A solution of terbutaline sulfate for inhalation and its preparation method

Abstract

The present invention relates to the field of medical technology, and in particular to a solution for nebulized inhalation of terbutaline sulfate and a preparation method thereof. The solution achieves a performance breakthrough through the molecular synergy of polysorbate-modified cyclodextrin: first, hydroxypropyl-β-cyclodextrin and polysorbate 80 are activated and covalently grafted to form a modified carrier with a core-shell structure, and then compounded with terbutaline sulfate, sodium chloride, disodium edetate and sodium bisulfite. The present invention effectively solves the technical problems of low atomization efficiency, high risk of burst release and poor stability of traditional preparations through the stable core-shell structure formed by chemical grafting, combined with the synergistic effect of chelating agents and antioxidants, and provides a safer and more efficient inhalation solution for the treatment of respiratory diseases.

Description

Technical Field

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

[0002] Terbutaline sulfate is a selective β 2 -receptor agonist, which is widely used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Its inhalation aerosol preparation has become the first choice in clinical practice because it can directly act on the lung target tissue, has a rapid onset of action, and has few systemic side effects. However, the existing commercially available inhalation solutions generally have the following problems: First, the atomization efficiency is low, and the atomization time is as long as 8 - 12 minutes, resulting in poor patient compliance; second, the risk of drug sudden release is high, and the cumulative release rate within 30 minutes exceeds 40%, which is likely to cause adverse reactions such as bronchospasm; third, the stability is insufficient, and it is easily oxidized and degraded during storage, and the total impurity content increases, affecting safety and effectiveness.

[0003] In traditional techniques, hydroxypropyl-β-cyclodextrin (HP-β-CD) is often used as a drug carrier to improve solubility, but its inclusion ability is limited, and it is difficult to optimize atomization performance and sustained-release characteristics simultaneously. In addition, although directly adding a surfactant (such as polysorbate 80) can reduce the surface tension, there are problems such as unstable adsorption and uneven dispersion in the physical mixing system, and drug crystallization or aggregation is likely to occur during long-term storage. In the existing technology, although the combination of excipients (such as antioxidants and chelating agents) can partially improve stability, the effect of a single component is limited, and it is difficult to synergistically inhibit multiple degradation pathways. For example, relying solely on disodium edetate (EDTA) to chelate metal ions cannot effectively scavenge reactive oxygen species; although sodium bisulfite alone has antioxidant effects, its inhibitory effect on metal ion-catalyzed degradation is insufficient.

[0004] More critically, the existing technology has not solved the contradiction between drug sustained release and atomization performance. In traditional preparations, when pursuing high atomization efficiency, drug sudden release often occurs due to too low surface tension, and in the sustained-release design, the pulmonary deposition rate may be reduced due to a wide particle size distribution (GSD>2.0) or the MMAD deviating from the optimal range (1 - 5μm). Therefore, there is an urgent need to develop a new type of preparation that can achieve controlled sustained release while improving atomization efficiency through molecular structure design and the synergistic effect of excipients, and has 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 inhalation of terbutaline sulfate and a preparation method thereof, so as to solve the problems of low atomization efficiency, high risk of sudden release, poor stability of the existing inhalation solution, and difficulty in balancing the contradiction between sustained release and atomization performance.

[0006] For the above purposes, the present invention provides a method for preparing a solution for nebulization inhalation of terbutaline sulfate, comprising the following steps:

[0007] (1) Dissolve hydroxypropyl-β-cyclodextrin in absolute ethanol, subject it to 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, under nitrogen protection, stir and react at room temperature for 10-14 h, perform ultrafiltration using an ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin;

[0008] (2) Add the polysorbate-modified cyclodextrin to water for injection, heat to 55-65 °C, stir for 20-40 min, then add terbutaline sulfate, stir at a speed of 700-900 rpm for 5-7 h, then cool to room temperature, add sodium chloride, disodium edetate and sodium bisulfite, and stir for 20-40 min to obtain a mixed solution;

[0009] (3) Adjust the pH of the mixed solution to 3.8-4.2 with hydrochloric acid, then make up the volume to 1000 mL with water for injection, filter through a filter membrane, then pass nitrogen for 10-20 min, and finally dispense into pre-sterilized containers, 2.5 mL per vial, to obtain the solution for nebulization inhalation of terbutaline sulfate;

[0010] In the step (1), the dosage ratio of hydroxypropyl-β-cyclodextrin, absolute 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;

[0011] 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.

[0012] In the step (1), the frequency of the ultrasonic treatment is 35-45 kHz, the power is 150-250 W, and the time is 10-20 min.

[0013] In the step (1), the cut-off molecular weight of the ultrafiltration membrane is 9-11 kDa.

[0014] The beneficial effects of the present invention:

[0015] The solution of terbutaline sulfate for inhalation provided by the present invention has significant comprehensive advantages, showing excellent atomization performance, stability and drug utilization rate. First of all, the atomization time of this inhalation solution is short, and the efficiency is increased by about 30% compared with the commercially available preparations, significantly reducing the inhalation operation time of patients and improving medication compliance. At the same time, the residual amount after atomization is less than 5%, and the drug utilization rate is over 95%, significantly reducing drug waste and reflecting higher economy and effectiveness. Measured by a new generation of impactors, the mass median aerodynamic diameter (MMAD) of the atomized particles is 1-5 μm, and the geometric standard deviation (GSD) ≤ 2.0, meeting the best requirements for pulmonary deposition. The narrow particle size distribution ensures that drug particles can be efficiently deposited in the pulmonary target areas (such as alveoli and bronchi), thus significantly improving the bioavailability.

[0016] In addition, this solution has excellent sustained-release performance, and the cumulative release rate within 30 minutes is less than 20%, effectively avoiding the risk of bronchospasm caused by the burst release effect and improving the medication safety. At the same time, the cumulative release rate within 8 hours is higher than 90%, prolonging the drug action time and reducing the daily dosing frequency (from the traditional 4-6 times to 2-3 times), further improving patient compliance and quality of life.

[0017] The present invention also shows 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 that the drug has a very low degradation degree during storage. Thanks to the inclusion effect of polysorbate-modified cyclodextrin and the molecular synergistic mechanism, it effectively isolates the influence of the external environment and reduces the risks of oxidation, decomposition and hydrolysis. At the same time, after long-term storage of the solution, the atomization performance hardly changes, maintaining good physical structure and dispersibility, avoiding drug crystallization, sedimentation or aggregation phenomena, and ensuring the safety and effectiveness of the drug.

[0018] In summary, through unique molecular design and stability optimization, the present invention has greatly improved the performance of the inhalation solution, providing a safer, more efficient and convenient treatment option for patients. Detailed implementation modes

[0019] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with specific embodiments.

[0020] Example 1:

[0021] (1) Dissolve 15 g of hydroxypropyl-β-cyclodextrin in 150 mL of absolute ethanol, and subject it to 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, stir and activate at 25 °C for 0.5 h, add 0.5 g of polysorbate 80, and under nitrogen protection, stir and react at room temperature for 10 h. Perform ultrafiltration using a 9 kDa ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin;

[0022] (2) Add 15.5 g of polysorbate-modified cyclodextrin to 700 mL of injection water, heat up to 55 °C, stir for 20 min, then add 1.5 g of terbutaline sulfate, stir at a speed of 700 rpm for 5 h, then cool down to room temperature, add 0.8 g of sodium chloride, 0.06 g of disodium edetate and 0.03 g of sodium bisulfite, and stir for 20 min to obtain a mixed solution;

[0023] (3) Adjust the pH of the mixed solution to 3.8 with hydrochloric acid, then make up the volume to 1000 mL with injection water, filter through a 0.22 μm double-layer sterile filter membrane, then pass nitrogen for 10 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain the terbutaline sulfate solution for inhalation.

[0024] Example 2:

[0025] (1) Dissolve 15 g of hydroxypropyl-β-cyclodextrin in 200 mL of absolute ethanol, and subject it to ultrasonic treatment (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, stir and activate at 30 °C for 1 h, add 1 g of polysorbate 80, and under nitrogen protection, stir and react at room temperature for 12 h. Perform ultrafiltration using a 10 kDa ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin;

[0026] (2) Add 16 g of polysorbate-modified cyclodextrin to 800 mL of injection water, heat up to 60 °C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at a speed of 800 rpm for 6 h, then cool down to room temperature, add 0.9 g of sodium chloride, 0.08 g of disodium edetate and 0.05 g of sodium bisulfite, and stir for 30 min to obtain a mixed solution;

[0027] (3) Adjust the pH of the mixed solution to 4 with hydrochloric acid, then make up the volume to 1000 mL with injection water, filter through a 0.22 μm double-layer sterile filter membrane, then pass nitrogen for 15 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain the terbutaline sulfate solution for inhalation.

[0028] Example 3:

[0029] (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 250 mL of absolute 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, stir and activate at 35 °C for 1.5 h, add 1.5 g of polysorbate 80, and under nitrogen protection, stir and react at room temperature for 14 h. Perform ultrafiltration using an 11 kDa ultrafiltration membrane, and dry in vacuo to obtain polysorbate-modified cyclodextrin;

[0030] (2) Add 16.5 g of polysorbate-modified cyclodextrin to 900 mL of injection water, heat up to 65 °C, stir for 40 min, then add 2.5 g of terbutaline sulfate, stir at a speed of 900 rpm for 7 h, then cool down to room temperature, add 1 g of sodium chloride, 0.1 g of disodium edetate, and 0.08 g of sodium bisulfite, and stir for 40 min to obtain a mixed solution;

[0031] (3) Adjust the pH of the mixed solution to 4.2 with hydrochloric acid, then make up the volume to 1000 mL with injection water, filter through a 0.22 μm double-layer sterile filter membrane, then pass nitrogen for 20 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain a terbutaline sulfate inhalation solution.

[0032] Comparative Example 1:

[0033] The difference between Comparative Example 1 and Example 2 is that: in step (2), the polysorbate-modified cyclodextrin is replaced with hydroxypropyl-β-cyclodextrin;

[0034] The specific steps are as follows:

[0035] (1) Add 16 g of hydroxypropyl-β-cyclodextrin to 800 mL of injection water, heat up to 60 °C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at a speed of 800 rpm for 6 h, then cool down to room temperature, add 0.9 g of sodium chloride, 0.08 g of disodium edetate, and 0.05 g of sodium bisulfite, and stir for 30 min to obtain a mixed solution;

[0036] (2) Adjust the pH of the mixed solution to 4 with hydrochloric acid, then make up the volume to 1000 mL with injection water, filter through a 0.22 μm double-layer sterile filter membrane, then pass nitrogen for 15 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain a terbutaline sulfate inhalation solution.

[0037] Comparative Example 2:

[0038] The difference between Comparative Example 2 and Example 2 lies in that in step (2), polysorbate-modified cyclodextrin is replaced with a mixture of hydroxypropyl-β-cyclodextrin and polysorbate at a weight ratio of 15:1;

[0039] The specific steps are as follows:

[0040] (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 a speed of 800 rpm for 6 h, then cool to room temperature, add 0.9 g of sodium chloride, 0.08 g of disodium edetate and 0.05 g of sodium bisulfite, and stir for 30 min to obtain a mixed solution;

[0041] (2) Adjust the pH of the mixed solution to 4 with hydrochloric acid, then make up the volume to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, then purge with nitrogen for 15 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain the terbutaline sulfate nebulization solution for inhalation.

[0042] Comparative Example 3:

[0043] The difference between Comparative Example 3 and Example 2 lies in that disodium edetate is not added in step (2);

[0044] The specific steps are as follows:

[0045] (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 200 mL of absolute ethanol, perform ultrasonic treatment (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, stir and activate at 30 °C for 1 h, add 1 g of polysorbate 80, under nitrogen protection, stir and react at room temperature for 12 h, perform ultrafiltration using a 10 kDa ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin;

[0046] (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 a speed of 800 rpm for 6 h, then cool to room temperature, add 0.9 g of sodium chloride and 0.05 g of sodium bisulfite, and stir for 30 min to obtain a mixed solution;

[0047] (3) Adjust the pH of the mixed solution to 4 with hydrochloric acid, then make up the volume to 1000 mL with water for injection, filter through a 0.22 μm double-layer sterile filter membrane, then purge with nitrogen for 15 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain the terbutaline sulfate nebulization solution for inhalation.

[0048] Comparative Example 4:

[0049] The difference between Comparative Example 4 and Example 2 is that: in step (2), sodium bisulfite was not added;

[0050] The specific steps are as follows:

[0051] (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 200 mL of absolute ethanol, and perform ultrasonic treatment (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, stir and activate at 30 °C for 1 h, add 1 g of polysorbate 80, under nitrogen protection, stir and react at room temperature for 12 h, perform ultrafiltration using a 10 kDa ultrafiltration membrane, and vacuum dry to obtain polysorbate-modified cyclodextrin;

[0052] (2) Add 16 g of polysorbate-modified cyclodextrin to 800 mL of injection water, heat up to 60 °C, stir for 30 min, then add 2 g of terbutaline sulfate, stir at a speed of 800 rpm for 6 h, then cool down to room temperature, add 0.9 g of sodium chloride and 0.08 g of disodium edetate, and stir for 30 min to obtain a mixed solution;

[0053] (3) Adjust the pH of the mixed solution to 4 with hydrochloric acid, then make up the volume to 1000 mL with injection water, filter through a 0.22 μm double-layer sterile filter membrane, then pass nitrogen for 15 min, and finally dispense into pre-sterilized PE containers, 2.5 mL per vial, to obtain the terbutaline sulfate inhalation solution.

[0054] Performance test:

[0055] Atomization performance test: Take 3 vials of dispensed samples (2.5 mL per vial), use a jet nebulizer, record the atomization time and residual amount, take the average value, and collect the atomized particles with NGI to measure the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD), take the average value, and the results are shown in Table 1.

[0056] Sustained-release performance test: Take 3 vials of dispensed samples (2.5 mL per vial), use PBS buffer containing 0.1% polysorbate 80 and pH 7.4 as the simulated lung fluid, at 37 °C ± 0.5 °C and a rotation speed of 50 rpm, use a dissolution tester to measure the cumulative release rate of terbutaline sulfate within 30 min and within 8 h, take the average value, and the results are shown in Table 1.

[0057] Table 1 Test results of atomization performance and sustained-release performance

[0058]

[0059] Data analysis:

[0060] As can be seen from the data of Examples 1-3 in Table 1, the terbutaline sulfate inhalation solution provided by the present invention has excellent atomization performance and a short atomization time. Compared with similar commercially available preparations (usually 8-12 min), the efficiency is increased by about 30%. The short atomization time can significantly reduce the inhalation operation time of patients and improve compliance. The residual amount after atomization is less than 5%, indicating that the drug utilization rate is as high as over 95%, effectively reducing drug waste. Measured by a Next Generation Impactor (NGI), the Mass Median Aerodynamic Diameter (MMAD) of the atomized particles is 1-5 μm, and the Geometric Standard Deviation (GSD) ≤ 2.0, meeting the FDA requirements for pulmonary deposition of inhalation preparations. The narrow particle size distribution (GSD ≤ 2.0) ensures that most of the drug particles can be deposited in the alveoli and bronchi, significantly improving the bioavailability.

[0061] As can be seen from the data of Examples 1-3 in Table 1, the 30-min cumulative release rate of the terbutaline sulfate inhalation solution provided by the present invention is less than 20%, effectively avoiding the risk of bronchospasm caused by the burst release effect and improving the medication safety. The 8-h cumulative release rate is higher than 90%, effectively prolonging the drug action time and reducing the daily dosing frequency (from the traditional 4-6 times to 2-3 times), significantly improving the patient compliance.

[0062] As can be seen from the data of Example 2 and Comparative Example 1 in Table 1, compared with hydroxypropyl-β-cyclodextrin, the polysorbate-modified cyclodextrin prepared by the present invention can effectively improve the atomization performance of the terbutaline sulfate inhalation solution, reduce the atomization time and 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, which is mainly due to the unique molecular synergistic mechanism between polysorbate and cyclodextrin. The hydrophobic palmitic acid chain of polysorbate 80 can be embedded in the β-cyclodextrin cavity, and the hydrophilic polyoxyethylene 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. Moreover, the polyoxyethylene 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 the burst release of the drug.

[0063] As can be seen from the data of Example 2 and Comparative Example 2 in Table 1, compared with direct mixing, grafting polysorbate onto cyclodextrin can further reduce the atomization time, the residual rate, the Mass Median Aerodynamic Diameter and Geometric Standard Deviation of the atomized particles. Most importantly, the 30-min cumulative release rate is significantly reduced, which mainly stems from the stable synergistic structure formed by chemical grafting. Through covalent grafting, the hydrophobic chain segment of polysorbate binds to the cyclodextrin cavity to form a tighter "core-shell" structure. At the same time, the hydrophilic polyoxyethylene chains are evenly distributed on the molecular surface, significantly enhancing the molecular stability and functionality of the system.

[0064] Stability performance test: Take 6 dispensed samples (2.5 mL each), divide them into 2 groups, place them at 25 °C and 45 °C respectively for 3 months, then sample and detect the total impurity content, atomization time change rate and residue change rate of terbutaline sulfate inhalation solution in each group, and take the average value. The results are shown in Table 2.

[0065] Table 2 Results of stability test

[0066]

[0067] Data analysis:

[0068] From the data of Examples 1 - 3 in Table 1, it can be seen that the terbutaline sulfate inhalation solution prepared by the present invention has excellent chemical and physical stability. First of all, the low total impurity content (below 0.5% at 25 °C and below 2% at 45 °C) indicates that the drug has a very low degree of degradation during storage. Thanks to the inclusion effect of polysorbate-modified cyclodextrin, it can effectively isolate the influence of the external environment (such as oxygen, humidity and light), reducing the risks of drug oxidation, decomposition and hydrolysis. Secondly, the atomization performance hardly changes after the stability test (such as the atomization time, residue rate, mass median aerodynamic diameter and geometric standard deviation remain consistent), indicating that the system maintains good physical structure and dispersibility during storage. This benefits from the molecular network structure of the modified cyclodextrin and the surface activity of polysorbate, which can effectively prevent drug crystallization, sedimentation or aggregation, while maintaining the uniformity and rheological properties of the solution. This excellent stability ensures the safety, effectiveness and consistency of the drug during long-term storage and use, providing a reliable guarantee for practical applications.

[0069] From the data of Example 2 and Comparative Example 1 in Table 1, it can be seen that compared with hydroxypropyl-β-cyclodextrin, the polysorbate-modified cyclodextrin prepared by the present invention can effectively improve the stability of terbutaline sulfate inhalation solution, which is mainly because the polysorbate-modified cyclodextrin significantly enhances the stability of terbutaline sulfate inhalation solution from both chemical and physical aspects by enhancing the inclusion effect, improving the dispersibility and anti-environment change ability.

[0070] From the data of Example 2 and Comparative Example 2 in Table 1, it can be seen that grafting polysorbate onto cyclodextrin can further improve the stability of terbutaline sulfate nebulization inhalation solution compared with direct mixing. This is mainly because polysorbate forms a covalent bond with cyclodextrin through chemical grafting, significantly enhancing the intermolecular binding force and avoiding the physical adsorption instability that may occur in the direct mixing system. This stable core-shell structure can more effectively encapsulate drug molecules, reduce the degradation of drugs and the generation of impurities during storage, and the grafting system can maintain key parameters such as the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the nebulized particles after long-term storage through its stable molecular structure, ensuring that the nebulization performance hardly changes.

[0071] From the data of Example 2 and Comparative Examples 3-4 in Table 1, it can be seen that disodium edetate and sodium bisulfite synergistically improve the stability of terbutaline sulfate nebulization inhalation solution. This is mainly due to the synergistic effect of disodium edetate and sodium bisulfite through chelation and antioxidant protection, fundamentally inhibiting the oxidative degradation and impurity generation of terbutaline sulfate and significantly improving the stability of the nebulization inhalation solution.

[0072] Those of ordinary skill in the art should understand that the discussion of any of the above embodiments is only exemplary and is not intended to imply that the scope of the present invention is limited to these examples; under the concept of the present invention, the technical features in the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations in different aspects of the present invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. A method for preparing a terbutaline sulfate solution for aerosol inhalation, characterized in that: The following steps are involved: (1) Disperse 15 g of hydroxypropyl-β-cyclodextrin in 150-250 mL of anhydrous ethanol, perform ultrasonic treatment to form a suspension, add 0.3-0.7 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.12-0.22 g of N-hydroxysuccinimide, activate by stirring at 25-35°C for 0.5-1.5 h, add 0.5-1.5 g of polysorbate 80, react by stirring 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 15.5-16.5 g of polysorbate-modified cyclodextrin to 700-900 mL of water for injection, heat to 55-65°C, stir for 20-40 min, then add 1.5-2.5 g of terbutaline sulfate, stir at 700-900 rpm for 5-7 h, cool to room temperature, add 0.8-1 g of sodium chloride, 0.06-0.1 g of edetate disodium and 0.03-0.08 g of sodium bisulfite, stir for 20-40 min, and obtain a mixed solution; (3) Adjust the pH of the mixture 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 containers, 2.5 mL per vial, to obtain a solution for nebulized inhalation of terbutaline sulfate.

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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