An inhaled aerosol pharmaceutical composition containing indacaterol and a preparation method thereof

Abstract

An aerosol pharmaceutical composition and its preparation method, the composition comprising indacaterol or its salt, magnesium stearate and a propellant, and is prepared by uniformly mixing each component and filling it into an aluminum can. This aerosol product overcomes the problems of the indacaterol suspension aerosol that needs to be pre-made into engineering particle granules with excipients, has a complex preparation process and poor controllability, and better meets the clinical needs.

Description

Technical Field

[0001] The present invention relates to an inhaled aerosol pharmaceutical composition and a preparation method thereof, and particularly relates to an inhaled aerosol pharmaceutical composition containing indacaterol and a preparation method thereof, belonging to the technical field of inhaled aerosols. Background Art

[0002] There are approximately 42 million asthma patients and 28 million chronic obstructive pulmonary disease (COPD) patients globally. In the past decade, with the global air pollution and environmental deterioration, the incidence and mortality of asthma have shown an upward trend, and more than 180,000 people die from asthma every year. Another analysis shows that by 2020, COPD will rise from the current sixth place in the global causes of death to the third place. Bronchodilators can improve airflow limitation and are the main means for treating COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2019 pointed out that for patients with a comprehensive assessment of COPD grade B, the initial treatment is recommended to choose a long-acting bronchodilator alone. Currently, long-acting β2-agonists (LABAs) or long-acting anticholinergic drugs are still the first choice for improving their symptoms and reducing acute exacerbations.

[0003] Indacaterol is a new generation of long-acting LABA, inhaled once a day, and its bronchodilation effect can last for 24 hours. Indacaterol is a partial agonist of the β2 receptor, close to a full agonist, with a receptor affinity equivalent to formoterol and an intrinsic activity higher than salmeterol, so it takes effect more rapidly and takes effect within 5 minutes after the first dose. Indacaterol mainly causes airway smooth muscle relaxation by activating intracellular adenylate cyclase to catalyze the conversion of ATP into cAMP and reducing the release of free calcium ions; indacaterol can inhibit the release of various inflammatory mediators such as histamine, leukotrienes, and prostaglandins by mast cells and play an anti-inflammatory role by inhibiting neutrophil infiltration and reducing vascular permeability. Indacaterol can improve the dyspnea symptoms and quality of life of COPD patients and reduce the number of acute exacerbations. Indacaterol can improve the lung function and dyspnea symptoms of patients in the stable phase, and has the same efficacy as salmeterol and formoterol in improving the quality of life and reducing acute exacerbations of COPD.

[0004] The existing marketed indacaterol single-agent or compound preparations containing indacaterol mainly use the dry powder inhalation method for administration, including The dry powder inhalation method for administration requires patients to learn the drug inhalation method. For some severe COPD patients, they may not be able to achieve the inhalation ability, and the drug cannot be effectively delivered to the lungs or the delivered dose decreases, resulting in a decrease in the drug efficacy. Therefore, it is necessary to develop other inhaled preparation dosage forms, and aerosols are a new option.

[0005] CN103874483B discloses an inhaled aerosol pharmaceutical composition containing indacaterol. In this composition, indacaterol needs to be prepared into spherical engineered particles through special processes such as spray drying with a carrier, and then prepared into an aerosol. The preparation method is complex, with poor controllability and high production costs.

[0006] In summary, the preparation methods of the reported suspension indacaterol aerosol preparations are complex and have poor controllability. Therefore, it is necessary to develop a new type of indacaterol aerosol. Summary of the Invention

[0007] The present invention provides an inhaled aerosol pharmaceutical composition, which comprises an active ingredient indacaterol or a pharmaceutically acceptable salt thereof, magnesium stearate, and a propellant. Optionally, the active ingredient and / or magnesium stearate are in a micronized form.

[0008] Further, the pharmaceutically acceptable salt of the active ingredient indacaterol is indacaterol maleate or its micronized form, or indacaterol acetate or its micronized form, and the propellant is selected from at least one of trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, 1,1,1,2 - tetrafluoroethane, and 1,1,1,2,3,3,3 - heptafluoropropane.

[0009] Further, the weight percentage content of each component in the composition is: 0.0012% - 3% of indacaterol or a pharmaceutically acceptable salt thereof as the active ingredient, 0.0005% - 0.162% of magnesium stearate, and the balance is the propellant. Optionally, indacaterol or a pharmaceutically acceptable salt thereof is in its micronized form.

[0010] In some embodiments, the composition further comprises at least one of the active ingredients glycopyrronium bromide, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone dipropionate, and their respective weight percentage contents in the composition are 0.0006% - 1.5%. Optionally, the active ingredients glycopyrronium bromide, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone dipropionate are in their micronized forms.

[0011] In some embodiments, the weight percentage content of each component in the composition is: 0.06% - 1.2% of indacaterol maleate, 0.0006% - 1.5% of glycopyrronium bromide, 0.005% - 1.5% of mometasone furoate, 0.0045% - 0.081% of magnesium stearate, and the balance is the propellant. Optionally, indacaterol maleate, glycopyrronium bromide, and mometasone furoate are in their micronized forms. Optionally, magnesium stearate is in its micronized form.

[0012] In one embodiment, the composition contains per 10,000 g: indacaterol maleate 36.0 g, glycopyrronium bromide 19.5 g, magnesium stearate 2.9 g, and the balance is 1,1,1,2-tetrafluoroethane. Optionally, indacaterol maleate and / or glycopyrronium bromide and / or magnesium stearate are in their micronized forms.

[0013] In one embodiment, the composition contains per 10,000 g: indacaterol maleate 30.0 g, glycopyrronium bromide 16.0 g, mometasone furoate 30.0 g, magnesium stearate 2.0 g, and the balance is 1,1,1,2-tetrafluoroethane. Optionally, indacaterol maleate and / or glycopyrronium bromide and / or mometasone furoate and / or magnesium stearate are in their micronized forms.

[0014] In one embodiment, the composition contains per 10,000 g: indacaterol maleate 6.00 g, glycopyrronium bromide 3.00 g, mometasone furoate 12.00 g, magnesium stearate 1.05 g, and the balance is 1,1,1,2-tetrafluoroethane. Optionally, indacaterol maleate and / or glycopyrronium bromide and / or mometasone furoate and / or magnesium stearate are in their micronized forms.

[0015] In some embodiments, the composition further contains other specific excipients, and the other specific excipients are selected from at least one of oleic acid, phospholipid, Tween-80, polyvinylpyrrolidone, and polyethylene glycol.

[0016] Furthermore, the weight percentage content of the other specific excipients in the composition is 0.0020% to 5%.

[0017] In one embodiment, the composition contains per 10,000 g: micronized indacaterol maleate 36.0 g, micronized glycopyrronium bromide 19.5 g, magnesium stearate 2.9 g, polyvinylpyrrolidone-K25 or Tween-80 1.0 g, or oleic acid 0.51 g, and the balance is 1,1,1,2-tetrafluoroethane; optionally, magnesium stearate is in its micronized form.

[0018] Furthermore, the particle size distribution of each micronized component is D 90 ≤20 μm, preferably D 90 ≤10 μm, more preferably D 90 ≤5 μm.

[0019] The present invention also provides a preparation method of the above drug composition, which includes the following steps:

[0020] (1) Mix the active ingredients and magnesium stearate evenly to obtain a mixture;

[0021] (2) Add the prescribed amount of propellant to the mixture obtained in step (1), mix evenly to obtain a liquid medicine, and add an equal amount of the propellant lost by volatilization as necessary.

[0022] (3) Fill the liquid medicine prepared in step (2) into an aluminum can, and press on a metering valve to obtain the product.

[0023] In some embodiments, at least one of oleic acid, phospholipid, Tween-80, polyvinylpyrrolidone, and polyethylene glycol is further added in step (2).

[0024] In some embodiments, the active ingredient includes indacaterol, indacaterol maleate, or indacaterol acetate; preferably, the active ingredient further includes at least one of glycopyrronium bromide, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone dipropionate.

[0025] In some embodiments, the present invention also provides a method for preparing the above drug composition, which includes the following steps:

[0026] (1) Using an air jet mill, first micronize each active ingredient individually or co-micronize them, and then mix them evenly with magnesium stearate to obtain a mixture; or first mix each active ingredient and magnesium stearate evenly together, and then use an air jet mill for co-micronization to obtain a mixture;

[0027] (2) Add a prescribed amount of propellant to the mixture obtained in step (1), mix evenly to obtain a liquid medicine, and supplement the volatilized propellant in equal amounts if necessary.

[0028] (3) Fill the liquid medicine prepared in step (2) into an aluminum can, and press on a metering valve to obtain the product.

[0029] In some embodiments, at least one of oleic acid, phospholipid, absolute ethanol, Tween-80, polyvinylpyrrolidone, and polyethylene glycol is further added in step (2).

[0030] Advantages and beneficial effects of the present invention:

[0031] The preparation process of the inhaled aerosol drug composition containing indacaterol provided by the present invention is simple and controllable, overcoming the problems that the existing indacaterol suspension inhaled aerosol needs to be made into engineering particle granules with excipients first, and the preparation process is complex and the controllability is poor, and successfully realizes the preparation of the indacaterol aerosol preparation, and this indacaterol aerosol preparation better meets the clinical needs.

[0032] The product of the present invention has excellent in vitro particle size distribution performance of the drug, can reach a relatively high FPF value (fine particle fraction%, FPF%), and has a relatively high percentage of inhalable components.

[0033] The corresponding relationship between the English code of the propellant and its chemical name in the present invention is as follows:

[0034] Aerosol English code Aerosol chemical name CFC11 Trichlorofluoromethane CFC12 Dichlorodifluoromethane CFC114 Dichlorotetrafluoroethane HFA-134a 1,1,1,2-Tetrafluoroethane HFA-227 1,1,1,2,3,3,3-Heptafluoropropane

[0035] In the present invention, the FPF value of the sample is measured using a Nextgeneration impactor (NGI) pharmaceutical impactor produced by Copley Scientific, UK. Specific embodiments

[0036] The above-mentioned inventive concept of the present invention will be further described in detail below in conjunction with specific embodiments. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following embodiments. Without departing from the above-mentioned technical idea of the present invention, various substitutions and changes made according to ordinary technical knowledge and customary means in the art shall be included within the scope of the present invention.

[0037] Examples 1 - 5

[0038] Formulation:

[0039]

[0040] Preparation method:

[0041] (1) Use an air jet mill to crush the indacaterol maleate raw material so that the particle size D 90 is less than 5 μm.

[0042] (2) Weigh the indacaterol maleate and excipients magnesium stearate, polyvinylpyrrolidone, and polyethylene glycol in the amounts specified in each example, and put them into a mixing barrel. Add HFA-134a according to the prescription amounts specified in the above examples. Turn on the stirring of the mixing barrel (stirring speed 30 rpm), and stir for 30 minutes. If there is evaporation of the liquid medicine, replenish the liquid medicine to the original weight with a propellant before filling. Start filling, and fill the mixed liquid medicine into an aluminum can with a Pamasol Suspension filler, and press on a metering valve to obtain the product.

[0043] Place the samples of the above examples in a stability retention box at 40°C and RH 75%, and examine the change in the FPF value after 6 months. Measurement method: Use an NGI pharmaceutical impactor to test at a flow rate of 15 L / min.

[0044] Test results:

[0045]

[0046] The results show that in Example 5 without magnesium stearate, during the stability study, the FPF value of indacaterol maleate decreased significantly.

[0047] Examples 6 - 8

[0048] Formulation:

[0049]

[0050] Preparation method:

[0051] (1) Use an air jet mill to crush each of the raw materials of indacaterol maleate, glycopyrronium bromide, and mometasone furoate separately, so that the particle size D of each raw material 90 is less than 5 μm.

[0052] (2) Weigh the prescribed amounts of the raw materials of indacaterol maleate, glycopyrronium bromide, mometasone furoate, and the auxiliary material magnesium stearate, and put them into the mixing tank. Add HFA-134a according to the prescription amounts stated in the above examples. Start the stirring of the mixing tank (stirring speed 30 rpm), and stir for 30 minutes. If there is any evaporation of the liquid medicine, replenish the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0053] Examples 9 to 11

[0054] Prescription:

[0055]

[0056]

[0057] Preparation method:

[0058] (1) Use an air jet mill to crush each of the raw materials of indacaterol maleate, glycopyrronium bromide, and fluticasone propionate separately, so that the particle size D of each raw material 90 is uniformly less than 5 μm.

[0059] (2) Weigh the prescribed amounts of the raw materials of indacaterol, glycopyrronium bromide, and fluticasone propionate, and the auxiliary material magnesium stearate, and put them into the mixing tank. Add HFA-134a according to the prescription amounts stated in the above examples. Start the stirring of the mixing tank (stirring speed 30 rpm), and stir for 30 minutes. If there is any evaporation of the liquid medicine, replenish the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0060] Place the samples of Examples 6 to 11 in a stability retention box at 40°C and RH 75%, and investigate the change in the FPF value after 6 months. Determination method: Use an NGI pharmaceutical impactor and test at a flow rate of 15 L / minute.

[0061] Test results:

[0062]

[0063] The results showed that in the stability study of Examples 6 to 11, after being stored for 6 months, the decline of the FPF value of each active ingredient was relatively small, and the FPF value was stable.

[0064] Examples 12 to 21

[0065] Formulation:

[0066]

[0067]

[0068] Preparation method:

[0069] (1) Use an air jet mill to pulverize the indacaterol maleate API to make the particle size D 90 less than 5 μm.

[0070] (2) Weigh the prescribed amount of indacaterol maleate API and the excipient magnesium stearate, and put them into the mixing barrel. Add HFA-134a, CFC-12, and HFA-227 according to the formulation amounts stated in the above examples. Start the stirring of the mixing barrel (stirring speed 30 rpm) for 30 minutes. If there is any evaporation of the liquid medicine, make up the liquid medicine to the original weight with the propellant before filling. Start filling, and fill the mixed liquid medicine into the aluminum cans using a Pamasol Suspension filler, and press on the metering valve to obtain the product.

[0071] Use an NGI pharmaceutical impactor to measure the FPF values of the samples of Examples 12, 13, 15, and 20 at a flow rate of 15 L / min. At the same time, place the samples of the preferred examples in a stability retention box at 40 °C and RH 75%, and examine the change of the FPF value after 3 months.

[0072] Test results:

[0073]

[0074] The test results showed that when the formulation did not contain magnesium stearate, the FPF value of indacaterol maleate decreased significantly during the accelerated stability test, but when the formulation contained magnesium stearate, the FPF value of indacaterol maleate remained basically stable after 6 months of accelerated testing.

[0075] Examples 22 to 33

[0076] Formulation:

[0077]

[0078]

[0079] Preparation method:

[0080] (1) Use an air jet mill to separately perform air jet milling on the indacaterol maleate and glycopyrronium bromide bulk drugs, so that the particle size D of each bulk drug 90 is less than 5 μm.

[0081] (2) Weigh the prescribed amounts of indacaterol maleate, glycopyrronium bromide bulk drugs and the auxiliary material magnesium stearate, and put them into a mixing barrel. Add HFA-134a according to the prescription amounts stated in the above-mentioned examples. Start the stirring of the mixing barrel (stirring speed 30 rpm), and stir for 30 minutes. If there is any volatilization of the liquid medicine, supplement the liquid medicine to the original weight with a propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into an aluminum can, and press on a metering valve to obtain the product.

[0082] Use an NGI pharmaceutical impactor to measure the FPF value of each example sample at a flow rate of 15 L / min.

[0083] Test results:

[0084]

[0085] The test results show that when glycopyrronium bromide is introduced into the binary system of indacaterol maleate and magnesium stearate, the FPF value of indacaterol maleate does not change significantly. At the same time, we also surprisingly found that in the system containing magnesium stearate, the FPF value of glycopyrronium bromide is higher.

[0086] Examples 34 - 45

[0087] Prescription:

[0088]

[0089]

[0090] Preparation method:

[0091] (1) Use an air jet mill to separately perform air jet milling on the indacaterol and glycopyrronium bromide bulk drugs, so that the particle size D of each bulk drug 90 is less than 5 μm.

[0092] (2) Weigh the prescription amounts of indacaterol and glycopyrronium bromide bulk drugs and the excipient magnesium stearate, and put them into the mixing tank. Add oleic acid, phospholipids, absolute ethanol, Tween 80, polyethylene glycol, polyvinylpyrrolidone, and HFA-134a according to the prescription amounts stated in the above-mentioned examples. Start the stirring of the mixing tank (stirring speed: 30 rpm) for 30 minutes. If there is any evaporation of the liquid medicine, replenish the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0093] Use an NGI pharmaceutical impactor to measure the FPF values of the samples in Examples 34 to 45 at a flow rate of 15 L / min.

[0094] Test results:

[0095]

[0096] The test results show that adding other excipients to the ternary system containing indacaterol, glycopyrronium bromide, and magnesium stearate does not affect the FPF values of the prepared samples.

[0097] Place the samples of each of the above examples in a stability retention box at 40°C and 75% RH, and investigate the changes in impurities of each product after 6 months.

[0098] Test results of the HPLC content (%) of impurities:

[0099]

[0100] The test results show that in the ternary system containing indacaterol, glycopyrronium bromide, and magnesium stearate, the excipients phospholipids, oleic acid, polyethylene glycol, polyvinylpyrrolidone, and Tween 80 have little effect on the chemical stability of the product.

[0101] The structural formulas of impurity I and impurity J of glycopyrronium bromide in the above table are:

[0102]

[0103] Examples 46 - 50

[0104] Prescription:

[0105]

[0106] Preparation method:

[0107] (1) Use an air jet mill to perform air jet milling on the indacaterol maleate and glycopyrronium bromide bulk drugs respectively, so that the particle size D of each bulk drug 90 is less than 5 μm.

[0108] (2) Weigh the prescribed amounts of indacaterol maleate, glycopyrronium bromide bulk drugs and the excipient magnesium stearate, and put them into the mixing tank. Add HFA-134a according to the prescription amounts stated in the above-mentioned examples. Start the stirring of the mixing tank (stirring speed: 30 rpm), and stir for 30 minutes. If there is any volatilization of the liquid medicine, replenish the liquid medicine to its original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0109] Use an NGI pharmaceutical impactor to measure the FPF values of the samples of each example at a flow rate of 15 L / minute.

[0110] Test results:

[0111]

[0112] The test results show that in the ternary system products containing indacaterol maleate, glycopyrronium bromide and magnesium stearate, we found that with the increase in the amount of magnesium stearate used, the FPF values of indacaterol maleate can maintain a relatively high level, and at the same time, the FPF values of glycopyrronium bromide increase significantly.

[0113] Examples 51 - 63

[0114] Prescription:

[0115]

[0116] Preparation method:

[0117] (1) Use an air jet mill to perform air jet milling on the indacaterol maleate, glycopyrronium bromide, mometasone furoate bulk drugs and magnesium stearate respectively, so that the particle sizes D 90 of each bulk drug and excipient are less than 5 μm.

[0118] (2) Weigh the prescribed amounts of indacaterol maleate, glycopyrronium bromide, mometasone furoate bulk drugs and the excipient magnesium stearate, and put them into the mixing tank. Add HFA-134a according to the prescription amounts stated in the above-mentioned examples. Start the stirring of the mixing tank (stirring speed: 30 rpm), and stir for 30 minutes. If there is any volatilization of the liquid medicine, replenish the liquid medicine to its original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0119] Use an NGI pharmaceutical impactor to measure the FPF values of the samples of each example at a flow rate of 15 L / minute.

[0120] Test results:

[0121]

[0122]

[0123] The test results show that in the system of indacaterol maleate, glycopyrronium bromide and magnesium stearate, the quaternary system product formed by adding mometasone furoate has relatively high FPF values for each active pharmaceutical ingredient, and the differences between the examples are small.

[0124] Examples 64 - 67

[0125] Prescription:

[0126]

[0127] Preparation method:

[0128] (1) Use a jet mill to perform jet milling on the active pharmaceutical ingredients of indacaterol, glycopyrronium bromide, and fluticasone propionate respectively, so that the particle size D 90 is less than 5 μm.

[0129] (2) Weigh the prescribed amounts of the active pharmaceutical ingredients of indacaterol, glycopyrronium bromide, and fluticasone propionate, as well as the excipient magnesium stearate, and put them into a mixing tank. Add HFA - 134a according to the prescription amounts stated in the above examples. Start the stirring of the mixing tank (stirring speed 30 rpm) for 30 minutes. If there is any evaporation of the liquid medicine, replenish the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0130] Use an NGI pharmaceutical impactor to measure the FPF values of the samples of each example at a flow rate of 15 L / min.

[0131] Test results:

[0132]

[0133] The test results show that in the quaternary system product composed of indacaterol, glycopyrronium bromide, fluticasone propionate and magnesium stearate, the FPF values of each active pharmaceutical ingredient are relatively high, and the differences between the examples are small.

[0134] Examples 68 - 70

[0135] Prescription:

[0136]

[0137] Preparation method:

[0138] (1) Use an air jet mill to perform air jet milling on indacaterol acetate, glycopyrronium bromide, fluticasone propionate bulk drugs and magnesium stearate respectively, so that the particle size D of each bulk drug and excipient 90 is less than 5 μm.

[0139] (2) Weigh the micro-pulverized prescription amounts of indacaterol acetate, glycopyrronium bromide, fluticasone propionate bulk drugs and the micro-pulverized excipient magnesium stearate, and put them into a mixing barrel. Add HFA-134a according to the prescription amounts stated in the above examples. Turn on the stirring of the mixing barrel (stirring speed 30 rpm), and stir for 30 minutes. If there is any volatilization of the liquid medicine, supplement the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0140] Use an NGI pharmaceutical impactor to measure the FPF value of each example sample at a flow rate of 15 L / min.

[0141] Test results:

[0142]

[0143] The test results show that in the quaternary system product composed of indacaterol acetate, glycopyrronium bromide, fluticasone propionate and magnesium stearate, the FPF values of each bulk drug are relatively high, and the differences between examples are small.

[0144] Examples 71-74

[0145] Prescription:

[0146]

[0147] Preparation method:

[0148] (1) Place the indacaterol maleate, glycopyrronium bromide bulk drugs and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then perform air jet milling on the mixture, so that the particle size D of the pulverized mixture 90 is less than 5 μm.

[0149] (2) Weigh the micro-pulverized prescription amounts of the raw and auxiliary material mixture, and put them into a mixing barrel. Add HFA-134a according to the prescription amounts stated in the above examples. Turn on the stirring of the mixing barrel (stirring speed 30 rpm), and stir for 30 minutes. If there is any volatilization of the liquid medicine, supplement the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0150] Using an NGI pharmaceutical impactor, the FPF values of the samples of each example were measured at a flow rate of 15 L / min.

[0151] Test results:

[0152]

[0153] The test results show that different propellants have no significant effect on the FPF value of the product, and the FPF values of the samples prepared with each propellant are close.

[0154] Examples 75 - 78

[0155] Formulation:

[0156]

[0157] Preparation method:

[0158] (1) For Examples 75 and 76, the indacaterol maleate and glycopyrronium bromide APIs were separately micronized by air jet milling to make the particle size D of each micronized API 90 less than 5 μm. For Examples 77 and 78, the indacaterol maleate, glycopyrronium bromide APIs and magnesium stearate were placed in a three-dimensional mixer and mixed three-dimensionally for 30 minutes, and then the mixture was micronized by air jet milling to make the particle size D of the micronized mixture 90 less than 5 μm.

[0159] (2) For Examples 75 and 76, the micronized APIs and magnesium stearate in the prescribed amounts were weighed. For Examples 77 and 78, the micronized mixture of APIs and excipients in the prescribed amounts was weighed and put into the mixing tank. HFA-134a was added according to the prescription amounts stated in the above examples. The stirring of the mixing tank was started (stirring speed 30 rpm) and the stirring time was 30 minutes. If there was volatilization of the liquid medicine, the liquid medicine was replenished to the original weight with the propellant before filling. Filling was started, and the mixed liquid medicine was filled into aluminum cans using a Pamasol Suspension filler, and a metering valve was pressed on to obtain the product.

[0160] Using an NGI pharmaceutical impactor, the FPF values of the samples of each example were measured at a flow rate of 15 L / min.

[0161] Test results:

[0162]

[0163] The test results show that after glycopyrronium bromide was micronized together with indacaterol maleate and magnesium stearate, the FPF value of glycopyrronium bromide was higher than that of the samples prepared by separately micronizing the APIs.

[0164] Examples 79 - 85

[0165] Formulation:

[0166]

[0167] (1) Place indacaterol maleate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then perform air-flow pulverization on the mixture so that the particle size D of the pulverized mixture 90 is less than 5 μm.

[0168] (2) Weigh the micronized mixture of raw and auxiliary materials in the prescribed amount, and put it into the mixing barrel. Add HFA-134a according to the prescription amount stated in the above-mentioned embodiment. Start the stirring of the mixing barrel (stirring speed: 30 rpm), and stir for 30 minutes. If there is any volatilization of the liquid medicine, supplement the liquid medicine to the original weight with the propellant before filling. Start filling, and fill the mixed liquid medicine into the aluminum cans with a Pamasol Suspension filler, and press on the metering valve to obtain the product.

[0169] Place the samples of the above-mentioned respective embodiments in a stability retention box at 40 °C and RH 75%, and examine the change in the FPF value of each product after 6 months.

[0170] Test results:

[0171]

[0172]

[0173] The test results show that: for the products prepared by co-micronization of the active pharmaceutical ingredient and magnesium stearate, when placed under accelerated conditions, the change in their FPF values is very small, and the physical stability of the products is good.

[0174] Examples 86 - 90

[0175] Prescription:

[0176]

[0177] (1) Place indacaterol maleate, glycopyrronium bromide and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then perform air-flow pulverization on the mixture so that the particle size D of the pulverized mixture 90 is less than 5 μm.

[0178] (2) Weigh the micronized prescription amount of the raw and auxiliary material mixture and put it into the mixing barrel. Add HFA-134a according to the prescription amount stated in the above embodiments. Start the stirring of the mixing barrel (stirring speed: 30 rpm) for 30 minutes. If there is any volatilization of the liquid medicine, supplement the liquid medicine to the original weight with the propellant before filling. Start filling, and use the Pamasol Suspension filler to fill the mixed liquid medicine into the aluminum cans, then press on the metering valve to obtain the product.

[0179] Place the samples of the above respective embodiments in a stability retention box at 40°C and RH 75%, and examine the changes in the FPF values of each product after 6 months.

[0180] Test results:

[0181]

[0182] The test results show that after micronizing the mixture of indacaterol maleate, glycopyrronium bromide and magnesium stearate, the prepared samples were placed under accelerated conditions for 6 months, and there was no significant change in the FPF value, indicating good physical stability of indacaterol maleate and glycopyrronium bromide. At the same time, it was also found that after glycopyrronium bromide was pulverized together with indacaterol and magnesium stearate, the FPF value of glycopyrronium bromide was higher than that of the samples prepared by separately pulverizing the active pharmaceutical ingredients.

[0183] Examples 91 - 94

[0184] Prescription:

[0185]

[0186] (1) Place indacaterol acetate or indacaterol, glycopyrronium bromide and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then carry out air flow pulverization on the mixture so that the particle size D of the pulverized mixture 90 is less than 5 μm.

[0187] (2) Weigh the micronized prescription amount of the raw and auxiliary material mixture and put it into the mixing barrel. Add HFA-134a according to the prescription amount stated in the above embodiments. Start the stirring of the mixing barrel (stirring speed: 30 rpm) for 30 minutes. If there is any volatilization of the liquid medicine, supplement the liquid medicine to the original weight with the propellant before filling. Start filling, and use the Pamasol Suspension filler to fill the mixed liquid medicine into the aluminum cans, then press on the metering valve to obtain the product.

[0188] Place the samples of the above respective embodiments in a stability retention box at 40°C and RH 75%, and examine the changes in the FPF values of each product after 6 months.

[0189] Test results:

[0190]

[0191] The test results show that: when indacaterol acetate or indacaterol is co - micronized with glycopyrronium bromide and magnesium stearate, the prepared product has no obvious change in the FPF value during storage and has good physical stability.

[0192] Examples 95 - 103

[0193] Prescription:

[0194]

[0195]

[0196] (1) Place indacaterol maleate, glycopyrronium bromide and magnesium stearate in a three - dimensional mixer for three - dimensional mixing for 30 minutes, and then perform air - jet milling on the mixture to make the particle size D of the milled mixture 90 less than 5 μm.

[0197] (2) Weigh the micronized mixture of the original excipients in the prescription amount, and put it into the mixing barrel. Add HFA - 134a according to the prescription amount stated in the above examples. Turn on the stirring of the mixing barrel (stirring speed: 30 rpm), and stir for 30 minutes. If there is evaporation of the liquid medicine, replenish the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0198] Place the samples of the above - mentioned examples in a stability retention box at 40 °C and RH 75%, and investigate the change of the FPF value of each product after 6 months.

[0199] FPF (%) test results:

[0200]

[0201] The test results show that: by increasing the proportion of the active ingredient and magnesium stearate in the prescription, after being placed under accelerated conditions for 6 months, the FPF value of the samples has no obvious change, and the product has good physical stability.

[0202] Examples 104 - 115

[0203] Prescription:

[0204]

[0205]

[0206] (1) Place indacaterol maleate, glycopyrronium bromide, and magnesium stearate in a three-dimensional mixer and perform three-dimensional mixing for 30 minutes. Then, subject the mixture to air jet milling to make the particle size D of the milled mixture 90 less than 5 μm; separately subject each glucocorticoid raw material drug to air jet milling to make its particle size reach D 90 less than 5 μm.

[0207] (2) Weigh the micronized mixture of the original auxiliary materials and the corresponding prescription amount of the micronized glucocorticoid raw material drug, and put them into the mixing barrel. Add HFA-134a according to the prescription amount stated in the above example. Turn on the stirring of the mixing barrel (stirring speed 30 rpm) and stir for 30 minutes. If there is any volatilization of the liquid medicine, replenish the liquid medicine to the original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, and press on the metering valve to obtain the product.

[0208] Place the samples of the above respective examples in a stability retention box at 40 °C and RH 75%, and examine the change in the FPF value of each product after 6 months.

[0209] FPF (%) test results:

[0210]

[0211]

[0212] The test results show that after the co-micronization of indacaterol maleate, glycopyrronium bromide, and magnesium stearate, and the addition of another glucocorticoid raw material drug, the products prepared have no significant change in the FPF values of the three active ingredients and good physical stability after being placed for 6 months under accelerated conditions.

[0213] Examples 116 - 121

[0214] Prescription:

[0215]

[0216] (1) Place indacaterol maleate, glycopyrronium bromide, and magnesium stearate in a three-dimensional mixer and perform three-dimensional mixing for 30 minutes. Then, subject the mixture to air jet milling to make the particle size D of the milled mixture 90 less than 5 μm; separately subject each glucocorticoid raw material drug to air jet milling to make its particle size reach D 90 less than 5 μm.

[0217] (2) Weigh the micronized mixture of the original excipients and active ingredients in the prescribed amounts, as well as the micronized glucocorticoid API in the corresponding prescribed amounts, and put them into the mixing tank. Add HFA-134a according to the prescribed amounts stated in the above embodiments. Start the stirring of the mixing tank (stirring speed: 30 rpm) for 30 minutes. If there is any evaporation of the liquid medicine, replenish the liquid medicine to its original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, then press on the metering valve to obtain the product.

[0218] Use an NGI pharmaceutical impactor to measure the FPF values of the samples of each embodiment at a flow rate of 15 L / minute.

[0219] FPF (%) test results:

[0220] Example Indacaterol maleate Glycopyrronium bromide Fluticasone propionate 116 50.42 47.99 48.59 117 50.89 48.37 44.62 Indacaterol maleate Glycopyrronium bromide Budesonide 118 49.12 48.28 46.52 119 51.34 49.49 44.08 Indacaterol maleate Glycopyrronium bromide Beclomethasone dipropionate 120 52.01 48.98 47.09 121 50.39 47.49 44.54

[0221] The test results show that: the glucocorticoid API in different prescribed amounts has no significant effect on the FPF values of indacaterol maleate and glycopyrronium bromide. For the triple-compound aerosol prepared by co-micronizing indacaterol maleate, glycopyrronium bromide and magnesium stearate, the FPF values of indacaterol maleate and glycopyrronium bromide are relatively high.

[0222] Examples 122 - 133

[0223] Prescription:

[0224]

[0225] (1) Place indacaterol maleate, glycopyrronium bromide and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then perform air jet milling on the mixture to make the particle size D of the milled mixture 90 less than 5 μm.

[0226] (2) Weigh the micronized mixture of the original excipients and active ingredients in the prescribed amounts, as well as the corresponding prescribed amounts of excipients, and put them into the mixing tank. Add HFA-134a according to the prescribed amounts stated in the above embodiments. Start the stirring of the mixing tank (stirring speed: 30 rpm) for 30 minutes. If there is any evaporation of the liquid medicine, replenish the liquid medicine to its original weight with the propellant before filling. Start filling, and use a Pamasol Suspension filler to fill the mixed liquid medicine into aluminum cans, then press on the metering valve to obtain the product.

[0227] Place the samples of each of the above embodiments in a stability retention box at 40°C and RH 75%, and investigate the changes in the FPF values and impurities of each product after 6 months.

[0228] Test results:

[0229]

[0230]

[0231] The test results show that when one of polyvinylpyrrolidone, Tween 80, and oleic acid is contained in the prescription, the FPF values of indacaterol maleate and glycopyrronium bromide are improved to a certain extent. For all the products of the examples, there is no significant change in the FPF value after being placed under accelerated conditions for 6 months.

[0232] Test results of the HPLC content (%) of impurities:

[0233]

[0234] The test results show that for Examples 122 - 133, after being placed under accelerated conditions for 6 months, the increase in product impurities is slow and the chemical stability is good.

Claims

1. An inhalation aerosol pharmaceutical composition, characterized in that, By weight percentage, it contains 0.0012% to 3% of micronized indacaterol maleate, 0.0005% to 0.162% of micronized magnesium stearate, and a propellant; The propellant is selected from at least one of trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, and 1,1,1,2,3,3,3-heptafluoropropane.

2. The pharmaceutical composition according to claim 1, wherein The composition further contains at least one of micronized glycopyrronium bromide, micronized mometasone furoate, micronized fluticasone propionate, micronized budesonide, and micronized beclomethasone dipropionate, and their respective weight percentages in the composition are 0.0006% to 1.5%.

3. The pharmaceutical composition according to claim 2, wherein The weight percentages of the components in the composition are: 0.06% to 1.2% of micronized indacaterol maleate, 0.0006% to 1.5% of micronized glycopyrronium bromide, 0.005% to 1.5% of micronized mometasone furoate, 0.0045% to 0.081% of magnesium stearate, and the balance is the propellant.

4. The pharmaceutical composition according to claim 2, characterized in that, Per 10,000 g of the composition, it contains 36.0 g of micronized indacaterol maleate, 19.5 g of micronized glycopyrronium bromide, 2.9 g of magnesium stearate, and the balance is 1,1,1,2-tetrafluoroethane.

5. The pharmaceutical composition according to claim 2, characterized in that, Per 10,000 g of the composition, it contains 6.00 g of micronized indacaterol maleate, 3.00 g of micronized glycopyrronium bromide, 12.00 g of micronized mometasone furoate, 1.05 g of magnesium stearate, and the balance is 1,1,1,2-tetrafluoroethane.

6. The pharmaceutical composition according to claim 2, characterized in that, Per 10,000 g of the composition, it contains 30.0 g of micronized indacaterol maleate, 16.0 g of micronized glycopyrronium bromide, 30.0 g of micronized mometasone furoate, 2.0 g of magnesium stearate, and the balance is 1,1,1,2-tetrafluoroethane.

7. The pharmaceutical composition according to claim 4, wherein Per 10,000 g of the composition, it further contains 1.0 g of polyvinylpyrrolidone-K25 or 1.0 g of Tween-80, or 0.51 g of oleic acid.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The particle size distribution of each micronized component is D90 ≤ 5 μm.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, characterized in that, It includes the following steps: (1) Using a jet mill, first mix all the active ingredients and magnesium stearate evenly together, and then perform co-micronization using a jet mill to obtain a mixture; (2) Add the prescribed amount of propellant to the mixture obtained in step (1), mix evenly to obtain a liquid medicine, and supplement the volatilized and lost propellant in equal amounts if necessary; (3) Fill the liquid medicine obtained in step (2) into an aluminum can and press on a metering valve to obtain the product.

10. The preparation method according to claim 9, characterized in that, In step (2), at least one of oleic acid, Tween-80, and polyvinylpyrrolidone K25 is further added.

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