WO2025170026A1 - Nasal administration device and nasal administration system - Google Patents

Abstract

[Problem] To effectively deliver a to-be-administered substance to inside the brain of a mammal in a minimally invasive manner. [Solution] A nasal administration device 1 comprises a needle 10 having a puncture section 12 for transnasally delivering a to-be-administered substance A to inside the brain of a mammal. In a state where an opening section (tip opening section 14) of the puncture section 12 is disposed in a cribriform foramen X3 and where the proportion of the puncture length of the tip of the opening section (tip opening section 14) of the puncture section 12 in the cribriform foramen X3 relative to the entire length between the nasal cavity-side opening and the olfactory bulb-side opening of the cribriform foramen X3 is 60-100%, the to-be-administered substance A is administered inside the brain through the opening section.

Description

Nasal administration device, nasal administration system

The present invention relates to a nasal administration device and nasal administration system that administers a substance such as a drug intranasally and delivers it to the brain of a mammal.

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.

Research is underway into drug delivery via cerebrospinal fluid (CSF) as a more effective method of administering drugs to the brain than oral or intravenous administration. Currently known methods include nasal spray, in which drugs are sprayed into the nasal cavity; intraventricular administration, in which drugs are administered directly into the ventricles of the brain; and intrathecal administration, in which drugs are injected into the spinal canal.

However, although the nasal spray method is minimally invasive, it has an extremely low drug penetration rate. Intraventricular administration involves drilling the skull and administering directly to 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 to achieve medicinal effects, and it cannot be considered minimally invasive, so there are many challenges to overcome before it can be put into practical use.

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

US Patent Application Publication No. 2021/0023295

The method described in Patent Document 1 involves sustained drug release under the olfactory mucosa, which is composed of the olfactory epithelium and the lamina propria, which contains many blood vessels and lymphatic vessels. Therefore, drugs are easily absorbed by the blood vessels and lymphatic vessels in the lamina propria, and lymphatic vessels in particular tend to direct the drug in the direction of excretion from the brain, limiting the amount of drug that reaches the brain.

The present inventors believed that there was room for improvement in nasal administration, which is known as a minimally invasive route for drug delivery to the brain through nasal sprays and submucosal administration of olfactory fluids, and investigated methods that could improve the rate of drug transfer into the brain. Through further investigation, the present inventors hypothesized that the low efficiency of drug delivery to the brain was due to the flow of CSF seeping from the brain into the nasal cavity, which inhibits drug delivery to the brain. They then proceeded to research a new nasal administration method that could circumvent this inhibiting factor. As a result, the present inventors discovered that the efficiency of delivery of the administered substance to the brain could be dramatically improved by administering the drug directly into the cribriform pores formed in the cribriform plate and, in addition, by appropriately controlling the penetration ratio of the tip opening formed in the needle portion of the device relative to the cribriform pores, which led to the development of the present invention.

At least one embodiment of the present invention has been made in consideration of the above 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.

The above object of the present invention is achieved by any one of the following (1) to (9):

(1) A nasal administration device equipped with a needle having a puncture portion for transnasally delivering a substance to be administered into the brain of a mammal, wherein the opening of the puncture portion is positioned within a cribriform cavity, and the substance is administered into the brain through the opening while the ratio of the puncture length of the tip of the opening into the cribriform cavity to the total length between the nasal cavity opening and the olfactory bulb opening of the cribriform cavity is between 60% and 100%.

(2) The nasal administration device described in (1) above, wherein the nasal administration device 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 that has 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.

(3) The nasal administration device according to (2) above, has a hub portion to which a container 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 lumen of the cannula portion.

(4) A nasal administration device according to any one of (1) to (3) above, wherein the needle tip of the puncture section has an open end with a cutting edge on the tip side, and the total length of the puncture section is 0.35 mm or more and 5.4 mm or less.

(5) The nasal administration device described in (2) above, wherein the total length of the cannula portion is 55 mm or more and 410 mm or less.

(6) A nasal administration device according to (2) or (3) above, wherein the contact portion of the stopper portion is the distal end surface of the cannula portion that contacts the olfactory epithelium, the radially longest portion of the contact portion has a length of 0.2 mm or more and 15 mm or less, and the outer diameter of the base end of the puncture portion is 0.1 mm or more and 2.1 mm or less.

(7) The nasal administration device described in (2) or (6) above, wherein the cross-sectional shape of the contact portion of the stopper portion is circular or elliptical.

(8) The nasal administration device according to (1) or (2) above, wherein the nasal administration device has a storage section that stores the substance to be administered, and the substance stored in the storage section is configured to be discharged through the opening of the puncture section.

(9) A nasal administration system comprising: a nasal administration device according to any one of (1) to (8) above; and a guide catheter having an insertable/removable lumen in at least a portion of the nasal administration device, the guide catheter guiding the needle portion of the nasal administration device inserted into the lumen to the cribriform hole formed in the cribriform plate.

According to the present invention, the tip opening of the puncture section is positioned within the sieve hole, and the puncture ratio of the tip of the tip opening to the total length of the sieve hole is controlled to between 60% and 100%, allowing the substance to be administered into the brain through the tip opening. This allows the substance to be delivered efficiently to brain tissue in a minimally invasive manner via a delivery medium such as cerebrospinal fluid or the olfactory nerve. This is particularly effective because it allows the 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 by bypassing the blood-brain barrier. Furthermore, the present invention administers the substance within the sieve hole formed in the cribriform plate after passing through the lamina propria of the olfactory mucosa, which is rich in blood vessels and lymphatic vessels. This allows the substance to be delivered to brain tissue by minimizing the amount of blood flowing into the blood vessels and lymphatic vessels while suppressing leakage into the nasal cavity.

FIG. 1 is a diagram showing an intranasal administration system according to this embodiment. A figure showing the needle tip of the nasal administration device puncturing the sieve hole. 1A and 1B are diagrams illustrating an example of use of the nasal administration device according to this embodiment. 1A and 1B are diagrams illustrating an example of use of the nasal administration device according to this embodiment. 1A and 1B are diagrams illustrating an example of use of the nasal administration device according to this embodiment. 1A and 1B are diagrams illustrating an example of use of the nasal administration device according to this embodiment. 1A and 1B are diagrams illustrating an example of use of the nasal administration device according to this embodiment. FIG. 1 shows the nasal administration device prepared in Test 1. 1 is a table showing the results of Test 1. 1 is a graph showing the results of Test 1. FIG. 10 is a diagram for explaining the contrast position in the CT image of Test 1. 10 is a CT image of Sample 14, an example of Test 1, after administration of the substance to be administered (contrast agent). 10 is a CT image of Sample 5, a comparative example of Test 1, after administration of the substance to be administered (contrast agent). FIG. 1 shows the nasal administration device prepared in Test 2. 10 is a table showing the results of Test 2. 10 is a graph showing the results of Test 2. FIG. 10 is a diagram for explaining the contrast position in the CT image of Test 2. 10 is a CT image of Sample 12, an example of Test 2, taken after administration of the substance to be administered (contrast agent). 10 is a CT image of Sample 3, which is a comparative example of Test 2, after administration of the substance to be administered (contrast agent). This is a table showing the specifications of the nasal administration devices used in Tests 3, 4, and 5, and the test results of each test. 10 is a CT image of Sample 14, an example of Test 3, after administration of the substance to be administered (contrast agent). 10 is a CT image of Sample 15, an example of Test 4, after administration of the substance to be administered (contrast agent). FIG. 1 shows the nasal administration device used in Test 5. 10 is a CT image of Sample 16, an example of Test 5, after administration of the substance to be administered (contrast agent).

The following describes in detail the modes for carrying out the present invention, with reference to the drawings. The embodiments shown here are illustrative examples to embody the technical ideas of the present invention, and do not limit the present invention. Furthermore, all other modes, examples, operational techniques, etc. 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.

Furthermore, for the convenience of illustration and ease of understanding, the drawings attached to this specification may be represented schematically and converted from the actual product in terms of scale, aspect ratio, shape, etc., as appropriate, but these are merely examples and do not limit the interpretation of the present invention.

In this specification, the "cribriform foramen X3" punctured by the puncture portion 12 of the needle portion 10 of the nasal administration device 1 is a foramen 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. Numerous 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 of these foramen that can be punctured by the puncture portion 12 that has penetrated the olfactory mucosa Y2.

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

As shown in Figure 1, the nasal administration system 200 includes a nasal administration device 1 and a guide catheter 100.

The nasal administration system 200 places the guide catheter 100 in the nasal cavity Z1 with the tip side facing the cribriform plate X2, inserts the nasal administration device 1 into the guide catheter 100, and places the opening (tip opening 14) of the puncture portion 12 of the needle portion 10 within the cribriform hole X3 formed in the cribriform plate X2. The nasal administration system 200 administers the substance A to the brain in a state in which the ratio of the puncture length of the tip of the tip opening 14 into the cribriform hole X3 to the total length of the cribriform hole X3 (the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the cribriform hole X3) is between 60% and 100%. 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.

<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 housing portion 40.

The nasal administration device 1 is a nasal administration device 1 equipped with 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 administers the substance A through the tip opening 14 while the opening (tip opening 14) of the puncture portion 12 is positioned within the sieve hole X3 and the ratio of the puncture length of the tip of the tip opening 14 into the sieve hole X3 to the total length of the sieve hole X3 is 60% or more and 100% or less. The nasal administration device 1 can also be described as "a nasal administration device for transnasally delivering a substance to be administered into the brain of a mammal, configured so that a tip opening provided in a puncture part located at the tip is positioned within the cribriform cavity, and substance A to be administered is administered while the ratio of the puncture length of the tip of the tip opening into the cribriform cavity to the total length between the nasal cavity opening and the olfactory bulb opening is 60% or more and 100% or less" or "a nasal administration device for use in a nasal administration method for transnasally delivering a substance to be administered into the brain of a mammal using a nasal administration device, having a puncture part protruding at the tip end and a tip opening provided in the puncture part, and the nasal administration method includes administering the substance to be administered into the brain while the tip opening is positioned within the cribriform cavity, and the ratio of the puncture length of the tip of the tip opening into the cribriform cavity to the total length between the nasal cavity opening and the olfactory bulb opening is 60% or more and 100% or less."

The nasal administration device 1 of the present invention delivers the subject A to the brain by placing the tip opening 14 of the puncture portion 12 within the sieve hole X3 and administering the subject A through the tip opening 14 into the sieve hole X3. This administration method is a novel method developed by the present inventors through extensive research to avoid the impeding factor behind the extremely low drug transfer rate to the brain achieved by known minimally invasive nasal administration methods. Administering the subject A into the sieve hole X3 using this device dramatically improves the transfer rate of the subject A to the brain. This is thought to be due to the fact that administering the subject A with the needle portion 10 punctured within the sieve hole X3 applies fluid pressure to the subject A that resists the flow of cerebrospinal fluid C and prevents it from leaking into the nasal cavity Z1. Therefore, the substance A administered into the sieve hole X3 through the tip opening 14 flows toward the brain tissue B through the olfactory bulb side opening of the sieve hole X3 against the flow of cerebrospinal fluid C, and can be delivered to the brain with an extremely high migration rate via delivery vehicles such as cerebrospinal fluid C and the olfactory nerve Y5.

Furthermore, the nasal administration device 1 administers the substance A with the tip opening 14 of the puncture portion 12 positioned within the sieve hole X3. However, to deliver the substance A to brain tissue B with high efficiency, the ratio of the puncture length (puncture amount) of the tip of the tip opening 14 to the overall length of the sieve hole X3 is also extremely important. This "puncture ratio" is obtained from the ratio of the puncture length of the tip of the tip opening 14 into the sieve hole X3 to the "total length of the sieve hole X3," which is the length of the shortest point between the nasal cavity opening and the olfactory bulb opening in the thickness direction of the sieve hole X3 (in other words, the length of the needle portion 10 puncturing the sieve hole X3, which is the ratio of the puncture length of the needle portion 10 from the tip of the needle portion 10 to the base end, including the tip opening 14).

When administering substance A into sieve hole X3, if the tip opening 14 is positioned on the nasal cavity opening side of sieve hole X3, a fluid pressure sufficient to counteract the flow of cerebrospinal fluid C seeping out of sieve hole X3 is applied. However, because the administration position is close to the nasal cavity opening, there is a possibility that some of the substance A may leak into nasal cavity Z1, which may result in insufficient effectiveness.

In order to avoid these issues, the nasal administration device 1 efficiently delivers the administered substance A to the brain while preventing leakage into the nasal cavity Z1 by positioning the tip opening 14 within the sieve hole X3 and setting the percentage of the tip of the tip opening 14 penetrating the sieve hole X3 to between 60% and 100% of the total length of the sieve hole X3. When the nasal administration device 1 sets the percentage of the tip of the tip opening 14 penetrating the sieve hole X3 to 60% or more, the substance A can be reliably administered into the sieve hole X3 without leaking into the nasal cavity Z1, and when it sets the percentage to 100% or less, damage to brain tissue B due to penetration through the olfactory bulb side opening of the sieve hole X3 can be prevented.

The aforementioned range of the penetration rate of the tip opening 14 relative to the sieve hole X3 (60% or more and 100% or less) is set to ensure that there is no or very little leakage of the administered substance A into the nasal cavity Z1 and that the administered substance A is delivered 100% successfully to the brain tissue B side. In other words, if the tip opening 14 is punctured into the sieve hole X3 with a penetration rate of 60% or more, the administered substance A can be reliably delivered to the brain tissue B side. However, when the nasal administration device 1 administers the administered substance A with the tip of the tip opening 14 punctured within the sieve hole X3, even if the penetration rate is less than 60% (e.g., 50% or more and 100% or less), the substance A can be delivered to the brain tissue B side at a higher transfer rate than conventional nasal administration methods, even if the penetration rate is less than 60% (e.g., 50% or more and 100% or less), even if the success rate does not reach 100% as with a penetration rate of 60% or more. Therefore, the nasal administration device 1 is capable of delivering the substance A to brain tissue B even if the penetration rate of the tip of the tip opening 14 is less than 60%. However, when considering administration to humans, conditions for a 100% success rate are important, so it is preferable that the penetration rate be between 60% and 100%.

The nasal administration device 1 can be used in combination with the guide catheter 100 as the nasal administration system 200, or it can be used alone.

<Needle>
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 the 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 exposed from the distal end of the cannula portion 30 during puncturing.

The needle shaft portion 11 corresponds to the main body of the needle portion 10 and has an inner cavity 21a that communicates with the inner cavity 31a of the hub portion 20 or the cannula portion 30. A base-end opening 15 is formed at the base end of the needle shaft portion 11. The needle shaft portion 11 is connected to the hub portion 20 via the base-end opening 15 so that it can communicate with the hub portion 20.

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. However, the needle shaft 11 may be shorter than the overall length of the cannula 30, with the proximal end positioned within the lumen 31a of the cannula 30. When configured in this manner, the substance to be administered A flows through the lumen 31a of the cannula 30 to the proximal opening 15.

The puncturing portion 12 is formed at the tip end of the needle shaft portion 11. A needle tip portion 12a is formed at the tip 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 to the longitudinal direction at the tip end. The inner edge of the blade surface 13 defines a tip opening 14 that connects the inner cavity of the needle shaft portion 11 to the outside. When administering the subject A, the tip opening 14 is positioned within the sieve hole X3 with at least a portion of the puncturing portion 12 puncturing the sieve hole X3. By being positioned within the sieve hole X3, the subject A can be delivered to the brain against the cerebrospinal fluid C flowing out from the sieve hole X3. Note that the needle tip portion 12a is not limited to a pointed shape with a blade surface 13 at the tip, and may be a straight cylindrical shape or a cylindrical shape with a rounded, approximately hemispherical tip.

From the viewpoint of ease of puncturing the sieve hole X3 and the delivery of the administered substance A, the puncturing portion 12 has an outer diameter of 0.1 mm to 2.1 mm, and 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 0.35 mm to 5.4 mm, long enough to position the tip opening 14 within at least the sieve hole X3. 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 set appropriately depending on the thickness of the olfactory mucosa Y2 of the mammal to be punctured, the overall length of the sieve hole X3, etc.

The needle portion 10 can be made from metals such as stainless steel (e.g., SUS304 or SUS316L), titanium, or resin materials. However, in addition to the materials mentioned above, the constituent materials of the needle portion 10 are not particularly limited as long as they are usable in the medical field and suitable for the needle portion 10.

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

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 in order to puncture the olfactory mucosa, etc., 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.

<Hub section>
The hub portion 20 holds the proximal end of the needle shaft portion 11 of the needle portion 10 and/or the proximal 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 proximal opening 15 of the needle portion 10 are in communication with each other.

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

The connection part 22 is provided on the base end side of the hub part 20 and connects to the storage part 40 to maintain communication between the hub part 20 and the storage part 40. In this embodiment, the connection part 22 is connected to the storage part 40 via a connecting member 50 such as a tube. However, the connection part 22 may also be configured to directly and detachably fit together with the shape of the tip end of the storage part 40 (e.g., luer taper type, luer lock type). The connection part 22 is not particularly limited as long as it is configured to at least connect the storage part 40 and the hub part 20 so that the administered substance A can flow through them.

<Cannula section>
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.

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 from a separate, detachable or fixed member that can be positioned on the tip side of the cannula portion 30, and the abutment portion 32a may be formed from a portion of this separate member that comes into contact with the olfactory epithelium Y3.

When the puncturing portion 12 of the needle part 10 punctures the sieve hole X3, the stopper portion 32 functions as a stopper to prevent the needle tip portion 12a of the puncturing portion 12 from puncturing too deeply by bringing the abutting portion 32a into contact with the olfactory epithelium Y3 as shown in Figure 2.

Furthermore, when the needle 10 is punctured, the stopper portion 32 stabilizes the puncture position of the nasal administration device 1 by bringing the abutment portion 32a into contact with the olfactory epithelium Y3. This allows the needle 10 to puncture the target sieve hole X3 without misalignment. Note that it is preferable that the stopper portion 32 be pressed slightly against the olfactory epithelium Y3 so that the puncture position of the nasal administration device 1 is fixed.

When the abutting portion 32a is the tip surface of the cannula portion 30, the length (maximum width) of the longest radial portion of the tip surface of the cannula portion 30 preferably has 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 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 abutting 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 abutting portion 32a can be appropriately set to be at least larger than the diameter of the needle portion 10 so that the stopper function of preventing the needle portion 10 from over-puncturing the sieve hole X3 is exerted.

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. Furthermore, the cannula portion 30 may be formed in part or entirely 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 inserted while deforming to conform to 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.

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

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

The cannula portion 30 may be configured to be integrally arranged with the hub portion 20, or may be configured to be detachable from the hub portion 20.

<Containment Unit>
Storage section 40 stores substance A to be administered to sieve hole X3. Storage section 40 has a storage space 41 that stores substance A, and a liquid delivery section 42 that delivers 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 substance A can flow therethrough.

The storage unit 40 is connected to the hub unit 20 so as to be able to communicate with the needle unit 10. The tip opening 42a of the liquid delivery unit 42, formed at the tip of the liquid delivery unit 42, is in communication with the base opening 15 of the needle unit 10 through the lumen 21a of the hub unit 20. This allows the substance 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 substance A stored in the storage space 41 can be adjusted; for example, a syringe with a plunger can be used. Note that the storage unit 40 is not limited to a syringe; it can be any device that can store at least the substance A and allow the substance A to flow to the needle unit 10 via the hub unit 20. The storage unit 40 may also be connected so that the liquid delivery unit 42 and hub unit 20 are able to communicate with each other when attached to a medical device having an operation unit that can control the amount and timing of the substance A discharged.

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, a 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.

<Subject to be administered>
The substance A to be administered is contained in the container 40 and administered transnasally into the brain of a mammal. The substance A to be administered transnasally into the brain of a mammal is released through the tip opening 14 while the tip opening 14 of the puncturing part 12 is disposed within the sieve hole X3, and the ratio of the puncture length of the tip of the tip opening 14 into the sieve hole X3 to the total length of the sieve hole X3 is 60% or more and 100% or less, where the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the sieve hole X3 is the total length of the sieve hole X3. The substance A is then delivered to brain tissue B through the sieve hole X3. The substance A to be administered can also be described as "a substance to be administered transnasally into the brain of a mammal through the tip opening using a nasal administration device having a puncture portion protruding toward the tip side and a tip opening provided in the puncture portion, with the tip opening positioned within a cribriform cavity, and the ratio of the puncture length of the tip of the tip opening into the cribriform cavity to the total length of the cribriform cavity, when the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the cribriform cavity is defined as the total length of the cribriform cavity, being 60% or more and 100% or less."

As an example, the administered substance A is 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 cells. 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, and idursulfase beta. Suitable drugs include therapeutic agents for central nervous system (CNS) disorders such as epilepsy, Huntington's disease, and Parkinson's disease, and diagnostic agents such as contrast agents and radiopharmaceuticals. The administered substance A is not limited to drugs intended for treatment or diagnosis, and may also be a composition that can be administered intracerebrally to improve or enhance the function of brain tissue B. It may also be encapsulated in a transport carrier such as microbubbles, liposomes, or exosomes.

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

As shown in Figure 1, the guide catheter 100 has a catheter body 110 made of a tubular member having an inner lumen 111 that runs longitudinally from the tip to the base end.

The guide catheter 100 can be made from materials such as metals and resins that can be used in the medical field; for example, SUS304 can be used.

The distal end of the catheter body 110 may be provided with a curved section arranged adjacent to the distal end, curving away from the axis of the catheter body 110. The outer surface of the guide catheter 100 may also be subjected to circumferential processing such as spiral cutting or various surface treatments to improve insertability.

The catheter body 110 may be used in a straight state as shown in Figure 1, or may 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.

Here are some example 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°.

The guide catheter 100 can be combined with the nasal administration device 1 and supplied to the market as a nasal administration system 200. Furthermore, 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.

[How to use the device]
Next, a method of using the nasal administration device 1 will be described.

The method of use described below includes a procedure corresponding to a preparatory stage in which the nasal administration device 1 is placed in a predetermined position and administration of the substance A to be administered is initiated, as well as a procedure for 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 at least through the external nostril and puncturing the olfactory mucosa Y2 with the needle portion 10 while puncturing the sieve hole X3 of the cribriform plate X2 to position the tip opening 14 of the puncturing portion 12 within the sieve hole X3, setting the puncture ratio, which is the ratio of the puncture length of the tip of the tip opening 14 into the sieve hole X3 to the total length of the sieve hole X3, to between 60% and 100%, when the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the sieve hole X3 is the total length of the sieve hole X3, to 60% or more and 100% or less, and administering the substance A to be administered through the tip opening 14 positioned within the sieve hole X3 at the puncture ratio.

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.

Next, as shown in Figure 3B, the user inserts the needle portion 10 into the olfactory mucosa Y2 (in the order of the olfactory epithelium Y3 and the lamina propria Y4).

Next, as shown in Figure 3C, the user further advances the needle portion 10 into 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 comes into contact with 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, and the puncturing portion 12 can be punctured without misalignment toward the sieve hole X3 to be punctured.

Furthermore, while the tip opening 14 is positioned within the sieve hole X3, the nasal administration device 1 is set in a state in which the ratio of the puncture length of the tip of the tip opening 14 into the sieve hole X3 to the total length of the sieve hole X3, where the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the sieve hole X3 is the total length of the sieve hole X3, is between 60% and 100%. When the needle portion 10 has completed puncturing the sieve hole X3 and the tip opening 14 is positioned within the sieve hole X3 at this puncture ratio, the nasal administration device 1 can begin administering the substance A to be administered.

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

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

As explained above, the nasal administration device 1 according to this embodiment is a nasal administration device 1 equipped with a needle portion 10 having a puncture portion 12 for transnasally delivering an administration substance A into the brain of a mammal, and while the puncture portion 12 is positioned within a sieve hole X3, the administration substance A is administered into the brain through the opening while the ratio of the puncture length of the tip of the opening (tip opening 14) of the puncture portion 12 into the sieve hole X3 to the total length between the nasal cavity opening and the olfactory bulb opening of the sieve hole X3 is between 60% and 100%.

With this configuration, the tip opening 14 of the puncture section 12 is positioned within the sieve hole X3, and the puncture ratio of the tip of the tip opening 14 relative to the total length of the sieve hole X3 is controlled to between 60% and 100%. By administering the subject A, such as a drug, through the tip opening 14, the subject A can be minimally invasively delivered to brain tissue B via a delivery medium such as cerebrospinal fluid C or the olfactory nerve Y5. This is particularly effective because it allows high-molecular-weight therapeutic drugs, such as proteins and antibodies, which are currently difficult to administer to brain tissue, to be efficiently delivered to brain tissue while bypassing the blood-brain barrier. Furthermore, because the subject 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 cribriform plate X2, leakage into the nasal cavity Z1 is suppressed, while the amount of the subject A flowing into the blood vessels and lymphatic vessels is minimized. Furthermore, compared to the conventional methods of administering substance A to brain tissue B, such as intrathecal administration, nasal spray, and intraventricular administration, the present invention allows substance A to be delivered to the brain in a minimally invasive and extremely efficient manner.

The nasal administration system 200 according to this embodiment includes the nasal administration device 1 described above, 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 cribriform hole X3 of the cribriform plate X2.

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 for safe and accurate nasal administration.

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.

[Test 1]
In Test 1, rat corpses were used as subjects, and nasal administration was carried out according to the puncture ratio of the puncture site relative to the cribriform foramina of the cribriform plate, and the presence or absence of leakage of the administered substance into the nasal cavity for each puncture ratio was evaluated.

The nasal administration device used in Test 1 had the following specifications. Figure 4 shows a diagram of the nasal administration device produced in Test 1. In Test 1, three types of nasal administration devices with different exposed needle tip lengths (exposed lengths of 1.1 mm, 2 mm, and 2.5 mm) were prepared.

The needle portion 10 was made by cutting a 27G needle with a hub (product name: Blunt Needle 27G x 1.5, manufactured by Nipro Corporation) with an outer diameter of 0.4 mm and an inner diameter of 0.23 mm 15 mm from the base end, and then 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) to the 27G needle so that the exposed length was 1.1 mm (1100 μm). A microsyringe (product name: Gastight Syringe 1710TLL, manufactured by Hamilton) was attached to the base end of the hub portion 20 as the housing portion 40. Similarly, devices with exposed needle tip lengths of 2 mm (2000 μm) and 2.5 mm (2500 μm) were also fabricated. The exposed length of the needle tip corresponds to the total length of the puncture portion. The cannula portion 30 was made from the cut 27G needle.

Test 1 was conducted according to the test procedures shown below.

First, the male rats (slc: SD rats (19-26 weeks old), manufactured by Nippon SLC) were euthanized with carbon dioxide. The tip of the nose was removed using a router so that the puncture site could reach the area deep inside the olfactory epithelium where the olfactory nerves are concentrated.

Next, a benchtop precision universal testing machine (product name: Autograph AGS-X 1kNX, manufactured by Shimadzu Corporation) with a 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.

Next, the aforementioned microsyringe was operated 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) to administer 30 μL of contrast agent (product name: Isovist Injection 240, manufactured by Bayer Yakuhin) at 20 μL/min, and the syringe was left 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.

After leaving the specimens to rest 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 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 reconstruction conditions were a contrast threshold of 0-0.055 (Log). The positions of the skull and cribriform plate, as well as the needle position, 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.

In the "Example" and "Comparative Example" in Test 1, the needle puncture status was not confirmed in real time, but rather the contrast agent was administered while the needle was inserted toward the area where the olfactory nerves are concentrated, and the contrast image was confirmed using a micro-CT system, with the contrast agent administered while the needle puncture site was inserted into the cribriform foramen. Furthermore, the difference in the puncture rate between the Example and Comparative Example is thought to be due to the fact that the puncture pressure was constant (0.8 N) in both the Example and Comparative Example, but the difference in the puncture rate into the cribriform foramen was due to issues such as the puncture angle of the needle relative to the cribriform plate.

The results of Test 1 were as follows:
Figure 5 is a table showing the results of Test 1, and Figure 6 is a graph showing the results of Test 1. In the table of Figure 5, the puncture length (µm) for each sample number is the length from the tip of the puncture portion punctured into the sieve hole, the sieve hole length (µm) is the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the sieve hole, and the puncture rate (%) is the ratio of the puncture length of the puncture portion to the sieve hole length (puncture length/sieve hole length). The graph shown in Figure 6 plots leakage into the nasal cavity/no leakage. The dot distribution in the lower part of the graph indicates samples with leakage into the nasal cavity, and the dot distribution in the upper part of the graph indicates samples with no leakage into the nasal cavity.

As shown in Figures 5 and 6, Samples 13-19 had a puncture rate of 60% or more and 100% or less, while Samples 1-12 had a puncture rate of less than 60%. Furthermore, as shown in Figure 6, there was a significant difference in the distribution of whether or not leakage into the nasal cavity occurred between Samples 1-12 and Samples 13-19. Therefore, Samples 13-19 were designated as Examples, and Samples 1-12 as Comparative Examples. Based on the results in Figures 5 and 6, it was confirmed that "positioning the tip opening of the puncture part in the cribriform hole of the cribriform plate, and ensuring that the ratio of the puncture length of the tip of the tip opening into the cribriform hole to the total length of the cribriform hole is 60% or more and 100% or less" can be one criterion for ensuring 100% successful transnasal intracerebral administration without leakage of the administered substance (contrast agent) into the nasal cavity.

Figure 7 shows the cross-sectional position when the test results of Test 1 were captured, Figure 8 is a photograph of Sample 14, an example of Test 1, after administration of the substance (contrast agent), and Figure 9 is a photograph of Sample 5, a comparative example of Test 1, after administration of the substance (contrast agent). As shown in Figure 7, the photograph of the example shown in Figure 8 and the photograph of the comparative example shown in Figure 9 are photographs taken when the rat, the subject, is cut along a cutting line (line D-D') extending from the mouth to the occipital side. Figure 8(a) is a CT image illustrating the distribution of the contrast agent in the example, and Figure 8(b) is a CT image illustrating the puncture state of the nasal administration device in the example. Figure 9(a) is a CT image illustrating the distribution of the contrast agent in the comparative example, and Figure 9(b) is a CT image illustrating the puncture state of the nasal administration device in the comparative example. Note that the images shown in Figures 8(a) and 9(a) are 3D data, while the images shown in Figures 8(b) and 9(b) are 2D data, and both are images near position A1 shown in Figure 7.

As shown in Figure 8(b), Sample 14, the example, was administered in a state in which the tip opening of the puncture part 12 was punctured into the cribriform hole X3 of the cribriform plate X2 at a puncture rate of 68%. As a result, as shown in Figure 8(a), the contrast agent (subject A) migrated to the brain tissue B side, with no leakage into the nasal cavity Z1. In contrast, as shown in Figure 9(b), Sample 5, the comparative example, was administered in a state in which the tip opening of the puncture part 12 was punctured at a puncture rate of 20%. As shown in Figure 9(a), most of the contrast agent after administration leaked into the nasal cavity Z1, with almost no migration into the brain tissue B side being observed.

As described above, the results of Test 1 confirmed that when the tip opening 14 of the puncture portion 12 was placed in the sieve hole X3 formed in the cribriform plate X2 and the puncture ratio of the tip of the tip opening 14 to the total length of the sieve hole X3 was between 60% and 100%, the administered substance A 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 only connects to the nasal cavity Z1 side and the olfactory bulb Y1 side, if the administered substance A did not leak into the nasal cavity Z1, it can be determined that the administered substance A was delivered to the olfactory bulb Y1 side, which is brain tissue B. Therefore, if the nasal administration device 1 of the present invention is used to place the tip opening 14 of the puncture portion 12 in the sieve hole X3 of the sieve plate X2, and administer the substance A with the tip of the tip opening 14 puncturing between 60% and 100% of the total length of the sieve hole X3, the substance A can be administered with a fluid pressure that counteracts the flow of cerebrospinal fluid C seeping out of the sieve hole X3, preventing leakage into the nasal cavity Z1 and enabling efficient delivery to brain tissue B. Furthermore, because the structure of the sieve hole X3 in the rat and human subjects in Test 1 is equivalent, the results of Test 1 demonstrate that the substance A can be efficiently delivered to brain tissue B by administering the substance A nasally to a human brain using the nasal administration device of the present invention with the needle portion 10 puncturing between 60% and 100% of the sieve hole X3.

[Test 2]
In Test 2, live cynomolgus monkeys were used as subjects, and nasal administration was carried out according to the puncture ratio of the puncture site relative to the cribriform foramina of the cribriform plate, and the presence or absence of leakage of the administered substance into the nasal cavity for each puncture ratio was evaluated.

The nasal administration device in Test 2 had the following specifications. Figure 10 shows a structural diagram of the nasal administration device 1 ((a) in the figure) and guide catheter 100 ((b) in the figure) produced in Test 2.

Five types of nasal administration devices 1 were prepared, each with a different exposed needle tip length (exposed lengths: 0.3 mm, 1 mm, 2 mm, 2.4 mm, and 3 mm).

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, leaving 1 mm of the inner catheter exposed at its distal end, to create a double-lumen catheter. Next, an 18G hub-equipped needle (product name: Terumon Bevel Needle 18G1 1/2, Terumo Corporation) was cut 10 mm from its proximal end, and the proximal end of the double-lumen catheter was fitted to the distal end of the hub and bonded with UV adhesive. Next, the inner catheter was cut so that 7 mm of the inner catheter was exposed from the outer catheter, and the gap between the catheters was filled with epoxy adhesive (product name: Bond Quick 30, Konishi Co., Ltd.) to smooth the gap. The hub portion 20 of the manufactured nasal administration device is the hub portion of the 18G hubbed needle described above, and the cannula portion 30 is composed of a double-lumen catheter.

Five types of devices were fabricated by positioning 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) so that the exposed length from the tip of the inner catheter in the cannula portion 30 configured as above was 0.3 mm, 1 mm, 2 mm, 2.4 mm, and 3 mm, and bonding it with UV adhesive. A microsyringe (product name: Gastight Syringe 1710TLL, manufactured by Hamilton) was attached as the storage portion 40 to the proximal end of the hub portion 20 of each device.

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 φ0.82, an inner diameter of φ0.68, and a curved tip with a 45° bend angle, or had a straight section with a spiral cut to make it flexible and bendable.

Test 2 was conducted according to the test procedures shown below.

First, the test subjects, cynomolgus monkeys (male, 3 years 7 months to 3 years 11 months), were anesthetized. The anesthetic and administration method were as follows: Induction anesthesia: Ketalar intramuscular injection 500 mg, Administration route: intramuscular administration, Dose: 10 mg/kg (0.2 mL/kg).
Maintenance anesthesia: Propofol injection for animals 1% "Mylan", route of administration: intravenous administration, dosage: 0.5 to 30 mg/kg/hour (0.05 to 3 mL/kg/hour).

Next, a 16-channel X-ray CT scanner (product name: Bright Speed Elite, manufactured by GE Healthcare) was used to perform an imaging scan, and a guide catheter was inserted into one of the subject's nasal cavities while checking the contrast image. During insertion, the tip opening of the guide catheter was adjusted to face the cribriform plate, with the tip positioned directly below the cribriform plate.

Next, the fabricated device was inserted into a guide catheter, and the olfactory mucosa was punctured to 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, Ltd.) at 20 μL/min using a microsyringe pump (product name: IC3200, manufactured by KD Scientific). Immediately after administration, the contrast agent was visualized using the aforementioned X-ray CT scanner, confirming that it had been administered to the olfactory mucosa. Furthermore, by confirming that the guide catheter had not moved, it was confirmed that the puncture site had penetrated the cribriform foramen.

The test results are shown in Figures 11 and 12.

In the table in Figure 11, the puncture length (μm) for each sample number is the length from the tip of the puncture part that punctured the cribriform cavity, the cribriform cavity length (μm) is the length of the shortest point between the nasal cavity opening and the olfactory bulb opening of the cribriform cavity, and the puncture rate (%) is the ratio of the puncture length of the puncture part to the cribriform cavity length (puncture length/cribriform cavity length). The graph in Figure 12 plots whether leakage into the nasal cavity occurred or not. The distribution of points in the lower part of the graph indicates samples with leakage into the nasal cavity, and the distribution of points in the upper part of the graph indicates samples with no leakage into the nasal cavity.

As shown in Figures 11 and 12, Samples 9 to 13 had a penetration rate of 60% or more and 100% or less, while Samples 1 to 8 had a penetration rate of less than 60%. Furthermore, as shown in Figure 11, there was a significant difference in the distribution of whether or not leakage into the nasal cavity occurred between Samples 1 to 8 and Samples 9 to 13. Therefore, Samples 9 to 13 were designated as Examples, and Samples 1 to 8 as Comparative Examples. Based on the results in Figures 11 and 12, it was confirmed that "positioning the tip opening of the needle portion in the sieve hole of the cribriform plate, and ensuring that the penetration length of the tip of the tip opening into the sieve hole relative to the total length of the sieve hole is 60% or more and 100% or less" is one criterion for ensuring 100% successful transnasal intracerebral administration without leakage of the administered substance (contrast agent) into the nasal cavity.

Figure 13 shows the cross-sectional positions when the test results of Test 2 were captured. Figure 14 is a photograph of Sample 12, an example of Test 1, after administration of the substance to be administered (contrast agent). Figure 15 is a photograph of Sample 3, a comparative example of Test 1, after administration of the substance to be administered (contrast agent). As shown in Figure 13, the photograph of the example shown in Figure 14 and the photograph of the comparative example shown in Figure 15 are photographs taken when the subject, a cynomolgus monkey, is cut along a cutting line (line E-E') extending from the mouth to the occipital side. Figure 14(a) is a CT image illustrating the distribution of the contrast agent in the example, and Figure 14(b) is a CT image illustrating the puncture state of the nasal administration device in the example. Figure 15(a) is a CT image illustrating the distribution of the contrast agent in the comparative example, and Figure 15(b) is a CT image illustrating the puncture state of the nasal administration device in the comparative example.

As shown in Figure 14(b), Sample 12, which serves as an example, was administered with a penetration rate of 86% at the puncture site, and as shown in Figure 14(a), the contrast agent migrated to the brain tissue B side, with no leakage into the nasal cavity. In contrast, as shown in Figure 15(b), Sample 3, which serves as a comparative example, was administered with a penetration rate of 10% at the puncture site, and as shown in Figure 15(a), the contrast agent leaked into the nasal cavity after administration, with no migration into the brain tissue B side being confirmed.

Furthermore, in Test 2, Sample 6 (puncture rate: 33%) showed no leakage. The cynomolgus monkeys used in Test 2 had cribriform cavities about 2.5 times larger in volume than the rats used in Test 1, and because the properties of the olfactory nerves differ from individual to individual, they are susceptible to individual differences, and it is thought that even with a puncture rate of less than 60%, there was no leakage into the nasal cavity.

As described above, the results of Test 2 confirmed that when the tip opening 14 of the puncture portion 12 was placed in the sieve hole X3 formed in the cribriform plate X2 and the puncture ratio of the tip of the tip opening 14 to the total length of the sieve hole X3 was between 60% and 100%, the administered substance A 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 only connects to the nasal cavity Z1 side and the olfactory bulb Y1 side, if the administered substance A did not leak into the nasal cavity Z1, it can be determined that the administered substance A was delivered to the olfactory bulb Y1 side, which is brain tissue B. Therefore, if the nasal administration device 1 of the present invention is used to place the tip opening 14 of the puncture portion 12 in the sieve hole X3 of the sieve plate X2, and administer the substance A with the tip of the tip opening 14 puncturing the sieve hole X3 at a rate of 60% to 100% of the total length of the sieve hole X3, the substance A can be administered with a fluid pressure that counteracts the flow of cerebrospinal fluid C seeping out of the sieve hole X3, preventing leakage into the nasal cavity Z1 and enabling efficient delivery to brain tissue B. Furthermore, because the structures of the sieve holes X3 in the cynomolgus monkeys and humans used as subjects in Test 2 are equivalent, the results of Test 2 demonstrate that the substance A can be efficiently delivered to brain tissue B by administering the substance A nasally to a human brain using the nasal administration device of the present invention with the needle portion 10 puncturing the sieve hole X3 at a rate of 60% to 100%.

In addition, Sample 7, used as a comparative example, had a penetration rate of 59%, resulting in leakage into the nasal cavity, while Sample 8 had the same penetration rate of 59% as Sample 7, resulting in no leakage into the nasal cavity. The results of Test 2 confirmed that when the penetration rate exceeds 60%, delivery to brain tissue B without leakage into the nasal cavity is possible with a 100% success rate. However, it was also confirmed that even when the penetration rate of the tip opening is less than 60%, as in Samples 7 and 8, administration without leakage into the nasal cavity was possible with a high probability of 50%. Therefore, administration of the substance to be administered using the nasal administration device of the present invention is considered to be less invasive than currently known administration methods such as nasal spray, intraventricular administration, and intrathecal administration, has a superior transfer rate to brain tissue B, and can rapidly deliver a sufficient dose to the brain, even when the penetration rate of the tip opening relative to the total length of the cribriform opening is less than 60% (e.g., 50% to 100%). However, when considering administration to humans, conditions that result in a 100% success rate are important, so it can be said that the optimal puncture rate is between 60% and 100%.

[Test 3]
In Test 3, live cynomolgus monkeys were used as subjects, and nasal administration was carried out according to the puncture ratio of the puncture portion 12 relative to the sieve holes X3 of the cribriform plate X2, and the presence or absence of leakage of the administered substance A into the nasal cavity Z1 was evaluated for each puncture ratio.

The difference from Test 2 is that the needle tip (outer diameter 0.1 mm, inner diameter 0.09 mm, total length 15 mm, blade length 0.1 mm, made of SUS304) was positioned so that the exposed length from the tip of the inner catheter in the cannula portion 30 configured as described above was 2.0 mm, and adhered with UV adhesive to create a nasal administration device. A microsyringe (product name: Gastight Syringe 1001LT, manufactured by Hamilton) was attached as the storage portion 40 to the proximal end of the hub portion 20 of the device.

Next, the prepared device was inserted into a guide catheter, and the olfactory mucosa was punctured by the exposed length of the puncture section. The aforementioned microsyringe was then operated to administer 0.5 mL of contrast agent (product name: Gadovist Intravenous Injection, Bayer Yakuhin, Ltd.) at 20 μL/min using a microsyringe pump (product name: IC3200, manufactured by KD Scientific). Note that in conducting Test 3, the treatment of the subject and the placement of the guide catheter were the same as in Test 2.

Figure 16 shows the test results of Test 3. Figure 17 is a CT image illustrating the distribution of contrast agent when the cynomolgus monkey subject shown in Figure 13 was cut along the cutting line (line E-E') extending from the mouth side to the occipital side. As shown in Figure 16, Sample 14, the example, was administered with a puncture ratio of 100% for sieve hole X3 (sieve hole length: 2.0 mm). Therefore, as shown in Figure 17, the contrast agent to be administered A migrated to the brain tissue B side, and no leakage into the nasal cavity was confirmed.

[Test 4]
In Test 4, live cynomolgus monkeys were used as subjects, and nasal administration was carried out according to the puncture ratio of the puncture portion 12 relative to the sieve holes X3 of the cribriform plate X2, and the presence or absence of leakage of the administered substance A into the nasal cavity Z1 was evaluated for each puncture ratio.

The difference from Tests 2 and 3 is that the needle tip (outer diameter 0.2 mm, inner diameter 0.09 mm, total length 15 mm, blade length 0.1 mm, made of SUS304) was positioned so that the exposed length from the tip of the inner catheter in the cannula portion 30 configured as described above was 2.0 mm, and adhered with UV adhesive to create a nasal administration device. A microsyringe (product name: Gastight Syringe 1002TLL, manufactured by Hamilton) was attached as the storage portion 40 to the proximal end of the hub portion 20 of the device.

Next, the prepared device was inserted into a guide catheter, and the olfactory mucosa was punctured by the exposed length of the puncture section. The aforementioned microsyringe was then operated to administer 2.0 mL of contrast agent (product name: Omnipaque 240 Injection, GE Healthcare Pharma Co., Ltd.) at 20 μL/min using a microsyringe pump (product name: IC3200, manufactured by KD Scientific). Note that in conducting Test 4, the treatment of the subject and the placement of the guide catheter were the same as in Test 2.

Figure 16 shows the test results of Test 4. Figure 18 is a CT image illustrating the distribution of contrast agent when the cynomolgus monkey subject shown in Figure 13 was cut along the cutting line (line E-E') extending from the mouth side to the occipital side. As shown in Figure 16, Sample 15, the example, was administered with a puncture rate of 91% of the sieve hole X3 (sieve hole length: 2.2 mm). As shown in Figure 18, the contrast agent to be administered A migrated to the brain tissue B side, and no leakage into the nasal cavity was confirmed.

[Test 5]
In Test 5, a live cynomolgus monkey (5 years and 5 months old, male) was used as the subject, and nasal administration was carried out according to the puncture ratio of the puncture portion 12 relative to the cribriform holes X3 of the cribriform plate X2, and the presence or absence of leakage of the administered substance A into the nasal cavity Z1 for each puncture ratio was evaluated.

As shown in Figure 19, the nasal administration device 1A used in Test 5 comprises a needle portion 10, a hub portion 20, and a storage portion 40. The nasal administration device 1A differs from the device configuration shown in Figure 10a in that it does not include the cannula portion 30, and the tip of the puncture portion 12 is pre-curved to allow direct puncture into the sieve hole X3 of the cribriform plate X2 without using a guide catheter 100. The nasal administration device 1A was fabricated as follows.

First, a SUS pipe with an outer diameter of 0.2 mm, an inner diameter of 0.09 mm, and a total length of 200 mm was inserted into a SUS pipe with an outer diameter of 0.5 mm, an inner diameter of 0.36 mm, and a total length of 100 mm. The tips were aligned flush and bonded with an epoxy adhesive (product name: Bond Quick 30, manufactured by Konishi Co., Ltd.) to create a double-walled SUS pipe. Next, a 22G hubbed needle (product name: Terumon Bevel Needle 22G1 1/2, manufactured by Terumo Corporation) was cut 10 mm from the base end, and the base end of the double-walled SUS pipe was fitted to the tip of the hub and bonded with UV adhesive. The hub portion 20 of the device is the hub portion of the 22G hubbed needle described above, and the needle shaft portion 11 is composed of the double-walled SUS pipe.

The puncture section 12 was fabricated by positioning the needle tip (outer diameter 0.5 mm, inner diameter 0.36 mm, total length 100 mm, blade length 0.09 mm, made of SUS304) so that the exposed length from the tip of the needle shaft 11 configured as described above was 2.0 mm, and bonding it with UV adhesive. A microsyringe (product name: Gastight Syringe 1710TLL, manufactured by Hamilton) was attached as the storage section 40 to the base end of the hub section 20 of the device.

Next, the fabricated device was inserted into the monkey's nasal cavity, and using the principle of leverage, the olfactory mucosa was punctured the length of the curved puncture section. The aforementioned microsyringe was then manipulated to administer 0.03 mL of contrast agent (product name: Omnipaque 240 Injection, GE Healthcare Pharma Co., Ltd.) at 20 μL/min using a microsyringe pump (product name: IC3200, manufactured by KD Scientific). Note that in conducting Test 5, the subjects were treated in the same manner as in Test 2.

Figure 16 shows the test results of Test 5. Figure 20 shows CT images of the cynomolgus monkey subject shown in Figure 13, taken along the section line (E-E') from the mouth to the occipital region. (a) in the figure is a CT image for explaining the distribution of contrast agent in Test 5, and (b) in the figure is a CT image for explaining the puncture state of the nasal administration device in Test 5. As shown in Figure 16, Sample 16, which serves as the example, was administered with a puncture rate of 57% of the sieve hole X3 (sieve hole length: 2.1 mm). However, as shown in Figure 20(b), the contrast agent to be administered (subject A) migrated to the brain tissue B side, and no leakage into the nasal cavity was observed.

As explained above, Samples 1 to 13 of the aforementioned Test 2 shown in Figure 11 were examples in which the needle outer diameter was 0.2 mm, but as shown in Figure 16, Sample 16, when the needle outer diameter was 0.5 mm, no leakage into the nasal cavity was confirmed even at a puncture depth of less than 60%. Furthermore, as shown in Figure 16, Samples 14 and 15 had deeper puncture ratios (91%, 100%) than the samples of Test 2 shown in Figure 11, and therefore no leakage into the nasal cavity was confirmed.

This application is based on Japanese Patent Application No. 2024-017856, filed February 8, 2024, the disclosure of which is incorporated herein by reference in its entirety.

1. Nasal administration device,
10 needle part (10a inner cavity),
11 needle shaft section,
12 Puncture part (12a needle tip part),
13 Blade surface,
14 tip opening;
15 proximal opening;
20 Hub portion 21 Main body portion (21a inner cavity),
22 connection part,
30 cannula part,
31 main body,
32 stopper portion (32a abutment portion),
40 storage section,
41 storage space,
42 liquid delivery section (tip opening 42a),
50 connecting member,
100 guide catheter,
110 catheter body,
111 lumen,
200 Nasal administration system,
A. Subject to administration,
B. Brain tissue;
C. Cerebrospinal fluid (CSF),
X1 ethmoid bone,
X2 sieve plate,
X3 sieve hole,
Y1 olfactory bulb,
Y2 olfactory mucosa,
Y3 olfactory epithelium,
Y4 lamina propria,
Y5 olfactory nerve,
Z1 Nasal cavity.

Claims (9)

A nasal administration device comprising a needle portion having a puncture portion for delivering a substance to be administered transnasally into the brain of a mammal,
A nasal administration device in which the opening of the puncture section is positioned within a cribriform cavity, and the ratio of the puncture length of the tip of the opening into the cribriform cavity to the total length between the nasal cavity opening and the olfactory bulb opening is 60% or more and 100% or less, and the substance to be administered is administered into the brain through the opening. the nasal administration device is configured as a tubular member and has a cannula portion that is disposed over the needle portion so that the puncture portion is exposed;
the opening is provided on the distal end side of the puncture part,
a stopper portion having an abutment portion that abuts against the olfactory epithelium of the olfactory mucosa is formed at the tip of the cannula portion;
The nasal administration device of claim 1, wherein the opening is positioned within the cribriform plate with the abutment portion of the stopper portion in contact with the olfactory epithelium. the nasal administration device has a hub portion to which a storage portion containing the substance to be administered can be attached,
The nasal administration device of claim 2, wherein 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 lumen of the cannula portion. The nasal administration device of claim 1, wherein the needle tip of the puncture section has an open end with a cutting edge on the tip side, and the total length of the puncture section is 0.35 mm or more and 5.4 mm or less. The nasal administration device of claim 2, wherein the total length of the cannula portion is 55 mm or more and 410 mm or less. the abutment portion of the stopper portion is a distal end surface of the cannula portion that contacts the olfactory epithelium,
The length of the longest part in the radial direction of the contact portion is 0.2 mm or more and 15 mm or less,
The nasal administration device of claim 3, wherein the outer diameter of the base end of the puncture portion is 0.1 mm or more and 2.1 mm or less. The nasal administration device of claim 2, wherein the cross-sectional shape of the abutment portion of the stopper portion is circular or elliptical. The nasal administration device according to claim 1 or 2, wherein the nasal administration device has a storage section that stores the substance to be administered, and the substance stored in the storage section is configured to be discharged through the opening of the puncture section. A nasal administration device according to any one of claims 1 to 8;
a guide catheter having an insertable and removable lumen in at least a portion of the nasal administration device, the guide catheter guiding the needle portion of the nasal administration device inserted into the lumen into the sieve hole formed in the cribriform plate;
A nasal administration system comprising: