Indacaterol maleate pharmaceutical composition for inhalation as well as preparation method and application of indacaterol maleate pharmaceutical composition

Abstract

The invention relates to an indacaterol maleate pharmaceutical composition for inhalation as well as a preparation method and application of the indacaterol maleate pharmaceutical composition. Specifically, the invention discloses an inhalation pharmaceutical composition combining a long-acting beta2 receptor stimulant and a long-acting muscarinic receptor antagonist, and the composition does not contain a metal chelating agent, shows a higher fine particle dosage under high concentration, and has good stability. The invention also discloses application of the pharmaceutical composition in prevention and / or treatment of respiratory system diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular, it relates to an inhaled pharmaceutical composition of indacaterol maleate and rufinadol and a preparation method and application thereof. BACKGROUND

[0002] Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by irreversible airflow limitation, the pathological core of which is the abnormal inflammatory response of airway and lung tissue to harmful particles or gases, which covers multiple phenotypes such as chronic bronchitis and emphysema. With disease progression, patients develop persistent dyspnea, loss of mobility and repeated acute exacerbations, with high mortality and disability, and has become the third leading cause of death worldwide.

[0003] Existing treatment focuses on relieving symptoms and slowing disease progression, but still faces the following key challenges:

[0004] Although inhaled corticosteroids (ICS) can inhibit inflammation, hormone therapy is not sensitive in COPD patients, ICS cannot effectively control progressive airway inflammation, nor can it reverse lung function decline, and the effect on severe patients with frequent acute exacerbations is significantly insufficient.

[0005] Inhaled bronchodilators, as the cornerstone of chronic obstructive pulmonary disease (COPD) treatment, achieve symptom control and pathological improvement through multidimensional mechanisms, and their core value is reflected in the following aspects:

[0006] Long-acting beta2 receptor agonists (LABA) (such as formoterol, indacaterol) selectively activate airway beta2 receptors, increase intracellular cAMP levels, and rapidly dilate bronchi;

[0007] Long-acting muscarinic receptor antagonists (LAMA) (such as tiotropium, rufinadol) block M3 receptor-mediated smooth muscle contraction signals and long-acting inhibit cholinergic nerve tension.

[0008] Clinical effect: the combination of LABA / LAMA can maintain 24-hour bronchodilation, significantly relieve dyspnea, wheezing and night symptoms, and reduce the risk of acute exacerbation by 30%-40%.

[0009] In the prior art, ethylenediaminetetraacetic acid (EDTA) is often introduced into the formula of inhaled drugs as a metal ion chelating agent, which can complex transition metal ions (such as Fe 3+ , Cu 2+) inhibit drug oxidation / hydrolysis reaction, while assisting in regulating osmotic pressure and pH stability. However, the strong chelating properties of EDTA can disrupt airway mucosa ion balance, induce local tissue osmotic pressure abnormalities and inflammatory mediator release, significantly increase the risk of airway hyperresponsiveness (such as cough, bronchospasm, etc.) in COPD patients, and long-term use can more likely damage the mucociliary clearance function, forming a vicious cycle of stimulation-inflammation. This phenomenon seriously restricts the application safety of EDTA-containing preparations in the treatment of chronic respiratory diseases.

[0010] In addition, in the prior art, the disclosed indacaterol / rilmenapril combination is mostly low-dose (such as indacaterol ≤ 50 μg / time), which only meets the needs of mild to moderate COPD, and due to the dose limitation, it is only suitable for mild to moderate patients, and the clinical efficacy coverage is low.

[0011] Therefore, there is an urgent need in the art to develop an inhaled pharmaceutical composition for LABA and LAMA combination for preventing and / or treating asthma and / or chronic obstructive pulmonary disease to avoid the shortcomings of the prior art. SUMMARY

[0012] The purpose of the present application is to provide a maleic acid indacaterol rilmenapril inhalation solution and a preparation method and use thereof. Specifically, the inhalation solution can efficiently and stably prevent and / or treat respiratory diseases at a high concentration.

[0013] In a first aspect of the present application, a metal-chelator-free inhaled pharmaceutical composition is provided, comprising a long-acting β2 receptor agonist or a pharmaceutically acceptable salt thereof and a long-acting muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof,

[0014] wherein,

[0015] the long-acting β2 receptor agonist is maleic acid indacaterol;

[0016] the long-acting muscarinic receptor antagonist is rilmenapril;

[0017] the content of the maleic acid indacaterol is 50-140 μg / ml; and / or

[0018] the weight ratio of the indacaterol and rilmenapril is 5:1-1:1.

[0019] In another preferred embodiment, the content of the maleic acid indacaterol is 100-140 μg / ml.

[0020] In another preferred embodiment, the weight ratio of the indacaterol and rilmenapril is 3:1-1:1.

[0021] In another preferred embodiment, the composition further comprises a solubilizer selected from the group consisting of polysorbate 20, polysorbate 80, or a combination thereof; preferably, the solubilizer is polysorbate 80.

[0022] In another preferred embodiment, the composition further comprises a buffer selected from the group consisting of citric acid / sodium citrate, citric acid / disodium hydrogen carbonate, or a combination thereof; preferably, the buffer is citric acid / disodium hydrogen carbonate.

[0023] In another preferred embodiment, the content of the rafenaminustab is 20-100 μg / mL; preferably, 20-60 μg / mL.

[0024] In another preferred embodiment, the content of the solubilizer is 100-1000 μg / mL.

[0025] In another preferred embodiment, preferably, 100-800 μg / mL; more preferably, 100-400 μg / mL.

[0026] In another preferred embodiment, the pH value of the composition is 3.0-6.5.

[0027] In another preferred embodiment, the pH value of the composition is 3.5-6.0; preferably, 3.5-5.5; more preferably, 4.0-5.0.

[0028] In another preferred embodiment, the composition further comprises an osmotic pressure regulator selected from the group consisting of sodium chloride, lactose, glucose, glycerol, or a combination thereof.

[0029] In another preferred embodiment, the osmotic pressure regulator is sodium chloride.

[0030] In another preferred embodiment, the content of the osmotic pressure regulator is 2-10 mg / mL; preferably, 3-9 mg / mL.

[0031] In a second aspect of the present application, a preparation method of the composition according to the first aspect of the present application is provided, comprising the following steps:

[0032] (S1) dissolving a buffer and an osmotic pressure regulator in water for injection, adjusting the pH value to obtain a solvent solution;

[0033] (S2) dissolving a solubilizer in the solvent solution to obtain a mixed solution;

[0034] (S3) homogenizing a long-acting β2 receptor agonist in a surfactant-containing solution, and then adding a long-acting muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof into the other solvent solution, stirring to dissolve, adding water to the preparation amount, and filtering to obtain the composition according to the first aspect of the present application.

[0035] In a third aspect, the present application provides use of the composition according to the first aspect of the present application for the manufacture of a medicament for the prevention and / or treatment of respiratory diseases.

[0036] In another preferred embodiment, the disease is asthma or chronic obstructive pulmonary disease.

[0037] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 The deposition amount of each level of indacaterol maleate fine particle dose under different specifications of the prescription is shown.

[0039] Figure 2 The deposition amount of each level of rafenina fine particle dose under different specifications of the prescription is shown.

[0040] Figure 3 The deposition amount of each level of indacaterol maleate fine particle dose under different types and amounts of solubilizers in the prescription is shown.

[0041] Figure 4 The deposition amount of each level of rafenina fine particle dose under different types and amounts of solubilizers in the prescription is shown.

[0042] Figure 5 The deposition amount of each level of indacaterol maleate fine particle dose in the prescription of different buffer pairs is shown.

[0043] Figure 6 The deposition amount of each level of rafenina fine particle dose in the prescription of different buffer pairs is shown. DETAILED DESCRIPTION

[0044] The present inventors have developed an inhaled pharmaceutical composition through extensive and in-depth research. The composition comprises indacaterol maleate or a pharmaceutically acceptable salt thereof and rafenina or a pharmaceutically acceptable salt thereof, and does not contain a metal chelating agent. The composition remains a clear solution at a high concentration and can maintain good stability, and has excellent prevention and / or treatment of respiratory diseases. On this basis, the present inventors have completed the present application.

[0045] TERMS

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs

[0047] As used herein, the terms "comprising," "including," "containing," and variations thereof, are inclusive, not exclusive, and are used interchangeably with "consisting essentially of. In other words, the terms include "consisting of."

[0048] As used herein, the following abbreviations have the following meanings:

[0049] FPD: fine particle dose;

[0050] FPF: fine particle fraction;

[0051] MMAD: mass median aerodynamic diameter;

[0052] GSD: geometric standard deviation.

[0053] Chronic Obstructive Pulmonary Disease (COPD)

[0054] Definitions

[0055] Chronic Obstructive Pulmonary Disease, abbreviated as COPD, is a chronic inflammatory disease of the airways that is characterized by progressive airflow limitation. The main symptoms of the patients are cough, sputum and progressive worsening of breathlessness. COPD is a preventable and treatable disease with predominantly smoking as the cause, but also air pollution and genetic factors.

[0056] Prevalence

[0057] COPD has a high prevalence, high mortality and heavy social and economic burden, and has become an important public health problem affecting human health. Epidemiological survey studies have shown that in China, the number of COPD patients is as high as 43 million, and the prevalence rate in people aged 40 and above is as high as 9.9%, i.e. about 1 in 10 people has COPD.

[0058] Symptoms

[0059] • Chronic cough: often the earliest symptom, which can last a lifetime as the disease progresses, often more obvious in the morning, and night cough or expectoration.

[0060] • Cough and sputum: generally white mucus or serous foam sputum, occasionally with blood, more sputum in the morning. During acute exacerbation, sputum volume increases, and purulent sputum can be present.

[0061] • Shortness of breath or dyspnea: is the hallmark symptom of COPD, which occurs in early labor, and gradually worsens over time, so that even at rest, the patient feels shortness of breath.

[0062] • Wheezing and chest tightness: Some patients, especially severe patients or during acute exacerbation, may have wheezing.

[0063] Asthma

[0064] Asthma, also known as bronchial asthma, is a chronic inflammatory disease of the respiratory tract. After chronic inflammation, airway reactivity increases, and when exposed to various risk factors, airway obstruction and airflow obstruction occur, resulting in recurrent wheezing, dyspnea, chest tightness and cough.

[0065] Asthma prevalence: The global burden of asthma is severe. In 2021, there were about 260 million asthma patients worldwide, and about 436,000 deaths. The asthma prevalence rate of people aged 20 and above in China is 4.2%, with about 45.7 million asthma patients. Since 2010, the asthma prevalence rate of young people and adults in China has been on the rise.

[0066] Compared with the prior art, the advantages of the present application mainly lie in:

[0067] 1. The composition described in the present application is in a clear solution state at high concentrations, has a stable atomization rate, and avoids adverse reactions.

[0068] 2. The composition described in the present application has high fine particle dose (FPD) and low MMAD, improved efficacy, and can effectively reduce the frequency of medication.

[0069] 3. The total effective lung deposition amount of the composition described in the present application is high, which can improve patient compliance.

[0070] 4. The composition described in the present application has low total impurity ratio, high safety and low risk of side effects.

[0071] 5. The composition described in the present application has stable pH value and osmotic pressure, which can reduce the irritability of administration.

[0072] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually carried out according to the conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0073] Indacaterol maleate: manufacturer: Shandong Suli Pharmaceutical Co., Ltd. batch number: T801042210001 Roflumilast manufacturer: Hubei Gedian Renfu Pharmaceutical Co., Ltd. batch number: LN220203

[0074] Preparation of inhalation solutions of different specifications in examples 1-3

[0075] A prescription information

[0076]

[0077] B Process step (batch: 600 mL)

[0078] 1. Weigh 540 g of water for injection into container 1, and sequentially add citric acid 0.422 g, sodium citrate 0.294 g, sodium chloride 1.8 g, stir and dissolve, detect pH, and adjust pH to 4.0 ± 0.05 using 1 mol / L sodium hydroxide solution;

[0079] 2. Weigh 0.12 g of polysorbate 20 into container 2, and add 50 ml of the auxiliary solution prepared in step 1, stir and dissolve;

[0080] 3. Add the prescribed amount of indacaterol maleate to the container in step 2, and use a ZLE-B500 type laboratory homogenizing emulsifier to homogenize and stir, at a homogenizing speed of 3000 rpm for 30 min;

[0081] 4. Transfer the solution prepared in step 3 to container 1, stir for 24 hours to dissolve indacaterol maleate, and then add the prescribed amount of rufinamide, stir for 30 min to dissolve, and add water to 600 ml;

[0082] 5. Filter using a 0.22 um filter membrane;

[0083] 6. Sample the intermediate product solution to detect pH and content;

[0084] 7. Fill, 3.0-3.3 ml per bottle;

[0085] 8. Package using aluminum-plastic composite film bags and store in the warehouse.

[0086] C Detection method

[0087] 1. Content:

[0088] Chromatographic conditions:

[0089] Detection wavelength: 230 nm;

[0090] Column temperature: 30℃;

[0091] Flow rate: 1.0 ml / min;

[0092] Injection volume: 20 μl;

[0093] Time: 15 min;

[0094] Solvent: mobile phase.

[0095] Mobile phase and solvent: pH 3.1 phosphate buffer: acetonitrile (70:30). pH 3.1 phosphate buffer: accurately weigh sodium dihydrogen phosphate monohydrate 3.7 g, add water 1000 ml to dissolve, adjust pH to 3.1 ± 0.1 with phosphoric acid solution.

[0096] Control solution: accurately measure 1 ml of indacaterol maleate control stock solution and 1 ml of rufinamide control stock solution into the same 20 ml volumetric flask, dilute to the mark with solvent, shake well, and obtain.

[0097] Test solution: take 2 samples, accurately measure 2 ml or 1 ml from each, respectively, into a 10 ml volumetric flask, dilute to the mark with solvent, shake well.

[0098] 2. Related substances:

[0099] Chromatographic conditions:

[0100] Detection wavelength: 210 nm;

[0101] Column temperature: 40°C;

[0102] Flow rate: 0.7 ml / min;

[0103] Injection volume: 50 μl;

[0104] Time: 70 min;

[0105] Solvent: mobile phase.

[0106] Elution gradient program:

[0107]

[0108]

[0109] Mobile phase A: sodium perchlorate buffer-acetonitrile (90:10);

[0110] Mobile phase B: sodium perchlorate buffer-acetonitrile (20:80);

[0111] Solvent: acetonitrile-0.1% phosphate (3:7)

[0112] Perchloric acid solution: accurately measure 2 ml of perchloric acid into a 20 ml volumetric flask, dilute to the mark with water, shake well.

[0113] Sodium perchlorate buffer: weigh 6.12 g of sodium perchlorate, dissolve in 1000 ml of water, mix well, and adjust the pH to 2.5 with perchloric acid solution.

[0114] Solvent: Accurately weigh 0.2 ml of phosphoric acid into 200 ml of water and mix well. Accurately weigh 140 ml of acetonitrile and 60 ml of water, mix well and filter.

[0115] Test solution: Indacaterol maleate and rufinamide inhalation solution was directly injected.

[0116] 3. Fine particle dose:

[0117] Chromatographic conditions:

[0118] Detection wavelength: 230 nm;

[0119] Column temperature: 30°C;

[0120] Flow rate: 1 ml / min;

[0121] Injection volume: 100 μl;

[0122] Time: 15 min;

[0123] Solvent: Mobile phase.

[0124] Mobile phase and solvent: pH 3.1 phosphate buffer: acetonitrile (70:30). pH 3.1 phosphate buffer: accurately weigh 3.7 g of sodium dihydrogen phosphate monohydrate into 1000 ml of water and dissolve. Adjust the pH to 3.1 ± 0.1 with phosphoric acid solution.

[0125] Reference solution: accurately weigh 1 ml of indacaterol maleate reference stock solution and 2 ml of rufinamide reference stock solution into the same 50 ml volumetric flask, dilute to the mark with solvent and mix well. Accurately weigh 1 ml into a 10 ml volumetric flask, dilute to the mark with solvent and mix well.

[0126] Test solution: according to Inhalation preparations, Fine particle air dynamics characteristics determination method (Chinese Pharmacopoeia 2020 edition four general rules 0951), the device 3 (i.e. NGI) was used, the assembled impactor and L type connecting pipe were pre-cooled in the cooling device (5℃) for at least 90 minutes (the first use was at least 90 min, and then at least 30 min, and the S1 temperature was measured, and the determination temperature should be less than 10℃), the outlet of the impactor was connected with the vacuum pump, the vacuum pump was started, the flow meter was connected with the L type connecting pipe, the flow control valve was adjusted to make the gas flow rate of the L type connecting pipe inlet 15 L / min (±5%), and the flow meter was removed. 2 bottles of the product were taken, placed in a Schering bottle, mixed uniformly, 3 ml was accurately taken and added into the atomization cup, the atomization device was placed according to the actual use direction, the suction nozzle was connected to the L type connecting pipe through the suction nozzle adapter. The atomization pump was opened, the time was counted, the atomization time was 5 minutes, the atomizer was closed, the vacuum pump was closed, and the impactor was removed. The active substance in the atomizer and the mouthpiece was collected with the solvent into a 100 ml volumetric flask, diluted with the solvent to the mark, and used as the atomizer residual test solution; the deposited drug in the L type connecting pipe and the atomization adapter was collected with the solvent into a 25 ml volumetric flask, diluted with the solvent to the mark, and used as the artificial throat test solution; the deposited drug in S1-S7 and MOC levels was collected with the solvent into 8 25 ml volumetric flasks, respectively, diluted with the solvent to the mark, and used as the test solution of each level.

[0127] 4. Delivery rate and total amount of delivery:

[0128] Chromatographic conditions:

[0129] Detection wavelength: 230 nm;

[0130] Column temperature: 30℃;

[0131] Flow rate: 1 ml / min;

[0132] Injection volume: 100 μl;

[0133] Time: 15 min;

[0134] Solvent: mobile phase.

[0135] Mobile phase and solvent: pH 3.1 phosphate buffer: acetonitrile (70:30). pH 3.1 phosphate buffer: accurately weigh sodium dihydrogen phosphate monohydrate 3.7 g, add water 1000 ml to dissolve, and adjust the pH to 3.1±0.1 with phosphoric acid solution.

[0136] Control solution: accurately take 1 ml of indacaterol maleate control solution stock solution and 2 ml of rufinamide control solution stock solution into the same 50 ml volumetric flask, dilute to the mark with solvent, shake well; accurately take 1 ml, add solvent to a 10 ml volumetric flask, dilute to the mark, and shake well.

[0137] Test solution: The breathing pattern was as follows: tidal volume: 500 ml; breathing frequency: 15 cycles / min; breathing waveform: sinusoidal; inspiration-expiration ratio: 1:1. The filter paper was placed in the filter paper device, which was then connected to the breathing simulator, and the mouthpiece of the nebulizer was connected to the filter paper device through the mouthpiece adapter. Two test samples were taken, mixed in a Schlenk flask, and 3 ml was accurately measured and placed in the nebulization cup. The breathing simulator was set to the breathing pattern shown in the table below. The breathing simulator was turned on, and the working time of the breathing simulator was timed for 10 min. The nebulizer was started at the beginning of the breathing cycle, and when the nebulization was 1 min, the nebulizer was turned off, and the breathing simulator was paused. The filter membrane in the filter paper device was removed and placed in a small beaker, and the filter membrane was washed multiple times with solvent. The solution was transferred to a 50 ml volumetric flask through a funnel, and the solvent was diluted to the mark. This was the delivery rate test solution. A new filter membrane was placed in the filter paper device, and the device was installed. The nebulizer was started, and the breathing simulator was resumed until the end of the working time. The nebulizer was turned off, and the filter membrane was removed. The filter membrane was washed multiple times with solvent, and the solution was transferred to a 100 ml volumetric flask through a funnel. The solvent was diluted to the mark, and this was the total delivery test solution. The filter membrane that lost the aerosol was removed, washed multiple times with solvent, and the solution was transferred to a 100 ml volumetric flask through a funnel. The solvent was diluted to the mark, and this was the aerosol loss test solution. The solvent was added first, and the active substance on the nebulizer was collected in a 100 ml volumetric flask. The solvent was diluted to the mark, and this was the nebulizer residue test solution.

[0138] D Test results

[0139]

[0140] ND: Not detected.

[0141] E Fine particle dose statistics

[0142]

[0143] F Experimental conclusion

[0144] From the D test results, it can be seen that the basic physicochemical properties (such as appearance) of different specifications are basically consistent, indicating that each specification without the addition of metal chelating agents (such as EDTA) can still maintain good stability and is not affected by changes in drug concentration. It also indicates that the weight ratio of indacaterol and rilmenimast is between 3:1 and 1:1, which can achieve good therapeutic effect.

[0145] From the E fine particle dose statistics, it can be seen that the FPF of different specifications is basically consistent. The nebulizer residue rate of Example 3 is still low in the case of high-dose indacaterol, and the deposition amount of each level is comparable to that of Examples 1 and 2. The FPF values of indacaterol and rilmenimast are above 59%, which indicates that high-concentration indacaterol (130 μg / ml) does not cause the viscosity of the nebulization liquid to rise or the particles to agglomerate.

[0146] The amount of each layer of indacaterol and rufinamide fine particle dose deposited at different weight ratios is shown in Table 1. Figure 1 and Figure 2 .

[0147] Example 4-7 Influence of Different Amounts and Types of Solubilizers The prescription information is compared with Example 3, and the different specifications are as follows:

[0148]

[0149]

[0150] B Process steps (batch: 600 mL)

[0151] 1. Weigh 540 g of water for injection into container 1, and sequentially add citric acid 0.422 g, sodium citrate 0.294 g, and sodium chloride 1.8 g, stir to dissolve, and detect the pH, and use 1 mol / L sodium hydroxide solution to adjust the pH to 4.0±0.05;

[0152] 2. Weigh the prescribed amount of polysorbate 20 / polysorbate 80 into container 2, and add 50 ml of the auxiliary material solution prepared in step 1, and stir to dissolve;

[0153] 3. Add the prescribed amount of indacaterol maleate to the container in step 2, and use a ZLE-B500 type laboratory homogenizing emulsifier to homogenize and stir, at a homogenizing speed of 3000 rpm for 30 min;

[0154] 4. Transfer the solution prepared in step 3 to container 1, and stir for 24 hours to dissolve the indacaterol maleate, and then add the prescribed amount of rufinamide, and stir for 30 min to dissolve, and add water to 600 ml;

[0155] 5. Filter using a 0.22 um filter membrane;

[0156] 6. Sample the intermediate product solution to detect the pH and content;

[0157] 7. Fill, 3.0-3.3 ml per bottle;

[0158] 8. Package using aluminum-plastic composite film bags, and store in the warehouse.

[0159] C Detection method

[0160] Same as Examples 1-3

[0161] D Detection results

[0162]

[0163]

[0164] ND: Not detected.

[0165] E Fine particle dose statistics

[0166]

[0167]

[0168] F Experimental conclusion:

[0169] From the D test results, the quality indicators of different solubilizers are basically the same, and the total impurities are ≤1%, which shows that different solubilizers or the amount of solubilizer does not affect the stability of the drug composition.

[0170] From the E results, the use of different amounts of polysorbate 20 (Examples 3-6) fine particle dose has equivalent results, and has no significant effect on fine particle dose (FPD) and atomization uniformity (FPF, MMAD), which shows the broad adaptability of the amount of surfactant.

[0171] In Example 7, when the solubilizer is polysorbate 80, the FPD value of indacaterol is as high as 109.72, which shows that polysorbate 80 has a delivery enhancement effect on high-concentration indacaterol.

[0172] Under the condition of different amounts and types of solubilizers, the deposition amount of indacaterol and rilmenimast micro-particle dose at each level is shown in Figure 3 and Figure 4 .

[0173] Example 8: Effect of different pH buffers on types

[0174] A formulation information

[0175] Example 3 is used as a control, and the specification formulation of this example is as follows:

[0176]

[0177]

[0178] B Process steps (batch: 600 mL)

[0179] 1. Weigh 540 g of water for injection into container 1, and add the prescribed amount of citric acid / sodium citrate or the prescribed amount of citric acid / disodium hydrogen phosphate, and the prescribed amount of sodium chloride, respectively, and stir to dissolve. Test the pH, and adjust the pH to 4.0±0.05 using 1 mol / L sodium hydroxide solution;

[0180] 2. Weigh the prescribed amount of polysorbate 20 into container 2, add 50 ml of the auxiliary material solution prepared in step 1, and stir to dissolve;

[0181] 3. Add the prescribed amount of indacaterol maleate into the container of step 2, and homogenize the mixture using a ZLE-B500 laboratory homogenizer at a speed of 3000 rpm for 30 min;

[0182] 4. Transfer the solution prepared in step 3 into container 1, and stir for 24 h to dissolve indacaterol maleate. Then add the prescribed amount of rufinamide, and stir for 30 min to dissolve. Finally, add water to 600 ml;

[0183] 5. Filter using a 0.22-μm filter;

[0184] 6. Sample the intermediate product solution to determine the pH and content;

[0185] 7. Fill, 3.0-3.3 ml per bottle;

[0186] 8. Package using an aluminum-plastic composite film bag, and store in a warehouse.

[0187] C Test method

[0188] Same as examples 1-3

[0189] D Test results

[0190]

[0191]

[0192] ND: Not detected.

[0193] E Fine particle dose histogram

[0194]

[0195] F Experimental conclusion:

[0196] As shown by the D test results, the quality indicators are basically the same for different buffer prescriptions, indicating that different buffers do not affect the stability of the drug composition.

[0197] As shown by the E results, when citric acid-disodium hydrogen phosphate is used as the buffer, the FPD value is better than that of example 3, and the MMAD is maintained between 1-5 μm, which can ensure more drug deposition in the lungs and achieve better therapeutic effect.

[0198] Under different buffers, the fine particle dose of indacaterol and rufinamide in each layer is as shown in Figure 5 and Figure 6 .

[0199] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without the specific details that are set forth herein. Further, it should be noted that, in this application, "exemplary" or "for example" is used on a purely illustrative basis to aid the reader in understanding the application. Any process steps, or sequences of steps, or examples, or embodiments, or materials, or components, or compounds, or elements, or techniques described herein are understood not to be limiting, but are exemplary.

Claims

1. A metal-chelator-free pharmaceutical composition for inhalation comprising a long-acting β2 receptor agonist or a pharmaceutically acceptable salt thereof and a long-acting muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof, wherein the long-acting β2 receptor agonist is indacaterol maleate; the long-acting muscarinic receptor antagonist is rufinacian; the content of the indacaterol maleate is 50-140 μg / ml; and / or the weight ratio of the indacaterol to the rufinacian is 5:1-1:

1. the content of the indacaterol maleate is 100-140 μg / ml; and / or the weight ratio of the indacaterol to the rufinacian is 3:1-1:

1. The composition further comprises a solubilizer selected from the group consisting of polysorbate 20, polysorbate 80, or a combination thereof; preferably, the solubilizer is polysorbate 80. The composition further comprises a buffer selected from the group consisting of citric acid / sodium citrate, citric acid / dibasic sodium phosphate, or a combination thereof; preferably, the buffer is citric acid / dibasic sodium phosphate. The content of the rufinacian is 20-100 μg / mL; preferably, 20-60 μg / mL. The content of the solubilizer is 100-1000 μg / mL.

2. The composition of claim 1, wherein The pH value of the composition is 3.0-6.

5. The composition further comprises an osmotic pressure regulator selected from the group consisting of sodium chloride, lactose, glucose, glycerol, or a combination thereof.

3. The composition of claim 1, wherein The preparation method comprises the following steps:

4. The composition of claim 1, wherein (S1) dissolving a buffer and an osmotic pressure regulator in water for injection, adjusting the pH value to obtain an excipient solution; 5. The composition of claim 1, wherein (S2) dissolving a solubilizer in the excipient solution to obtain a mixed solution; 6. The composition of claim 1, wherein (S3) homogenizing a long-acting β2 receptor agonist in a surfactant-containing solution, and then adding the long-acting muscarinic receptor antagonist or a pharmaceutically acceptable salt thereof and other excipients into the mixed solution, stirring to dissolve, adding water to the preparation amount, and filtering to obtain the composition of claim 1.

7. The composition of claim 1, wherein The composition is used for preparing a medicament for preventing and / or treating respiratory diseases.

8. The composition of claim 1, wherein ​ 9. A process for the preparation of a composition as claimed in claim 1, characterized in that, ​ ​ ​ ​ 10. Use of a composition according to claim 1, characterized in that, ​

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