability compared to Comparative Example Sample A, which has an unsmoothed tip diameter section, and was also confirmed to suppress the reduction in cytotoxic activity. From these results, it was found that in a puncture needle with a small diameter tube, the effect of mechanical stress on cells is reduced by smoothing the inner surface of the tip diameter section, and the effect of mechanical stress can be reduced more effectively by making the intermediate diameter section tapered.

[0114] Based on the test results from Tests 1 to 5, the puncture needles using the shapes of Samples 1 to 6 demonstrate that when biopharmaceuticals, including those requiring advanced delivery technology such as cell-based therapies, are used as the administered substance, mechanical stress on the modality can be effectively reduced.

[0115] This application is based on Japanese Patent Application No. 2025-050902, filed on 26 March 2025, the disclosures of which are cited in their entirety by reference.

[0116] 10 Puncture section, 11 Opening, 20 Tip narrow section, 21 Opening, 30 Intermediate narrow section, 31 Tapered section, 31a First tapered section, 31b Second tapered section, 32 Intermediate section, 40 Base large diameter section, 41 Connecting section, 50 Hub section, 60 Marker section, 70 Reinforcement material, 100, 100A Puncture needle, 101 Tip section, 102 Base end section, 110 Lumen, 200 Administration device, 210 Tip section, L1 Straight line connecting the inner surface of the intermediate section and the inner surface of the base end of the tip narrow section, L2 Straight line connecting the inner surface of the intermediate section 32 and the inner surface of the tip of the base large diameter section.

Claims

1. A puncture needle having a longitudinal axis, a proximal end, and a tip, comprising: a lumen communicating from the proximal end to the tip in the longitudinal axis direction; a puncture portion provided at the tip and capable of puncturing a living organism; and a narrow tip portion communicating with the puncture portion with a constant inner diameter, wherein the cross-sectional area of ​​the narrow tip portion is 0.08 mm². ２ A puncture needle having the following characteristics, wherein at least in the tip-sized portion, the arithmetic mean roughness (Ra) of the inner surface is 0.11 μm or less, and the arithmetic mean height (Sa) of the inner surface is 0.30 μm or less.

2. The puncture needle according to claim 1, wherein the arithmetic mean roughness (Ra) is 0.09 μm or less.

3. The puncture needle according to claim 1, wherein the arithmetic mean height (Sa) is 0.20 μm or less.

4. The puncture needle according to claim 1, wherein the inner diameter of the tip portion is 0.05 mm or more and 0.3 mm or less.

5. The puncture needle according to claim 1, wherein the length of the tip portion is 1 m or more.

6. The puncture needle according to claim 1, wherein the proximal end of the puncture needle is provided with a proximal large-diameter portion, and between the proximal large-diameter portion and the tip narrow-diameter portion, there is an intermediate narrow-diameter portion whose inner diameter gradually decreases from the proximal end to the tip.

7. The puncture needle according to claim 6, wherein the intermediate diameter reduction portion has a relay portion, the relay portion has an inner diameter of 1.0 mm or more, or 10 / 3 or more of the inner diameter of the tip diameter reduction portion, and the first inclination angle of the straight line L1 connecting the inner surface of the relay portion and the inner surface of the base end of the tip diameter reduction portion with respect to the longitudinal axis is 25 degrees or less.

8. The puncture needle according to claim 7, wherein the second inclination angle of the straight line L2 connecting the intermediate portion and the inner surface of the tip portion of the large-diameter base portion with respect to the longitudinal axis is greater than the first inclination angle.

9. The puncture needle according to claim 6, wherein the inclination angle of the intermediate diameter reduction portion increases continuously from the tip of the intermediate diameter reduction portion to the base of the intermediate diameter reduction portion.

10. The puncture needle according to claim 7, wherein the first inclination angle is 6 degrees or more and 12 degrees or less.

11. The puncture needle according to claim 7, wherein, in a simulation using numerical fluid analysis, the maximum shear stress on the axis of the longitudinal axis within the lumen of the intermediate diameter reduction portion, calculated under a flow rate of 1 mL per minute, is 1.5 Pa or less.

12. The puncture needle according to claim 6, wherein the proximal diameter portion is configured to be connectable to an administration device at the proximal end.

13. The puncture needle according to claim 1, wherein the puncture portion has an opening on the side of the tip that communicates with the lumen.

14. The puncture needle according to any one of claims 1 to 13, wherein the substance administered to the target through the puncture site is a biopharmaceutical containing one or more high molecular weight components arbitrarily selected from cells, antibodies, nucleic acids, and proteins.

15. A puncture needle having a longitudinal axis, a proximal end, and a tip, wherein the needle has a lumen that communicates from the proximal end to the tip in the direction of the longitudinal axis, a proximal large-diameter portion provided on the proximal end side, a puncture portion provided on the tip that can penetrate a living body, a tip narrow-diameter portion that communicates with the puncture portion with a constant inner diameter, and an intermediate narrow-diameter portion disposed between the proximal large-diameter portion and the tip narrow-diameter portion, the intermediate narrow-diameter portion having an intermediate portion, the intermediate narrow-diameter portion having an inner diameter of 1.0 mm or more, or 10 / 3 or more of the inner diameter of the tip narrow-diameter portion, and the first inclination angle of the straight line L1 connecting the inner surface of the intermediate portion and the inner surface of the proximal end of the tip narrow-diameter portion with respect to the longitudinal axis is 25 degrees or less.

16. The puncture needle according to claim 15, wherein the second inclination angle of the straight line L2 connecting the intermediate portion and the inner surface of the tip portion of the large-diameter base portion with respect to the longitudinal axis is greater than the first inclination angle.

17. The puncture needle according to claim 15, wherein the proximal diameter portion is configured to be connectable to an administration device at the proximal end.

18. The puncture needle according to claim 15, wherein the puncture portion has an opening on the side of the tip that communicates with the lumen.

19. The puncture needle according to claim 15, wherein the inclination angle of the intermediate diameter reduction portion increases continuously from the tip of the intermediate diameter reduction portion to the base of the intermediate diameter reduction portion.

20. The puncture needle according to claim 15, wherein, in a simulation using numerical fluid analysis, the maximum shear stress on the axis of the longitudinal axis within the lumen of the intermediate diameter reduction portion, calculated under a flow rate of 1 mL per minute, is 1.6 Pa or less.

21. The puncture needle according to claim 15, wherein the inner diameter of the tip portion is 0.1 mm or more and 1.0 mm or less.

22. The puncture needle according to claim 15, wherein the first inclination angle is 6 degrees or more and 12 degrees or less.

23. The puncture needle according to claim 15, wherein the length of the tip with a narrow diameter is 1 m or more.

24. The cross-sectional area of ​​the aforementioned narrow tip portion is 0.071 mm². ２ The puncture needle according to claim 15, wherein, at least in the tip-sized portion, the arithmetic mean roughness (Ra) of the inner surface is 0.11 μm or less, and the arithmetic mean height (Sa) of the inner surface is 0.30 μm or less.

25. The puncture needle according to claim 24, wherein the arithmetic mean roughness (Ra) is 0.09 μm or less.

26. The puncture needle according to claim 24, wherein the arithmetic mean height (Sa) is 0.20 μm or less.

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