A nasal drop for treating acute and chronic rhinitis, sinusitis, allergic rhinitis and a preparation method thereof

Abstract

The present application relates to a kind of treating acute and chronic rhinitis, nasal sinusitis, allergic rhinitis nose drops and preparation method.Its components include neomycin sulfate, chlorpheniramine maleate, naphazoline hydrochloride, excipient and solvent, wherein, 1000ml nose drops contain neomycin sulfate 9.75-5 million units, chlorpheniramine maleate 0.3-1.0g, naphazoline hydrochloride 0.3-1.0g.The present application nose drops has antibacterial, anti-inflammatory, anti-allergic effect, can also shrink blood vessel and improve the symptom of nasal congestion caused by rhinitis, non-invasive, and easy to carry, easy to use, rapid effect, can shorten the course of disease, patient use compliance is good, cure rate is high;It has good curative effect on acute and chronic rhinitis, nasal sinusitis, allergic rhinitis and the like.The preparation method of the present application has simple and easy processing technology, good repeatability, and is convenient for industrialized production.

Description

Technical Field

[0001] This invention relates to a nasal pharmaceutical preparation, and more particularly to a nasal drop for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis, and its preparation method. Background Technology

[0002] Rhinitis and sinusitis are common clinical diseases that can induce various upper respiratory tract infections. In recent years, air pollution has become increasingly severe, leading to a rise in the inhalation of harmful and allergenic substances through the nose, resulting in a significant increase in the incidence of rhinitis and sinusitis. Children and adolescents, whose nasal mucosal barriers are not fully developed and whose antibacterial capacity and immune function are low, have poor tolerance to various harmful gases and allergens, making them a high-risk group for these diseases. In particular, symptoms such as memory loss caused by chronic sinusitis seriously affect patients' academic performance.

[0003] Currently, there are no ideal drugs or methods for treating sinusitis and rhinitis in clinical practice. Systemic medications, whether oral or injected, are partially destroyed by the gastrointestinal tract and liver or diverted into the bloodstream during absorption and distribution, resulting in very low effective concentrations reaching the nasal and sinus lesions. This makes it difficult to achieve therapeutic effects and can induce drug resistance in bacteria, leading to chronic conditions. Therefore, the efficacy is poor and the cure rate is low. Commonly used topical medications, such as nasal drops, only constrict blood vessels to relieve nasal congestion caused by rhinitis. Their pharmacological action is singular, their efficacy is unsatisfactory, and they have significant side effects, potentially causing drug-induced rhinitis. Laser therapy uses the high temperature generated by a laser beam to burn away inflamed tissue and pathogens. However, because the laser beam cannot reach the sinus cavities, it can only be used to treat rhinitis and nasal polyps, and is ineffective for sinusitis. Furthermore, laser therapy is invasive, cumbersome to operate, and expensive. Aspiration therapy involves using a needle to puncture the lateral wall of the nasal cavity to enter the sinus cavity. Secretions and pus are first aspirated, and then medication is injected into the sinus cavity to treat sinusitis. While effective, this method is invasive, painful, and often unsustainable for patients, thus failing to consolidate the therapeutic effect. Nasal sprays deliver medication directly into the nasal cavity, producing local antibacterial and anti-inflammatory effects, and can be used to treat rhinitis. However, because the medication cannot be sprayed directly into the nasal cavity, it is almost ineffective for sinusitis.

[0004] The above-mentioned drugs and methods either have too low an effective drug concentration to actually reach the lesion site in the nasal cavity and sinuses; or have a single pharmacological effect with significant toxic side effects; or the drug cannot reach the sinus cavity; or the method is invasive, causing pain for patients and making it difficult for them to persist; or the operation method is cumbersome and expensive. Therefore, the drugs and methods currently used in clinical treatment of sinusitis and rhinitis have drawbacks such as slow onset of action, poor efficacy, long treatment course, low cure rate, significant toxic side effects, and high costs for patients. Summary of the Invention

[0005] The purpose of this invention is to overcome the above-mentioned deficiencies and, based on the pathogenesis, pathophysiology, and anatomical characteristics of the nasal cavity and sinus cavities of sinusitis and rhinitis, provide a compound drug preparation for treating acute and chronic sinusitis, rhinitis, and allergic rhinitis, as well as its preparation method. This compound preparation has synergistic effects, including antibacterial, anti-inflammatory, anti-allergic, and vasoconstrictive effects on the nasal mucosa. It also has a unique optimal dosage that achieves an effective therapeutic dose. The three active ingredients work synergistically, reducing the content of individual drugs and thus significantly improving efficacy and reducing toxic side effects.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions:

[0007] A nasal drop for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis, characterized in that the nasal drop is composed of: neomycin sulfate, chlorpheniramine maleate, naphazoline hydrochloride, excipients, and solvent, wherein each 1000ml of nasal drop contains 975,000 to 5,000,000 units of neomycin sulfate, 0.3 to 1.0g of chlorpheniramine maleate, and 0.3 to 1.0g of naphazoline hydrochloride.

[0008] Preferably, the excipients include a preservative, wherein the preservative is ethylparaben. The excipients comprise a pharmaceutically acceptable formulation for nasal drops. The preservative is any pharmaceutically acceptable antibacterial agent suitable for nasal drops.

[0009] Preferably, each 1000ml of nasal drops contains 0.10 to 0.40g of ethylparaben.

[0010] Preferably, the excipients include an osmotic pressure regulator, wherein the osmotic pressure regulator is sodium chloride, and the concentration is 8.9 g of sodium chloride per 1000 ml of nasal drops. The osmotic pressure regulator can be any pharmaceutically acceptable osmotic pressure regulator suitable for nasal drops.

[0011] Preferably, the solvent is ethanol and purified water.

[0012] Preferably, each 1000ml of nasal drops contains 1.625 million units of neomycin sulfate, 0.4g of chlorpheniramine maleate, and 0.4g of naphazoline hydrochloride.

[0013] Preferably, the nasal drops comprise neomycin sulfate, chlorpheniramine maleate, naphazoline hydrochloride, ethylparaben, sodium chloride, ethanol, and purified water, wherein each 1000 ml of nasal drops contains 1.625 million units of neomycin sulfate, 0.4 g of chlorpheniramine maleate, 0.4 g of naphazoline hydrochloride, 0.25 g of ethylparaben, 8.9 g of sodium chloride, 2.5 mL of ethanol, and purified water.

[0014] A method for preparing nasal drops for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis, the specific steps of which are as follows:

[0015] Take the prescribed amount of preservative, dissolve it in ethanol to prepare a 10% ethanol solution; add the obtained preservative ethanol solution to hot purified water, cool, and then add chlorpheniramine maleate, naphazoline hydrochloride, neomycin sulfate, and osmotic pressure regulator in sequence, stir to dissolve, filter, add purified water to the total volume, stir evenly, and dispense to obtain the final product.

[0016] Preferably, the preservative is ethylparaben and the osmotic pressure regulator is sodium chloride.

[0017] Application of a nasal drop for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis in nasal diseases.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The active ingredient in this invention, naphazoline hydrochloride, is an α-receptor agonist that constricts nasal mucosal blood vessels, reduces vascular exudate, and alleviates nasal mucosal swelling and congestion. Clinically, it is used to treat allergic rhinitis caused by colds, inflammatory nasal congestion, and acute and chronic rhinitis. The active ingredient, chlorpheniramine maleate (also known as chlorpheniramine), is an H1 receptor antagonist and an antihistamine with anti-allergic effects. It is mainly used for rhinitis, skin and mucous membrane allergies, and to relieve cold symptoms such as tearing, sneezing, and runny nose. The active ingredient, neomycin sulfate, is an aminoglycoside antibiotic effective against both Gram-positive and Gram-negative bacteria. It is often formulated as eye drops and has good effects against Staphylococcus and Corynebacterium. This allows the invention to have antibacterial and anti-inflammatory effects while treating rhinitis and sinusitis. The preparation of this invention has antibacterial, anti-inflammatory, anti-allergic, and vasoconstrictive effects, and is suitable for acute and chronic sinusitis, allergic rhinitis, etc.

[0020] 1. This invention is a nasal drop for treating rhinitis, sinusitis, and allergic rhinitis, which takes effect by being directly instilled into the nasal cavity. The nasal drop overcomes the shortcomings of oral and injectable formulations, where some drugs are destroyed by the gastrointestinal tract, liver, or diverted into the bloodstream during absorption and distribution, thus achieving a very low effective concentration that actually reaches the lesion site in the nasal cavity and sinus cavity.

[0021] 2. This invention utilizes the α-receptor agonist naphazoline hydrochloride, the antihistamine chlorpheniramine maleate, and the aminoglycoside antibiotic neomycin. Therefore, in addition to its vasoconstrictive effects in relieving nasal congestion caused by rhinitis and its anti-allergic properties, it also possesses antibacterial and anti-inflammatory effects and will not cause drug-induced rhinitis. The combined use of these three ingredients can exert a synergistic pharmacological effect, enhancing efficacy and reducing the toxic side effects of long-term use.

[0022] 3. This invention is a nasal drop that takes effect when dropped into the nasal cavity. It is non-invasive, easy to carry, convenient to use, and has good patient compliance.

[0023] 4. Compared with nasal sprays on the market, the liquid of this invention can not only reach the nasal cavity but also flow into the sinuses, thus having a better effect on rhinitis and sinusitis.

[0024] 5. Experimental studies have proven that the proportions of the formula used in this invention are optimal, and the efficacy of the drug will decrease if the proportions are adjusted.

[0025] 6. The preparation method of the present invention has a simple and easy processing technology with good repeatability, which is convenient for industrial production.

[0026] The following detailed description of specific embodiments of the present invention will make the technical solution of the present invention easier to understand and master. Detailed Implementation

[0027] Example 1

[0028] Each 1000ml of the preparation contains 0.25g of ethylparaben, 1.625 million units of neomycin sulfate, 0.4g of chlorpheniramine maleate, 0.4g of naphazoline hydrochloride, 8.9g of sodium chloride, 2.5mL of ethanol and purified water.

[0029] Examples 2-6 and Comparative Examples 1-4 are set up as shown in the table below.

[0030]

[0031] A method for preparing nasal drops for treating acute and chronic sinusitis and rhinitis, the specific steps of which are as follows:

[0032] Take the prescribed amount of preservative, dissolve it in ethanol to prepare a 10% ethanol solution; add the obtained preservative ethanol solution to 250 mL of hot purified water at 100°C, cool, and then add chlorpheniramine maleate, naphazoline hydrochloride, neomycin sulfate, and osmotic pressure regulator in sequence, stir to dissolve, filter, add purified water to the total volume, stir evenly, and dispense to obtain the final product.

[0033] In the above methods, each component is prepared by preparing raw materials and processing them according to the proportions specified in the examples.

[0034] Meanwhile, existing nasal sprays were added as comparative examples: Comparative Example 5 (naphthylazolin hydrochloride nasal drops, 1000ml of solution contains 1g of naphazoline, Guangzhou Baiyunshan Pharmaceutical Group Co., Ltd. Baiyunshan Hejigong Pharmaceutical Factory) and Comparative Example 6 (compound naphazoline spray, 1000ml of solution contains 0.5g of naphazoline and 1g of chlorpheniramine maleate, Nanjing Xingyin Pharmaceutical Group Co., Ltd.).

[0035] Inhibitory Effect of Nasal Drops in Experimental Example 1 on Increased Capillary Permeability of Nasal Mucosa Induced by Histamine in Rats

[0036] 1. Experimental Purpose

[0037] An animal model was established by increasing the capillary permeability of nasal mucosa in rats induced by histamine, and the inhibition rates of each prescription on the effect of histamine were investigated and compared to provide a theoretical basis for the efficacy of drugs in treating rhinitis and sinusitis.

[0038] 2. Experimental Principle

[0039] Histamine is an inflammatory mediator. Its release can cause an increase in local capillary permeability and infiltration of inflammatory cells, allowing pigments to penetrate through blood vessels, and the OD value can be measured by ultraviolet spectrophotometry.

[0040] 3. Materials and Reagents

[0041] 3.1 Experimental Animals

[0042] SPF-grade male SD rats, weighing 150 - 200 g, from the Experimental Animal Center of Sun Yat-sen University. The experimental animal production license number is: SCXK(Guangdong)2011 - 0029; the experimental animal quality certificate number is: 44008500012088. The disposal of animals during the experiment conforms to animal ethics standards.

[0043] 3.1.1 Rearing Conditions

[0044] Temperature: 20 - 25 °C; Humidity: 40% - 70%

[0045] Ventilation rate: greater than 10 times / hour

[0046] Rearing density: 6 rats / cage

[0047] Illumination time: 12 hours (lights on at 7:00 am - lights off at 7:00 pm)

[0048] 3.1.2 Feed and Drinking Water

[0049] SPF-grade feed for mice and rats, freely available for intake, stored in a dedicated feed room, kept ventilated, clean and dry. The conventional nutritional component indicators of the feed are detected by the Guangdong Provincial Experimental Animal Testing Institute (referring to the national standard of the People's Republic of China GB14924.3 - 2010), and detected twice a year.

[0050] Drinking water is freely available through animal drinking bottles. The drinking water is sterilized at 121 °C (1.0 kg / cm 2 ) for 30 minutes, and meets the "Drinking Pure Water Quality Standard" (CJ94 - 2005).

[0051] 3.2 Instruments

[0052] TLE 104 electronic balance, Mettler Toledo Instruments (Shanghai) Co., Ltd.; CO2 incubator, PYX-DHS, Forma Scientific; TU-1800 UV-Vis spectrophotometer, Beijing Purkinje General Instrument Co., Ltd.; surgical scissors, ophthalmic forceps, etc.

[0053] 3.3 Reagents

[0054] Examples and comparative examples (Sun Yat-sen Memorial Hospital, Sun Yat-sen University); sodium pentobarbital, histamine, and Evans blue (provided by the School of Pharmacy, Sun Yat-sen University).

[0055] 4. Experimental Methods

[0056] 4.1 Grouping

[0057] Fourteen groups were formed, including Examples 1-6, Comparative Examples 1-6, the saline group, and the diphenhydramine group, with 10 SD rats in each group.

[0058] 4.2 Administration

[0059] The six example groups and six comparative groups were administered nasal drops according to the corresponding prescriptions. The saline group and the diphenhydramine (concentration of 12.5 mg / mL) group were administered saline and compound diphenhydramine nasal drops respectively, for 7 consecutive days, three times a day, two drops in each nostril each time.

[0060] 4.3 Determination of inhibition rate

[0061] 45 minutes after the last administration, administer 0.1 mL / 100 g of 3% sodium pentobarbital. -1 Anesthesia, 1.5% Evans Blue Sky Pollen Solution 1mL·100g -1 Each group used the newly prepared 10 -3 mol.L -1 Histamine solution was administered via nasal drops, 50 μL per side. Five minutes after nasal drops, the chest of each animal was opened, the right atrium was cut open, and the aorta was punctured through the left ventricle. Physiological saline was instilled until the outflow from the right atrium became clear. The nasal cavity was dissected in the midsagittal plane, and the entire nasal mucosa of the respiratory area was removed, cut into 2 mm × 2 mm pieces, weighed with an electronic balance, and placed in a stoppered test tube containing 5 mL of formamide. The tube was placed in a 37°C incubator and filtered after 48 hours. The inhibition rate against histamine was calculated using a UV-Vis spectrophotometer at a wavelength of 620 nm [Inhibition rate (%) = (OD value of saline group - OD value of drug group) / OD value of saline group × 100%].

[0062] 5. Statistical Methods

[0063] All measurement data are adopted. The significance of the difference in means was tested using SPSS 10.0 statistical software through analysis of variance.

[0064] 6. Experimental results

[0065] Table 1 Inhibition rates of antihistamine in each case of Biyantong Nasal Drops (n = 10)

[0066]

[0067] Note: Compared with the normal saline group, *p < 0.05, **p < 0.01

[0068] Through the comparison of the examples, the results show that when all three active ingredients are present, with the increase of the dosage, the inhibition rate of the prescription on the increase of capillary permeability caused by histamine is higher and higher, and different excipients have no significant effect on the change of capillary permeability; while through the comparison of Comparative Examples 1-4, it shows that the inhibition rate will decrease no matter which active ingredient is lacking, especially chlorpheniramine maleate; Comparative Examples 5 and Comparative Example 6 can reach a certain inhibition rate, but lower than that of the examples. At the same time, it can be seen that the antihistamine effect of Example 1 is more obvious than that of the positive control diphenhydramine nasal drops group.

[0069] Experimental Example 2 Effect of nasal drops on ovalbumin sensitization (allergic rhinitis model)

[0070] 1. Experimental purpose

[0071] To compare the effects of each example and comparative example in treating allergic rhinitis and provide a theoretical basis for its treatment of allergic rhinitis.

[0072] 2. Experimental principle

[0073] Ovalbumin can induce allergic symptoms such as nose scratching, running nose, and sneezing in rats, with an increase in mucosal eosinophils (EOS) and an increase in IgE content. Ovalbumin rats are a commonly used model for allergic rhinitis.

[0074] 3. Materials and reagents

[0075] 3.1 Experimental animals

[0076] SPF-grade SD rats, both male and female, weighing 150 - 200 g, from the Experimental Animal Center of Sun Yat-sen University. The experimental animal production license number is: SCXK (Guangdong) 2011 - 0029; the experimental animal quality certificate number is: 44008500012088. The handling of animals during the experiment conforms to animal ethics standards.

[0077] 3.1.1 Feeding conditions

[0078] Temperature: 20°C - 25°C; humidity 40% - 70%

[0079] Ventilation frequency: more than 10 times / hour

[0080] Stocking density: 6 birds / cage

[0081] Lighting time: 12 hours (lights on at 7:00 AM to lights off at 7:00 PM)

[0082] 3.1.2 Feed and drinking water

[0083] SPF-grade rat and mouse feed is provided freely and stored in a dedicated feed room that is well-ventilated, clean, and dry. Routine nutritional components of the feed are tested twice annually by the Guangdong Provincial Laboratory Animal Testing Institute (in accordance with the People's Republic of China National Standard GB14924.3-2010).

[0084] Drinking water is provided freely to the animals via water bottles. The drinking water is purified at 121℃ (1.0 kg / cm³). 2 The water is sterilized for 30 minutes and meets the "Drinking Water Quality Standard" (CJ94-2005).

[0085] 3.2 Instruments

[0086] TLE 104 electronic balance, Mettler Toledo Instruments (Shanghai) Co., Ltd.; CO2 incubator, PYX-DHS, Forma Scientific; inverted optical microscope, IX51-32PH, Olympus; TDZ4-WS centrifuge, Changsha Xiangyi Centrifuge Instrument Co., Ltd.; surgical scissors, ophthalmic forceps, etc.

[0087] 3.3 Reagents

[0088] Examples and comparative examples (Sun Yat-sen Memorial Hospital, Sun Yat-sen University); sodium pentobarbital and ovalbumin sensitization solution (provided by the School of Pharmacy, Sun Yat-sen University); loratadine (Xi'an Janssen Pharmaceutical Co., Ltd.).

[0089] 4. Experimental Methods

[0090] 4.1 Modeling

[0091] Rats were injected intraperitoneally with 1 mL of ovalbumin sensitization solution every other day for a total of 7 times. This was the basic sensitization. After the basic sensitization was completed, 10 μL of 5% ovalbumin challenge solution was dripped into each nostril every other day. The behavioral changes (scratching nose, runny nose, sneezing, etc.) of the rats were observed within 30 minutes after the challenge. The behavioral scores of the experimental rats were recorded. The total score was calculated according to the standard summation method. A total score of 5 or more for each rat was considered a successful model, and a score of less than 5 was considered a failed model (see Table 2 for the scoring criteria).

[0092] Table 2. Symptom Grading Criteria for Allergic Rhinitis in Rats

[0093]

[0094] 4.2 Grouping and Dosing

[0095] Rats that successfully developed the model were randomly divided into fourteen groups: Examples 1-6, Comparative Examples 1-6, Blank Group, and Loratadine (1 mg / kg) Group, with 10 SD rats in each group. The rats were given intranasal administration after challenge, once daily for 14 consecutive days until the end of the experiment. Rats in the saline group received saline intranasal administration.

[0096] 4.3 Specimen Collection and Testing

[0097] After the experiment, the rats were given 0.1 mL / 100 g of 3% sodium pentobarbital. -1 The animal was anesthetized and fixed in a supine position on the operating table. The abdominal wall was cut open to expose the abdominal aorta, and blood was collected from the aorta. The blood was placed in a sample collection tube and allowed to stand at room temperature for 2 hours. Then, the tube was centrifuged at 2000 rpm for 10 minutes, and the supernatant was collected and transferred to 1.5 mL EP tubes. The tubes were then frozen at -80°C for later analysis. The levels of interferon-γ (INF-γ), interleukin-4 (IL-4), and immunoglobulin E (IgE) in rat serum were detected using ELISA.

[0098] 5. Statistical Methods

[0099] All measurement data are adopted. The significance of the difference in means was tested using SPSS 10.0 statistical software through analysis of variance.

[0100] 6. Experimental Results

[0101] 6.1 Behavioral Observation

[0102] After model stimulation, the animals exhibited obvious symptoms such as nose scratching, runny nose, and sneezing, with the symptoms significantly reduced in the medication group. After scoring using Table 2, there was a significant difference between the medication group and the saline group. The scores for each group are shown in Table 3.

[0103] Table 3. Rating scale for the treatment of allergic rhinitis model with Rhinitis-Relieving Nasal Drops in various cases (n=10)

[0104]

[0105] Note: Compared with the saline group, *p<0.05, **p<0.01

[0106] The results showed that each embodiment significantly reduced the symptoms of nasal scratching, runny nose, and sneezing in rats with ovalbumin-induced allergic rhinitis, and the anti-allergic rhinitis effect became more significant with increasing concentration of the active ingredient. Comparative Examples 1-4 showed less significant relief of the above symptoms, while Comparative Examples 5 and 6 also showed significant symptom relief. Example 1 showed a stronger anti-allergic rhinitis effect than the loratadine positive group.

[0107] 6.2 Changes in cytokines

[0108] Table 4. Changes in cytokines after administration of Rhinitis Relief Nasal Drops in different cases (n=10)

[0109]

[0110]

[0111] Note: Compared with the saline group, *p<0.05, **p<0.01

[0112] The results showed that each treatment group increased serum INF-γ concentration and decreased serum IL-4 and IgE concentrations, thereby alleviating the inflammatory response. Comparative Examples 1-4 had no significant effect on the three factors, Comparative Examples 5 and 6 could alleviate the inflammatory response to some extent, while the Examples showed significant effects on each factor with concentration correlation.

[0113] Experimental Example 3: Toxicity Study of the Ciliaries on the Upper Mandibles of Bullfrogs

[0114] 1. Experimental Objective

[0115] The comparison of the cilia toxicity of each embodiment and comparative example to bullfrog provides a theoretical basis for the mucosal irritation of the nasal drops.

[0116] 2. Experimental Principle

[0117] The palatal mucosa of bullfrogs is quite sensitive and can easily be damaged when exposed to highly irritating drugs, causing the palatal cilia to stop moving. Therefore, the duration of palatal cilia movement after administration of different drugs can be used to indirectly reflect the mucosal irritation caused by the drug.

[0118] 3. Materials and Reagents

[0119] 3.1 Laboratory Animals

[0120] Bullfrog, 500g±50g.

[0121] 3.2 Instruments

[0122] TLE 104 electronic balance, Mettler Toledo Instruments (Shanghai) Co., Ltd.; Leica optical microscope; surgical scissors, ophthalmic forceps, etc.

[0123] 3.3 Reagents

[0124] Examples and comparative examples (Sun Yat-sen Memorial Hospital, Sun Yat-sen University); 1% sodium deoxycholate (provided by the School of Pharmacy, Sun Yat-sen University).

[0125] 4. Experimental Methods

[0126] 4.1 Grouping

[0127] Forty-two bullfrogs were randomly divided into fourteen groups: the saline group served as the blank control group, the 1% sodium deoxycholate group served as the positive control group, and the remaining groups were six example groups and six comparative groups.

[0128] 4.2 Methods

[0129] The bullfrogs were secured supine to a piece of cardboard with rope. 0.5 mL of medication (approximately 10 drops) was applied to the palatine mucosa, ensuring complete immersion. This position was maintained for 30 minutes. The bullfrogs' mouths and mucosa were then gently rinsed with saline solution to remove any debris. The mucosa between the eyes was carefully cut out, measuring 2 mm × 2 mm. Three portions of mucosa were obtained from each bullfrog. These portions were then gently rinsed clean with saline solution. The mucosa was placed face up on a glass slide, and 0.2 mL of saline solution was applied to the surface. A coverslip was then placed on top, and the movement of the cilia on the mucosa was observed using a 10×40x optical microscope. The sample was then placed in a sealed chromatography tank containing a small amount of pure water, where the water vapor level was near saturation. Samples were removed and observed every half hour. If the cilia continued to move, the sample was returned to the chromatography tank until the movement stopped. The time from the start of medication to the cessation of cilia movement was defined as the ciliary movement time.

[0130] The ratio of the duration of continuous ciliary movement in the drug-treated bullfrog to that in the saline-treated bullfrog is the relative percentage of continuous ciliary movement time. The method for determining the reversibility of the drug's cilia toxicity is as follows: immediately after observing the cessation of ciliary movement, rinse the infiltrated mucosa with saline, and then observe whether the ciliary movement resumes; if it does, the drug's cilia toxicity is considered reversible.

[0131] 5. Statistical Methods

[0132] All measurement data are adopted. The significance of the difference in means was tested using SPSS 10.0 statistical software through analysis of variance.

[0133] 6. Experimental Results

[0134] Immediately after removing the mucosa, microscopic observation revealed that the mucosal surface and cilia in the saline group were clear and intact, with active cilia movement and rhythmic beating. In the 1% sodium deoxycholate group, significantly inactivated tissue was visible to the naked eye; microscopic observation showed that the cilia quickly stopped beating, indicating severe mucosal damage, with most cilia detached, the surface disordered, and many detached cells visible around the mucosa. Examples 3 and 4 showed partial mucosal damage, while the remaining examples and comparative examples showed minimal cilia detachment. The specific duration of ciliary movement in each group is shown in Table 5.

[0135] Table 5. Results of the toxicity of Rhinitis-Relieving Nasal Drops to the maxillary cilia of bullfrogs in various cases (n=9)

[0136]

[0137] Note: Compared with the saline group, *p<0.05, **p<0.01

[0138] The results showed that the duration of continuous ciliary movement in Examples 3 and 4 was significantly different from that in the saline group, while the other drug administration groups were not significantly different from the saline group, i.e., there was no obvious mucosal irritation.

[0139] Experimental Case 4 Clinical Study

[0140] The nasal drops for rhinitis produced according to Example 1 are an in-house preparation of our hospital and have been used in our hospital for many years. Their efficacy and safety have been confirmed by clinical experts.

[0141] This study will conduct clinical trials on the nasal drops prepared in Examples 1-6 and Comparative Examples 1-6.

[0142] 1. Research Subjects

[0143] 1.1 Case Selection

[0144] All enrolled patients were admitted to the outpatient and inpatient departments of the Department of Otolaryngology at Sun Yat-sen Memorial Hospital, Sun Yat-sen University.

[0145] 1.2 Diagnostic criteria

[0146] The diagnostic criteria for allergic rhinitis (HAR) were formulated with reference to the "Principles and Recommendations for the Diagnosis and Treatment of Allergic Rhinitis" (Editorial Committee of Chinese Journal of Otorhinolaryngology Head and Neck Surgery, Otorhinolaryngology Branch of Chinese Medical Association, 2004, Lanzhou), as shown in Table 6.

[0147] Table 6 Diagnostic Criteria

[0148]

[0149] Note: Diagnosis is mainly based on the first two items.

[0150] 1.3 Grading and Quantification Standards for Symptoms and Signs

[0151] Table 7. Quantitative Standards for Grading Major Symptoms

[0152]

[0153]

[0154] * Indicates a single, consecutive quantity; # This indicates the number of times you blow your nose in a day.

[0155] Table 8. Quantitative Standards for Grading Physical Signs

[0156]

[0157] 1.4 Disease Severity Grading Standards

[0158] Referring to the WHO's ARIA 2001 working group's grading of the disease based on disease course, onset, and impact on patients' quality of life, and the 2015 Tianjin guidelines' classification of mild, moderate, and severe based on the impact of symptoms on quality of life, see Table 9.

[0159] Table 9. Criteria for Grading Disease Severity

[0160]

[0161] 2. Inclusion and exclusion criteria for cases

[0162] 2.1 Case Inclusion Criteria

[0163] (1) Meets the Western medical diagnosis of allergic rhinitis;

[0164] (2) Disease duration ≥ years;

[0165] (3) Age between 8 and 60 years old, gender not limited;

[0166] (4) None of the study participants had received any treatment in the week prior to enrollment;

[0167] (5) Informed consent holders.

[0168] 2.2 Case Exclusion Criteria

[0169] (1) Patients who need to take aspirin, glucocorticoids, or long-acting corticosteroids for a long period of time or within the last 3 months;

[0170] (2) Patients who intend to become pregnant, are pregnant, or are breastfeeding;

[0171] (3) Comorbid serious organic diseases of the heart, brain, kidneys, liver, etc.;

[0172] (4) Patients with bronchial asthma or atopic dermatitis;

[0173] (5) Those with nasal diseases such as significant nasal septum deviation, nasal polyps or chronic sinusitis;

[0174] (6) Individuals with serious illnesses such as nausea or tumors;

[0175] (7) Patients with hysteria or mental illness;

[0176] (8) Those who are currently receiving specific immunotherapy or have used antihistamines within 3 days;

[0177] (9) Those who are currently participating in other drug clinical trials.

[0178] 2.3 Criteria for Case Exclusion and Dropout

[0179] (1) Subjects who cannot take the medication on time or fail to follow up on time during the observation period, making it impossible to determine their efficacy;

[0180] (2) Other factors were used to assess the efficacy and tolerability of this treatment;

[0181] (3) Those who stop treatment on their own before completing half of the treatment course;

[0182] (4) Patients who interrupt treatment due to severe adverse reactions.

[0183] 2.4 Handling of Lost Cases

[0184] (1) When a subject is lost, contact the subject by means of telephone or other means to find out the reason and check the record of the last time the medication was administered, and collect relevant data as much as possible;

[0185] (2) For lost patients who do not respond well to treatment, appropriate treatment should be given based on the patient’s condition;

[0186] (3) Researchers must provide detailed explanations and classifications of the reasons for case loss in the case reports. The efficacy of treatments exceeding half the course of treatment should be statistically analyzed.

[0187] (4) All relevant information about the observed cases should be recorded in detail and retained.

[0188] 2.5 End the experiment early

[0189] (1) If a patient experiences discomfort during the experiment and it may affect their life safety, the experiment should be stopped immediately; patients who have completed more than 1 / 2 of the treatment course should be included in the efficacy statistics.

[0190] (2) The therapeutic drugs used in the study were not effective and were not of research significance;

[0191] (3) The study has significant biases in its design or implementation, and the efficacy evaluation is questioned.

[0192] 3. Research Methods

[0193] 3.1 Grouping

[0194] The allergic rhinitis patients included in the trial were divided into 12 groups: Examples 1-6 and Comparative Examples 1-6, with 50 patients in each group, for a total of 600 patients. After statistical processing, there were no significant differences in gender, disease duration, age, and disease severity among the groups, making them comparable.

[0195] 3.2 Research Plan

[0196] The formulations used in each group were provided by the Pharmacy of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, and were in 10mL bottles. Each group used the corresponding prescription nasal drops, three times a day (morning, noon, and evening), two drops per nostril each time. Treatment continued for 21 days. Before each use of the medication, gently blow out any clear nasal discharge from each nostril to ensure that each drop is instilled into the nasal cavity.

[0197] During this period, each patient is required to discontinue the use of other nasal drops.

[0198] 3.3 Observation Items

[0199] 3.3.1 General Items

[0200] Name, gender, age, course of illness, date, occupation, telephone number, address, history of systemic diseases, past medical history, etc. should all be recorded in detail.

[0201] 3.3.2 Indicators

[0202] The main symptoms and nasal signs were recorded. Patient signs and main symptoms were observed and recorded before treatment and on days 7, 14, and 21. The patient's diet, sleep, and medication time were also recorded. The level of eosinophil cationic protein in peripheral blood was measured before treatment and on day 21 of treatment.

[0203] 3.3.3 Scoring

[0204] Examination records before treatment and on days 7, 14, and 21: the relationship between the inferior turbinate and the nasal floor and nasal septum; whether there is swelling of the inferior turbinate, the degree of swelling, and changes in the color of its mucosa; whether the middle turbinate is visible, and whether the nasal septum is deviated or whether nasal polyps have formed, etc. Recorded as 0, 1, 2, and 3 points respectively, depending on the condition.

[0205] The patient's main symptoms were observed and recorded before treatment and on days 7, 14, and 21. The scores were recorded as 0, 1, 2, and 3 points, respectively, depending on the severity of the condition.

[0206] 4. Research Results

[0207] The comparison results of the total scores of the 8 groups before treatment, 7 days after treatment, 14 days after treatment, and 21 days after treatment are shown in Table 10.

[0208] Table 10 Comparison of total scores during treatment in 8 groups (n=50)

[0209]

[0210]

[0211] The corresponding therapeutic effects can be found in Table 11.

[0212] Table 11 Comparison of treatment efficacy in 8 groups (n=50)

[0213]

[0214] It can be seen that, after treatment, all six prescriptions in the examples and Comparative Examples 5 and 6 improved from severe rhinitis to mild rhinitis after 21 days of treatment. Among them, Examples 1 and Examples 3-6 achieved mild rhinitis after 14 days of treatment, while the condition of the first five prescriptions in the comparative examples improved but remained at a moderate level.

[0215] 5. Adverse Reactions

[0216] No significant adverse reactions or toxic side effects occurred in any group of patients during treatment.

[0217] Experimental conclusions

[0218] Based on the above animal and clinical trials, the nasal drops in each example showed good efficacy in treating allergic rhinitis and effectively inhibited increased capillary permeability of the nasal mucosa. However, ciliary toxicity experiments demonstrated that the higher doses in Examples 3 and 4 caused some irritation to the nasal mucosa. Comparative Examples 1-4 lacked certain active ingredients, resulting in insignificant efficacy in each experiment. Comparative Examples 5 and 6, as marketed formulations, showed some symptom relief, but their effects were not as significant as in Example 1. It is evident that although the dosage of individual components is reduced when the three drugs are used in combination, the synergistic effect between the components still results in good efficacy. Furthermore, the comparison between Examples 5 and 6 and Example 1 demonstrates that the excipients used did not significantly affect the efficacy.

[0219] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A nasal drop for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis, characterized in that, The nasal drops are composed of the following ingredients per 1000ml: 1.625 million units of neomycin sulfate, 0.4g of chlorpheniramine maleate, 0.4g of naphazoline hydrochloride, 0.25g of ethylparaben, 8.9g of sodium chloride, 2.5mL of ethanol, and purified water.

2. A method for preparing nasal drops for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis as described in claim 1, comprising the following specific steps: Take the prescribed amount of ethylparaben, dissolve it in ethanol to prepare a 10% ethanol solution; add the obtained ethylparaben ethanol solution to hot purified water, cool, and then add chlorpheniramine maleate, naphazoline hydrochloride, neomycin sulfate, and sodium chloride in sequence, stir to dissolve, filter, add purified water to the total volume, stir evenly, and dispense to obtain the final product.

3. The use of the nasal drops as described in claim 1 in the preparation of a medicament for treating acute and chronic rhinitis, sinusitis, and allergic rhinitis.

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