Temperature-sensitive gel nose drop as well as preparation method and application thereof

Abstract

The invention relates to a temperature-sensitive gel nose drop and a preparation method and application thereof, and belongs to the technical field of biological medicines.The temperature-sensitive gel nose drop is composed of a temperature-sensitive gel matrix, active ingredients and pharmaceutic adjuvants, the temperature-sensitive gel matrix comprises poloxamer 407 and poloxamer 188, the active ingredients comprise matrine and oxymatrine, and the pharmaceutic adjuvants comprise the temperature-sensitive gel matrix, the active ingredients and the pharmaceutic adjuvants. The pharmaceutic adjuvants comprise one or more of a solvent, a humectant, an antioxidant, a preservative, a wetting agent, a thickening agent, a coloring agent, a wetting agent and a buffering agent. The temperature-sensitive gel nose drop disclosed by the invention is simple in preparation process, controllable in cost and suitable for large-scale production. The thermo-sensitive gel nose drop can improve the expression level of serum IgE, IL-4 and IFN-gamma, improves the symptom of allergic rhinitis by correcting Th1 / Th2 imbalance, is suitable for clinical treatment and prevention of allergic rhinitis, and has a remarkable clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and relates to a thermosensitive gel nasal drops and its preparation method and use, in particular to a thermosensitive gel nasal drops for nasal administration, its preparation method and its use in the preparation of drugs for treating allergic rhinitis. Background Art

[0002] Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa mediated by immunoglobulin E (IgE), and its clinical manifestations include nasal itching, sneezing, runny nose and nasal congestion, etc., which seriously affect the quality of life of patients. Although current first-line treatment drugs such as nasal corticosteroids, antihistamines and leukotriene receptor antagonists can relieve symptoms, long-term use may cause local side effects such as nasal dryness and nosebleeds, and even systemic adverse reactions (such as adrenal suppression or cardiotoxicity). Traditional nasal liquid preparations (such as nasal drops and sprays) are difficult to achieve continuous and effective therapeutic effects due to problems such as poor physicochemical stability, short drug residence time (the nasal mucus ciliary clearance time is only 15 - 20 minutes), and low bioavailability. In recent years, in-situ thermosensitive gels have become a research hotspot in the field of nasal drug delivery due to their unique phase transition characteristics (liquid administration, gel formation at body temperature) and mucoadhesion. Such preparations can significantly prolong the residence time of drugs in the nasal cavity, improve bioavailability, and achieve a sustained release effect, providing new ideas for improving the treatment of allergic rhinitis.

[0003] Active ingredients of traditional Chinese medicine have shown unique potential in the treatment of inflammatory diseases due to their multi-target action mechanisms and low toxicity and side effects. Matrine (MAT) and oxymatrine (OMAT), as the core active ingredients of traditional Chinese medicine Sophora flavescens Ait., have been proven to have anti-inflammatory, immunomodulatory and anti-allergic effects. However, existing research has mostly focused on the exploration of the pharmacodynamic effects of their single application (such as in the fields of anti-tumor and anti-viral), and their application in the treatment of allergic rhinitis still has significant limitations: the single drug has a single action target and is difficult to comprehensively regulate the complex inflammatory network; high doses may cause adverse reactions such as gastrointestinal irritation or central inhibition; and the synergistic mechanism and optimal ratio of their combined application have not been revealed in the existing technology. In addition, although the advantages of thermosensitive gels in nasal drug delivery have been widely recognized, the research on loading matrine and oxymatrine into a thermosensitive gel system in combination is still blank.

[0004] Therefore, developing a thermosensitive gel nasal drops based on their synergistic effect, which can enhance the curative effect through dual anti-inflammatory pathways and reduce the administration frequency and side effects by utilizing the sustained release characteristics of the gel, has important clinical significance and innovative value. Summary of the Invention

[0005] In view of the problems existing in the existing drugs for the treatment of allergic rhinitis, such as insufficient curative effect, significant side effects, and short residence time of traditional preparations, the present invention provides a thermosensitive gel nasal drops based on the synergistic effect of matrine (MAT) and oxymatrine (OMAT), and its preparation method and application. By combining two active ingredients and utilizing the sustained-release characteristics of the thermosensitive gel, the curative effect is significantly improved and the toxic and side effects are reduced.

[0006] A thermosensitive gel nasal drops is composed of a thermosensitive gel matrix, active ingredients, and pharmaceutical excipients. The thermosensitive gel matrix includes poloxamer 407 and poloxamer 188. The active ingredients are composed of matrine and oxymatrine. The pharmaceutical excipients include one or more of solvents, humectants, antioxidants, preservatives, wetting agents, thickeners, colorants, wetting agents, and buffers.

[0007] Furthermore, in the thermosensitive gel nasal drops, by mass percentage, poloxamer 407 accounts for 15%-20%, and poloxamer 188 accounts for 1%-5%. The two work together to regulate the gelation temperature (33°C - 36°C) and gel strength.

[0008] Furthermore, in the thermosensitive gel nasal drops, by mass percentage, matrine accounts for 0.5%-5%, and oxymatrine accounts for 0.5%-5%.

[0009] Furthermore, the humectants include glycerol, 1,3-propanediol, sodium hyaluronate, trehalose, sorbitol, polyethylene glycol, olive oil, almond oil, and aloe extract. The antioxidants include vitamin E, vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, propyl gallate, butylated hydroxytoluene, and butylated hydroxyanisole.

[0010] Furthermore, a thermosensitive gel nasal drops contains the following components by mass percentage:

[0011] Thermosensitive gel matrix: poloxamer 407 15%-20%, poloxamer 188 1%-5%;

[0012] Active ingredients: matrine 0.5%-5%, oxymatrine 0.5%-5%, and the mass ratio of the two is 1:(0.5 - 2);

[0013] Pharmaceutical excipients: humectant 2%-7%, antioxidant 0.01%-0.05%, and the balance is water; among them, the humectant is selected from one or more of glycerol, 1,3-propanediol, and polyethylene glycol, and the antioxidant is selected from one or more of vitamin E, vitamin C, and propyl gallate.

[0014] Even further, a thermosensitive gel nasal drops contains the following components by mass percentage:

[0015] Thermosensitive gel matrix: 15%-20% of poloxamer 407, 1%-5% of poloxamer 188;

[0016] Active ingredients: 0.5%-3.5% of matrine, 0.5%-3.5% of oxymatrine; and the mass ratio of the two is 1:1;

[0017] Pharmaceutical excipients: 3%-7% of glycerol, 0.01%-0.02% of vitamin E, and the balance is injection water.

[0018] The thermosensitive gel nasal drops disclosed by the present invention are in a liquid state below 25°C and are transformed into a semi-solid gel at a nasal cavity temperature of 33°C-36°C.

[0019] The present invention combines matrine and oxymatrine in a mass ratio and loads them into a thermosensitive gel system to enhance the anti-inflammatory efficacy through a synergistic effect.

[0020] The present invention also provides a preparation method for the above-mentioned thermosensitive gel nasal drops, which is prepared by a cold dissolution method and includes the following steps:

[0021] Add poloxamer 407, poloxamer 188 and a humectant to sterile water, and fully swell in a 4°C refrigerator as a matrix;

[0022] Weigh matrine and oxymatrine according to the mass ratio, add them to the matrix, stir until completely dissolved, add an antioxidant, and continue stirring to obtain a uniform and transparent gel.

[0023] Verification of gelling properties: It is in a liquid state at 25°C and rapidly transforms into a semi-solid gel at 33.5°C.

[0024] The present invention is verified by a toad nasal cilia toxicity test. The thermosensitive gel nasal drops preparation is safe and non-toxic, and can relieve rhinitis symptoms such as nasal itching, sneezing, and runny nose. In addition, it can also regulate the level of serum inflammatory factors and reduce the pathological degree of nasal mucosa. Experiments have confirmed that the combined use of matrine and oxymatrine has a better efficacy than the single-component group and is comparable to budesonide.

[0025] The thermosensitive gel nasal drops disclosed by the present invention achieve synergistic enhancement through a dual anti-inflammatory pathway, which can inhibit Th2-type inflammatory factors IL-4 and IgE, and simultaneously up-regulate Th1-type factor IFN-γ.

[0026] Therefore, the present invention also provides the application of the thermosensitive gel nasal drops in the preparation of drugs for treating allergic rhinitis.

[0027] Advantages of the present invention:

[0028] The preparation process of the thermosensitive gel nasal drops disclosed by the present invention is simple, the cost is controllable, and it can be produced on a large scale.

[0029] The thermosensitive gel nasal drops disclosed by the present invention can improve the expression levels of serum IgE, IL-4, and IFN-γ, correct the Th1 / Th2 imbalance, improve the symptoms of allergic rhinitis, and are applicable to the clinical treatment and prevention of allergic rhinitis, showing significant clinical application prospects.

[0030] The thermosensitive gel nasal drops disclosed by the present invention utilize the thermosensitive property of poloxamer. By optimizing the proportion of poloxamer, it can achieve liquid administration at 25°C and gel state retention at 33°C - 36°C, forming an adhesive gel layer in the nasal cavity, prolonging the residence time of the drug in the nasal cavity, and thus extending the drug action time. The thermosensitive gel nasal drops disclosed by the present invention can regulate the Th1 / Th2 immune balance and reduce nasal mucosa pathological damage by combining matrine and oxymatrine, providing a multi-target treatment plan for allergic rhinitis. Description of the Drawings

[0031] Figure 1 It is the appearance diagram of the matrine-oxymatrine combined thermosensitive gel in the present invention at different temperatures; wherein A is the appearance diagram at 25°C; B is the appearance diagram at 33.5°C.

[0032] Figure 2 It is the influence of the matrine-oxymatrine combined thermosensitive gel in the present invention on the nasal cilia morphology; wherein A is the normal control group; B is the gel group; C is the blank gel group; D is the sodium deoxycholate group.

[0033] Figure 3 It is the change diagram of the levels of IgE, IL-4, and IFN-γ in the sera of guinea pigs with allergic rhinitis in each group of the present invention (n = 6, mean ± SD); wherein A is the change diagram of the IgE level; B is the change diagram of the IL-4 level; C is the change diagram of the IFN-γ level; Note: * P < 0.05, ** P < 0.01, $ P < 0.05, $$ P < 0.01, * vs model group, $ vs combined group, one-way ANOVA.

[0034] Figure 4These are histopathological sections of the nasal mucosa tissues of guinea pigs with allergic rhinitis in each group of the present invention; among them, A is the normal control group, and A-1 and A-2 are enlarged views of the red-framed area and the yellow-framed area respectively; B is the AR model group, and B-1 and B-2 are enlarged views of the red-framed area and the yellow-framed area respectively; C is the matrine group, and C-1 and C-2 are enlarged views of the red-framed area and the yellow-framed area respectively; D is the oxymatrine group, and D-1 and D-2 are enlarged views of the red-framed area and the yellow-framed area respectively; E is the matrine-oxymatrine combination group, and E-1 and E-2 are enlarged views of the red-framed area and the yellow-framed area respectively; F is the budesonide group, and F-1 and F-2 are enlarged views of the red-framed area and the yellow-framed area respectively. Detailed implementation manners

[0035] As described below, these are only the preferred detailed implementation manners of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solutions of the present invention and its inventive concept, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

[0036] Example 1: Preparation of a thermosensitive gel nasal drops by combining matrine and oxymatrine

[0037]

[0038] Preparation method:

[0039] Add poloxamer 407, poloxamer 188 and glycerol into sterile water, and fully swell in a 4°C refrigerator as the matrix;

[0040] Add matrine and oxymatrine into the matrix at a mass ratio of 1:1 simultaneously, stir until completely dissolved, add vitamin E, and continue stirring to obtain a homogeneous and transparent liquid gel, which rapidly transforms into a semi-solid gel when the temperature reaches 33.5°C, and the gelation characteristics are as Figure 1 shown in A-1B.

[0041] Verification of gelation temperature: It is liquid at 25°C (see Figure 1 A), and transforms into a semi-solid gel within 30 seconds at 33.5°C (see Figure 1 B).

[0042] Example 2: Preparation of a thermosensitive gel nasal drops by using matrine alone

[0043]

[0044] Preparation method:

[0045] Prepare the thermosensitive gel matrix according to the same steps as in Example 1;

[0046] Matrine and vitamin E were added, and stirred for 30 minutes until evenly mixed, forming a uniform and transparent liquid gel at room temperature.

[0047] Example 3: Preparation of Oxymatrine Thermosensitive Gel Nasal Drops for Single Use

[0048]

[0049]

[0050] Preparation method:

[0051] Prepare the thermosensitive gel matrix according to the same steps as in Example 1;

[0052] Add oxymatrine and vitamin E, and stir for 30 minutes until evenly mixed, forming a uniform and transparent liquid gel at room temperature.

[0053] Example 4: Preparation of Thermosensitive Gel Nasal Drops by Combining Matrine and Oxymatrine

[0054]

[0055] Preparation method:

[0056] Prepare the thermosensitive gel matrix according to the steps in Example 1;

[0057] Add matrine and oxymatrine into the matrix at a mass ratio of 1:1 and stir for 30 minutes until evenly mixed, forming a uniform and transparent liquid gel at room temperature.

[0058] Example 5: Preparation of Thermosensitive Gel Nasal Drops by Combining Matrine and Oxymatrine

[0059]

[0060] Preparation method:

[0061] Prepare the thermosensitive gel matrix according to the steps in Example 1;

[0062] Add matrine and oxymatrine into the matrix at a mass ratio of 1:1 and stir for 30 minutes until evenly mixed, forming a uniform and transparent liquid gel at room temperature.

[0063] Example 6: Preparation of Thermosensitive Gel Nasal Drops by Combining Matrine and Oxymatrine

[0064]

[0065]

[0066] Preparation method:

[0067] Prepare the thermosensitive gel matrix according to the steps in Example 1;

[0068] Matrine and oxymatrine are added to the matrix simultaneously at a mass ratio of 1:0.5, and stirred for 30 minutes until evenly mixed to form a uniform and transparent liquid gel at room temperature.

[0069] Example 7: Preparation of a thermosensitive gel nasal drops by the combined application of matrine and oxymatrine

[0070]

[0071] Preparation method:

[0072] Prepare the thermosensitive gel matrix according to the steps of Example 1;

[0073] Matrine and oxymatrine are added to the matrix simultaneously at a mass ratio of 1:2, and stirred for 30 minutes until evenly mixed to form a uniform and transparent liquid gel at room temperature.

[0074] Example 8: Preparation of a thermosensitive gel nasal drops by the combined application of matrine and oxymatrine

[0075]

[0076] Preparation method:

[0077] Prepare the thermosensitive gel matrix according to the steps of Example 1;

[0078] Matrine and oxymatrine are added to the matrix simultaneously at a mass ratio of 1:1, and stirred for 30 minutes until evenly mixed to form a uniform and transparent liquid gel at room temperature.

[0079] Example 9: Preparation of a thermosensitive gel nasal drops by the combined application of matrine and oxymatrine

[0080]

[0081] Preparation method:

[0082] Prepare the thermosensitive gel matrix according to the steps of Example 1;

[0083] Matrine and oxymatrine are added to the matrix simultaneously at a mass ratio of 1:1, and stirred until completely dissolved to obtain a uniform and transparent liquid gel at room temperature.

[0084] Example 10: Verification of nasal cilia toxicity experiment

[0085] Experimental method:

[0086] 1. Sample preparation: Matrine-oxymatrine thermosensitive gel nasal drops (MAT-OMTin-situ gel, treatment group) and blank gel (without active ingredients, blank matrix group) were prepared according to the method of Example 1, and 1% sodium deoxycholate solution (positive control group) and physiological saline (normal control group) were prepared.

[0087] 2. Animal handling:

[0088] Select healthy toads and use frog needles to destroy the brain and medulla to make it painless;

[0089] The toads' maxilla were divided into four groups and evenly coated with 0.5 mL of normal saline, 1% sodium deoxycholate, treatment group gel and blank gel respectively to ensure that the mucosa was completely immersed and kept in contact for 30 minutes.

[0090] 3. Sample processing:

[0091] The treated area was irrigated with saline and the buccal mucosa tissue was obtained by dissection;

[0092] After removing blood clots and debris, the mucosa was spread on a glass slide (ciliary side facing up), and the frequency and morphology of ciliary beats were observed under a microscope (100×, 400×);

[0093] The samples were placed in a distilled water saturated steam environment, and the ciliary beating state was recorded every 10 minutes until it completely stopped, and the total beating duration was calculated;

[0094] After washing with PBS, the recovery of ciliary movement was re-measured.

[0095] Experimental results:

[0096] Table 1: Effects of matrine-oxymatrine combined with thermosensitive gel on the beating time of toad palate mucociliary filaments (n=6, mean±SD)

[0097]

[0098] Relative percentage = experimental group time / normal control group time × 100;

[0099] Compared with the normal control group, * P < 0.05; ** P﹤0.01;

[0100] Cilia morphology analysis ( Figure 2 ):

[0101] Normal control group ( Figure 2 A): Cilia are neatly arranged and beat regularly, and the mucosal epithelium is intact;

[0102] Treatment group and blank gel group ( Figure 2Group B, 2C): The cilia morphology, beating frequency, and duration were not significantly different from those of the normal group, indicating no damage to the nasal mucosa. The beating time was approximately 12 hours.

[0103] Sodium deoxycholate group ( Figure 2 D): The cilia structure was completely destroyed, the epithelium peeled off, and there was no beating activity.

[0104] Conclusion:

[0105] The thermosensitive gel nasal drops of the present invention have no significant inhibition on the nasal cilia movement of toads (relative percentage > 98%), and the mucosa morphology is intact, indicating its good safety for nasal administration. The positive control sodium deoxycholate verified the sensitivity of the experimental model due to the severe damage to the cilia structure.

[0106] Example 11: Observation and scoring of rhinitis symptoms

[0107] Experimental method:

[0108] Animal grouping and modeling:

[0109] Forty-eight healthy guinea pigs were selected. After 5 days of domestication, they were randomly divided into 6 groups (n = 8): normal control group (saline), AR model group, matrine group (2% MAT, prepared according to Example 2), oxymatrine group (2% OMAT, prepared according to Example 3), combination group (1% MAT + 1% OMAT, prepared according to Example 1), and budesonide group (positive control).

[0110] Sensitization stage: The AR model group and each treatment group were intraperitoneally injected with ovalbumin suspension (0.5 mg antigen + 30 mg aluminum hydroxide adjuvant, 1 mL saline) once a day for 7 consecutive days.

[0111] Challenge stage: 5% ovalbumin was instilled into the nasal cavity (50 μL per side) once a day for 5 consecutive days.

[0112] Symptom scoring:

[0113] Within 30 minutes after the last challenge, the nasal itching, sneezing, and rhinorrhea symptoms of the guinea pigs were observed and scored according to the criteria in Table 2 (total score ≥ 5 indicates successful modeling).

[0114] Scoring before and after treatment: The score before treatment was recorded after modeling, and the score after treatment was recorded 10 days after administration.

[0115] Table 2: Symptom scoring standard table

[0116]

[0117]

[0118] Experimental results:

[0119] Table 3: Comparison of nasal symptom behavioral scores in each group of guinea pigs (n = 6, mean ± SD)

[0120]

[0121] Symptom scores before treatment, compared with the normal control group, # P < 0.05, ## P < 0.01; Symptom scores after treatment, compared with the AR model group, * P < 0.05, ** P < 0.01; One-way ANOVA test.

[0122] The symptom score after treatment in the combined group (4.17 ± 0.75) was significantly lower than that in the single-drug group (matrine group 4.50 ± 1.22, oxymatrine group 4.83 ± 1.17, ** P < 0.01), indicating that the combination of the two can synergistically relieve nasal allergic symptoms.

[0123] Example 12: Detection of serum inflammatory factor levels

[0124] Experimental method:

[0125] Sample collection: After the last administration according to the method of Example 11, the guinea pigs were fasted for 12 hours, anesthetized with intraperitoneal injection of 10% chloral hydrate (300 mg / kg), and blood was collected from the abdominal aorta;

[0126] Serum separation: The blood was allowed to stand at room temperature for 1 hour, centrifuged at 1000 rpm for 10 minutes at 4°C, and the supernatant was stored at -80°C;

[0127] ELISA detection: The concentrations of serum IgE, IL-4 and IFN-γ were measured according to the kit instructions.

[0128] Experimental results ( Figure 3 ):

[0129] The changes in the levels of IgE, IL-4, and IFN-γ in the serum of each group of guinea pigs were measured experimentally. The results were as Figure 3 shown. Compared with the normal control group, the mean value of IgE concentration (μg / mL) in the serum of guinea pigs in the AR model group increased from 21.64 to 57.02, and the mean value of IL-4 concentration (pg / mL) increased from 3.78 to 12.06. The contents of both increased significantly ( ** P < 0.01); The mean value of IFN-γ concentration (pg / mL) decreased from 14.34 to 4.56, and the content decreased significantly ( ** P < 0.01), indicating successful model establishment. Compared with the AR model group, the contents of IgE and IL-4 in the serum of guinea pigs in each drug treatment group were significantly reduced ( **P < 0.01), the content of IFN-γ increased significantly ( ** P < 0.01), the effect of the budesonide group was more exact; when comparing the three matrine treatment groups, the combined group had a more significant decrease in IgE compared with the matrine group and the oxymatrine group ( $$ P < 0.01) and the level of IL-4 ( $ P < 0.05), and increased the level of IFN-γ ( $ P < 0.05), and the effect was close to that of budesonide. The effects of the matrine group and the oxymatrine group were comparable, and there was no significant difference between groups (P > 0.05).

[0130] Example 13: Histopathological evaluation of nasal mucosa

[0131] Experimental method:

[0132] Sample treatment: After sacrificing the guinea pigs, the nasal mucosa was dissected, fixed with 4% paraformaldehyde, and sectioned (4 μm) after paraffin embedding;

[0133] Staining and observation: H&E staining, and the integrity of the mucosa and inflammatory infiltration were evaluated by an optical microscope (100×, 400×).

[0134] Experimental results ( Figure 4 ):

[0135] Normal control group ( Figure 4 A): The cilia were intact and not damaged, the epithelial structure of the mucosa layer was intact, arranged regularly and neatly, the cells were uniform, the edges were clear, the morphology was complete, and they were arranged loosely;

[0136] AR model group ( Figure 4 B): The cilia structure was damaged, the epithelial cells exfoliated, and there were edema in the lamina propria and lymphocyte infiltration;

[0137] Single drug group ( Figure 4 C, 4D): The mucosal structure improved but there was still mild edema;

[0138] Combined group ( Figure 4 E): The mucosal epithelium was intact, the cilia were arranged neatly, there was slight edema in the lamina propria, and there were very few inflammatory cells;

[0139] Budesonide group ( Figure 4 F): The mucosa was close to normal, and inflammatory cells were occasionally seen;

[0140] Combined application can significantly repair the pathological damage of the nasal mucosa, and the effect is better than that of single drug and is equivalent to that of budesonide.

Claims

1. A thermosensitive gel nasal drops, characterized in that, It is composed of a temperature-sensitive gel matrix, active ingredients and pharmaceutical excipients. The temperature-sensitive gel matrix includes poloxamer 407 and poloxamer 188. The active ingredients are composed of matrine and oxymatrine. The pharmaceutical excipients include one or more of a solvent, a humectant, an antioxidant, a preservative, a wetting agent, a thickening agent, a coloring agent, a wetting agent, and a buffer.

2. The thermosensitive gel nasal drops according to claim 1, characterized in that, In the temperature-sensitive gel nasal drops, by mass percentage, poloxamer 407 accounts for 15%-20%, and poloxamer 188 accounts for 1%-5%.

3. The thermosensitive gel nasal drops according to claim 1, characterized in that, In the temperature-sensitive gel nasal drops, by mass percentage, matrine accounts for 0.5%-5%, and oxymatrine accounts for 0.5%-5%.

4. The thermosensitive gel nasal drops according to claim 1, characterized in that, The humectant includes glycerol, 1,3-propanediol, sodium hyaluronate, trehalose, sorbitol, polyethylene glycol, olive oil, almond oil, and aloe extract; the antioxidant includes vitamin E, vitamin C, sodium sulfite, sodium bisulfite, sodium thiosulfate, propyl gallate, butylated hydroxytoluene, and butylated hydroxyanisole.

5. A thermosensitive gel nasal drop according to any one of claims 2-4, characterized in that, It contains the following components by mass percentage: Temperature-sensitive gel matrix: poloxamer 407 15%-20%, poloxamer 188 1%-5%; Active ingredients: matrine 0.5%-5%, oxymatrine 0.5%-5%, and the mass ratio of the two is 1:(0.5-2); Pharmaceutical excipients: humectant 2%-7%, antioxidant 0.01%-0.05%, and the balance is water; among them, the humectant is selected from one or more of glycerol, 1,3-propanediol, and polyethylene glycol, and the antioxidant is selected from one or more of vitamin E, vitamin C, and propyl gallate.

6. The thermosensitive gel nasal drops according to claim 5, wherein It contains the following components by mass percentage: Temperature-sensitive gel matrix: poloxamer 407 15%-20%, poloxamer 188 1%-5%; Active ingredients: matrine 0.5%-3.5%, oxymatrine 0.5%-3.5%; and the mass ratio of the two is 1:1; Pharmaceutical excipients: glycerol 3%-7%, vitamin E 0.01%-0.02%, and the balance is injection water.

7. A thermosensitive gel nasal drop according to claim 1, characterized in that, This temperature-sensitive gel nasal drops is in a liquid state below 25°C and transforms into a semi-solid gel at the nasal cavity temperature of 33°C-36°C.

8. A method for preparing the thermosensitive gel nasal drops according to claim 1, comprising the following It includes: Adding poloxamer 407, poloxamer 188 and a humectant to sterile water and swelling fully in a 4°C refrigerator as the matrix; Weighing matrine and oxymatrine according to the mass ratio and adding them to the matrix, stirring until completely dissolved, adding an antioxidant, and continuing to stir to obtain a homogeneous and transparent gel.

9. Use of the temperature-sensitive gel nasal drops according to claim 1 in the preparation of a drug for treating allergic rhinitis.

10. The application according to claim 9, wherein, This temperature-sensitive gel nasal drops achieves synergistic effects through a dual anti-inflammatory pathway. This pathway inhibits Th2-type inflammatory factors IL-4 and IgE, and simultaneously upregulates Th1-type factor IFN-γ.

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