CN115998680A

CN115998680A - Inhalation solution pharmaceutical composition and preparation method thereof

Info

Publication number: CN115998680A
Application number: CN202210912500.7A
Authority: CN
Inventors: 张轩邈; 毛华; 周洋; 邹孟玮; 杨必坤
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2019-10-11
Filing date: 2020-10-12
Publication date: 2023-04-25
Also published as: WO2021068961A1; CN113853197B; CN115337292A; TW202114640A; CN113853197A

Abstract

The invention provides an inhalation solution pharmaceutical composition and a preparation method thereof, wherein the composition comprises indacaterol or salt thereof, a pH regulator, water, and optional osmotic pressure regulator and buffer ion pair, and is prepared by dissolving each component in water. The pharmaceutical composition is particularly suitable for aerosol formation of active substances by means of a nebulizer for administration to patients by inhalation in asthma and COPD symptoms.

Description

Inhalation solution pharmaceutical composition and preparation method thereof

Technical Field

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

Background

There are approximately 4200 ten thousand asthmatics and 2800 ten thousand Chronic Obstructive Pulmonary Disease (COPD) patients worldwide. Over the last decade, with global air pollution and environmental deterioration, the incidence and mortality of asthma is on the rise, with over 18 tens of thousands of deaths annually from asthma. Another analysis shows that COPD will climb from the sixth to the third of the current global causes of death by 2020. The clinical COPD therapeutic drugs mainly comprise long-acting beta 2-receptor agonist (LABA), long-acting anticholinergic drug (LAMA) and steroid hormone, and the drugs are administrated by local pulmonary inhalation, so that the curative effect is good and the safety is good.

Indantrole is a novel long-acting beta 2-receptor agonist (LABA) produced by North China pharmaceutical company, switzerland, which has been marketed in more than 70 countries and regions worldwide in 2009, and approved by the China national drug administration, 2012, month 6, which is the first LABA-like single formulation in China to be used for treating COPD. The existing indacaterol single-component inhalation preparation on the market has only

(indacaterol maleate inhaled powder spray) the powder spray. Administration of dry powder inhalation requires that the patient learn to inhale the drugThe method requires that the patient has better lung function to inhale the medicine, and for some patients with severe COPD, the lung function is poor, and the inhalation airflow required by inhalation of the powder fog agent can not be achieved, so that the medicine can not be effectively delivered to the lung or the inhaled dosage is insufficient, and the curative effect of the medicine is reduced. With aerosol inhalation administration, patients need no special training, and particularly for severe COPD patients, a sufficient dose of the drug can be inhaled by normal breathing, so that development of indacaterol inhalation solutions is necessary to meet the clinical needs of such patients.

CN103860463a discloses a solution containing indacaterol maleate and an inhalation spray thereof, and the concentration of indacaterol maleate in the published prescription is very low and is only 2.0mcg/mL to 15mcg/mL. When the inhalation solution is clinically used, the atomization time is generally required to be controlled within 10 minutes, and if the volume of the atomization solution is too large, the atomization time can be obviously increased and cannot meet the clinical requirement, and the volume of the inhalation solution is generally required to be controlled within 3 mL. Assume that indacaterol maleate is inhaled into solution (drug concentration 15 mcg/mL) in total amount of drug and marketed

The specification (150 mcg in indacaterol) of the indacaterol maleate inhaled powder spray is consistent, and the volume of the atomized solution needs to be more than 10mL and is far higher than that of the conventional atomized solution. Obviously, the concentration of the drug in the indacaterol maleate inhaled solution is too low, so that the volume of the atomized solution is too large and the atomized inhalation time is too long, and the clinical requirement cannot be met. The inventors of the present invention tried to directly increase the amount of indacaterol maleate added to increase the concentration thereof in an aqueous solution based on the examples in CN103860463a, but failed to achieve. The method is influenced by poor dissolution property of the indacaterol maleate in water, and the indacaterol maleate is easier to separate out in water solution; in addition, indacaterol maleate has poor stability in aqueous solutions, especially at higher concentrations. The development of a storage stable inhalation solution with a higher indacaterol maleate content is therefore a problem to be solved in the art. Heretofore (of)There has been no report on the inhalation of indacaterol maleate at high concentration.

(indacaterol bromide inhalation powder spray) is a novel inhalation preparation for treating COPD, and the product is a compound powder spray containing two bronchodilators, wherein indacaterol is a long-acting beta 2-receptor agonist (LABA), and glycopyrrolate is a long-acting anticholinergic (LAMA) drug. As the first LABA/LAMA medicament on the market in the world, the indacaterol bromide can excite the beta 2 receptor while blocking the M3 receptor, has strong synergistic effect, can obviously improve the lung function compared with single-medicament treatment, and brings better treatment means for treating COPD. However, the product only has one dosage form of inhalation powder fog agent, and for some patients with severe COPD, the lung function is poor, so that the inhalation airflow required by inhalation powder fog agent can not be achieved, the medicine can not be effectively delivered to the lung or the delivery dosage is reduced, and the curative effect of the medicine is reduced. By aerosol inhalation, patients do not need special training, and particularly for severe COPD patients, a sufficient dose of medicine can be inhaled by adopting a normal breathing mode. Therefore, the compound inhalation solution of indacaterol bromide is developed, and the requirements of clinical patients can be well met. However, no research report on indacaterol bromide compound inhalation solution exists so far.

Disclosure of Invention

In order to solve the defects in the prior art, the invention aims to provide an inhaled solution pharmaceutical composition containing indacaterol or salt thereof, wherein the concentration of the drug in the composition is high enough to meet the clinical requirement on the volume of the inhaled solution, and the content is released in a mist form by means of a manual pump, ultrasonic spraying, an air compressor and the like when the composition is used, so that the composition is a preparation for pulmonary inhalation. In addition, the high concentration of sodium chloride in the composition can help to reduce respiratory tract irritation and keep the particle size of the fogdrops stable.

The invention also aims to provide a stable indacaterol bromide compound inhalation solution prescription and a preparation method thereof, wherein the preparation has high drug concentration and good chemical stability, and can well meet clinical requirements.

The technical scheme of the invention is as follows:

an inhalation solution pharmaceutical composition comprising the active ingredient indacaterol or a pharmaceutically acceptable salt thereof, a pH adjustor and water, wherein the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof is 23.2mcg/mL to 231.5mcg/mL in terms of indacaterol, and the pH thereof is 2.0 to 5.5.

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

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

In one embodiment, the pH regulator is selected from one or more 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 and disodium hydrogen phosphate, and the pH value of the pharmaceutical composition is 2.5-5.0.

In one embodiment, the pharmaceutical composition further comprises other excipients selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs.

In one embodiment, the solubilizing agent is selected from at least one of polysorbate, polyethylene glycol castor oil, polyoxyethylated castor oil, lecithin.

In one embodiment, the osmolality adjusting agent 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 a citric acid-sodium citrate buffer pair, a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, a sodium bicarbonate-sodium carbonate buffer pair, an acetic acid-sodium acetate buffer pair, and a tartaric acid-sodium tartrate buffer pair, wherein the concentration of the buffer ion pair is 1mM to 50mM. The concentration of the buffer ion pair is calculated as the total molar concentration of the acid groups in the buffer ion pair, for example, a citric acid-sodium citrate buffer pair is prepared at a concentration of 6mM, wherein 6mM refers to the molar concentration of the acid groups of 6mM, and the buffer ion pair can be prepared by adding 4mmol of citric acid and 2mmol of sodium citrate to 1000mL of water.

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

In one embodiment, the citric acid-sodium citrate buffer pair may be formulated with citric acid and sodium hydroxide using citric acid selected from one or more of anhydrous citric acid, citric acid monohydrate.

In one embodiment, the citric acid-sodium citrate buffer pair may be formulated with citric acid and sodium citrate, the citric acid used being selected from one or more combinations of anhydrous citric acid, citric acid monohydrate, and sodium citrate used being selected from one or more combinations of anhydrous sodium citrate, sodium citrate dihydrate, sodium citrate pentahydrate.

In one embodiment, the pH4.0 citric acid-sodium citrate buffer pair of the present invention may be formulated from citric acid and sodium citrate in an aqueous solution, wherein the molar ratio of citric acid to sodium citrate is 2:1. For example, a pH4.0 buffer pair of citric acid-sodium citrate at a concentration of 5mM can be prepared by adding 3.34mmol of citric acid and 1.67mmol of sodium citrate to 1000mL of water.

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

In one embodiment, the amount of the osmoregulation agent is from 0.1% to 0.9% when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is from 23.2mcg/mL to 77.2mcg/mL, calculated as indacaterol.

In one embodiment, the amount of the osmoregulation agent is from 0.1% to 0.7% when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is from 77.3mcg/mL to 231.5mcg/mL, calculated as indacaterol.

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

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

In one embodiment, when the short chain alcohol is ethanol, the weight percent content is 0.02% -0.08%.

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

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

In one embodiment, the pharmaceutical composition further comprises at least one of the active ingredients glycopyrrolate, tiotropium bromide, ipratropium bromide, ubenimum bromide, aclidinium bromide, budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, the concentrations of these active ingredients in the pharmaceutical composition being each independently from 20mcg/mL to 500mcg/mL.

In one embodiment, the pharmaceutical composition further comprises glycopyrronium bromide in an amount of 0.05 to 0.5g per 1000mL of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 3g to 7g of sodium chloride, 0.6g to 2.8g of citric acid monohydrate, 0.4g to 2.0g of sodium citrate dihydrate, a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol maleate 0.108g, glycopyrronium bromide 0.058g, citric acid monohydrate 0.699g, sodium citrate dihydrate 0.492g, sodium chloride 6g, pH regulator appropriate amount to adjust pH to 4.0, and water to 1000mL.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, 0.6g to 2.8g of citric acid monohydrate, 0.4g to 2.0g of sodium citrate dihydrate, a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, 0.6g to 2.8g of citric acid monohydrate, 0.4g to 2.0g of sodium citrate dihydrate, and a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 3g to 7g of sodium chloride, a citric acid-sodium citrate buffer pair is obtained by reacting 0.5g to 4g of citric acid monohydrate with 0.1g to 0.8g of sodium hydroxide, a pH regulator is used for properly regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, a citric acid-sodium citrate buffer pair is obtained by reacting 0.5g to 4g of citric acid monohydrate with 0.1g to 0.8g of sodium hydroxide, a pH regulator is used for properly regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

In one embodiment, the pharmaceutical composition comprises per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, a citric acid-sodium citrate buffer pair obtained by reacting 0.5g to 4g of citric acid monohydrate with 0.1g to 0.8g of sodium hydroxide, a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

Further, the pH regulator is one or more 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 or disodium hydrogen phosphate.

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

In the invention, mcg is expressed in micrograms by mass, namely mug.

The citric acid used in the present invention is citric acid monohydrate. The same technical effects as with citric acid monohydrate can be achieved with anhydrous citric acid or other types of citric acid hydrates and are also within the scope of the present invention.

Sodium citrate used in the present invention is sodium citrate dihydrate. The same technical effect as that of sodium citrate dihydrate can be achieved by using anhydrous sodium citrate or other types of sodium citrate hydrate such as sodium citrate pentahydrate, and the use of sodium citrate dihydrate is also within the scope of the invention.

The invention also provides a preparation method of the indacaterol inhalation solution pharmaceutical composition, which comprises the following steps:

(a) Adding auxiliary materials with the prescription amount into water, wherein the auxiliary materials are at least one selected from solubilizer, osmotic pressure regulator, buffer ion pair and short chain alcohol, stirring to disperse and dissolve the auxiliary materials, and regulating the pH value of the solution to be 2.0-5.5 by using a pH regulator;

(b) Adding the prescription amount of indacaterol or pharmaceutically acceptable salt thereof into the auxiliary material solution prepared in the step (a), stirring and dissolving; optionally, at least one of glycopyrronium bromide, tiotropium bromide, ipratropium bromide, ubenimex and aclidinium bromide is added and stirred for dissolution.

Optionally, the pharmaceutical solution obtained in (b) above is sterilized by filtration, for example with a filter membrane of less than or equal to 0.22 μm, to obtain a sterile pharmaceutical solution.

Optionally, adding at least one of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate and fluticasone furoate into the sterile medicinal solution, and stirring and dispersing uniformly.

Alternatively, the resulting sterile pharmaceutical solution may be packaged, for example in a penicillin bottle, glass ampoule or plastic ampoule, to provide an indacaterol inhalation solution pharmaceutical composition.

In one embodiment, the present invention provides a method for preparing a pharmaceutical composition of indacaterol inhalation solution, the method comprising the steps of:

(a) Adding auxiliary materials with prescription amount into water, wherein the auxiliary materials are at least one selected from solubilizer, osmotic pressure regulator, buffer ion pair and short chain alcohol; stirring uniformly to disperse and dissolve auxiliary materials, and then adjusting the pH value of the solution to a target value of 2.0-5.5 by using a pH regulator;

(b) Adding the prescription amount of indacaterol or pharmaceutically acceptable salt thereof into the auxiliary material solution prepared in the step (a), stirring and dissolving;

(c) Filtering and sterilizing the medicine solution obtained in the step (b) by using a filter membrane smaller than or equal to 0.22 mu m to obtain a sterile medicine solution;

(d) Filling the sterile drug solution obtained in the step (c) into a penicillin bottle, a glass ampoule or a plastic ampoule to obtain the indacaterol inhalation solution drug composition.

(b) Adding the prescription amount of indacaterol or pharmaceutically acceptable salt thereof into the auxiliary material solution prepared in the step (a), adding at least one of glycopyrronium bromide, tiotropium bromide, ipratropium bromide, ubenimex bromide and aclidinium bromide, stirring and dissolving;

In one embodiment, the invention also provides another preparation method of the indacaterol inhalation solution pharmaceutical composition, which comprises the following steps:

(d) Adding at least one of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate and fluticasone furoate into the sterile medicinal solution obtained in the step (c), and stirring and dispersing uniformly.

(e) Filling the sterile drug suspension obtained in the step (d) into a penicillin bottle, a glass ampoule or a plastic ampoule to obtain the indacaterol inhalation solution drug composition.

The indacaterol inhalation solution pharmaceutical composition provided by the invention overcomes the defect that the existing indacaterol inhalation solution is low in concentration and cannot be clinically applied, and sodium chloride with higher concentration can be added in the prescription and the high concentration of indacaterol is kept, so that the concentration of indacaterol in an inhalation solution preparation is greatly improved, the preparation of an indacaterol inhalation solution preparation large-scale preparation is smoothly realized, and the high-concentration indacaterol inhalation solution better meets clinical requirements. The indacaterol bromide compound inhalation solution composition provided by the invention is reported for the first time, the concentration of the medicine in the preparation is high, the preparation has good chemical stability, and the clinical requirement can be well met; on the other hand, the FPF value difference of the inhalation solution of the invention under different air flow rates is smaller (the dry powder inhalation preparation is larger), and patients with different inhalation capacities can be suitable (the dry powder inhalation preparation is not suitable for patients with weak inhalation capacities), so that the medication compliance of the patients is improved.

Detailed Description

The invention will be further described in connection with test examples and examples which will enable those skilled in the art to more fully understand the invention, but without limiting the invention in any way.

Test examples 1 to 8: investigation of the solubility of indacaterol maleate in solutions of different pH

The preparation method comprises the following steps: 1000mL of water is measured, a proper amount of hydrochloric acid is added to adjust the pH value to the pH value specified in the prescription, the error range is not more than +/-0.05, then 0.5g of indacaterol maleate raw material medicine is added, stirring is carried out for 24 hours at 25 ℃, and the concentration of the sample is detected after filtration.

Detection result:

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

Test examples 9 to 14: the stability of indacaterol solutions at different pH conditions was investigated.

Test example 9

Test example 10

Test example 11

Test example 12

Test example 13

Test example 14

Indantrole maleate

0.15g

pH

3.0

3.5

4.0

4.5

5.0

5.5

Adding water to

1000mL

The preparation method comprises the following steps: 1000mL of water is measured respectively, the pH value of the solution is regulated to the pH value specified in the prescription by a proper amount of hydrochloric acid, the error range is not more than +/-0.05, then 0.15g of indacaterol maleate raw material medicine is added respectively, stirring is carried out overnight, the mixture is filtered and filled in ampoule bottles, and the ampoule bottles are placed at the temperature of 4 ℃ and the temperature of 25 ℃ respectively, and the relevant substances of the samples are inspected in 1, 2 and 3 months respectively.

Detection result:

the test results showed that the impurity amounts of test examples 9 to 14 were not significantly changed from the comparison of 0 days at 4℃and that the impurity amounts of test examples 9 to 14 were increased with the increase in temperature. The inventors have also found that the amount of impurities in the solution at pH5.0 to 5.5 exceeds 1% for 3 months at 25 ℃. So that in the solution with pH of 3.0-4.5, the indacaterol maleate is more stable at 25 ℃.

Since the results of test examples 9 to 14 show that indacaterol maleate is more stable in a solution having a pH of 3.0 to 5.5 at low temperature, it is necessary to examine whether indacaterol maleate can have higher solubility even at low temperature.

Test examples 15 to 18: examination of the solubility of indacaterol maleate in solutions of different pH values during low-temperature storage

	Test example 15	Test example 16	Test example 17	Test example 18
					Indantrole maleate	0.3g	0.3g	0.3g	0.3g
Hydrochloric acid	Proper amount of	/	/	/
					Citric acid-sodium citrate buffer pair	/	5mM	5mM	5mM
pH	3.0	4.0	4.5	5.0
					Adding water to	1000mL	1000mL	1000mL	1000mL

1000mL of water is measured, a proper amount of hydrochloric acid is added in test example 15, and the pH is adjusted to 3.00+/-0.05; test examples 16 to 18 were added with 0.699g of citric acid and 0.492g of sodium citrate, stirred and dissolved, the pH was adjusted to the prescribed pH, the error range was not more than.+ -. 0.05, then 0.3g of indacaterol maleate was added, stirred overnight, filtered and packaged in ampoules, stored in a refrigerator at 2-8℃and tested for sample concentration and pH at 0 time and 72 hours, respectively. The sample in the ampoule is filtered to remove undissolved drug particles prior to concentration testing. The detection result is as follows:

From the above detection results, it can be seen that the solubility of indacaterol maleate is higher when the pH of the solution is controlled to be 3.0-4.0 under the low temperature condition. Whereas when pH > 4.0, the solubility starts to drop significantly and decreases with increasing pH; the drug concentration does not change significantly during the low temperature preservation process.

In the inhalation solution, an osmotic pressure regulator is required to be added, and sodium chloride is often used for regulating the osmotic pressure of the solution. However, the invention discovers that sodium chloride can influence the solubility of the indacaterol maleate in the research, so that the influence of sodium chloride with different concentrations on the solubility of the indacaterol maleate needs to be examined.

Test examples 19 to 27: investigation of the Effect of sodium chloride concentration on Indamterol maleate solubility

The preparation method comprises the following steps: 1000mL of water was measured, and 0.699g of citric acid and 0.492g of sodium citrate were added to test examples 19 to 21; test examples 22 to 24 were added with 1.398g of citric acid and 0.984g of sodium citrate; test examples 25 to 27 were added with 2.796g of citric acid and 1.968g of sodium citrate, stirred until completely dissolved, and then added with the corresponding sodium chloride, stirred until completely dissolved; adding proper amount of hydrochloric acid to adjust the pH to 4.00+/-0.05, then adding 0.3g of indacaterol maleate raw material medicine, stirring overnight, filtering and packaging in ampoule bottles. The concentration and pH of the liquid medicine were tested. Simultaneously placing in a refrigerator at 2-8deg.C for 3 days and 7 days respectively, and measuring sample concentration and pH value. The sample in the ampoule is filtered to remove possible precipitated drug particles prior to concentration testing.

The detection result is as follows:

the above results show that in the solution containing sodium chloride, the solubility of indacaterol maleate was reduced (white granular precipitate could 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 the standing process. Meanwhile, the invention discovers 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 in the placing process.

To determine the concentration of citric acid-sodium citrate buffer in solution, the effect of different concentrations of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution was studied.

Test examples 28 to 32: examination of 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
						Indantrole maleate	0.2g	0.2g	0.2g	0.2g	0.2g
Citric acid-sodium citrate buffer pair	-	5mM	20mM	30mM	50mM
						Sodium chloride	6g	6g	6g	6g	6g
Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
						Adding water to	1000mL	1000mL	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water was measured, and 0.699g, 1.398g, 4.194g and 6.990g of citric acid, 0.492g, 1.968g, 2.952g and 4.920g of sodium citrate, respectively, were added to test examples 29 to 32, and stirred until completely dissolved. Then 6g of sodium chloride is added in each of the test examples 28 to 32, and the mixture is stirred until the mixture is completely dissolved; adding a proper amount of hydrochloric acid to adjust the pH to 4.00+/-0.05, then adding 0.2g of indacaterol maleate raw material medicine, stirring overnight, filtering, and then sub-packaging in ampoule bottles to test the concentration and the pH value of a sample. The sample in the ampoule is filtered to remove possible precipitated drug particles prior to concentration testing. And simultaneously placing the materials in a refrigerator at the temperature of 2-8 ℃ for 7 days respectively, and then detecting again. The sample in the ampoule is filtered to remove possible precipitated drug particles prior to concentration testing.

The detection result is as follows:

the results of tests according to test examples 28-32 show that the citric acid-sodium citrate buffer pair can increase the solubility of indacaterol maleate in sodium chloride solution and can reduce the risk of precipitation of indacaterol maleate during the standing process.

Test example 33: it was examined whether a high concentration and stable indacaterol maleate solution could be prepared according to the formulation of example 1 in patent CN103860463 a.

Prescription:

indantrole maleate	0.1g
		Citric acid	1.5g
Sodium citrate	4g
		Sodium chloride	2g
Water and its preparation method	1000mL

Remarks: the concentrations of the other excipients in the formulation were the same as in example 1 of CN103860463a except that the concentration of indacaterol maleate was increased.

Weighing each auxiliary material according to the prescription amount, adding the auxiliary materials into 1000mL of water, stirring until the auxiliary materials are completely dissolved, then adding 0.1g of indacaterol maleate, stirring until the pH is regulated to 5.0+/-0.05 after the dissolution, filtering, filling the mixture into an ampoule bottle, detecting the concentration of a sample, and simultaneously placing the sample in a refrigerator at the temperature of 2-8 ℃ for 7 days, and detecting the concentration of the sample. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	day 0	For 7 days
			Concentration in indacaterol (mcg/mL)	77.27	60.46

After 7 days of standing, the indacaterol maleate concentration was reduced and a precipitate was observed in the ampoule. The above results indicate that a high concentration indacaterol maleate solution could not be prepared according to the recipe of example 1 in patent CN103860463 a.

Test example 34: examine whether a high-concentration and stable indacaterol maleate solution could be prepared according to the formulation of example 3 in patent CN103860463a

Prescription:

indantrole maleate	0.02g
		Disodium hydrogen phosphate	2g
Dipotassium hydrogen phosphate	7.5g
		Sodium chloride	0.5g
Sodium formaldehyde sulfoxylate	22.5mg
		Ethylene diamine tetraacetic acid mono-calcium disodium salt	50mg
Water and its preparation method	1000mL

Remarks: the concentrations of the other excipients in the formulation were the same as in example 3 of CN103860463a except that the concentration of indacaterol maleate was increased.

Weighing each auxiliary material according to the prescription amount, adding the auxiliary materials into 1000mL of water, stirring until the auxiliary materials are completely dissolved, then adding 0.02g of indacaterol maleate, stirring until the pH is regulated to 6.5+/-0.05 after the dissolution, filtering, filling the mixture into an ampoule bottle, detecting the concentration of a sample, and simultaneously placing the sample in a refrigerator at the temperature of 2-8 ℃ for 7 days, and detecting the concentration of the sample. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	day 0	For 7 days
			Concentration in indacaterol (mcg/mL)	15.42	5.17

After 7 days of standing, the indacaterol maleate concentration was reduced and a precipitate was observed in the ampoule. The above results indicate that a high concentration indacaterol maleate solution could not be prepared according to the recipe of example 3 in patent CN103860463 a.

Examples 1 to 8:

prescription:

the preparation method comprises the following steps: 1000mL of water is measured, 0.1g of polysorbate-80 is added for dissolution, the pH is regulated to the prescribed pH by hydrochloric acid, the error range is not more than +/-0.05, then the corresponding amount of indacaterol maleate is added, stirring and dissolution are carried out at room temperature, filtration is carried out, and then the obtained product is filled in an ampoule bottle, and the concentration of the sample and related substances are detected. The sample in the ampoule is filtered to remove possible precipitated drug particles prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Related substances (%)
			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 pH range of 2.0-5.0, a solution of indacaterol maleate having a concentration of 100-300 mcg/mL can be obtained.

Examples 9 to 11:

prescription:

	example 9	Example 10	Example 11
				Indantrole maleate	0.2g	0.2g	0.2g
Polyethylene glycol castor oil	/	/	1g
				Lecithin	/	1g	/
Polyoxyethylated castor oil	0.4g	/	/
				pH	4.0	4.0	4.0
Adding water to	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, corresponding amounts of polyethylene glycol castor oil, lecithin and polyoxyethylene castor oil are respectively added according to the above examples, the pH is regulated to 4.0+/-0.05 by hydrochloric acid after complete dissolution, then 0.2g of indacaterol maleate is added, stirring and dissolution are carried out at room temperature, filtration is carried out, and the mixture is filled in an ampoule bottle, and the concentration of a sample and related substances are detected. The sample in the ampoule is filtered to remove possible precipitated drug particles prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Related toSubstance (%)
			Example 9	154.20	0.132
Example 10	159.29	0.121
			Example 11	155.59	0.133

The results show that: the prepared inhalation solution content and related substances meet the requirements.

Examples 12 to 13:

	example 12	Example 13
			Indantrole maleate	0.05g	0.05g
Sulfuric acid	Proper amount of	/
			Lysine	/	Proper amount of
pH	4.0	4.0
			Adding water to	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, the pH value is respectively regulated to 4.0+/-0.05 by sulfuric acid or lysine, 0.05g of indacaterol maleate is added, the mixture is stirred and dissolved at room temperature, filtered and then the mixture is filled in an ampoule bottle, and the concentration of a sample and related substances are detected. The sample in the ampoule is filtered to remove possible precipitated drug particles prior to concentration testing.

Detection result

The results show that: amino acid or sulfuric acid is used as a pH regulator, so that the related substances of the indacaterol maleate solution are not influenced, and the related substances of the solution meet the requirements.

Examples 14 to 19:

the preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are added, and stirring is carried out until the mixture is completely dissolved, and then 6g of sodium chloride is added, and stirring is carried out until the mixture is completely dissolved; adding appropriate amount of hydrochloric acid to adjust pH to 4.00+ -0.05, adding corresponding ethanol, propylene glycol, and glycerol, and stirring to mix well. 1000mL of the corresponding solution is measured, 0.15g of indacaterol maleate is added, the mixture is stirred overnight, and the mixture is filtered and split charging is carried out, and the content and the pH value are tested. The concentration and pH were measured after 3 days and 7 days in a refrigerator at 2-8deg.C. The sample is filtered to remove possible precipitated drug particles prior to concentration testing.

Detection result:

the results show that: the mixed solution system containing short-chain alcohol can prepare preparations with qualified content.

Examples 20 to 24:

the preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are added in examples 20 to 22; examples 23 to 24 were added with 2.796g of citric acid and 1.968g of sodium citrate, stirred until completely dissolved, respectively added with corresponding amounts of sodium chloride, after complete dissolution, adjusted to pH 4.00.+ -. 0.05 with hydrochloric acid, then added with corresponding amounts of indacaterol maleate, stirred overnight, filtered and sub-packaged, and tested for concentration and related substances. The sample is filtered to remove possible precipitated drug particles prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Related substances (%)
			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 result shows that when the concentration of the indacaterol solution is 38.6-77.2 mcg/mL, the concentration of sodium chloride is 0.3-0.9% and the content and the pH value are not influenced, and when the concentration of the indacaterol solution is 115.8-192.9 mcg/mL, the concentration of sodium chloride is 0.3-0.6% and the content and the pH value are not influenced.

Examples 25 to 28:

name of the name	Example 25	Example 26	Example 27	Example 28
					Indantrole maleate	0.15g	0.15g	0.15g	0.15g
Citric acid-sodium citrate buffer pair	5mM	5mM	5mM	5mM
					Sodium chloride	3g	4g	5g	6g
Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of
					Adding water to	1000mL	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are added, the prescribed amount of sodium chloride is added after dissolution, stirring and dissolution are carried out, the pH is regulated to 4.00+/-0.05 by a proper amount of hydrochloric acid, finally 0.15g of indacaterol maleate medicine is added, stirring is carried out overnight, and after filtration, split charging is carried out, and the concentration and related substances are tested. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Related substances (%)
			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 show that: at a concentration of 115.8mcg/mL of indacaterol solution, different concentrations of sodium chloride had no effect on its content and related substances.

Examples 29 to 34:

prescription:

the preparation method comprises the following steps: 1000mL of water was measured, and 0.699g of citric acid and 0.492g of sodium citrate were added in examples 29 to 31; examples 32-34 were added with 4.194g of citric acid and 2.952g of sodium citrate, stirred until complete dissolution, 6g of sodium chloride was added, respectively, after complete dissolution, the pH was adjusted to 4.00.+ -. 0.05 with hydrochloric acid, then the corresponding amounts of indacaterol maleate and glycopyrrolate were added, stirred overnight, filtered and sub-packaged, and the concentrations, related substances and pH were tested. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

the results show that in the aqueous solution containing sodium chloride and citrate, the concentration of indacaterol can reach 115.8-154.4 mcg/mL at the glycopyrrolate concentration of 50-100mcg/mL, and related substances are not obviously increased.

Examples 35 to 37:

	example 35	Example 36	Example 37
				Indantrole maleate	0.15g	0.15g	0.15g
Glycopyrronium bromide	0.1g	0.2g	0.2g
				Polysorbate-80	/	/	0.05g
Citric acid-sodium citrate buffer pair	20mM	20mM	20mM
				Sodium chloride	3g	3g	3g
Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of
				Adding water to	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, 2.796g of citric acid and 1.968g of sodium citrate are added, stirring is carried out until the mixture is completely dissolved, then sodium chloride and polysorbate-80 are added, and stirring is carried out until the mixture is completely dissolved; adding proper amount of hydrochloric acid to adjust the pH to 4.00+/-0.05, then adding 0.15g of indacaterol maleate and glycopyrrolate, stirring for dissolving, filtering, and then packaging in ampoule bottles, and respectively testing the concentration and related substances of the two medicines. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

the results show that: the content of both medicaments meets the requirements, and there is no compatibility problem between the medicaments.

Meanwhile, the samples of the example 24 and the examples 35-37 are placed in an incubator at 5+/-2 ℃ to examine the changes of related substances and pH values during the placing process.

Detection result:

the results show that: in the sample placing process of the example 24 and the examples 35 to 37, the pH value change is not obvious, the related substances of indacaterol are slightly increased, but the speed is increased slowly, the glycopyrronium bromide impurity is not changed basically, and the sample stability is good.

Examples 38 to 43:

the preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid, 0.492g of sodium citrate and 5g of sodium chloride are added in the examples 41-43, the mixture is stirred until the mixture is completely dissolved, the pH is regulated to the corresponding pH by hydrochloric acid, and the error range is not more than +/-0.05; examples 38 to 40 were added with 5g of sodium chloride, and after stirring and dissolution, the pH was adjusted to the corresponding pH with hydrochloric acid, the error range was not more than.+ -. 0.05, and finally each example was added with the prescribed amount of the drug, stirred and dissolved, filtered, and then packaged in ampoules, and the concentrations were tested, respectively. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Glycopyrronium bromide concentration (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: an inhalation solution having a proper concentration can be prepared in a solution containing 0.5% sodium chloride and having a pH of 2 to 5.

Examples 44 to 49:

the preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are added, and stirred until the mixture is completely dissolved, and the prescribed amount of sodium chloride is respectively added, and stirred until the mixture is completely dissolved; adding proper amount of hydrochloric acid to adjust the pH to 4.00+/-0.05, then adding 0.15g of indacaterol acetate or indacaterol and the prescribed amount of glycopyrronium bromide raw material, stirring until the raw material is completely dissolved, filtering, and testing the concentration respectively. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

the test results show that: indanterol acetate or indacaterol can be prepared into a compound inhalation solution with glycopyrronium bromide.

Examples 50 to 53:

	example 50	Example 51	Example 52	Example 53
					Indantrole (Indantrole)	0.15g	0.15g	0.15g	0.15g
Glycopyrronium bromide	0.1g	/	/	/
					Tiotropium bromide	/	0.1g	/	/
Isopropiontolium bromide	/	/	0.1g	/
					Wumei ammonium bromide	/	/	/	0.1g
Citric acid-sodium citrate buffer pair	5mM	5mM	5mM	5mM
					Sodium chloride	3g	3g	3g	3g
Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of
					Adding water to	1000mL	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are added, and stirring is carried out until the mixture is completely dissolved, and then 3g of sodium chloride is added, and stirring is carried out until the mixture is completely dissolved; adding appropriate amount of hydrochloric acid to adjust pH to 4.00+ -0.05, adding the above medicines with the amounts shown in the above table, stirring to dissolve completely, filtering, packaging in ampoule bottles, and testing concentration respectively. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

the results show that the indacaterol and different long-acting anticholinergic (LAMA) medicaments can be prepared into compound inhalation solution, and the content meets the requirements.

Examples 54 to 59:

the preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are respectively added in examples 54-57, stirring is carried out until the mixture is completely dissolved, the prescribed amount of sodium chloride is respectively added, stirring is carried out until the mixture is completely dissolved, and a proper amount of hydrochloric acid is added to adjust the pH to 4.00+/-0.05; examples 58 to 59 were added with sodium chloride in the prescribed amount, stirred and dissolved, and then added with an appropriate amount of hydrochloric acid to adjust the pH to 3.00.+ -. 0.05; according to all the examples, indacaterol maleate and glycopyrrolate are added respectively according to the prescription, after the medicine is stirred overnight and dissolved, mometasone furoate or fluticasone propionate is added, after the medicine is stirred uniformly, the medicine is split into ampoule bottles, and the concentration is tested respectively. The detection results are as follows:

The test results show that: in the solution containing 0.3% of sodium chloride and pH of 3-4, the indacaterol, the long-acting anticholinergic (LAMA) drugs of different types and steroid hormone form ternary compound inhalation solution, and the content meets the requirements.

Examples 60 to 65:

the preparation method comprises the following steps: 1000mL of water is measured, the prescription amount of citric acid and sodium citrate are added, and stirring is carried out until the citric acid and the sodium citrate are completely dissolved, and then the prescription amount of sodium chloride is added, and stirring is carried out until the sodium chloride is completely dissolved; adding proper amount of hydrochloric acid to adjust the pH to 4.00+/-0.05, adding the Indamterol acetate and glycopyrrolate with the prescription amount shown in the table, stirring overnight until the raw materials are completely dissolved, adding the mometasone furoate or the fluticasone propionate or the fluticasone furoate with the prescription amount, stirring uniformly, subpackaging in ampoule bottles, and respectively testing the concentration. The detection results are as follows:

the test results show that: indanterol acetate and glycopyrrolate can be prepared into ternary compound inhalation solution with different steroid hormones.

Examples 66 to 71:

the preparation method comprises the following steps: 1000mL of water is measured, the buffer salt with the prescription amount is added, and the mixture is stirred until the mixture is completely dissolved, and then 3g of sodium chloride is added, and the mixture is stirred until the mixture is completely dissolved; adding appropriate amount of hydrochloric acid to adjust pH to the pH value set in the table, adding the prescribed amount of medicine, stirring to dissolve completely, filtering, packaging in ampoule bottles, and testing concentration respectively. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	indene (I) compoundConcentration of Dattro meter (mcg/mL)	Glycopyrronium bromide concentration (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 to 76:

	example 72	Example 73	Example 74	Example 75	Example 76
						Indantrole maleate	0.15g	0.15g	0.15g	0.15g	0.15g
Glycopyrronium bromide	0.1g	0.1g	0.1g	0.1g	0.1g
						Citric acid-sodium citrate buffer pair	--	5mM	20mM	5mM	5mM
Mannitol (mannitol)	50g	50g	50g	25g	5g
						Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Adding water to	1000mL	1000mL	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, 0.699g of citric acid and 0.492g of sodium citrate are added in examples 73 and 75-76, 2.796g of citric acid and 1.968g of sodium citrate are added in example 74, mannitol is added according to the prescription after stirring and dissolving, the mixture is stirred and dissolved, the pH is regulated to 4.00+/-0.05 by using a proper amount of hydrochloric acid, and finally the prescribed amounts of indacaterol maleate and glycopyrrolate are added, stirred and dissolved, filtered and split into ampoule bottles for testing the concentration respectively. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Glycopyrronium bromide concentration (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 detection result shows that: mannitol is used as osmotic pressure regulator to prepare compound inhalation solution with satisfactory content.

Examples 77 to 81:

	example 77	Example 78	Example 79	Example 80	Example 81
						Indantrole maleate	0.15g	0.15g	0.15g	0.15g	0.15g
Glycopyrronium bromide	0.1g	0.1g	0.1g	0.1g	0.1g
						Citric acid-sodium citrate buffer pair	5mM	5mM	5mM	10mM	20mM
Sodium chloride	3g	4g	5g	5g	5g
						Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Adding water to	1000mL	1000mL	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water was measured, and 0.699g of citric acid and 0.492g of sodium citrate were added in examples 77 to 79; example 80 citric acid 1.398g, sodium citrate 0.984g were added; in example 81, 2.796g of citric acid and 1.968g of sodium citrate were added, and after stirring and dissolution, sodium chloride was added according to the prescription, stirring and dissolution were performed, the pH was adjusted to 3.00.+ -. 0.05 with an appropriate amount of hydrochloric acid, and finally, the prescribed amounts of indacaterol maleate and glycopyrrolate were added, stirred and dissolved, filtered, and then packaged in ampoule bottles, and the concentrations were measured, respectively. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Glycopyrronium bromide concentration (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 detection result shows that: the solution with pH of 3.0 contains citric acid buffer salts with different concentrations, and can prepare binary compound inhalation solution with the content meeting the requirements.

Examples 82 to 86:

name of the name	Example 82	Example 83	Example 84	Example 85	Example 86
						Indantrole maleate	0.25g	0.05g	0.15g	0.15g	0.15g
Glycopyrronium bromide	0.1g	0.3g	0.1g	0.1g	0.1g
						Citric acid-sodium citrate buffer pair	5mM	5mM	5mM	10mM	40mM
Sodium chloride	3g	4g	5g	5g	5g
						Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Adding water to	1000mL	1000mL	1000mL	1000mL	1000mL

The preparation method comprises the following steps: 1000mL of water is measured, 1.051g of citric acid and 0.228g of sodium hydroxide are added in examples 82 to 84; example 85 citric acid 2.102g and sodium hydroxide 0.456g were added; in example 86, 8.408g of citric acid and 1.824g of sodium hydroxide were added, sodium chloride was added according to the prescription in each example after stirring and dissolution, the pH was adjusted to 3.00.+ -. 0.05 with an appropriate amount of hydrochloric acid, and finally, the prescribed amounts of indacaterol maleate and glycopyrrolate were added, stirred and dissolved, filtered and packaged in ampoules, and the concentrations were measured separately. Filtration is required to remove undissolved drug prior to concentration testing.

Detection result:

	concentration in indacaterol (mcg/mL)	Glycopyrronium bromide concentration (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 detection result shows that: in the solution with pH of 3.0, the binary compound inhalation solution with the content meeting the requirements can be prepared by adopting a citric acid buffer pair solution prepared from citric acid and sodium hydroxide.

Examples 87 to 91:

name of the name	Example 87	Example 88	Example 89	Example 90	Example 91
						Indantrole maleate	0.12g	0.12g	0.12g	0.12g	0.12g
Glycopyrronium bromide	0.06g	0.06g	0.06g	0.06g	0.06g
						Mometasone furoate	/	/	/	0.15g	0.15g
Citric acid-sodium citrate buffer pair	5mM	5mM	5mM	5mM	50mM
						Sodium chloride	4g	5g	6g	4g	5g
Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
						Adding water to	1000mL	1000mL	1000mL	1000mL	1000mL

1000mL of water is measured, 1.051g of citric acid and 0.228g of sodium hydroxide are added in examples 87-90; example 91 citric acid 10.51g and sodium hydroxide 2.28g were added. In each example, after citric acid and sodium hydroxide are stirred and dissolved, sodium chloride is added according to the prescription in each example, stirring and dissolving are carried out, the pH is regulated to 4.00+/-0.05 by a proper amount of hydrochloric acid, and finally, the prescription amount of indacaterol maleate and glycopyrronium bromide are added, and stirring and dissolving are carried out. Examples 87 to 89 were filtered and then dispensed into ampoule bottles, and the concentrations were measured. Examples 90 to 91 were filtered, and then mometasone furoate was added in prescribed amounts, and after high-speed shearing dispersion of mometasone furoate, the mixture was dispensed into ampules and tested for concentration, respectively.

Detection result:

the detection result shows that: in the solution with pH of 4.0, the binary compound inhalation solution and the ternary compound inhalation preparation with the content meeting the requirements can be prepared by adopting a citric acid buffer pair solution prepared from citric acid and sodium hydroxide.

Examples 92 to 96:

name of the name	Example 92	Example 93	Example 94	Example 95	Example 96
						Indantrole maleate	0.12g	0.12g	0.12g	0.12g	0.12g
Mometasone furoate	0.5g	0.3g	0.4g	0.15g	0.05g
						Citric acid-sodium citrate buffer pair	5mM	5mM	5mM	5mM	50mM
Sodium chloride	4g	5g	6g	4g	5g
						Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Adding water to	1000mL	1000mL	1000mL	1000mL	1000mL

1000mL of water is measured, 1.051g of citric acid and 0.228g of sodium hydroxide are added in the examples 92-95; example 96 citric acid 10.51g and sodium hydroxide 2.28g were added. In each example, after citric acid and sodium hydroxide are stirred and dissolved, sodium chloride is added according to the prescription, stirring and dissolving are carried out, a proper amount of hydrochloric acid is used for adjusting the pH value to 4.00+/-0.05, finally, the prescription amount of indacaterol maleate is added, stirring and dissolving are carried out, the prescription amount of mometasone furoate is added after filtration, and the mometasone furoate is split-packaged in ampoule bottles after high-speed shearing and dispersion, and the concentration is tested respectively.

Detection result:

	concentration in indacaterol (mcg/mL)	Mometasone furoate concentration (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 detection result shows that: in the solution with pH of 4.0, citric acid buffer pair solution prepared by citric acid and sodium hydroxide is adopted, so that the indacaterol mometasone furoate binary compound inhalation solution with the content meeting the requirement can be prepared.

Examples 97 to 99:

Name of the name	Example 97	Example 98	Example 99
				Indantrole maleate	0.005g	0.005	0.12
Disodium hydrogen phosphate	2g	/	/
				Dipotassium hydrogen phosphate	7.5g	/	/
Sodium chloride	0.5g	4g	4g
				Sodium formaldehyde sulfoxylate	0.0225g	/	/
Ethylenediamine tetraacetic acid-calcium disodium salt	0.05g	/	/
				Citric acid-sodium citrate buffer pair	/	5mM	5mM
Hydrochloric acid	/	Proper amount of	Proper amount of
				Adding water to	1000mL	1000mL	1000mL

Note that: example 97 was prepared with reference to the recipe of example 3 in patent CN103860463 a.

In examples 98 and 99, 1000mL of water was measured, 1.051g of citric acid and 0.228g of sodium hydroxide were added, and after stirring and dissolution, 4g of sodium chloride was added, stirring and dissolution were performed, the pH was adjusted to 4.00.+ -. 0.05 with an appropriate amount of hydrochloric acid, and finally, the prescribed amount of indacaterol maleate was added, stirring and dissolution was performed, and the mixture was packaged in ampoule bottles. Example 97 1000mL of water was measured, 2g of disodium hydrogen phosphate, 7.5g of dipotassium hydrogen phosphate, 0.5g of sodium chloride, 0.0225g of sodium formaldehyde sulfoxylate and 0.05g of ethylenediamine tetraacetic acid-calcium disodium were added, a buffer solution with a pH of 6.5 was obtained after stirring and dissolution, then 0.005g of indacaterol maleate was added, and after stirring and dissolution, the mixture was dispensed into ampoule bottles. The above 3 samples were placed in an incubator at 25.+ -. 2 ℃ to examine the changes of the substances during the placing of the samples.

Detection result:

the detection result shows that: referring to example 97 prepared according to the example recipe in patent CN103860463a, the impurity increase in example 97 is significant during the room temperature standing process, and the impurity amount after 3 months of standing is more than 1%. Examples 98 and 99 showed a slight increase in impurity after 3 months of placement, and there was no significant difference in impurity growth between the two examples.

Example 100:

name of the name	Example 100
		Indantrole maleate	35.6mg
Glycopyrronium bromide	19.5mg
		Lactose and lactose	24.9g
Magnesium stearate	0.03g

Pulverizing indacaterol maleate and glycopyrrolate with jet mill to obtain particle diameter D ₉₀ And (3) uniformly mixing indacaterol maleate, glycopyrrolate and magnesium stearate, gradually mixing with lactose in an equal progressive manner, and filling the obtained total mixed powder into capsules.

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

The FPF values of the formulations were determined using a new generation pharmaceutical impactor (Next generation impactor, NGI) for examples 34, 68, 79, 82, 87, 100. Different flow rates are used to simulate the variation of the FPF values in different embodiments under different breathing modes.

Detection result:

the detection result shows that: the inhalation solutions of examples 34, 68, 79, 82 and 87 have no obvious difference in FPF values at different flow rates, and the proportion of micro particles reaching the lung in the preparation is not different due to different inhalation capacities of people; however, the powder aerosol of example 100 has a large difference in FPF value at different flow rates, the FPF value at a low flow rate is significantly lower, and glycopyrronium bromide is significantly lower, so that the powder aerosol has a certain limitation in use for patients with weak respiratory ability.

Examples 101 to 106:

the preparation method comprises the following steps: 1000mL of water is measured, the prescription amount of citric acid and sodium citrate are added, and stirring is carried out until the citric acid and the sodium citrate are completely dissolved, and then the prescription amount of sodium chloride is added, and stirring is carried out until the sodium chloride is completely dissolved; adding proper amount of hydrochloric acid to adjust the pH to 4.00+/-0.05, adding the prescription amount of indacaterol maleate and aclidinium bromide shown in the table, stirring overnight until the raw material medicine is completely dissolved, adding the prescription amount of budesonide or ciclesonide or beclomethasone propionate, stirring uniformly, packaging in ampoule bottles, and respectively testing the concentration. The detection results are as follows:

the test results show that: indanterol maleate and aclidinium bromide can be combined with different steroid hormone medicaments to prepare ternary compound inhalation solution.

Examples 107 to 112:

name of the name	Example 109	Example 110	Example 111	Example 112
					Indantrole maleate	0.108g	0.108g	0.08g	0.13g
Glycopyrronium bromide	/	0.058g	0.046g	0.07g
					Acetic acid sodium salt	/	/	/	/
Ascorbic acid	/	/	/	/
					Citric acid	0.699g	0.699g	0.699g	0.699g
Sodium citrate	0.492g	0.492g	0.492g	0.492g
					Sodium chloride	6g	6g	6g	6g
Hydrochloric acid	Proper amount of	Proper amount of	Proper amount of	Proper amount of
					Adding water to	1000mL	1000mL	1000mL	1000mL

Example 107 and example 108 are samples prepared according to the prescription procedure of example 1 and example 2, respectively, in patent CN103860463 a.

Example 109: measuring the prescribed amount of water, adding the prescribed amount of citric acid and sodium citrate, stirring and dissolving, adding the prescribed amount of sodium chloride, stirring and dissolving, adjusting the pH to 4.00+/-0.05 with a proper amount of hydrochloric acid, finally adding the prescribed amount of indacaterol maleate, stirring and dissolving, filtering, and sub-packaging in ampoule bottles.

Examples 110 to 112: respectively measuring the water with the prescription amount, adding the citric acid with the prescription amount and the sodium citrate, stirring and dissolving, adding the sodium chloride with the prescription amount, stirring and dissolving, adjusting the pH to 4.00+/-0.05 with a proper amount of hydrochloric acid, finally adding the indacaterol maleate and the glycopyrrolate with the prescription amount, stirring and dissolving, filtering, and sub-packaging in ampoule bottles.

The samples of examples 107 to 110 were placed in an incubator at 25.+ -. 2 ℃ to examine the changes in the substances involved in the placing of the samples.

Detection result:

the detection result shows that: referring to the samples of examples 107 and 108 prepared according to the prescriptions of examples 1 and 2 in patent CN103860463a, the content of indacaterol related substances increases significantly during the room temperature standing process, and the content exceeds 0.8% -1.0% after 3 months of standing. The sample of the example 109 and the sample of the implementation 110 prepared according to the technical scheme of the invention only slightly increases the content of the indacaterol related substances after being placed for 3 months at room temperature, and the indacaterol maleate stability is obviously better than that of the sample of the example 1 and the sample of the example 2 in CN 103860463A; and there was no significant difference in the growth of indenterol related substances between the samples of examples 109 and 110, indicating that the addition of glycopyrrolate to the compositions of the present invention did not affect the stability of indenterol maleate, and that there was no compatibility problem between indenterol maleate and glycopyrrolate.

Claims

1. An inhalation solution pharmaceutical composition comprising the active ingredient indacaterol or a pharmaceutically acceptable salt thereof, a pH adjustor and water, wherein the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof is 23.2mcg/mL to 231.5mcg/mL in terms of indacaterol, and the pH of the pharmaceutical composition is 2.0 to 5.5.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of indacaterol as an active ingredient is indacaterol maleate or indacaterol acetate, the pH regulator is at least one 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 and disodium hydrogen phosphate, and the pH value of the pharmaceutical composition is 2.5-5.0.

3. The pharmaceutical composition according to claim 1 or 2, further comprising other specific excipients selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs.

4. A pharmaceutical composition according to claim 3, wherein the solubilising agent is selected from at least one of polysorbate, polyethylene glycol castor oil, polyoxyethylated castor oil, lecithin.

5. A pharmaceutical composition according to claim 3, wherein the osmolality adjusting agent is selected from at least one of sodium chloride or mannitol.

6. The pharmaceutical composition of claim 3, wherein the buffer ion pair is selected from the group consisting of a citric acid-sodium citrate buffer pair, a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, an acetic acid-sodium acetate buffer pair, a sodium bicarbonate-sodium carbonate buffer pair, a tartaric acid-sodium tartrate buffer pair, and the concentration of the buffer ion pair is 1mM to 50mM.

7. The pharmaceutical composition of any one of claims 1-6, further comprising a short chain alcohol selected from one or more of ethanol, propylene glycol, glycerol.

8. The pharmaceutical composition according to any one of claims 3 to 7, wherein,

when the concentration of the indacaterol or the pharmaceutically acceptable salt thereof is 23.2 mcg/mL-77.2 mcg/mL calculated by indacaterol, the weight percentage content of the osmotic pressure regulator is 0.1% -0.9%; or,

when the concentration of the indacaterol or the pharmaceutically acceptable salt thereof is 77.3 mcg/mL-231.5 mcg/mL calculated by indacaterol, the weight percentage of the osmotic pressure regulator is 0.1% -0.7%.

9. The pharmaceutical composition according to any one of claims 7 to 8, wherein,

when the short-chain alcohol is ethanol, the weight percentage content of the short-chain alcohol is 0.02-0.08%; or alternatively

When the short-chain alcohol is propylene glycol, the weight ratio of the propylene glycol to water is 1:4-200; or alternatively

When the short-chain alcohol is glycerol, the weight ratio of the glycerol to the water is 1:20-200.

10. The pharmaceutical composition according to any one of claims 1 to 9, further comprising at least one of the active ingredients glycopyrrolate, tiotropium bromide, ipratropium bromide, ubenimex, aclidinium bromide, budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, the concentrations of these active ingredients in the pharmaceutical composition being each independently 20mcg/mL to 500mcg/mL.

11. An inhalation solution pharmaceutical composition comprising per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 3g to 7g of sodium chloride, 0.6g to 2.8g of citric acid monohydrate, 0.4g to 2.0g of sodium citrate dihydrate, a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL; preferably, the pharmaceutical composition comprises per 1000 mL: indamterol maleate 0.108g, glycopyrronium bromide 0.058g, citric acid monohydrate 0.699g, sodium citrate dihydrate 0.492g, sodium chloride 6g, pH regulator appropriate amount to adjust pH to 4.0, and water to 1000mL.

12. An inhalation solution pharmaceutical composition comprising per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, 0.6g to 2.8g of citric acid monohydrate, 0.4g to 2.0g of sodium citrate dihydrate, a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

13. An inhalation solution pharmaceutical composition comprising per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, 0.6g to 2.8g of citric acid monohydrate, 0.4g to 2.0g of sodium citrate dihydrate, and a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

14. An inhalation solution pharmaceutical composition comprising per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 3g to 7g of sodium chloride, a citric acid-sodium citrate buffer pair is obtained by reacting 0.5g to 4g of citric acid monohydrate with 0.1g to 0.8g of sodium hydroxide, a pH regulator is used for properly regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

15. An inhalation solution pharmaceutical composition comprising per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, a citric acid-sodium citrate buffer pair is obtained by reacting 0.5g to 4g of citric acid monohydrate with 0.1g to 0.8g of sodium hydroxide, a pH regulator is used for properly regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

16. An inhalation solution pharmaceutical composition comprising per 1000 mL: indamterol or pharmaceutically acceptable salt thereof accounts for 0.04g to 0.23g of indacaterol, 0.02g to 0.2g of glycopyrrolate, 0.04g to 0.5g of mometasone furoate, 3g to 7g of sodium chloride, a citric acid-sodium citrate buffer pair obtained by reacting 0.5g to 4g of citric acid monohydrate with 0.1g to 0.8g of sodium hydroxide, a proper amount of pH regulator is used for regulating the pH to 2.5 to 5.0, and water is added to 1000mL.

17. The inhalation solution pharmaceutical composition according to any one of claims 11 to 16, wherein the pH adjustor is selected from at least 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, disodium hydrogen phosphate.

18. A process for the preparation of an inhalation solution pharmaceutical composition according to any one of claims 1 to 17 comprising the steps of:

(b) Adding the prescription amount of indacaterol or pharmaceutically acceptable salt thereof into the auxiliary material solution prepared in the step (a), stirring and dissolving; optionally, adding at least one of glycopyrronium bromide, tiotropium bromide, ipratropium bromide, ubenimex and aclidinium bromide, stirring and dissolving;

(c) Optionally, filtering and sterilizing the drug solution obtained in the step (b) with a filter membrane smaller than or equal to 0.22 mu m to obtain a sterile drug solution; optionally, adding at least one of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate and fluticasone furoate, and stirring and dispersing uniformly;

(d) Optionally, filling the sterile pharmaceutical solution obtained in (c) in a penicillin bottle, a glass ampoule or a plastic ampoule to obtain the indacaterol inhalation solution pharmaceutical composition.