TW202114640A - Inhalation solution pharmaceutical composition and preparation method therefor - Google Patents

Abstract

An inhalation solution pharmaceutical composition and a preparation method therefor. The composition comprises indacaterol or salts thereof, a pH regulator, and water, and an optional osmotic pressure regulator and a buffer ion pair, and is prepared by dissolving ingredients into water. The pharmaceutical composition is suitable for forming a mist from an active substance with the aid of a nebulizer for administration to patients in asthma and COPD symptoms by means of inhalation.

Description

Inhalation solution pharmaceutical composition and preparation method thereof

The invention relates to an inhalation solution pharmaceutical composition, in particular to an inhalation solution pharmaceutical composition containing indacaterol, and belongs to the field of pharmaceutical preparations.

There are approximately 42 million asthma patients and 28 million chronic obstructive pulmonary disease (COPD) patients worldwide. In the past ten years, with the global air pollution and environmental deterioration, the incidence and mortality of asthma have been on the rise, and more than 180,000 people die of asthma each year. Another analysis shows that by 2020, COPD will rise from the sixth largest cause of death in the world to third. Clinically, the treatment drugs for COPD mainly include long-acting β2-receptor agonists (LABA), long-acting anticholinergic drugs (LAMA) and steroid hormones. These drugs are administered by local lung inhalation with good curative effect and Security is good.

Indacaterol is a new type of long-acting β2-receptor agonist (LABA), produced by Novartis Pharmaceuticals, Switzerland. It has been marketed in more than 70 countries and regions around the world since 2009. It was approved by the China National Food and Drug Administration in June 2012. Approved for listing in China, it is China's first single LABA formulation approved for the treatment of COPD. The existing listed indacaterol only unilateral Ang Run ^® inhalation formulation (powder for inhalation indacaterol maleate) this kind of inhalation dosage forms. The dry powder inhalation method requires the patient to learn the method of inhalation and the patient needs to have good lung function to inhale the drug. For some severe COPD patients, their lung function is poor and may not be able to reach the inhalation airflow required for inhalation of powder aerosol. Therefore, the drug cannot be effectively delivered to the lungs or the inhaled dose is insufficient, which reduces the efficacy of the drug. However, the use of aerosol inhalation for administration does not require special training for patients. Especially for patients with severe COPD, a sufficient dose of the drug can be inhaled by normal breathing. Therefore, it is necessary to develop indacaterol inhalation solution to meet the clinical needs of such patients Demand.

CN103860463A discloses a solution containing indacaterol maleate and its inhalation spray. The concentration of indacaterol maleate in the published prescription is very low, only 2.0 mcg/mL-15 mcg/mL. In clinical use, the inhalation solution generally requires the atomization time to be controlled within 10 minutes. If the volume of the atomization solution is too large, the atomization time will increase significantly and cannot meet the clinical needs. Generally, the volume of the inhalation solution needs to be controlled within 3 mL. Suppose indacaterol maleate inhalation solution (drug concentration 15 mcg / mL) in the total amount of the drug already listed Ang Run ^® (indacaterol maleate powder for inhalation) specifications (Dart indene Luo Ji 150 mcg) remains the same, the volume of the atomized solution needs to be more than 10 mL, which is much higher than the volume of the conventional atomized solution. Obviously, the concentration of the drug in the indacaterol maleate inhalation solution is too low, which causes the volume of the aerosol solution to be too large and the aerosol inhalation time is too long, which cannot meet the clinical needs. Based on the examples in CN103860463A, the inventor of the present case tried to directly increase the amount of indacaterol maleate added to increase its concentration in the aqueous solution, but failed to achieve it. Affected by the poor solubility of indacaterol maleate in water, indacaterol maleate is easier to precipitate in aqueous solution; in addition, the stability of indacaterol maleate in aqueous solution is also poor, especially This is especially true at higher concentrations. Therefore, the development of a storage-stable inhalation solution with a higher content of indacaterol maleate is an urgent problem to be solved in this field. So far, there has been no research report on high-concentration indacaterol maleate inhalation solution.

Jierun ^® (inden Dart Luoge Long bromide powder for inhalation) inhalation formulation is a new treatment of COPD, which is the product of inhalation compound containing two bronchodilators, wherein the long-acting indacaterol β2-receptor agonist (LABA), glycopyrrolate is a long-acting anticholinergic (LAMA) drug. As the world's first LABA/LAMA drug on the market, indacaterol glycopyrronium bromide can agonize β2 receptors while blocking M3 receptors. It has a powerful synergistic effect and can significantly improve lung function compared with monotherapy. , Bringing better treatment methods for the treatment of COPD. However, the product has only one dosage form of inhalation powder. For some patients with severe COPD, due to their poor lung function, the inhalation airflow required for inhalation of the powder may not be reached, and the drug cannot be effectively delivered to the lungs or the delivered dose is reduced. , Which reduces the efficacy of the drug. The use of aerosol inhalation to administer medicine does not require special training for patients, especially for patients with severe COPD, a sufficient dose of medicine can be inhaled by normal breathing. Therefore, the development of a compound inhalation solution of indacaterol glycopyrronium bromide can well meet the clinical needs of such patients. However, so far there is no research report on indacaterol glycopyrronium bromide compound inhalation solution.

In order to solve the deficiencies of the prior art, an object of the present invention is to provide a pharmaceutical composition of inhalation solution containing indacaterol or its salt, the concentration of the drug in the composition is high enough to meet the clinical requirements for the volume of the inhalation solution, When in use, the contents are released in a mist form with the help of manual pump, ultrasonic spray, air compressor and other pressure. It is a preparation for lung inhalation. In addition, the high concentration of sodium chloride in the composition can help reduce respiratory tract irritation and keep the droplet size stable.

Another object of the present invention is to provide a stable indacaterol compound inhalation solution prescription and preparation method thereof. The drug concentration in the preparation is high and the preparation has good chemical stability, which can well meet the clinical needs. demand. The technical scheme of the present invention is as follows:

A pharmaceutical composition for an inhalation solution, which comprises an active ingredient indacaterol or a pharmaceutically acceptable salt thereof, a pH adjusting agent, and water, wherein the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof is the same as that of indacaterol. Terol count is 23.2 mcg/mL~231.5 mcg/mL, and its pH is 2.0~5.5.

In one embodiment, the pharmaceutically acceptable salt of the active ingredient indacaterol includes indacaterol maleate or indacaterol acetate.

In one embodiment, the inhalation solution pharmaceutical composition of the present invention contains 30 mcg to 300 mcg of indacaterol maleate per 1 mL, and its pH is 3.0 to 4.0.

In one embodiment, the pH adjusting agent is selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate The pH of the pharmaceutical composition is 2.5-5.0.

In one embodiment, the pharmaceutical composition further comprises other adjuvants, and the other adjuvants are selected from at least one of a solubilizer, an osmotic pressure regulator, and a buffer ion pair.

In one embodiment, the solubilizer is selected from at least one of polysorbate, polyethylene glycol castor oil, polyoxyethylene castor oil, and lecithin.

In one embodiment, the osmotic pressure regulator is selected from at least one of sodium chloride or mannitol.

In one embodiment, the buffer ion pair is selected from the group consisting of citric acid-sodium citrate buffer pair, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, sodium bicarbonate-sodium carbonate buffer pair, acetic acid-sodium acetate buffer pair, Tartrate-sodium tartrate buffer pair, the concentration of the buffer ion pair is 1 mM-50 mM. The concentration of the buffer ion pair mentioned here is calculated based on the total molar concentration of acid radicals that play a buffering role in the buffer ion pair. For example, a citric acid-sodium citrate buffer pair with a concentration of 6 mM is prepared. The 6mM means that the molar concentration of citrate is 6mM, which can be prepared by adding 4 mmol of citric acid and 2 mmol of sodium citrate to 1000 mL of water.

In one embodiment, the concentration of the buffer ion pair is 3 mM to 30 mM.

In one embodiment, the citric acid-sodium citrate buffer pair can be prepared with citric acid and sodium hydroxide, and the citric acid used is selected from one or more combinations of anhydrous citric acid and citric acid monohydrate.

In one embodiment, the citric acid-sodium citrate buffer pair can be prepared with citric acid and sodium citrate, and the citric acid used is selected from one or more combinations of anhydrous citric acid and citric acid monohydrate, The sodium citrate used is selected from one or more combinations of anhydrous sodium citrate, sodium citrate dihydrate, and sodium citrate pentahydrate.

In one embodiment, the pH 4.0 citric acid-sodium citrate buffer pair of the present invention can be prepared from citric acid and sodium citrate in an aqueous solution, wherein the citric acid and sodium citrate are added in an amount of moles The ratio is 2:1. For example, to prepare a pH 4.0 citric acid-sodium citrate buffer pair with a concentration of 5 mM, it can be prepared by adding 3.34 mmol of citric acid and 1.67 mmol of sodium citrate to 1000 mL of water.

In one embodiment, the pharmaceutical composition further comprises a short-chain alcohol selected from one or a combination of ethanol, propylene glycol, and glycerol.

In one embodiment, when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is 23.2 mcg/mL~77.2 mcg/mL based on indacaterol, the osmotic pressure regulator The content is 0.1% ~0.9%.

In one embodiment, when the weight percentage of the indacaterol or its pharmaceutically acceptable salt is 77.3 mcg/mL~231.5 mcg/mL, the osmotic pressure regulator The content is 0.1%~0.7%.

In one embodiment, in the pharmaceutical composition of the inhalation solution of the present invention, the content of the indacaterol maleate is 30 mcg/mL-100 mcg/mL, and the content of the osmotic pressure regulator is 0.3 g/mL. mL ~0.9 g/mL.

In one embodiment, in the inhalation solution pharmaceutical composition of the present invention, the content of indacaterol maleate is 100 mcg/mL~300 mcg/mL, and the content of the osmotic pressure regulator is 0.3 g/mL. mL ~0.7 g/mL.

In one embodiment, when the short-chain alcohol is ethanol, its weight percentage is 0.02% to 0.08%.

In one embodiment, when the short-chain alcohol is propylene glycol, the weight ratio of propylene glycol to water is 1:4 to 200.

In one embodiment, when the short-chain alcohol is glycerol, the weight ratio of glycerol to water is 1:20~200.

In one embodiment, the pharmaceutical composition further comprises the active ingredients glycopyrrolate, tiotropium bromide, ipratropium bromide, umetopium bromide, adesonium bromide, budesonide, ciclesonide , At least one of beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, and the concentration of these active ingredients in the pharmaceutical composition is each independently 20 mcg/mL~500 mcg/mL.

In one embodiment, the pharmaceutical composition further comprises glycopyrrolate, and every 1000 mL of the pharmaceutical composition contains the glycopyrrolate from 0.05 to 0.5 g.

In one embodiment, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, glycopyrrolate 0.02g~0.2g, chlorine Sodium phosphate 3g~7g, citric acid monohydrate 0.6g~2.8g, sodium citrate dihydrate 0.4g~2.0g, pH adjuster appropriate to adjust pH to 2.5~5.0, water to 1000mL.

In one embodiment, the pharmaceutical composition per 1000 mL contains: 0.108 g indacaterol maleate, 0.058 g glycopyrrolate, 0.699 g citric acid monohydrate, 0.492 g sodium citrate dihydrate, sodium chloride 6g, adjust the pH to 4.0 with a proper amount of pH adjuster, and add water to 1000mL.

In one embodiment, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, mometasone furoate 0.04g~0.5g, chlorine Sodium phosphate 3g~7g, citric acid monohydrate 0.6g~2.8g, sodium citrate dihydrate 0.4g~2.0g, pH adjuster appropriate to adjust pH to 2.5~5.0, water to 1000mL.

In one embodiment, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, 0.04 g to 0.23 g based on indacaterol, glycopyrrolate 0.02 g to 0.2 g, bran Mometasone acid 0.04g~0.5g, sodium chloride 3g~7g, citric acid monohydrate 0.6g~2.8g, sodium citrate dihydrate 0.4g~2.0g, pH adjuster appropriate to adjust pH to 2.5~5.0, add water To 1000mL.

In one embodiment, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, glycopyrrolate 0.02g~0.2g, chlorine Sodium hydroxide 3g~7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g~4g citric acid monohydrate and 0.1g~0.8g sodium hydroxide, pH adjuster, adjust the pH to 2.5~5.0, add water to 1000mL.

In one embodiment, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, mometasone furoate 0.04g~0.5g, chlorine Sodium hydroxide 3g~7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g~4g citric acid monohydrate and 0.1g~0.8g sodium hydroxide, pH adjuster, adjust the pH to 2.5~5.0, add water to 1000mL.

In one embodiment, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, 0.04 g to 0.23 g based on indacaterol, glycopyrrolate 0.02 g to 0.2 g, bran Mometasone acid 0.04g~0.5g, sodium chloride 3g~7g, citric acid-sodium citrate buffer pair obtained by the reaction of citric acid monohydrate 0.5g~4g and sodium hydroxide 0.1g~0.8g, pH adjuster appropriate amount Adjust the pH to 2.5~5.0, and add water to 1000mL.

Further, the above-mentioned pH adjusting agent is selected from one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate or disodium hydrogen phosphate, or Many kinds.

In one embodiment, the citric acid-sodium citrate buffer pair of the present invention is prepared from citric acid and sodium citrate in an aqueous solution. This buffer pair can also be prepared in other ways, such as using citric acid and sodium hydroxide in an aqueous solution, or using sodium citrate and hydrochloric acid in an aqueous solution.

In the present invention, the mcg is the quality unit microgram, that is, μg.

The citric acid used in the present invention is all citric acid monohydrate. The use of anhydrous citric acid or other types of citric acid hydrates can also achieve the same technical effect as the use of citric acid monohydrate, which also belongs to the scope of the present invention.

The sodium citrate used in the present invention is all sodium citrate dihydrate. The use of anhydrous sodium citrate or other types of sodium citrate hydrate such as sodium citrate pentahydrate can also achieve the same technical effect as the use of sodium citrate dihydrate, which also belongs to the scope of the present invention.

The present invention also provides a preparation method of indacaterol inhalation solution pharmaceutical composition, which comprises the following steps: (a) Add a prescription amount of excipients to the water, the excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols, stir to disperse and dissolve the excipients, and adjust the pH of the solution to the target with a pH regulator Value 2.0~5.5; (b) Add the prescription amount of indacaterol or its pharmaceutically acceptable salt to the excipient solution prepared in (a), stir to dissolve; optionally, add glycopyrrolate, tiotropium, iso At least one of Protropium Bromide, Umetium Bromide, and Alclidium Bromide is stirred and dissolved.

Optionally, filter and sterilize the drug solution obtained in (b) above, for example, filter and sterilize with a filter membrane less than or equal to 0.22 μm to obtain a sterile drug solution.

Optionally, at least one of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, and fluticasone furoate is added to the sterile drug solution, and the mixture is stirred and dispersed evenly.

Optionally, the obtained sterile pharmaceutical solution is divided into a vial, a glass ampoule or a plastic ampoule, for example, to obtain the indacaterol inhalation solution pharmaceutical composition.

In one embodiment, the present invention provides a preparation method of indacaterol inhalation solution pharmaceutical composition, the preparation method includes the following steps: (a) Add a prescription amount of excipients to the water, the excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, adjust the pH of the solution with a pH regulator To the target value 2.0~5.5; (b) Add the prescription amount of indacaterol or its pharmaceutically acceptable salt to the excipient solution prepared in (a), and stir to dissolve; (c) Filter and sterilize the drug solution obtained in (b) with a filter membrane less than or equal to 0.22 μm to obtain a sterile drug solution; (d) Filling the sterile drug solution obtained in (c) into a vial, glass ampoule or plastic ampoule to obtain an indacaterol inhalation solution pharmaceutical composition.

The present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution. The preparation method includes the following steps: (a) Add a prescription amount of excipients to the water, the excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, adjust the pH of the solution with a pH regulator To the target value 2.0~5.5; (b) Add a prescription amount of indacaterol or a pharmaceutically acceptable salt thereof to the excipient solution prepared in (a), and add glycopyrrolate, tiotropium, ipratropium, and Umi At least one of ammonium bromide and aclidinium bromide, stirring and dissolving; (c) Filter and sterilize the drug solution obtained in (b) with a filter membrane less than or equal to 0.22 μm to obtain a sterile drug solution; (d) Filling the sterile drug solution obtained in (c) into a vial, glass ampoule or plastic ampoule to obtain an indacaterol inhalation solution pharmaceutical composition.

In one embodiment, the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution. The preparation method includes the following steps: (a) Add a prescription amount of excipients to the water, the excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, adjust the pH of the solution with a pH regulator To the target value 2.0~5.5; (b) Add the prescription amount of indacaterol or its pharmaceutically acceptable salt to the excipient solution prepared in (a), and stir to dissolve; (c) Filter and sterilize the drug solution obtained in (b) with a filter membrane less than or equal to 0.22 μm to obtain a sterile drug solution; (d) Add at least one of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate to the sterile drug solution obtained in (c), and stir to disperse Evenly. (e) Filling the sterile drug suspension obtained in (d) into a vial, glass ampoule or plastic ampoule to obtain an indacaterol inhalation solution pharmaceutical composition.

In one embodiment, the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution. The preparation method includes the following steps: (a) Add a prescription amount of excipients to the water, the excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, adjust the pH of the solution with a pH regulator To the target value 2.0~5.5; (b) Add a prescription amount of indacaterol or a pharmaceutically acceptable salt thereof to the excipient solution prepared in (a), and add glycopyrrolate, tiotropium, ipratropium, and Umi At least one of ammonium bromide and aclidinium bromide, stirring and dissolving; (c) Filter and sterilize the drug solution obtained in (b) with a filter membrane less than or equal to 0.22 μm to obtain a sterile drug solution; (d) Add at least one of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate to the sterile drug solution obtained in (c), and stir to disperse Evenly. (e) Filling the sterile drug suspension obtained in (d) into a vial, glass ampoule or plastic ampoule to obtain an indacaterol inhalation solution pharmaceutical composition.

The pharmaceutical composition of indacaterol inhalation solution provided by the present invention overcomes the shortcomings of the existing indacaterol inhalation solution that the concentration is low and cannot be used clinically, and a higher concentration of sodium chloride can be added to the prescription and the indacaterol can be maintained. The high concentration of indacaterol greatly increases the concentration of indacaterol in the inhalation solution preparation, and smoothly realizes the preparation of large-scale preparations of indacaterol inhalation solution preparations. This high-concentration indacaterol inhalation solution better meets the requirements To meet the clinical needs. The indacaterol glycopyrrolate compound inhalation solution composition provided by the present invention is the first report. The drug concentration in the preparation is high and the preparation has good chemical stability, which can well meet the clinical needs; on the other hand, The difference in FPF value of the inhalation solution of the present invention at different air flow rates is small (the dry powder inhalation preparation is larger), and it can be applied to patients with different inhalation capabilities (the dry powder inhalation preparation is not suitable for patients with weak inhalation ability), which improves The patient's medication compliance.

Hereinafter, the present invention will be further described in combination with test examples and examples, so that those skilled in the art can understand the present invention more comprehensively, but the present invention is not limited in any way.

Experiment 1~8 : Study the solubility of indacaterol maleate in different pH solutions Test example 1 Test example 2 Test example 3 Test Example 4 Test Example 5 Test Example 6 Test Example 7 Test Example 8 Indacaterol maleate 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Right amount Right amount pH 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add appropriate amount of hydrochloric acid to adjust the pH to the pH value stated in the prescription, and the error range does not exceed ±0.05, then add 0.5 g of indacaterol maleate raw material, and stir for 24 hours at 25°C. Check the sample concentration after filtering.

Test results: Test example 1 Test example 2 Test example 3 Test Example 4 Test Example 5 Test Example 6 Test Example 7 Test Example 8 Concentration based on indacaterol (mcg/mL) 245.99 227.00 205.92 194.95 160.67 122.66 85.23 78.79

The test results show that in a solution with a pH of 2.0-5.5, about 100-300 mcg of indacaterol maleate can be dissolved per 1 ml, and the solubility of indacaterol maleate is higher in a low pH solution. .

Test Examples 9-14 : To study the stability of indacaterol solution under different pH conditions. Test Example 9 Test Example 10 Test Example 11 Test Example 12 Test Example 13 Test Example 14 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g pH 3.0 3.5 4.0 4.5 5.0 5.5 Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water separately, adjust the pH of the solution to the pH value stated in the prescription with an appropriate amount of hydrochloric acid, and the error range does not exceed ±0.05, and then add 0.15g of indacaterol maleate raw material and stir overnight. Filter and fill them in ampoules, place them at 4°C and 25°C, and check the relevant substances in the samples in January, 2 and March.

Test results: Test example Survey index 0 days 4℃ 25℃ January February March January February March Test Example 9 Total impurities (%) 0.126 0.125 0.178 0.192 0.198 0.335 0.349 Test Example 10 Total impurities (%) 0.126 0.126 0.192 0.185 0.207 0.294 0.344 Test Example 11 Total impurities (%) 0.124 0.126 0.175 0.188 0.248 0.399 0.515 Test Example 12 Total impurities (%) 0.123 0.126 0.167 0.177 0.293 0.559 0.466 Test Example 13 Total impurities (%) 0.128 0.138 0.179 0.189 0.434 0.816 1.124 Test Example 14 Total impurities (%) 0.128 0.155 0.191 0.195 0.615 1.189 1.429

The test results show that under the condition of 4° C., the impurity amount of Test Example 9-14 has no obvious change compared with 0 days, and the impurity amount of Test Example 9-14 has increased with the increase of temperature. The inventor also found that in a solution with a pH of 5.0 to 5.5, the amount of impurities exceeded 1% for 3 months at 25°C. Therefore, in a pH 3.0-4.5 solution, indacaterol maleate is more stable at 25°C.

Because the results of test examples 9-14 show that indacaterol maleate is more stable in low-temperature storage in a solution with a pH of 3.0-5.5, it is necessary to investigate whether indacaterol maleate can still be stored at low temperature. Has a higher solubility.

Test examples 15~18 : To investigate the solubility of indacaterol maleate in different pH solutions when stored at low temperature Test Example 15 Test Example 16 Test Example 17 Test Example 18 Indacaterol maleate 0.3 g 0.3 g 0.3 g 0.3 g hydrochloric acid Right amount / / / Citric acid-sodium citrate buffer pair / 5 mM 5 mM 5 mM pH 3.0 4.0 4.5 5.0 Add water to 1000 mL 1000 mL 1000 mL 1000 mL

Measure 1000 mL of water, add appropriate amount of hydrochloric acid in Test Example 15 to adjust the pH to 3.00±0.05; Test Example 16-18 add 0.699 g of citric acid and 0.492 g of sodium citrate, stir and dissolve, adjust the pH to the prescribed pH, the error range No more than ±0.05, then add 0.3 g of indacaterol maleate, stir overnight, filter and dispense into ampoules, store in a refrigerator at 2-8°C, test the concentration and pH of the sample at 0 time and 72 hours respectively value. Before the concentration test, the sample in the ampoule needs to be filtered to remove undissolved drug particles. The test results are: 0 h 72 h Concentration based on indacaterol (mcg/mL) pH Concentration based on indacaterol (mcg/mL) pH Test Example 15 228.98 3.00 229.68 3.04 Test Example 16 230.84 3.97 232.46 4.00 Test Example 17 200.74 4.48 201.20 4.47 Test Example 18 108.36 4.99 104.65 4.99

It can be seen from the above test results that the solubility of indacaterol maleate is higher when the pH of the solution is controlled at 3.0-4.0 under low temperature conditions. When the pH>4.0, the solubility began to decrease significantly, and decreased with the increase of pH; during the cryopreservation, the drug concentration did not change significantly.

In the inhalation solution, an osmotic pressure regulator needs to be added, and sodium chloride is commonly used to adjust the osmotic pressure of the solution. However, the present invention found in the research that sodium chloride will affect the solubility of indacaterol maleate, so it is necessary to investigate the effect of different concentrations of sodium chloride on the solubility of indacaterol maleate.

Test Examples 19 to 27: The effects of NaCl concentration on the solubility of the indacaterol maleate Test Example 19 Test Example 20 Test Example 21 Test Example 22 Test Example 23 Test Example 24 Test Example 25 Test Example 26 Test Example 27 Indacaterol maleate 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g 0.3 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 10 mM 10 mM 10 mM 20 mM 20 mM 20 mM Sodium chloride 3 g 6 g 9 g 3 g 6 g 9 g 3 g 6 g 9 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate for test examples 19-21; add 1.398 g of citric acid and 0.984 g of sodium citrate for test examples 22-24; add lemon for test examples 25-27 Acid 2.796 g, sodium citrate 1.968 g, stir until completely dissolved, then add the corresponding sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, then add 0.3 g of indacaterol maleate raw material Stir the medicine overnight, filter and dispense into ampoules. Test the concentration and pH of the chemical solution. At the same time, they were placed in a refrigerator at 2-8°C for 3 days and 7 days respectively to determine the concentration and pH of the sample. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.

The test results are: 0 h 3 days 7 days Concentration based on indacaterol (mcg/mL) pH Concentration based on indacaterol (mcg/mL) pH Concentration based on indacaterol (mcg/mL) pH Test Example 19 237.78 4.01 213.70 3.94 211.39 3.97 Test Example 20 193.79 3.98 110.44 3.95 86.36 3.98 Test Example 21 120.40 3.97 74.09 3.92 62.51 3.98 Test Example 22 241.26 3.96 238.94 3.99 240.33 3.99 Test Example 23 240.79 3.97 167.40 3.99 126.65 3.98 Test Example 24 147.49 3.96 97.94 3.99 74.09 4.00 Test Example 25 234.54 4.01 232.46 3.95 233.61 3.94 Test Example 26 225.28 4.03 201.43 4.00 141.93 3.97 Test Example 27 152.81 3.99 92.61 4.00 71.08 4.00

The above test results show that the solubility of indacaterol maleate is reduced in a solution containing sodium chloride (white granular precipitates can be observed). And the higher the concentration of sodium chloride, the lower the solubility of indacaterol maleate, and the easier it is to precipitate during storage. At the same time, the present invention finds that the citric acid-sodium citrate buffer pair can improve the solubility of indacaterol maleate in a solution containing sodium chloride, and reduce the risk of drug precipitation during storage.

In order to clarify the concentration of citric acid-sodium citrate buffer in the solution, it is necessary to study the influence of different concentrations of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution.

Test Examples 28~32 : To investigate the effect of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution

prescription: Test Example 28 Test Example 29 Test Example 30 Test Example 31 Test Example 32 Indacaterol maleate 0.2 g 0.2 g 0.2 g 0.2 g 0.2 g Citric acid-sodium citrate buffer pair - 5 mM 20 mM 30 mM 50 mM Sodium chloride 6 g 6 g 6 g 6 g 6 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add citric acid 0.699 g, 1.398 g, 4.194 g, 6.990 g, sodium citrate 0.492 g, 1.968 g, 2.952 g, 4.920 g, and stir until it is completely dissolved. . Test examples 28~32 add 6 g of sodium chloride and stir until it is completely dissolved; add an appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, then add 0.2 g of indacaterol maleate raw material, stir overnight, filter and divide Test the concentration and pH of the sample in an ampoule. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles. At the same time, they were placed in a refrigerator at 2-8°C for 7 days and then tested again. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.

The test results are: 0 h 7 days Concentration based on indacaterol (mcg/mL) pH Concentration based on indacaterol (mcg/mL) pH Traits Test Example 28 93.38 4.02 73.32 4.02 There are granular precipitates Test Example 29 152.07 4.03 147.49 4.01 Colorless and clear Test Example 30 150.82 4.00 149.76 4.00 Colorless and clear Test Example 31 152.24 3.99 152.06 4.01 Colorless and clear Test Example 32 150.29 4.00 149.77 4.02 Colorless and clear

According to the test results of Test Examples 28-32, the citric acid-sodium citrate buffer pair can increase the solubility of indacaterol maleate in sodium chloride solution, and can reduce the indacaterol maleate during storage. The risk of precipitation.

Test Example 33 : To investigate whether a high-concentration and stable indacaterol maleate solution can be prepared according to the prescription of Example 1 in patent CN103860463A.

prescription: Indacaterol maleate 0.1 g Citric acid 1.5 g Sodium citrate 4 g Sodium chloride 2 g water 1000 mL

Remarks: Except for the increased concentration of indacaterol maleate in the prescription, the concentrations of other excipients are consistent with Example 1 in patent CN103860463A.

Weigh each excipient according to the above prescription, add 1000 mL of water, stir until completely dissolved, then add 0.1 g of indacaterol maleate drug, stir and dissolve, adjust the pH to 5.0±0.05, filter and fill in an ampoule In, test the concentration of the sample, and store the sample in a refrigerator at 2~8℃ for 7 days to test the concentration of the sample. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: 0 days 7 days Concentration based on indacaterol (mcg/mL) 77.27 60.46

After being left for 7 days, the concentration of indacaterol maleate decreased, and a precipitate was observed in the ampoule. The above results indicate that a high-concentration indacaterol maleate solution cannot be prepared according to the prescription of Example 1 in patent CN103860463A.

Test Example 34 : To investigate whether a high-concentration and stable indacaterol maleate solution can be prepared according to the prescription of Example 3 in patent CN103860463A

prescription: Indacaterol maleate 0.02 g Disodium phosphate 2 g Dipotassium phosphate 7.5 g Sodium chloride 0.5 g Sodium formaldehyde sulfoxylate 22.5 mg Ethylenediaminetetraacetic acid monocalcium disodium 50 mg water 1000 mL

Remarks: Except for the increased concentration of indacaterol maleate in the prescription, the concentrations of other excipients are consistent with Example 3 in patent CN103860463A.

Weigh each excipient according to the above prescription, add 1000 mL of water, stir until completely dissolved, then add 0.02 g of indacaterol maleate, stir and dissolve, adjust the pH to 6.5±0.05, filter and fill in an ampoule In, test the concentration of the sample, and store the sample in a refrigerator at 2~8℃ for 7 days to test the concentration of the sample. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: 0 days 7 days Concentration based on indacaterol (mcg/mL) 15.42 5.17

After being left for 7 days, the concentration of indacaterol maleate decreased, and a precipitate was observed in the ampoule. The above results indicate that a high-concentration indacaterol maleate solution cannot be prepared according to the formulation of Example 3 in patent CN103860463A. Examples 1~8

prescription: name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Indacaterol maleate 0.1 g 0.3 g 0.1 g 0.3 g 0.1 g 0.3 g 0.1 g 0.3 g Polysorbate-80 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g 1 g pH 2.0 2.0 3.0 3.0 4.0 4.0 5.0 5.0 Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water and add 0.1 g of polysorbate-80 to dissolve it, adjust the pH to the prescribed pH with hydrochloric acid, and the error range does not exceed ±0.05, and then add the corresponding amount of indacaterol maleate. , Stir and dissolve at room temperature, filter and fill in an ampoule to detect the concentration of the sample and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.

Test results: Concentration based on indacaterol (mcg/mL) relative substance(%) Example 1 77.41 0.133 Example 2 229.76 0.138 Example 3 76.64 0.129 Example 4 231.07 0.117 Example 5 78.87 0.122 Example 6 230.23 0.123 Example 7 76.95 0.163 Example 8 228.98 0.149

The results show that in the range of pH 2.0 to 5.0, indacaterol maleate solution with a concentration of 100 to 300 mcg/mL can be obtained. Examples 9~11

prescription: Example 9 Example 10 Example 11 Indacaterol maleate 0.2 g 0.2 g 0.2 g Polyethylene Glycol Castor Oil / / 1 g Lecithin / 1 g / Polyoxyethylene castor oil 0.4 g / / pH 4.0 4.0 4.0 Add water to 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add corresponding amounts of polyethylene glycol castor oil, lecithin, and polyoxyethylene castor oil according to the above-mentioned examples. After it is completely dissolved, adjust the pH to 4.0±0.05 with hydrochloric acid, and then add it to the horse. 0.2 g of indacaterol lysate was stirred and dissolved at room temperature, filtered and filled in an ampoule to detect the concentration of the sample and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.

Test results: Concentration based on indacaterol (mcg/mL) relative substance(%) Example 9 154.20 0.132 Example 10 159.29 0.121 Example 11 155.59 0.133

The results show that the content and related substances of the prepared inhalation solution meet the requirements. Examples 12~13 Example 12 Example 13 Indacaterol maleate 0.05 g 0.05 g sulfuric acid Right amount / Lysine / Right amount pH 4.0 4.0 Add water to 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, adjust the pH to 4.0±0.05 with sulfuric acid or lysine respectively, add 0.05 g of indacaterol maleate, stir to dissolve at room temperature, filter and fill in an ampoule , To detect the concentration of the sample and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.

Test results Concentration based on indacaterol (mcg/mL) relative substance(%) Example 12 39.05 0.124 Example 13 38.70 0.127

The results show that: amino acid or sulfuric acid as a pH regulator will not affect the related substances in indacaterol maleate solution, and the related substances in the solution meet the requirements. Examples 14-19: Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5 mM 5 mM 5 mM Sodium chloride 6 g 6 g 6 g 6 g 6 g 6 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Ethanol 0.8 g 0.2 g / / / / Propylene Glycol / / 20 g 5 g / / Glycerol / / / / 5 g 1 g Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate, stir until completely dissolved, then add 6 g of sodium chloride, and stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, then Add the corresponding ethanol, propylene glycol, and glycerol, and stir to make the mixture uniform. Measure 1000 mL of the corresponding solution, add 0.15 g of indacaterol maleate, stir overnight, filter, and dispense, and test the content and pH value. Test the concentration and pH value after 3 days and 7 days in the refrigerator at 2-8°C. Before the concentration test, the sample needs to be filtered to remove possible precipitated drug particles.

Test results: 0 h 3 days 7 days Concentration based on indacaterol (mcg/mL) pH Concentration based on indacaterol (mcg/mL) pH Concentration based on indacaterol (mcg/mL) pH Example 14 115.53 3.95 115.88 4.01 115.19 3.99 Example 15 116.00 3.98 116.00 4.03 115.07 4.02 Example 16 117.15 4.03 117.85 3.97 117.50 3.98 Example 17 116.11 3.95 116.23 3.99 114.96 3.96 Example 18 118.43 3.97 116.92 3.94 116.23 3.96 Example 19 115.53 3.99 116.11 4.04 115.65 4.00

The results show that: a mixed solution system containing short-chain alcohols can prepare qualified preparations. Examples 20~24: Example 20 Example 21 Example 22 Example 23 Example 24 Indacaterol maleate 0.05 g 0.1 g 0.1 g 0.25 g 0.15 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 20 mM 20 mM Sodium chloride 3 g 6 g 9 g 3 g 6 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 20-22; add 2.796 g of citric acid and 1.968 g of sodium citrate in Examples 23-24, stir until completely dissolved, add separately After the corresponding amount of sodium chloride is completely dissolved, adjust the pH to 4.00±0.05 with hydrochloric acid, and then add the corresponding amount of indacaterol maleate drug, stir overnight, filter, and distribute, and test the concentration and related substances. Before the concentration test, the sample needs to be filtered to remove possible precipitated drug particles.

Test results: Concentration based on indacaterol (mcg/mL) relative substance(%) Example 20 38.94 0.127 Example 21 80.03 0.132 Example 22 78.18 0.137 Example 23 193.33 0.112 Example 24 115.42 0.125

The results show that when the concentration of indacaterol solution is 38.6~77.2 mcg/mL, the concentration of sodium chloride of 0.3%~0.9% will not affect the content and pH value, and the concentration of indacaterol solution is 115.8~192.9mcg/mL When the concentration of sodium chloride is 0.3%~0.6%, the content and pH value will not be affected. Examples 25-28: name Example 25 Example 26 Example 27 Example 28 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5 mM Sodium chloride 3 g 4 g 5 g 6 g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid, 0.492 g of sodium citrate, dissolve, add the prescribed amount of sodium chloride, stir to dissolve, adjust the pH to 4.00±0.05 with an appropriate amount of hydrochloric acid, and finally add indene maleate Dacaterol drug 0.15 g, stirred overnight, filtered and divided into aliquots to test the concentration and related substances. The undissolved drug needs to be filtered out before the concentration test.

Test results: Concentration based on indacaterol (mcg/mL) relative substance(%) Example 25 116.00 0.142 Example 26 119.35 0.133 Example 27 114.84 0.152 Example 28 115.53 0.139

The results showed that when the concentration of indacaterol solution was 115.8 mcg/mL, different concentrations of sodium chloride had no effect on its content and related substances. Examples 29~34:

prescription: Example 29 Example 30 Example 31 Example 32 Example 33 Example 34 Indacaterol maleate 0.15 g 0.15 g 0.2 g 0.15 g 0.15 g 0.2 g Glycopyrrolate 0.05 g 0.1 g 0.1 g 0.05 g 0.1 g 0.1 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 30 mM 30 mM 30 mM Sodium chloride 6 g 6 g 6 g 6 g 6 g 6 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 29 to 31; add 4.194 g of citric acid and 2.952 g of sodium citrate in Examples 32 to 34, stir until completely dissolved, add separately 6 g of sodium chloride, after it is completely dissolved, adjust the pH to 4.00±0.05 with hydrochloric acid, and then add the corresponding amount of indacaterol maleate and glycopyrrolate, stir overnight, filter and dispense, test the concentration, related Substances and pH. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Related substances of indacaterol (%) Related substances of glycopyrrolate (%) pH Example 29 116.11 50.15 0.179 not detected 4.03 Example 30 115.53 98.70 0.182 0.051 4.00 Example 31 151.88 99.40 0.170 not detected 4.00 Example 32 118.31 49.95 0.154 not detected 4.01 Example 33 116.46 102.30 0.192 not detected 4.04 Example 34 151.11 101.70 0.176 not detected 3.99

The results show that in the aqueous solution containing sodium chloride and citrate, when the concentration of glycopyrrolate is 50-100 mcg/mL, the concentration of indacaterol can reach 115.8-154.4 mcg/mL, and the related substances are not obvious. increase. Examples 35~37: Example 35 Example 36 Example 37 Indacaterol maleate 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.2 g 0.2 g Polysorbate-80 / / 0.05 g Citric acid-sodium citrate buffer pair 20 mM 20 mM 20 mM Sodium chloride 3 g 3 g 3 g hydrochloric acid Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 2.796 g of citric acid and 1.968 g of sodium citrate, stir until completely dissolved, then add sodium chloride and polysorbate-80, and stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ±0.05, then add 0.15 g of indacaterol maleate and glycopyrrolate, stir to dissolve, filter and divide into ampoules to test the concentration of the two drugs and related substances. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Related substances of indacaterol (%) Related substances of glycopyrrolate (%) Example 35 116.11 99.80 0.133 not detected Example 36 114.49 204.60 0.119 0.050 Example 37 115.42 201.60 0.130 not detected

The results show that the content of the two drugs meets the requirements, and there is no compatibility problem between the drugs.

At the same time, the samples of Example 24 and Examples 35 to 37 were placed in a thermostat at 5±2° C. to investigate the changes in related substances and pH values of the samples during the placement process.

Test results: Example 24 Example 35 Example 36 Example 37 Related substances of indacaterol (%) pH Related substances of indacaterol (%) Related substances of glycopyrrolate (%) pH Related substances of indacaterol (%) Related substances of glycopyrrolate (%) pH Related substances of indacaterol (%) Related substances of glycopyrrolate (%) pH 0 0.125 4.03 0.133 not detected 4.02 0.119 not detected 4.02 0.13 not detected 3.96 March 0.169 4.00 0.179 not detected 4.05 0.199 not detected 4.00 0.207 not detected 4.00 June 0.211 4.01 0.199 not detected 3.97 0.252 not detected 3.96 0.264 not detected 3.98 September 0.242 3.97 0.239 0.050 4.00 0.273 not detected 3.97 0.289 0.058 3.94 December 0.303 4.00 0.289 0.053 4.02 0.311 0.052 3.97 0.313 0.063 4.00

The results showed that the pH value of the samples of Example 24 and Examples 35~37 did not change significantly during the placing process, the related substances of indacaterol increased slightly, but the growth rate was slow, the impurity of glycopyrrolate was basically unchanged, and the samples were stable Good sex. Examples 38~43: Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.1 g 0.2 g 0.1 g 0.2 g 0.1 g Citric acid-sodium citrate buffer pair / / / 5 mM 5 mM 5 mM Sodium chloride 5 g 5 g 5 g 5 g 5 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount pH 2.00 3.00 3.00 4.00 4.00 5.00 Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid, 0.492 g of sodium citrate, and 5 g of sodium chloride in Examples 41 to 43, stir until completely dissolved, adjust the pH to the corresponding pH with hydrochloric acid, the error range does not exceed ± 0.05; Examples 38-40 add 5 g of sodium chloride, stir and dissolve, adjust the pH with hydrochloric acid to the corresponding pH, the error range does not exceed ±0.05, and finally add the prescription amount of the drug in each example, stir to dissolve, filter and dispense Test the concentration separately in an ampoule. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Example 38 116.23 100.32 Example 39 115.53 100.74 Example 40 115.19 202.42 Example 41 117.15 99.81 Example 42 116.11 204.20 Example 43 115.53 100.84

The test results show that in a solution containing 0.5% sodium chloride and a pH of 2 to 5, an inhalation solution with a suitable concentration can be prepared. Examples 44~49: Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Indacaterol acetate 0.15 g 0.15 g 0.15 g 0.15 g / / Indacaterol / / / / 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.2 g 0.1 g 0.2 g 0.1 g 0.2 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5 mM 5 mM 5 mM Sodium chloride 3 g 3 g 5 g 5 g 5 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate, stir until completely dissolved, then add the prescribed amount of sodium chloride, and stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, Then add 0.15 g of indacaterol acetate or indacaterol and the prescription amount of glycopyrrolate crude drug, stir until completely dissolved, and test the concentration after filtration. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration of indacaterol acetate (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Concentration of indacaterol (mcg/mL) Example 44 151.05 99.91 / Example 45 148.80 201.42 / Example 46 149.25 102.20 / Example 47 150.32 203.64 / Example 48 / 99.49 148.05 Example 49 / 197.80 150.30

The test results show that both indacaterol acetate or indacaterol can be combined with glycopyrrolate to prepare a compound inhalation solution. Examples 50~53: Example 50 Example 51 Example 52 Example 53 Indacaterol 0.15 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g / / / Tiotropium Bromide / 0.1g / / Ipratropium bromide / / 0.1g / Umetium Bromide / / / 0.1g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5mM Sodium chloride 3 g 3 g 3 g 3 g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate, stir until completely dissolved, then add 3 g of sodium chloride, and stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, Then add the prescribed amount of medicine as shown in the above table, stir until it is completely dissolved, filter and dispense into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration of indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Tiotropium bromide concentration (mcg/mL) Concentration of ipratropium bromide (mcg/mL) Concentration of Umetium Bromide (mcg/mL) Example 50 150.37 100.2 / / / Example 51 148.05 / 102.2 / / Example 52 149.16 / / 100.9 / Example 53 149.34 / / / 101.4

The results showed that both indacaterol and different long-acting anticholinergic (LAMA) drugs can be made into a compound inhalation solution, and the content meets the requirements. Examples 54~59: Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.2 g 0.1 g 0.2 g 0.2 g 0.2 g Mometasone furoate 0.1 g 0.15 g / / 0.15 g / Fluticasone propionate / / 0.1 g 0.15 g / 0.15 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5 mM / / Sodium chloride 3 g 3 g 3 g 3 g 3 g 3 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 54 to 57, stir until completely dissolved, then add the prescribed amount of sodium chloride, stir until completely dissolved, add appropriate amount of hydrochloric acid to adjust pH to 4.00±0.05; Examples 58~59 add the prescription amount of sodium chloride, stir to dissolve, add appropriate amount of hydrochloric acid to adjust the pH to 3.00±0.05; all the examples add indacaterol maleate and glycopyrrolate according to the prescription Ammonium, stir overnight after the drug is dissolved, add mometasone furoate or fluticasone propionate, stir evenly, dispense into ampoules, and test the concentration separately. The test results are as follows: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Concentration of mometasone furoate (mcg/mL) Concentration of fluticasone propionate (mcg/mL) Example 54 114.49 100.32 100.40 / Example 55 118.31 202.41 150.15 / Example 56 116.81 102.22 / 101.37 Example 57 116.11 199.66 / 148.82 Example 58 115.07 198.88 149.55 / Example 59 116.69 201.62 / 149.74

The test results show that in a solution containing 0.3% sodium chloride and a pH of 3 to 4, indacaterol is a three-element compound inhalation solution composed of different types of long-acting anticholinergic (LAMA) drugs and steroid hormones. , The content meets the requirements. Examples 60~65: Example 65 Example 61 Example 62 Example 63 Example 64 Example 65 Indacaterol acetate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.3g 0.5g 0.1 0.2g 0.03g Mometasone furoate 0.1 g 0.2g / / / / Fluticasone propionate / / 0.1g 0.3g / / Fluticasone furoate / / / / 0.1g 0.5g Citric acid-sodium citrate buffer pair 1 mM 15 mM 2 mM 5mM 10 mM 50 mM Sodium chloride 3 g 3 g 3 g 3 g 3 g 3 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add prescription amount of citric acid and sodium citrate, stir until completely dissolved, then add prescription amount of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, then add The prescription amount of indacaterol acetate and glycopyrronium bromide shown in the table, stir overnight until the API is completely dissolved, then add the prescription amount of mometasone furoate or fluticasone propionate or fluticasone furoate, stir evenly, and dispense into Test the concentration separately in ampoules. The test results are as follows: Concentration of indacaterol acetate (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Concentration of mometasone furoate (mcg/mL) Concentration of fluticasone propionate (mcg/mL) Concentration of fluticasone furoate (mcg/mL) Example 60 148.34 100.32 99.83 / / Example 61 148.02 303.91 200.18 / / Example 62 148.82 494.03 / 98.72 / Example 63 151.69 100.70 / 297.69 / Example 64 149.12 204.40 / / 98.63 Example 65 148.35 30.27 / / 498.03

The test results show that indacaterol acetate and glycopyrrolate can be combined with different steroid hormones to prepare a ternary compound inhalation solution. Examples 66~71: Example 66 Example 67 Example 68 Example 69 Example 70 Example 71 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.10g 0.06g 0.06g Glycopyrrolate 0.1 g 0.1g 0.2g 0.3g 0.4g 0.05g Citric acid-sodium citrate buffer pair - 1 mM 25 mM 50 mM - - Acetic acid-sodium acetate buffer pair - - - - 5mM 5mM Sodium chloride 3 g 3 g 3 g 3 g 3 g 3 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Solution pH 2.0 2.5 4.5 5 5.5 6.0 Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add the prescribed amount of buffer salt, stir until completely dissolved, then add 3 g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to the pH set in the table, and then add The prescribed amount of medicine is stirred until it is completely dissolved, filtered and then divided into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Example 66 115.53 100.42 Example 67 114.38 102.73 Example 68 116.11 202.22 Example 69 77.72 299.10 Example 70 45.80 399.69 Example 71 45.94 51.17 Examples 72~76: Example 72 Example 73 Example 74 Example 75 Example 76 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.1g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair - 5 mM 20 mM 5 mM 5 mM Mannitol 50 g 50 g 50 g 25 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Example 73 and Examples 75 to 76, and add 2.796 g of citric acid and 1.968 g of sodium citrate in Example 74. After stirring and dissolving, In each example, add mannitol according to the prescription, stir to dissolve, adjust the pH to 4.00±0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate, stir to dissolve, filter and dispense into ampoules In, test the concentration separately. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Example 72 116.11 100.20 Example 73 117.73 100.52 Example 74 115.42 103.17 Example 75 114.84 99.42 Example 76 118.31 100.71

The test results show that mannitol, as an osmotic pressure regulator, can prepare a compound inhalation solution with a content that meets the requirements. Examples 77~81: Example 77 Example 78 Example 79 Example 80 Example 81 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.1g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 10 mM 20 mM Sodium chloride 3 g 4 g 5 g 5 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 77 to 79; add 1.398 g of citric acid and 0.984 g of sodium citrate in Example 80; add 2.796g of citric acid in Example 81 , Sodium citrate 1.968 g, after stirring and dissolving, in each example, add sodium chloride according to the prescription, stir and dissolve, adjust the pH to 3.00±0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate , Stir to dissolve, filter and dispense into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Example 77 116.23 100.23 Example 78 117.15 99.83 Example 79 115.19 102.90 Example 80 115.53 101.45 Example 81 116.11 101.27

The test results show that the pH3.0 solution contains different concentrations of citrate buffer salt, and a binary compound inhalation solution meeting the requirements can be prepared. Examples 82~86: name Example 82 Example 83 Example 84 Example 85 Example 86 Indacaterol maleate 0.25 g 0.05 g 0.15 g 0.15 g 0.15 g Glycopyrrolate 0.1 g 0.3g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 10 mM 40 mM Sodium chloride 3 g 4 g 5 g 5 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 82 to 84; add 2.102 g of citric acid and 0.456 g of sodium hydroxide in Example 85; add 8.408 g of citric acid in Example 86 , Sodium hydroxide 1.824 g, after stirring and dissolving, add sodium chloride according to the prescription in each example, stir to dissolve, adjust the pH to 3.00±0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate , Stir to dissolve, filter and dispense into ampoules to test the concentration. The undissolved drug needs to be filtered out before the concentration test.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Example 82 190.13 101.23 Example 83 38.90 299.72 Example 84 116.00 100.23 Example 85 115.49 99.74 Example 86 114.43 100.29

The test results show that: in a pH 3.0 solution, a citric acid buffer solution prepared with citric acid and sodium hydroxide can prepare a binary compound inhalation solution with a content that meets the requirements. Examples 87~91: name Example 87 Example 88 Example 89 Example 90 Example 91 Indacaterol maleate 0.12 g 0.12 g 0.12 g 0.12 g 0.12 g Glycopyrrolate 0.06 g 0.06 g 0.06 g 0.06g 0.06 g Mometasone furoate / / / 0.15 g 0.15 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5 mM 50 mM Sodium chloride 4g 5 g 6 g 4 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 87 to 90; add 10.51 g of citric acid and 2.28 g of sodium hydroxide in Example 91. After stirring and dissolving the citric acid and sodium hydroxide in each example, sodium chloride was added in each example according to the prescription, stirred and dissolved, adjusted to pH 4.00±0.05 with an appropriate amount of hydrochloric acid, and finally added the prescription amount of indacaterol maleate and Glycopyrrolate, stir to dissolve. Examples 87 to 89 were separated into ampoules after being filtered, and the concentrations were tested respectively. In Examples 90-91, the prescribed amount of mometasone furoate was added after filtration, the mometasone furoate was dispersed by high-speed shear, and then divided into ampoules to test the concentration.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of glycopyrrolate (mcg/mL) Concentration of mometasone furoate (mcg/mL) Example 87 92.43 58.32 - Example 88 91.62 59.67 - Example 89 92.31 61.33 - Example 90 90.75 60.54 149.33 Example 91 95.81 59.82 151.46

The test results show that: in a pH 4.0 solution, a citric acid buffer solution prepared by citric acid and sodium hydroxide can prepare a binary compound inhalation solution and a ternary compound inhalation preparation that meet the requirements. Examples 92~96: name Example 92 Example 93 Example 94 Example 95 Example 96 Indacaterol maleate 0.12 g 0.12 g 0.12 g 0.12 g 0.12 g Mometasone furoate 0.5 g 0.3 g 0.4 g 0.15 g 0.05 g Citric acid-sodium citrate buffer pair 5 mM 5 mM 5 mM 5 mM 50mM Sodium chloride 4g 5 g 6 g 4 g 5 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 92 to 95; add 10.51 g of citric acid and 2.28 g of sodium hydroxide in Example 96. After the citric acid and sodium hydroxide were stirred and dissolved in each example, sodium chloride was added in each example according to the prescription, stirred and dissolved, adjusted to pH 4.00±0.05 with an appropriate amount of hydrochloric acid, and finally added the prescription amount of indacaterol maleate. Stir to dissolve, add the prescribed amount of mometasone furoate after filtration, disperse mometasone furoate at high-speed shear, and dispense it into ampoules to test the concentration.

Test results: Concentration based on indacaterol (mcg/mL) Concentration of mometasone furoate (mcg/mL) Example 92 91.72 507.63 Example 93 90.56 294.31 Example 94 91.16 405.66 Example 95 93.25 147.58 Example 96 94.67 53. 12

The test results show that: in a pH 4.0 solution, a citric acid buffer pair solution prepared by citric acid and sodium hydroxide can prepare indacaterol mometasone furoate binary compound inhalation solution with a content that meets the requirements. Examples 97~99: name Example 97 Example 98 Example 99 Indacaterol maleate 0.005 g 0.005 0.12 Disodium phosphate 2 g / / Dipotassium phosphate 7.5 g / / Sodium chloride 0.5 g 4 g 4 g Sodium formaldehyde sulfoxylate 0.0225 g / / Ethylenediaminetetraacetic acid-calcium disodium 0.05 g / / Citric acid-sodium citrate buffer pair / 5 mM 5 mM hydrochloric acid / Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL

Note: Example 97 refers to the formulation preparation of Example 3 in patent CN103860463A

In Example 98 and Example 99, respectively measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide, stir to dissolve, add 4 g of sodium chloride, stir to dissolve, adjust the pH to 4.00±0.05 with an appropriate amount of hydrochloric acid, and finally Add the prescription amount of indacaterol maleate, stir to dissolve and distribute into ampoules. Example 97 Measure 1000 mL of water, add 2 g of disodium hydrogen phosphate, 7.5 g of dipotassium hydrogen phosphate, 0.5 g of sodium chloride, 0.0225 g of sodium formaldehyde sulfoxylate, and 0.05 of ethylenediaminetetraacetic acid-calcium disodium g. Stir and dissolve to obtain a buffer solution with a pH of 6.5, then add 0.005 g of indacaterol maleate, stir to dissolve and dispense into ampoules. The samples of the above three examples were placed in a thermostat at 25±2° C. to investigate the changes of related substances during the placing of the samples.

Test results: relative substance(%) Example 97 Example 98 Example 99 0 0.184 0.120 0.117 January 0.752 0.189 0.176 March 1.297 0.224 0.207

The test results show that: referring to Example 97 prepared by the example prescription in the patent CN103860463A, the impurities in Example 97 increased significantly during the room temperature storage process, and the amount of impurities exceeded 1% after being placed for 3 months. In Examples 98 and 99, the impurity increased slightly after being left for 3 months, and there was no significant difference in impurity growth between the two examples. Example 100: name Example 100 Indacaterol maleate 35.6 mg Glycopyrrolate 19.5 mg lactose 24.9 g Magnesium stearate 0.03 g

The indacaterol maleate and glycopyrrolate are pulverized and pretreated with a jet mill to make the particle size D ₉₀ <5μm, and then indacaterol maleate, glycopyrrolate and magnesium stearate are mixed uniformly , And then gradually mixed with lactose according to the same amount of stepwise addition, and the obtained total mixed powder is filled in the capsule.

In inhaled preparations, the fine particle fraction (Fine Particle Fraction, FPF) reflects the proportion of the amount of medicine that can enter the lungs in the inhaled preparation. The larger the FPF value, the more the proportion of drugs in the inhaled preparation that can enter the lungs, the higher the delivery efficiency of the inhaled preparation, and the better the treatment effect on lung diseases.

In Example 34, Example 68, Example 79, Example 82, Example 87, and Example 100, the FPF value of the preparation was determined by using Next generation impactor (NGI). Using different flow rates to compare the changes of FPF values in different embodiments under different breathing modes.

Test results: Example number NGI flow rate 15L/min flow rate 60L/min flow rate Example 100 FPF of indacaterol maleate (%) 41.2 54.5 FPF value of glycopyrrolate (%) 30.3 44.6 Example 34 FPF of indacaterol maleate (%) 48.7 53.7 FPF value of glycopyrrolate (%) 52.3 55.4 Example 68 FPF of indacaterol maleate (%) 52.3 54.8 FPF value of glycopyrrolate (%) 50.6 52.7 Example 79 FPF of indacaterol maleate (%) 47.4 53.2 FPF value of glycopyrrolate (%) 50.4 51.9 Example 82 FPF of indacaterol maleate (%) 48.7 53.2 FPF value of glycopyrrolate (%) 51.2 50.4 Example 87 FPF of indacaterol maleate (%) 49.2 52.2 FPF value of glycopyrrolate (%) 51.1 56.1

The test results show that the FPF values of the inhaled solutions of Example 34, Example 68, Example 79, Example 82, and Example 87 are not significantly different at different flow rates. The breathing capacity of the powder is different; and the FPF value of the powder aerosol of Example 100 at different flow rates is quite different. The FPF value at low flow rates is significantly lower, and the glycopyrrolate is more significantly lower, so the powder aerosol It has certain limitations for patients with weak breathing ability, and the inhalation solution of the present invention overcomes this shortcoming. Examples 101~106: Example 101 Example 102 Example 103 Example 104 Example 105 Example 106 Indacaterol maleate 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g 0.15 g Aclidinium bromide 0.1 g 0.3g 0.4g 0.1 0.04 g 0.2 g Budesonide 0.1 g 0.3g / / / / Ciclesonide / / 0.1g 0.4g / / Beclomethasone dipropionate / / / / 0.1g 0.5g Citric acid-sodium citrate buffer pair 1 mM 15 mM 2 mM 4 mM 10 mM 50 mM Sodium chloride 3 g 2 g 5 g 3 g 6 g 3 g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Preparation method: Measure 1000 mL of water, add prescription amount of citric acid and sodium citrate, stir until completely dissolved, then add prescription amount of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00±0.05, then add The prescription amount of indacaterol maleate and aclidinium bromide shown in the table, stir overnight until the raw material is completely dissolved, then add the prescription amount of budesonide or ciclesonide or beclomethasone propionate and stir well , Dispense into ampoules and test the concentration separately. The test results are as follows: Concentration based on indacaterol (mcg/mL) Concentration of aclidinium bromide (mcg/mL) Concentration of budesonide (mcg/mL) Ciclesonide concentration (mcg/mL) Concentration of beclomethasone dipropionate (mcg/mL) Example 101 147.26 104.17 98.62 / / Example 102 153.15 299.75 302.54 / / Example 103 149.04 406.63 / 97.43 / Example 104 150.77 99.54 / 402.16 / Example 105 148.51 39.73 / / 102.35 Example 106 149.69 197.67 / / 497.82

The test results show that indacaterol maleate and aclidinium bromide can be combined with different steroid hormone drugs to prepare a ternary compound inhalation solution. Examples 107~112: name Example 109 Example 110 Example 111 Example 112 Indacaterol maleate 0.108 g 0.108 g 0.08 g 0.13 g Glycopyrrolate / 0.058 g 0.046 g 0.07 g Sodium acetate / / / / ascorbic acid / / / / Citric acid 0.699 g 0.699 g 0.699 g 0.699 g Sodium citrate 0.492 g 0.492 g 0.492 g 0.492 g Sodium chloride 6 g 6 g 6 g 6 g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000 mL 1000 mL 1000 mL 1000 mL

Example 107 and Example 108 are samples prepared according to the recipe process of Example 1 and Example 2 in patent CN103860463A, respectively.

Example 109: Measure the prescription amount of water, add the prescription amount of citric acid and sodium citrate, stir to dissolve, add the prescription amount of sodium chloride, stir to dissolve, adjust the pH to 4.00±0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount Indacaterol maleate, stir to dissolve and filter, and dispense into ampoules.

Example 110~Example 112: Measure the prescription amount of water, add the prescription amount of citric acid and sodium citrate, stir to dissolve, add the prescription amount of sodium chloride, stir to dissolve, adjust the pH to 4.00±0.05 with an appropriate amount of hydrochloric acid , Finally add the prescription amount of indacaterol maleate and glycopyrrolate, stir to dissolve and filter, and dispense into ampoules.

The samples of Example 107 to Example 110 were placed in a thermostat at 25±2° C. to investigate the changes of related substances during the placement of the samples.

Test results: Example 107 Example 108 Example 109 Example 110 Related substances of indacaterol (%) Related substances of indacaterol (%) Related substances of indacaterol (%) Related substances of indacaterol (%) Related substances of glycopyrrolate (%) 0 month 0.143 0.165 0.131 0.135 not detected 1 month 0.415 0.358 0.196 0.184 0.026 3 months 1.037 0.862 0.257 0.213 0.039

The test results show that the samples of Example 107 and Example 108 prepared with reference to the formulations of Example 1 and Example 2 in the patent CN103860463A, the content of related substances of indacaterol increased significantly during the room temperature storage process, and the content of indacaterol related substances increased significantly after being placed for 3 months. It exceeds 0.8%~1.0%. However, the samples of Example 109 and Implementation 110 prepared according to the technical scheme of the present invention only slightly increased the content of related substances in indacaterol after being placed at room temperature for 3 months, and the stability of indacaterol maleate was significantly better than that of CN103860463A. In the samples of Example 1 and Example 2; and there was no significant difference in the growth of related substances of indacaterol between the samples of Example 109 and Example 110, indicating that the addition of glycopyrrolate in the composition of the present invention does not It will affect the stability of indacaterol maleate. There is no compatibility problem between indacaterol maleate and glycopyrrolate.

no

Claims (18)

A pharmaceutical composition for an inhalation solution, which comprises an active ingredient indacaterol or a pharmaceutically acceptable salt thereof, a pH adjusting agent, and water, wherein the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof is the same as that of indacaterol. The terol count is 23.2 mcg/mL to 231.5 mcg/mL, and the pH value of the pharmaceutical composition is 2.0 to 5.5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of the active ingredient indacaterol is indacaterol maleate or indacaterol acetate, and the pH adjusting agent is selected from hydrochloric acid, sulfuric acid At least one of acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and disodium hydrogen phosphate, and the pH of the pharmaceutical composition is 2.5~ 5.0. The pharmaceutical composition according to claim 1 or 2, further comprising other specific excipients, and the other specific excipients are selected from at least one of a solubilizer, an osmotic pressure regulator, and a buffer ion pair. The pharmaceutical composition according to claim 3, wherein the solubilizer is at least one selected from the group consisting of polysorbate, polyethylene glycol castor oil, polyoxyethylene castor oil, and lecithin. The pharmaceutical composition according to claim 3, wherein the osmotic pressure regulator is selected from at least one of sodium chloride and mannitol. The pharmaceutical composition according to claim 3, wherein the buffer ion pair is selected from the group consisting of citric acid-sodium citrate buffer pair, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, acetic acid-sodium acetate buffer pair, bicarbonate Sodium-sodium carbonate buffer pair, tartaric acid-sodium tartrate buffer pair, the concentration of the buffer ion pair is 1 mM-50 mM. The pharmaceutical composition according to any one of claims 1 to 6, further comprising a short-chain alcohol selected from one or a combination of ethanol, propylene glycol, and glycerol. The pharmaceutical composition according to any one of claims 3 to 7, wherein: When the concentration of the indacaterol or its pharmaceutically acceptable salt is 23.2 mcg/mL~77.2 mcg/mL based on indacaterol, the weight percentage of the osmotic pressure regulator is 0.1%~ 0.9%; or, When the concentration of the indacaterol or its pharmaceutically acceptable salt is 77.3 mcg/mL~231.5 mcg/mL based on indacaterol, the weight percentage of the osmotic pressure regulator is 0.1%~0.7 %. The pharmaceutical composition according to any one of claims 7 to 8, wherein When the short-chain alcohol is ethanol, its weight percentage is 0.02%~0.08%; or When the short-chain alcohol is propylene glycol, the weight ratio of the propylene glycol to water is 1:4 to 200; or When the short-chain alcohol is glycerol, the weight ratio of the glycerol to water is 1:20~200. The pharmaceutical composition according to any one of claims 1 to 9, further comprising the active ingredients glycopyrrolate, tiotropium bromide, ipratropium bromide, umaminium bromide, aclidinium bromide, budesonide At least one of Germany, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, and the concentration of these active ingredients in the pharmaceutical composition is each independently 20 mcg/mL ~500 mcg/mL. An inhalation solution pharmaceutical composition, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, glycopyrrolate 0.02g~0.2g, Sodium chloride 3g~7g, citric acid monohydrate 0.6g~2.8g, sodium citrate dihydrate 0.4g~2.0g, pH adjuster appropriate to adjust pH to 2.5~5.0, water is added to 1000mL; preferably, the Each 1000mL pharmaceutical composition contains: 0.108g indacaterol maleate, 0.058g glycopyrrolate, 0.699g citric acid monohydrate, 0.492g sodium citrate dihydrate, 6g sodium chloride, pH adjuster to adjust pH To 4.0, add water to 1000mL. An inhalation solution pharmaceutical composition, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, mometasone furoate 0.04g~0.5g, Sodium chloride 3g~7g, citric acid monohydrate 0.6g~2.8g, sodium citrate dihydrate 0.4g~2.0g, a proper amount of pH adjuster adjust the pH to 2.5~5.0, and water to 1000mL. An inhalation solution pharmaceutical composition, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, glycopyrrolate 0.02g~0.2g, Mometasone furoate 0.04g~0.5g, sodium chloride 3g~7g, citric acid monohydrate 0.6g~2.8g, sodium citrate dihydrate 0.4g~2.0g, pH adjuster appropriate to adjust pH to 2.5~5.0, water Add to 1000mL. An inhalation solution pharmaceutical composition, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, glycopyrrolate 0.02g~0.2g, Sodium chloride 3g~7g, a citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g~4g of citric acid monohydrate and 0.1g~0.8g of sodium hydroxide, adjust the pH to 2.5~5.0 with appropriate amount of pH adjuster, add water To 1000mL. An inhalation solution pharmaceutical composition, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, mometasone furoate 0.04g~0.5g, Sodium chloride 3g~7g, a citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g~4g of citric acid monohydrate and 0.1g~0.8g of sodium hydroxide, adjust the pH to 2.5~5.0 with appropriate amount of pH adjuster, add water To 1000mL. An inhalation solution pharmaceutical composition, the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol 0.04g~0.23g, glycopyrrolate 0.02g~0.2g, Mometasone furoate 0.04g~0.5g, sodium chloride 3g~7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g~4g citric acid monohydrate and 0.1g~0.8g sodium hydroxide, pH regulator Adjust the pH appropriately to 2.5~5.0, and add water to 1000mL. The inhalation solution pharmaceutical composition according to any one of claims 11 to 16, wherein the pH adjusting agent is selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acids, and sodium hydroxide , At least one of sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate. The preparation method of the inhalation solution pharmaceutical composition according to any one of claims 1 to 17, which comprises the following steps: (a) Add a prescription amount of excipients to the water, the excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols, stir to disperse and dissolve the excipients, and adjust the pH of the solution to the target with a pH regulator Value 2.0~5.5; (b) Add the prescription amount of indacaterol or its pharmaceutically acceptable salt to the excipient solution prepared in (a), stir to dissolve; optionally, add glycopyrrolate, tiotropium, iso At least one of propiotropium bromide, umaminium bromide, and aclidinium bromide is stirred and dissolved; (c) Optionally, filter and sterilize the drug solution obtained in (b) with a filter membrane less than or equal to 0.22 μm to obtain a sterile drug solution; optionally, add sterile budesonide and ciclesonide At least one of Germany, beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, stir and disperse evenly; (d) Optionally, filling the sterile drug solution obtained in (c) into a vial, glass ampoule or plastic ampoule to obtain an indacaterol inhalation solution pharmaceutical composition.