Oxymetazoline hydrochloride nasal drops and preparation process thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to oxymetazoline hydrochloride nasal drops and a preparation process thereof. According to the oxymetazoline hydrochloride nasal drops, oxymetazoline hydrochloride serves as a main drug, and specific functional auxiliary materials are matched, wherein a stability auxiliary is composed of edetate disodium, vitamin E polyethylene glycol succinate and sodium cyclamate, and sodium cyclamate has the dual effects of stabilizing the main drug and preliminarily modifying the taste; the flavoring agent is composed of sodium cyclamate and hydroxypropyl methyl cellulose in a synergistic manner, specifically covers the bitter taste of the main medicine, and further comprises an osmotic pressure regulator, a preservative, a pH regulator and a solvent. Compared with the prior art, the preparation has the remarkable advantages that the stability of the preparation is greatly improved, the bitter taste of liquid medicine is obviously improved, the medication experience of a patient is improved, parameters of a preparation process are clear and controllable, and the preparation is suitable for industrial large-scale production and has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a hydroxypropanediamine hydrochloride nasal drop and a preparation process thereof. BACKGROUND

[0002] The information disclosed in this BACKGROUND section is only for the purpose of increasing the understanding of the background of the application and should not be taken as an acknowledgement or any form of suggestion that this information forms prior art that is publicly known.

[0003] As an imidazoline derivative, hydroxypropanediamine hydrochloride is an adrenergic receptor agonist widely used in clinical practice. It has a strong and lasting peripheral vasoconstrictive effect. Its mechanism of action is to directly stimulate the alpha receptors on the nasal mucosa vascular smooth muscle, rapidly relieving mucosal hyperemia and edema, and thus improving the symptoms of nasal congestion.

[0004] Chinese Patent with Publication No. CN107362141A discloses a hydroxypropanediamine hydrochloride nasal spray and a preparation method thereof. The components and their amounts of the nasal spray are as follows: hydroxypropanediamine hydrochloride 2.5-5 g, zinc pectin 50-100 g, povidone K30 50-80 g, osmotic pressure regulator 15-400 g, buffer agent in appropriate amount, and purified water added to 10,000 mL. The pH value of the nasal spray is 5.5-6.5. Chinese Patent with Publication No. CN119367284A discloses a stable hydroxypropanediamine hydrochloride preparation and a preparation method thereof. The hydroxypropanediamine hydrochloride preparation is composed of hydroxypropanediamine hydrochloride, rutin, pH regulator, preservative, isotonic agent, and water. The intermolecular interaction between hydroxypropanediamine hydrochloride and rutin forms a complex system, which improves the stability of the hydroxypropanediamine hydrochloride preparation.

[0005] Although the existing technology has made many improvements on the stability of hydroxypropanediamine hydrochloride, the existing preparations and preparation processes still have many technical defects that need to be solved: (1) In terms of formulation stability, the molecular structure of hydroxypropanediamine hydrochloride is easily affected by light, temperature, and pH value fluctuations, leading to degradation, a decrease in the content of effective components, an increase in impurities, and a direct impact on the stability of drug efficacy and the safety of drug use. In the existing preparation process, most of the formulations only use conventional pH regulators and preservatives in combination, lack targeted stability design, and make the formulation prone to changes in properties during storage, which not only shortens the product shelf life, but also increases the risk of adverse reactions due to the accumulation of degradation products.

[0006] (2) Hydroxy methylnorin hydrochloride itself has obvious bitter taste, and the existing nasal drops preparation does not optimize the taste design for this characteristic. When patients use the drug, the drug solution is easy to flow along the posterior naris to the oral cavity, and the bitter taste will directly stimulate the taste buds, causing nausea, taste discomfort and other feelings; some patients will also cause appetite to decrease in a short time due to the bitter taste, especially for children and elderly patients with more sensitive taste, the adverse experience is more prominent.

[0007] Therefore, the development of a kind of hydroxy methylnorin hydrochloride nasal drops which can accurately solve the stability problem, targeted optimization of taste, and at the same time taking into account the simplicity of preparation process, becomes the key requirement of the current drug preparation field for the development of nasal decongestants, and is also the core starting point and goal of the technical innovation of the present application. SUMMARY

[0008] The core goal of the present application is to provide a kind of hydroxy methylnorin hydrochloride nasal drops which can accurately improve the stability of the preparation, targetedly reduce the bitter taste, and the preparation process is simple and controllable.

[0009] (I) The formula of hydroxy methylnorin hydrochloride nasal drops The hydroxy methylnorin hydrochloride nasal drops described in the present application take weight parts as the measurement basis, and the formula composition is as follows: Main drug: hydroxy methylnorin hydrochloride 0.1-0.5 parts, stability aid: total amount 1.4-4.3 parts, consisting of edetate disodium 0.1-0.5 parts, vitamin E polyethylene glycol succinate (TPGS) 1-3 parts, sodium clyclamate 0.3-0.8 parts, sodium clyclamate has the dual functions of stabilizing the main drug and preliminarily masking the taste. Masking agent: total amount 1.3-3.8 parts, consisting of sodium clyclamate 0.3-0.8 parts and hydroxypropyl methylcellulose (HPMC) 1-3 parts; Osmotic pressure regulator: 7-10 parts, selected from at least one of sodium chloride, potassium chloride, glycerol, mannitol; Preservative: 0.05-0.2 parts, selected from at least one of benzalkonium chloride, hydroxyphenyl ethyl ester, phenoxyethanol, potassium sorbate; pH regulator: appropriate amount, selected from acetic acid-sodium acetate buffer, sodium dihydrogen phosphate-sodium hydrogen phosphate buffer, citric acid-sodium citrate buffer, for adjusting the pH value of the drug solution to 5.0-6.0; Solvent: appropriate amount, consisting of anhydrous ethanol and water for injection; Anhydrous ethanol is used to dissolve vitamin E polyethylene glycol succinate, and water for injection is used as the main solvent to ensure the safety and solubility of the drug solution.

[0010] (II) Preparation process of hydroxy methylnorin hydrochloride nasal drops The preparation process described in the present application constructs a functional system through sub-steps to ensure that each component cooperates to fully play its role. The specific steps are as follows: (1) Main drug-stability aid synergistic system construction Take the prescribed amount of vitamin E polyethylene glycol succinate, add 40-80 ml of anhydrous ethanol, place in a 60-70°C constant temperature water bath, stir at 300-400 rpm for 15-20 min until completely dissolved; cool at a rate of 5°C / 5 min, when the temperature drops to 45-55°C, add the specified amount of oxymetazoline hydrochloride, keep the temperature at 300 rpm for 10-15 min until the main drug is completely dissolved; continue to cool at a rate of 5°C / 5 min to 35-45°C, take the specified amount of edetate disodium, dissolve in an appropriate amount of 35-45°C water for injection, and slowly add, stir at 250-300 rpm for 8-10 min until the mixture is uniform; cool at a rate of 5°C / 5 min to 25-35°C, take the specified amount of sodium cyclamate, dissolve in an appropriate amount of 30°C water for injection, and slowly add, stir at 250 rpm for 5-8 min, and keep at 25-35°C for standby; (2) Flavoring agent pretreatment and mixing with excipients Take the specified amount of hydroxypropyl methylcellulose, add an appropriate amount of 0-8°C water for injection, and stir at 200-250 rpm for 10 min; transfer to a 25-35°C constant temperature water bath and continue to stir at 200 rpm for 30 min until the hydroxypropyl methylcellulose is fully swollen; add the osmotic pressure regulator and preservative in sequence, and stir at 250-300 rpm for 5-8 min at 25-35°C until completely dissolved.

[0011] (3) Total mixing of the drug solution and pH adjustment Slowly transfer the main drug system prepared in step 1 into the excipient colloid of step 2, and stir at 300-350 rpm during the transfer; add a pH adjuster at 25-35°C to adjust the pH of the drug solution to 5.0-6.0; add water for injection at 25-35°C to make up to the full amount, and stir at 300 rpm for 20-30 min until the drug solution is uniform.

[0012] (4) Filtration and sterilization The drug solution is microfiltered using a 0.45μm filter membrane to remove small impurities and possible microorganisms in the drug solution; the filtered drug solution is sterilized to ensure that the preparation meets the sterile requirements and avoids infection caused by nasal administration.

[0013] (5) Filling and quality inspection.

[0014] Compared with the prior art, the present application has the following significant technical effects: (1) The stability of the preparation is significantly improved The oxymetazoline hydrochloride nasal drops of the embodiments 1-3 of the present application still maintain a content of 98.5% or more, and the content of impurity I is 0.27% or less within 10 days through the influencing factor test (high temperature 40℃±2℃ / RH 75%±5%, high humidity 25℃±2℃ / RH 90%±5%, illumination 4500lx±500lx), and the anti-external environmental interference ability is strong. The long-term sample test (25℃±2℃ / RH 60%±10% in the dark and sealed) shows that the content of oxymetazoline hydrochloride in the drug solution still maintains 98.8% or more after 12 months, and the impurity content is 0.20% or less, which is much better than the comparative examples without the stability aid or missing any stability aid, effectively prolongs the product shelf life, and protects the effectiveness and safety of the drug.

[0015] (2) The bitter taste problem is obviously optimized, and the patient compliance is improved Through the sensory evaluation verification of 30 subjects, the present application effectively masks the bitter taste of the main drug through the synergistic taste-correcting effect of sodium cyclamate and hydroxypropyl methyl cellulose, shortens the bitter taste residual time, is especially suitable for children and elderly patients with sensitive taste, and significantly improves the medication compliance.

[0016] (3) The preparation process has strong controllability and is suitable for industrialized production In the preparation process of the present application, the parameters such as temperature, stirring rate and cooling rate are clear and easy to control, and each step is designed with strong pertinence, so that the product quality fluctuation caused by operation difference can be avoided, the process does not need special and expensive equipment, and the industrialized production is easy to realize, so that the present application has good industrial application prospect. DETAILED DESCRIPTION

[0017] In order to make the purpose, technical scheme of the present application more clear and obvious, the following embodiments are used to further explain the present application, but the protection scope of the present application is not limited to these embodiments, and the embodiments are only used to explain the present application. Those skilled in the art should understand that any change or equivalent replacement without departing from the concept of the present application is included in the protection scope of the present application.

[0018] Embodiment 1: oxymetazoline hydrochloride nasal drops Formula: Preparation process: (1) Main drug-stability aid synergistic system construction: take the prescription amount of vitamin E polyethylene glycol succinate, add 60 ml of anhydrous ethanol, place in a 65°C constant temperature water bath, stir (350 rpm) for 18 min until completely dissolved; reduce the temperature at a rate of 5°C / 5 min, when the temperature drops to 50°C, add the specified amount of oxymetazoline hydrochloride, keep the temperature stirring (300 rpm) for 12 min until the main drug is completely dissolved; continue to reduce the temperature at a rate of 5°C / 5 min to 40°C, take the specified amount of edetate disodium, dissolve in appropriate amount of 40°C water for injection, then slowly add, stir (280 rpm) for 9 min until the mixture is uniform; reduce the temperature at a rate of 5°C / 5 min to 30°C, take the specified amount of sodium cyclamate, dissolve in appropriate amount of 30°C water for injection, then slowly add, stir (250 rpm) for 6 min, keep (30°C) for standby.

[0019] (2) Flavor pre-treatment and excipient mixing: take the specified amount of hydroxypropyl methyl cellulose, add appropriate amount of 4°C water for injection, stir (220 rpm) for 10 min; transfer to a 30°C constant temperature water bath, continue to stir (200 rpm) for 30 min until the hydroxypropyl methyl cellulose is fully swollen; add the osmotic pressure regulator and preservative in turn, keep stirring (250-300 rpm) at 30°C for 7 min until completely dissolved.

[0020] (3) Total drug solution mixing and pH adjustment: slowly transfer the main drug system prepared in step (1) into the excipient colloid of step (2), stirring (320 rpm) during transfer; add 30°C pH adjuster to adjust pH to 5.5, add 30°C water for injection to make up to the full amount, stir (300 rpm) for 25 min until the drug solution is uniform.

[0021] (5) Filling and quality inspection.

[0022] Example 2 Oxymetazoline hydrochloride nasal drops Formula: Preparation process: (1) Main drug-stability aid synergistic system construction: take the prescription amount of vitamin E polyethylene glycol succinate, add 40 ml of anhydrous ethanol, place in a 60°C constant temperature water bath, stir (300 rpm) for 15 min until completely dissolved; cool at a rate of 5°C / 5 min, when the temperature drops to 45°C, add the specified amount of oxymetazoline hydrochloride, keep the temperature stirring (300 rpm) for 10 min until the main drug is completely dissolved; continue to cool at a rate of 5°C / 5 min to 35°C, take the specified amount of edetate disodium, dissolve in appropriate amount of 35°C water for injection, then slowly add, stir (250 rpm) for 8 min until the mixture is uniform; cool at a rate of 5°C / 5 min to 25°C, take the specified amount of sodium cyclamate, dissolve in appropriate amount of 30°C water for injection, then slowly add, stir (250 rpm) for 5 min, keep (25°C) for standby.

[0023] (2) Flavor pre-treatment and excipient mixing: take the specified amount of hydroxypropyl methyl cellulose, add appropriate amount of 0°C water for injection, stir (200 rpm) for 10 min; transfer to a 25°C constant temperature water bath, continue to stir (200 rpm) for 30 min until the hydroxypropyl methyl cellulose is fully swollen; add the osmotic pressure regulator and preservative in turn, keep stirring (250 rpm) at 25°C for 5 min until completely dissolved.

[0024] (3) Total drug solution mixing and pH adjustment: slowly transfer the main drug system prepared in step (1) into the excipient colloid of step (2), stirring (300 rpm) during transfer; add 25°C pH adjuster to adjust pH to 5.0, add 25°C water for injection to make up to the full amount, stir (300 rpm) for 20 min until the drug solution is uniform.

[0025] (5) Filling and quality inspection.

[0026] Example 3 Oxymetazoline hydrochloride nasal drops Formula: Preparation process: (1) Main drug-stability aid synergistic system construction: take the prescription amount of vitamin E polyethylene glycol succinate, add 80 ml of anhydrous ethanol, place in a 70°C constant temperature water bath, stir (400 rpm) for 20 min until completely dissolved; cool at a rate of 5°C / 5 min, when the temperature drops to 55°C, add the specified amount of oxymetazoline hydrochloride, keep the temperature at 300 rpm for 15 min until the main drug is completely dissolved; continue to cool at a rate of 5°C / 5 min to 45°C, take the specified amount of edetate disodium, dissolve in an appropriate amount of 45°C water for injection, and slowly add, stir (300 rpm) for 10 min until the mixture is uniform; cool at a rate of 5°C / 5 min to 35°C, take the specified amount of sodium cyclamate, dissolve in an appropriate amount of 30°C water for injection, and slowly add, stir (250 rpm) for 8 min, and keep at 35°C for standby.

[0027] (2) Flavor pre-treatment and excipient mixing: take the specified amount of hydroxypropyl methylcellulose, add an appropriate amount of 8°C water for injection, stir (250 rpm) for 10 min; transfer to a 35°C constant temperature water bath, continue to stir (200 rpm) for 30 min until the hydroxypropyl methylcellulose is fully swollen; add the osmotic pressure regulator and preservative in turn, keep stirring (300 rpm) at 35°C for 5-8 min until completely dissolved.

[0028] (3) Total drug solution mixing and pH adjustment: slowly transfer the main drug system prepared in step (1) to the excipient colloid in step (2), stirring (350 rpm) while transferring; add 35°C pH adjuster to adjust pH to 6.0, add 35°C water for injection to make up to full amount, stir (300 rpm) for 30 min until the drug solution is uniform.

[0029] (5) Filling and quality inspection.

[0030] Stability aid stability effect verification experiment Experimental design All groups use the formula (except for the stability aid) or / and preparation process (except for the stability aid pre-treatment) of Example 1, only change the composition of the stability aid: Table 1 Experimental design of Comparative Examples 1-4 Investigation conditions Influencing factor test (accelerated degradation, investigate short-term stability) High temperature condition: 40°C±2°C, relative humidity (RH) 75%±5%, sealed storage High humidity condition: 25°C±2°C, RH 90%±5%, sealed storage Lighting condition: 4500lx±500lx (visible light + near ultraviolet), 25°C±2°C, sealed storage Assessment time points: 0 days (initial), 5 days, 10 days Long-term sample retention test (to examine actual storage stability) Storage conditions: 25℃±2℃, RH 60%±10%, sealed away from light (simulating commercial storage). Assessment time points: October (initial), March, June, December Detection indicators and methods The determination was performed according to the High Performance Liquid Chromatography (HPLC) method (General Chapter 0512) of the Chinese Pharmacopoeia. The test solution was prepared by taking the sample. The reference solution was prepared by accurately weighing an appropriate amount of oxymetazoline hydrochloride reference standard, dissolving it in the mobile phase, and quantitatively diluting it to prepare a solution containing 0.5 mg per ml. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; methanol-water-triethylamine-phosphoric acid (550:450:5:1.5) (adjusting the pH to 7.3 with phosphoric acid or triethylamine) was used as the mobile phase; the detection wavelength was 279 nm; the injection volume was 10 μl. System suitability requirements: The theoretical plate number, calculated based on the oxymetazoline peak, should not be less than 2000. The resolution between the oxymetazoline peak and adjacent impurity peaks should meet the requirements. Assay: Accurately measure the reference solution and the test solution, inject them separately into the HPLC system, record the chromatograms, and calculate the peak area using the external standard method.

[0031] Related substance impurities I were determined according to the high performance liquid chromatography method (General Rule 0512) in the Chinese Pharmacopoeia.

[0032] Table 2. Stability test results of Examples 1-3 and Comparative Examples 1-5 Table 2 shows that Examples 1-3 exhibit significantly better stability under three accelerated degradation conditions: high temperature, high humidity, and light. The content of oxymetazoline hydrochloride remained basically stable within 10 days, with fewer impurities generated and strong resistance to external environmental interference.

[0033] Table 3. Long-term stability test results Table 3 simulates actual storage conditions and examines stability over 12 months. It shows that after 12 months, the oxymetazoline hydrochloride content in Examples 1-3 remains above 98.8%, and the impurity content is ≤0.20%, which meets the requirements for efficacy and safety of long-term use and can effectively extend the product's shelf life.

[0034] Flavoring agent effect verification experiment Experimental Design All groups used the formulation (except for the flavoring agent) and preparation process of Example 1, only changing the composition of the flavoring agent: Table 4 Experimental Design Schemes for Comparative Examples 6-8 Subject selection Number of participants: 30 (10 healthy adults, 10 children aged 6-12, and 10 seniors aged 60 and above) Exclusion criteria: ① Abnormal taste (e.g., dulled or sensitive bitter taste); ② Acute exacerbation of rhinitis or nasal mucosal damage; ③ Allergy to oxymetazoline hydrochloride or its excipients; ④ Use of medications that affect taste (e.g., antibiotics, antidepressants) within the past week. Ethical requirements: Informed consent must be signed, and the experiment must be approved by the ethics committee (in accordance with ethical guidelines for human trials). Sensory evaluation methods (1) Administration method (simulating clinical nasal drops) Subjects were seated with their heads tilted back 30°. Two drops of the sample (approximately 0.1 mL / drop) were instilled into each nostril. The head was held in this tilted-back position for 1 minute (simulating the flow of the drug solution from the posterior nasal cavity to the oral cavity). After 1 minute, the subjects returned to their normal position and their taste was evaluated.

[0035] (2) Evaluation indicators and scales The 9-point Hedonic Scale was used in conjunction with the "incidence of adverse reactions" assessment. All assessments were completed within 5 minutes after drug administration (to avoid taste memory bias), and sample numbering was performed using a randomized and blinded method (subjects were unaware of their sample group). Table 5 Evaluation Criteria Duplicate evaluation Each group of samples was evaluated 2 hours apart (to avoid taste fatigue). Each subject evaluated each of the 4 groups of samples once, and the average of the 3 repeated evaluations was taken (if the deviation of a single evaluation is >2 points, the data should be excluded and re-evaluated).

[0036] Table 6 Scoring Statistics Table 6 shows that the oxymetazoline hydrochloride nasal drops of the present invention have the best taste-correcting effect among three groups of people: healthy people, children, and the elderly, and can effectively solve the bitterness problem of oxymetazoline hydrochloride. Comparative Examples 6-8 show that the effect of using a single taste-correcting agent or without a taste-correcting agent is poor, indicating that the two taste-correcting agents need to be used in combination to simultaneously reduce bitterness, shorten residue, and avoid discomfort, which is especially suitable for children and the elderly with sensitive taste.

Claims

1. A nasal drop solution containing oxymetazoline hydrochloride, characterized in that, The formulation of the oxymetazoline hydrochloride nasal drops, by weight, is as follows: 0.1-0.5 parts oxymetazoline hydrochloride, 1.4-4.3 parts stabilizing agent, 1.3-3.8 parts flavoring agent, 7-10 parts osmotic pressure regulator, 0.05-0.2 parts preservative, appropriate amount of pH regulator, and appropriate amount of solvent; the stabilizing agent is disodium edetate, polyethylene glycol succinate, and sodium cyclohexane.

2. The oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The stabilizing agent is 0.1-0.5 parts of disodium edetate, 1-3 parts of vitamin E polyethylene glycol succinate, and 0.3-0.8 parts of sodium cyclohexane.

3. The oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The flavoring agent is 0.3-0.8 parts of sodium cyclohexane and 1-3 parts of hydroxypropyl methylcellulose.

4. The oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The pH adjuster is selected from acetate-sodium acetate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, and citrate-sodium citrate buffer.

5. The oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The preservative is selected from at least one of benzalkonium chloride, ethylparaben, phenoxyethanol, and potassium sorbate.

6. The oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, glycerol, and mannitol.

7. The oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The solvents are anhydrous ethanol and water for injection.

8. A preparation process for the oxymetazoline hydrochloride nasal drops according to claim 1, characterized in that, The preparation process includes the following steps: (1) Construction of the synergistic system of main drug-stabilizing adjuvant: Vitamin E polyethylene glycol succinate was added to anhydrous ethanol and stirred in a water bath at 60-70℃ until dissolved. The temperature was lowered to 45-55℃, oxymetazoline hydrochloride was added, and the temperature was maintained at 45-55℃ and stirred until dissolved. The temperature was lowered to 35-45℃, disodium edetate was dissolved in water for injection and added to the above solution. The mixture was stirred at 35-45℃ and cooled to 25-35℃. Sodium cyclohexane was dissolved in water for injection at 30℃ and added to the above solution. The mixture was stirred at 25-35℃ and kept warm for later use. (2) Flavoring agent pretreatment and excipient mixing: Hydroxypropyl methylcellulose is dissolved in water for injection at 0-8℃, stirred, heated to 25-35℃ to swell, and stirred; osmotic pressure regulator and preservative are added in sequence, and stirred. (3) Mixing the total drug solution and adjusting the pH: Mix the solutions from steps (1) and (2), add a pH adjuster at 25-35℃, add water for injection to make up to the total volume, and stir; (4) Filtration and aseptic treatment; (5) Filling and quality inspection.

9. The preparation process according to claim 8, characterized in that, The pH adjuster adjusts the pH to 5.0-6.

0.

10. The preparation process according to claim 8, characterized in that, The cooling rate is 5℃ / 5min. (1) Construction of the synergistic system of active pharmaceutical ingredient and stabilizing adjuvant: Take the prescribed amount of vitamin E polyethylene glycol succinate, add 40-80 ml of anhydrous ethanol, place in a constant temperature water bath at 60-70℃, and stir (300-400 rpm) for 15-20 min until completely dissolved; cool down at a rate of 5℃ / 5 min, and when the temperature drops to 45-55℃, add the prescribed amount of oxymetazoline hydrochloride, and maintain this temperature while stirring (300 rpm) for 10-15 min until the active pharmaceutical ingredient is completely dissolved. Continue cooling at a rate of 5℃ / 5min to 35-45℃. Take the specified amount of disodium edetate, dissolve it in an appropriate amount of water for injection at 35-45℃, and slowly add it to the solution. Stir (250-300rpm) for 8-10min until the mixture is homogeneous. Continue cooling at a rate of 5℃ / 5min to 25-35℃. Take the specified amount of sodium cyclohexane, dissolve it in an appropriate amount of water for injection at 30℃, and slowly add it to the solution. Stir (250rpm) for 5-8min, and keep warm (25-35℃) for later use. (2) Flavoring agent pretreatment and excipient mixing: Take the specified amount of hydroxypropyl methylcellulose, add an appropriate amount of water for injection at 0-8℃, and stir (200-250 rpm) for 10 min; transfer to a constant temperature water bath at 25-35℃, and continue stirring (200 rpm) for 30 min until the hydroxypropyl methylcellulose is fully swollen; add the osmotic pressure regulator and preservative in sequence, and keep stirring at 25-35℃ (250-300 rpm) for 5-8 min until completely dissolved; (3) Mixing and pH adjustment of the drug solution: Slowly transfer the main drug system prepared in step (1) into the excipient colloid in step (2) while stirring (300-350 rpm); add pH adjuster at 25-35℃ to adjust the pH to 5.0-6.0, add water for injection at 25-35℃ to make up to the full volume, and stir (300 rpm) for 20-30 min until the drug solution is uniform; (4) Filtration and sterilization: Microfiltration through a 0.45μm filter membrane and sterilization; (5) Filling and quality inspection.

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