A mouse nasal administration device

Abstract

The application provides a micro-dosing device, and a mouse nasal administration device.

Description

Technical Field

[0001] This invention relates to the field of medical technology, and in particular to a nasal drug delivery device for mice. Background Technology

[0002] Intranasal drug delivery is a rapidly developing therapeutic field with enormous potential in treating central nervous system diseases. Clinical studies have shown that intranasal insulin can improve verbal memory in cognitively impaired elderly individuals and patients with early-stage Alzheimer's disease (AD). Intranasal administration of midazolam has been shown to be effective in 87% of patients with prolonged seizure duration, while rectal administration of diazepam was effective in only 60 patients. Besides intranasal drug delivery to the brain, the use of therapeutic stem cells and engineered extracellular vesicles for intranasal treatment of central nervous system diseases is gradually becoming a research hotspot. Research on intranasal stem cell therapy for neonatal ischemic brain injury, Parkinson's disease, and malignant brain tumors has made some progress. Extracellular vesicles are secreted by cells, with a diameter of 30nm-1000nm, possessing a phospholipid bilayer structure, good biocompatibility, and the ability to carry proteins or nucleic acids from the paternal cell. Intranasal administration of astrocyte A1 type exosomes differentiated from mesenchymal stem cells can alleviate neuroinflammation and prevent abnormal neurological development and memory impairment following status epilepticus. Furthermore, the targeting and efficacy of extracellular vesicles can be increased by processing the parent cells (such as plasmid transfection) or modifying the extracellular vesicles themselves (such as electroporation of siRNA, linking to targeting peptides). Guo et al. found that extracellular vesicles generated by mesenchymal stem cells administered intranasally can migrate across the blood-brain barrier to the spinal cord injury area, and the siRNA they carry can help nerve growth.

[0003] The blood-brain barrier (BBB) ​​is a selectively permeable tissue structure located between the circulating blood and the brain parenchyma, composed of capillary endothelial cells, pericytes, and astrocytes. Tight junction proteins between endothelial cells generate high transendothelial resistance, allowing limited permeability of the BBB to only certain lipophilic, small-molecule substances with specific transporters. Although BBB permeability increases in disease states, the extent and duration of BBB disruption in pathological conditions of the central nervous system are poorly understood. Therefore, the presence of the BBB still poses a challenge to the peripheral delivery of most central nervous system therapeutics to the brain. Besides reaching the central nervous system via the bloodstream, nasal administration can reach the brain parenchyma through the nasal mucosa, primarily the olfactory epithelium via the olfactory nerve, trigeminal nerve, or cerebrospinal fluid circulation. Most drugs can bypass the BBB, delivering them directly and rapidly to the brain, avoiding drug metabolism and systemic side effects associated with peripheral circulation.

[0004] While nasal administration offers unique advantages in terms of brain access, its efficiency is affected by factors such as nasal cavity volume, respiratory airflow, drug dosage, rate of administration, and the subject's head position. In animal experiments, nasal administration is currently mostly achieved by anesthetizing mice with a mixture of 1-3% isoflurane and oxygen, placing them in a supine position with their head at approximately 70-90° to their body, and using a pipette to drop 5-10 μL of the drug solution onto the outer edge of one nostril, allowing it to enter the nasal cavity with the mouse's respiration. Although this traditional method is simple and easy to perform, it still has several drawbacks in practice. For example, the instability of gas anesthesia can lead to mice regaining consciousness or resisting administration midway, resulting in a lower than expected dosage; while the supine head position facilitates drug contact with the olfactory epithelium, it also makes it easier for the drug to enter peripheral organs such as the lungs and kidneys; manual handling and pipette administration mean that only one mouse can be administered at a time, leading to individual dosing time differences for multiple groups of mice, which can affect the observation of drug distribution and efficacy at the same time point after administration. With the widespread development of basic research, efficient and practical transnasal delivery experimental devices have become an urgent problem to be solved.

[0005] Currently, there are few improved nasal drug delivery devices that address traditional methods. Kanazawa et al. designed a temporarily openable inhalation mask. Mice were placed on a horizontal soft board with their limbs secured by medical tape. The mask maintained anesthesia with inhaled gas. The mask could be briefly opened, and 1-2 μL of medication could be dripped into one nostril using a pipette. Medication was administered alternately to the left and right nostrils, with a 30-second interval. This method makes reliable nasal drug delivery possible in mice under stable anesthesia, but it does not solve the problem of medication loss due to the supine position. Related experimental studies have found that the forward-downward head position is more suitable for non-human primates for treatment via olfaction or the trigeminal nerve. Based on this, existing technology has designed an adjustable mouse seat frame with four mouse seats and a "chair strap" similar to a seatbelt. The seats can be electrically heated to keep the mice warm. After intraperitoneal anesthesia, the chair was adjusted to an appropriate height and heated. The anesthetized mouse was placed on the chair with its back against the backrest and its head naturally drooping forward. The chair straps provided fixation and support for the mouse's forelimbs. Then, 2 μL of medication was administered to one nostril of the mouse using a pipette. Since at least four mice could be administered the medication sequentially, the time interval between administration to one nostril of the first and fourth mice was sufficient to administer the medication to the other nostril of the first mouse. This method of fixing the mice in a chair effectively changed their position and allowed for simultaneous administration to multiple mice, greatly improving the efficiency of administration to a single mouse and significantly shortening the administration time for the same batch. Furthermore, sitting mice administered AlexaFluor488-labeled RVG9 ​​peptide-siRNA via the nose showed stronger fluorescence signals in their brains compared to supine mice. Whole-brain scans revealed significant accumulation of siRNA in major brain regions, including the olfactory bulb, cortex, hippocampus, thalamus, hypothalamus, midbrain, and cerebellum. However, it requires a complete set of devices including a seat frame, seat, and heating system, and still suffers from drawbacks such as inaccurate dosage during manual administration. Maigler et al. found that using a 10ul microsyringe connected to a neonatal catheter to administer medication specifically to the olfactory mucosa region can effectively increase brain entry efficiency and reduce peripheral drug loss, but catheter placement requires highly skilled operators and poses a certain risk of respiratory inhibition in mice. Summary of the Invention

[0006] In view of the above situation and to overcome the shortcomings of the existing technology, the present invention provides a micro-drug delivery device and a mouse nasal drug delivery device, aiming to achieve automated drug delivery in the study of nasal delivery of therapeutic drugs or exosomes for the treatment of central nervous system diseases, while improving the efficiency of nasal delivery of therapeutic substances to the brain.

[0007] The technical solution to the problem solved by this invention is as follows:

[0008] The first aspect of the present invention provides a micro-drug delivery device, including a micro-injector, a connecting tube, and a conduit; one end of the connecting tube is connected to the outlet of the micro-injector, and the other end is connected to the inlet of the conduit; the drug flows from the outlet of the micro-injector into the conduit through the connecting tube, and flows out through the outlet of the conduit; the direction of the conduit is configured such that the drug in the conduit flows in a reverse "Z" shape, thereby realizing automatic drug delivery.

[0009] In some embodiments of the present invention, the microsyringe is a pointed microsyringe, and the outlet of the microsyringe is an open, sharp bevel; the inlet of the conduit is pointed, has an open, sharp bevel, and matches the bevel of the outlet of the pointed microsyringe.

[0010] In some embodiments of the present invention, the catheter outlet is a pointed tip with a sharp bevel in an open state.

[0011] In some embodiments of the present invention, the catheter is selected as a PE10 catheter.

[0012] A second aspect of the present invention provides a nasal drug delivery device for mice, comprising the aforementioned micro-drug delivery device and a mouse restraint device; the mouse restraint device comprises, from bottom to top, a base, a lifting frame, and a placement frame; the lifting frame is used to adjust the height of the placement frame to adapt to the height of the catheter outlet; the placement frame is provided with a mouse placement slot, the mouse placement slot being adapted to the body size of the mouse, and a food trough in the middle of the mouse placement slot, the food trough including a groove for placing food and a platform for placing the mouse's forelimbs, facilitating the mouse to maintain a sitting posture.

[0013] In some embodiments of the present invention, the bottom of the base is provided with wheels to facilitate the movement of the mouse restraint device.

[0014] In some embodiments of the present invention, the lifting frame includes a lifting base and a lifting top, and a lifting assembly is connected between the lifting base and the lifting top. The lifting assembly includes a first bracket and a second bracket rotatably connected in the middle by a rotating shaft structure. The first bracket and the second bracket are provided with a hydraulic telescopic rod between the rotating shaft and the lifting base. The hydraulic telescopic rod is connected to the first bracket or the second bracket through a connection point located on the first bracket or the second bracket. The telescopic end of the hydraulic telescopic rod is connected to the connection point, and the other end is connected to the lifting base. The height of the lifting frame is adjusted by extending and retracting the hydraulic telescopic rod.

[0015] In some embodiments of the present invention, the frame of the placement rack is a boat-shaped structure with a low bow and high stern or a hollow right-angled trapezoid.

[0016] In some embodiments of the present invention, the frame of the placement rack is a boat-shaped structure with a low head and a high tail. The mouse placement slot is located in the receiving cavity of the boat-shaped structure. The side of the mouse placement slot is "S"-shaped and the bottom is elliptical, which can adapt to the body shape of the mouse and facilitate fixing the mouse's sitting posture. The food trough is located in the steep middle section of the "S" shape of the mouse placement slot, close to the position where the mouse's nasal cavity is placed during use.

[0017] In some embodiments of the present invention, the placement rack is a hollow right-angled trapezoidal body, the mouse placement slot is disposed in the receiving cavity of the hollow right-angled trapezoidal body, the side of the mouse placement slot is trapezoidal and the bottom is rectangular, which can adapt to the body shape of the mouse and facilitate fixing the sitting posture of the mouse, and the food trough is disposed in the middle section of the inclined side of the mouse placement slot, which is close to the position of the mouse's nasal cavity when in use.

[0018] In some embodiments of the present invention, the angle α between the inclined surface of the right trapezoid and the horizontal plane is 20° to 40°.

[0019] In some embodiments of the present invention, the upper surface of the base is provided with a first retaining groove that matches the shape of the lifting base of the lifting frame, and the upper surface of the lifting top seat of the lifting frame is provided with a second retaining groove that matches the shape of the bottom surface of the placement frame.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. The micro-drug delivery device provided by the present invention connects the micro-sampler and the catheter through a connecting tube, and sets the catheter to a reverse "Z" shape to ensure smooth flow of drug solution, accurate flow rate control, realize automatic drug delivery, and reduce the dosage error between multiple mice.

[0022] 2. The nasal drug delivery device for mice provided by the present invention is safe and efficient. By setting a mouse placement slot and a food slot adapted to the size of the mouse on the placement rack of the mouse fixation device, it is easy for the mouse to maintain a sitting posture, which effectively increases the efficiency of drug delivery to the brain. Since the received drug comes from the same syringe, it not only improves the drug delivery efficiency, but also eliminates the heterogeneity caused by drug delivery from different syringes.

[0023] 3. The mouse nasal drug delivery device provided by the present invention is easy to move by the walking wheels on the mouse fixing device base, which can greatly shorten the drug delivery interval for multiple mice and avoid affecting the observation of drug distribution and efficacy at the same time point after drug delivery. Attached Figure Description

[0024] Figure 1 This is a schematic diagram of a mouse restraint device according to an embodiment of the present invention.

[0025] Figure 2This is a schematic diagram of the micro-drug delivery device in one embodiment of the present invention.

[0026] Figure 3 This is a schematic diagram of the lifting frame in one embodiment of the present invention.

[0027] Figure 4 This is a schematic diagram of the base structure in one embodiment of the present invention.

[0028] Figure 5 This is a schematic diagram of the placement rack in one embodiment of the present invention.

[0029] Figure 6 This is a schematic diagram of the structure of a food trough in one embodiment of the present invention.

[0030] Figure 7 This is a schematic diagram of the use of a nasal drug delivery device for mice according to an embodiment of the present invention.

[0031] Reference numerals: 1-Microsyringe; 2-Connecting tube; 3-Instrument; 4-Base; 5-Lifting frame; 6-Placement frame; 11-Microsyringe outlet; 31-Instrument inlet; 32-Instrument outlet; 41-Wheel; 51-Lifting base; 52-Lifting top seat; 53-Lifting assembly; 530-Rotating shaft; 531-First support; 532-Second support; 533-Hydraulic telescopic rod; 534-Elastic support rod; 54-Connection point; 61-Mouse placement slot; 611-Food trough; 611a-Groove; 611b-Platform; 612-Side of mouse placement slot; X-Micro pump. Detailed Implementation

[0032] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

[0033] It should be understood that the structures, proportions, sizes, etc., depicted in the accompanying drawings are merely for illustrative purposes to aid those skilled in the art and to facilitate understanding. They are not intended to limit the scope of the invention and therefore have no substantial technical significance. Any modifications to the structure, changes in proportions, or adjustments to size, without affecting the effectiveness and objectives of the invention, should still fall within the scope of the technical content disclosed herein. Furthermore, the terms "upper," "lower," "left," "right," "middle," and "one" used in this specification are merely for clarity and not intended to limit the scope of the invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of the invention.

[0034] In this invention, the sitting posture is specifically that the back is against a rear support and the head is naturally drooping forward and downward.

[0035] The first aspect of the present invention provides a micro-drug delivery device, such as... Figure 2 As shown, the device includes a microsyringe 1, a connecting tube 2, and a conduit 3. One end of the connecting tube 2 is connected to the outlet 11 of the microsyringe, and the other end is connected to the inlet 31 of the conduit. The drug flows from the outlet 11 of the microsyringe into the conduit 3 via the connecting tube 2 and out through the outlet 32 ​​of the conduit. The direction of the conduit 3 is designed so that the drug flows in a reverse "Z" shape, which is beneficial for controlling the drug flow rate. In this invention, the microsyringe 1 is connected to a micropump for precise and uniform delivery of the drug solution. There are no special restrictions on the type of the microsyringe 1, as long as it can achieve the corresponding function. For example, it can be a flat-tipped microsyringe or a pointed-tipped microsyringe. There are no special restrictions on the material of the connecting tube 2, as long as it can ensure smooth passage of the drug solution. The tube diameter needs to match the diameter of the microsyringe 1 to achieve a tight connection. There are no special restrictions on the material of the conduit 3, as long as it can ensure smooth passage of the drug solution. The tube diameter needs to match the diameter of the connecting tube 2 to achieve a tight connection. In some embodiments of the present invention, such as Figure 2 As shown, the catheter 3 has an inverted "Z" shape. Generally, micro-syringes with a diameter of 100ul or more have a large inner diameter, making it difficult for the drug solution to form and maintain a droplet directly at the needle tip. The inverted "Z" shape design has three advantages: First, the inner diameter of the connected catheter is smaller, making it easier to form droplets suitable for absorption by the nasal cavity of small animals; second, it allows the drug in the catheter to flow in an inverted "Z" shape. When the liquid flows through the bend of the catheter, the flow rate slows down, which is conducive to the stable formation and slight dwell of the droplet at the end of the catheter, waiting for the mouse's next respiratory movement, and being naturally inhaled with the airflow; third, it can appropriately raise the droplet plane, which is closer to the natural position of the mouse's nasal cavity, and only requires slight adjustments with a lifting frame afterward.

[0036] In some embodiments of the present invention, such as Figure 2 As shown, the micro-syringe 1 is a pointed micro-syringe, and the outlet 11 of the micro-syringe is an open, sharp bevel. The inlet 31 of the conduit is pointed and has an open, sharp bevel, which matches the bevel of the outlet 11 of the pointed micro-syringe, thereby increasing the matching area between the inlet 31 of the conduit and the outlet 11 of the pointed micro-syringe and improving the smoothness of drug flow.

[0037] In some embodiments of the present invention, such as Figure 2 As shown, the catheter outlet 32 ​​is a pointed tip with a sharp, open bevel, which facilitates the formation of a droplet of the drug solution and its stay at the end of the catheter outlet 32, making it convenient for mice to inhale through their nasal cavity.

[0038] In some embodiments of the present invention, the catheter 3 is a PE10 catheter. The inner and outer diameters of the PE10 catheter are 0.28 mm and 0.61 mm, respectively. It is milky white and semi-transparent in appearance. Its small inner diameter makes it easy to form droplets suitable for absorption in the nasal cavity of small animals. It is semi-transparent and easy to observe.

[0039] A second aspect of the present invention provides a nasal drug delivery device for mice, as described in the reference. Figure 1 and Figure 7 The device includes the aforementioned micro-drug administration device and mouse restraint device; the mouse restraint device, from bottom to top, includes a base 4, a lifting frame 5, and a placement frame 6; the lifting frame 5 is used to adjust the height of the placement frame 6 to adapt to the outlet height of the catheter 3; Reference Figure 1 , Figure 5 , Figure 6 , Figure 7 The placement rack 6 is equipped with a mouse placement slot 61, which is adapted to the body size of the mouse. A food trough 611 is located in the middle of the mouse placement slot 61, including a groove 611a for placing food and a platform 611b for placing the mouse's forelimbs, facilitating the mouse's sitting posture. The connection method between the base 4, the lifting frame 5, and the placement rack 6 is not particularly limited, as long as their relative positions remain constant during use. Examples include direct stacking, snap-fit ​​connection, interlocking connection, bolt and nut connection, and adhesive bonding. Direct stacking or interlocking connection is preferred for ease of storage and replacement due to wear. The type of lifting frame 5 is not limited, as long as it allows for height adjustment of the placement rack 6. The connection method between the food trough 611 and the placement rack 6 is not limited; it can be a fixed connection or a detachable connection. The material of the food trough 611 is not limited, but a transparent material is preferred for easy observation. The food trough 611 is preferably positioned 1 cm below the tip of the mouse's nose after the mouse is placed. The groove 611a of the food trough 611 is used to place food with scents that mice like, such as chocolate or honey. The platform 611b of the food trough 611 is used to place the mouse's forelimbs to stabilize the mouse's sitting posture. Moreover, stimulating the sense of smell with scent can help the drug be absorbed by the olfactory epithelium and enter the brain more effectively.

[0040] In some embodiments of the present invention, such as Figure 4 As shown, the base 4 is equipped with wheels 41 at its bottom to facilitate the movement of the mouse restraint device. The number and size of the wheels 41 are not particularly limited, as long as they enable rapid and stable movement of the base and the mouse restraint device. (Refer to...) Figure 4 There are usually 4.

[0041] In some embodiments of the present invention, such as Figure 3As shown, the lifting frame 5 includes a lifting base 51 and a lifting top 52. A lifting assembly 53 is connected between the lifting base 51 and the lifting top 52. The lifting assembly 53 includes a first bracket 531 and a second bracket 532 rotatably connected at their middle portions via a rotating shaft structure 530. A hydraulic telescopic rod 533 is provided between the first bracket 531 and the second bracket 532 and the rotating shaft 530 and the lifting base 51. The hydraulic telescopic rod 533 is connected to the first bracket 531 or the second bracket 532 via a connection point 54 located on the first bracket 531 or the second bracket 532. The telescopic end of the hydraulic telescopic rod 533 is connected to the connection point 54, and the other end is connected to the lifting base 51. The height of the lifting frame 5 is adjusted by extending and retracting the hydraulic telescopic rod 533. In some embodiments of the present invention, such as... Figure 1 As shown, the lifting frame 5 includes a lifting top seat 52 and two sets of lifting components 53 disposed at the bottom of the lifting top seat 52. Each set of lifting components 53 includes a first bracket 531 and a second bracket 532 rotatably connected in the middle by a rotating shaft structure 530, and an elastic support rod 534 connecting the top end of the first bracket 531 (i.e. the end in contact with the lifting top seat 52) ​​and the bottom end (i.e. the support end) of the second bracket 532. The height of the lifting frame 5 can be adjusted by adjusting the opening and closing angle of the first support rod 531 and the second support rod 532.

[0042] In some embodiments of the present invention, the frame of the placement rack 6 is a ship-shaped structure with a low bow and high stern (e.g., Figure 1 and Figure 7 (as shown) or a hollow right-angled trapezoid (such as) Figure 5 As shown). Preferably, the angle between the inclined plane of the hollow right trapezoid and the horizontal plane (e.g., ...) Figure 5 The angle α shown is 20°~40°. Placing the frame 6 at this angle is more suitable for mice to maintain a sitting posture, and 30° is more preferred.

[0043] In some embodiments of the present invention, the frame of the placement rack 6 is a boat-shaped structure with a low head and a high tail. The mouse placement slot 61 is located in the receiving cavity of the boat-shaped structure. The side 612 of the mouse placement slot is "S"-shaped and the bottom is elliptical, which can adapt to the body shape of the mouse and facilitate fixing the mouse's sitting posture. The food trough 611 is located in the steep middle section of the "S" shape of the mouse placement slot 61, which is close to the position where the mouse's nasal cavity is placed when in use.

[0044] In some embodiments of the present invention, the placement rack 6 is a hollow right-angled trapezoidal body, the mouse placement slot 61 is disposed in the receiving cavity of the hollow right-angled trapezoidal body, the side 612 of the mouse placement slot is trapezoidal and the bottom is rectangular, which can adapt to the body shape of the mouse and facilitate fixing the sitting posture of the mouse. The food trough 611 is disposed in the middle section of the inclined side of the mouse placement slot 61, which is close to the position where the mouse's nasal cavity is placed when in use.

[0045] In some embodiments of the present invention, the frame of the placement rack 6 has dimensions of 50~70×110~130×40~60mm (width×length×height), and the mouse placement slot 61 has dimensions of 30~40×90~110×20~40mm (width×length×height), suitable for placing mice weighing 18~25 g. In other embodiments of the present invention, the frame of the placement rack 6 has dimensions of 70~90×140~160×40~60mm (width×length×height), preferably 80×150×50mm, and the mouse placement slot has dimensions of 30~40×90~110×20~40mm (width×length×height), preferably 35×100×30mm, suitable for mice weighing more than 25 g.

[0046] In some preferred embodiments of the present invention, the frame of the placement rack 6 has a width × length × height of 60 × 120 × 50 mm, the mouse placement slot 61 has a width × length × height of 35 × 100 × 30 mm, and is used to place mice weighing 18~25 g. The outer length of the food trough 611 is set to 30 mm, the inner length is set to 25 mm, the outer width is set to 20 mm, and the inner width is set to 15 mm. The height of the groove 611a is set to 20 mm, which can accommodate mouse food blocks. The height of the platform 611b is set to 10 mm, which is convenient for placing the mouse's forelimbs.

[0047] In some embodiments of the present invention, the upper surface of the base 4 is provided with a first fixing groove that matches the shape of the lifting base of the lifting frame 5, and the upper surface of the lifting top seat of the lifting frame 5 is provided with a second fixing groove that matches the shape of the bottom surface of the frame of the placement frame 6. During assembly, the lifting base of the lifting frame 5 is embedded in the first fixing groove on the upper surface of the base 4, and the bottom surface of the frame of the placement frame 6 is embedded in the second fixing groove on the upper surface of the lifting top seat of the lifting frame 5 to achieve a fitting connection and avoid displacement during use.

[0048] Working principle: such as Figure 2The micro-drug delivery device shown allows the drug solution to flow out at a certain speed through the micro-injector 1 after the injection speed of the micro-injector 1 is set on the micro-pump X. Because the connecting tube 2 matches the inclined surface of the inlet 31 of the catheter with the inclined surface of the outlet 11 of the micro-injector, the drug solution smoothly enters the catheter 3 and flows in a reverse "Z" shape within the catheter 3, eventually settling in droplets. Figure 2 At the 32-point tip of the middle catheter outlet, the drug flows smoothly and the flow rate is accurately controlled, enabling automatic drug delivery and reducing dosage errors among multiple mice.

[0049] like Figure 1 The mouse restraint device shown places the mouse in the placement frame 6 at the top of the device. The height of the lifting frame 5 is adjusted so that the mouse's nasal cavity is positioned within the device. Figure 2 The catheter outlet 32 ​​of the micro-dose delivery device is located 0.5 cm above the tip. The first drop of medication remaining at the tip of the catheter outlet 32 ​​can be inhaled into the nasal cavity by a mouse through normal sniffing. After the first drop is inhaled, a second drop forms at the pre-set needle insertion speed, also in drop form, and remains at the tip of the catheter outlet 32 ​​at the appropriate interval, and can again be inhaled into the nasal cavity by the mouse through normal sniffing. This process is repeated to complete the drug delivery.

[0050] Build multiple Figure 1 The mouse restraint device shown is used to place the mouse in the mouse placement slot 61 of the uppermost placement frame 6 of the mouse restraint device, maintaining a sitting posture. The tip of the mouse's nose is adjusted to be 1 cm above the upper end of the food trough 611. The height of the lifting frame 5 is adjusted so that the mouse's nasal cavity is positioned... Figure 2 Multiple mice can be secured at once at a point 0.5 cm above the tip of the catheter outlet 32. The first drop of medication remaining at the tip of the catheter outlet 32 ​​can be inhaled into the nasal cavity by the first mouse through normal sniffing. During the time it takes for the second drop of medication to form, the first mouse can be moved away by moving the wheels 41 at the bottom of the mouse-fixing device base 4. The second mouse can then be moved... Figure 1 The second mouse is moved to the base 4 of the mouse restraint device by the wheels 41 at the bottom. This allows the second drop of medication, which is currently in a droplet position at the tip of the catheter outlet 32, to be inhaled into the nasal cavity by the second mouse through normal sniffing. This process can be repeated for multiple mice. Furthermore, since the medication received by these multiple mice originates from the same microsyringe, the drug administration efficiency is improved, and the heterogeneity caused by administration via different microsyringes is eliminated.

[0051] Application Examples

[0052] Taking intranasal administration to two mice as an example, according to Figure 2The micro-drug delivery device is connected as shown, with the bevel of the catheter inlet 31 matching the bevel of the pointed micro-syringe outlet 11. The micro-syringe outlet 11 is connected to the catheter inlet 31 via the connecting tube 2, and the catheter 3 is oriented in a reverse "Z" shape. The tip of the catheter outlet 32 ​​is at... Figure 2 At the position shown, inject 500 μL of drug solution into microsyringe 1, set the injection rate to 2 μL / min on the microsyringe control plane, and start the device to allow the drug solution to flow through connecting tube 2 and conduit 3. When the first drop of drug solution appears... Figure 2 When the catheter tip (32) is reached, it indicates that the drug delivery device is ready and the injection process is paused.

[0053] Two mice were anesthetized by intraperitoneal injection of a mixture of ketamine (60 mg / kg) and thiazide (5 mg / kg). Figure 7 As shown, after the mice were anesthetized, they were placed in two separate machines. Figure 1 The mouse restraint device shown consists of a base 4, a lifting frame 5, and a placement frame 6 stacked from bottom to top. The mouse is placed in the top placement frame 6 in a seated position. The food trough 611 is positioned 1 cm below the tip of the mouse's nose after placement, and contains food with scents that mice like, such as chocolate or honey. The height of the lifting frame 5 is adjusted so that the mouse's nasal cavity is positioned within the... Figure 2 0.5 cm above the tip of the middle catheter outlet 32.

[0054] Initiating the injection allows the mouse to inhale the first drop of medication, which rests at the tip of the catheter outlet 32, into one nostril through normal sniffing. During the time it takes for the second drop to form, the first mouse is removed via the wheels 41 at the bottom of the base 4, and a second mouse is brought in from the second restraint device, ensuring its nostril is also positioned correctly. Figure 2 0.5 cm above the tip of the central catheter outlet 32, so that it remains in a droplet shape. Figure 2 The second drop of medication at the tip of the duct exit 32 was inhaled into one nostril by the second mouse through normal sniffing. The experiment was repeated so that the third drop was inhaled into the other nostril by the first mouse, and the fourth drop into the other nostril by the second mouse, and so on.

[0055] Stop the injection once the required dose has been reached.

[0056] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A nasal drug delivery device for mice, characterized in that, Includes micro-dose delivery devices and mouse restraint devices; The micro-drug delivery device includes a micro-injector (1), a connecting tube (2), and a catheter (3); one end of the connecting tube (2) is connected to the outlet (11) of the micro-injector, and the other end is connected to the inlet (31) of the catheter; the drug flows from the outlet (11) of the micro-injector through the connecting tube (2) into the catheter (3), and flows out through the outlet (32) of the catheter, thus realizing automatic drug delivery; the direction of the catheter (3) is set so that the drug in the catheter flows in an anti-Z-shaped pattern. The microsyringe is a pointed microsyringe with the outlet (11) of the microsyringe being an open, sharp bevel. The inlet (31) of the catheter is pointed and has an open, sharp bevel, which matches the bevel of the outlet (11) of the microsyringe. The outlet (32) of the catheter is pointed and has an open, sharp bevel, which facilitates the formation of a droplet of the drug solution at the end of the outlet (32), making it convenient for mice to inhale through their nasal cavity. The mouse restraint device includes, from bottom to top, a base (4), a lifting frame (5), and a placement frame (6); the lifting frame (5) is used to adjust the height of the placement frame (6) to match the height of the tube (3) outlet; the placement frame (6) is provided with a mouse placement slot (61), which is adapted to the size of the mouse; a food trough (611) is provided in the middle of the mouse placement slot (61), which includes a groove (611a) for placing food and a platform (611b) for placing the mouse's forelimbs, so that the mouse can maintain a sitting posture with its back against the rear support and its head naturally drooping forward and downward.

2. The nasal drug delivery device for mice as described in claim 1, characterized in that, The base (4) is equipped with wheels (41) at the bottom to facilitate the movement of the mouse fixation device.

3. The nasal drug delivery device for mice as described in claim 1, characterized in that, The lifting frame (5) includes a lifting base (51) and a lifting top seat (52). A lifting assembly (53) is connected between the lifting base (51) and the lifting top seat (52). The lifting assembly (53) includes a first bracket (531) and a second bracket (532) that are rotatably connected in the middle by a rotating shaft structure (530). The first bracket (531) and the second bracket (532) are provided with a hydraulic telescopic rod (533) between the rotating shaft structure (530) and the lifting base (51). The hydraulic telescopic rod (533) is connected to the first bracket (531) or the second bracket (532) through a connection point (54) located on the first bracket (531) or the second bracket (532). The telescopic end of the hydraulic telescopic rod (533) is connected to the connection point (54), and the other end is connected to the lifting base (51). The height of the lifting frame (5) can be adjusted by extending and retracting the hydraulic telescopic rod (533).

4. The nasal drug delivery device for mice as described in claim 1, characterized in that, The frame of the placement rack (6) is a ship-shaped structure with a low head and high stern or a hollow right-angled trapezoid.

5. The nasal drug delivery device for mice as described in claim 4, characterized in that, The frame of the placement rack (6) is a boat-shaped structure with a low head and high tail. The mouse placement slot (61) is located in the cavity of the boat-shaped structure. The side (612) of the mouse placement slot is "S" shaped and the bottom is elliptical, which can adapt to the body shape of the mouse and make it easy to fix the mouse's sitting posture. The food trough (611) is located in the steep middle section of the "S" shape of the mouse placement slot (61) and is close to the position of the mouse's nasal cavity when in use. Alternatively, the placement rack (6) is a hollow right-angled trapezoid. The mouse placement slot (61) is located in the cavity of the hollow right-angled trapezoid. The side (612) of the mouse placement slot is trapezoidal and the bottom is rectangular, which can adapt to the body shape of the mouse and make it easy to fix the mouse's sitting posture. The food trough (611) is located in the middle section of the inclined side of the mouse placement slot (61) and is close to the position of the mouse's nasal cavity when in use.

6. The nasal drug delivery device for mice as described in claim 5, characterized in that, The angle α between the inclined plane of the right trapezoid and the horizontal plane is 20°~40°.

7. The nasal drug delivery device for mice as described in claim 1, characterized in that, The upper surface of the base (4) is provided with a first fixing groove that matches the shape of the lifting base of the lifting frame (5), and the upper surface of the lifting top seat of the lifting frame (5) is provided with a second fixing groove that matches the shape of the bottom surface of the frame of the placement frame (6).

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