Intranasal infusion device for animals and associated methods

Abstract

An intranasal infusion device includes a base having a top surface and an opposing bottom surface with an opening extending therethrough. The bottom surface is configured to be secured to a nasal bone of an animal. An infusion adapter extends from the top surface of the base and is aligned with the opening in the base. An upper portion of the infusion adapter includes an infusion port configured to receive a fluid to be infused into a nasal cavity of the animal. An infusion tube extends from the bottom surface of the base and is aligned with the opening in the base. A lower portion of the infusion tube is configured to be positioned to extend within an opening drilled through the nasal bone of the animal for the fluid to be infused into the nasal cavity of the animal.

Description

10457-606PC0INTRANASAL INFUSION DEVICE FOR ANIMALS AND ASSOCIATED METHODSCross-Reference To Related Applications

[0001] The present application claims the benefit of U.S. Provisional Patent Application Serial Number 63 / 723,359 filed November 21, 2024, all of which is fully incorporated by reference.Technical Field

[0002] The present disclosure relates to nasal substance administration devices, and, more particularly, to an intranasal diffusion device for animals and associated methods.Background

[0003] Many substances / drugs are administered into the nose. These include opioid overdose reversal drugs, anti-seizure medications, migraine medications, hormone treatments and medicines to treat / prevent allergies, colds, and flues including nasally-administered vaccines, corticosteroids, antihistamines and decongestants. In addition to these on-label medicinal uses of the nasal route of administration, the nasal route of administration is the preferred route of entry of drugs of abuse. Nasal administration confers multiple advantages of interest given that it is able to bypass the blood brain barrier and hepatic metabolism leading to rapid bioavailability which results in faster onset of action of drugs, as well as being a less invasive route of administration with lower systemic side-effects.

[0004] Well-developed infusion devices which are designed to dispense precise and reliable doses into the nose are available for application and testing of candidate drugs / therapies in humans. However, in early-stage therapeutic design, validation and testing, which frequently occurs in pre-clinical rodent models (e.g„ mice) and in other animals, no devices are available for precise and reliable intranasal substance administration. This presents a major void which has debilitated the drug development industry to design and test drugs which could be used to treat multitudes of medical conditions - in both human patients and companion animal patients.10457-606PC0Further the lack of a reliable intranasal drug delivery paradigm represents a void in the ability to model drug abuse in humans, and therefore, to effectively develop therapeutics through pre- clinical testing in rodents.

[0005] Current preclinical methods to administer drugs intranasally in rodents have done so by delivering the fluids using pipette tips directly into the nose while the animal is restrained in a supine position, and manually distributing the doses across both nostrils. Other methods have resorted to attaching polyurethane tubing to a syringe and delivering the fluids into the nose while the animal is anesthetized. Additionally, one can revert to placing an animal in a gas chamber wherein vaporized drugs can be delivered for later assessment of outcomes. While these methods have highlighted the importance and viability of the intranasal route to deliver drugs, they do not achieve precision and reliability of drug delivery.

[0006] Further, sedation and differences in handling of the animals when needing to restrain them can add variability to the accuracy with which the drug can be delivered, not to mentioned that this mechanism can lead to expulsion of some of the fluid due to the pressure caused by the pipette / syringe. Additionally, these mechanisms have limitations that require the experimenter to deliver higher volumes, which can lead to the fluid being inhaled into the lungs altering the kinetics of the nasal route. Additionally, traditional methods manually deliver these volumes to achieve their desired volume, which can add variability due to experimenter error and further stress to the animal. Finally, delivery of vaporized drugs fails to achieve control over dosing since this is reliant upon the animal to inhale the drug a set number of times, not to mention, exposure of animals to vapor will result in the vapor likely entering the body through alternative routes of administration (dermal, ocular, oral).Summary

[0007] An intranasal infusion device includes a base having a top surface and an opposing bottom surface with an opening extending therethrough. The bottom surface is configured to be secured to a nasal bone of an animal. An infusion adapter extends from the top surface of the base and is aligned with the opening in the base. An upper portion of the infusion adapter includes an infusion port configured to receive a fluid to be infused into a nasal cavity of the animal. An infusion tube extends from the bottom surface of the base and is aligned with the opening in the base. A lower portion of the infusion tube is configured to be positioned to extend10457-606PC0 within an opening drilled through the nasal bone of the animal for the fluid to be infused into the nasal cavity of the animal.

[0008] The opposing ends of the base may include a front tab extending frontwards of the base, and a rear tab extending rearwards of the base. The bottom surface of the base, and a bottom surface of the front and rear tabs may be configured to provide a surface area for an adhesive to be applied to secure the intranasal infusion device to the nasal bone of the animal.

[0009] The rear tab may include an opening extending therethrough to provide additional surface area for the adhesive. The base may include a lower level and an upper level, with the front and rear tabs being in the lower level, and with the infusion adapter being carried by the upper level. Opposing ends of the upper level may be recessed from the front and rear tabs in the lower level.

[0010] The infusion port may be configured to be coupled to an infusion line to receive the fluid. A first magnet may be carried by the base.

[0011] The first magnet may be aligned with a second magnet carried by an infusion line extending into the infusion port so that the first and second magnets are brought together with their opposite poles facing each other to secure the infusion line to the base. An upper surface of the first magnet may be aligned with the opening extending through the upper surface of the base.

[0012] Another aspect is directed to a method of using an intranasal infusion device as described above. The method includes making an incision in the animal to expose a nasal bone, drilling an opening through the nasal bone and into a nasal cavity of the animal, and using an adhesive to secure a bottom surface of the intranasal infusion device to the exposed nasal bone. A lower portion of the infusion tube is positioned to extend within the opening drilled through the nasal bone of the animal. A fluid is provided to the infusion port to be infused into the nasal cavity of the animal via the infusion tube.Brief Description of the Drawings

[0013] FIG. 1 is a perspective view of an intranasal infusion device for an animal in which various aspects of the disclosure may be implemented

[0014] FIG. 2A is a side view of the intranasal infusion device illustrated in FIG. 1 showing10457-606PC0 dimensions.

[0015] FIG. 2B is a front view of the intranasal infusion device illustrated in FIG. 1 showing dimensions.

[0016] FIG. 3 is a side view of the intranasal infusion device illustrated in FIG. 1 implanted within an animal and coupled to an infusion system for delivering a fluid into a nasal cavity of the animal.

[0017] FIG. 4A is a microscopic view of the infusion tube of the intranasal infusion device illustrated in FIG. 1 delivering a target volume of fluid.

[0018] FIG. 4B is a graph illustrating rapid delivery of the target volume of fluid by the intranasal infusion device illustrated in FIG. 4A.

[0019] FIG. 5 is a flowchart for using the intranasal infusion device illustrated in FIG. 1 to deliver a fluid into the nasal cavity of an animal.Detailed Description

[0020] The present description is made with reference to the accompanying drawings, in which exemplary embodiments are shown. However, many different embodiments may be used, and thus the description should not be construed as limited to the particular embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete. Like numbers refer to like elements throughout.

[0021] Referring now to FIG. 1, an intranasal infusion device 20 for delivering fluid to be infused into the nasal cavity of an animal will be discussed. The animal may be a rodent, such as a mouse, for example. The intranasal infusion device 20 may also be referred to as a nasal access port (NAP). The intranasal infusion device 20 is able to deliver drugs in freely-moving animals, with no need of repeated sedation. This makes it possible to deliver controlled microliter doses at desired rates. This advantageously overcomes experimenter error by giving precise control over dosage and kinetics of drug delivery, while also being able to observe behavioral phenotypes that are crucial when developing preclinical models during the drug developing and testing process.

[0022] The intranasal infusion device 20 is surgically implanted. The surgery is straightforward and includes making an incision in the animal to expose a nasal bone, drilling an opening through the nasal bone and into a nasal cavity of the animal, and using an adhesive to secure a bottom surface of the intranasal infusion device to the exposed nasal bone. The intranasal10457-606PC0 infusion device 20 includes an infusion tube 50 that is positioned to extend within the opening drilled through the nasal bone of the animal for delivering fluid into the nasal cavity of the animal. The surgery advantageously mimics the noninvasive advantage that is desired by this route of administration.

[0023] The intranasal infusion device 20 includes a base 22 having a top surface 24 and an opposing bottom surface 26 with an opening extending therethrough. The opening is represented by a dashed line 28 that extends through the base 22. The bottom surface 26 of the base 22 is configured to be secured to the nasal bone of an animal.

[0024] An infusion adapter 60 extends from the top surface 24 of the base 22 and is aligned with the opening 28 in the base 22. An upper portion of the infusion adapter 60 includes an infusion port 62 configured to receive a fluid to be infused into a nasal cavity of the animal. The infusion port 62 includes soft silicone in which an infusion line can be inserted therethrough and into the infusion adapter 60.

[0025] The infusion tube 50 extends from the bottom surface 26 of the base 22 and is aligned with the opening 28 in the base 22. A lower portion of the infusion tube 50 is configured to be positioned to extend within an opening drilled through the nasal bone of the animal for the fluid to be infused into the nasal cavity of the animal.

[0026] The base 22 includes a front tab 30 extending frontwards of the base, and a rear tab 32 extending rearwards from an opposing end of the base. The bottom surface 26 of the base 22, and a bottom surface of the front and rear tabs 30, 32 are configured to provide a surface area for an adhesive to be applied to secure the intranasal infusion device 20 to the nasal bone of the animal. The rear tab 32 includes an opening 34 extending therethrough to provide additional surface area for the adhesive.

[0027] The base 22 includes a lower level 40 and an upper level 42. The front and rear tabs 30, 32 are in the lower level 40. The infusion adapter 60 is earned by the upper level 42. Opposing ends of the upper level 42 are recessed from the front and rear tabs 30, 32 in the lower level.

[0028] The infusion port 62 is configured to be coupled to an infusion line to receive the fluid. The infusion line is to be secured to the base 22 using a magnetic injector. A first magnet 44 is carried by the base 22. The base 22 includes a recessed area that holds the first magnet 44, with an upper surface of the first magnet 44 being aligned with the opening 28 extending through the upper surface 26 of the base 22. The first magnet 44 is to be aligned with a second magnet10457-606PC0 carried by the magnetic injector so that the first magnet 44 and the second magnet are brought together with their opposite poles facing each other to secure the infusion line to the base 22.

[0029] Referring now to FIGS. 2A and 2B, dimensions of the intranasal infusion device 20 will be discussed. The following dimensions are example dimensions and are not to be limiting as the size of the intranasal infusion device 20 may vary based on a size of the animal. A length of the base 22 may be about 9.8 mm, and the infusion tube 50 may extend downwards from the base 22 by about 1.3 mm. A diameter of the infusion tube 50 may be less than 1 mm. A height of the base 22 between the upper and lower surfaces 24, 26 of the base 22 may be about 2.5 mm, and a width of the base 22 may be about 3.00 mm.

[0030] The intranasal infusion device 20 is a lightweight surgical implantation device, and typically weighs less than 1.5 grams. The intranasal infusion device 20 is configured to be fluid tight, able to be disconnected from a fluid infusion line with little force, and small enough to fit on the nasal bone of even small animals (e.g., a mouse).

[0031] Refering now to FIG. 3, the intranasal infusion device 20 implanted within an animal 70 and coupled to an infusion system for delivering a fluid 88 into a nasal cavity of the animal 70 will be discussed. As noted above, the animal 70 may be a rodent, such as a mouse, for example. The intranasal infusion device 20 has been validated after implantation onto the nasal bone of a mouse 70 to provide fluid infusions.

[0032] To accomplish this, the animal 70 was anesthetized while strictly adhering to ethical and veterinarian guidelines, following a midline incision across the frontal and nasal bones. A 1 mm hole was drilled through an ipsilateral nasal bone, and the infusion tube 50 of the intranasal infusion device 20 was lowered through the hole. The intranasal infusion device 20 was then secured to the skull with an adhesive that is typically used for cranial implants in small animals. The adhesive may be dental cement, for example.

[0033] An infusion system may then be coupled to the intranasal infusion device 20 for delivering a fluid 88 into the nasal cavity of the animal 70. The infusion system includes an infusion device 80 that provides the fluid to a reservoir 82. The infusion device 80 is depicted as a syringe, for example. Alternatively, the infusion device 80 may be a pump or valve, for example. The fluid from the reservoir 82 then travels through an infusion line 84 coupled to the infusion port 62 on the infusion adapter 60.

[0034] Once the intranasal infusion device 20 has been implanted in the animal 70, the infusion10457-606PC0 device 80 can be connected to an infusion line 84 (including by means of a fluid-tight swivel to prevent kinking of the line) which terminated to an injector attachment 86. The injector attachment 86 is magnetic, and may also be referred to as a magnetic injector. The magnetic injector 86 can temporarily mate onto the intranasal infusion device 20 to achieve a fluid-tight seal for fluid delivery into the nasal cavity of the animal 70.

[0035] The magnetic injector 86 includes a second magnet that is brought in close proximity to the first magnet 44 carried by the base 22. The first magnet 44 and the second magnet are brought together with their opposite poles facing each other to secure the infusion line 84 to the base 22. The magnetic coupling of the two magnets may be decoupled with minimal force. After coupling of the infusion line 84 to the intranasal infusion device 20, the animal 70 is then able to freely behave.

[0036] Referring now to FIGS. 4A and 4B, intranasal delivery of fluids into the animal 70 will be discussed. When the intranasal infusion device 20 has been connected to a fluid infusion pump, the intranasal infusion device 20 achieves short latency when expunging fluids. Using time-lapse microscopy, an intranasal infusion device 20 is positioned diagonally under the microscope to image delivery of a target volume of fluid 88 through the infusion tube 50. The intranasal infusion device 20 is attached to an infusion line 84 backfilled with a solution.

[0037] To visualize the movement of a fluid solution, a dye fluorescein (1% solution in ddH20) is mixed. The fluorescent dye, which when excited by blue light, emits green fluorescence light which can be captured by the microscope. The fluid is then driven with a syringe pump controlled to deliver 1 pL aliquots every 15s, as shown in image 100 in FIG. 4B. Upon triggering of the pump the dye was expunged with a short latency (tens of milliseconds) measured as changes in fluorescence intensity, in which peak fluorescence indicated expunging of the target volume (IpL) at 102.

[0038] In summary, rapid fluid dynamics may be achieved by the intranasal infusion device 20. The intranasal infusion device 20 is attached to an infusion line 84 backfilled with 1% fluorescein dye, oriented to visualize delivery of a target volume through the infusion tube 50 using time lapse microscopy. Fluorescence intensity upon infusion onset demonstrates that the intranasal infusion device 20 achieves short latency (<2ms) between pump-triggered expunging of single Ipl target volume.

[0039] Another aspect is directed to a method for using the intranasal infusion device 20 to10457-606PC0 deliver a fluid 88 into the nasal cavity of an animal 70. Referring now to the flowchart 200 in FIG. 3, from the start (Block 202), the method includes making an incision in the animal 70 to expose a nasal bone at Block 204. An opening is drilled through the nasal bone and into a nasal cavity of the animal 70 at Block 206. An adhesive is used to secure a bottom surface of the intranasal infusion device 20 to the exposed nasal bone at Block 208, with a lower portion of the infusion tube positioned to be positioned to extend within the opening drilled through the nasal bone of the animal. The fluid 88 is provided to the infusion port at Block 210 to be infused into the nasal cavity of the animal 70 via the infusion tube 50. The method ends at Block 212.

[0040] Many modifications and other embodiments will come to the mind of one skilled in the art having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is understood that the foregoing is not to be limited to the example embodiments, and that modifications and other embodiments are intended to be included within the scope of the appended claims.

Claims

10457-606PC0CLAIMS:

1. An intranasal infusion device comprising: a base having a top surface and an opposing bottom surface with an opening extending therethrough, with the bottom surface configured to be secured to a nasal bone of an animal; an infusion adapter extending from the top surface of the base and aligned with the opening in the base, with an upper portion of the infusion adapter including an infusion port configured to receive a fluid to be infused into a nasal cavity of the animal; and an infusion tube extending from the bottom surface of the base and aligned with the opening in the base, with a lower portion of the infusion tube configured to be positioned to extend within an opening drilled through the nasal bone of the animal for the fluid to be infused into the nasal cavity of the animal.

2. The intranasal infusion device according to claim 1 wherein opposing ends of the base comprise: a front tab extending frontwards of the base; and a rear tab extending rearwards of the base; wherein the bottom surface of the base, and a bottom surface of the front and rear tabs are configured to provide a surface area for an adhesive to be applied to secure the intranasal infusion device to the nasal bone of the animal.

3. The intranasal infusion device according to claim 2 wherein the rear tab includes an opening extending therethrough to provide additional surface area for the adhesive.

4. The intranasal infusion device according to claim 2 wherein the base includes a lower level and an upper level, with the front and rear tabs being in the lower level, with the infusion adapter being carried by the upper level, and with opposing ends of the upper level being recessed from the front and rear tabs in the lower level.

5. The intranasal infusion device according to claim 1 wherein the infusion port is configured to be coupled to an infusion line to receive the fluid.10457-606PC06. The intranasal infusion device according to claim 5 comprising a first magnet carried by the base, with the first magnet to be aligned with a second magnet carried by an infusion line extending into the infusion port so that the first and second magnets are brought together with their opposite poles facing each other to secure the infusion line to the base.

7. The intranasal infusion device according to claim 6 wherein the base includes a recessed area that holds the first magnet, with an upper surface of the first magnet being aligned with the opening extending through the upper surface of the base.

8. A method of using an intranasal infusion device for an animal comprising a base having a top surface and an opposing bottom surface with an opening extending therethrough, an infusion adapter extending from the top surface of the base and aligned with the opening in the base, with an upper portion of the infusion adapter including an infusion port, and an infusion tube extending from the bottom surface of the base and aligned with the opening in the base, the method comprising: making an incision in the animal to expose a nasal bone; drilling an opening through the nasal bone and into a nasal cavity of the animal; using an adhesive to secure a bottom surface of the intranasal infusion device to the exposed nasal bone, with a lower portion of the infusion tube positioned to extend within the opening drilled through the nasal bone of the animal; and providing a fluid to the infusion port to be infused into the nasal cavity of the animal via the infusion tube.

9. The method according to claim 8 wherein opposing ends of the base comprise: a front tab extending frontwards of the base; and a rear tab extending rearwards of the base; wherein the bottom surface of the base, and a bottom surface of the front and rear tabs are configured to provide a surface area for the adhesive.10457-606PC010. The method according to claim 9 wherein the rear tab includes an opening extending therethrough to provide additional surface area for the adhesive.

11. The method according to claim 9 wherein the base includes a lower level and an upper level, with the front and rear tabs being in the lower level, with the infusion adapter being carried by the upper level, and with opposing ends of the upper level being recessed from the front and rear tabs in the lower level.

12. The method according to claim 8 comprising coupling an infusion line to the infusion port to provide the fluid.

13. The method according to claim 8 comprising a first magnet carried by the base, with the first magnet to be aligned with a second magnet carried by an infusion line extending into the infusion port so that the first and second magnets are brought together with their opposite poles facing each other to secure the infusion line to the base.

14. The method according to claim 13 wherein the base includes a recessed area that holds the first magnet, with an upper surface of the first magnet being aligned with the opening extending through the upper surface of the base.

15. The method according to claim 8 wherein the animal is a rodent.

Images