TW202128159A - Pharmaceutical composition of aerosol inhalant containing indacaterol and preparation method thereof - Google Patents

Abstract

Disclosed is a pharmaceutical composition of an aerosol inhalant and a preparation method thereof. The pharmaceutical composition comprises indacaterol or a salt thereof, magnesium stearate, and a propellant. The pharmaceutical composition is prepared by means of uniformly mixing the aforementioned components and filling the same into an aluminum can. The aerosol inhalant avoids the complexity and poor controllability of the conventional process of preparing an aerosol inhalant of indacaterol suspension into engineered particles with auxiliary materials. The aerosol inhalant is more suitable for clinical demands.

Description

Inhalation aerosol pharmaceutical composition containing indacaterol and preparation method thereof

The invention relates to an inhalation aerosol pharmaceutical composition and a preparation method thereof, in particular to an inhalation aerosol pharmaceutical composition containing indacaterol and a preparation method thereof, and belongs to the technical field of inhalation aerosols.

There are approximately 42 million asthma patients and 28 million chronic obstructive pulmonary disease (COPD) patients worldwide. In the past ten years, with the global air pollution and environmental deterioration, the incidence and mortality of asthma have been on the rise, and more than 180,000 people die of asthma each year. Another analysis shows that by 2020, COPD will climb from the sixth largest cause of death in the world to third. Bronchodilators can improve airflow limitation and are the main treatment for COPD. The 2019 COPD Global Initiative (GOLD) pointed out that COPD comprehensively evaluates patients with grade B, and the initial treatment recommends a long-acting bronchodilator monotherapy. At present, long-acting β2-receptor agonists (LABA) or long-acting anticholinergic drugs are still the first choice for improving symptoms and reducing acute exacerbations.

Indacaterol is a new generation of long-acting LABA, inhaled once a day, and its bronchial expansion effect can last for 24 hours. Indacaterol is a partial agonist of the β2 receptor, which is close to a full agonist. Its receptor affinity is equivalent to formoterol, and its intrinsic activity is higher than salmeterol, so it takes effect more quickly, 5 minutes after the first dose Effective within. Indacaterol mainly catalyzes the conversion of ATP into cAMP by activating intracellular adenylate cyclase, reducing the release of free calcium ions and causing airway smooth muscle relaxation; indacaterol can inhibit the release of mast cells such as histamine, leukotrienes and prostate A variety of inflammatory mediators such as hormones, and play an anti-inflammatory effect by inhibiting neutrophil infiltration and reducing vascular permeability. Indacaterol can improve the symptoms and quality of life of COPD patients, and reduce the number of acute exacerbations. Indacaterol can improve the pulmonary function and dyspnea symptoms of patients in stable stage. It has the same effect as salmeterol and formoterol in improving the quality of life and reducing the acute exacerbation of COPD.

The currently marketed single prescriptions of indacaterol or compound preparations containing indacaterol are mainly administered by dry powder inhalation, including Angrun® and Jierun®. Dry powder inhalation requires the patient to learn the method of inhalation. For some severe COPD patients, the inhalation capacity may not be achieved, the drug cannot be effectively delivered to the lungs or the delivered dose is reduced, which reduces the efficacy of the drug. Therefore, it is necessary to develop other inhalation formulations, among which aerosol is a new choice.

CN103874483B discloses an inhalation aerosol pharmaceutical composition containing indacaterol, wherein indacaterol needs to be prepared into spherical engineered particles with a carrier through a special process such as spray drying, and then prepared into an aerosol, and a preparation method Complex, poor controllability, and high production cost.

In summary, the currently reported suspension-type indacaterol aerosol preparations are complicated in preparation methods and poor in controllability. Therefore, it is necessary to develop a new type of indacaterol aerosol.

The present invention provides an aerosol pharmaceutical composition for inhalation, which comprises the active ingredient indacaterol or a pharmaceutically acceptable salt thereof, magnesium stearate and a propellant, optionally, the active ingredient and/or stearin Magnesium acid is in micronized form.

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 three At least one of chlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane .

Further, the weight percentage of each component in the composition is: the active ingredient indacaterol or its pharmaceutically acceptable salt 0.0012%~3%, magnesium stearate 0.0005%~0.162%, the balance It is a propellant. Optionally, indacaterol or a pharmaceutically acceptable salt thereof is in its micronized form.

In some embodiments, the composition further comprises at least one of the active ingredients glycopyrrolate, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone propionate, each of which is in the composition The percentage by weight in the content is 0.0006%~1.5%. Optionally, the active ingredients glycopyrrolate, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone propionate are in their micronized form.

In some embodiments, the weight percentage of each component in the composition is: indacaterol maleate 0.06%~1.2%, glycopyrrolate 0.0006%~1.5%, mometasone furoate 0.005% ~1.5%, magnesium stearate 0.0045%~0.081%, the balance is propellant. Optionally, indacaterol maleate, glycopyrrolate, mometasone furoate are their micronized forms. Optionally, magnesium stearate is in its micronized form.

In one embodiment, the composition contains 36.0 g of indacaterol maleate, 19.5 g of glycopyrrolate, 2.9 g of magnesium stearate per 10,000 g, and the balance is 1,1,1,2-tetra Fluoroethane. Optionally, indacaterol maleate and/or glycopyrrolate and/or magnesium stearate are in their micronized form.

In one embodiment, the composition contains 30.0 g of indacaterol maleate, 16.0 g of glycopyrrolate, 30.0 g of mometasone furoate, 2.0 g of magnesium stearate, and the balance per 10000 g. 1,1,2-Tetrafluoroethane. Optionally, indacaterol maleate and/or glycopyrrolate and/or mometasone furoate and/or magnesium stearate are in their micronized form.

In one embodiment, the composition contains 6.00g indacaterol maleate, 3.00g glycopyrrolate, 12.00g mometasone furoate, 1.05g magnesium stearate, and the balance per 10000g. 1,1,2-Tetrafluoroethane. Optionally, indacaterol maleate and/or glycopyrrolate and/or mometasone furoate and/or magnesium stearate are in their micronized form.

In some embodiments, the composition further comprises other specific excipients, and the other specific excipients are selected from at least one of oleic acid, phospholipids, Tween-80, polyvinylpyrrolidone, and polyethylene glycol.

Further, the weight percentage of the other specific auxiliary materials in the composition is 0.0020% to 5%.

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

Further, the particle size of the micronized each component distribution D ₉₀ ≤20μm, preferably D ₉₀ ≤10μm, even more preferably D ₉₀ ≤5μm.

The present invention also provides a preparation method of the above-mentioned pharmaceutical composition, which comprises the following steps: (1) Mix the active ingredient and magnesium stearate uniformly to obtain a mixture; (2) Add the prescribed amount of propellant to the mixture obtained in step (1), mix evenly to obtain a liquid, and if necessary, add the same amount of propellant lost by volatilization; (3) Fill the liquid medicine obtained in step (2) into the aluminum can, and press the metering valve to get it.

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

In some embodiments, the active ingredient includes indacaterol, indacaterol maleate, or indacaterol acetate; preferably, the active ingredient also includes glycopyrrolate, mometasone furoate, propane At least one of fluticasone acid, budesonide, and beclomethasone dipropionate. In some embodiments, the present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which includes the following steps: (1) Using a jet mill, the active ingredients are first micronized individually or co-micronized, and then mixed with magnesium stearate to obtain a mixture; or the active ingredients and magnesium stearate are mixed together first, and then used The jet mill performs co-micronization to obtain a mixture; (2) Add the prescribed amount of propellant to the mixture obtained in step (1), mix evenly to obtain a liquid, and if necessary, add the same amount of propellant lost by volatilization; (3) Fill the liquid medicine obtained in step (2) into the aluminum can, and press the metering valve to get it.

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

The advantages and beneficial effects of the present invention: The preparation process of the inhalation aerosol pharmaceutical composition containing indacaterol provided by the present invention is simple and controllable, which overcomes the need for the existing indacaterol suspension inhalation aerosol to be combined The auxiliary materials are made into engineered particles, and the preparation process is complicated and the controllability is poor. The preparation of indacaterol aerosol formulations is successfully realized, and this indacaterol aerosol formulation better meets the clinical needs.

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

The corresponding relationship between the English code of the propellant and its chemical name in the present invention is as follows: English code of propellant Chemical name of propellant CFC11 Trichlorofluoromethane CFC12 Dichlorodifluoromethane CFC114 Dichlorotetrafluoroethane HFA-134a 1,1,1,2-Tetrafluoroethane HFA-227 1,1,1,2,3,3,3-Heptafluoropropane

The FPF value of the sample in the present invention is determined by the Next generation impactor (NGI) medicinal impactor produced by Copley Scientific in the United Kingdom.

The above-mentioned inventive content of the present invention will be further described in detail below in conjunction with specific embodiments. However, it should not be understood that the scope of the above-mentioned subject of the present invention is limited to the following embodiments. Without departing from the above-mentioned technical idea of the present invention, various substitutions and changes based on common technical knowledge and conventional means in the field should be included in the scope of the present invention.

Examples 1~5

prescription: Example Unit: g Indacaterol maleate Magnesium stearate Polyvinylpyrrolidone Polyethylene glycol HFA-134a 1 6.00 0.12 0 0 9993.88 2 6.00 0.5 0.5 0 9993.00 3 6.00 0.45 0 0.45 9993.10 4 6.00 0.90 1.0 1.0 9991.10 5 6.00 0 0 0 9994.00

Preparation:

(1) Use a jet mill to pulverize indacaterol maleate raw materials so that the fineness D _{90 of} the raw materials is less than 5 μm.

(2) Weigh the prescription amount of indacaterol maleate and the auxiliary materials magnesium stearate, polyvinylpyrrolidone and polyethylene glycol in each embodiment, and put them into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of the above examples were placed in a 40°C, RH 75% stability sample box, and the FPF value changes after 6 months were investigated. Measurement method: NGI medicinal impactor is used for testing at a flow rate of 15 L/min.

Test results: Example 0 month March June FPF ( % ) 1 51.47 48.77 48.49 2 48.62 47.92 46.21 3 49.33 47.52 46.72 4 48.09 46.47 45.24 5 50.03 44.25 41.98

The results showed that in Example 5 without magnesium stearate, the FPF value of indacaterol maleate decreased significantly during the stability inspection.

Examples 6~8

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Mometasone furoate Magnesium stearate HFA-134a 6 6.00 3.00 0 0.12 9990.88 7 6.00 3.00 6.00 0.45 9984.55 8 6.00 3.00 9.00 0.90 9981.10

Preparation:

(1) Use a jet mill to pulverize the raw materials of indacaterol maleate, glycopyrrolate and mometasone furoate, so that the fineness D _{90 of} each raw material is less than 5μm.

(2) Weigh the prescription amount of indacaterol maleate, glycopyrrolate, mometasone furoate and magnesium stearate, and put them into the mixing tank. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

Examples 9~11

prescription: Example Unit: g Indacaterol Glycopyrrolate Fluticasone propionate Magnesium stearate HFA-134a 9 6.00 3.00 0 0.12 9990.88 10 6.00 3.00 6.00 0.45 9984.55 11 6.00 1.00 11.00 0.90 9981.10

Preparation:

(1) Use a jet mill to pulverize the raw materials of indacaterol maleate, glycopyrrolate and fluticasone propionate, so that the fineness D _{90 of} each raw material is less than 5μm.

(2) Weigh the prescription amount of indacaterol, glycopyrrolate, fluticasone propionate and magnesium stearate, and put them into the mixing tank. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of Examples 6-11 were placed in a 40°C, RH 75% stability retention sample box, and the FPF value changes after 6 months were investigated. Measurement method: NGI medicinal impactor is used for testing at a flow rate of 15 L/min.

Test results: FPF ( % ) Example 0 month June Indacaterol maleate Glycopyrrolate Mometasone furoate Indacaterol maleate Glycopyrrolate Mometasone furoate 6 52.43 36.42 / 50.02 34.48 / 7 49.89 34.87 37.22 46.28 34.08 33.89 8 50.89 34.98 34.59 47.98 33.29 32.01 Example Indacaterol Glycopyrrolate Fluticasone propionate Indacaterol Glycopyrrolate Fluticasone propionate 9 47.86 35.89 / 45.32 34.78 / 10 49.86 36.12 44.78 45.31 34.98 38.04 11 51.11 37.02 44.98 47.98 35.22 39.54

The results showed that: in the stability investigation of Examples 6 to 11, after 6 months of storage, the FPF value of each active ingredient decreased slightly, and the FPF value was stable.

Examples 12~21

prescription: Example Unit: g Indacaterol maleate Magnesium stearate HFA-134a CFC-12 HFA-227 12 0.12 — 9999.88 — — 13 2.00 — 9998.00 — — 14 20.00 1.00 9979.00 — — 15 200.00 10.00 9,790.00 — — 16 300.00 15.00 9685.00 — — 17 0.12 — — — 9999.88 18 2.00 0.10 — 9,997.90 — 19 20.00 1.00 — — 9980.00 20 200.00 10.00 — 9,790.00 — twenty one 300.00 15.00 — — 9700.00

Preparation:

(1) Use a jet mill to pulverize indacaterol maleate raw materials so that the fineness D _{90 of} the raw materials is less than 5 μm.

(2) Weigh the prescription amount of indacaterol maleate raw material and magnesium stearate as the auxiliary material, and put them into the mixing tank. Add HFA-134a, CFC-12, and HFA-227 in the prescribed amount according to the above-mentioned examples. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

Using an NGI pharmaceutical impactor, the FPF values of the samples of Example 12, Example 13, Example 15, and Example 20 were measured at a flow rate of 15 L/min. At the same time, the sample of the preferred embodiment was placed in a 40°C, RH 75% stability sample box, and the FPF value change after 3 months was investigated.

Test results: Example 0 month March June FPF ( % ) 12 50.47 43.77 41.17 13 45.69 40.92 39.31 15 49.59 48.52 46.62 20 47.47 47.19 45.30

The test results showed that when the prescription did not contain magnesium stearate, the FPF value of indacaterol maleate decreased significantly when the sample was subjected to the accelerated stability test. However, when the prescription contained magnesium stearate, the test was accelerated at 6 months. The FPF value of indacaterol lysate remained basically stable.

Examples 22~33

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate HFA-134a twenty two 6.00 3.00 - 9991.00 twenty three 6.00 3.00 0.45 9990.55 twenty four 7.00 3.50 0.53 9,988.97 25 8.00 4.00 0.60 9,987.40 26 9.00 4.50 0.68 9985.82 27 6.00 0.50 0.33 9993.17 28 6.00 1.00 0.35 9992.65 29 6.00 2.00 0.40 9991.60 30 6.00 4.00 0.50 9,989.50 31 6.00 5.00 0.55 9,988.45 32 6.00 8.00 0.70 9985.30 33 6.00 12.00 0.90 9981.10

Preparation:

(1) Use a jet mill to separately pulverize indacaterol maleate and glycopyrrolate raw materials to make the fineness D _{90 of} each raw material less than 5μm.

(2) Weigh the prescription amount of indacaterol maleate and glycopyrrolate raw materials and the auxiliary material magnesium stearate, and put them into the mixing tank. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol maleate Glycopyrrolate twenty two 45.21 29.13 twenty three 48.25 34.98 twenty four 49.32 34.25 25 47.52 35.21 26 48.69 36.41 27 47.23 36.22 28 49.15 35.45 29 48.09 34.09 30 50.01 35.09 31 48.32 34.79 32 47.98 36.42 33 48.97 34.17

The test results showed that when glycopyrrolate was introduced into the binary system of indacaterol maleate and magnesium stearate, the FPF value of indacaterol maleate did not change significantly. At the same time, we were surprised to find that it contains In the magnesium stearate system, glycopyrrolate has a higher FPF value.

Examples 34~45

prescription: Example Unit: g Indacaterol Glycopyrrolate Magnesium stearate Oleic acid Phospholipids Absolute ethanol Tween 80 Polyethylene glycol Polyvinylpyrrolidone HFA-134a 34 6.00 3.00 0.45 — — — 2.20 — — 9,988.35 35 6.00 3.00 0.45 — — — 0.44 — — 9,999.11 36 6.00 3.00 0.45 — — — — 20.0 — 9,970.55 37 6.00 3.00 0.45 — — — — 4.00 — 9986.55 38 6.00 3.00 0.45 — — — — — 1.00 9989.55 39 6.00 3.00 0.45 — — — — — 0.20 9990.35 40 6.00 3.00 0.45 100.0 — — — — — 9,989.55 41 6.00 3.00 0.45 20.0 — — — — — 9,970.55 42 6.00 3.00 0.45 — 100.0 — — — — 9,989.55 43 6.00 3.00 0.45 — 20.0 — — — — 9,970.55 44 6.00 3.00 0.45 — — 500.0 — — — 9490.55 45 6.00 3.00 0.45 — — 100.0 — — — 9,989.55

Preparation:

(1) Use a jet mill to pulverize indacaterol and glycopyrrolate raw materials by jet pulverization, so that the fineness D _{90 of} each raw material is less than 5 μm.

(2) Weigh the prescription amount of indacaterol and glycopyrrolate raw materials and the auxiliary material magnesium stearate, and put them into the mixing tank. Add oleic acid, phospholipids, absolute ethanol, Tween 80, polyethylene glycol, polyvinylpyrrolidone, and HFA-134a in the prescribed amount according to the above-mentioned examples. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF values of the samples of Examples 34 to 45 were measured at a flow rate of 15 L/min using an NGI pharmaceutical impactor.

Test results: Example FPF ( % ) Indacaterol Glycopyrrolate 34 50.31 37.21 35 49.02 36.25 36 48.98 35.22 37 50.14 34.87 38 48.21 36.01 39 48.94 35.42 40 51.21 38.03 41 50.07 36.97 42 49.45 36.14 43 48.32 37.28 44 55.48 36.78 45 52.13 35.42

The test results show that the FPF value of the prepared sample is not affected by adding other auxiliary materials to the ternary system containing indacaterol, glycopyrrolate and magnesium stearate.

The samples of each of the above examples were placed in a 40°C, RH 75% stability sample box, and the changes in the impurities of each product after 6 months were investigated.

HPLC content of impurities (%) test results: Example 34 Example 35 Example 36 Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.131 0.065 0.139 not detected 0.161 0.075 0.159 not detected 0.122 0.059 0.129 March not detected 0.154 0.095 0.198 not detected 0.172 0.082 0.169 not detected 0.149 0.077 0.185 June 0.023 0.179 0.121 0.224 not detected 0.188 0.098 0.189 not detected 0.187 0.103 0.203 Example 37 Example 38 Example 39 Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.136 0.055 0.128 not detected 0.149 0.075 0.152 not detected 0.121 0.057 0.149 March not detected 0.149 0.075 0.148 not detected 0.163 0.098 0.189 not detected 0.149 0.098 0.187 June not detected 0.198 0.099 0.223 0.019 0.198 0.121 0.232 not detected 0.182 0.124 0.221 Example 40 Example 41 Example 42 Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.122 0.087 0.169 not detected 0.181 0.055 0.157 not detected 0.119 0.071 0.162 March not detected 0.189 0.121 0.203 not detected 0.232 0.099 0.198 0.023 0.159 0.112 0.192 June not detected 0.225 0.204 0.241 not detected 0.268 0.176 0.231 0.034 0.201 0.189 0.231 Example 43 Example 44 Example 45 Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.140 0.082 0.159 0.087 0.161 0.085 0.177 0.051 0.151 0.105 0.189 March not detected 0.179 0.114 0.200 0.142 0.221 0.142 0.219 0.102 0.201 0.169 0.229 June 0.029 0.198 0.169 0.242 0.202 0.249 0.221 0.289 0.198 0.236 0.203 0.298

The test results show that in the ternary system containing indacaterol, glycopyrrolate and magnesium stearate, the excipients phospholipid, oleic acid, polyethylene glycol, polyvinylpyrrolidone, and Tween 80 have a greater impact on the chemical stability of the product. small.

The structural formulas of glycopyrrolate impurity I and impurity J in the above table are:

Examples 46~50 Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate HFA-134a 46 6.00 3.00 0.05 9990.95 47 6.00 3.00 0.27 9990.73 48 6.00 3.00 0.63 9990.37 49 6.00 3.00 0.81 9990.19 50 6.00 3.00 1.08 9989.92

Preparation:

(1) Use a jet mill to separately pulverize indacaterol maleate and glycopyrrolate raw materials to make the fineness D _{90 of} each raw material less than 5μm.

(2) Weigh the prescription amount of indacaterol maleate and glycopyrrolate raw materials and the auxiliary material magnesium stearate, and put them into the mixing tank. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol maleate Glycopyrrolate 46 47.36 31.78 47 48.98 34.78 48 48.67 36.46 49 48.21 36.98 50 50.33 38.27

The test results showed that in the ternary system products containing indacaterol maleate, glycopyrrolate and magnesium stearate, we found that the FPF value of indacaterol maleate increased with the increase in the amount of magnesium stearate. Both can maintain a high level, while the FPF value of glycopyrrolate has been significantly improved.

Examples 51~63

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Mometasone furoate Magnesium stearate HFA-134a 51 6.00 3.00 0.50 0.48 9990.02 52 6.00 3.00 1.00 0.50 9,989.50 53 6.00 3.00 3.00 0.60 9,987.40 54 6.00 3.00 6.00 0.75 9,984.25 55 6.00 3.00 9.00 0.90 9981.10 56 6.00 3.00 12.00 1.05 9,977.95 57 6.00 3.00 6.00 0.30 9,984.70 58 6.00 3.00 6.00 1.20 9983.80 59 6.00 3.00 6.00 1.50 9983.50 60 6.00 150.00 6.00 16.20 9821.80 61 6.00 0.06 6.00 0.60 9987.34 62 6.00 3.00 150.00 7.95 9833.05 63 6.00 3.00 0.06 0.45 9990.49

Preparation:

(1) Use a jet mill to pulverize indacaterol maleate, glycopyrrolate, mometasone furoate raw materials and magnesium stearate respectively, so that the fineness D _{90 of} each raw material and excipients is less than 5μm.

(2) Weigh the prescription amount of indacaterol maleate, glycopyrrolate, mometasone furoate raw materials and magnesium stearate, and put them into the mixing tank. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol maleate Glycopyrrolate Mometasone furoate 51 49.58 35.66 34.25 52 48.23 34.39 33.79 53 48.79 37.39 33.98 54 50.23 35.47 33.24 55 48.45 36.39 35.41 56 47.39 34.29 34.39 57 49.07 37.82 33.34 58 49.38 36.43 35.09 59 52.17 35.97 34.28 60 50.79 32.79 33.79 61 47.69 38.45 36.48 62 48.49 36.46 32.48 63 52.31 39.47 38.17

The test results show that in the system of indacaterol maleate, glycopyrrolate and magnesium stearate, the quaternary system product formed by adding mometasone furoate has a higher FPF value for each API, and The differences between the examples are small.

Examples 64~67

prescription: Example Unit: g Indacaterol Glycopyrrolate Fluticasone propionate Magnesium stearate HFA-134a 64 6.00 3.00 3.00 0.12 9,987.88 65 6.00 3.00 6.00 0.45 9984.55 66 6.00 3.00 9.00 0.90 9981.10 67 6.00 3.00 12.00 1.47 9,977.53

Preparation:

(1) Use a jet mill to pulverize indacaterol, glycopyrrolate, and fluticasone propionate raw materials by jet pulverization, so that the fineness D _{90 of} each raw material is less than 5 μm.

(2) Weigh the prescription amount of indacaterol, glycopyrrolate, fluticasone propionate and magnesium stearate, and put them into the mixing tank. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol Glycopyrrolate Fluticasone propionate 64 47.64 33.79 36.72 65 49.23 34.28 36.03 66 50.11 34.98 36.29 67 48.79 35.33 34.98

The test results show that in the quaternary system products composed of indacaterol, glycopyrrolate, fluticasone propionate and magnesium stearate, the FPF value of each bulk drug is higher, and the difference between the examples is small.

Examples 68~70

prescription: Example Unit: g Indacaterol acetate Glycopyrrolate Fluticasone propionate Magnesium stearate HFA-134a 68 6.00 3.00 0 0.12 9990.88 69 6.00 3.00 6.00 0.45 9984.55 70 6.00 3.00 9.00 0.90 9981.10

Preparation:

(1) Airflow pulverization of indacaterol acetate, glycopyrrolate, fluticasone propionate and magnesium stearate with a jet mill, respectively, so that the fineness D _{90 of} each bulk drug and excipient is less than 5 μm.

(2) Weigh the micronized prescription amount of indacaterol acetate, glycopyrrolate, fluticasone propionate raw materials and micronized auxiliary material magnesium stearate, and put them into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol acetate Glycopyrrolate Fluticasone propionate 68 47.63 35.21 36.12 69 49.22 36.77 34.57 70 48.26 33.98 34.89

The test results show that in the quaternary system products composed of indacaterol acetate, glycopyrrolate, fluticasone propionate and magnesium stearate, the FPF value of each bulk drug is higher, and the difference between the examples is small.

Examples 71~74

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate CFC11 CFC12 CFC114 HFA-227 71 6.00 3.00 0.2 9990.8 - - - 72 6.00 3.00 0.45 - 9990.55 - - 73 6.00 3.00 0.90 - - 9990.10 74 6.00 3.00 0.90 - - - 9990.10

Preparation:

(1) Place indacaterol maleate, glycopyrronium bromide crude drug and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then perform jet pulverization to make the pulverized mixture fine. _{90 is} less than 5μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and put it into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol maleate Glycopyrrolate 71 47.98 42.21 72 45.69 43.62 73 46.99 44.32 74 49.22 46.94

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 by the propellants are close.

Examples 75~78

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate HFA-134a 75 twenty four 12 0.45 9,963.55 76 twenty four 12 0.9 9963.10 77 twenty four 12 0.45 9,963.55 78 twenty four 12 0.9 9963.10

Preparation:

(1) In Examples 75 and 76, the raw materials of indacaterol maleate and glycopyrrolate were respectively subjected to jet pulverization, so that the fineness D ₉₀ of each raw material after pulverization was less than 5 μm. In Examples 77 and 78, indacaterol maleate, glycopyrrolate raw material and magnesium stearate were placed in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then the mixture was jet-pulverized to make the pulverized mixture The fineness D _{90 is} less than 5 μm.

(2) In Examples 75 and 76, the micronized prescription amount of the crude drug and magnesium stearate were weighed, and in Examples 77 and 78, the micronized prescription amount of the raw and auxiliary material mixture was weighed and put into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured using an NGI pharmaceutical impactor at a flow rate of 15 L/min.

Test results: Example FPF ( % ) Indacaterol maleate Glycopyrrolate 75 48.30 41.96 76 49.22 40.54 77 50.37 47.98 78 53.25 49.11

The test results show that after glycopyrrolate and indacaterol and magnesium stearate are pulverized together, the FPF value of glycopyrrolate is higher than that of the samples prepared after the raw materials are separately pulverized.

Examples 79~85

prescription: Example Unit: g Indacaterol maleate Magnesium stearate HFA-134a 79 6.00 0.1 9993.90 80 6.00 0.3 9993.70 81 6.00 0.5 9993.50 82 6.00 0.7 9993.30 83 3.00 0.1 9,996.90 84 3.00 0.15 9996.85 85 3.00 0.3 9996.70

(1) After placing indacaterol maleate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, the mixture is subjected to jet pulverization so that the fineness D _{90 of the} pulverized mixture is less than 5 μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and put it into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of each of the above examples were placed in a 40°C, RH 75% stability retention sample box, and the FPF value changes of each product after 6 months were investigated.

Test results: FPF ( % ) Example 0 month March June 79 50.42 49.48 50.11 80 49.47 48.48 48.99 81 53.17 52.18 51.28 82 52.09 51.29 51.57 83 49.12 49.02 48.73 84 52.47 52.17 52.02 85 48.33 48.98 48.28

The test results show that the product prepared by co-micronization of the raw material drug and magnesium stearate, placed under accelerated conditions, has little change in FPF value and good physical stability of the product.

Examples 86~90

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate HFA-134a 86 3.5 3.50 0.35 9992.65 87 3.5 1.75 0.26 9994.49 88 3.5 0.88 0.22 9995.40 89 3.5 1.75 0.13 9994.62 90 3.5 1.75 0.53 9994.22

(1) Place indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then pulverize the mixture by jet to make the fineness D _{90 of the} pulverized mixture less than 5μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and put it into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of each of the above examples were placed in a 40°C, RH 75% stability retention sample box, and the FPF value changes of each product after 6 months were investigated.

Test results: FPF ( % ) Example 0 month March June Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate 86 47.98 43.25 47.64 43.07 47.29 42.89 87 52.33 45.79 52.02 45.24 51.87 45.10 88 50.08 46.79 49.23 46.17 49.86 45.68 89 48.21 43.78 48.07 43.98 47.64 43.32 90 49.07 45.98 49.11 45.09 48.52 44.78

The test results show that after micronizing the mixture of indacaterol maleate, glycopyrrolate and magnesium stearate, the prepared sample is placed under accelerated conditions for 6 months, and the FPF value does not change significantly. Maleic acid Indacaterol and glycopyrrolate have good physical stability. At the same time, it was also found that after glycopyrrolate and indacaterol and magnesium stearate were pulverized together, the FPF value of glycopyrrolate was higher than that of the samples prepared after the raw materials were separately pulverized.

Examples 91~94

prescription: Example Unit: g Indacaterol acetate Indacaterol Glycopyrrolate Magnesium stearate HFA-134a 91 3.0 - 1.75 0.24 9992.65 92 3.0 - 1.50 0.24 9994.49 93 - 2.8 1.75 0.24 9995.40 94 - 2.8 1.40 0.24 9994.62

(1) Place indacaterol acetate or indacaterol, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then pulverize the mixture by jet to make the pulverized mixture fine D _{90 is} less than 5 μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and put it into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of each of the above examples were placed in a 40°C, RH 75% stability retention sample box, and the FPF value changes of each product after 6 months were investigated.

Test results: FPF ( % ) Example 0 month March June Indacaterol acetate Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate 91 54.72 46.79 52.17 47.32 53.89 46.77 92 50.39 45.98 50.86 46.98 49.78 46.02 Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate Indacaterol Glycopyrrolate 93 50.79 49.22 51.08 48.78 50.69 48.88 94 49.98 47.64 49.23 49.23 49.88 48.29

The test results show that the product obtained by mixing indacaterol acetate or indacaterol with glycopyrrolate and magnesium stearate together has no significant change in FPF value and good physical stability. .

Examples 95~103

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate HFA-134a 95 12 6.7 0.94 9980.37 96 twenty four 13.0 1.85 9,961.15 97 36 19.5 2.90 9941.60 98 48 26.7 3.74 9921.57 99 60 33.3 4.67 9902.04 100 72 40 5.60 9,882.40 101 36 20.0 1.40 9942.60 102 36 20.0 5.60 9938.40 103 36 20.0 8.40 9935.60

(1) Place indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then pulverize the mixture by jet to make the fineness D _{90 of the} pulverized mixture less than 5μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and put it into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of each of the above examples were placed in a 40°C, RH 75% stability retention sample box, and the FPF value changes of each product after 6 months were investigated.

FPF (%) test results: Example 0 month March June Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate 95 49.65 46.78 51.23 47.12 50.47 46.89 96 52.33 48.25 51.22 47.48 50.79 46.79 97 51.09 46.46 50.19 46.03 50.61 46.13 98 49.81 44.32 50.14 45.31 50.01 45.01 99 47.96 46.11 47.69 46.64 48.01 46.98 100 54.23 45.44 53.41 45.17 52.14 46.02 101 51.09 45.73 50.49 44.98 50.17 46.91 102 50.44 46.17 50.19 45.47 49.69 46.02 103 51.19 48.03 51.02 47.65 49.89 47.07

The test results showed that: increasing the proportion of the raw materials and magnesium stearate in the prescription, leaving for 6 months under accelerated conditions, the FPF value of the sample did not change significantly, and the physical stability of the product was good.

Examples 104~115

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate Fluticasone propionate Mometasone furoate Budesonide Beclomethasone dipropionate HFA-134a 104 30 10 2.0 10 - - - 9948.00 105 30 20 2.5 15 - - - 9,932.50 106 30 30 3.0 20 - - - 9917.00 107 30 10 2.0 - 10 - - 9948.00 108 30 16 2.0 - 30 - - 9922.00 109 30 30 3.0 - 20 - - 9917.00 110 30 10 2.0 - - 10 - 9948.00 111 30 20 2.5 - - 15 - 9,932.50 112 30 30 3.0 - - 20 - 9917.00 113 30 10 2.0 - - - 10 9948.00 114 30 20 2.5 - - - 15 9,932.50 115 30 30 3.0 - - - 20 9917.00

(1) Place indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then pulverize the mixture by jet to make the fineness D _{90 of the} pulverized mixture less than 5μm; each glucocorticoid raw material drug is also separately air-pulverized to make its fineness D ₉₀ less than 5μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and the corresponding prescription amount of micronized glucocorticoid raw material medicine, and put them into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of each of the above examples were placed in a 40°C, RH 75% stability retention sample box, and the FPF value changes of each product after 6 months were investigated.

FPF(%) test result: Example 0 month March June Indacaterol maleate Glycopyrrolate Fluticasone propionate Indacaterol maleate Glycopyrrolate Fluticasone propionate Indacaterol maleate Glycopyrrolate Fluticasone propionate 104 51.07 46.07 39.41 51.23 46.29 40.09 49.98 47.12 40.11 105 52.27 45.47 38.44 50.39 45.96 38.12 51.61 45.56 38.64 106 48.98 44.49 39.69 49.69 44.98 38.96 49.65 45.19 38.23 Indacaterol maleate Glycopyrrolate Mometasone furoate Indacaterol maleate Glycopyrrolate Mometasone furoate Indacaterol maleate Glycopyrrolate Mometasone furoate 107 49.96 48.47 36.47 51.02 46.03 37.36 50.49 48.13 37.64 108 48.19 45.96 36.01 49.69 46.47 36.79 50.12 46.23 36.54 109 50.39 44.46 34.98 49.39 45.48 35.48 48.81 46.21 34.74 Indacaterol maleate Glycopyrrolate Budesonide Indacaterol maleate Glycopyrrolate Budesonide Indacaterol maleate Glycopyrrolate Budesonide 110 52.33 45.47 40.69 51.39 46.32 41.09 50.47 45.02 40.65 111 50.34 45.96 41.17 50.66 46.09 41.25 51.36 45.49 41.02 112 48.69 47.07 42.09 48.56 47.01 40.25 49.05 47.41 40.69 Indacaterol maleate Glycopyrrolate Beclomethasone dipropionate Indacaterol maleate Glycopyrrolate Beclomethasone dipropionate Indacaterol maleate Glycopyrrolate Beclomethasone dipropionate 113 47.69 44.99 41.39 48.01 44.69 40.69 49.21 45.21 40.12 114 49.69 45.98 42.98 50.36 45.59 41.73 50.21 45.69 41.00 115 50.44 46.47 44.14 49.49 46.93 44.01 50.05 46.48 43.15

The test results show that after indacaterol maleate, glycopyrrolate and magnesium stearate are co-micronized, another glucocorticoid raw material is added to prepare the product, and the product is placed under accelerated conditions for 6 months. The FPF value of the active ingredient does not change significantly, and the physical stability is good.

Examples 116~121

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate Fluticasone propionate Budesonide Beclomethasone dipropionate HFA-134a 116 20 10 2.5 0.06 - - 9,967.44 117 20 10 2.5 150 - - 9817.50 118 20 10 2.5 - 0.06 - 9,967.44 119 20 10 2.5 - 150 - 9817.50 120 20 10 2.5 - - 0.06 9,967.44 121 20 20 2.5 - - 150 9817.50

(1) Place indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then pulverize the mixture by jet to make the fineness D _{90 of the} pulverized mixture less than 5μm; each glucocorticoid raw material drug is also separately air-pulverized to make its fineness D ₉₀ less than 5μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture, and the corresponding prescription amount of micronized glucocorticoid raw material medicine, and put them into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The FPF value of each example sample was measured at a flow rate of 15 L/min using an NGI pharmaceutical impactor.

FPF(%) test result: Example Indacaterol maleate Glycopyrrolate Fluticasone propionate 116 50.42 47.99 48.59 117 50.89 48.37 44.62 Indacaterol maleate Glycopyrrolate Budesonide 118 49.12 48.28 46.52 119 51.34 49.49 44.08 Indacaterol maleate Glycopyrrolate Beclomethasone dipropionate 120 52.01 48.98 47.09 121 50.39 47.49 44.54

The test results show that the glucocorticoid raw materials of different prescriptions have no significant effect on the FPF value of indacaterol maleate and glycopyrrolate. Indacaterol maleate, glycopyrrolate and stearin are used. The three compound aerosols prepared after co-micronization of magnesium acid, indacaterol maleate and glycopyrrolate have higher FPF values.

Examples 122~133

prescription: Example Unit: g Indacaterol maleate Glycopyrrolate Magnesium stearate Polyvinylpyrrolidone Tween 80 Oleic acid Polyethylene glycol HFA-134a 122 35 20 2.75 0.5 - - - 9,941.75 123 36 19.5 2.90 1.0 - - - 9,940.60 124 35 20 2.75 1.5 - - - 9940.75 125 35 20 2.75 - 0.5 - - 9,941.75 126 36 19.5 2.90 - 1.0 - - 9,940.60 127 35 20 2.75 - 1.5 - - 9940.75 128 35 20 2.75 - - 0.25 - 9942.00 129 36 19.5 2.90 - - 0.51 - 9,941.09 130 35 20 2.75 - - 1.0 - 9941.25 131 35 20 2.75 - - - 0.5 9,941.75 132 35 20 2.75 - - - 1.0 9941.25 133 35 20 2.75 - - - 1.5 9940.75

(1) Place indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, then pulverize the mixture by jet to make the fineness D _{90 of the} pulverized mixture less than 5μm.

(2) Weigh the micronized prescription amount of raw and auxiliary material mixture and the corresponding prescription amount of auxiliary materials, and put them into the mixing barrel. Add HFA-134a in the prescribed amount according to the above example. Turn on the mixing tank (mixing speed 30rpm), the mixing time is 30 minutes. If the liquid medicine is volatile, use a propellant to replenish the liquid medicine to its original weight before filling. Start filling, fill the mixed liquid into the aluminum can with Pamasol Suspension filler, press the metering valve, and it is ready.

The samples of the above examples were placed in a 40°C, RH 75% stability retention sample box, and the FPF value and impurity changes of each product after 6 months were investigated.

Test results: FPF ( % ) Example 0 month March June Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate 122 58.21 52.02 62.15 53.12 60.65 52.69 123 60.89 56.80 59.77 55.55 59.27 56.09 124 58.44 51.69 58.14 51.78 58.39 51.96 125 56.86 54.38 57.07 54.02 56.89 53.98 126 53.68 54.78 54.33 54.02 53.98 54.12 127 58.01 51.32 57.64 50.96 57.23 51.98 128 54.81 46.55 56.96 46.25 55.42 46.78 129 56.44 49.04 53.96 50.02 54.69 49.14 130 52.73 48.17 50.02 48.69 49.89 48.26 131 48.62 45.72 49.67 46.04 50.12 45.98 132 48.56 44.86 50.94 44.69 50.49 45.69 133 50.29 46.11 48.28 45.89 49.02 45.48

The test results show that when the prescription contains one of polyvinylpyrrolidone, Tween 80, and oleic acid, the FPF values of indacaterol maleate and glycopyrrolate have a certain increase. All the products of the examples were placed under accelerated conditions for 6 months, and the FPF value did not change significantly.

HPLC content of impurities (%) inspection results: Example 122 Example 123 Example 124 Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.052 0.052 0.121 not detected 0.057 0.069 0.141 not detected 0.032 0.060 0.111 March not detected 0.047 0.071 0.146 not detected 0.052 0.082 0.176 not detected 0.057 0.067 0.139 June not detected 0.067 0.119 0.171 not detected 0.059 0.132 0.189 not detected 0.052 0.098 0.164 Example 125 Example 126 Example 127 Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.025 0.047 0.109 not detected 0.054 0.065 0.145 not detected 0.032 0.054 0.129 March not detected 0.039 0.068 0.138 not detected 0.062 0.089 0.185 not detected 0.048 0.072 0.164 June not detected 0.044 0.089 0.162 not detected 0.059 0.104 0.192 not detected 0.059 0.063 0.179 Example 128 Example 129 Example 130 Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.045 0.032 0.129 not detected 0.042 0.051 0.132 not detected 0.029 0.052 0.150 March not detected 0.039 0.051 0.151 not detected 0.044 0.058 0.165 not detected 0.043 0.086 0.172 June not detected 0.050 0.059 0.190 not detected 0.062 0.063 0.184 not detected 0.049 0.092 0.194 Example 131 Example 132 Example 133 Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Glycopyrrolate Indacaterol maleate Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities Impurity I Impurity J Unknown total miscellaneous Total impurities 0 month not detected 0.045 0.032 0.169 not detected 0.039 0.052 0.149 not detected 0.049 0.032 0.139 March not detected 0.043 0.056 0.182 not detected 0.049 0.076 0.152 not detected 0.063 0.046 0.147 June not detected 0.067 0.072 0.209 not detected 0.042 0.091 0.187 not detected 0.069 0.068 0.184

The test results show that the impurities in the products of Examples 122 to 133 are stored for 6 months under accelerated conditions, and the product has good chemical stability.

without

without

without

Claims (15)

An aerosol pharmaceutical composition for inhalation, which is characterized in that it comprises micronized indacaterol or a pharmaceutically acceptable salt thereof, magnesium stearate and a propellant, optionally, the magnesium stearate is a micronized powder化form. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of micronized indacaterol is micronized indacaterol maleate or micronized indacaterol acetate, and The propellant is selected from trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- At least one of heptafluoropropane. The pharmaceutical composition according to claim 1 or 2, wherein the weight percentage of each component in the composition is: micronized indacaterol or its pharmaceutically acceptable salt 0.0012%~3 %, magnesium stearate is 0.0005%~0.162%, the balance is propellant. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition further comprises micronized glycopyrrolate, micronized mometasone furoate, micronized fluticasone propionate, and micronized At least one of budesonide and micronized beclomethasone propionate, each of which has a weight percentage of 0.0006% to 1.5% in the composition. The pharmaceutical composition according to claim 4, wherein the weight percentage of each component in the composition is: micronized indacaterol maleate 0.06% to 1.2%, and micronized glycopyrrolate Ammonium 0.0006%~1.5%, micronized mometasone furoate 0.005%~1.5%, magnesium stearate 0.0045%~0.081%, the balance is propellant. The pharmaceutical composition according to claim 4, wherein the composition contains 36.0 g of micronized indacaterol maleate, 19.5 g of micronized glycopyrrolate, and 2.9 g of magnesium stearate per 10,000 g. , The balance is 1,1,1,2-tetrafluoroethane. The pharmaceutical composition according to claim 4, characterized in that, per 10,000 g, the composition contains: 6.00 g of micronized indacaterol maleate, 3.00 g of micronized glycopyrrolate, and micronized mometasone furoate 12.00g, 1.05g magnesium stearate, the balance is 1,1,1,2-tetrafluoroethane. The pharmaceutical composition according to claim 4, wherein, per 10,000 g, the composition contains: 30.0 g of micronized indacaterol maleate, 16.0 g of micronized glycopyrrolate, and micronized mometasone furoate 30.0g, 2.0g magnesium stearate, the balance is 1,1,1,2-tetrafluoroethane. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition further comprises other specific excipients, and the other specific excipients are selected from oleic acid, phospholipids, Tween-80, poly At least one of vinylpyrrolidone and polyethylene glycol. The pharmaceutical composition according to claim 9, wherein the weight percentage of the other specific excipients in the composition is 0.0020% to 5%. The pharmaceutical composition according to claim 6, wherein the composition further comprises 1.0 g of polyvinylpyrrolidone-K25 or Tween-80, or 0.51 g of oleic acid per 10000 g. The requested item 1 to 11 according to any one of the pharmaceutical composition, wherein the particle size of each micronized component distribution of the D ₉₀ ≤20μm, preferably D ₉₀ ≤10μm, even more preferably D ₉₀ ≤ 5μm. The preparation method of the pharmaceutical composition according to any one of claims 1 to 12, characterized in that it comprises the following steps: (1) Using a jet mill, the active ingredients are first micronized individually or co-micronized, and then mixed with magnesium stearate to obtain a mixture; or the active ingredients and magnesium stearate are mixed together first, and then used The jet mill performs co-micronization to obtain a mixture; (2) Add the prescribed amount of propellant to the mixture obtained in step (1), mix evenly to obtain a liquid, and if necessary, add the same amount of propellant lost by volatilization; (3) Fill the liquid medicine obtained in step (2) into the aluminum can, and press the metering valve to get it. The preparation method according to claim 13, characterized in that at least one of oleic acid, phospholipids, Tween-80, polyvinylpyrrolidone and polyethylene glycol is further added in the step (2). The preparation method according to claim 13 or 14, characterized in that the active ingredient comprises indacaterol, indacaterol maleate or indacaterol acetate; preferably, the active ingredient also comprises indacaterol At least one of pyrrolone bromide, mometasone furoate, fluticasone propionate, budesonide, and beclomethasone propionate.