Terbutaline sulfate solution for aerosol inhalation and preparation method of terbutaline sulfate solution

Abstract

The invention relates to the technical field of medicines, in particular to a terbutaline sulfate aerosol inhalation solution and a preparation method thereof. The solution realizes a performance breakthrough through a molecular synergistic effect of polysorbate modified cyclodextrin: firstly, hydroxypropyl-beta-cyclodextrin and polysorbate 80 are activated and covalently grafted to form a modified carrier with a core-shell structure, and then the modified carrier is compounded with terbutaline sulfate, sodium chloride, edetate disodium and sodium hydrogen sulfite to prepare the solution. The stable core-shell structure formed through chemical grafting is combined with the synergistic effect of the chelating agent and the antioxidant, the technical problems that a traditional preparation is low in atomization efficiency, high in burst release risk and poor in stability are effectively solved, and a safer and more efficient inhalation solution is provided for treatment of respiratory diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a terbutaline sulfate solution for atomized inhalation and a preparation method thereof. Background Art

[0002] Terbutaline sulfate is a selective β2 receptor agonist widely used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Its nebulized inhalation preparation has become the preferred dosage form in clinical practice because it can directly act on target lung tissues, has a rapid onset of action, and has few systemic side effects. However, existing commercially available nebulized inhalation solutions generally have the following problems: first, the nebulization efficiency is low, the nebulization time is as long as 8-12 minutes, and patient compliance is poor; second, the risk of drug burst release is high, with the cumulative release rate exceeding 40% in 30 minutes, which can easily induce adverse reactions such as bronchospasm; third, the stability is insufficient, and it is easily oxidized and degraded during storage, resulting in an increase in the total impurity content, affecting safety and effectiveness.

[0003] Traditionally, hydroxypropyl-β-cyclodextrin (HP-β-CD) is often used as a drug carrier to improve solubility, but its inclusion capacity is limited, making it difficult to simultaneously optimize atomization performance and sustained-release properties. Furthermore, while the direct addition of surfactants (such as polysorbate 80) can reduce surface tension, physical mixing systems suffer from unstable adsorption and uneven dispersion, and long-term storage can easily lead to drug crystallization or aggregation. Excipient combinations (such as antioxidants and chelating agents) can partially improve stability, but the effects of individual components are limited, making it difficult to synergistically inhibit multiple degradation pathways. For example, relying solely on edetate disodium (EDTA) to chelate metal ions is ineffective in scavenging reactive oxygen species; while sodium bisulfite alone has antioxidant properties, it is insufficient to inhibit metal ion-catalyzed degradation.

[0004] More critically, existing technologies fail to resolve the conflict between sustained drug release and aerosol performance. Traditional formulations, in pursuit of high aerosol efficiency, often suffer from burst drug release due to excessively low surface tension. Meanwhile, sustained-release designs can reduce lung deposition rates due to wide particle size distributions (GSD > 2.0) or MMAD deviations from the optimal range (1-5μm). Therefore, there is an urgent need to develop a novel formulation that, through the synergistic effects of molecular structure design and excipients, achieves controlled sustained release while improving aerosol efficiency and possessing excellent chemical and physical stability. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a solution for nebulized inhalation of terbutaline sulfate and a preparation method thereof, so as to solve the problems of low atomization efficiency, high risk of burst release, poor stability, and difficulty in balancing the contradiction between sustained release and atomization performance of existing atomized inhalation solutions.

[0006] Based on the above purpose, the present invention provides a method for preparing a terbutaline sulfate solution for aerosol inhalation, comprising the following steps: (1) Disperse hydroxypropyl-β-cyclodextrin in anhydrous ethanol, ultrasonically treat to form a suspension, add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide, stir and activate at 25-35°C for 0.5-1.5 h, add polysorbate 80, stir and react at room temperature under nitrogen protection for 10-14 h, ultrafilter using an ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin; (2) Add polysorbate-modified cyclodextrin to water for injection, heat to 55-65°C, stir for 20-40 minutes, then add terbutaline sulfate, stir at 700-900 rpm for 5-7 hours, then cool to room temperature, add sodium chloride, disodium edetate and sodium bisulfite, stir for 20-40 minutes to obtain a mixed solution; (3) Adjust the pH of the mixture to 3.8-4.2 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a filter membrane, and then pass nitrogen for 10-20 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate; In the step (1), the ratio of hydroxypropyl-β-cyclodextrin, anhydrous ethanol, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide and polysorbate 80 is 15 g: 150-250 mL: 0.3-0.7 g: 0.12-0.22 g: 0.5-1.5 g; In the step (2), the dosage ratio of polysorbate-modified cyclodextrin, water for injection, terbutaline sulfate, sodium chloride, disodium edetate and sodium bisulfite is 15.5-16.5 g:700-900 mL:1.5-2.5 g:0.8-1 g:0.06-0.1:0.03-0.08.

[0007] 2. The method for preparing a terbutaline sulfate solution for aerosol inhalation according to claim 1, characterized in that the ultrasonic treatment in step (1) has a frequency of 35-45 kHz, a power of 150-250 W, and a time of 10-20 min.

[0008] 3. The method for preparing a terbutaline sulfate solution for aerosol inhalation according to claim 1, wherein the molecular weight cut-off of the ultrafiltration membrane in step (1) is 9-11 kDa.

[0009] Beneficial effects of the present invention: The terbutaline sulfate solution for nebulized inhalation provided by the present invention has significant comprehensive advantages, and exhibits excellent nebulization performance, stability, and drug utilization. First, the nebulization time of the solution for nebulized inhalation is relatively short, and the efficiency is improved by about 30% compared with commercially available preparations, which significantly reduces the time spent on the patient's inhalation operation and improves medication compliance. At the same time, the residual amount after nebulization is less than 5%, and the drug utilization rate is as high as over 95%, which significantly reduces drug waste and reflects higher economy and effectiveness. As measured by a new generation impactor, the mass median aerodynamic diameter (MMAD) of the nebulized particles is 1-5μm, and the geometric standard deviation (GSD) is ≤2.0, which meets the optimal requirements for lung deposition. The narrow particle size distribution ensures that the drug particles can be efficiently deposited in the target areas of the lungs (such as the alveoli and bronchi), thereby significantly improving bioavailability.

[0010] In addition, the solution exhibits excellent sustained-release properties, with a cumulative release rate of less than 20% over 30 minutes, effectively avoiding the risk of bronchospasm caused by a burst release effect and improving medication safety. Furthermore, the 8-hour cumulative release rate exceeds 90%, extending the duration of drug action and reducing the number of daily doses (from the traditional 4-6 to 2-3), further improving patient compliance and quality of life.

[0011] This invention also demonstrates significant advantages in chemical and physical stability. The low total impurity content (less than 0.5% at 25°C and less than 2% at 45°C) indicates minimal drug degradation during storage. This is due to the inclusion complexation and molecular synergy of the polysorbate-modified cyclodextrin, which effectively isolates the drug from environmental influences and reduces the risks of oxidation, decomposition, and hydrolysis. Furthermore, the solution exhibits virtually no change in atomization performance after long-term storage, maintaining excellent physical structure and dispersibility. This prevents drug crystallization, sedimentation, or aggregation, ensuring drug safety and efficacy.

[0012] In summary, the present invention significantly improves the performance of the solution for nebulized inhalation through unique molecular design and stability optimization, providing patients with a safer, more efficient and convenient treatment option. DETAILED DESCRIPTION

[0013] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to specific embodiments. Example

[0014] (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 150 mL of anhydrous ethanol and perform ultrasonic treatment (frequency 35 kHz, power 150 W, time 10 min) to form a suspension. Add 0.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.12 g of N-hydroxysuccinimide, and activate by stirring at 25 °C for 0.5 h. Add 0.5 g of polysorbate 80, and react by stirring at room temperature for 10 h under nitrogen protection. Ultrafiltration is performed using a 9 kDa ultrafiltration membrane and vacuum drying is performed to obtain polysorbate-modified cyclodextrin. (2) Add 15.5 g of polysorbate-modified cyclodextrin to 700 mL of water for injection, heat to 55 °C, stir for 20 min, then add 1.5 g of terbutaline sulfate, stir at 700 rpm for 5 h, cool to room temperature, add 0.8 g of sodium chloride, 0.06 g of disodium edetate, and 0.03 g of sodium bisulfite, stir for 20 min, and obtain a mixed solution; (3) Adjust the pH of the mixture to 3.8 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 10 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate. Example

[0015] (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 200 mL of anhydrous ethanol and ultrasonically treat (frequency 40 kHz, power 200 W, time 15 min) to form a suspension. Add 0.5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.17 g of N-hydroxysuccinimide, and activate with stirring at 30 °C for 1 h. Add 1 g of polysorbate 80 and stir at room temperature under nitrogen protection for 12 h. Ultrafiltration is performed using a 10 kDa ultrafiltration membrane and vacuum drying is performed to obtain polysorbate-modified cyclodextrin. (2) Add 16 g of polysorbate-modified cyclodextrin to 800 mL of water for injection, heat to 60 °C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at 800 rpm for 6 h, cool to room temperature, add 0.9 g of sodium chloride, 0.08 g of disodium edetate, and 0.05 g of sodium bisulfite, stir for 30 min, and obtain a mixed solution; (3) Adjust the pH of the mixture to 4 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 15 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate. Example

[0016] (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 250 mL of anhydrous ethanol and perform ultrasonic treatment (frequency 45 kHz, power 250 W, time 20 min) to form a suspension. Add 0.7 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.22 g of N-hydroxysuccinimide, and activate by stirring at 35 °C for 1.5 h. Add 1.5 g of polysorbate 80, and react by stirring at room temperature under nitrogen protection for 14 h. Ultrafiltration is performed using an 11 kDa ultrafiltration membrane and vacuum drying is performed to obtain polysorbate-modified cyclodextrin. (2) Add 16.5 g of polysorbate-modified cyclodextrin to 900 mL of water for injection, heat to 65 °C, stir for 40 min, then add 2.5 g of terbutaline sulfate, stir at 900 rpm for 7 h, cool to room temperature, add 1 g of sodium chloride, 0.1 g of disodium edetate, and 0.08 g of sodium bisulfite, stir for 40 min, and obtain a mixed solution; (3) Adjust the pH of the mixture to 4.2 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 20 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate.

[0017] Comparative Example 1: The difference between Comparative Example 1 and Example 2 is that the polysorbate-modified cyclodextrin in step (2) is replaced by hydroxypropyl-β-cyclodextrin; The specific steps are as follows: (1) Add 16 g of hydroxypropyl-β-cyclodextrin to 800 mL of water for injection, heat to 60°C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at 800 rpm for 6 h, cool to room temperature, add 0.9 g of sodium chloride, 0.08 g of disodium edetate, and 0.05 g of sodium bisulfite, stir for 30 min to obtain a mixed solution; (2) Adjust the pH of the mixture to 4 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 15 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate.

[0018] Comparative Example 2: The difference between Comparative Example 2 and Example 2 is that the polysorbate-modified cyclodextrin in step (2) is replaced by a mixture of hydroxypropyl-β-cyclodextrin and polysorbate in a weight ratio of 15:1; The specific steps are as follows: (1) Add 15 g of hydroxypropyl-β-cyclodextrin and 1 g of polysorbate to 800 mL of water for injection, heat to 60°C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at 800 rpm for 6 h, cool to room temperature, add 0.9 g of sodium chloride, 0.08 g of disodium edetate, and 0.05 g of sodium bisulfite, stir for 30 min, and obtain a mixed solution; (2) Adjust the pH of the mixture to 4 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 15 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate. Comparative Example 3: The difference between Comparative Example 3 and Example 2 is that: no disodium edetate is added in step (2); The specific steps are as follows: (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 200 mL of anhydrous ethanol and ultrasonically treat (frequency 40 kHz, power 200 W, time 15 min) to form a suspension. Add 0.5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.17 g of N-hydroxysuccinimide, and activate with stirring at 30 °C for 1 h. Add 1 g of polysorbate 80 and stir at room temperature under nitrogen protection for 12 h. Ultrafiltration is performed using a 10 kDa ultrafiltration membrane and vacuum drying is performed to obtain polysorbate-modified cyclodextrin. (2) Add 16 g of polysorbate-modified cyclodextrin to 800 mL of water for injection, heat to 60 °C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at 800 rpm for 6 h, cool to room temperature, add 0.9 g of sodium chloride and 0.05 g of sodium bisulfite, stir for 30 min, and obtain a mixed solution; (3) Adjust the pH of the mixture to 4 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 15 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate.

[0019] Comparative Example 4: The difference between Comparative Example 4 and Example 2 is that: sodium bisulfite is not added in step (2); The specific steps are as follows: (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 200 mL of anhydrous ethanol and ultrasonically treat (frequency 40 kHz, power 200 W, time 15 min) to form a suspension. Add 0.5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.17 g of N-hydroxysuccinimide, and activate with stirring at 30 °C for 1 h. Add 1 g of polysorbate 80 and stir at room temperature under nitrogen protection for 12 h. Ultrafiltration is performed using a 10 kDa ultrafiltration membrane and vacuum drying is performed to obtain polysorbate-modified cyclodextrin. (2) Add 16 g of polysorbate-modified cyclodextrin to 800 mL of water for injection, heat to 60 °C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at 800 rpm for 6 h, then cool to room temperature, add 0.9 g of sodium chloride and 0.08 g of disodium edetate, stir for 30 min to obtain a mixed solution; (3) Adjust the pH of the mixture to 4 with hydrochloric acid, then dilute to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, and then pass nitrogen for 15 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL each, to obtain a solution for nebulized inhalation of terbutaline sulfate.

[0020] Performance testing: Nebulization performance test: Three aliquots (2.5 mL each) were taken using a jet nebulizer. The nebulization time and residual volume were recorded and averaged. The aerosolized particles were collected using NGI, and the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were measured and averaged. The results are shown in Table 1.

[0021] Sustained-release performance test: Three aliquots (2.5 mL each) were taken and PBS buffer containing 0.1% polysorbate 80, pH 7.4, was used as simulated lung fluid. The cumulative release rate of terbutaline sulfate within 30 minutes and 8 hours was measured using a dissolution apparatus at 37°C ± 0.5°C and 50 rpm. The average value was taken. The results are shown in Table 1.

[0022] Table 1 Test results of atomization performance and sustained release performance

[0023] Data Analysis: As shown in Table 1, the data from Examples 1-3 indicate that the terbutaline sulfate solution for nebulized inhalation provided by the present invention exhibits excellent atomization performance and a short atomization time, achieving an efficiency improvement of approximately 30% compared to similar commercially available formulations (typically 8-12 minutes). This short atomization time significantly reduces patient inhalation time and improves compliance. The residual volume after atomization is less than 5%, indicating a drug utilization rate exceeding 95%, effectively reducing drug waste. The mass median aerodynamic diameter (MMAD) of the aerosolized particles, as measured by a new generation impactor (NGI), ranged from 1 to 5 μm, with a geometric standard deviation (GSD) of ≤2.0, meeting FDA lung deposition requirements for inhaled formulations. The narrow particle size distribution (GSD ≤ 2.0) ensures that the majority of the drug particles are deposited in the alveoli and bronchi, significantly enhancing bioavailability.

[0024] As can be seen from the data of Examples 1-3 in Table 1, the 30-minute cumulative release rate of the terbutaline sulfate solution for aerosol inhalation provided by the present invention is less than 20%, effectively avoiding the risk of bronchospasm caused by the burst release effect and improving medication safety. The 8-hour cumulative release rate is greater than 90%, effectively prolonging the drug's duration of action, reducing the number of daily doses (from the traditional 4-6 times to 2-3 times), and significantly improving patient compliance.

[0025] From the data of Example 2 and Comparative Example 1 in Table 1, it can be seen that, relative to hydroxypropyl-β-cyclodextrin, the polysorbate-modified cyclodextrin prepared by the present invention can effectively improve the atomization performance of the terbutaline sulfate nebulized inhalation solution, reduce the atomization time, reduce the residual amount, and effectively reduce the mass median aerodynamic diameter and geometric standard deviation of the atomized particles. At the same time, the 30-min cumulative release rate is significantly reduced. This is mainly due to the unique molecular synergistic mechanism between polysorbate and cyclodextrin. The hydrophobic palmitate chain of polysorbate 80 can be embedded in the β-cyclodextrin cavity, and the hydrophilic polyethylene oxide chain extends outward to form a "core-shell" structure. This "core-shell" structure can effectively reduce the surface tension of the solution and significantly improve the atomization effect. In addition, the polyethylene oxide chain can form a dynamic hydration layer on the surface of the drug-cyclodextrin inclusion complex, thereby significantly reducing the 30-min cumulative release rate and preventing sudden drug release.

[0026] From the data of Example 2 and Comparative Example 2 in Table 1, it can be seen that, compared with direct mixing, grafting polysorbate onto cyclodextrin can further reduce the atomization time, reduce the residual rate, the mass median aerodynamic diameter and the geometric standard deviation of the atomized particles, and most importantly, significantly reduce the 30-min cumulative release rate. This is mainly due to the stable synergistic structure formed by chemical grafting. Through covalent grafting, the hydrophobic chain segment of polysorbate is combined with the cyclodextrin cavity to form a tighter core-shell structure. At the same time, the hydrophilic polyoxyethylene chain is evenly distributed on the molecular surface, which significantly enhances the molecular stability and functionality of the system.

[0027] Stability performance test: Six subpackaged samples (2.5 mL each) were taken and divided into two groups. The samples were placed at 25°C and 45°C for three months. After that, the total impurity content, nebulization time change rate, and residual amount change rate of each group of terbutaline sulfate nebulized inhalation solution were tested. The average values ​​were taken. The results are shown in Table 2.

[0028] Table 2 Stability test results

[0029] Data Analysis: The data from Examples 1-3 in Table 1 demonstrate that the terbutaline sulfate solution for nebulized inhalation prepared by the present invention exhibits excellent chemical and physical stability. First, the low total impurity content (less than 0.5% at 25°C and less than 2% at 45°C) indicates minimal drug degradation during storage. This is due to the inclusion complexation of the polysorbate-modified cyclodextrin, which effectively isolates the drug from environmental influences (such as oxygen, humidity, and light), reducing the risk of drug oxidation, decomposition, and hydrolysis. Second, the nebulization performance remained virtually unchanged after stability testing (e.g., nebulization time, residual rate, mass median aerodynamic diameter, and geometric standard deviation remained consistent), demonstrating that the system maintained excellent physical structure and dispersibility during storage. This is attributed to the molecular network structure of the modified cyclodextrin and the surface activity of the polysorbate, which effectively prevent drug crystallization, sedimentation, or aggregation while maintaining the homogeneity and rheological properties of the solution. This excellent stability ensures the safety, efficacy, and consistency of the drug during long-term storage and use, providing reliable support for practical applications.

[0030] As can be seen from the data of Example 2 and Comparative Example 1 in Table 1, the polysorbate-modified cyclodextrin prepared by the present invention can effectively improve the stability of the terbutaline sulfate solution for nebulized inhalation compared to hydroxypropyl-β-cyclodextrin. This is mainly because the polysorbate-modified cyclodextrin significantly improves the stability of the terbutaline sulfate solution for nebulized inhalation from both chemical and physical aspects by enhancing the inclusion complexation, improving the dispersibility and resistance to environmental changes.

[0031] The data from Example 2 and Comparative Example 2 in Table 1 demonstrate that, compared to direct mixing, grafting polysorbate onto cyclodextrin further improves the stability of terbutaline sulfate nebulized inhalation solution. This is primarily due to the covalent bond formed between polysorbate and cyclodextrin through chemical grafting, significantly enhancing intermolecular binding and avoiding the physical adsorption instability that can occur in direct mixing systems. This stable core-shell structure more effectively encapsulates drug molecules, reducing drug degradation and impurity formation during storage. Furthermore, the grafted system, through its stable molecular structure, maintains key parameters such as the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the aerosolized particles even after long-term storage, ensuring virtually unchanged aerosol performance.

[0032] As can be seen from the data of Example 2 and Comparative Examples 3-4 in Table 1, disodium edetate and sodium bisulfite synergistically improve the stability of the terbutaline sulfate solution for nebulized inhalation. This is mainly due to the synergistic effect of disodium edetate and sodium bisulfite through chelation and antioxidant protection, which fundamentally inhibits the oxidative degradation and impurity formation of terbutaline sulfate, thereby significantly improving the stability of the solution for nebulized inhalation.

[0033] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention is limited to these examples. Within the scope of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

Claims

1. A method for preparing a terbutaline sulfate solution for aerosol inhalation, characterized in that: The following steps are involved: (1) Disperse hydroxypropyl-β-cyclodextrin in anhydrous ethanol, perform ultrasonic treatment to form a suspension, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, stir and activate at 25-35°C for 0.5-1.5 h, add polysorbate 80, stir and react at room temperature for 10-14 h under nitrogen protection, perform ultrafiltration using an ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin; (2) Add polysorbate-modified cyclodextrin to water for injection, heat to 55-65°C, stir for 20-40 minutes, then add terbutaline sulfate, stir at 700-900 rpm for 5-7 hours, then cool to room temperature, add sodium chloride, disodium edetate and sodium bisulfite, stir for 20-40 minutes to obtain a mixed solution; (3) Adjust the pH of the mixed solution to 3.8-4.2 with hydrochloric acid, and then make up to 1000 mL with water for injection, filter through a filter membrane, and then pass nitrogen for 10-20 minutes. Finally, dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain a solution for nebulized inhalation of terbutaline sulfate; In the step (1), the dosage ratio of hydroxypropyl-β-cyclodextrin, anhydrous ethanol, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide and polysorbate 80 is 15 g: 150-250 mL: 0.3-0.7 g: 0.12-0.22 g: 0.5-1.5 g; In the step (2), the dosage ratio of polysorbate-modified cyclodextrin, water for injection, terbutaline sulfate, sodium chloride, disodium edetate and sodium bisulfite is 15.5-16.5 g:700-900 mL:1.5-2.5 g:0.8-1 g:0.06-0.1:0.03-0.

08.

2. The method for preparing a terbutaline sulfate atomization inhalation solution according to claim 1, wherein The frequency of the ultrasonic treatment in step (1) is 35-45 kHz, the power is 150-250 W, and the time is 10-20 min.

3. The method for preparing the terbutaline sulfate solution for atomization inhalation according to claim 1, characterized in that: The molecular weight cut-off of the ultrafiltration membrane in step (1) is 9-11 kDa.

4. The method for preparing the terbutaline sulfate solution for atomization inhalation according to claim 1, characterized in that: The filter membrane in step (3) is a 0.22 μm double-layer sterile filter membrane.

5. A solution for aerosol inhalation of terbutaline sulfate, characterized in that: The terbutaline sulfate solution for aerosol inhalation is obtained by the preparation method of any one of claims 1 to 4.

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