A nose drop preparation for alleviating motion sickness and its preparation method and application

Abstract

The application belongs to the technical field of biotechnology, and provides a nasal drop preparation for relieving motion sickness, a preparation method and application thereof, wherein the nasal drop preparation is prepared by loading L-mintol into exosomes derived from a mouse hippocampal neuron cell line HT22 through ultrasonic method, and the nasal drop preparation can be directly introduced into the brain through the nasal mucosa-olfactory nerve pathway, precisely target the brain regions related to motion sickness, avoid the gastrointestinal digestion and liver first-pass effect, and has the advantages of safe components, small side effects, rapid effect, convenient use and sustained release function.

Description

Technical Field

[0001] This invention relates to the field of biotechnology, specifically to a nasal drop preparation for relieving motion sickness, its preparation method, and its application. Background Technology

[0002] Motion sickness (MS) is an autonomic nervous system dysfunction caused by information conflict between the vestibular, visual, and proprioceptive systems. Symptoms include headache, nausea, vomiting, cold sweats, fatigue, and drowsiness, severely impacting the quality of life of susceptible individuals. Epidemiological studies show that approximately 30% of the population has experienced significant motion sickness, with an incidence rate as high as 50% in autonomous driving scenarios. The incidence rate of visual motion sickness induced by high-intensity military operations and the application of AR / VR technology is even higher, reaching 60%.

[0003] Currently, commonly used medications for motion sickness treatment mainly include anticholinergic drugs (such as scopolamine), first-generation antihistamines (such as dimenhydrinate), calcium channel blockers (such as cinnarizine), and dopamine receptor antagonists. Scopolamine transdermal patches need to be used 6-8 hours in advance and are prone to causing side effects such as dry mouth, blurred vision, and drowsiness; dimenhydrinate has a short duration of action and also causes drowsiness; promethazine requires intramuscular injection, which is inconvenient and may cause respiratory depression; long-term use of dopamine receptor antagonists may also cause extrapyramidal symptoms.

[0004] In recent years, traditional Chinese medicine ingredients such as ginger and menthol (MNT) have been used to alleviate motion sickness due to their relatively high safety profile. However, oral administration has drawbacks, including slow gastrointestinal absorption, significant first-pass effect in the liver, and low dose reaching the brain. Furthermore, patients experiencing severe vomiting may be unable to swallow the medication properly. Exosomes (EXO), extracellular vesicles with a diameter of 30-200 nm, possess advantages such as good biocompatibility, low immunogenicity, ability to cross the blood-brain barrier, and strong targeting, making them a novel drug delivery carrier. Nasal drops can directly reach the brain via the nasal mucosa-olfactory nerve pathway, offering rapid onset of action and avoiding the first-pass effect. However, there are currently no commercially available nasal drop formulations for motion sickness. Therefore, there is an urgent need to provide a nasal drop formulation for alleviating motion sickness, along with its preparation method and application, to overcome the shortcomings in current practical applications. Summary of the Invention

[0005] The purpose of this invention is to provide a nasal drop preparation for relieving motion sickness, its preparation method, and its application, thereby addressing the problems mentioned in the background art.

[0006] The present invention is achieved as follows: a nasal drop formulation for relieving motion sickness, comprising drug-loaded exosomes, wherein the drug-loaded exosomes are exosomes derived from the mouse hippocampal neuronal cell line HT22 loaded with L-menthol.

[0007] As a further aspect of the present invention: the concentration of L-menthol in the drug-loaded exosomes is 0.78 mM, and the dose of the exosomes is 1.2 × 10⁻⁶. 9 particles / only.

[0008] The present invention also provides a method for preparing the nasal drop formulation for relieving motion sickness as described above, comprising the following steps:

[0009] S1. Prepare a complete culture medium containing EXO;

[0010] S2. Extraction of EXO from HT22 using density gradient centrifugation;

[0011] S3. Ultrasound-assisted loading of EXO with MNT yields drug-loaded exosomes EXO-MNT;

[0012] S4. Prepare drug-loaded exosomes into nasal drops.

[0013] As a further aspect of the present invention, the specific steps of step S1 are as follows:

[0014] Fetal bovine serum was ultracentrifuged at 100,000g for 15 hours at 4℃ to remove EXO; filtered through a 0.22μm filter and aliquoted for cryopreservation.

[0015] When HT22 cells reached 70% confluence, the cells were washed twice with D-PBS, and then EXO-free serum-free medium was added. The cell supernatant was collected after 48 hours.

[0016] As a further aspect of the present invention, the specific steps of step S2 are as follows:

[0017] Centrifuge at 4℃, 800g for 10 min, and collect the supernatant;

[0018] Centrifuge at 2000g for 10 minutes at 4℃, and collect the supernatant;

[0019] Centrifuge at 16000g for 30 minutes at 4℃, and collect the supernatant;

[0020] Transfer the supernatant to an ultracentrifuge tube, centrifuge at 120,000g-150,000g for 70 min at 4°C, discard the supernatant, and wash the precipitate with sterile pre-cooled PBS.

[0021] Balance the solution again, centrifuge at high speed, discard the supernatant, and resuspend the precipitate in 20-50 μL of sterile pre-cooled PBS.

[0022] As a further aspect of the present invention, step S3 specifically involves the following steps:

[0023] Exosomes were treated with 200 μL of hypotonic lysis buffer containing 10 mM Tris, 10 mM MgCl2 and 1 mM phenylmethylsulfonyl fluoride at pH 7.4 for 30 min.

[0024] Sonicate on ice for 5 seconds at 20% amplitude, centrifuge at 16000g for 30 minutes, and discard the supernatant;

[0025] Resuspend the precipitate in 1 mM MNT solution and sonicate on ice for 2 min.

[0026] Centrifuge at 16000g for 30 min, discard the supernatant, wash the precipitate with PBS to obtain EXO-MNT.

[0027] The present invention also provides the use of the nasal drop formulation described above in the preparation of a drug for relieving motion sickness.

[0028] As a further aspect of the present invention: the nasal drop preparation is administered via nasal drops, with each dose being 20 μL.

[0029] As a further aspect of the present invention: the nasal drops are administered 30 minutes before motion sickness stimulation.

[0030] As a further aspect of the present invention: the motion sickness includes motion sickness induced by transportation and motion sickness induced by special military operations related to vestibular function.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] This invention utilizes an ultrasound-assisted method to prepare HT22-derived EXO-MNT for the treatment of MS. Compared to previous MS treatments, EXO-MNT exhibits fewer side effects, with no adverse reactions such as confusion, drowsiness, or dizziness observed in mice. The nasal drop administration method effectively avoids the drawback of patients with severe vomiting being unable to take medication orally as in traditional methods. Because nasal drops allow direct access to the brain, they reduce gastrointestinal absorption and the first-pass effect of the liver, facilitating precise targeting of brain regions closely related to MS.

[0033] Behavioral experiments showed that the EXO-MNT group mice exhibited greater improvement in motor skills than the MNT group mice. In the balance beam test, the EXO-MNT group mice showed a significant decrease in both crossing time and the number of slips, while the MNT group only showed a decreasing trend. Furthermore, compared to the MNT group, the EXO-MNT group mice also showed a decreasing trend in both crossing time and the number of slips. In the cylinder test, the EXO-MNT group mice showed a significant decrease in the percentage of single-leg gripping and a significant increase in the percentage of double-leg gripping, while the MNT group only showed a decreasing or increasing trend.

[0034] ELISA results showed that the recovery rates of AVP, CORT, NA, EPI, β-EP, and ACTH levels in the serum of mice in the EXO-MNT group were significantly better than those in the MNT group, indicating that hormone levels in MS mice gradually returned to normal after intranasal administration of EXO-MNT. These results collectively demonstrate that intranasal administration of EXO-MNT is more effective than MNT in treating MS mice. Attached Figure Description

[0035] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0036] Figure 1 This is a schematic diagram of a rotary speed-adjustable motion sickness inducing device.

[0037] Figure 2 Transmission electron micrograph of HT22-derived exosomes;

[0038] Figure 3 Transmission electron microscopy image of drug-loaded exosome EXO-MNT;

[0039] Figure 4 A schematic diagram of the dose-response curve for L-menthol nasal drops;

[0040] Figure 5 The graph shows the results of the balance beam experiment for each group of mice, where A represents the time to pass and B represents the number of times the feet slipped.

[0041] Figure 6 The results of the cylinder experiment for each group of mice are shown in the figure. A represents the percentage of times the mice paddled the wall with one leg, and B represents the percentage of times the mice paddled the wall with both legs.

[0042] Figure 7 The graph shows the results of serum hormone level detection in mice of each group. Detailed Implementation

[0043] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0044] The present invention will be further explained below with reference to specific embodiments.

[0045] This invention provides a nasal drop formulation for relieving motion sickness (MS) by administering the medication via nasal drops. It comprises the following components: an EXO prepared using a mouse hippocampal neuronal cell line (HT22), an ultrasound-assisted drug delivery system (MNT), and a nasal drop formulation for drug administration.

[0046] In this embodiment, the present invention develops a nasal administration method for EXO-loaded MNTs that combines safe ingredients, precise targeting, simple operation, rapid onset of action, and exosome sustained release function, in order to alleviate the adverse reactions of MS.

[0047] This invention also provides a method for preparing the nasal drop formulation for relieving motion sickness as described above, comprising the following steps:

[0048] S1. Prepare a complete culture medium containing EXO;

[0049] Specifically:

[0050] Fetal bovine serum (FBS) was ultracentrifuged at 100,000 g for 15 h at 4 ℃ to remove EXO from the serum; filtered through a 0.22 μm filter and aliquoted for cryopreservation.

[0051] When HT22 cells reached 70% confluence, they were washed twice with Dulbecco's phosphate-buffered saline (D-PBS), and then EXO-free serum-free medium was added. After 48 h, the cell supernatant was collected and stored at -80 °C for later use.

[0052] S2. Extraction of EXO from HT22 using density gradient centrifugation;

[0053] Specifically: Centrifuge at 800 g for 10 min at 4 ℃, and collect the supernatant; centrifuge at 2000 g for 10 min at 4 ℃, and collect the supernatant; centrifuge at 16000 g for 30 min at 4 ℃, and collect the supernatant; transfer the supernatant to an ultracentrifuge tube, centrifuge at 120000 g-150000 g for 70 min at 4 ℃, discard the supernatant completely, and the precipitate will be contaminated with proteins and exosomes. Wash with sterile pre-chilled PBS to remove the contaminated proteins; balance the liquid again, ultracentrifuge under the same conditions as the previous step, wash the precipitate, and discard the supernatant as completely as possible. If there is no visible precipitate, the supernatant can be centrifuged again; resuspend the precipitate in 20-50 μL of sterile pre-chilled PBS, store at -80 °C for later use, and avoid repeated freeze-thaw cycles.

[0054] S3. Ultrasound-assisted loading of EXO with MNT yields drug-loaded exosomes EXO-MNT;

[0055] Specifically:

[0056] The exosomes obtained in the previous step were treated with 200 μL of hypotonic lysis buffer containing 10 mM Tris, 10 mM MgCl2 and 1 mM phenylmethanesulfonyl fluoride at pH 7.4 for 30 min. After sonication on ice (amplitude 20%) for 5 s, the mixture was centrifuged at 16000 g for 30 min, resuspended in 1 mM MNT solution, sonicated on ice for 2 min (sonication 20 s, pause for 5 s, repeated 5 times), centrifuged at 16000 g for 30 min, the supernatant was discarded and the mixture was resuspended, washed once with PBS to obtain EXO-MNT.

[0057] S4. Prepare drug-loaded exosomes into nasal drops.

[0058] The present invention also provides the use of the nasal drop formulation described above in the preparation of a drug for relieving motion sickness.

[0059] In this embodiment, EXO-MNT was administered via nasal drops: Mice were lightly anesthetized with 2% isoflurane, and 20 μL of EXO-MNT was slowly administered by alternately dripping it into the left and right nostrils using a pipette. The animals were kept in a supine position for at least 10 minutes to allow for full absorption of the drug by the nasal mucosa.

[0060] This invention establishes an MS model and verifies the drug loading effect:

[0061] In this embodiment, the MS model was established according to the technical solution disclosed in patent CN201375509Y. Half an hour before rotation, mice were administered EXO, MNT, EXO-MNT, and saline solution as a control group via intranasal drops. After modeling, behavioral experiments or blood hormone levels were measured in the animals to verify the drug loading effect.

[0062] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments:

[0063] Example 1: Extraction, loading, and validation of EXO:

[0064] HT22 cells were revived and cultured in T25 flasks in Dulbecco's modified eagle medium (DMEM) containing 10% FBS and 1% penicillin-dextrose antibiotics. When cell confluence reached 80%, the supernatant was discarded, and the cells were washed twice with pre-chilled sterile PBS. Digestion was then performed in a 37°C incubator for 1 min using 0.25% trypsin-ethylenediaminetetraacetic acid (EDTA) digestion solution. The cells were removed from the flasks, and digestion was terminated by adding DMEM complete medium. The mixture was then transferred to 15 mL centrifuge tubes, centrifuged at 800 g for 5 min, and the supernatant was discarded. The cells were resuspended in 1 mL of DMEM complete medium and cultured in T75 flasks. Subculture was repeated at a 1:3 ratio until cells were cultured in a 5-layer cell factory. At this point, once the cell confluence reaches 70%, discard the supernatant, wash twice with pre-cooled sterile PBS, add 500 mL of DMEM medium containing 10% EXO-free FBS, and culture for 48 h. Collect the cell supernatant and store it at -80 ℃ for later use.

[0065] EXO was extracted using density gradient centrifugation. A portion of the EXO was then loaded onto MNTs using ultrasonication.

[0066] EXO and EXO-MNT were validated. 10 μL of EXO or EXO-MNT suspension was mixed with an equal volume of 4% paraformaldehyde fixative (PFA) solution and allowed to stand at room temperature for 10 min. A copper mesh was held horizontally on a table using self-locking tweezers, with the front side facing up. 10 μL of sample was added to the copper mesh and allowed to precipitate for 1 min. The surface liquid was then absorbed with filter paper. 10 μL of 2% uranium acetate was added to the copper mesh for negative staining for 40 s. The surface liquid was absorbed with filter paper, and the mesh was allowed to dry at room temperature for several minutes. The electron microscopy results were then photographed and observed.

[0067] Example 2: Effective dose of MNT administered via the nose:

[0068] In this embodiment, the MS model was established with reference to the technical solution disclosed in patent CN201375509Y. The rotary speed-adjustable rat motion sickness inducing device contains a large disc and a small disc fixed on the large disc. The large and small discs are electrically connected to the drive motors and control circuits of the large and small discs, respectively. The diameter of the large disc is 100 cm, and the diameter of the small disc is 30 cm. The small disc is fixed around the periphery of the large disc, and the distance between their axes is 20-45 cm. During operation, the angular velocity of the large disc is adjusted to 150 ° / s using a voltage regulator, rotating clockwise for 15 s and then counterclockwise for 15 s, alternating between the two. The alternation of directions generates an acceleration and deceleration of 90 ° / s. The angular velocity of the small disc is 450 ° / s. During the experiment, each rat is placed in a 50 mL dark-colored centrifuge tube, and gauze is placed under its rump to secure it. The centrifuge tube is then installed on the small disc with the rat's head facing outwards and nose downwards, tilted at 30 °. Next, the switch was turned on and the device was rotated for 2 hours. The control group mice were placed near the rotating device for 2 hours, receiving the same sham stimulation as the rotation group, but without exposure to actual rotational motion (e.g., ...). Figure 1 ).

[0069] Before rotation, mice were administered MNT at doses of 0.1 mM, 0.64 mM, 1 mM, 2 mM, and 5 mM, respectively. Based on the results, nonlinear regression was used to fit the dose-response curves. Next, based on the obtained ED... 50 Administer the drug to animals.

[0070] Example 3: Nasal administration of MNT-EXO can effectively relieve MS:

[0071] An MS model was established using Example 2. Before modeling, mice were administered 20 μL of physiological saline solution with a concentration of 1.2 × 10⁻⁶ ppm via intranasal drops. 9 EXO particles were prepared in PBS solution, 0.78 mM MNT, and EXO-MNT (concentrations were the same as those of EXO and MNT mentioned above). After modeling, the sustained-release function of the drug was verified.

[0072] Behavioral experiments to test the efficacy of MNT-EXO:

[0073] Balance beam test (BBT): A self-made wooden beam, 120 cm long and 1.2 cm wide, was used to guide the animal to walk naturally from one end. Before the experiment, the animals were trained for 3 days to ensure they could walk across the balance beam normally. The entire experiment was video-recorded, recording the time it took the mice to cross the beam and the number of times their feet slipped.

[0074] Cylinder test (CT): An opaque cylinder with a height of 20 cm and an inner diameter of 13 cm was made. Each time, the animal was placed into the cylinder from the same position and allowed to move freely for 6 minutes. The percentage of times the mouse scratched the cylinder with one foot and two feet in the last 5 minutes was recorded.

[0075] Enzyme-linked immunosorbent assay (ELISA) was used to assess the efficacy of MNT-EXO.

[0076] The levels of arginine vasopressin (AVP), corticosterone (CORT), noradrenaline (NA), epinephrine (EPI), beta-endorphin (β-EP), and adrenocorticotropic hormone (ACTH) in serum were measured. Whole blood samples were collected in sterile, enzyme-free plain EP tubes. After the samples were incubated at room temperature for 1 h, they were centrifuged at 3000 rpm for 10 min, and the supernatant was collected into new EP tubes. 96-well microplates were coated overnight at 4 °C; blocked with PBS containing 1% bovine serum albumin (BSA) for 1 h; gradient standards and test samples were added, and incubated at 37 °C for 1 h; after sequential incubation with the detection antibody and horseradish peroxidase (HRP)-labeled secondary antibody, 3,3',5,5'-tetramethylbenzidine (TMB) substrate was used for color development, and the reaction was terminated with 2 M H2SO4; absorbance at 450 nm was measured using a microplate reader, and a four-parameter logistic curve was fitted to calculate the sample concentration.

[0077] All data were analyzed using Graphpad Prism 9, and are expressed as mean ± standard error (x ± SEM). Behavioral experiment and ELISA data were analyzed using one-way ANOVA; p < 0.05 was considered statistically significant.

[0078] The results of the embodiments are analyzed below:

[0079] For EXO derived from HT22 and EXO-MNT obtained by ultrasound, electron microscopy revealed that EXO possesses a saucer-like structure with a double membrane (e.g., Figure 2 For EXO-MNT, electron microscopy revealed irregular protrusions on the EXO surface, accompanied by scleral vegetations, confirming successful drug loading (e.g., ...). Figure 3 ).

[0080] For ED of MNT administered via nasal drops 50 The detection method uses nonlinear regression to fit the dose-response curve, and the ED is obtained from the fitting. 50 It is 0.78 mM (e.g.) Figure 4 ).

[0081] BBT results showed that compared with the saline group, the EXO-MNT group mice had significantly reduced passage time and number of slips, while the MNT group only showed a decreasing trend; compared with the MNT group, the EXO-MNT group mice showed a decreasing trend in both passage time and number of slips; these results collectively indicate that intranasal administration of EXO-MNT improved motor function in MS mice (e.g., Figure 5 ).

[0082] CT results showed that, compared with the saline group, the percentage of single-leg wall-crawling in the EXO-MNT group was significantly decreased, while the percentage of double-leg wall-crawling was significantly increased. The MNT group only showed a decreasing or increasing trend, indicating that intranasal administration of EXO-MNT improved the motor balance function of MS mice (e.g., Figure 6 ).

[0083] ELISA results showed that, compared with the saline group, the levels of AVP, CORT, NA, EPI, and ACTH in the serum of EXO-MNT group mice were significantly decreased, while the level of β-EP was significantly increased. In contrast, the levels of CORT and NA in the serum of MNT group mice were only decreased, while the level of β-EP was increased. Furthermore, the decrease or increase in concentration was lower than that in the EXO-MNT group, indicating that after intranasal administration of EXO-MNT, the hormone levels in MS mice gradually returned to normal (e.g., ...). Figure 7 ).

[0084] In summary, this invention utilizes ultrasound-assisted preparation of HT22-derived EXO-MNT for the treatment of MS. Compared to previous MS treatments, EXO-MNT exhibits fewer side effects, with no adverse reactions such as confusion, drowsiness, or dizziness observed in mice. The nasal instillation method effectively avoids the drawback of patients with severe vomiting being unable to take medication orally. Because nasal instillation allows direct access to the brain, it reduces gastrointestinal absorption and the first-pass effect of the liver, facilitating precise targeting of brain regions closely related to MS. For BBT (Brain-Body ... ELISA results showed that the recovery rates of AVP, CORT, NA, EPI, β-EP, and ACTH levels in the serum of mice in the EXO-MNT group were significantly better than those in the MNT group, indicating that hormone levels in MS mice gradually returned to normal after intranasal administration of EXO-MNT. These results collectively demonstrate that intranasal administration of EXO-MNT is more effective than MNT in treating MS mice.

[0085] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A nasal drop preparation for relieving motion sickness, characterized in that, The drug-loaded exosomes are derived from the mouse hippocampal neuronal cell line HT22 and loaded with L-menthol.

2. The nasal drop preparation for relieving motion sickness according to claim 1, characterized in that, The concentration of L-menthol in the drug-loaded exosomes was 0.78 mM, and the dose of the exosomes was 1.2 × 10⁻⁶. 9 particles / only.

3. A method for preparing a nasal drop formulation for relieving motion sickness as described in claim 1 or 2, characterized in that, Includes the following steps: S1. Prepare a complete culture medium containing EXO; S2. Extraction of EXO from HT22 using density gradient centrifugation; S3. Ultrasound-assisted loading of EXO with MNT yields drug-loaded exosomes EXO-MNT; S4. Prepare drug-loaded exosomes into nasal drops.

4. The preparation method according to claim 3, characterized in that, The specific steps of step S1 are as follows: Fetal bovine serum was ultracentrifuged at 100,000g for 15 hours at 4℃ to remove EXO; filtered through a 0.22μm filter and aliquoted for cryopreservation. When HT22 cells reached 70% confluence, the cells were washed twice with D-PBS, and then EXO-free serum-free medium was added. The cell supernatant was collected after 48 hours.

5. The preparation method according to claim 3, characterized in that, The specific steps of step S2 are as follows: Centrifuge at 4℃, 800g for 10 min, and collect the supernatant; Centrifuge at 2000g for 10 minutes at 4℃, and collect the supernatant; Centrifuge at 16000g for 30 minutes at 4℃, and collect the supernatant; Transfer the supernatant to an ultracentrifuge tube, centrifuge at 120,000g-150,000g for 70 min at 4°C, discard the supernatant, and wash the precipitate with sterile pre-cooled PBS. Balance the solution again, centrifuge at high speed, discard the supernatant, and resuspend the precipitate in 20-50 μL of sterile pre-cooled PBS.

6. The preparation method according to claim 3, characterized in that, The specific steps of step S3 are as follows: Exosomes were treated with 200 μL of hypotonic lysis buffer containing 10 mM Tris, 10 mM MgCl2 and 1 mM phenylmethylsulfonyl fluoride at pH 7.4 for 30 min. Sonicate on ice for 5 seconds at 20% amplitude, centrifuge at 16000g for 30 minutes, and discard the supernatant; Resuspend the precipitate in 1 mM MNT solution and sonicate on ice for 2 min. Centrifuge at 16000g for 30 min, discard the supernatant, wash the precipitate with PBS to obtain EXO-MNT.

7. The use of a nasal drop formulation as described in claim 1 or 2 in the preparation of a medicament for relieving motion sickness.

8. The application according to claim 7, characterized in that, The nasal drop preparation is administered via nasal drops, with a dose of 20 μL per administration.

9. The application according to claim 8, characterized in that, The nasal drops are administered 30 minutes before the motion sickness stimulus.

10. The application according to claim 7, characterized in that, The motion sickness mentioned includes motion sickness induced by transportation and motion sickness induced by special military operations related to vestibular function.

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