Unit dose pharmaceutical composition as well as preparation method and application thereof

Abstract

The present invention relates to a pharmaceutical composition of an inhalation solution comprising unit dose of indacenroguron bromide, a method for preparing the same, and a use thereof. The unit dose composition is prepared by dissolving a specific amount of active ingredients, an osmotic pressure regulator, a buffer ion pair, a pH regulator and other auxiliary material components in water, the active substances form aerosol by means of an atomizer, the aerosol is applied to asthma and COPD patients in an inhalation mode, and the unit dose composition has the advantages of being high in effectiveness, good in safety, good in patient compliance and the like.

Description

Technical Field

[0001] The invention relates to an inhalation solution pharmaceutical composition, in particular to an inhalation solution pharmaceutical composition containing indacaterol and glycopyrrolate in a unit dose, a preparation method and application thereof, and belongs to the field of pharmaceutical preparations. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a chronic airway disease characterized by persistent airflow limitation, which is progressive and can induce chronic respiratory failure in severe cases. There are currently about 28 million COPD patients worldwide. COPD patients have obvious clinical symptoms, their airways are obstructed to a certain extent, their condition worsens, they develop lung dysfunction, and have difficulty breathing; the disease recurs and may even threaten the patient's life and health.

[0003] At present, the commonly used nebulized bronchodilator inhalation solutions in clinical practice are all short-acting bronchodilators, mainly including salbutamol, terbutaline, ipratropium bromide and compound ipratropium bromide salbutamol inhalation solution (drug information is shown in the table below). The duration of action is mostly 3 to 6 hours. They are mostly used in the treatment of acute exacerbation of COPD or acute asthma attack in hospitalized or emergency patients. Among them, ipratropium bromide solution for inhalation and compound ipratropium bromide solution can be used for long-term maintenance treatment of COPD, which requires nebulization inhalation 3 to 4 times a day, with a high frequency of medication and extremely inconvenient use.

[0004]

[0005] SABA: short-acting beta2-adrenergic receptor agonist;

[0006] SAMA: short-acting muscarinic receptor antagonist

[0007] A total of four bronchodilator (LAMA or LABA) inhalation solutions for the maintenance treatment of COPD have been marketed internationally (see the table below for relevant information), but no long-acting bronchodilator β2-receptor agonist (LABA) or compound long-acting (at least once a day) inhalation preparations containing the long-acting bronchodilator β2-receptor agonist (LABA) have been marketed.

[0008]

[0009] LABA: long-acting β2-adrenergic receptor agonist;

[0010] LAMA: long-acting muscarinic receptor antagonist

[0011] The first LAMA / LABA compound inhalation preparation approved in China for maintenance treatment of COPD in adults is indacaterol glycopyrronium bromide inhalation powder, with the trade name "Jie Run / Ultibro". It was developed by Novartis Pharmaceuticals and first approved in the EU and Japan in September 2013. It was subsequently launched in more than 30 countries including Canada and Australia, and was approved in China on December 28, 2017. The product consists of LABA indacaterol maleate and LAMA glycopyrronium bromide. It directly relaxes smooth muscle and inhibits the action of acetylcholine, which indirectly causes smooth muscle relaxation and produces an additive effect of bronchial dilation. It is used to treat COPD in adults. The results of relevant clinical studies show that indacaterol glycopyrronium bromide inhalation powder is significantly better than salmeticasone inhalation powder (Seretide) in improving the lung function of COPD patients, and has good safety and effectiveness. However, Ultibro is an inhalation powder inhaler (DPI), which mainly relies on the internal resistance of the device and the turbulence generated by the patient's active inhalation to deagglomerate the drug powder into fine drug particles and inhale them into the body. Since the inhalation device resistance of the inhalation powder inhaler is large, it will reduce the user's inspiratory flow rate. Therefore, when using it, the patient needs to inhale quickly and forcefully, and the optimal inspiratory flow rate must be achieved and last for 2 to 3 seconds. The inhalation device of indacaterol gronium bromide inhalation powder inhaler (Ultibro) is Breezhaler, and the minimum and optimal inspiratory flow rates required are 50L / min. For some COPD patients with severe lung function impairment, their inhalation ability often cannot reach the optimal inspiratory flow rate required for inhalation powder inhalers, so they cannot be effectively delivered to the lungs or the inhaled dose is insufficient or the inhaled dose is not constant enough each time, which affects the efficacy, resulting in poor symptom control and increased acute exacerbation (Chinese expert consensus on the standardized application of inhalation devices for stable chronic airway diseases [J]. Chinese Journal of Tuberculosis and Respiratory Diseases, 2019, 42(4): 241.).In addition, the inhalation technique of dry powder inhalers includes device preparation before inhalation, exhalation before inhalation, inhalation speed and method, and breath holding after inhalation. The operation is relatively complicated. Literature reports that the error rate of patients using dry powder inhalers is 4% to 94%. Common usage errors are: (1) not exhaling before drug inhalation; (2) not holding the breath after drug inhalation; (3) improper positioning of the device; (4) incorrect loading of the drug; (5) not inhaling deeply and forcefully, etc. ("Inhalation device: an important link in the management of chronic obstructive pulmonary disease", Liu Jinming, Chinese Journal of Tuberculosis and Respiratory Diseases, 2019, 42(002): 122-124; "Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD", Lavorini F, Magnan A, Dubus JC, et al., Respiratory Medicine, 2008, 102(4): 593-604.).

[0012] However, for some severe COPD patients, clinical symptoms include dyspnea, large amounts of sputum in the respiratory tract, coughing up purulent sputum accompanied by other symptoms, or when mechanical ventilation is required, they cannot actively inhale to generate turbulence to inhale drug particles into the body. On the other hand, COPD patients are mostly elderly patients with low cultural levels, and it is difficult for them to understand and master the operation and use of DPI devices. The operation error rate is higher and the teaching difficulty is greater. Therefore, for special populations, especially the elderly and critically ill patients, the patient's ability to use the inhalation device must be comprehensively considered when selecting an inhalation device. The patient's preference for the inhalation device, understanding ability, inhalation skills, etc. will also affect the patient's satisfaction and compliance with treatment.

[0013] In summary, based on the unmet clinical needs of COPD patients and the current situation of inconvenience and / or incorrect use of inhaled powder inhalers for special populations, the present invention improves the indacaterol bromide inhaled powder inhaler (Jie Run / Ultibro) that has been on the market, and the effect is direct and rapid, and the patient does not need special training, and can inhale a sufficient dose of the drug by normal breathing, which can effectively alleviate the patient's dyspnea and improve their quality of life. Overcoming many deficiencies in the prior art, it can achieve accurate dosage each time, improve the effectiveness and safety of drug use, and has important clinical and social significance. Summary of the invention

[0014] An object of the present invention is to provide an indacaterol bromide maleate compound preparation suitable for treating COPD patients, which can achieve accurate dosing for various patients and achieve medication effectiveness and safety.

[0015] Another object of the present invention is to provide a solution for convenient medication for a specific group of COPD patients, so as to meet the standardized medication needs of COPD patients, such as the elderly and frail, those with low inspiratory flow rate, those with severe disease, and those who have difficulty using inhalation powder aerosols.

[0016] Another object of the present invention is to provide a long-acting compound preparation, which can prolong the medication interval of patients and improve the compliance of patients with medication while meeting the requirements of medication effectiveness and safety.

[0017] Accordingly, the present invention:

[0018] In one aspect, a unit dose pharmaceutical composition is provided, specifically:

[0019] A unit dose pharmaceutical composition comprising indacaterol maleate and glycopyrrolate as active ingredients, wherein: the content of indacaterol maleate is in the amount of indacaterol C 24 H 28 N2O3 is selected from 132μg-516μg; glycopyrronium bromide content, glycopyrronium C 19 H 28 NO3 is selected from 72μg-279μg.

[0020] In some embodiments, the unit dose pharmaceutical composition as described above, wherein: indacaterol C 24 H 28 In terms of N2O3, the content of indacaterol maleate is selected from 174-391 μg; in terms of glycopyrronium C 19 H 28 The content of glycopyrrolate is selected from 94-211.5 μg based on NO3.

[0021] In some embodiments, the unit dose pharmaceutical composition as described above, wherein:

[0022] Indacaterol C 24 H 28 The content of indacaterol maleate is selected from 132 μg to 265 μg, or selected from 162 to 231 μg, based on N2O3;

[0023] Glycopyrronium C 19 H 28 The content of glycopyrrolate is selected from 72 μg-145 μg based on NO3.

[0024] In some embodiments, the pharmaceutical composition as described above, wherein: indacaterol C 24 H 28Calculated as N2O3, the content of indacaterol maleate is selected from 132 μg, 133 μg, 134 μg, 135 μg, 136 μg, 137 μg, 138 μg, 139 μg, 140 μg, 141 μg, 142 μg, 143 μg, 144 μg, 145 μg, 146 μg, 147 μg, 148 μg, 149 μg, 150 μg, 151 μg, 152 μg, 153 μg, 154 μg, 155 μg, 156 μg, 157 μg, 158 μg, 159 μg, 160 μg, 161 μg, 162 μg, 163 μg, 164 μg, 165 μg, 166 μg, 167 μg, 168 μg, 169 μg, 170 μg, 171 μg, 172 μg, 173 μg, 174 μg, 175 μg, 176 μg, 177 μg, 178 μg, 179 μg, 180 μg, 181 μg, 182 μg, 183 μg, 184 μg, 185 μg, 186 μg, 187 μg, 188 μg, 189 μg, 190 μg, 191 μg, 192 μg, 193 μg, 194 μg, 195 μg, 196 μg, 197 μg, 198 μg, 199 μg, 200 μg, 201 μg, 202 μg, 203 μg, 204 μg, 205 μg, 206 μg, 207 μg, 208 μg, 209 μg, 210 μg, 211 μg, 212 μg, 213 μg, 214 μg, 215 μg, 216 μg, 217 μg, 218 μg, 219 μg, 220 μg, 221 μg, 222 μg, 223 μg, 224 μg, 225 μg, 226 μg, 227 μg, 228 μg, 229 μg, 230 μg, 231 μg, 232 μg, 233 μg, 234 μg, 235 μg, 236 μg, 237 μg, 238 μg, 239 μg, 240 μg, 241 μg, 242 μg, 243 μg, 244 μg, 245 μg, 246 μg, 247 μg, 248 μg, 249 μg, 250 μg, 251 μg, 252 μg, 253 μg, 254 μg, 255 μg, 256 μg, 257 μg, 258 μg, 259 μg, 260 μg, 261 μg, 262 μg, 263 μg, 264 μg or 265 μg;

[0025] or selected from 162 μg, 163 μg, 164 μg, 165 μg, 166 μg, 167 μg, 168 μg, 169 μg, 170 μg, 171 μg, 172 μg, 173 μg, 174 μg, 175 μg, 176 μg, 177 μg, 178 μg, 179 μg, 180 μg, 181 μg, 182 μg, 183 μg, 184 μg, 185 μg, 186 μg, 187 μg, 188 μg, 189 μg, 190 μg, 191 μg, 192 μg, 193 μg, 194 μg, 195 μg, 196 μg, 197 μg, 198 μg, 199 μg, 200 μg, 201 μg, 202 μg, 203 μg, 204 μg, 205 μg, 206 μg, 207 μg, 208 μg, 209 μg, 210 μg, 211 μg, 212 μg, 213 μg, 214 μg, 215 μg, 216 μg, 217 μg, 218 μg, 219 μg, 220 μg, 221 μg, 222 μg, 223 μg, 224 μg, 225 μg, 226 μg, 227 μg, 228 μg, 229 μg, 230 μg or 231 μg;

[0026] or selected from 196 μg, 197 μg, 198 μg, 199 μg, 200 μg, 201 μg, 202 μg, 203 μg, 204 μg, 205 μg, 206 μg, 207 μg, 208 μg, 209 μg, 210 μg, 211 μg, 212 μg, 213 μg, 214 μg, 215 μg, 216 μg, 217 μg, 218 μg, 219 μg, 220 μg, 221 μg, 222 μg, 223 μg, 224 μg, 225 μg, 226 μg, 227 μg, 228 μg, 229 μg, 230 μg, 231 μg, 232 μg, 233 μg, 234 μg, 235 μg, 236 μg, 237 μg, 238 μg, 239 μg, 240 μg, 241 μg, 242 μg, 243 μg, 244 μg, 245 μg, 246 μg, 247 μg, 248 μg, 249 μg, 250 μg, 251 μg, 252 μg, 253 μg, 254 μg, 255 μg, 256 μg, 257 μg, 258 μg, 259 μg, 260 μg, 261 μg, 262 μg, 263 μg, 264 μg or 265 μg.

[0027] In some embodiments, the pharmaceutical composition as described above, with glycopyrronium C 19 H 28In terms of NO3, the content of glycopyrronium bromide is selected from 72μg, 73μg, 74μg, 75μg, 76μg, 77μg, 78μg, 79μg, 80μg, 81μg, 82μg, 83μg, 84μg, 85μg, 86μg, 87μg, 88μg, 89μg, 90μ g, 91μg, 92μg, 93μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 101μg, 102μg, 103μg, 104μg, 105μg, 106μg, 107μg, 108μg, 109μg, 1 10μg, 111μg, 112μg, 113μg, 114μg, 115μg, 116μg, 117μg, 118μg, 119μg, 120μg, 121μg, 122μg, 123μg, 124μg, 125μg, 126μg, 127μg, 128μg, 129μg, 130μg, 131μg, 132μg, 133μg, 134μg, 135μg, 136μg, 137μg, 138μg, 139μg, 140μg, 141μg, 142μg, 143μg, 144μg or 145μg;

[0028] Or selected from 92μg, 93μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 101μg, 102μg, 103μg, 104μg, 105μg, 106μg, 10 7μg, 108μg, 109μg, 110μg, 111μg, 112μg, 113μg, 114μg, 115μg, 116μg, 117μg, 118μg, 119μg, 120μg or 121μg;

[0029] Or selected from 116μg, 117μg, 118μg, 119μg, 120μg, 121μg, 122μg, 123μg, 124μg, 125μg, 126μg, 127μg, 128μg, 129μg, 130μ g, 131μg, 132μg, 133μg, 134μg, 135μg, 136μg, 137μg, 138μg, 139μg, 140μg, 141μg, 142μg, 143μg, 144μg or 145μg.

[0030] In some embodiments, the unit dose pharmaceutical composition as described above is based on indacaterol C 24 H 28 N2O3 divided by glycopyrronium C 19 H 28 NO3, the mass ratio of indacaterol maleate to glycopyrrolate is selected from 1.5 to 2.3,

[0031] In some embodiments, the pharmaceutical composition as described above is based on indacaterol C 24 H 28 N2O3 divided by glycopyrronium C 19 H 28 NO3, the mass ratio of indacaterol maleate to glycopyrrolate is selected from 1.7 to 2.2,

[0032] In some embodiments, the pharmaceutical composition as described above is based on indacaterol C 24 H 28 N2O3 divided by glycopyrronium C 19 H 28 NO3, the mass ratio of indacaterol maleate and glycopyrrolate is selected from 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9 or 2.18.

[0033] In some embodiments, the unit-dose pharmaceutical composition as described above further comprises a buffer pair, a pH adjuster, and an osmotic pressure adjuster, and is prepared into any pharmaceutically acceptable dosage form, wherein the pharmaceutically acceptable dosage form is in the form of an inhalation solution.

[0034] In some embodiments, the unit dose pharmaceutical composition as described above, wherein:

[0035] The buffer pair is selected from a citric acid-sodium citrate buffer pair, a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, a sodium bicarbonate-sodium carbonate buffer pair, an acetic acid-sodium acetate buffer pair, a tartaric acid-sodium tartrate buffer pair, or a citric acid-sodium citrate buffer pair;

[0036] The pH adjuster is selected from a combination of one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, or selected from one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, and maleic acid;

[0037] In some embodiments, the osmotic pressure regulator is selected from at least one of sodium chloride or mannitol, preferably sodium chloride.

[0038] In some embodiments, the unit dose pharmaceutical composition as described above, wherein:

[0039] The buffer pair is selected from citric acid-sodium citrate; wherein the concentration of the citric acid-sodium citrate buffer pair is selected from 1mM to 50mM, or from 1mM to 20mM, or from 2mM to 10mM;

[0040] The pH adjuster is selected from hydrochloric acid or sodium hydroxide;

[0041] The osmotic pressure regulator is selected from sodium chloride;

[0042] In some embodiments, the pH of the pharmaceutical composition is 3.5-4.5, or selected from pH = 4.0 ± 0.1.

[0043] In some embodiments, the unit-dose pharmaceutical composition as described above, wherein the volume specification of the inhalation solution is selected from 1-4 mL, such as 1 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, or selected from 3 mL.

[0044] In some embodiments, the unit-dose pharmaceutical composition as described above is suitable for administration by inhalation through a nebulizer, wherein the nebulization rate of the nebulizer is 0.05 to 1.5 ml / min, or the nebulization rate of the nebulizer is 0.1 to 0.6 ml / min.

[0045] In some embodiments, as described above in the unit dose pharmaceutical composition, the nebulizer is a compressed air nebulizer, wherein the compressed air nebulizer is selected from PARI JuniorBOY nebulizer, PARI BOY nebulizer, PARI BOY Pro nebulizer, PARI TurboBOY nebulizer, PARI COMPACT N nebulizer, Philips cn-c-0101 nebulizer, Philips InnoSpire Dluxe atomizer, Philips CN-B-0303 atomizer, Omron NE-C900 atomizer, Omron NE-C28 atomizer, Omron GC830 atomizer, Omron GC813 atomizer, Yuyue 403T atomizer, Yuyue 403M atomizer, Yuyue 403D atomizer, Yuyue 403H atomizer, Jiuan KS-WH200-D atomizer, Jiaruikang JLN-2321AS atomizer, Jiaruikang JLN-2306AS atomizer, Jiaruikang JLN-2304HDD atomizer, Jiaruikang JLN-2317AS atomizer, Jiaruikang JLN-2311HD atomizer, preferably PARI JuniorBOY atomizer, PARIBOY atomizer, PARI BOY Pro atomizer, PARI TurboBOY atomizer, PARI COMPACT N atomizer, Philips InnoSpire Dluxe atomizer, Philips CN-B-0303 atomizer.

[0046] In some embodiments, as described above in the pharmaceutical composition, the nebulizer is a vibrating mesh nebulizer, wherein the vibrating mesh nebulizer is selected from Jiuan VP-M3A nebulizer, Jiaruikang JLN-MB001 nebulizer, Omron NE-U100J nebulizer, Philips DK012 nebulizer, Yuyue M105 nebulizer, PARI NebulizerSystem type atomizer, preferably Jiuan VP-M3A type atomizer, Philips DK012 type atomizer, Yuyue M105 type atomizer, PARI Nebulizer System type atomizer.

[0047] In another aspect, the present invention provides a use of a unit dose pharmaceutical composition as described above, specifically:

[0048] The use of the pharmaceutical composition as described in any of the preceding items, which is administered to a subject in need of treatment once a day or once every two days.

[0049] In some embodiments, the pharmaceutical composition as described above, the subject suffers from asthma and / or chronic obstructive pulmonary disease (COPD).

[0050] In some embodiments, the inhalation solution pharmaceutical composition as described above is used in the preparation of a medicament for treating asthma and / or chronic obstructive pulmonary disease (COPD).

[0051] In another aspect, the present invention provides a method for preparing a unit dose pharmaceutical composition as described above, specifically:

[0052] The method for preparing the pharmaceutical composition as described above comprises the following steps:

[0053] (a) adding a prescribed amount of an excipient to water, wherein the excipient is selected from at least one of an osmotic pressure regulator and a buffer ion pair, stirring to disperse and dissolve the excipient and adjusting the pH of the solution to a target value of 2.0 to 5.5 with a pH regulator;

[0054] (b) Add the prescribed amount of indacaterol maleate and glycopyrrolate to the excipient solution prepared in (a), and stir to dissolve.

[0055] Optionally, the drug solution obtained in the above (b) is filtered and sterilized, for example, using a filter membrane with a diameter of less than or equal to 0.22 μm to obtain a sterile drug solution.

[0056] Optionally, the obtained sterile drug solution is packaged, for example, filled into vials, glass ampoules or plastic ampoules to obtain an indacaterol bromide inhalation solution pharmaceutical composition.

[0057] In some embodiments, the method for preparing the indacaterol glycopyrronium bromide inhalation solution pharmaceutical composition as described above comprises the following steps:

[0058] 1) Add 80-95% of the batch prescription amount of water for injection, turn on the agitator, and heat the water in the preparation tank to control the temperature at 26°C to 30°C;

[0059] 2) Add the batch prescription amount of excipients into the liquid preparation tank, stir until the solution is clear and uniform, and maintain the temperature at 26℃~30℃;

[0060] 3) Evacuate the liquid preparation tank for 5 minutes, and then introduce nitrogen for no less than 20 minutes;

[0061] 4) adjusting the pH of the solution to 4.0±0.1 with a pH adjuster;

[0062] 5) Add the prescribed amount of indacaterol maleate and glycopyrrolate into the preparation tank, stir until the solution is clear and uniform, and maintain the temperature at 26°C to 30°C;

[0063] 6) Adjust the pH to 4.0±0.1 with pH adjuster, make up the volume of the drug solution to the final volume with water for injection, stir until the solution is uniform, and lower the temperature to 18℃~22℃;

[0064] 7) Sterile filter the solution using a 0.22 μm filter;

[0065] 8) The liquid medicine is aseptically filled using a blow-fill-seal integrated machine, and the inner packaging is a low-density polyethylene ampoule;

[0066] 9) Carry out light inspection, labeling and packaging.

[0067] In another aspect, the present invention provides a pharmaceutical kit and a product of manufacture of a unit dose of the pharmaceutical composition as described above, specifically:

[0068] A pharmaceutical kit comprising: one or more doses of a pharmaceutical composition according to any one of claims 1 to 8; and instructions comprising one or more forms of information selected from the group consisting of information indicating the disease state for which the pharmaceutical composition is administered, storage information of the pharmaceutical composition, administration information, and instructions on how to administer the pharmaceutical composition.

[0069] A manufactured article comprising: one or more doses of a pharmaceutical composition according to any one of claims 1 to 8; and packaging materials.

[0070] In some embodiments, the article of manufacture as described above, wherein the packaging material comprises a container for containing the plurality of doses of the pharmaceutical composition.

[0071] In some embodiments, the article of manufacture as described above, wherein the container comprises a label that displays one or more of the following: the disease state for which the composition is administered, storage information, dosing information, and / or instructions on how to administer the composition.

[0072] As described above, the single-dose inhalation solution pharmaceutical composition, wherein the structural formula of indacaterol maleate is as follows:

[0073]

[0074] As described above, the single-dose inhalation solution pharmaceutical composition, wherein the structural formula of the glycopyrrolate is as follows:

[0075]

[0076] Beneficial effects of the present invention:

[0077] (1) The unit-dose pharmaceutical composition of the present invention exhibits excellent therapeutic effect and safety.

[0078] (2) The unit-dose pharmaceutical composition of the present invention can meet the needs of long-term treatment of asthma and / or COPD patients (once a day or once every two days). Compared with similar products already on the market, it is easy to use and has good patient compliance.

[0079] (3) The unit-dose pharmaceutical composition of the present invention has a higher satisfaction and better compliance for patients with severe COPD whose clinical symptoms include dyspnea or who require mechanical ventilation. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 The average ΔFEV1-time curve of all subjects in Experimental Example 1;

[0081] Figure 2 This is the semi-logarithmic curve of the mean plasma drug concentration-time of indacaterol in Test Example 3;

[0082] Figure 3 This is the mean plasma drug concentration-time semi-logarithmic curve of glycopyrrolate in Test Example 3;

[0083] Figure 4 This is the semi-logarithmic curve of the mean plasma drug concentration-time of indacaterol in Test Example 4;

[0084] Figure 5 This is the mean plasma drug concentration-time semi-logarithmic curve of glycopyrrolate in Test Example 4;

[0085] Figure 6 This is the relative baseline change curve of FEV1 in Experimental Example 4.

[0086] In the accompanying drawings, HL231 is a unified product code for the indacaterol glycopyrronium bromide inhalation solution pharmaceutical composition of the present invention. For example, HL231 261ug / 141ug means that the indacaterol glycopyrronium bromide inhalation solution pharmaceutical composition of the present invention is administered at a unit dose of 261μg of indacaterol and 141μg of glycopyrronium. The meanings of other dosage writings are similar. DETAILED DESCRIPTION

[0087] The present invention will be further described below in conjunction with test examples and embodiments, which will enable professionals and technicians in the field to more fully understand the present invention, but will not limit the present invention in any way.

[0088] Example 1-9: Preparation of Indacaterol Bromide Inhalation Solution

[0089] Preparation method:

[0090] Add 90% of the water for injection of the drug solution to the dispensing tank, add the batch prescription amount of citric acid, sodium hydroxide and sodium chloride according to the batch prescription amount in Table 1, stir and dissolve, and adjust the pH value of the solution to 4.0±0.1 with an appropriate amount of hydrochloric acid or sodium hydroxide solution. Then add the batch prescription amount of glycopyrrolate and indacaterol maleate, while controlling the solution temperature to between 20 and 35°C, and continue to stir until the drug is completely dissolved. After the raw material is completely dissolved, according to the batch size and the density of the drug solution, replenish the water for injection to the full amount of the batch prescription, and continue to stir for 10 minutes. Filter and sterilize with a filter membrane less than or equal to 0.22μm. Use a blowing, filling and sealing machine to fill the filtered and sterilized drug solution into a low-density polyethylene plastic ampoule. After filling, each low-density polyethylene plastic ampoule contains 3mL of drug solution.

[0091] Table 1 Batch formulation of indacaterol bromide maleate inhalation solution production scale

[0092]

[0093] Example 10: Preparation of Indacaterol Bromide Inhalation Solution Placebo

[0094] Preparation method:

[0095] Add 90% of the water for injection into the dispensing tank. According to Table 2, add the batch prescription amount of citric acid, sodium hydroxide and sodium chloride, stir to dissolve, and adjust the pH value of the solution to 4.0±0.1 with an appropriate amount of hydrochloric acid or sodium hydroxide solution. According to the batch size and density of the drug solution, add the water for injection to the full amount of the batch prescription and continue stirring for 10 minutes. Filter and sterilize with a filter membrane less than or equal to 0.22μm. Use a blowing, filling and sealing machine to fill the filtered and sterilized drug solution into low-density polyethylene plastic ampoules. After filling, each low-density polyethylene plastic ampoule contains 3mL of drug solution.

[0096] Table 2 Batch formulation of indacaterol bromide inhalation solution placebo production scale

[0097] Element Batch prescription quantity (g) Citric acid 105.1 Sodium hydroxide 22.8 Hydrochloric acid / sodium hydroxide (for pH adjustment) Moderate Sodium chloride 900 Water for injection Add to 100L

[0098] Example 11-12 Preparation of Indacaterol Bromide Inhalation Solution

[0099] Preparation method:

[0100] Add 94% of the water for injection of the drug solution to the dispensing tank, add the batch prescription amount of citric acid, sodium hydroxide and sodium chloride according to the batch prescription amount in Table 3, stir to dissolve, and adjust the pH value of the solution to 4.0±0.1 with an appropriate amount of hydrochloric acid or sodium hydroxide solution. Then add the batch prescription amount of glycopyrrolate and indacaterol maleate, while controlling the solution temperature to between 20 and 35°C, and continue to stir until the drug is completely dissolved. After the raw material is completely dissolved, according to the batch size and the density of the drug solution, replenish the water for injection to the full amount of the batch prescription, and continue to stir for 10 minutes. Sterilize by filtering with a filter membrane less than or equal to 0.22μm. Use a blowing, filling and sealing machine to fill the filtered and sterilized drug solution into a low-density polyethylene plastic ampoule. After filling, each low-density polyethylene plastic ampoule contains 3mL of drug solution.

[0101] Table 3 Batch formulation of indacaterol bromide maleate inhalation solution production scale

[0102]

[0103] Test Example 1: Safety and efficacy evaluation of indacaterol bromide inhalation solution

[0104] Experimental Design:

[0105] Randomized, single-dose, single-blind, placebo- and active-controlled, crossover design.

[0106] Purpose of the test:

[0107] To study the bronchodilator effect (FEV1AUC0-12h) and safety of different doses of indacaterol bromide inhalation solution in patients with chronic obstructive pulmonary disease (COPD) after single oral inhalation for different periods.

[0108] Trial Endpoints:

[0109] Primary endpoint: ΔFEV1 AUC0-12h

[0110] Safety endpoints: including adverse events, vital signs, 12-lead electrocardiogram and laboratory test indicators

[0111] Secondary endpoint: ΔFEV1AUC0-24h

[0112] Subjects: 83 patients with moderate to severe chronic obstructive pulmonary disease (COPD) in stable stage, both male and female.

[0113] Trial Drugs:

[0114] 1. Test preparation: Indacaterol bromide inhalation solution was prepared according to Example 1-9. Nebulizer inhalation device: PARI BOY air compression nebulizer; Storage conditions: 2-8°C;

[0115] 2. Positive control: (Indacaterol bromide inhalation powder, 110μg / 50μg, single dose), produced by Novartis. Inhalation device: Storage conditions: sealed, moisture-proof, and stored at no more than 25°C;

[0116] 3. Placebo: Indacaterol bromide inhalation solution placebo, prepared with reference to Example 10. Nebulizer inhalation device: PARI BOY air compression nebulizer; Storage conditions: stored below 25°C.

[0117] Test method:

[0118] The patients were randomly divided into two groups and each group was treated with different doses of indacaterol bromide inhalation solution, positive control ( (indacaterol / glycopyrrolate (110 μg / 50 μg)) and indacaterol glycopyrrolate inhalation solution placebo, each treatment cycle consisted of 1 day of treatment, with at least 14 days of washout during the 2-week period.

[0119] Indacaterol bromide inhalation solution and indacaterol bromide inhalation solution placebo were administered using a PARI BOY air-compressed nebulizer. pass The patients were given the drug by dry powder inhaler (DPI). The personnel who performed the pulmonary function test were blinded and compound ipratropium bromide (ipratropium bromide salbutamol) was used as rescue medication. The last visit was conducted 14 days after the last study treatment.

[0120] Treatment duration:

[0121] The expected treatment period is approximately 14 weeks, including a 2-week screening period, a 2-week run-in period, five 1-day treatment periods, four 14-day washout periods, and a final visit 14 days after the last treatment.

[0122] Inclusion and Exclusion Criteria:

[0123] Subjects must meet all of the following criteria to be eligible to participate in this study:

[0124] 1) Outpatients aged ≥40 years, regardless of gender;

[0125] 2) patients diagnosed with COPD according to the GLOD criteria;

[0126] 3) Current smokers or former smokers (e.g., at least 1 pack / day for 10 years) with a smoking history of ≥10 pack-years (smoking index (pack-year) = daily smoking (packs) × time (years), 1 pack = 20 cigarettes), or with a history of exposure to biofuels;

[0127] 4) At the screening visit (visit 1), after inhalation of bronchodilators (bronchodilators refer to sequential inhalation of 84 μg ipratropium bromide and 400 μg salbutamol 1 hour later), forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) < 0.7; FEV1 after inhalation of bronchodilators ≤ 80% of the expected value, ≥ 30% of the expected value;

[0128] 5) Patients who can cooperate with the pulmonary function test after training (acceptability and repeatability meet ATS / ERS standards);

[0129] 6) No regular COPD treatment before participating in this study; or COPD treatment drugs prohibited by the protocol can be discontinued during the screening and treatment period (except for salbutamol sulfate inhalation aerosol as an emergency drug);

[0130] 7) Have not participated in other interventional clinical studies that may affect the results of this study in the past 4 weeks;

[0131] 8) Voluntarily sign the informed consent form.

[0132] Subjects who meet any of the following conditions are not eligible to participate in this study:

[0133] 1) Subjects with other clinically significant respiratory diseases other than COPD, including but not limited to: α-1 antitrypsin deficiency, cystic fibrosis, severe asthma, active bronchiectasis, bronchiolitis obliterans, active pulmonary tuberculosis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, pulmonary edema, interstitial lung disease, other active pulmonary diseases and lung cancer;

[0134] 2) Other clinically significant cardiovascular diseases (such as unstable ischemic heart disease, congestive heart failure, uncontrolled hypertension (systolic blood pressure>160mmHg or diastolic blood pressure>100mmHg, regardless of whether antihypertensive treatment is used), uncontrolled coronary artery disease, myocardial infarction, arrhythmia, history of long QT syndrome or QTc prolongation (QTcF interval ≥450ms, corrected by Fridericia's formula), paroxysmal atrial fibrillation), renal, nervous, endocrine, immune, psychiatric, gastrointestinal, liver or blood system diseases / abnormalities. The investigator believes that if the disease worsens during the trial, it may pose a risk to the subject or affect the analysis of the study results;

[0135] 3) Patients with paradoxical bronchospasm, angle-closure glaucoma, symptomatic benign prostatic hyperplasia (except patients with stable prostatic hyperplasia), bladder neck obstruction, or a history of severe renal damage or urinary retention, or any other contraindications to anticholinergic drugs as determined by the investigator;

[0136] 4) Suffering from cancer (except patients with in situ cervical cancer, squamous cell carcinoma of the skin, basal cell carcinoma, etc. who have been cured for more than 5 years);

[0137] 5) Patients with a history of allergy to anticholinergic / muscarinic receptor antagonists, long-acting or short-acting β2-adrenergic receptor agonists, sympathomimetic amines, lactose / milk protein (dairy product) intolerance, or allergy to indacaterol, glycopyrrolate, or any known component of the drug delivery system;

[0138] 6) hospitalization for COPD or pneumonia within 12 weeks before screening (visit 1);

[0139] 7) Treatment for acute exacerbation of COPD (antibiotics, systemic glucocorticoids, hospitalization or emergency treatment, etc.) within 12 weeks before screening (visit 1);

[0140] 8) The average number of moderate to severe COPD acute exacerbations was ≥ 2 times / year within 3 years before screening;

[0141] 9) Blood eosinophil count>600 / mm3 at screening (visit 1);

[0142] 10) Use of any prohibited medication before screening (visit 1);

[0143] 11) Suffering from acute (viral or bacterial) upper or lower respiratory tract infection, sinusitis, pharyngitis, urinary tract infection and other diseases within 6 weeks before the start of the study; patients who develop respiratory tract infection after screening and before treatment cannot participate in the study, but are allowed to be screened again 6 weeks after the respiratory tract infection is relieved;

[0144] 12) Those with positive results in any test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or syphilis treponema pallidum antibody (TPPA);

[0145] 13) Those who donated blood including blood components or lost a large amount of blood (≥450mL), received blood transfusion or used blood products within 3 months before screening (visit 1);

[0146] 14) Pregnant or lactating women, or female subjects with positive pregnancy test results; subjects (or their partners) who have fertility plans or sperm and egg donations during the entire trial period and within 3 months after the end of the study; subjects who are unwilling to take one or more physical contraceptive measures during the trial period and within 3 months after the end of the study;

[0147] 15) Clinically significant apnea requiring the use of a continuous positive airway pressure (CPAP) device or a non-invasive positive pressure ventilation (NIPPV) device;

[0148] 16) Patients who need long-term oxygen therapy for more than 12 hours a day;

[0149] 17) Patients who had undergone lobectomy or lung volume reduction surgery within 12 months before the start of the study;

[0150] 18) Subjects who are judged by other researchers to be unsuitable for participation.

[0151] Withdrawal and Dosage Stopping Rules:

[0152] If the subject's FEV1 decreases by ≥20% compared with the baseline value during the screening period, the researcher will comprehensively evaluate whether the subject should continue to participate in this study.

[0153] If any subject experienced an SAE or TRAE (treatment-related adverse event) of grade 3 or above, subsequent dosing was stopped for that subject.

[0154] If any death, ≥2 similar SAEs, or ≥2 similar TRAEs of grade 3 or higher occurred in subjects treated at the three dose levels of indacaterol bromide inhalation solution, the corresponding dose was suspended. All grades were based on CTCAE V5.0.

[0155] If a subject withdraws from the study for non-toxicity reasons (such as personal choice, noncompliance, or other), the subject may be replaced.

[0156] Safety Assessment

[0157] All subjects were observed for any adverse events that occurred during the clinical study, including abnormal clinical symptoms and vital signs, laboratory tests (blood routine, blood biochemistry, urine routine), and abnormalities in the 12-lead electrocardiogram. Their clinical manifestations, severity, time of occurrence, end time, treatment measures and outcomes were recorded, and their correlation with the study drug was determined.

[0158] Pulmonary function tests

[0159] Spirometry was performed in accordance with the “Guidelines for Pulmonary Function Examination-Spirometry Examination” published by the Chinese Medical Association.

[0160] Before medication: FEV1 values ​​were measured 45 min (±5 min) and 15 min (±5 min) before medication at each visit, and the average value was taken as the baseline FEV1 value of this cycle;

[0161] After medication: perform pulmonary function tests at 15min (±5min), 30min (±5min), 1h (±5min), 2h (±5min), 4h (±10min), 6h (±10min), 8h (±10min), 10h (±10min), 12h (±10min), 23h 15min (±10min), and 23h 45min (±10min) after medication in each cycle, and obtain the FEV1 value at each time point.

[0162] Statistical analysis methods

[0163] (1) Security

[0164] Safety assessments included adverse events, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), and clinical laboratory tests. All adverse events (AEs), treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) were summarized by system organ class and preferred term for each dose level. All TEAEs, TRAEs, and SAEs were summarized by incidence, severity, and relationship to the trial drug.

[0165] Clinical laboratory tests and vital signs for each dose group are summarized descriptively.

[0166] (2) Pharmacodynamics

[0167] Individual FEV1 values ​​before and after the start of dosing were tabulated. The baseline FEV1 value was subtracted from the FEV1 value at each planned time point after dosing to obtain the baseline-corrected FEV1 value (ΔFEV1). The ΔFEV1 at each planned time point was descriptively summarized, and for each dosing group, the ΔFEV1-time curve for each subject and the average ΔFEV1-time curve for all subjects were plotted, as well as the semi-logarithmic curves corresponding to the two curves (displayed on a logarithmic scale with a base of 10).

[0168] Win Nonlin statistical analysis software was used to calculate the ΔFEV1AUC of each subject according to the actual measurement time.

[0169] Experimental data and result analysis (the average ΔFEV1-time curve of all subjects is attached Figure 1 ):

[0170] After a single administration of 132μg / 72μg, 261μg / 141μg, 516μg / 279μg of the indacaterol bromide inhalation solution of the present invention and the positive control (Jierun), ΔFEV1AUC0-12h, ΔFEV1AUC0-24h, ΔFEV1AUC0-4h, and ΔFEV1 peak values ​​were significantly better than those of the placebo control group (P<0.0001). The bronchodilator effect of the indacaterol bromide inhalation solution of the present invention is positively correlated with the dose. There was no statistical difference in ΔFEV1AUC0-24h between each dosage group of the indacaterol bromide inhalation solution of the present invention and the positive control Jierun.

[0171] Dizziness is a common adverse reaction in the instructions for use of Jierun; in this study, 3 subjects (3.9%) in the Jierun (110μg / 50μg) group experienced 3 ADRs. The single maximum exposure dose of the indacaterol bromide inhalation solution of the present invention is 516μg / 279μg, and no serious ADRs or deaths occurred. No COPD patients withdrew from the study due to drug-related AEs. The results show that the indacaterol bromide inhalation solution of the present invention is well tolerated and safe for COPD patients when used once.

[0172] Conclusions

[0173] 1. After a single administration of each dose of indacaterol bromide inhalation solution, the ΔFEV1AUC0-12h was significantly different from that of the placebo; the ΔFEV1 24 hours after each dose was significantly improved compared with the placebo, indicating that the efficacy of this product can last up to 24 hours.

[0174] 2. The safety evaluation results showed that each dose was well tolerated after a single administration, the incidence of adverse reactions was low, and no new safety signals were found; no drug-related serious adverse events (SAEs) occurred.

[0175] Test Example 2: Evaluation of Patient Compliance with Indacaterol Bromide Inhalation Solution

[0176] In the above-mentioned test example 1, according to the GLOD standard, some patients were diagnosed with severe COPD. We conducted a treatment satisfaction survey on this type of severe COPD patients with indacaterol glycopyrronium bromide inhalation solution and indacaterol glycopyrronium bromide inhalation powder, and compared them. A self-made treatment satisfaction questionnaire was used for evaluation, with 10 questions, 10 points for each question, and a total score of 100 points, where a score greater than or equal to 90 points was very satisfied, 76 to 89 points were satisfied, and less than or equal to 75 points were dissatisfied. Total satisfaction = (very satisfied + satisfied) / number of survey cases × 100%.

[0177] Test results and analysis

[0178] The results of the patient compliance experiment show that the indacaterol glycopyrronium bromide maleate pharmaceutical composition of the present invention with a specification of 3 ml is more convenient to use and has higher patient satisfaction than the positive control indacaterol glycopyrronium bromide inhalation powder.

[0179] Experimental Example 3: Evaluation of the pharmacokinetics and safety tolerance of a single inhalation of indacaterol bromide inhalation solution in healthy volunteers Experimental design:

[0180] Randomized, open, single-dose, crossover design.

[0181] Purpose of the test:

[0182] Indacaterol bromide inhalation solution was used as the test drug, and indacaterol bromide inhalation powder capsules (110 μg / 50 μg, To investigate the PK characteristics of different doses of indatroglycopronium bromide inhalation solution orally inhaled in healthy adults under fasting state, evaluate the safety and tolerability of indatroglycopronium bromide inhalation solution, and compare the PK characteristics of indatroglycopronium bromide inhalation solution and control drug.

[0183] Trial Endpoints:

[0184] Primary endpoints: Cmax, AUC0-t, AUC0-∞.

[0185] Safety endpoints: including adverse events, vital signs, 12-lead electrocardiogram and laboratory test indicators

[0186] Secondary endpoints: Tmax, t1 / 2, λz, etc.

[0187] Subjects: 16 healthy subjects, both male and female.

[0188] Trial Drugs:

[0189] 1. Test preparation: Indacaterol bromide inhalation solution was prepared according to Example 1-9. Nebulizer inhalation device: PARI BOY air compression nebulizer; Storage conditions: 2-8°C;

[0190] 2. Positive control: (Indacaterol bromide inhalation powder, 110μg / 50μg, single dose), produced by Novartis. Inhalation device: Storage conditions: sealed, moisture-proof, and stored at no more than 25°C;

[0191] Test method:

[0192] The subjects were randomly divided into two groups and each group was randomly divided into two groups. (indacaterol / glycopyrrolate (110 μg / 50 μg)), blood samples were collected at pre-set time points, with at least a 14-day washout period during the two-week period.

[0193] Indacaterol bromide inhalation solution was administered using a PARI BOY air-compressed nebulizer. pass Administration by dry powder inhaler (DPI).

[0194] Test cycle:

[0195] The trial period is expected to be approximately 63 days, including a screening period, a dosing evaluation period, a washout period, and a post-trial physical examination, a total of 6 phases.

[0196] Inclusion and Exclusion Criteria:

[0197] Subjects must meet all of the following criteria to be eligible to participate in this study:

[0198] 1) Aged ≥ 18 years old, both male and female;

[0199] 2) Male volunteers weigh ≥50.0kg, female volunteers weigh ≥45.0kg, and body mass index (BMI) is between 19 and 26 kg / m 2 Between, including critical value;

[0200] 3) Volunteers voluntarily sign a written informed consent.

[0201] Subjects who meet any of the following conditions are not eligible to participate in this study:

[0202] 1) Patients with a history of allergy to indacaterol, glycopyrrolate or any drug excipients, as well as those with a known history of allergic diseases or allergic constitution;

[0203] 2) Volunteers with congenital galactosemia, glucose and galactose malabsorption syndrome, or lactase deficiency;

[0204] 3) Patients with glaucoma, prostatic hypertrophy, urinary retention, or any other disease that the researchers consider contraindicated for anticholinergic drugs;

[0205] 4) Those who had viral or bacterial upper or lower respiratory tract, sinus or middle ear, and urinary tract infections within 4 weeks before screening;

[0206] 5) Patients who have had or are currently suffering from any serious clinical disease such as circulatory system, endocrine system, nervous system, digestive system, respiratory system, urogenital system, hematology, immunology, psychiatry and metabolic disorders, or any other disease that may interfere with the test results;

[0207] 6) Have a history of allergy to drugs, food or other substances;

[0208] 7) Patients who had undergone surgery within 4 weeks before the trial or planned to undergo surgery during the study;

[0209] 8) Those who have taken any medicine or health care products (including Chinese herbal medicine) within 14 days before the trial;

[0210] 9) Those who have used any drugs that inhibit or induce liver metabolism of drugs within 30 days before the trial (such as inducers - barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole; inhibitors - SSRI antidepressants, cimetidine, diltiazem, macrolides, nitroimidazoles, sedatives, hypnotics, verapamil, fluoroquinolones, antihistamines);

[0211] 10) Participated in any clinical trial and took any clinical trial drugs within 3 months before the trial;

[0212] 11) Those who donated blood or lost a large amount of blood (≥200mL, excluding menstrual blood loss for women), received blood transfusion or used blood products within 3 months before enrollment;

[0213] 12) Pregnant or lactating women, volunteers who have fertility plans or sperm or egg donations during the trial and within 3 months after the end of the trial, or volunteers who cannot use one or more non-drug contraceptive measures during the trial and within 3 months after the end of the trial;

[0214] 13) Those who have special dietary requirements and cannot follow the unified diet;

[0215] 14) Those who drink excessive amounts of tea, coffee and / or caffeinated beverages (more than 8 cups, 1 cup = 250 mL) every day;

[0216] 15) Smokers or those who smoked more than 5 cigarettes a day in the three months before the test or those who could not stop using any tobacco products during the test;

[0217] 16) Alcoholics or regular drinkers within 6 months before the test, that is, those who drink more than 14 units of alcohol per week (1 unit = 360 mL beer or 45 mL of 40% alcohol liquor or 150 mL of wine) or those who cannot stop using any alcoholic products during the test;

[0218] 17) Drug abusers or those who have used soft drugs (such as marijuana) within 3 months before the test or those who have taken hard drugs (such as phencyclidine, etc.) within 1 year before the test;

[0219] 18) Abnormal vital signs (systolic blood pressure <90mmHg or >140mmHg, diastolic blood pressure <50mmHg or >90mmHg; heart rate <50bpm or >100bpm) or abnormal physical examination, electrocardiogram, pulmonary function test (FEV1, FVC <80% predicted value), laboratory test abnormalities with clinical significance (subject to the judgment of the clinical research physician);

[0220] 19) Volunteers who may not be able to complete this study due to other reasons or who the researchers believe should not be included;

[0221] 20) After training, volunteers are unable to correctly master the method of drug inhalation.

[0222] Exit criteria:

[0223] 1) The researcher considers it necessary to stop the trial from the perspective of medical ethics.

[0224] 2) Patients who have experienced serious adverse events (SAE) and are not suitable to continue the trial.

[0225] 3) The researcher judges that withdrawal from the study is in the best interests of the volunteer.

[0226] 4) Poor compliance of volunteers, including the following situations:

[0227] a) Volunteers fail to take medication and undergo examinations as required;

[0228] b) Volunteers use other drugs and / or foods that may affect the safety evaluation and pharmacokinetic test results;

[0229] c) The volunteer has other behaviors that may affect the test results;

[0230] 5) Volunteers voluntarily withdraw.

[0231] Termination criteria:

[0232] 1) According to the adverse event criteria, more than 1 / 2 of the volunteers experienced grade 2 adverse events, and more than 1 / 4 of the volunteers experienced grade 3-4 adverse events, indicating that the volunteers were clearly intolerant.

[0233] 2) Major errors were found in the clinical trial protocol during the trial, making it difficult to evaluate the drug.

[0234] 3) The applicant requests termination under the premise of fully protecting the rights and safety of volunteers.

[0235] 4) The State Food and Drug Administration or the Ethics Committee orders the termination of the trial for some reason.

[0236] Safety Assessment:

[0237] All subjects were observed for any adverse events that occurred during the clinical study, including abnormal clinical symptoms and vital signs, laboratory tests (blood routine, blood biochemistry, urine routine), and abnormalities in the 12-lead electrocardiogram. Their clinical manifestations, severity, time of occurrence, end time, treatment measures and outcomes were recorded, and their correlation with the study drug was determined.

[0238] PK Sample Collection / Analysis:

[0239] Blood samples were collected from 18 blood sampling points at 0h (within 60 minutes before administration) and 5min, 10min, 15min, 20min, 40min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, 96h, 120h, and 144h after administration, with 4mL of forearm venous blood collected each time. The drug concentrations of indacaterol and glycopyrronium in plasma were determined by HPLC-MS / MS.

[0240] Statistical analysis methods

[0241] (1) Security

[0242] Safety assessments included adverse events, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), and clinical laboratory tests. All adverse events (AEs), treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) were summarized by system organ class and preferred term for each dose level. All TEAEs, TRAEs, and SAEs were summarized by incidence, severity, and relationship to the trial drug.

[0243] Clinical laboratory tests and vital signs for each dose group are summarized descriptively.

[0244] (2) Pharmacokinetics

[0245] Phoenix WinNonlin software was used to calculate the pharmacokinetic parameters of indacaterol and glycopyrronium using a non-compartmental model: AUC 0-t , AUC 0-∞ , C max , T max ,t 1 / 2 , z , and descriptive analysis was performed by formulation group to comprehensively reflect the characteristics of drug absorption, distribution, metabolism and excretion in volunteers.

[0246] The power function model was used to analyze and evaluate the indacaterol glycopyrronium bromide inhalation solution C of the present invention. maxIf the 90% confidence interval (CI) of the power function model coefficient (β) falls within the linear interval (0.8-1.25), it is judged to be linear.

[0247] A mixed effects model was used to explore the effects of formulation and gender on the main pharmacokinetic parameters (C max , AUC 0-t , AUC 0-∞ The effect of logarithmically transformed primary PK endpoint (C max , AUC 0-t , AUC 0-∞ ) were used for analysis, and the least square means of indacaterol glycopyrronium bromide inhalation solution and control drugs were calculated, and the geometric mean ratio (GMR) and its 90% confidence interval (CI) were calculated.

[0248] Experimental data and results analysis (the mean plasma drug concentration-time semi-logarithmic curves of indacaterol and glycopyrrolate are shown in the attached Figure 2 , 3 ):

[0249] When healthy subjects were given a single dose of 132 μg / 72 μg, 261 μg / 141 μg, and 516 μg / 279 μg of the indacaterol and glycopyrronium bromide inhalation solution of the present invention, both indacaterol and glycopyrronium showed a linear PK trend, and the increase in exposure was positively correlated with the increase in dose.

[0250] Compared with the positive control, the exposure of the indacaterol glycopyrronium bromide inhalation solution of the present invention at a dose of 261 μg / 141 μg was significantly higher than that of the positive control. 0-∞ , AUC 0-t and C max The results were comparable, and the geometric mean ratio and 90% CI fell within the 80%-125% equivalence interval.

[0251] In the study, 2 cases (12.5%) of 2 ADRs occurred, including 1 case each in the 132μg / 72μg and 516μg / 279μg groups of the indacaterol bromide inhalation solution of the present invention, which were supraventricular extrasystole and ventricular extrasystole, both of which were grade 1 and occurred 14 days after administration. They have been cured and are transient. No adverse reactions occurred in the 261μg / 141μg group.

[0252] The study concluded that the indacaterol and glycopyrronium bromide inhalation solution of the present invention was used in healthy people for single and cross administration, and the C max , AUC increases with increasing dose, and the safety is good.

[0253] Test Example 4: Study on the PK / PD characteristics (pharmacokinetic-pharmacodynamic characteristics) of different doses of indacaterol bromide inhalation solution of the present invention in patients with chronic obstructive pulmonary disease (COPD) after single oral inhalation at different periods

[0254] Experimental Design:

[0255] Multicenter, randomized, single-dose, crossover design.

[0256] Purpose of the test:

[0257] Indacaterol bromide inhalation solution was used as the test drug, and indacaterol bromide inhalation powder capsules (110 μg / 50 μg, To study the PK characteristics of different doses of indatroglycopronium bromide inhalation solution orally inhaled by COPD patients as a control drug, evaluate the safety and tolerability of indatroglycopronium bromide inhalation solution, and compare the PK / PD characteristics of indatroglycopronium bromide inhalation solution and control drugs.

[0258] Trial Endpoints:

[0259] Primary endpoint: C max , AUC 0-t , AUC 0-∞ .

[0260] Secondary endpoint: ΔFEV1AUC 0-12h , ΔFEV1AUC 0-24h , T max ,t 1 / 2 , z wait.

[0261] Subjects: 18 COPD patients aged 40 years and above, both male and female.

[0262] Trial Drugs:

[0263] 1. Test preparation: Indacaterol bromide inhalation solution was prepared according to Examples 11-12. Nebulizer inhalation device: PARI BOY air compression nebulizer; Storage conditions: 2-8°C;

[0264] 2. Positive control: (Indacaterol bromide inhalation powder, 110μg / 50μg, single dose), produced by Novartis. Inhalation device: Storage conditions: sealed, moisture-proof, and stored at no more than 25°C;

[0265] Test method:

[0266] The subjects were randomly assigned to receive different doses of indacaterol bromide inhalation solution (doses as follows) and positive control ( (indacaterol / glycopyrrolate (110 μg / 50 μg)), blood samples were collected at pre-set time points, with at least a 14-day washout period during the two-week period.

[0267]

[0268] PK Sample Collection / Analysis:

[0269] Blood samples were collected from 15 blood sampling points before and after medication, 5min, 15min, 30min, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, 96h, 120h, and 144h, with 4mL of forearm venous blood collected each time. The drug concentrations of indacaterol and glycopyrronium in plasma were determined by HPLC-MS / MS.

[0270] PD index collection:

[0271] The FEV1 value was measured 45min (±5min) and 15min (±5min) before medication at each cycle visit, and the average value was taken as the FEV1 baseline value of this cycle;

[0272] After medication: perform pulmonary function tests at 20min (±5min), 1h (±5min), 2h (±5min), 4h (±10min), 6h (±10min), 8h (±10min), 12h (±10min), 23h 15min (±10min), and 23h 45min (±10min) after medication in each cycle, and obtain the FEV1 value at each time point.

[0273] Inclusion and exclusion criteria: Patient inclusion criteria (the following criteria must be met):

[0274] 1. Outpatients aged ≥40 years at the screening visit (visit 1), regardless of gender;

[0275] 2. Patients diagnosed with chronic obstructive pulmonary disease (COPD) according to the GOLD criteria;

[0276] 3. Current smokers or former smokers (e.g. at least 1 pack / day for 10 years) who have smoked ≥ 10 pack-years (smoking index (pack-year) = daily smoking amount (packs) × time (years), 1 pack = 20 cigarettes), or have a history of exposure to biofuels;

[0277] 4. At the screening visit (visit 1), the forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) after inhalation of bronchodilators was <0.7; 30% of the expected value ≤ FEV1 after inhalation of bronchodilators <80% of the expected value (after inhalation of bronchodilators means 1 hour after sequential inhalation of 84 μg (or equivalent dose) ipratropium bromide and 400 μg salbutamol);

[0278] 5. Patients who can cooperate with the pulmonary function test after training (acceptability and repeatability meet ATS / ERS standards);

[0279] 6. No regular COPD treatment was performed before participating in this study; or COPD treatment drugs prohibited by the protocol may be discontinued during the screening introduction period and treatment period (except for salbutamol sulfate inhalation aerosol as an emergency drug).

[0280] 7. Tolerant to nebulized inhalation therapy. After guidance, the patient can correctly use the nebulizer, inhaled powder and reliever medication, and correctly fill in the diary card;

[0281] 8. Have not participated in other interventional clinical studies or lung disease rehabilitation programs that may affect the results of this study in the past 4 weeks;

[0282] 9. Voluntarily sign the informed consent form.

[0283] Subjects who meet any of the following conditions are not eligible to participate in this study:

[0284] Exclusion criteria (one of the following will be considered as exclusion):

[0285] 1. Patients with other clinically significant respiratory diseases other than COPD, including but not limited to: alpha-1 antitrypsin deficiency, cystic fibrosis, significant asthma, active bronchiectasis, bronchiolitis obliterans, active tuberculosis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, pulmonary edema, interstitial lung disease, other active lung diseases and lung cancer;

[0286] 2. Other clinically significant cardiovascular diseases (such as unstable ischemic heart disease, congestive heart failure, uncontrolled hypertension (systolic blood pressure>160mmHg or diastolic blood pressure>100mmHg, regardless of whether antihypertensive treatment is used), uncontrolled coronary artery disease, myocardial infarction, arrhythmia, history of long QT syndrome or QTc prolongation (QTcF interval>450ms, corrected by Fridericia's formula), paroxysmal atrial fibrillation), renal, nervous, endocrine, immune, mental, gastrointestinal, liver or blood system diseases / abnormalities. The investigator believes that if the disease worsens during the trial, it may pose a risk to the patient or affect the analysis of the study results;

[0287] 3. Patients with paradoxical bronchospasm, angle-closure glaucoma, symptomatic benign prostatic hyperplasia (except patients with stable prostatic hyperplasia), bladder neck obstruction, or a history of severe renal damage or urinary retention, or any other history of contraindications to anticholinergic drugs as determined by the investigator;

[0288] 4. Suffering from cancer (except patients with cervical cancer in situ, squamous cell carcinoma of the skin, basal cell carcinoma, etc. who have been cured for more than 5 years);

[0289] 5. Have a history of allergy to anticholinergic / muscarinic receptor antagonists, long-acting or short-acting β2-adrenergic receptor agonists, sympathomimetic amines, lactose / milk protein (dairy product) intolerance, allergy to indacaterol, glycopyrrolate, or any known ingredients in the delivery system;

[0290] 6. Hospitalization for COPD or pneumonia within 12 weeks before screening (visit 1);

[0291] 7. Patients who had received treatment for acute exacerbation of COPD (antibiotics, systemic glucocorticoids, hospitalization or emergency treatment, etc.) within 12 weeks before screening (visit 1);

[0292] 8. The average number of moderate to severe COPD acute exacerbations in the three years before screening is ≥ 2 times / year;

[0293] 9. Blood eosinophil count>600 / mm3 at screening (visit 1);

[0294] 10. Use of any prohibited medications before the screening (visit 1) pulmonary function test;

[0295] 11. Suffering from acute (viral or bacterial) upper or lower respiratory tract infection, sinusitis, pharyngitis, urinary tract infection and other diseases within 6 weeks before screening (visit 1); patients with respiratory tract infection after screening and before treatment cannot participate in the study, but are allowed to be screened again 6 weeks after the respiratory tract infection is relieved;

[0296] 12. During the screening lead-in period, the 12-lead electrocardiogram shows clinically significant abnormalities that may pose a risk to the patient as determined by the investigator;

[0297] 13. Patients who had undergone lobectomy or lung volume reduction surgery within 12 months before the start of the study;

[0298] 14. Patients who need long-term oxygen therapy for more than 12 hours a day;

[0299] 15. Clinically significant apnea requiring the use of a continuous positive airway pressure (CPAP) device or a non-invasive positive pressure ventilation (NIPPV) device;

[0300] 16. Patients with a history of alcoholism or drug abuse known or suspected in the past 2 years;

[0301] 17. Pregnant or lactating women, or female subjects with positive pregnancy test results; subjects (or their partners) who have fertility plans or sperm and egg donations during the entire trial period and within 3 months after the end of the study; subjects who are unwilling to take one or more physical contraceptive measures during the trial period and within 3 months after the end of the study;

[0302] 18. Those who donated blood including blood components or lost a large amount of blood (≥450mL), received blood transfusion or used blood products within 3 months before screening (visit 1);

[0303] 19. Those with positive results for any of the tests for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or Treponema pallidum antibodies (TPPA) (if the latter three are positive, further testing of the corresponding hepatitis B virus deoxyribonucleic acid (HBV DNA) titer, hepatitis C virus ribonucleic acid (HCV RNA) titer, or Treponema pallidum titer is required. Those exceeding the lower limit of detection of the assay shall be excluded from this study);

[0304] 20. Patients who are judged by other researchers to be unsuitable for participation.

[0305] Statistical analysis methods

[0306] Security

[0307] Safety assessments included adverse events, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), and clinical laboratory tests. All adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse reactions, and serious adverse events (SAEs) were summarized by system organ class and preferred term for each dose level. All TEAEs, TRAEs, and SAEs were summarized by incidence, severity, and relationship to the trial drug.

[0308] Pharmacokinetics

[0309] PK concentration data were statistically summarized and tabulated by formulation at each planned sampling time point defined in the protocol. The mean drug concentration-time curves (linear and semi-logarithmic) were plotted for each formulation group. The PK concentration data of individual patients were plotted against drug concentration-time curves (linear and semi-logarithmic) according to the actual sampling time.

[0310] The blood drug concentration data were calculated using Phoenix WinNonlin software through a non-compartmental model to calculate the pharmacokinetic parameters of indacaterol and glycopyrronium: AUC 0-t , AUC 0-∞ , C max , T max ,t 1 / 2 , z , and conduct descriptive analysis by preparation to comprehensively reflect the characteristics of drug absorption, distribution, metabolism and excretion in patients.

[0311] Pharmacodynamics

[0312] The FEV1 at each time point was summarized and analyzed according to the group, and the number of cases (missing), arithmetic mean, standard deviation, median value, minimum value, and maximum value were listed. A descriptive summary of ΔFEV1 at each planned time point was made, and for each dosing group, the change in FEV1 relative to baseline at each visit was summarized, and the results were presented in a line graph (mean ± standard deviation, least squares mean ± standard error).

[0313] The ΔFEV1AUC of each patient was calculated using the trapezoidal method according to the actual measurement time. 0-12h Mixed effect model was used to compare ΔFEV1AUC between groups. 0-12h The model is based on ΔFEV1AUC 0-12h As dependent variables, preparation type, medication sequence and medication cycle were used as fixed effects, subjects were used as random effects (nested in medication sequence), and FEV1 before each cycle of medication was included in the model as a covariate. The least squares means, standard errors, 95% CIs and P values ​​of the adjusted changes in each group and the differences between groups were listed.

[0314] Experimental data and results analysis (the mean plasma drug concentration-time semi-logarithmic curves of indacaterol and glycopyrrolate are shown in the attached Figure 4 , 5 ; Changes in FEV1 relative to baseline are shown in the Appendix Figure 6 ):

[0315] After COPD patients were given a single dose of the indacaterol glycopyrronium bromide inhalation solution 261 μg / 120 μg, 261 μg / 141 μg and the positive control (Jierun), the PK characteristics of the two dose groups of indacaterol were similar to those of Jierun, with Cmax of about 85%-86% and AUC of about 93%-94% of that of Jierun, and the exposure was equivalent to that of Jierun; the Cmax of the glycopyrronium 261 μg / 120 μg group was about 1.54 μg / 1.20 μg, and the AUC of the glycopyrronium 261 μg / 120 μg group was about 1.57 ... max The AUC of glycopyrronium 261μg / 120μg and 261μg / 141μg groups were approximately 82% and 100% of that of Jerun, respectively. The exposure of glycopyrronium 261μg / 141μg was similar to that of Jerun, while the exposure of 261μg / 120μg was lower (similar to the dose ratio of glycopyrronium in the 261μg / 141μg group (85%)).

[0316] ΔFEV1AUC 0-12h There was no statistical difference between the 261 μg / 141 μg and 261 μg / 120 μg dosage groups of the indacaterol bromide inhalation solution of the present invention (Δ=0.2519 L*h, P=0.1176); there was no statistical difference between the various dosages of the indacaterol bromide inhalation solution of the present invention and Jierun (P>0.05).

[0317] Only one subject in the positive control group (Jierun group) had one ADR (increased blood uric acid), and no ADR occurred in each group of the indacaterol glycopyrronium bromide inhalation solution of the present invention.

[0318] Research conclusions:

[0319] The indacaterol and glycopyrronium bromide inhalation solution of the present invention is used for COPD patients in a single or cross-over manner. The C max , AUC is proportional to the dose, and the safety is good. The AUC exposure of 261μg / 141μg indacaterogronium bromide inhalation solution of the present invention is equivalent to that of the positive control (Jierun) (100%).

[0320] Test Example 5: A multicenter, randomized, parallel, positive-controlled clinical study on the safety and efficacy of indacaterol bromide inhalation solution in the treatment of chronic obstructive pulmonary disease (COPD)

[0321] Experimental Design:

[0322] Randomized, single-blind, positive-controlled, parallel design.

[0323] Purpose of the test:

[0324] To evaluate the efficacy and safety of indacaterol bromide inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD).

[0325] Trial Endpoints:

[0326] Primary endpoint: trough FEV1 at week 26 (average of 45 minutes before dosing and 15 minutes before dosing).

[0327] Secondary endpoints: incidence of moderate and severe COPD exacerbations within 26 and 52 weeks.

[0328] Safety endpoints: including adverse events, vital signs, 12-lead electrocardiogram and laboratory test indicators

[0329] Participants: 474 patients with stable chronic obstructive pulmonary disease (COPD), both male and female.

[0330] Trial Drugs:

[0331] 1. Test preparation: Indacaterol bromide inhalation solution was prepared according to Example 12. Nebulizer inhalation device: PARIBOY air compression nebulizer; Storage conditions: 2-8°C;

[0332] 2. Positive control: Ultibro (indacaterol bromide inhalation powder, 110 μg / 50 μg, single dose), produced by Novartis. Inhalation device: Breezhaler; Storage conditions: sealed, moisture-proof, and stored at no more than 25°C;

[0333] Test method:

[0334] A total of 474 COPD patients were randomly assigned in a 1:1 ratio to indacaterol bromide inhalation solution or a positive control group (indacaterol bromide inhalation powder, Patients took the drug continuously for 52 weeks until the end of the project, with a treatment visit at W6, W12, W18, W26, W34, W42, and W52, and lung function tests and safety checks were performed at each visit.

[0335] Indacaterol bromide inhalation solution was administered using a PARI BOY air-compressed nebulizer, and Ultibro was administered via a Breezhaler dry powder inhaler (DPI). The person performing the spirometry was masked, and albuterol sulfate inhalation aerosol was used as rescue medication. The final visit was conducted 14 days after the last study treatment.

[0336] Treatment duration:

[0337] The treatment period is approximately 58 weeks, including a 4-week screening period, a 52-week treatment period, and a 2-week safety visit after the last treatment.

[0338] Inclusion and Exclusion Criteria:

[0339] Subjects must meet all of the following criteria to be eligible to participate in this study:

[0340] 1) At the screening visit (visit 1), age ≥ 40 years old, regardless of gender;

[0341] 2) Patients with chronic obstructive pulmonary disease (COPD) who meet the GOLD 2023 diagnostic criteria [GOLD 2023 criteria: patients have chronic respiratory symptoms such as dyspnea, chronic cough or sputum, and / or have a history of exposure to risk factors, and lung function test results show: forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) after using bronchodilators <0.7)];

[0342] 3) At the Screening Visit (Visit 1):

[0343] Forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) < 0.7 after using bronchodilators;

[0344] FEV1 < 80% predicted after inhaled bronchodilator;

[0345] 4) modified Medical Research Committee Respiratory Scale (mMRC) score ≥ 2 at the screening visit (visit 1);

[0346] 5) Voluntarily sign the informed consent form.

[0347] Subjects who meet any of the following conditions are not eligible to participate in this study:

[0348] 1) Currently suffering from any of the following diseases: α-1 antitrypsin deficiency, asthma, active pulmonary tuberculosis, lung cancer, pulmonary edema, cystic fibrosis, bronchiolitis obliterans, sarcoidosis, or clinically significant pulmonary fibrosis, pulmonary hypertension, interstitial lung disease, active bronchiectasis that the study physician determines will pose a safety risk to the patient and / or affect the analysis of study results;

[0349] 2) History of previous or current severe cardiovascular disease, including but not limited to:

[0350] · Heart function class III / IV during the screening period (according to the New York Heart Association (NYHA) heart function classification standard);

[0351] Acute myocardial infarction, unstable angina / acute coronary syndrome, percutaneous coronary intervention, or coronary artery bypass grafting within 6 months before screening;

[0352] Structural heart disease, such as hypertrophic cardiomyopathy, moderate to severe valvular disease;

[0353] Severe arrhythmias within 3 months before screening, such as atrial fibrillation with ventricular rate > 120 bpm, ventricular tachycardia, bradycardia (ventricular rate > 120 bpm)

[0354] <45bpm), second degree type II or higher atrioventricular block (except for implanted pacemakers or defibrillators), male QTcF>450ms or female QTcF

[0355] >470ms;

[0356] Patients with poorly controlled blood pressure (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg at the screening visit)

[0357] 3) patients with type 1 diabetes or poorly controlled type 2 diabetes (fasting blood glucose ≥10 mmol / L at screening);

[0358] 4) Having cancer (except for carcinoma in situ, squamous cell carcinoma of the skin and basal cell carcinoma that have been cured for more than 5 years at the time of screening), suspected malignant tumor or undetermined tumor;

[0359] 5) Patients with paradoxical bronchospasm, angle-closure glaucoma, symptomatic benign prostatic hyperplasia (except patients with stable prostatic hyperplasia), bladder neck obstruction, or a history of severe renal damage or urinary retention, or any other contraindications to anticholinergic drugs as determined by the investigator;

[0360] Note: Subjects with open-angle glaucoma who use medication to control intraocular pressure can be included in this study. All medications approved for controlling intraocular pressure are allowed, including topical ophthalmic non-selective beta-blockers (such as betaxolol, carteolol, levobunolol, metipranolol, or timolol) and prostaglandin analogs.

[0361] 6) Patients with other serious unstable renal, neurological, endocrine, immune, psychiatric, gastrointestinal, liver or blood system diseases / abnormalities, and the researchers judge that participation in this study may pose risks to the patients or affect the analysis of the study results;

[0362] 7) During the screening period (visit 1), the investigator determines that the patient's laboratory test results show clinically significant abnormalities that may pose a risk to the patient, including but not limited to one of the following:

[0363] a: Hematology: blood eosinophils ≥ 300 / mm 3 (0.3*10 -9 / L);

[0364] b: Glomerular filtration rate (eGFR) calculated using the CKD-EPI formula < 60 mL / min / 1.73 m 2 ;

[0365] c: Liver function: alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal value; total bilirubin (TBIL) > 1.5 times the upper limit of normal value.

[0366] 8) Hospitalization for COPD or pneumonia within 8 weeks before screening (visit 1) or during the screening period;

[0367] 9) Suffering from acute (viral or bacterial) upper or lower respiratory tract infection, sinusitis, pharyngitis, urinary tract infection and other diseases within 4 weeks before screening (visit 1) or during the screening period;

[0368] 10) Treatment of COPD acute exacerbation such as systemic steroids (e.g., oral or intravenous, intramuscular injection), hospitalization or emergency department visit within 8 weeks before screening (visit 1) or during the screening period;

[0369] 11) Patients with a history of allergy to anticholinergic / muscarinic receptor antagonists, long-acting or short-acting β2-adrenergic receptor agonists, sympathomimetic amines, lactose / milk protein (dairy product) intolerance, or allergy to indacaterol, glycopyrrolate, or any known component of the drug delivery system;

[0370] 12) had undergone lobectomy or lung volume reduction surgery within 12 months before screening;

[0371] 13) Patients who need long-term oxygen therapy for more than 12 hours a day;

[0372] 14) Clinically significant apnea requiring the use of a continuous positive airway pressure (CPAP) device or a non-invasive positive pressure ventilation (NIPPV) device;

[0373] 15) Patients with a history of known or suspected alcohol or drug abuse in the past 2 years;

[0374] 16) Pregnant or lactating women, or female subjects with positive pregnancy test results; subjects (or their partners) who have fertility plans or sperm and egg donations during the entire trial period and within 1 month after the end of the study; subjects who are unwilling to take one or more physical contraceptive measures during the trial period and within 1 month after the end of the study;

[0375] 17) Human immunodeficiency virus (HIV) antibody positive; hepatitis B surface antigen (HBsAg) positive and HBV-DNA exceeds the detection limit; hepatitis C virus (HCV) antibody positive and HCV-RNA exceeds the detection limit;

[0376] 18) Participation in other interventional clinical studies or lung disease rehabilitation programs that may affect the results of this study within 4 weeks before screening (visit 1);

[0377] 19) Patients who are judged as unsuitable to participate by other researchers.

[0378] Early exit criteria:

[0379] 1) The subject withdraws consent;

[0380] 2) The subject voluntarily withdraws;

[0381] 3) The investigator determines that the subject is not suitable for continuing the study treatment due to AE;

[0382] 4) Deviation from the clinical research protocol: The test results of the subject do not meet the inclusion criteria or the exclusion criteria of the protocol, or the subject cannot comply with the protocol. The researcher determines that the safety of the subject is affected or the research data is significantly affected. After the researcher's judgment, the subject is advised to withdraw;

[0383] 5) Other situations where the researcher deems it necessary to withdraw.

[0384] Safety Assessment:

[0385] Adverse events: All subjects were observed for any adverse events during the clinical study, including abnormal clinical symptoms and vital signs, laboratory tests (blood routine, blood biochemistry, urine routine), and abnormalities in the 12-lead electrocardiogram. Their clinical manifestations, severity, time of occurrence, end time, treatment measures and outcomes were recorded, and their correlation with the study drug was determined.

[0386] Pulmonary function test:

[0387] Spirometry was performed in accordance with the Guidelines for Pulmonary Function Examination-Spirometry Examination and related SOPs issued by the Chinese Medical Association.

[0388] Pulmonary function tests were performed at the corresponding time points before and after medication on the 1st, 43rd, 85th, 127th, 183rd, 239th, 295th, and 365th days, and the FEV1 values ​​at each time point were obtained.

[0389] Statistical analysis methods:

[0390] (1) Security

[0391] Safety assessments included adverse events, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), and clinical laboratory tests. All adverse events (AEs), treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) were summarized by system organ class and preferred term for each dose level. All TEAEs, TRAEs, and SAEs were summarized by incidence, severity, and relationship to the trial drug.

[0392] (2) Effectiveness

[0393] The primary endpoint of this study was a non-inferiority analysis of the indacaterol bromide inhalation solution of the present invention compared with Jerun in terms of the change in FEV1 trough value compared with baseline after 26 weeks of treatment.

[0394] The repeated measures mixed effects model (MMRM) was used to analyze the change in FEV1 trough values ​​from baseline between groups. The model used the change in FEV1 trough values ​​from baseline at 6, 12, 18, and 26 weeks of treatment as the dependent variable, the treatment group, whether the bronchial dilation test showed reversibility, and the severity of airflow limitation as fixed effects, the baseline FEV1 as a covariate, and the subject as a random effect, including the time effect (visit) and its interaction term with treatment and baseline FEV1. Variance estimation was based on an unstructured covariance matrix. If the model did not converge, a composite symmetric covariance structure was used. The Kenward-Roger method was used to estimate the denominator degrees of freedom. The least squares means and standard errors of the adjusted changes in the values ​​of each group were listed, and the least squares means and 95% confidence intervals of the difference in the change in FEV1 trough values ​​from baseline in the indaterroglopronic bromide inhalation solution group of the present invention relative to the Jerun group for 26 weeks of treatment were calculated.

[0395] For the incidence of moderate and severe COPD exacerbations within 26 and 52 weeks, a negative binomial distribution model was used to calculate the corresponding inter-group ratios and 95% confidence intervals (CI), and provide P values ​​for inter-group comparisons.

[0396] Research conclusions:

[0397] (1) The indacaterol bromide inhalation solution of the present invention has an excellent effect on improving the lung function of COPD patients.

[0398] (2) The indacaterol bromide inhalation solution of the present invention has a lower incidence of adverse reactions and good safety.

[0399] (3) In the indacaterol bromide inhalation solution treatment group of the present invention, the incidence of severe COPD acute exacerbation was lower than that in the positive control indacaterol bromide inhalation powder treatment group.

[0400] In summary, the unit-dose indacaterol bromide maleate pharmaceutical composition provided by the present invention has excellent efficacy and good safety, and has higher use satisfaction for patients, especially patients with moderate to severe COPD.

Claims

1. A unit dose pharmaceutical composition comprising indacaterol maleate and glycopyrrolate as active ingredients, wherein: Indacaterol C 24 H 28 In terms of N2O3, the content of indacaterol maleate is selected from 132 μg to 516 μg; and, in terms of glycopyrronium C 19 H 28 Based on NO3, the glycopyrrolate content is selected from 72 μg-279 μg.

2. The pharmaceutical composition of claim 1, wherein: Indacaterol C 24 H 28 In terms of N2O3, the content of indacaterol maleate is selected from 132 μg to 265 μg, or selected from 162 μg to 231 μg; Glycopyrronium C 19 H 28 The content of glycopyrrolate is selected from 72 μg-145 μg based on NO3.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein: In terms of indacaterol C 24 H 28 N2O3, the content of indacaterol maleate is selected from 132 μg, 133 μg, 134 μg, 135 μg, 136 μg, 137 μg, 138 μg, 139 μg, 140 μg, 141 μg, 142 μg, 143 μg, 144 μg, 145 μg, 146 μg, 147 μg, 148 μg, 149 μg, 150 μg, 151 μg, 152 μg, 153 μg, 154 μg, 155 μg, 156 μg, 157 μg, 158 μg, 159 μg, 160 μg, 161 μg, 162 μg, 163 μg, 164 μg, 165 μg, 166 μg, 167 μg, 168 μg, 169 μg, 170 μg, 171 μg, 172 μg, 173 μg, 174 μg, 175 μg, 176 μg, 177 μg, 178 μg, 179 μg, 180 μg, 181 μg, 182 μg, 183 μg, 184 μg, 185 μg, 186 μg, 187 μg, 188 μg, 189 μg, 190 μg, 191 μg, 192 μg, 193 μg, 194 μg, 195 μg, 196 μg, 197 μg, 198 μg, 199 μg, 200 μg, 201 μg, 202 μg, 203 μg, 204 μg, 205 μg, 206 μg, 207 μg, 208 μg, 209 μg, 210 μg, 211 μg, 212 μg, 213 μg, 214 μg, 215 μg, 216 μg, 217 μg, 218 μg, 219 μg, 220 μg, 221 μg, 222 μg, 223 μg, 224 μg, 225 μg, 226 μg, 227 μg, 228 μg, 229 μg, 230 μg, 231 μg, 232 μg, 233 μg, 234 μg, 235 μg, 236 μg, 237 μg, 238 μg, 239 μg, 240 μg, 241 μg, 242 μg, 243 μg, 244 μg, 245 μg, 246 μg, 247 μg, 248 μg, 249 μg, 250 μg, 251 μg, 252 μg, 253 μg, 254 μg, 255 μg, 256 μg, 257 μg, 258 μg, 259 μg, 260 μg, 261 μg, 262 μg, 263 μg, 264 μg or 265 μg; Or selected from 162μg, 163μg, 164μg, 165μg, 166μg, 167μg, 168μg, 169μg, 170μg, 171μg, 172μg, 173μg, 174μg, 175μg, 176μg, 177μg, 178μg, 179μg, 180μg, 181μg, 182μg, 183μg, 184μg, 185μg, 186μg, 187μg, 188μg, 189μg, 190μg, 191μg, 192μg, 193μg, 194μg, 195μg, 196μ g, 197μg, 198μg, 199μg, 200μg, 201μg, 202μg, 203μg, 204μg, 205μg, 206μg, 207μg, 208μg, 209μg, 210μg, 211μg, 212μg, 213μg, 21 4μg, 215μg, 216μg, 217μg, 218μg, 219μg, 220μg, 221μg, 222μg, 223μg, 224μg, 225μg, 226μg, 227μg, 228μg, 229μg, 230μg or 231μg; Or selected from 196μg, 197μg, 198μg, 199μg, 200μg, 201μg, 202μg, 203μg, 204μg, 205μg, 206μg, 207μg, 208μg, 209μg, 210μg, 211μg, 212μg, 213μg, 214μg, 215μg, 216μg, 217μg, 218μg, 219μg, 220μg, 221μg, 222μg, 223μg, 224μg, 225μg, 226μg, 227μg, 228μg, 229μg, 230μ g, 231μg, 232μg, 233μg, 234μg, 235μg, 236μg, 237μg, 238μg, 239μg, 240μg, 241μg, 242μg, 243μg, 244μg, 245μg, 246μg, 247μg, 24 8μg, 249μg, 250μg, 251μg, 252μg, 253μg, 254μg, 255μg, 256μg, 257μg, 258μg, 259μg, 260μg, 261μg, 262μg, 263μg, 264μg or 265μg; Calculated as glycopyrronium C 19 H 28 NO3, the content of glycopyrronium bromide is selected from 72 μg, 73 μg, 74 μg, 75 μg, 76 μg, 77 μg, 78 μg, 79 μg, 80 μg, 81 μg, 82 μg, 83 μg, 84 μg, 85 μg, 86 μg, 87 μg, 88 μg, 89 μg, 90 μg, 91 μg, 92 μg, 93 μg, 94 μg, 95 μg, 96 μg, 97 μg, 98 μg, 99 μg, 100 μg, 101 μg, 102 μg, 103 μg, 104 μg, 105 μg, 106 μg, 107 μg, 108 μg, 109 μg, 110 μg, 111 μg, 112 μg, 113 μg, 114 μg, 115 μg, 116 μg, 117 μg, 118 μg, 119 μg, 120 μg, 121 μg, 122 μg, 123 μg, 124 μg, 125 μg, 126 μg, 127 μg, 128 μg, 129 μg, 130 μg, 131 μg, 132 μg, 133 μg, 134 μg, 135 μg, 136 μg, 137 μg, 138 μg, 139 μg, 140 μg, 141 μg, 142 μg, 143 μg, 144 μg or 145 μg; Or selected from 92μg, 93μg, 94μg, 95μg, 96μg, 97μg, 98μg, 99μg, 100μg, 101μg, 102μg, 103μg, 104μg, 105μg, 106μg, 10 7μg, 108μg, 109μg, 110μg, 111μg, 112μg, 113μg, 114μg, 115μg, 116μg, 117μg, 118μg, 119μg, 120μg or 121μg; Or selected from 116μg, 117μg, 118μg, 119μg, 120μg, 121μg, 122μg, 123μg, 124μg, 125μg, 126μg, 127μg, 128μg, 129μg, 130μ g, 131μg, 132μg, 133μg, 134μg, 135μg, 136μg, 137μg, 138μg, 139μg, 140μg, 141μg, 142μg, 143μg, 144μg or 145μg.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein indacaterol C 24 H 28 N2O3 divided by glycopyrronium C 19 H 28 NO3, the mass ratio of indacaterol maleate and glycopyrrolate is selected from 1.5 to 2.3, or from 1.7 to 2.2, or from 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9 or 2.

18.

5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising a buffer pair, a pH regulator and an osmotic pressure regulator, and prepared into any pharmaceutically acceptable dosage form, wherein the pharmaceutically acceptable dosage form is in the form of an inhalation solution.

6. The pharmaceutical composition of claim 5, wherein: The buffer pair is selected from a citric acid-sodium citrate buffer pair, a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, a sodium bicarbonate-sodium carbonate buffer pair, an acetic acid-sodium acetate buffer pair or a tartaric acid-sodium tartrate buffer pair, preferably a citric acid-sodium citrate buffer pair; The pH adjuster is selected from a combination of one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acids, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and disodium hydrogen phosphate, preferably one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, and maleic acid; The osmotic pressure regulator is selected from at least one of sodium chloride and mannitol, preferably sodium chloride.

7. The pharmaceutical composition of claim 6, wherein: The buffer pair is selected from citric acid-sodium citrate, wherein the concentration of the citric acid-sodium citrate buffer pair is selected from 1mM to 50mM, or selected from 1mM to 20mM, or selected from 2mM to 10mM; The pH adjuster is selected from hydrochloric acid or sodium hydroxide; The osmotic pressure regulator is selected from sodium chloride; The pH of the pharmaceutical composition is selected from 3.5-4.5, or selected from pH=4.0±0.

1.

8. The pharmaceutical composition according to claim 7, wherein the volume specification of the inhalation solution is selected from 1 to 4 mL, or selected from 2 to 4 mL, or selected from 3 mL.

9. The pharmaceutical composition according to claims 1-8, which is administered by inhalation through a nebulizer, wherein the nebulization rate of the nebulizer is selected from 0.05 to 1.5 ml / min, or the nebulization rate of the nebulizer is selected from 0.1 to 0.6 ml / min.

10. The pharmaceutical composition according to claim 9, wherein the nebulizer can use a compressed air nebulizer, wherein the compressed air nebulizer is selected from PARI JuniorBOY nebulizer, PARI BOY nebulizer, PARI BOY Pro nebulizer, PARI TurboBOY nebulizer, PARI COMPACT N nebulizer, Philips cn-c-0101 nebulizer, Philips InnoSpire Dluxe atomizer, Philips CN-B-0303 atomizer, Omron NE-C900 atomizer, Omron NE-C28 atomizer, Omron GC830 atomizer, Omron GC813 atomizer, Yuyue 403T atomizer, Yuyue 403M atomizer, Yuyue 403D atomizer, Yuyue 403H atomizer, Jiuan KS-WH200-D atomizer, Jiaruikang JLN-2321AS atomizer, Jiaruikang JLN-2306AS atomizer, Jiaruikang JLN-2304HDD atomizer, Jiaruikang JLN-2317AS atomizer, Jiaruikang JLN-2311HD atomizer, preferably PARI JuniorBOY atomizer, PARI BOY atomizer, PARI BOY Pro atomizer, PARI Turbo BOY atomizer, PARI COMPACT N atomizer, Philips InnoSpire Dluxe atomizer or Philips CN-B-0303 atomizer.

11. The pharmaceutical composition according to claim 9, wherein the nebulizer can use a vibrating mesh nebulizer, wherein the vibrating mesh nebulizer is selected from Jiuan VP-M3A nebulizer, Jiaruikang JLN-MB001 nebulizer, Omron NE-U100J nebulizer, Philips DK012 nebulizer, Yuyue M105 nebulizer, PARI Nebulizer System, preferably Jiuan VP-M3A, Philips DK012, Yuyue M105 or PARI Nebulizer System type atomizer.

12. The pharmaceutical composition according to any one of claims 1 to 8, which is administered to a subject in need of treatment once a day or once every two days.

13. The pharmaceutical composition of claim 12, wherein the subject suffers from asthma and / or chronic obstructive pulmonary disease (COPD).

14. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for treating asthma and / or chronic obstructive pulmonary disease (COPD).

15. A method for preparing the pharmaceutical composition according to claims 1-8, comprising the following steps: (a) adding a prescribed amount of an excipient to water, wherein the excipient is selected from at least one of an osmotic pressure regulator and a buffer ion pair, stirring to disperse and dissolve the excipient and adjusting the pH of the solution to a target value of 2.0 to 5.5 with a pH regulator; (b) Add the prescribed amount of indacaterol maleate and glycopyrrolate to the excipient solution prepared in (a), and stir to dissolve. Optionally, the drug solution obtained in the above (b) is filtered and sterilized, for example, using a filter membrane with a diameter of less than or equal to 0.22 μm to obtain a sterile drug solution. Optionally, the obtained sterile drug solution is packaged, for example, filled into vials, glass ampoules or plastic ampoules to obtain an indacaterol bromide inhalation solution pharmaceutical composition.

16. A method for preparing the pharmaceutical composition according to claim 15, comprising the following steps: 1) Add 80-95% of the batch volume of water for injection, turn on the agitator, and raise the temperature so that the water in the preparation tank is controlled at 26°C to 30°C; 2) Add the required amount of auxiliary materials to the liquid preparation tank, stir until the solution is clear and uniform, and maintain the temperature at 26℃~30℃; 3) Evacuate the liquid preparation tank for 5 minutes, and then introduce nitrogen for no less than 20 minutes; 4) adjusting the pH of the solution to 4.0±0.1 with a pH adjuster; 5) Add the prescribed amount of indacaterol maleate and glycopyrrolate into the liquid preparation tank, stir until the solution is clear and uniform, and maintain the temperature at 26°C to 30°C; 6) Adjust the pH to 4.0±0.1 with pH adjuster, make up the volume of the drug solution to the final volume with water for injection, stir until the solution is uniform, and lower the temperature to 18℃~22℃; 7) Sterile filter the solution using a 0.22 μm filter; 8) The liquid medicine is aseptically filled by a blow-fill-seal machine, and the inner packaging is a low-density polyethylene ampoule; 9) Carry out light inspection, labeling and packaging.

17. A medicine kit comprising: One or more doses of a pharmaceutical composition according to any one of claims 1 to 8; and Instructions comprising one or more forms of information selected from the group consisting of information indicating the disease state for which the pharmaceutical composition is to be administered, storage information for the pharmaceutical composition, administration information, and instructions on how to administer the pharmaceutical composition.

18. An article of manufacture comprising: One or more doses of a pharmaceutical composition according to any one of claims 1 to 8; and Packaging materials.

19. The article of manufacture of claim 18, wherein the packaging material comprises a container for containing the plurality of unit doses of the pharmaceutical composition.

20. The article of manufacture according to claim 19, wherein the container comprises a label indicating one or more of the following: a disease state for which the composition is to be administered, storage information, dosing information, and / or instructions on how to administer the composition.

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