Aerosol inhalation solution for treating bronchial asthma as well as preparation method and application thereof

Abstract

The invention belongs to the field of bronchial asthma medicines, and particularly discloses an aerosol inhalation solution for treating bronchial asthma as well as a preparation method and application of the aerosol inhalation solution. The aerosol inhalation solution is prepared from the following components in concentration: 1 to 5 mg / mL of terbutaline sulfate, 2 to 4 mg / mL of tremella polysaccharide, 1.5 to 3 mg / mL of glutathione, 2 to 6 mg / mL of a mucus regulator or a discharge promoting agent, sodium hyaluronate, astaxanthin and a pH regulator. Preferably, the mucus conditioning agent or the cleanup promoting agent is ambroxol hydrochloride, and further, the pH conditioning agent is selected from one of hydrochloric acid, acetic acid-sodium acetate and citric acid-sodium citrate; preferably, the sodium hyaluronate is modified sodium hyaluronate; in view of the defect that terbutaline sulfate is not stable enough, the terbutaline sulfate is reasonably matched, so that the stability of a solution is improved, impurities in the solution are reduced, and the atomization performance is improved.

Description

Technical Field

[0001] The present invention belongs to the field of drugs for bronchial asthma, and specifically discloses an aerosol inhalation solution for treating bronchial asthma, a preparation method thereof, and an application thereof. Background Art

[0002] Bronchial asthma, abbreviated as asthma, is a common chronic inflammatory airway disease, mainly characterized by recurrent episodes of wheezing, shortness of breath, chest tightness or coughing, etc., which often occur or worsen at night and in the early morning. The onset of asthma is related to genetic and environmental factors, etc. Among them, genetic factors mainly determine the susceptible constitution of patients, while environmental factors such as various allergens, air quality, smoking, exercise, etc. are specific triggering factors. Common types of bronchial asthma include exercise-induced, drug-induced, occupational and allergic, etc.

[0003] The symptoms of asthma are mainly wheezing, shortness of breath, chest tightness or coughing. In severe cases, dyspnea and hypoxemia may occur. For patients who have been diagnosed with asthma, when the symptoms worsen or interfere with daily life, it is recommended to seek medical attention in a timely manner. It should be noted that asthma is not an infectious disease, so there is no need to worry about transmission through the air or contact.

[0004] If bronchial asthma is not diagnosed and treated in a timely manner, irreversible airway constriction and airway remodeling may occur with the prolongation of the disease course. It may develop into chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease is a common chronic disease with airflow obstruction characteristics of chronic bronchitis and / or emphysema, which can further develop into cor pulmonale and respiratory failure. It is related to abnormal inflammatory reactions to harmful gases and harmful particles, with a high disability rate and fatality rate. The incidence rate among people over 40 years old globally has reached as high as 9% - 10%.

[0005] Terbutaline Sulfate Aerosol Solution was developed by AstraZeneca and launched in Sweden in 1981. It is a β2-adrenergic receptor agonist that dilates the bronchi by selectively exciting the β2 receptor, and can increase the mucociliary clearance function reduced by obstructive lung diseases, thereby accelerating the clearance of mucus secretions. It has both anti-asthmatic and expectorant effects, and also has the effect of dilating the bronchi. Clinically, it is mainly used to relieve bronchospasm combined with bronchial asthma, chronic bronchitis, emphysema and other pulmonary diseases. It is mainly administered by aerosol inhalation, with the advantages of rapid onset, good absorption, good efficacy, high bioavailability, etc.

[0006] The main component of Terbutaline Sulfate Aerosol Solution, terbutaline sulfate, has the chemical name of (±)α-[(tert-butylamino)methyl]-3,5-dihydroxybenzyl alcohol sulfate (2:1). Its properties are unstable, and it is extremely easy to generate new impurities under the influence of metal ions, oxygen, light, etc., thus affecting the stability of the preparation and the safety of clinical use. Therefore, measures need to be taken to ensure that the impurities in the preparation product can be continuously controlled within a controllable range.

[0007] Therefore, how to improve the composition of terbutaline nebulizer, enhance its stability and nebulization performance after long-term storage is a problem worthy of research. SUMMARY OF THE INVENTION

[0008] In order to solve the above problems, the present invention discloses an aerosol inhalation solution for treating bronchial asthma, its preparation method and application.

[0009] The technical solution of the present invention is as follows:

[0010] An aerosol inhalation solution for treating bronchial asthma, the aerosol inhalation solution contains components in the following concentrations:

[0011]

[0012] Further, in the above aerosol inhalation solution for treating bronchial asthma, the mucolytic agent or expectorant is ambroxol hydrochloride.

[0013] Further, in the above aerosol inhalation solution for treating bronchial asthma, the pH regulator is selected from one of hydrochloric acid, acetic acid-sodium acetate, and citric acid-sodium citrate.

[0014] Further, in the above aerosol inhalation solution for treating bronchial asthma, the sodium hyaluronate is modified sodium hyaluronate, which is prepared by the following steps:

[0015] 1) By weight, add 1 part of sodium hyaluronate dry powder to 9 parts of aqueous solution containing 0.005 - 0.01 part of hyaluronidase, and enzymatically hydrolyze at 30 - 35 °C for 10 min to obtain 10 parts of sodium hyaluronate solution;

[0016] 2) Stir and add the sodium hyaluronate solution obtained in step 1) to a lysine solution with a concentration of 10 - 20 g / 100 mL at a rate of 1 - 5 mL / min, and the final volume ratio of the added sodium hyaluronate solution to the lysine solution is 1:1 - 2; after the addition is completed, stir at 30 - 35 °C for 1 - 4 h to obtain a sodium hyaluronate mixture;

[0017] 3) After stirring evenly at a rate of 800 rpm / min according to the mass ratio of sodium hyaluronate mixture, PEG4000, and chitosan of 100:10:2, add triethanolamine to adjust the pH of the system to between 6 - 7, and let it stand and age for 2 - 6 h to obtain a modified sodium hyaluronate solution;

[0018] 4) Vacuum freeze-dry the modified sodium hyaluronate solution obtained in step 3), with a vacuum degree below 25 Pa, a pre-freezing temperature below -50 °C for more than 4 h, a drying temperature: 0 - 25 °C, and a time of 16 - 48 h to obtain modified sodium hyaluronate.

[0019] Preferably, for the above atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0020]

[0021] Preferably, for the above atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0022]

[0023] The present invention also discloses a preparation method of the above atomization inhalation solution for treating bronchial asthma, which includes the following steps:

[0024] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, mucus regulator or expectorant, sodium hyaluronate, and astaxanthin in formula amounts with an appropriate amount of pure water;

[0025] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0, add pure water to make up the total volume, and then filter it twice through 0.45 μm and 0.22 μm filters to obtain a filtrate;

[0026] Step 3: Subpackage the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0027] On the other hand, the present invention discloses the application of the above atomization inhalation solution in the preparation of a drug for treating chronic obstructive pulmonary disease complicated with asthma.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention rationally combines terbutaline. In the formulation, terbutaline sulfate, tremella polysaccharide, glutathione, mucus regulator or expectorant, (modified) sodium hyaluronate, and astaxanthin are put into the formula. By making full use of the rapid-acting β2-adrenergic receptor agonist effect of terbutaline sulfate, it can effectively inhibit the release of histamine and other allergenic substances and prevent bronchospasm. Further, a medium- and long-acting mucus regulator or expectorant is used to promote mucus dissolution and excretion, alleviating the symptoms of chronic obstructive pulmonary disease. In addition, tremella polysaccharide, glutathione, etc. can play a long-term anti-inflammatory and anti-allergic role. With the encapsulation effect of sodium hyaluronate and the anti-inflammatory and antibacterial effects of astaxanthin, theoretically, it can improve the alleviating effect of this atomization inhalation solution on asthma and chronic obstructive pulmonary disease symptoms; more importantly, after the above combination, the stability of terbutaline sulfate solution is greatly improved, the generation of impurities is reduced, and the combination of the present invention can make the total dose of fine particles of 4-MOC grade terbutaline sulfate reach more than 88.5% of the labeled amount, significantly improving the atomization performance of the product of the present application. Description of the Drawings

[0030] Figure 1 Character detection in Test Example 1

[0031] Figure 2 Stability evaluation in Test Example 2, 12 months

[0032] Figure 3 Stability evaluation in Test Example 2, 24 months

[0033] Figure 4 Atomization performance test results in Test Example 3 Detailed implementation mode

[0034] An atomizing inhalation solution for treating bronchial asthma, the atomizing inhalation solution containing components in the following concentrations:

[0035]

[0036] The preparation method of the above atomizing inhalation solution includes the following steps:

[0037] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in the formula amount with an appropriate amount of pure water;

[0038] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate, add pure water to the full volume, and then filter twice through 0.45 μm and 0.22 μm to obtain a filtrate;

[0039] Step 3: Subpackage the filtrate obtained in Step 2 to obtain the atomizing inhalation solution for treating bronchial asthma;

[0040] Preferably,

[0041] The sodium hyaluronate is modified sodium hyaluronate, which is prepared by the following steps:

[0042] 1) By weight, add 1 part of sodium hyaluronate dry powder to 9 parts of aqueous solution containing 0.005 - 0.01 part of hyaluronidase, and enzymolyze at 30 - 35 °C for 10 min to obtain 10 parts of sodium hyaluronate solution;

[0043] 2) Stir and add the sodium hyaluronate solution obtained in Step 1 to the lysine solution with a concentration of 10 - 20 g / 100 mL at a rate of 1 - 5 mL / min. The final volume ratio of the added sodium hyaluronate solution to the lysine solution is 1:1 - 2; after the addition is completed, stir at 30 - 35 °C for 1 - 4 h to obtain a sodium hyaluronate mixture;

[0044] 3) After stirring evenly at a rate of 800 rpm / min according to the mass ratio of sodium hyaluronate mixture, PEG4000, and chitosan of 100:10:2, triethanolamine was added to adjust the pH of the system to between 6 and 7, and it was allowed to stand and age for 2 - 6 h to obtain a modified sodium hyaluronate solution;

[0045] 4) The modified sodium hyaluronate solution obtained in step 3) was subjected to vacuum freeze-drying, with a vacuum degree below 25 Pa, a pre-freezing temperature below -50 °C for more than 4 hours, a drying temperature of 0 - 25 °C, and a time of 16 - 48 h to obtain modified sodium hyaluronate.

[0046] The technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0047] Terbutaline sulfate was purchased from Chengdu Biaoyang Biotechnology Co., Ltd., CAS No.: 23031-32-5, product number WKQ-0010723, brand: Vicchi.

[0048] Tremella polysaccharide was purchased from Shanghai Yuanye Biotechnology Co., Ltd., specification BR, 60%, product number S28486.

[0049] Glutathione was purchased from Shandong Siyang Biotechnology Co., Ltd., brand: Yuansiyang.

[0050] Ambroxol hydrochloride was purchased from Shaanxi Panlong Yihai Pharmaceutical Co., Ltd., pharmaceutical grade, purity 99.6%.

[0051] Sodium hyaluronate was purchased from Shaanxi Panlong Yihai Pharmaceutical Co., Ltd., pharmaceutical grade, purity 99%.

[0052] Astaxanthin was purchased from Chengdu Purifa Technology Development Co., Ltd., pharmaceutical grade, analytical pure AR.

[0053] Example 1

[0054] An aerosol inhalation solution for treating bronchial asthma, the aerosol inhalation solution containing the following components in concentration:

[0055]

[0056] The pH regulator citric acid - sodium citrate was used to adjust the pH to 5 - 6;

[0057] The preparation method of the above aerosol inhalation solution includes the following steps:

[0058] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in the formula amount with an appropriate amount of pure water;

[0059] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate. After adding pure water to the full volume, filter it twice through 0.45 μm and 0.22 μm to obtain a filtrate;

[0060] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0061] Example 2

[0062] An atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0063]

[0064] The preparation method of the above atomization inhalation solution includes the following steps:

[0065] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in the formula amount with an appropriate amount of pure water;

[0066] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate. After adding pure water to the full volume, filter it twice through 0.45 μm and 0.22 μm to obtain a filtrate;

[0067] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0068] Example 3

[0069] An atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0070]

[0071] Adjust the pH to 5 - 6 with the pH regulator citric acid - sodium citrate;

[0072] The preparation method of the above atomization inhalation solution includes the following steps:

[0073] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in the formula amount with an appropriate amount of pure water;

[0074] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate. After adding pure water to make up the volume, filter it twice through 0.45 - micron and 0.22 - micron filters to obtain a filtrate.

[0075] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the nebulization inhalation solution for treating bronchial asthma.

[0076] Example 4

[0077] A nebulization inhalation solution for treating bronchial asthma, the nebulization inhalation solution contains components with the following concentrations:

[0078]

[0079]

[0080] The sodium hyaluronate is modified sodium hyaluronate, which is prepared by the following steps:

[0081] 1) By weight, add 1 part of sodium hyaluronate dry powder to 9 parts of aqueous solution containing 0.005 - 0.01 part of hyaluronidase, and enzymatically hydrolyze at 30 - 35 °C for 10 min to obtain 10 parts of sodium hyaluronate solution.

[0082] 2) Stir and add the sodium hyaluronate solution obtained in Step 1 to a lysine solution with a concentration of 10 - 20 g / 100 mL at a rate of 1 - 5 mL / min. The final volume ratio of the added sodium hyaluronate solution to the lysine solution is 1:1 - 2. After the addition, stir at 30 - 35 °C for 1 - 4 h to obtain a sodium hyaluronate mixture.

[0083] 3) Stir the sodium hyaluronate mixture, PEG4000, and chitosan evenly at a rate of 800 rpm / min according to the mass ratio of 100:10:2. Then add triethanolamine to adjust the pH of the system to between 6 and 7, and let it stand for aging for 2 - 6 h to obtain a modified sodium hyaluronate solution.

[0084] 4) Subject the modified sodium hyaluronate solution obtained in Step 3 to vacuum freeze - drying. The vacuum degree is below 25 Pa, the pre - freezing temperature is below - 50 °C for more than 4 h, the drying temperature is 0 - 25 °C, and the time is 16 - 48 h to obtain modified sodium hyaluronate.

[0085] The preparation method of the above - mentioned nebulization inhalation solution includes the following steps:

[0086] Step 1: Mix the formula amounts of terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin with an appropriate amount of pure water.

[0087] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate. After adding pure water to make up the volume, filter it twice through 0.45 - micron and 0.22 - micron filters to obtain the filtrate;

[0088] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0089] Comparative Example 1

[0090] An atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0091]

[0092]

[0093] The preparation method of the above - mentioned atomization inhalation solution includes the following steps:

[0094] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in the formula amount with an appropriate amount of pure water;

[0095] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate. After adding pure water to make up the volume, filter it twice through 0.45 - micron and 0.22 - micron filters to obtain the filtrate;

[0096] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0097] This comparative example does not contain tremella polysaccharide, glutathione, and astaxanthin, and the rest is the same as Example 2.

[0098] Comparative Example 2

[0099] An atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0100]

[0101] The preparation method of the above - mentioned atomization inhalation solution includes the following steps:

[0102] Step 1: Mix terbutaline sulfate, glutathione, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in the formula amount with an appropriate amount of pure water;

[0103] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 with citric acid - sodium citrate. After adding pure water to make up the volume, filter it twice through 0.45 - micron and 0.22 - micron filters to obtain the filtrate;

[0104] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0105] This comparative example does not contain tremella polysaccharide, and the others are the same as in Example 2.

[0106] Comparative Example 3

[0107] An atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0108]

[0109] The preparation method of the above atomization inhalation solution includes the following steps:

[0110] Step 1: Mix terbutaline sulfate, tremella polysaccharide, ambroxol hydrochloride, sodium hyaluronate, and astaxanthin in formula amounts with an appropriate amount of pure water;

[0111] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 using citric acid - sodium citrate, add pure water to the full volume, and then filter it twice through 0.45 μm and 0.22 μm to obtain a filtrate;

[0112] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0113] This comparative example does not contain glutathione, and the others are the same as in Example 2

[0114] Comparative Example 4

[0115] An atomization inhalation solution for treating bronchial asthma, the atomization inhalation solution contains components with the following concentrations:

[0116]

[0117] The preparation method of the above atomization inhalation solution includes the following steps:

[0118] Step 1: Mix terbutaline sulfate, tremella polysaccharide, glutathione, ambroxol hydrochloride, and sodium hyaluronate in formula amounts with an appropriate amount of pure water;

[0119] Step 2: Adjust the pH of the mixed solution obtained in Step 1 to 5.0 - 6.0 using citric acid - sodium citrate, add pure water to the full volume, and then filter it twice through 0.45 μm and 0.22 μm to obtain a filtrate;

[0120] Step 3: Aliquot the filtrate obtained in Step 2 to obtain the atomization inhalation solution for treating bronchial asthma.

[0121] This comparative example does not contain astaxanthin, and the others are the same as in Example 2.

[0122] Test Example 1

[0123] Quality evaluation

[0124] Take the atomized inhalation solutions prepared in Examples 1 to 4 and Comparative Examples 1 to 4, and according to the detection method of related substances in Terbutaline Sulfate in the second part of the Chinese Pharmacopoeia 2015 edition, detect the solution properties and the percentage content of related substances. The detection results are shown in Table 1 below and Figure 1 as shown.

[0125] Table 1 Detection of properties

[0126] Group Appearance Related Substances (%) Example 1 Colorless Clear Liquid 0.08 Example 2 Colorless Clear Liquid 0.07 Example 3 Colorless Clear Liquid 0.07 Example 4 Colorless Clear Liquid 0.04 Comparative Example 1 Colorless Liquid with Slight Precipitation 0.26 Comparative Example 2 Colorless Clear Liquid 0.15 Comparative Example 3 Colorless Clear Liquid 0.18 Comparative Example 4 Colorless Liquid with Slight Precipitation 0.21

[0127] As can be seen from Table 1 above, the relevant indicators of the terbutaline sulfate atomized inhalation solutions prepared in Examples 1 to 4 of the present invention all meet the quality standards. Compared with Example 2, in Comparative Examples 1-4, without adding tremella polysaccharide, glutathione or astaxanthin, the precipitation and related substances both increase. Therefore, the addition of the composition of tremella polysaccharide, glutathione and astaxanthin can significantly improve the quality of the terbutaline sulfate atomized inhalation solution of the formula of the present invention.

[0128] Test Example 2

[0129] Take the terbutaline sulfate atomized inhalation solutions prepared in Examples 1 to 4 and Comparative Examples 1 to 4, store them at 40 °C and RH75% for 12 months and 24 months, and according to the detection method in Terbutaline Sulfate in the second part of the Chinese Pharmacopoeia 2015 edition, detect the changes in indicators such as the percentage content of related substances. The detection results are shown in Table 2 below and Figure 2 - 3 as shown.

[0130] Table 2 Stability evaluation

[0131]

[0132] As can be seen from Table 2 above, the terbutaline sulfate atomized inhalation solutions prepared in Examples 1 to 4 of the present invention have excellent stability. Especially for Example 4, it remains clear after being stored at 40 °C and RH75% for 24 months, and there are no obvious changes in the content of related substances and the content.

[0133] Compared with Example 2, in Comparative Examples 1-4, without adding substances such as tremella polysaccharide, glutathione or astaxanthin, after the prepared terbutaline sulfate atomized inhalation solutions are stored for 12 months and 24 months under the same conditions, the content of related substances increases significantly, and the stability is poor; the addition of the composition of tremella polysaccharide, glutathione and astaxanthin can significantly improve the stability of the terbutaline sulfate atomized inhalation solution of the formula of the present invention.

[0134] Test Example 3

[0135] Detection of filtration sterilization effect

[0136] Finished products of terbutaline sulfate nebulization inhalation solution prepared in Examples 1-4 and Comparative Examples 1-4 in different batches were subjected to bacterial inspection. According to the bacterial inspection method in the second part of the Pharmacopoeia 2015 edition, the results are shown in Table 3 below.

[0137] Table 3 Bacterial inspection results

[0138] Group Test Results Example 1 Qualified Example 2 Qualified Example 3 Qualified Example 4 Qualified Comparative Example 1 Unqualified Comparative Example 2 Qualified Comparative Example 3 Qualified Comparative Example 4 Unqualified

[0139] From the test results of Comparative Example 4, it can be seen that the terbutaline sulfate nebulization inhalation solution described in Examples 1-4 can meet the sterilization requirements after two filtrations.

[0140] Test Example 4

[0141] Nebulization performance test

[0142] Samples prepared in Examples 1-4 and Comparative Examples 1-4 were combined with a German Pari nebulizer, and their key nebulization performance indicators were detected. An impact sampling collector (New Generation Impactor, NGI) was used to investigate the fine particle dose of the self-made samples (equipment specified in the general rules for inhalation preparations in the Chinese Pharmacopoeia). The investigation mainly focused on the total content of drug particles from the 4th stage to the MOC stage of the NGI (the powder particles in this interval are inhalable effective particles). The results are shown in Table 4 and Figure 4 .

[0143] Table 4 NGI detection drug content data table

[0144]

[0145]

[0146] It can be seen that the terbutaline sulfate nebulization inhalation solution prepared in Examples 1-4 of the present invention significantly improves the fine particle dose of the product. The total fine particle dose of terbutaline sulfate at the 4-MOC level can be as high as more than 88.5% of the labeled amount at most. After modifying sodium hyaluronate and adding the composition of tremella polysaccharide, glutathione and astaxanthin, the nebulization performance of the product of the present application is significantly improved.

[0147] As can be seen from the above examples, the stability of the terbutaline sulfate solution is greatly improved, the generation of impurities is reduced, and the compatibility of the present invention can make the total fine particle dose of terbutaline sulfate at the 4-MOC level as high as more than 88.5% of the labeled amount, significantly improving the nebulization performance of the product of the present application.

[0148] The above are several preferred embodiments of the present invention, which are described in a relatively specific and detailed manner. However, it should not be construed as a limitation on the scope of the present invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.

Claims

1. An atomized inhalation solution for treating bronchial asthma, characterized in that: The nebulized inhalation solution contains the following ingredients in the following concentrations:

2. The aerosol inhalation solution for treating bronchial asthma according to claim 1, characterized in that: The mucus regulator or excretion promoter is ambroxol hydrochloride.

3. The aerosol inhalation solution for treating bronchial asthma according to claim 1, characterized in that: The pH regulator is selected from one of hydrochloric acid, acetic acid-sodium acetate, and citric acid-sodium citrate.

4. The aerosol inhalation solution for treating bronchial asthma according to claim 1, characterized in that: The sodium hyaluronate is modified sodium hyaluronate, which is prepared by the following steps: 1) By weight, add 1 part of sodium hyaluronate dry powder to 9 parts of an aqueous solution containing 0.005-0.01 parts of hyaluronidase, and perform enzymolysis at 30-35° C. for 10 minutes to obtain 10 parts of sodium hyaluronate solution; 2) adding the sodium hyaluronate solution obtained in step 1) to a lysine solution having a concentration of 10-20 g / 100 mL at a rate of 1-5 mL / min with stirring, and the final volume ratio of the added sodium hyaluronate solution to the lysine solution is 1:1-2; after the addition is completed, stirring at 30-35° C. for 1-4 hours to obtain a sodium hyaluronate mixed solution; 3) After the sodium hyaluronate mixture, PEG4000 and chitosan are uniformly stirred at a rate of 800 rpm / min in a mass ratio of 100:10:2, triethanolamine is added to adjust the pH of the system to between 6 and 7, and the mixture is allowed to stand for 2 to 6 hours to obtain a modified sodium hyaluronate solution; 4) The modified sodium hyaluronate solution obtained in step 3) is subjected to vacuum freeze drying, with a vacuum degree of less than 25 Pa, a pre-freezing temperature of less than -50°C for more than 4 hours, a drying temperature of 0-25°C, and a drying time of 16-48 hours to obtain modified sodium hyaluronate.

5. The aerosol inhalation solution for treating bronchial asthma according to claim 4, characterized in that: The nebulized inhalation solution contains the following ingredients in the following concentrations:

6. The aerosol inhalation solution for treating bronchial asthma according to claim 5, characterized in that: The nebulized inhalation solution contains the following ingredients in the following concentrations:

7. A method for preparing a nebulized inhalation solution for treating bronchial asthma according to any one of claims 1 to 6, comprising the following steps: Step 1: Mix the formulated amount of terbutaline sulfate, Tremella polysaccharide, glutathione, mucus regulator or excretion promoter, sodium hyaluronate, and astaxanthin with an appropriate amount of pure water; Step 2: The pH of the mixed solution obtained in step 1 is adjusted to 5.0-6.0, pure water is added to the mixed solution to make up the total amount, and then the mixed solution is filtered twice through 0.45 micron and 0.22 micron to obtain a filtrate; Step 3: The filtrate obtained in step 2 is packaged to obtain the aerosol inhalation solution for treating bronchial asthma.

8. Use of the aerosol inhalation solution for treating bronchial asthma according to any one of claims 1 to 6 in the preparation of a medicament for treating chronic obstructive pulmonary disease combined with asthma.

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