Revefenacin triphenylacetate and powder aerosol for inhalation thereof

Abstract

Disclosed in the present invention are a revefenacin triphenylacetate and a powder aerosol for inhalation thereof. The revefenacin triphenylacetate of the present invention can be prepared into a powder aerosol for inhalation, which exhibits the effects of a high preparation stability, a high deposition fraction at the effective site in vivo, a good efficacy, and low side effects, thereby providing a new pharmaceutical choice for the treatment of COPD patients.

Description

A refenapyridine triphenylacetate and its inhalation powder Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, and specifically relates to a refenapyridine triphenylacetate and its inhalation powder. Background Technology

[0002] Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by airflow obstruction, involving chronic bronchitis and / or emphysema, which can further develop into pulmonary heart disease and respiratory failure. With increasing environmental pollution and an aging population, the number of COPD patients is rising annually, and respiratory diseases have become the third leading cause of death after cardiovascular and cerebrovascular diseases and malignant tumors. According to incomplete statistics, there are over 300 million COPD patients worldwide, with approximately 5 million deaths annually. The incidence of respiratory diseases in my country is approximately 6.9%, and it is showing a sudden and rapid upward trend.

[0003] The pathogenesis of COPD is complex and is generally considered to be related to the following mechanisms: 1. Inflammatory mechanism: Chronic inflammation of the airways, lung parenchyma, and pulmonary vessels is a characteristic change in COPD. Inflammatory cells such as neutrophils, macrophages, and T lymphocytes participate in the pathogenesis of COPD. 2. Protease-antiprotease imbalance mechanism: Proteolytic enzymes have a damaging and destructive effect on tissues; antiproteases have inhibitory functions on various proteases such as elastase, among which α1-antitrypsin (α1-AT) is the most active. Increased protease or insufficient antiprotease can lead to tissue damage and emphysema. 3. Oxidative stress mechanism: Oxides such as superoxide anions, hydroxyl radicals, hypochlorous acid, H2O2, and nitric oxide can directly act on and destroy many biochemical macromolecules such as proteins, lipids, and nucleic acids, leading to cell dysfunction or cell death. They can also damage the extracellular matrix, causing protease-antiprotease imbalance and promoting inflammatory responses. 4. Other mechanisms: These include autonomic nervous system dysfunction, malnutrition, and temperature changes.

[0004] The combined effects of these mechanisms ultimately lead to two important pathological changes: 1. Small airway disease, including small airway inflammation, small airway fibrosis, and mucus plugs in the small airway lumen, which significantly increase small airway resistance; 2. Emphysema, which reduces the normal tension of alveoli on the small airways, making them more prone to collapse. Simultaneously, emphysema significantly reduces the elastic recoil of alveoli. This combined effect of small airway disease and emphysema results in the characteristic persistent airflow limitation of COPD.

[0005] Inhaled medications are the preferred dosage form for treating COPD respiratory diseases. Common inhaled medications can be divided into two main categories according to their pharmacological effects: (1) Bronchodilators: Bronchodilators are the basic first-line treatment for COPD. They relax the smooth muscle of the airways, dilate the bronchi, improve airflow limitation, and thus alleviate the symptoms of COPD. The main bronchodilators include β2 receptor agonists, anticholinergic drugs, and methylxanthine drugs. They can be selected according to the drug's effects and the patient's treatment response. (2) Inhaled corticosteroids: Long-term monotherapy with ICS during the stable phase of COPD cannot stop the downward trend of FEV1 and has no significant improvement on mortality. Therefore, monotherapy with ICS is not recommended for patients with stable COPD.

[0006] Rafenazine is a long-acting anticholinergic drug that works by binding to M3 muscarinic receptors on bronchial smooth muscle, inhibiting tracheal constriction caused by the release of acetylcholine from parasympathetic nerve endings. Clinically, it is primarily used for maintenance therapy of chronic obstructive pulmonary disease (COPD), including maintenance therapy for chronic bronchitis and emphysema with dyspnea, as well as prevention of acute exacerbations. Currently, the marketed formulation of rafenazine is an inhaled solution, jointly developed by Theravance Biopharmaceuticals (Ireland) and Mylan Pharmaceuticals (USA), and approved by the US FDA in November 2018 under the brand name Yupelri.

[0007] The deposition rate of inhaled solution nebulizers in the lungs is very low, only 10% to 20%. Most patients can only receive nebulization treatment in hospitals, where the equipment is bulky and inconvenient to carry, greatly reducing the convenience of administration and affecting the treatment effect. The deposition rate of inhaled powder nebulizers in the lungs is significantly higher than that of inhaled solution nebulizers, reaching over 50%, and they are easy to carry, which can well meet the clinical administration needs.

[0008] The original research company has two patents on crystal forms that have been granted in China, namely CN101163677B and CN102470130B. CN101163677B discloses salt forms such as diphosphate, monosulfate, and hydrogen oxalate, as well as free base crystal forms I and II, protecting the diphosphate form. CN102470130B discloses crystal forms III and IV, which have an acceptable level of hygroscopicity, protecting crystal form III.

[0009] There are currently no reports of a triphenylacetic acid form of refenapyridine. Summary of the Invention

[0010] This invention investigated refennaxine triphenylacetate and prepared it into an inhalation powder. Through comparison of formulation performance and stability among different crystal forms, the refennaxine triphenylacetate crystal form was determined to have the best formulation performance. Furthermore, animal pharmacokinetic and tissue distribution studies revealed that the inhalation powder prepared using refennaxine triphenylacetate had lower peak plasma concentrations and systemic exposures, and higher deposition at the effective site, suggesting that the refennaxine triphenylacetate crystal form inhalation powder has better therapeutic efficacy and fewer side effects.

[0011] The specific technical solution of this invention is as follows:

[0012] A refennane triphenylacetate has the following structural formula:

[0013] The present invention also provides a refenapyridine inhalation formulation, which uses the refenapyridine triphenylacetate salt described in the present invention as the main active pharmaceutical ingredient.

[0014] The inhaled preparation can be an inhaled aerosol, an inhaled spray, or an inhaled powder.

[0015] The inhaled powder aerosol of the present invention further comprises one or more of a carrier and a dispersing agent.

[0016] The carrier is selected from one or more of lactose, dextran, and mannitol.

[0017] The dispersing agent is selected from one or more of sodium stearate, magnesium stearate, calcium stearate, and colloidal silica.

[0018] The carrier is preferably lactose.

[0019] The dispersing agent is magnesium stearate.

[0020] In the inhalation formulation of this invention, the particle size distribution of the refennaxine triphenylacetate raw material complex is D. 10 : 0.4~1.2μm; D 50 : 1.5~4μm; D 90 : 2.5~8μm. The preferred particle size distribution of the refennaxine triphenylacetate raw material complex is D. 10 : 0.5~0.8μm; D 50 : 2~3.5μm; D 90 3~7μm.

[0021] The preparation method of the inhaled powder aerosol of the present invention is as follows:

[0022] 1) After mixing a portion of magnesium stearate and refennax triphenylacetate raw materials, the mixture was transferred to an air jet mill for co-micronization to prepare a refennax complex with a particle size distribution.

[0023] 2) Place the remaining amount of magnesium stearate and the total amount of lactose in a TRV high-shear mixer, set the mixing speed and mixing time, and prepare a lactose premix.

[0024] 3) Add approximately 1 / 2 of the lactose premix, all of the revannasine complex, and the remaining approximately 1 / 2 of the lactose premix to the TRV mixing device in sequence, set the mixing speed and mixing time, and prepare the revannasine total mixture.

[0025] 4) Take the total mixture of refennaxine powder and fill it into capsules at a filling amount of 25mg±1mg to prepare refennaxine inhalation powder capsules that can be delivered to the lungs via a dry powder inhaler.

[0026] 5) The above-mentioned drug-loaded capsules are then packaged in double aluminum foil to obtain the final product.

[0027] The refinasine triphenylacetate salt described in this invention can be used to prepare drugs for treating COPD.

[0028] Advantages of this invention:

[0029] 1. The inhalation powder prepared from refennaxine triphenylacetate according to the present invention has a higher fine particle fraction compared with commercially available refennaxine inhalation solution.

[0030] 2. The inhalation powder prepared from rephenazine triphenylacetate according to the present invention has a higher fine particle fraction and formulation stability compared with inhalation powder prepared using other crystal forms (such as diphosphate, crystal form III).

[0031] 3. Animal pharmacokinetic and tissue distribution studies revealed that the inhaled powder formulation prepared using refennaxine triphenylacetate had lower peak plasma concentrations and systemic exposures, and higher deposition at the effective sites, suggesting that the refennaxine triphenylacetate inhaled powder formulation has better efficacy and fewer side effects. Attached Figure Description

[0032] Figure 1. 1H NMR spectrum of refinazine triphenylacetate.

[0033] Figure 2. Carbon NMR spectrum of refinazine triphenylacetate.

[0034] Figure 3. Mass spectrum of refennaxine triphenylacetate.

[0035] Figure 4. Infrared spectral image of rephenazine triphenylacetate.

[0036] Figure 5. Differential scanning calorimetry (DSC) curve of rephenazine triphenylacetate.

[0037] Figure 6. Thermogravimetric analysis (TG) curve of rephenazine triphenylacetate. Detailed Implementation

[0038] The present invention will now be described in detail with reference to specific embodiments and exemplary examples, but these descriptions should not be construed as limiting the present invention in any way. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and embodiments of the present invention without departing from the spirit and scope of the invention, and all such modifications and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims. Specific embodiments are described below:

[0039] Example 1: Preparation of refennaxine triphenylacetate

[0040] 10.0 g of refennaxine free base was added to a round-bottom flask, followed by 10 ml of acetone and 7.24 g of triphenylacetic acid. The mixture was stirred and heated to dissolve. The solution was then cooled to allow crystals to precipitate, filtered, and dried under vacuum to obtain the refennaxine triphenylacetic acid salts for each group.

[0041] Example 2: Preparation of refennaxine diphosphate (refer to Chinese Patent CN101163677B)

[0042] Dissolve 5.0 g of refennaxine free base in 50 ml of water and 15 ml of 1 M phosphoric acid. Adjust the pH to approximately 5.3 with 2.5 ml of 1 M phosphoric acid. Filter and lyophilize to obtain amorphous diphosphate. Dissolve the amorphous diphosphate in 20 ml of isopropanol:acetonitrile (1:1). Add 1 ml of water, heat to 60 °C, cool to 20–25 °C, and continue stirring for approximately 12 h. Filter and vacuum dry to obtain refennaxine diphosphate.

[0043] Example 3: Preparation of Refennaxine Crystal Form III (refer to Chinese Patent CN102470130B)

[0044] Dissolve 3.07 g of refennaxine free base in 15 ml of acetonitrile and stir at room temperature for about 80 min. Place the mixture in the shaker block for thermal cycling (0 °C to 40 °C in the 1 h zone) for 48 h. Add 15 ml of acetonitrile, then place the mixture back in the shaker block and maintain for 2 h. Filter and vacuum dry to obtain refennaxine crystal form III.

[0045] Example 4: Preparation of refennaxine monosulfate (refer to Chinese Patent CN101163677B)

[0046] Dissolve 44.2 g of refennaxine free base in 500 ml of H2O∶ACN (1∶1), slowly add about 145 ml of 1N sulfuric acid, and adjust the pH to about 3.3. Filter through a 0.2 micron filter and freeze-dry to obtain monosulfate.

[0047] Dissolve 3.0 g of refennax monosulfate in 165 ml of IPA:ACN (10:1), add to a 60 °C water bath and stir for 30 min, then heat to 70 °C and stir for 30 min, then cool to 60 °C and stir for 1 h. Cool to room temperature and let stand at room temperature for about 13 days, then filter and vacuum dry to obtain refennax monosulfate.

[0048] Example 5: Preparation of refennaxine monooxalate (refer to Chinese Patent CN101163677B)

[0049] Dissolve 51.0 g of refennaxine free base in 500 ml of H2O∶ACN (1∶1), slowly add about 170 ml of 1 M aqueous oxalic acid, and adjust the pH to about 3.0. Filter through a 0.2 micron filter and freeze-dry to obtain hydrogen oxalate.

[0050] Dissolve 3.2 g of hydrogen oxalate in 276 ml of 94% IPA / 6% H2O, and add to a 60°C water bath with stirring for 2.5 h. Cool to room temperature, let stand at room temperature for about 30 days, filter, and vacuum dry to obtain refennaxine monooxalate.

[0051] Example 6: Study on Salt Formation of Organic / Inorganic Acids

[0052] This example studied 39 acids, and only triphenylacetic acid could form a salt with refennaxine. The preparation process was the same as in Example 1, and the results are shown in Table 1.

[0053] Table 1. Screening results for refinasin salt formation

[0054] Example 7: Preparation of Refennax Triphenylacetate Inhalation Powder

[0055] 1) Weigh 0.087g of magnesium stearate and 2.446g of refennaxine triphenylacetate raw materials, stir and mix for 20 minutes, then transfer to an air jet mill and grind into micro-powder at a pressure of 5 bar to D. 10 : 0.6μm; D 50 : 2.7μm; D 90 5.0 μm, to obtain the refenapyridine complex.

[0056] 2) Weigh 0.313g of the remaining magnesium stearate and 327.154g of the total lactose in the prescription and place them in a TRV high-shear mixer. Mix at a mixing speed of 500.0r / min for 6min, then discharge to obtain the lactose premix.

[0057] 3) Add approximately 1 / 2 of the lactose premix, all of the revanasin complex, and the remaining approximately 1 / 2 of the lactose premix to the TRV mixing device in sequence. Set the mixing speed to 1350 r / min, mix for 3 min, and then discharge to obtain the total revanasin mixture.

[0058] 4) Take the total mixture of refennaxine powder and fill it into capsules at a filling amount of 25mg±1mg to prepare refennaxine inhalation powder capsules that can be delivered to the lungs via a dry powder inhaler.

[0059] 5) The above-mentioned drug-loaded capsules are then packaged in double aluminum foil to obtain the final product.

[0060] Table 2. List of prescriptions for refenapyridine inhalation powder (refenapyridine triphenylacetate)

[0061] Example 8: Preparation of Refennax diphosphate inhalation powder

[0062] 1) Weigh 0.087g of magnesium stearate and 2.191g of refennane diphosphate raw materials, stir and mix for 20 minutes, then transfer to an air jet mill and grind into micro-powder at a pressure of 5 bar to D. 10 : 0.6μm; D 50 : 2.5μm; D 90 : 4.9 μm, to obtain the refenapyridine complex.

[0063] 2) Weigh 0.313g of the remaining magnesium stearate and 327.409g of the total lactose in the prescription and place them in a TRV high-shear mixer. Mix at a mixing speed of 500.0r / min for 6min, then discharge to obtain the lactose premix.

[0064] 3) Add approximately 1 / 2 of the lactose premix, all of the revanasin complex, and the remaining approximately 1 / 2 of the lactose premix to the TRV mixing device in sequence. Set the mixing speed to 1350 r / min, mix for 3 min, and then discharge to obtain the total revanasin mixture.

[0065] 4) Take the total mixture of refennaxine powder and fill it into capsules at a filling amount of 25mg±1mg to prepare refennaxine inhalation powder capsules that can be delivered to the lungs via a dry powder inhaler.

[0066] 5) The above-mentioned drug-loaded capsules are then packaged in double aluminum foil to obtain the final product.

[0067] Table 3. List of prescriptions for refennaxine inhalation powder (refennaxine diphosphate)

[0068] Example 9: Preparation of Refennaxine Crystal Form III Inhalation Powder

[0069] 1) Weigh 0.087g of magnesium stearate and 1.650g of refennaxine crystal form III raw material, stir and mix for 20 minutes, then transfer to an air jet mill and grind into micro-powder at a pressure of 5 bar to D. 10 : 0.5μm; D 50 : 2.3μm; D 90: 4.5 μm, to obtain the refenapyridine complex.

[0070] 2) Weigh 0.313g of the remaining magnesium stearate and 327.950g of the total lactose in the prescription and place them in a TRV high-shear mixer. Mix at a mixing speed of 500.0r / min for 6min, then discharge to obtain the lactose premix.

[0071] 3) Add approximately 1 / 2 of the lactose premix, all of the revanasin complex, and the remaining approximately 1 / 2 of the lactose premix to the TRV mixing device in sequence. Set the mixing speed to 1350 r / min, mix for 3 min, and then discharge to obtain the total revanasin mixture.

[0072] 4) Take the total mixture of refennaxine powder and fill it into capsules at a filling amount of 25mg±1mg to prepare refennaxine inhalation powder capsules that can be delivered to the lungs via a dry powder inhaler.

[0073] 5) The above-mentioned drug-loaded capsules are then packaged in double aluminum foil to obtain the final product.

[0074] Table 4. List of prescriptions for refennaxine inhalation powder (refennaxine crystal form III)

[0075] Example 10: Preparation of Revannacin Monosulfate and Revannacin Monooxate Inhalation Powder

[0076] Weigh out 0.087g of magnesium stearate and 1.921g of refennaxine monosulfate raw materials, stir and mix for 20 minutes, then transfer to an air jet mill and pulverize at a pressure of 5 bar to form micronized powder (D). 10 : 0.7μm; D 50 : 2.7μm; D 90 The refenapyridine complex was obtained at a thickness of 5.5 μm. The refenapyridine monosulfate inhalation powder was prepared according to the method in Example 8.

[0077] Weigh out 0.087g of magnesium stearate and 1.899g of refennaxine monooxalic acid raw materials, stir and mix for 20 minutes, then transfer to an air jet mill and pulverize at a pressure of 5 bar to form D. 10 : 0.6μm; D 50 : 2.4μm; D 90 The particle size was 4.8 μm, and a refennaxine complex was obtained. A refennaxine crystalline monooxalate inhalation powder was prepared according to the method in Example 8.

[0078] Example 11: Stability Study of Different Refnacin Inhalation Powder Formulations

[0079] Different refennaxine inhalation powders prepared in Examples 8 to 10 were placed in an environment of 40℃±2℃ and RH75%±5%, and the changes in the product fine particle dose, fine particle fraction, content and related substances were measured at regular intervals. The results are shown in Table 5.

[0080] The relevant substance testing methods are as follows:

[0081] Method basis: High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0082] Chromatographic conditions:

[0083] High-performance liquid chromatograph (HPLC): Waters E2695; mobile phase: 0.01 mol / L ammonium dihydrogen phosphate buffer (adjusted to pH 2.9 with phosphoric acid) - acetonitrile (95:5) as mobile phase A, acetonitrile as mobile phase B; column temperature: 40℃; detection wavelength: 220 nm; column: YMC Triart C18 column (4.6 mm × 150 mm, 3 μm).

[0084] Gradient elution:

[0085] Solution preparation:

[0086] (1) Diluent: Mobile phase A.

[0087] (2) Test solution: Take 10 capsules of this product, transfer the contents to a 25ml volumetric flask, wash the capsule shells several times with 10ml of mobile phase A, add the washings to the volumetric flask, shake to dissolve, dilute to the mark with mobile phase A, and shake well to obtain the test solution.

[0088] (3) Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, and dilute to the mark with diluent.

[0089] Table 5 Stability Test Conditions

[0090] Table 6. Stability test results

[0091] Table 6 (Continued) shows the results of the stability test.

[0092] The inhaled powder prepared using refennaxine triphenylacetate exhibited significantly higher fine particle dose and fraction than those prepared using refennaxine diphosphate and crystal form III. In stability studies, the fine particle dose and fraction of the refennaxine triphenylacetate inhaled powder remained stable over 3 months of accelerated testing, while those of the refennaxine diphosphate and crystal form III inhaled powders showed a decreasing trend. Related substances (RMS) growth was slow in the refennaxine triphenylacetate inhaled powder over 3 months, while those of the refennaxine diphosphate and crystal form III inhaled powders showed a significant increase. The inhaled powders prepared using refennaxine monosulfate and refennaxine oxalate had the worst fine particle dose and fraction, and both showed the most significant RMS growth in stability studies.

[0093] In summary, the inhaled powder formulation prepared using refennaxine triphenylacetate showed the best performance in the stability study. Example 8: Pharmacokinetics of different refennaxine inhaled powder formulations in rats.

[0094] The rats used in this experiment were male SD rats (SPF grade), aged 9 months, weighing 180–220 g. Throughout the experiment, the rats had free access to food and water. A randomized block design was used to group the experimental SD rats into three groups: a refennaxine triphenylacetate crystal powder inhaler group, a refennaxine diphosphate inhaler group, and a refennaxine crystal form III inhaler group. The drugs were administered via oral and nasal inhalation to the rats at a dose of 375 μg / kg (calculated as refennaxine).

[0095] Venous blood (0.5 ml) was collected from the fundus venous plexus at 0.1 h, 0.2 h, 0.5 h, 2 h, 6 h, 12 h, 24 h, 48 h, 60 h, 72 h, 96 h, and 120 h post-administration and placed in pre-labeled EDTA (4 mM) anticoagulant EP tubes. After collection, the blood was placed on ice and then centrifuged at 4 °C, 8000 rpm, and 5 min to collect plasma. The plasma was transferred to 96-well plates and stored at -20 °C for LC-MS / MS analysis. The drug concentration in the plasma of EDTA (4 mM) anticoagulated SD rats was determined using LC / MS / MS (Agilent 6460). The relevant pharmacokinetic parameters for each group at each time point after administration were calculated using WinNonlin 5.2 software based on statistical distance theory. See Table 7 for details.

[0096] Table 7. Pharmacokinetics of different crystal / salt forms of refennax inhalation powder in rats.

[0097] In vivo pharmacokinetic results in rats showed that refennaxine triphenylacetate inhalation powder had the lowest peak plasma concentration (C0.05). max and AUC 0-∞ The results indicate that the refennax triphenylacetate inhalation powder is significantly safer than the refennax diphosphate inhalation powder group and the refennax crystal form III inhalation powder group.

[0098] Example 9: Tissue distribution of different crystal / salt forms of refennaxine inhalation powder in rats.

[0099] Formulation selection: Three different crystal / salt forms of refennaxine inhalation powder prepared in Examples 4-6

[0100] Dosing frequency: single dose

[0101] Route of administration: Inhalation via mouth and nose

[0102] Experimental animals: SD rats

[0103] Grouping: A total of 108 SD rats were divided into three groups: a 375 μg / kg (calculated as refenapyridine) inhalation powder group, a 375 μg / kg (calculated as refenapyridine) inhalation powder group, and a 375 μg / kg (calculated as refenapyridine) inhalation powder group (refenapyridine crystal form III), with 36 rats in each group. Drug concentrations were collected from bronchoalveolar lavage fluid, lung tissue, main trachea and bronchi, bladder, heart, liver, and kidneys 0.5 h after administration.

[0104] Table 8. Distribution of refennaxine in major organs and tissues of rats 0.5 h after inhalation of the two formulations.

[0105] Rafenacin is a long-acting anticholinergic drug with similar affinity to the M1-M5 subtypes of sarcosine receptors. In the airways, it exerts its pharmacological effects by inhibiting smooth muscle M3 receptors, thus causing bronchodilation. Smooth muscle M3 receptors are mainly located in the trachea and bronchi, which are the primary sites of action for rafenacin. The animal tissue distribution experiments described above showed that, 0.5 hours after inhalation administration, the concentration of refennaxine triphenylacetate inhaled powder in the lung tissue, main trachea, and bronchi was significantly higher than that of refennaxine diphosphate inhaled powder and refennaxine crystalline form III inhaled powder at the sites of efficacy. However, in areas where clinical side effects (such as urinary retention) might occur, such as the bladder and heart, the concentration of refennaxine triphenylacetate inhaled powder was significantly lower than that of the other two crystalline forms of refennaxine inhaled powder. This suggests that refennaxine triphenylacetate inhaled powder can produce a higher bronchodilatory effect than refennaxine diphosphate inhaled powder and refennaxine crystalline form III inhaled powder, and also produces fewer clinical side effects.

Claims

1. A refennaxine triphenylacetate, characterized in that... It has the following structural formula:

2. An inhaled formulation of refenapyridine, characterized in that... The main active ingredient of the drug is refenapyridine triphenylacetate as described in claim 1.

3. The inhalation formulation according to claim 2, characterized in that... The inhaled preparation is an inhaled aerosol, inhaled spray, or inhaled powder.

4. The inhalation formulation according to claim 3, characterized in that... The inhaled preparation is an inhaled powder.

5. The inhalation formulation according to claim 4, characterized in that... The inhaled powder contains one or more of a carrier and a dispersing agent.

6. The inhalation formulation according to claim 5, characterized in that... The carrier is selected from one or more of lactose, dextran, and mannitol; the dispersing agent is selected from one or more of sodium stearate, magnesium stearate, calcium stearate, and colloidal silica.

7. The inhalation formulation according to claim 6, characterized in that... The carrier is lactose; the dispersant is magnesium stearate.

8. The inhalation formulation according to claim 2, characterized in that... The particle size distribution of the refennane triphenylacetate is D. 10 : 0.4~1.2μm; D 50 : 1.5~4μm; D 90 : 2.5~8μm.

9. The inhalation formulation according to claim 8, characterized in that... The particle size distribution of the refennane triphenylacetate is D. 10 : 0.5~0.8μm; D 50 : 2~3.5μm; D 90 3~7μm.

10. The inhalation formulation according to any one of claims 2-9, characterized in that... The inhaled formulation has the following components in parts by weight: Refenapyridine triphenylacetate 0.2–20 parts; Lactose 972–999.3 parts; Magnesium stearate 0.5 to 8 parts.

11. The use of the refenapyridine triphenylacetate salt according to claim 1 in the preparation of a drug for treating COPD.

Images