Nasal administration device and nasal administration system

Abstract

[Problem] To effectively deliver, into the brain of a mammal, an object to be administered in a less invasive manner. [Solution] A nasal administration device 1 comprises a needle part 10 having a puncture part 12 for transnasally delivering, into the brain of a mammal, an object A to be administered, wherein in a state where the puncture part 12 is disposed in a sieve plate X2, the object A to be administered is administered into the brain via an opening part (distal end opening part 14) of the puncture part 12.

Description

Nasal administration device, nasal administration system

[0001] The present invention relates to a nasal administration device and a nasal administration system for administering a substance such as a drug via the nasal route and delivering it into the brain of a mammal.

[0002] In the brain, the blood-brain barrier (BBB) ​​strictly controls the transport of substances between the circulating blood and brain tissue, and the amount of drug delivered to the brain is extremely limited, especially when macromolecular drugs (proteins, antibodies, etc.) are administered orally or intravenously.

[0003] Research into drug transfer via cerebrospinal fluid (CSF) has been conducted as a method for administering drugs into the brain more effectively than oral or intravenous administration, and currently known methods include the nasal spray method, in which drugs are sprayed into the nasal cavity, the intraventricular administration method, in which drugs are administered directly into the ventricles of the brain, and the intrathecal administration method, in which drugs are injected into the spinal cavity.

[0004] However, although the nasal spray method is minimally invasive, the drug penetration rate is extremely low. Intraventricular administration involves drilling the skull and directly administering the drug into the ventricles, which carries the risk of injury from cerebral puncture. While intrathecal administration has a higher drug penetration rate than the nasal spray method, it is not yet effective enough, and it cannot be considered minimally invasive, so there are many challenges to its practical application.

[0005] Furthermore, Patent Document 1 discloses a drug delivery device that releases a drug slowly under the olfactory mucosa, addressing the issue of drug migration restrictions at the BBB.

[0006] US Patent Application Publication No. 2021 / 0023295

[0007] The method of Patent Document 1 involves sustained drug release under the olfactory mucosa, but the olfactory mucosa is composed of the olfactory epithelium and the lamina propria, which contains many blood vessels and lymphatic vessels. Therefore, the drug is easily absorbed by the blood vessels and lymphatic vessels in the lamina propria, and in particular, the lymphatic vessels tend to circulate the drug in the direction of excretion from the brain, limiting the amount of drug delivered to the brain.

[0008] The present inventors believed that there was room for improvement in the nasal administration methods known as minimally invasive brain drug delivery routes, such as nasal spray and submucosal administration, and investigated methods that could improve the drug delivery rate into the brain. Through further investigation, the present inventors hypothesized that the low brain delivery efficiency was due to the flow of CSF leaking from the brain into the nasal cavity, which inhibits drug delivery to the brain. They then conducted research into a novel nasal administration method that could circumvent this inhibiting factor. As a result, the present inventors discovered that direct administration of a drug into the cribriform pores formed in the cribriform plate dramatically improved the delivery efficiency of the administered substance into the brain, leading to the development of the present invention.

[0009] At least one embodiment of the present invention has been made in consideration of the above-mentioned circumstances, and specifically aims to provide a nasal administration device and nasal administration system that can effectively deliver a substance to be administered into the brain of a mammal in a minimally invasive manner.

[0010] The above object of the present invention is achieved by any one of the following (1) to (10).

[0011] (1) A nasal administration device having a needle portion with a puncture portion for delivering a substance to be administered transnasally into the brain of a mammal, wherein the substance to be administered is administered into the brain through an opening in the puncture portion when the puncture portion is positioned within the cribriform plate.

[0012] (2) A nasal administration device described in (1) above, wherein the puncture portion is positioned within the cribriform plate by inserting it into a cribriform hole formed in the cribriform plate through which the olfactory nerve extends from the olfactory bulb to the olfactory mucosa.

[0013] (3) The nasal administration device is a nasal administration device described in (1) or (2) above, which is composed of a tubular member and has a cannula portion that is arranged to cover the needle portion so that the puncture portion is exposed, the opening is provided on the tip side of the puncture portion, and the tip of the cannula portion is formed with a stopper portion having an abutment portion that abuts against the olfactory epithelium of the olfactory mucosa, and the opening is arranged within the cribriform plate with the abutment portion of the stopper portion in contact with the olfactory epithelium.

[0014] (4) The nasal administration device described in (3) above has a hub portion to which a storage portion containing the administered substance can be attached, and the hub portion holds the base end of the cannula portion and / or the base end of the needle shaft portion of the needle portion inserted through the inner cavity of the cannula portion.

[0015] (5) A nasal administration device described in any of (1) to (4) above, wherein the needle tip of the puncture part has an open end with a blade surface on the tip side, and the total length of the puncture part is 0.25 mm or more and 5.4 mm or less.

[0016] (6) A nasal administration device described in (3) above, wherein the total length of the cannula portion is 55 mm or more and 410 mm or less.

[0017] (7) A nasal administration device described in (3) or (4) above, wherein the abutment portion of the stopper portion is the tip surface of the cannula portion that contacts the olfactory epithelium, the length of the longest radial portion of the abutment portion is 0.2 mm or more and 15 mm or less, and the outer diameter of the base end side of the puncture portion is 0.1 mm or more and 2.1 mm or less.

[0018] (8) A nasal administration device described in (3) or (7) above, wherein the cross-sectional shape of the abutment portion of the stopper portion is circular or elliptical.

[0019] (9) The nasal administration device is a nasal administration device described in (1) or (2) above, which has a storage section that contains the substance to be administered and is configured so that the substance contained in the storage section can be discharged through the opening of the puncture section.

[0020] (10) A nasal administration system comprising: a nasal administration device described in any one of (1) to (9) above; and a guide catheter having an insertable and removable inner cavity in at least a portion of the nasal administration device, which guides the needle portion of the nasal administration device inserted into the cavity to the sieve hole formed in the cribriform plate.

[0021] According to the present invention, by administering a substance to be administered, such as a drug, through a tip opening provided on a needle portion while the tip opening is positioned within the cribriform plate, the substance can be minimally invasively delivered to brain tissue via a delivery medium such as cerebrospinal fluid or the olfactory nerve. This is particularly effective because it allows for efficient delivery of high-molecular-weight therapeutic drugs, such as proteins and antibodies, which are currently difficult to administer to brain tissue, to brain tissue while avoiding the blood-brain barrier. Furthermore, the present invention administers the substance to be administered through the lamina propria of the olfactory mucosa, which is rich in blood vessels and lymphatic vessels, and into the cribriform pores formed in the cribriform plate. This allows the substance to be delivered to brain tissue while minimizing the amount of the substance flowing into the blood vessels and lymphatic vessels and suppressing leakage into the nasal cavity.

[0022] 1 is a diagram showing a nasal administration system according to the present embodiment; FIG. 2 is a diagram showing a state in which the needle tip of the nasal administration device has been punctured into a sieve hole; FIG. 3 is a diagram showing an example of use of the nasal administration device according to the present embodiment; FIG. 4 is a diagram showing an example of use of the nasal administration device according to the present embodiment; FIG. 5 is a diagram showing an example of use of the nasal administration device according to the present embodiment; FIG. 6 is a diagram showing an example of use of the nasal administration device according to the present embodiment; FIG. 7 is a diagram showing an example of use of the nasal administration device according to the present embodiment; FIG. 8 is a diagram showing an example of use of the nasal administration device according to the present embodiment; FIG. 9 is a diagram showing a nasal administration device prepared in Test 1; FIG. 10 is a diagram for explaining the contrast position in the CT image of Test 1; FIG. 11 is a CT image of a sample serving as an example of Test 1 after administration of the substance to be administered (contrast agent); FIG. 12 is a CT image of a sample serving as a comparative example of Test 1 after administration of the substance to be administered (contrast agent); FIG. 13 is a diagram showing a nasal administration device prepared in Test 2; FIG. 14 is a diagram for explaining the contrast position in the CT image of Test 2; FIG. 15 is a CT image of a sample serving as an example of Test 2 after administration of the substance to be administered (contrast agent); FIG. 16 is a CT image of a sample serving as a comparative example of Test 2 after administration of the substance to be administered (contrast agent).

[0023] Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. The embodiments shown here are merely examples for embodying the technical idea of ​​the present invention and are not intended to limit the present invention. Furthermore, all other embodiments, examples, and operational techniques that can be conceived by those skilled in the art without departing from the spirit of the present invention are included in the scope and spirit of the present invention, as well as in the scope of the inventions set forth in the claims and their equivalents.

[0024] Furthermore, for the convenience of illustration and ease of understanding, the drawings attached to this specification may be expressed schematically by appropriately converting the actual objects in terms of scale, aspect ratio, shape, etc., but these are merely examples and do not limit the interpretation of the present invention.

[0025] In this specification, the "cribriform foramen X3" punctured by the puncturing portion 12 of the needle portion 10 of the nasal administration device 1 is a hole formed in the cribriform plate X2 of the ethmoid bone X1, which has a nasal cavity opening and an olfactory bulb opening as shown in Figure 2. The olfactory nerve (nerve axon) Y5 extends from the olfactory bulb Y1, which is part of brain tissue B, to olfactory cells distributed in the olfactory mucosa Y2 (composed of the olfactory epithelium Y3 and the lamina propria Y4) in the nasal cavity Z1. Many cribriform foramen X3 exist not only on the flat surface of the cribriform plate X2 as shown in Figure 2, but also on the midline, lateral wall, posterior wall of the olfactory cavity, etc. The cribriform foramen X3 to be punctured by the needle portion 10 of this device is any hole among all these holes that can be punctured by the puncturing portion 12 that has penetrated the olfactory mucosa Y2.

[0026] [Nasal Administration System] The nasal administration system 200 according to this embodiment will be described.

[0027] As shown in FIG. 1, the nasal administration system 200 includes a nasal administration device 1 and a guide catheter 100.

[0028] In the nasal administration system 200, the guide catheter 100 is placed in the nasal cavity Z1 with the tip side facing the cribriform plate X2, and the nasal administration device 1 is inserted into the guide catheter 100 so that the puncture portion 12 of the needle portion 10 is positioned within the cribriform plate X2, and the substance A to be administered is administered into the brain through the opening (tip opening 14) of the puncture portion 12. The nasal administration system 200 can deliver the substance A to the brain of a mammal such as a human via a delivery medium such as cerebrospinal fluid C or the olfactory nerve Y5.

[0029] <Nasal Administration Device> As shown in FIG. 1 or 2 , the nasal administration device 1 includes a needle portion 10, a hub portion 20, a cannula portion 30, and a storage portion 40.

[0030] The nasal administration device 1 is a nasal administration device 1 including a needle portion 10 having a puncture portion 12 for transnasally delivering an article A to be administered into the brain of a mammal, and with the puncture portion 12 of the needle portion 10 positioned within the cribriform plate X2, the article A to be administered is administered into the brain through an opening (tip opening 14) of the puncture portion 12. The nasal administration device 1 can also be described as "a nasal administration device for transnasally delivering an article to be administered into the brain of a mammal, configured such that a puncture portion positioned at a tip is positioned within the cribriform plate so that the article to be administered is administered into the brain through the tip opening provided in the puncture portion" or "a nasal administration device for use in a nasal administration method for transnasally delivering an article to be administered into the brain of a mammal using a nasal administration device, the nasal administration device having a puncture portion protruding toward the tip and a tip opening provided in the puncture portion, the nasal administration method including administering article A to be administered into the brain through the tip opening with the puncture portion positioned within the cribriform plate."

[0031] The nasal administration device 1 of the present invention delivers the substance A to the brain by disposing the puncture portion 12 within the sieve plate X2 and administering the substance A through the tip opening 14 of the puncture portion 12 into the sieve hole X3 or beyond the sieve hole X3 to the ventricle side of the brain, thereby delivering the substance A to the brain. This administration method is a novel method developed by the present inventors through extensive research to avoid this impediment, based on the hypothesis that the extremely low drug transfer rate to the brain using known minimally invasive nasal administration methods is due to the flow of cerebrospinal fluid C seeping from the brain into the nasal cavity Z1 inhibiting drug delivery to the brain. When the substance A is administered into the sieve plate X2 using this device, the transfer rate of the substance A to the brain is dramatically improved. This mechanism is thought to be due to the fact that the substance A is administered with the needle portion 10 punctured within the sieve hole X3, which applies hydraulic pressure to the substance A that resists the flow of cerebrospinal fluid C and prevents it from leaking into the nasal cavity Z1. Therefore, when the puncture portion 12 is placed within the cribriform plate X2, the substance A to be administered through the tip opening 14 flows toward the brain tissue B through the olfactory bulb side opening of the cribriform foramen X3 against the flow of cerebrospinal fluid C, or is administered directly into the ventricles, and can be delivered to the brain with an extremely high migration rate via delivery media such as cerebrospinal fluid C and the olfactory nerve Y5.

[0032] The nasal administration device 1 can be used in combination with a guide catheter 100 as a nasal administration system 200, or can be used alone.

[0033] <Needle portion> The needle portion 10 has a needle shaft portion 11, a puncturing portion 12 formed on the distal end side of the needle shaft portion 11, a distal opening portion 14 (corresponding to the "opening" in the claims) formed in a needle tip portion 12a of the puncturing portion 12, and a proximal opening portion 15 formed on the proximal end of the needle shaft portion 11. The needle portion 10 has a cylindrical shape with a lumen 10a that runs longitudinally from the distal opening portion 14 formed on the distal end side to the proximal opening portion 15 formed on the proximal end side. As shown in Figure 1, the needle shaft portion 11 of the needle portion 10 is disposed within the lumen 31a of the cannula portion 30, and the puncturing portion 12 is disposed exposed from the distal end of the cannula portion 30 during puncturing.

[0034] The needle shaft 11 corresponds to the main body of the needle 10, and has a lumen 21a that communicates with the lumen 31a of the hub 20 or the cannula 30. A proximal end opening 15 is formed at the proximal end of the needle shaft 11. The needle shaft 11 is connected to the hub 20 via the proximal end opening 15 so as to be able to communicate with it.

[0035] The needle shaft 11 is formed with a length approximately equal to the overall length of the cannula 30, and is inserted through the lumen 31a of the cannula 30 and connected to the hub 20 so that the proximal opening 15 and the lumen 21a of the hub 20 are in communication with each other. However, the needle shaft 11 may be shorter than the overall length of the cannula 30, with the proximal end disposed within the lumen 31a of the cannula 30. In this configuration, the substance A to be administered flows through the lumen 31a of the cannula 30 to the proximal opening 15.

[0036] The puncturing portion 12 is formed at the distal end of the needle shaft portion 11. A needle tip portion 12a is formed at the distal end of the puncturing portion 12. The needle tip portion 12a has an open end with a blade surface 13 formed by cutting the needle shaft portion 11 at an angle relative to the longitudinal direction at the distal end. The inner edge of the blade surface 13 defines a distal opening 14 that connects the inner cavity of the needle shaft portion 11 to the outside. When administering the subject A, the distal opening 14 is positioned within the sieve hole X3 or beyond the sieve plate X2 into the ventricle with the puncturing portion 12 positioned within the sieve hole X3 (i.e., with at least a portion of the puncturing portion 12 punctured into the sieve hole X3). Even if the distal opening 14 slightly reaches the brain tissue B beyond the sieve plate X2, damage to the brain tissue B is avoided as long as it does not come into direct contact with the olfactory bulb Y1, etc. By being positioned at least within the sieve holes X3 or beyond the sieve plate X2 into the ventricle, the substance A to be administered can flow toward the brain against the cerebrospinal fluid C flowing out from the sieve holes X3. The needle tip 12a is not limited to a pointed shape with a cutting edge 13 at the tip, but may also be a straight cylindrical shape or a cylindrical shape with a rounded, approximately hemispherical tip.

[0037] From the viewpoints of ease of puncturing the sieve holes X3 and the delivery of the substance A to be administered, the puncturing portion 12 has an outer diameter of 0.1 mm to 2.1 mm, more preferably 0.1 mm to 1.2 mm. The overall length of the puncturing portion 12, which is the axial length of the blade surface 13 shown in FIG. 1 (corresponding to the exposed length from the tip of the cannula portion 30 of the needle portion 10), is at least long enough to allow the tip opening 14 to be positioned within the sieve holes X3, and is 0.25 mm to 5.4 mm. The overall length of the puncturing portion 12 is the longitudinal length of the portion exposed from the cannula portion 30 of the needle portion 10, and is the length from the tip of the needle tip portion 12a along the longitudinal direction of the needle portion 10. The length of the puncturing portion 12 can be appropriately set depending on the thickness of the olfactory mucosa Y2 of the mammal to be punctured, the overall length of the sieve holes X3, etc.

[0038] The needle portion 10 can be made of a metal material such as stainless steel (e.g., SUS304 or SUS316L), titanium, or a resin material. However, the material of the needle portion 10 is not particularly limited as long as it is usable in the medical field and suitable for the needle portion 10, in addition to the materials mentioned above.

[0039] Furthermore, in order to improve the ease of puncturing the sieve holes X3, the needle portion 10 may be formed from a plastically deformable material or a shape-memory material, and when using the device, the orientation of the puncturing portion 12 may be changed to deform the needle shaft portion 11. In this case, the shape of the needle portion 10 may be deformed into any shape immediately before use, may be deformed in advance, or may be deformed in advance and then fine-tuned when used.

[0040] Furthermore, the needle portion 10 may use different materials for the puncture portion 12 exposed from the cannula portion 30 and the needle shaft portion 11. For example, the needle portion 10 may be made of a rigid material that does not or is difficult to deform so that the puncture portion 12 punctures the olfactory mucosa or the like, and the needle shaft portion 11 may be made of a material that can be deformed to match the shape of the guide catheter 100, etc.

[0041] <Hub portion> The hub portion 20 holds the base end of the needle shaft portion 11 of the needle portion 10 and / or the base end of the cannula portion 30 to allow the administration subject A to flow through. The hub portion 20 has a main body portion 21 and a connecting portion 22. The hub portion 20 is connected to the storage portion 40 in a state in which the tip opening 42a of the storage portion 40 and the base end opening 15 of the needle portion 10 are in communication with each other.

[0042] The main body portion 21 has an inner cavity 21a through which the subject A can flow, and connects the tip opening 42a of the connected storage portion 40 with the base opening 15 of the needle shaft portion 11 of the needle portion 10 or the inner cavity 31a of the cannula portion 30.

[0043] Connection part 22 is provided on the proximal end side of hub part 20 and connects to storage part 40 to maintain communication between hub part 20 and storage part 40. In the present embodiment, connection part 22 is connected to storage part 40 via a connecting member 50 such as a tube. However, connection part 22 may be of a type (such as a luer taper type or luer lock type) that matches the shape of the distal end side of storage part 40 so that the two are directly and detachably fitted together. Connection part 22 is not particularly limited as long as it is of a type that connects at least storage part 40 and hub part 20 so that the administration subject A can flow therethrough.

[0044] <Cannula Portion> The cannula portion 30 is a tubular member made of a flexible material, and has a tubular main body portion 31 having a lumen 31a that communicates from the distal end to the proximal end. As an example, the cannula portion 30 holds at least a part of the needle shaft portion 11 of the needle portion 10.

[0045] A stopper portion 32 having an abutment portion 32a that comes into contact with the olfactory epithelium Y3 of the olfactory mucosa Y2 is provided at the tip of the main body portion 31 of the cannula portion 30. In the embodiment shown in Fig. 1 , the stopper portion 32 is the tip portion of the main body portion 31, and the tip surface of the main body portion 31 functions as the abutment portion 32a. Note that in this embodiment, the stopper portion 32 is the tip portion of the main body portion 31, and the abutment portion 32a is the tip surface of the main body portion 31. However, the stopper portion 32 and the abutment portion 32a are not limited to these configurations, and the stopper portion 32 may be formed as a separate, detachable or fixed member that can be arranged on the tip side of the cannula portion 30, and the abutment portion 32a may be formed as a portion of this separate member that comes into contact with the olfactory epithelium Y3.

[0046] When the puncturing portion 12 of the needle portion 10 punctures the sieve hole X3, the stopper portion 32 functions as a stopper that prevents the needle tip portion 12a of the puncturing portion 12 from puncturing too deeply by bringing the abutment portion 32a into contact with the olfactory epithelium Y3 as shown in Figure 2.

[0047] Furthermore, when the needle 10 is puncturing the olfactory epithelium Y3, the stopper 32 brings the abutment portion 32a into contact with the olfactory epithelium Y3, thereby stabilizing the puncture position of the nasal administration device 1. This allows the needle 10 to puncture the sieve hole X3 to be punctured without misalignment. Note that the stopper 32 is preferably pressed against the olfactory epithelium Y3 so as to slightly sink into it, so that the puncture position of the nasal administration device 1 is fixed.

[0048] When the contact portion 32a is the distal end surface of the cannula portion 30, the length (maximum width) of the longest radial portion of the distal end surface of the cannula portion 30 is preferably a minor axis of 0.2 mm to 3.0 mm and a major axis of 0.2 mm to 15 mm when the cross-sectional shape of the cannula portion 30 is approximately circular (e.g., elliptical) similar to the structure of the upper nasal cavity. When the cross-sectional shape of the cannula portion 30 is circular, the diameter of the contact portion 32a is preferably 0.2 mm to 3.0 mm, and more preferably 0.2 mm to 2.1 mm. The maximum width of the contact portion 32a can be appropriately set to be at least larger than the diameter of the needle portion 10 so as to perform the stopper function of preventing the needle portion 10 from over-puncturing the sieve hole X3.

[0049] The cannula portion 30 may be formed in a straight cylindrical shape, or may be partially curved in order to facilitate insertion of the needle portion 10 into the sieve hole X3. Alternatively, the cannula portion 30 may be formed entirely or partially from a material that can be plastically deformed into any shape in order to facilitate insertion into the nasal cavity Z1 and insertion of the needle portion 10 into the sieve hole X3. This allows the cannula portion 30 to be deformed to fit the shape of the lumen of the guide catheter 100 when an insertion aid is used to guide the nasal administration device 1, such as the guide catheter 100, to the olfactory mucosa Y2.

[0050] The cannula portion 30 has a length such that its base end is exposed from the external nares and its tip can be inserted into the olfactory mucosa Y2 near the cribriform plate X2 to allow manipulation of the needle tip portion 12a, and has a total length of 55 mm to 410 mm.

[0051] The cannula portion 30 may be arranged so as to cover the entire length of the needle shaft portion 11 of the needle portion 10, or may be arranged so that the base end side of the needle shaft portion 11 is exposed.

[0052] The cannula portion 30 may be configured to be disposed integrally with the hub portion 20 or may be configured to be detachable from the hub portion 20 .

[0053] <Storage section> Storage section 40 stores the substance A to be administered to sieve hole X3. Storage section 40 has a storage space 41 that stores the substance A, and a liquid delivery section 42 that delivers the substance A in storage space 41 to hub section 20. In Figure 1, storage section 40 is connected to hub section 20 via a connecting member 50 such as a tube so that the substance A can flow through it.

[0054] The storage unit 40 is connected to the hub unit 20 so as to be able to communicate with the needle unit 10. A tip opening 42a of the liquid delivery unit 42 formed at the tip of the liquid delivery unit 42 communicates with the base opening 15 of the needle unit 10 through the lumen 21a of the hub unit 20. This allows the subject A stored in the storage unit 40 to flow to the needle shaft 11. The storage unit 40 is preferably configured so that the amount of the subject A stored in the storage space 41 can be adjusted, and for example, a syringe with a plunger or the like can be used. Note that the storage unit 40 is not limited to a syringe, and any device that can store at least the subject A and allow the subject A to flow to the needle unit 10 via the hub unit 20 may be used. Furthermore, the storage unit 40 may be connected so as to be able to communicate with the liquid delivery unit 42 and the hub unit 20 when attached to a medical device having an operation unit that can control the amount and timing of the subject A to be delivered.

[0055] When the nasal administration device 1 is inserted into the nasal cavity Z1 and the needle portion 10 is inserted into the sieve hole X3, the puncture angle is preferably between 0° and 48° relative to the opening surface of the nasal cavity-side opening of the sieve hole X3. Here, the puncture angle of "0°" refers to the puncture angle when the needle portion 10 is perpendicular to the opening surface of the nasal cavity-side opening of the sieve hole X3.

[0056] <Substance to be administered> Substance to be administered A is contained in the container 40 and administered transnasally into the brain of a mammal. Substance to be administered A is released through the tip opening 14 of the puncture part 12 arranged in the cribriform plate X2 and delivered to brain tissue B through the sieve holes X3. Substance to be administered A can also be said to be "an substance to be administered transnasally into the brain of a mammal through the tip opening using a nasal administration device having a puncture part protruding toward the tip side and a tip opening provided in the puncture part, with the puncture part arranged in the cribriform plate."

[0057] The substance to be administered A is, for example, a drug (liquid) intended to treat a specific disease. The drug contains at least one of a low-molecular-weight drug, a peptide, a protein, an antibody, and a cell. These ingredients are preferably suitable for administration to brain tissue B, with peptides, proteins, and antibodies being particularly preferred. Suitable compounds contained in the drug include cerliponase alpha, chloroprocaine hydrochloride, cytarabine, baclofen, ziconotide, remodulin, nalmefene hydrochloride, idursulfase beta, and the like. Suitable examples of the drug include therapeutic agents for central nervous system (CNS) diseases such as epilepsy, Huntington's disease, and Parkinson's disease, and diagnostic agents such as contrast agents and radiopharmaceuticals. The substance to be administered A is not limited to drugs intended for treatment or diagnosis, but may also be a composition that can be administered into the brain to improve or enhance the function of brain tissue B. The substance may also be encapsulated in a transport carrier such as microbubbles, liposomes, or exosomes.

[0058] <Guide Catheter> The guide catheter 100 is used as an insertion aid when inserting the nasal administration device 1 into the nasal cavity Z1.

[0059] As shown in FIG. 1, the guide catheter 100 has a catheter body 110 made of a tubular member having a lumen 111 passing through in the longitudinal direction from the distal end to the proximal end.

[0060] The guide catheter 100 can be made of a material such as metal or resin that can be used in the medical field, and as an example, SUS304 can be used.

[0061] The distal end of the catheter main body 110 may be provided with a curved portion disposed adjacent thereto that curves toward the distal end so as to move away from the axis of the catheter main body 110. In addition, the outer surface of the guide catheter 100 may be subjected to a circumferential process such as a spiral cut or various surface processes to improve insertability.

[0062] The catheter body 110 may be used in a straight state as shown in FIG. 1, or may be configured to be pre-shaped to facilitate insertion into the nasal cavity Z1, or may be configured to be plastically deformable by fine adjustment before or during use.

[0063] Here are examples of dimensions of the guide catheter 100. The guide catheter 100 can have a total length of 400 mm, an outer diameter of 2.1 mm, an inner diameter of 1.9 mm, and a bending angle of the curved portion 113 of 45°. Alternatively, the guide catheter 100 can have a total length of 90 mm, an outer diameter of 0.82 mm, an inner diameter of 0.68 mm, and a bending angle of the curved portion 113 of 45°.

[0064] The guide catheter 100 can be supplied to the market in combination with the nasal administration device 1 as a nasal administration system 200. In addition, the nasal administration device 1 or the guide catheter 100 can function as the nasal administration system 200 by utilizing either the nasal administration device 1 or the guide catheter 100 that is already supplied separately.

[0065] [Method of Using the Device] Next, a method of using the nasal administration device 1 described above will be described. The method of use described below includes a procedure corresponding to a preparatory stage from placing the nasal administration device 1 in a predetermined position until administration of the substance A to be administered is started, and a procedure of administering the substance A after the preparatory stage. The method of using the nasal administration device 1 includes the steps of inserting the nasal administration device 1 through at least the external nostril and puncturing the olfactory mucosa Y2 with the needle portion 10 and puncturing the cribriform hole X3 of the cribriform plate X2 to position the puncturing portion 12 within the cribriform plate X2, positioning the tip opening 14 within the cribriform hole X3 or beyond the cribriform plate X2 into a ventricle with the puncturing portion 12 positioned within the cribriform plate X2, and administering the substance A to be administered into the brain via the tip opening 14.

[0066] As shown in Figure 3A, a user such as a doctor inserts the nasal administration device 1 from the patient's external nostril toward the olfactory mucosa Y2. When inserting the nasal administration device 1 into the nasal cavity Z1, the patient's nose is anesthetized and the insertion position is confirmed using a rigid endoscope or the like. The nasal administration device 1 can be inserted using a straight instrument such as a rigid endoscope, or the device alone can be inserted directly into the nasal cavity Z1, or an insertion aid such as a guide catheter 100 can be used.

[0067] Next, as shown in FIG. 3B, the user inserts the needle portion 10 into the olfactory mucosa Y2 (the olfactory epithelium Y3, then the lamina propria Y4).

[0068] Next, as shown in FIG. 3C , the user further advances the needle portion 10 through the olfactory mucosa Y2, causing the needle tip 12a of the puncturing portion 12 to puncture the sieve hole X3. At this time, the abutment portion 32a of the stopper portion 32 of the cannula portion 30 contacts the olfactory epithelium Y3, thereby restricting the puncturing movement of the needle portion 10 and preventing the needle portion 10 from over-puncturing the sieve hole X3. Furthermore, when the stopper portion 32 is pressed against the olfactory epithelium Y3, the puncturing position of the nasal administration device 1 is stabilized, allowing the puncturing portion 12 to puncture the target sieve hole X3 without misalignment. When the puncturing portion 12 completes puncturing the sieve hole X3 and the tip opening 14 is positioned within the sieve hole X3 or beyond the sieve plate X2 and into the ventricle, the nasal administration device 1 can begin administering the substance A. FIG. 3C shows the tip opening 14 positioned within the sieve hole X3.

[0069] 3D , the user administers the substance A contained in the container 40. If the container 40 is a syringe, the user operates the plunger manually or using a syringe pump or the like to administer the substance A in the amount required for administration. As a result, the substance A is administered through the tip opening 14 of the puncture part 12 into the sieve holes X3. After administering the substance A, the user removes the nasal administration device 1 from the nasal cavity Z1, completing the series of processes.

[0070] As shown in Fig. 3E, the substance A administered into the sieve hole X3 flows toward the olfactory bulb side opening of the sieve hole X3 and is delivered to brain tissue B via delivery media such as cerebrospinal fluid C and olfactory nerve Y5. Note that in Figs. 3D and 3E, the cerebrospinal fluid C is not shown to make it easier to understand the flow of the substance A administered after administration.

[0071] As described above, the nasal administration device 1 of this embodiment is a nasal administration device 1 that includes a needle portion 10 having a puncture portion 12 for delivering the substance A to be administered transnasally into the brain of a mammal, and when the puncture portion 12 is positioned within the cribriform plate X2, the substance A to be administered is administered into the brain through the opening (tip opening 14) of the puncture portion 12.

[0072] With this configuration, the puncture unit 12 is punctured through the sieve hole X3 in the cribriform plate X2, and the distal end opening 14 provided in the puncture unit 12 is positioned within the sieve hole X3 or beyond the sieve plate X2 into the ventricle, and then the substance A to be administered, such as a drug, is administered through the distal end opening 14. This allows the substance A to be minimally invasively delivered to brain tissue B via a delivery medium such as cerebrospinal fluid C or the olfactory nerve Y5. In particular, when the substance A is a high-molecular-weight therapeutic drug, such as a protein or antibody, which is currently difficult to administer to brain tissue B, the substance A can be efficiently delivered to brain tissue B while avoiding the blood-brain barrier. Furthermore, because the substance A is administered through the olfactory mucosa Y2, which is rich in blood vessels and lymphatic vessels, and into the sieve hole X3 formed in the sieve plate X2, leakage into the nasal cavity Z1 is suppressed, and the amount of the substance A flowing into the blood vessels and lymphatic vessels is minimized. Furthermore, the present invention enables the substance A to be delivered to the brain in a minimally invasive and extremely efficient manner, compared to the intrathecal administration method, nasal spray method, and intraventricular administration method, which are conventionally known methods for delivering the substance A to brain tissue B.

[0073] The nasal administration system 200 of this embodiment includes the above-mentioned nasal administration device 1 and a guide catheter 100 having an inner cavity 111 through which at least a portion of the nasal administration device 1 can be inserted and removed, and guiding the needle portion 10 of the nasal administration device 1 inserted into the inner cavity 111 to the sieve hole X3 of the cribriform plate X2.

[0074] With this configuration, when the nasal administration device 1 is inserted into the nasal cavity Z1, the puncture portion 12 of the needle portion 10 can be guided into the sieve hole X3, allowing the nasal administration operation to be performed safely and accurately.

[0075] The effects of the present invention will be explained using the following examples and comparative examples, although the technical scope of the present invention is not limited to the following examples.

[0076] [Test 1] Test 1 used rat cadavers as subjects, and administered intranasally to the cribriform foramina of the cribriform plate (Example) and to the olfactory mucosa (Comparative Example), and evaluated whether or not the administered substance leaked into the nasal cavity in each sample.

[0077] The nasal administration device 1 produced in Test 1 had the following specifications: Figure 4 shows a structural diagram of the nasal administration device produced in Test 1.

[0078] The needle portion 10 was a 27G needle with a hub (product name: Blunt Needle 27G x 1 1 / 2, manufactured by Nipro Corporation) with an outer diameter of 0.4 mm and an inner diameter of 0.23 mm, cut 15 mm from the base end, and the needle tip (outer diameter 0.1 mm, inner diameter 0.06 mm, total length 15 mm, blade length 0.1 mm, made of SUS304) was attached to the 27G needle so that the exposed length was 2 mm (2000 μm). A microsyringe (product name: Gastight Syringe 1710TLL, manufactured by Hamilton) was attached to the base end of the hub portion 20 as the storage portion 40. The cannula portion 30 was a cut 27G needle. The exposed length of the needle tip corresponds to the total length of the puncture portion.

[0079] Test 1 was carried out according to the test procedure shown below.

[0080] First, male rats (slc: SD rats (23 weeks old), manufactured by Nippon SLC) were euthanized with carbon dioxide. The tip of the nose was resected using a router so that the puncture site could reach the area deep inside the olfactory epithelium where the olfactory nerves are concentrated.

[0081] Next, a benchtop precision universal testing machine (product name: Autograph AGS-X 1kNX, manufactured by Shimadzu Corporation) FORCE TRANSDUCER (product name: SSM-DAM-1000N, manufactured by Shimadzu Corporation) was used to press the needle of the device against the olfactory epithelium at 0.8 N in one of the subject's nostrils, stopping the device at that position.

[0082] Next, using a small benchtop tester (product name: Autograph EZ-SX 500N, manufactured by Shimadzu Corporation) FORCE TRANSDUCER (model number: SMT1-5N, manufactured by Shimadzu Corporation), the aforementioned microsyringe was operated to administer 30 μL of contrast agent (product name: Isovist Injection 240, manufactured by Bayer Yakuhin Co., Ltd.) at 20 μL / min, and the sample was allowed to stand for 5 minutes. The cribriform foramen was located near the skull (total length approximately 2 mm) where the olfactory nerves are concentrated deep inside the olfactory epithelium.

[0083] After leaving the specimens to stand for 5 minutes, each specimen was imaged using a tabletop micro-CT system (product name: Skyscan 1272, manufactured by Bruker Japan Co., Ltd.) to confirm the presence or absence of leakage of the contrast agent into the nasal cavity. The measurement conditions for the micro-CT system were rotation 0.5°, 360° imaging, filter Ai 0.5mm + Cu 0.038mm, pixel count 1344 x 896, resolution 15μm, and the image construction conditions were a contrast threshold of 0-0.055 (Log). The positions of the skull, cribriform plate, and needle were confirmed from the image, and it was confirmed whether the tip opening of the puncture part was located within the cribriform plate, where the olfactory nerves are concentrated, i.e., within the cribriform foramen.

[0084] In the "Example" and "Comparative Example" in Test 1, the needle puncture status was not confirmed in real time, and the contrast agent to be administered was administered with the needle punctured toward the area where the olfactory nerves are concentrated. The contrast images were confirmed using a micro-CT system, and the example in which the contrast agent was administered with the puncture part of the needle puncturing the cribriform foramen was designated an "Example," while the example in which the contrast agent was administered with the puncture part not reaching the cribriform foramen but positioned in the olfactory mucosa just before it was designated a "Comparative Example." The reason for the comparative example is thought to be that the puncture pressure was constant (0.8 N) in both the Example and the Comparative Example, and therefore the puncture angle of the needle relative to the cribriform plate prevented the cribriform foramen from being punctured.

[0085] The results of Test 1 were as follows:

[0086] FIG. 5 is a diagram showing the cross-sectional positions when the test results of Test 1 were captured, FIG. 6 is a photograph of an example of Test 1 after administration of the administered substance (contrast agent), and FIG. 7 is a photograph of a comparative example of Test 1 after administration of the administered substance (contrast agent). As shown in FIG. 5, the photograph of the example shown in FIG. 6 and the photograph of the comparative example shown in FIG. 7 are photographs taken when the rat, the subject, is cut along a section line (line D-D') extending from the mouth to the occipital side. FIG. 6(a) is a CT image illustrating the distribution of the contrast agent in the example, and FIG. 6(b) is a CT image illustrating the puncture state of the nasal administration device in the example. FIG. 7(a) is a CT image illustrating the distribution of the contrast agent in the comparative example, and FIG. 7(b) is a CT image illustrating the puncture state of the nasal administration device in the comparative example. Note that the images shown in FIGS. 6(a) and 7(a) are 3D data, and the images shown in FIGS. 6(b) and 7(b) are 2D data, and both are images of the vicinity of position A1 shown in FIG. 5.

[0087] As shown in Fig. 6(b), the sample serving as the example was administered with the tip opening of the puncturing portion 12 puncturing the cribriform hole X3 of the cribriform plate X2, and therefore, as shown in Fig. 6(a), the contrast agent to be administered A was administered through the tip opening and migrated toward the brain tissue B, with no leakage into the nasal cavity Z1. In contrast, as shown in Fig. 7(b), the sample serving as the comparative example was administered with the puncturing portion 12 puncturing the olfactory mucosa Y2, and therefore, as shown in Fig. 7(a), most of the contrast agent after administration leaked into the nasal cavity Z1, with almost no migration toward the brain tissue B.

[0088] As described above, the results of Test 1 confirmed that when the tip opening 14 of the puncture part 12 was placed in the sieve hole X3 formed in the sieve plate X2, the substance A administered through the tip opening 14 was administered to the brain tissue B side without leaking into the nasal cavity Z1. Since the sieve hole X3 has a nasal cavity-side opening and an olfactory bulb-side opening and communicates only with the nasal cavity Z1 side and the olfactory bulb Y1 side, if the substance A does not leak into the nasal cavity Z1, it can be determined that the substance A has been delivered to the olfactory bulb Y1 side, which is brain tissue B. Therefore, if the substance A is administered using the nasal administration device 1 of the present invention with the tip opening 14 of the puncture part 12 placed in the sieve hole X3 of the sieve plate X2, the substance A can be administered with a fluid pressure that opposes the flow of cerebrospinal fluid C seeping through the sieve hole X3, and it can be said that the substance A can be efficiently delivered to the brain tissue B while preventing leakage into the nasal cavity Z1. Furthermore, since the structure of the sieve pores X3 of the rats used as subjects in Test 1 and humans is equivalent, the results of Test 1 indicate that if the subject A is administered nasally to the human brain using the nasal administration device of the present invention, the subject A can be efficiently delivered to brain tissue B.

[0089] [Test 2] Test 2 used live cynomolgus monkeys as subjects, and administered intranasally to the cribriform foramina of the cribriform plate (Example) and to the olfactory mucosa (Comparative Example), and evaluated whether or not the administered substance leaked into the nasal cavity in each subject.

[0090] The nasal administration device in Test 2 had the following specifications: Figure 8 shows a structural diagram of the nasal administration device 1 ((a) in the figure) and guide catheter 100 ((b) in the figure) prepared in Test 2.

[0091] Two types of nasal administration devices 1 were prepared, each with a different exposed length of the needle tip (exposed length 0.3 mm and 3 mm).

[0092] First, an inner catheter (made of PEEK) with an outer diameter of 0.47 mm, an inner diameter of 0.37 mm, and a total length of 165 mm was inserted into an outer catheter (made of PEEK) with an outer diameter of 0.6 mm, an inner diameter of 0.52 mm, and a total length of 155 mm. The inner catheter was then bonded with UV adhesive with 1 mm of the inner catheter exposed distally from the outer catheter to create a double-lumen catheter. Next, an 18G hub-equipped needle (product name: Terumon Bevel Needle 18G1 1 / 2, manufactured by Terumo Corporation) was cut 10 mm from the base end. The inner catheter of the double-lumen catheter was then inserted into the needle tube from the tip of the cut hub, with the 1 mm of the inner catheter exposed distally, and the gap was bonded with UV adhesive. Next, the tip of the inner catheter was cut at the end of the double-lumen catheter opposite the end bonded to the hub needle, so that 7 mm of the inner catheter was exposed from the outer catheter. Next, the step between the catheters near the cut portion was filled in with an epoxy adhesive (product name: Bondquick 30, manufactured by Konishi Co., Ltd.) to smooth out the gap, thereby producing a double-lumen catheter structure. The hub portion 20 of the produced nasal administration device 1 was the hub portion of the 18G hub-equipped needle described above, and the cannula portion 30 was composed of a double-lumen catheter.

[0093] Two types of devices were fabricated by bonding the needle tip (outer diameter 0.1 mm, inner diameter 0.06 mm, total length 15 mm, blade length 0.1 mm, made of SUS304) with UV adhesive so that the exposed length from the tip of the inner catheter in the hub part of the above configuration was 0.3 mm and 3 mm. A microsyringe (product name: Gastight Syringe 1710TLL, manufactured by Hamilton) was attached as the storage part 40 to the proximal end side of the hub part 20 of each device.

[0094] The fabricated device was inserted into the nasal cavity using a guide catheter 100 as an insertion aid. The guide catheter 100 was made of SUS304, had a total length of 90 mm, an outer diameter of 0.82 mm, an inner diameter of 0.68 mm, and a bend angle of 45° at the curved tip. The guide catheter used had a spiral cut on the straight part to give it flexibility and make it bendable.

[0095] Test 2 was carried out according to the test procedure shown below.

[0096] First, a male cynomolgus monkey (3 years and 10 months old) was anesthetized. The anesthetics and administration methods were as follows: Induction anesthesia: Ketalar intramuscular injection 500 mg, administration route: intramuscular administration, dosage: 10 mg / kg (0.2 mL / kg); Maintenance anesthesia: Propofol injection for animals 1% "Mylan", administration route: intravenous administration, dosage: 0.5-30 mg / kg / hour (0.05-3 mL / kg / hour).

[0097] Next, a 16-channel X-ray CT scanner (product name: Bright Speed ​​Elite, manufactured by GE Healthcare) was used to perform imaging, and a guide catheter was inserted into one of the subject's nasal cavities while checking the contrast image. During insertion, the opening at the tip of the guide catheter was oriented toward the cribriform plate, and the tip was positioned immediately below the cribriform plate.

[0098] Next, the fabricated device was inserted into a guide catheter, and the olfactory mucosa was punctured by the exposed length of the puncture site. The aforementioned microsyringe was then operated to administer 30 μL of contrast agent (product name: Isovist Injection 240, Bayer Yakuhin Co., Ltd.) at 20 μL / min using a microsyringe pump (product name: IC3200, KD Scientific). Immediately after administration, the contrast agent was visualized using the aforementioned X-ray CT scanner to confirm administration of the contrast agent to the olfactory mucosa. Furthermore, by confirming that the guide catheter was not moving, it was confirmed that the puncture site had penetrated the cribriform foramen.

[0099] The results of Test 2 were as follows:

[0100] FIG. 9 is a diagram showing the cross-sectional position when the test results of Test 2 were captured, FIG. 10 is a photograph of an example of Test 1 after administration of the substance to be administered (contrast agent), and FIG. 11 is a photograph of a comparative example of Test 1 after administration of the substance to be administered (contrast agent). As shown in FIG. 9, the photograph of the example shown in FIG. 10 and the photograph of the comparative example shown in FIG. 11 are photographs taken when cut along a cutting line (E-E' line) extending from the mouth side to the occipital side. FIG. 10(a) is a CT image illustrating the distribution of the contrast agent in the example, and FIG. 10(b) is a CT image illustrating the puncture state of the nasal administration device in the example. FIG. 11(a) is a CT image illustrating the distribution of the contrast agent in the comparative example, and FIG. 11(b) is a CT image illustrating the puncture state of the nasal administration device in the comparative example.

[0101] As shown in Fig. 10(b), the sample serving as the example was administered with the tip opening of puncturing portion 12 puncturing sieve hole X3 (sieve hole length: 3.5 mm) in cribriform plate X2, so that the contrast agent to be administered A was administered through the tip opening and migrated to brain tissue B, with no leakage into nasal cavity Z1, as shown in Fig. 10(a). In contrast, as shown in Fig. 11(b), the sample serving as the comparative example was punctured into olfactory mucosa Y2, so that the contrast agent after administration leaked into nasal cavity Z1, with almost no migration to brain tissue B, as shown in Fig. 11(a).

[0102] As described above, the results of Test 2 confirmed that when the tip opening 14 of the puncture part 12 was placed in the sieve hole X3 formed in the sieve plate X2, the substance A administered through the tip opening 14 was administered to the brain tissue B side without leaking into the nasal cavity Z1. Since the sieve hole X3 has a nasal cavity-side opening and an olfactory bulb-side opening and communicates only with the nasal cavity Z1 side and the olfactory bulb Y1 side, if the substance A does not leak into the nasal cavity Z1, it can be determined that the substance A has been delivered to the olfactory bulb Y1 side, which is brain tissue B. Therefore, if the substance A is administered using the nasal administration device 1 of the present invention with the tip opening 14 of the puncture part 12 placed in the sieve hole X3 of the sieve plate X2, the substance A can be administered with a fluid pressure that opposes the flow of cerebrospinal fluid C seeping through the sieve hole X3, and it can be said that the substance A can be efficiently delivered to brain tissue B while preventing leakage into the nasal cavity Z1. Furthermore, since the structure of the sieve pores X3 of the cynomolgus monkeys, which were the subjects of Test 2, and humans are equivalent, the results of Test 2 indicate that if the subject A is administered nasally to the human brain using the nasal administration device of the present invention, the subject A can be efficiently delivered to brain tissue B.

[0103] This application is based on Japanese Patent Application No. 2024-017855, filed on February 8, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0104] DESCRIPTION OF SYMBOLS 1 Nasal administration device, 10 Needle portion (10a lumen), 11 Needle shaft portion, 12 Puncture portion (12a needle tip portion), 13 Blade surface, 14 Tip opening, 15 Base opening, 20 Hub portion 21 Main body portion (21a lumen), 22 Connection portion, 30 Cannula portion, 31 Main body portion, 32 Stopper portion (32a abutment portion), 40 Storage portion, 41 Storage space, 42 Liquid delivery portion (tip opening 42a), 50 Connection member, 100 Guide catheter, 110 Catheter main body, 111 Lumen, 200 Nasal administration system, A Subject to administration, B Brain tissue, C Cerebrospinal fluid (CSF), X1 Ethmoid bone, X2 Cribrosa plate, X3 Cribrosa foramen Y1 olfactory bulb, Y2 olfactory mucosa, Y3 olfactory epithelium, Y4 lamina propria, Y5 olfactory nerve, Z1 nasal cavity.

Claims

1. A nasal administration device comprising a needle with a puncture part for delivering a substance to be administered transnasally into the brain of a mammal, wherein the substance to be administered is administered into the brain through the opening of the puncture part when the puncture part is positioned within the cribriform plate.

2. The nasal administration device described in claim 1, wherein the puncture portion is positioned within the cribriform plate by inserting it into a cribriform hole formed in the cribriform plate through which the olfactory nerve extends from the olfactory bulb to the olfactory mucosa.

3. The nasal administration device of claim 1, wherein the nasal administration device has a cannula portion composed of a tubular member and positioned to cover the needle portion so that the puncture portion is exposed, the opening is provided on the tip side of the puncture portion, the tip of the cannula portion is formed with a stopper portion having an abutment portion that abuts against the olfactory epithelium of the olfactory mucosa, and the opening is positioned within the cribriform plate with the abutment portion of the stopper portion in contact with the olfactory epithelium.

4. The nasal administration device according to claim 3, wherein the nasal administration device has a hub portion to which a storage portion containing the substance to be administered can be attached, and the hub portion holds the base end of the cannula portion and / or the base end of the needle shaft portion of the needle portion inserted through the inner cavity of the cannula portion.

5. A nasal administration device as described in claim 1, wherein the needle tip of the puncture part is an open end with a blade surface on the tip side, and the total length of the puncture part is 0.25 mm or more and 5.4 mm or less.

6. The nasal administration device of claim 3, wherein the total length of the cannula portion is 55 mm or more and 410 mm or less.

7. A nasal administration device as described in claim 3, wherein the abutment portion of the stopper portion is the tip surface of the cannula portion that contacts the olfactory epithelium, the length of the longest radial portion of the abutment portion is 0.2 mm or more and 15 mm or less, and the outer diameter of the base end side of the puncture portion is 0.1 mm or more and 2.1 mm or less.

8. The nasal administration device described in claim 3, wherein the cross-sectional shape of the abutment portion of the stopper portion is circular or elliptical.

9. The nasal administration device of claim 1 or 2, which has a storage section that stores the substance to be administered and is configured so that the substance stored in the storage section can be discharged through the opening of the puncture section.

10. A nasal administration system comprising: a nasal administration device according to any one of claims 1 to 9; and a guide catheter having an insertable and retractable lumen in at least a portion of the nasal administration device, which guides the needle portion of the nasal administration device inserted into the lumen into the cribriform hole formed in the cribriform plate.

Images