Rafenasin triphenyl acetate and inhalation powder inhalation thereof

Abstract

The invention discloses a refenasin triphenyl acetate and an inhalation powder inhalation thereof. The refenasin triphenyl acetate can be prepared into inhalation powder inhalation, has the effects of good preparation stability, high deposition proportion in an effective part in a body, good curative effect and low side effect, and provides a new drug choice for treatment of COPD patients.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to refenacin triphenylacetate and an inhalation powder aerosol thereof. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by chronic bronchitis and / or emphysema with airflow obstruction, which can further develop into cor pulmonale and respiratory failure. With the aggravation of environmental pollution and the aging of the population, the number of COPD patients has increased year by year, 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 more than 300 million COPD patients worldwide, and about 5 million people die each year. The incidence of respiratory diseases in my country is about 6.9%.

[0003] The pathogenesis of COPD is complex and is generally believed to be related to the following mechanisms: 1. Inflammatory mechanism: Chronic inflammation of the airways, lung parenchyma and pulmonary blood vessels is a characteristic change of COPD. Inflammatory cells such as neutrophils, macrophages and T lymphocytes are involved in the pathogenesis of COPD; 2. Protease-antiprotease imbalance mechanism: Proteolytic enzymes have damaging and destructive effects on tissues; antiproteases have inhibitory functions on various proteases such as elastase, among which α1 antitrypsin (α1-AT) is the most active one. Increased proteases or insufficient antiproteases can lead to tissue structure destruction and emphysema; 3. Oxidative stress mechanism: Oxidants 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, nucleic acids, etc., leading to cell dysfunction or cell death, and can also destroy the extracellular matrix, causing protease-antiprotease imbalance and promoting inflammatory response. 4. Other mechanisms: including autonomic dysfunction, malnutrition and temperature changes.

[0004] The above mechanisms work together to eventually produce two important lesions: 1. Small airway lesions, including small airway inflammation, small airway fibrosis, and small airway lumen mucus plugs, which significantly increase small airway resistance; 2. Emphysematous lesions reduce the normal pulling force of the alveoli on the small airways, making the small airways more likely to collapse. At the same time, emphysema significantly reduces the elastic recoil of the alveoli. This small airway lesion works together with emphysematous lesions to cause the persistent airflow limitation characteristic of COPD.

[0005] Inhaled preparations are the preferred dosage form for the treatment of COPD respiratory diseases. Common inhaled drugs can be divided into two categories according to their pharmacological effects: (1) Bronchodilators: Bronchodilators are the basic first-line treatment for COPD. They relax airway smooth muscles to dilate the bronchi, improve airflow limitation, and thus alleviate the symptoms of COPD. The main bronchodilators are β2 receptor agonists, anticholinergic drugs, and methylxanthines, which can be selected based on the drug effects and the patient's treatment response. (2) Inhaled corticosteroids: Long-term single ICS treatment in the stable stage of COPD cannot prevent the downward trend of FEV1, and there is no significant improvement in mortality. Therefore, it is not recommended to use single ICS treatment for patients with stable COPD.

[0006] Revefenacin is a long-acting anticholinergic drug that inhibits the release of acetylcholine from parasympathetic nerve terminals and causes tracheal contraction by binding to the M3 muscarinic receptors on bronchial smooth muscle. It is mainly used in the maintenance treatment of chronic obstructive pulmonary disease, including the maintenance treatment of chronic bronchitis and emphysema with dyspnea and the prevention of acute attacks. The current marketed revefenacin preparation is the revefenacin solution for inhalation, which was jointly developed by Theravance Biopharmaceuticals of Ireland and Mylan Pharmaceuticals of the United States and was approved for marketing by the U.S. FDA in November 2018 under the trade name Yupelri.

[0007] The deposition rate of inhaled solution in the lungs after atomization is very low, only 10% to 20%. Most patients can only receive atomization treatment in the hospital. The equipment is large and inconvenient to carry, which greatly reduces the convenience of drug administration and affects the treatment effect. The lung deposition rate of inhaled powder aerosol is significantly higher than that of inhaled solution, reaching more than 50%, and it is easy to carry and can well meet the needs of clinical drug administration.

[0008] The original research company has two crystal form patents authorized 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 diphosphate. CN102470130B discloses crystal forms III and IV, which have acceptable hygroscopicity and protect crystal form III.

[0009] There is no report on the triphenylacetate form of revenacin. Summary of the invention

[0010] The present invention studies refenacin triphenylacetate and prepares it into an inhalation powder. By comparing the preparation performance and stability between different crystal forms, it is determined that the refenacin triphenylacetate crystal form has the best preparation performance. In addition, through animal pharmacokinetic tests and tissue distribution tests, it is found that the inhalation powder prepared using refenacin triphenylacetate has a lower blood drug peak concentration and systemic exposure, and its deposition in the effective part is higher, indicating that the refenacin triphenylacetate crystal form inhalation powder has better drug efficacy and lower drug side effects.

[0011] The specific technical solutions of the present invention are as follows:

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

[0013]

[0014] The present invention also provides a revenacin inhalation preparation, which adopts the revenacin triphenylacetate of the present invention as the main active ingredient of the medicine.

[0015] The inhalation preparation can be an inhalation aerosol, an inhalation spray, or an inhalation powder.

[0016] The inhalation powder aerosol of the present invention further comprises one or more of a carrier and a dispersing aid.

[0017] The carrier is selected from one or more of lactose, dextran and mannitol.

[0018] The dispersing aid is selected from one or more of sodium stearate, magnesium stearate, calcium stearate and colloidal silicon dioxide.

[0019] The carrier is preferably lactose.

[0020] The dispersing aid is magnesium stearate.

[0021] In the inhalation preparation of the present invention, the particle size distribution of the raw material complex of refenacin triphenylacetate is D 10 :0.4~1.2μm;D 50 :1.5~4μm;D 90 : 2.5 to 8 μm. Preferably, the particle size distribution of the raw material composite of refenacin triphenylacetate is D 10 :0.5~0.8μm;D 50 :2~3.5μm;D 90 :3~7μm.

[0022] The preparation method of the inhalation powder of the present invention is as follows:

[0023] 1) After mixing part of the magnesium stearate and refenacin triphenylacetate raw materials, the raw materials are transferred to a jet mill for co-micronization to prepare a refenacin complex having a particle size distribution.

[0024] 2) The remaining amount of magnesium stearate and the total amount of lactose are placed in a TRV high shear mixer, and the mixing speed and mixing time are set to prepare a lactose premix.

[0025] 3) Add about 1 / 2 of the lactose premix, all of the revenacin complex and the remaining about 1 / 2 of the lactose premix to the TRV mixing device in sequence, set the mixing speed and mixing time, and prepare the revenacin total mixture.

[0026] 4) Take the revenacin total mixture powder and fill it into capsules according to the filling amount of 25 mg±1 mg to prepare revenacin inhalation powder capsules that can be delivered to the lungs for administration through a dry powder inhalation device.

[0027] 5) Double-aluminum packaging is performed on the above-mentioned drug-loaded capsules to obtain the product.

[0028] The revenacin triphenylacetate of the present invention can be used for preparing medicine for treating COPD.

[0029] Advantages of the present invention:

[0030] 1. The inhalation powder prepared from the refenacin triphenylacetate of the present invention has a higher fine particle fraction than the commercially available refenacin inhalation solution.

[0031] 2. The inhalation powder prepared from the refenacin triphenylacetate of the present invention has a higher fine particle fraction and formulation stability compared with the inhalation powder prepared using other crystal forms (such as diphosphate, crystal form III).

[0032] 3. Animal pharmacokinetic tests and tissue distribution tests showed that the inhalation powder prepared with refenacin triphenylacetate had lower peak blood drug concentration and systemic exposure, and its deposition in the effective site was higher, indicating that refenacin triphenylacetate inhalation powder had better drug efficacy and lower drug side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 H NMR spectrum of refenacin triphenylacetate.

[0034] Figure 2 C NMR spectrum of refenacin triphenylacetate.

[0035] Figure 3 Mass spectrum of refenacin triphenylacetate.

[0036] Figure 4 Infrared test image of revenacin triphenylacetate.

[0037] Figure 5 Differential scanning calorimetry (DSC) curve of revenacin triphenylacetate.

[0038] Figure 6 Thermogravimetric analysis (TG) curve of revenacin triphenylacetate. DETAILED DESCRIPTION

[0039] The present invention is described in detail below in conjunction with specific implementation methods and exemplary embodiments, but these descriptions cannot be understood as any limitation of the present invention. Those skilled in the art understand that, without departing from the spirit and scope of the present invention, a variety of equivalent substitutions, modifications or improvements can be made to the technical solutions and implementation methods of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention shall be subject to the attached claims. Specific embodiments are described as follows:

[0040] Example 1 Preparation of revenacin triphenylacetate

[0041] Add 10.0 g of refenacin free base to a round-bottom flask, then add 10 ml of acetone, add 7.24 g of triphenylacetic acid, start stirring, heat up to dissolve, then cool down to crystallize, filter, and vacuum dry to obtain each group of refenacin triphenylacetate.

[0042] Example 2 Preparation of revenacin diphosphate (refer to Chinese patent CN101163677B)

[0043] Dissolve 5.0 g of refenacin free base in 50 ml of water and 15 ml of 1 M phosphoric acid. Adjust the pH to about 5.3 with 2.5 ml of 1 M phosphoric acid. Filter and freeze-dry to obtain an amorphous diphosphate. Dissolve the amorphous diphosphate in 20 ml of isopropanol: acetonitrile (1:1). Add 1 ml of water, raise the temperature to 60°C, lower the temperature to 20-25°C, continue stirring for about 12 hours, filter, and vacuum dry to obtain refenacin diphosphate.

[0044] Example 3 Preparation of revenacin crystal form III (refer to Chinese patent CN102470130B)

[0045] Dissolve 3.07 g of refenacin free base in 15 ml of acetonitrile and stir at room temperature for about 80 min. Place the mixture in an oscillator block for thermal cycling (0°C to 40°C in a 1 h block) for 48 h. Add 15 ml of acetonitrile and then place the mixture back in the oscillator block and keep for 2 h. Filter and vacuum dry to obtain refenacin Form III.

[0046] Example 4 Preparation of revenacin monosulfate (refer to Chinese patent CN101163677B)

[0047] Dissolve 44.2 g of refenacin free base in 500 ml of H2O:ACN (1:1), slowly add about 145 ml of 1N sulfuric acid, adjust the pH to about 3.3, filter through a 0.2 micron filter, and freeze-dry to obtain the monosulfate salt.

[0048] Dissolve 3.0 g of monosulfate in 165 ml of IPA:ACN (10:1), add to a 60°C water bath and stir for 30 min, heat to 70°C and stir for 30 min, cool to 60°C and stir for 1 h. Cool to room temperature, leave at room temperature for about 13 days, filter, and vacuum dry to obtain refenacin monosulfate.

[0049] Example 5 Preparation of revenacin monooxalate (refer to Chinese patent CN101163677B)

[0050] 51.0 g of revenacin free base was dissolved in 500 ml of H2O:ACN (1:1), and about 170 ml of 1M aqueous oxalic acid was slowly added to adjust the pH to about 3.0. The mixture was filtered through a 0.2 micron filter and freeze-dried to obtain the hydrogen oxalate salt.

[0051] Dissolve 3.2 g of hydrogen oxalate in 276 ml of 94% IPA / 6% H2O, add to a 60°C water bath and stir for 2.5 hours. Cool to room temperature, place at room temperature for about 30 days, filter, and vacuum dry to obtain revenacin monooxalate.

[0052] Example 6 Study on organic / inorganic acid salt formation

[0053] This example studies 39 acids, and ultimately only triphenylacetic acid can form a salt with revenacin. The preparation process is the same as in Example 1. The results are shown in Table 1.

[0054] Table 1 Screening results of refenacin salt

[0055] Serial number Types of Acid Salt formation 1 2-Chlorobenzoic acid Clear, no solid precipitation 2 2-Naphthalenesulfonic acid Clear, no solid precipitation 3 6M hydrochloric acid Clear, no solid precipitation 4 DL-lactic acid Clear, no solid precipitation 5 Sulfamic acid Clear, no solid precipitation 6 benzoic acid Clear, no solid precipitation 7 glacial acetic acid Clear, no solid precipitation 8 Propanetricarboxylic acid Clear, no solid precipitation 9 Succinic acid Clear, no solid precipitation 10 p-Toluenesulfonic acid Clear, no solid precipitation 11 Trans-cinnamic acid Clear, no solid precipitation 12 Fumaric Acid Clear, no solid precipitation 13 α-Cyclopentylmandelic acid Clear, no solid precipitation 14 ascorbic acid Clear, no solid precipitation 15 Trifluoroacetic acid Clear, no solid precipitation 16 Salicylic acid Clear, no solid precipitation 17 Glutaric acid Clear, no solid precipitation 18 Ethylsulfonic acid Clear, no solid precipitation 19 Oleic acid Clear, no solid precipitation 20 Palmitic acid Clear, no solid precipitation 21 Maleic acid Oily substance 22 Naphthalenesulfonic acid When adding dropwise, turbidity occurs, which becomes clear after dissolving 23 Isethionic acid When adding dropwise, turbidity occurs, which becomes clear after dissolving 24 Benzenesulfonic acid When adding dropwise, turbidity occurs, which becomes clear after dissolving 25 Phenylacetic acid When adding dropwise, turbidity occurs, which becomes clear after dissolving 26 1-Hydroxy-2-naphthoic acid When adding drops, it becomes turbid and then turns into oily substance 27 Citric acid When adding dropwise, solid precipitates and then turns into oil 28 Gluconic acid When added dropwise, it becomes turbid and then turns into a sticky solid. 29 DL-Malic Acid When added dropwise, it becomes turbid and then turns into a sticky solid. 30 D-Malic Acid When added dropwise, it becomes turbid and then turns into a sticky solid. 31 Hydrobromic acid When added dropwise, it becomes turbid and then turns into a sticky solid. 32 Triacylglycerol When adding dropwise, solid precipitates, lumps, and then turns into a sticky solid 33 tartaric acid Sticky ball 34 5-Nitroisophthalic acid Yellow powder and lumps, turn into sticky solid after standing 35 L-Malic Acid White sticky solid 36 Terephthalic acid White powder, undissolved acid, unsalted 37 Glutamate White powder, undissolved acid, unsalted 38 Diphenylacetic acid White powder, revenacin, unsalted 39 Triphenylacetic acid White powder, revenacin triphenylacetate

[0056] Example 7 Preparation of revenacin triphenylacetate inhalation powder

[0057] 1) Weigh 0.087g of magnesium stearate and 2.446g of refenacin triphenylacetate, stir and mix for 20min, transfer to a jet mill and grind to powder D at 5 bar pressure. 10 :0.6μm; D 50 :2.7μm; D 90 : 5.0 μm, and the refenacin complex was obtained.

[0058] 2) Weigh the remaining amount of magnesium stearate (0.313 g) and the total amount of lactose (327.154 g) and place them in a TRV high shear mixer, mix them at a mixing speed of 500.0 r / min for 6 min, and discharge the mixture to obtain a lactose premix.

[0059] 3) Add about 1 / 2 of the lactose premix, all of the refenacin complex and the remaining about 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, discharge, and obtain the refenacin total mixture.

[0060] 4) Take the revenacin total mixture powder and fill it into capsules according to the filling amount of 25 mg±1 mg to prepare revenacin inhalation powder capsules that can be delivered to the lungs for administration through a dry powder inhalation device.

[0061] 5) Double-aluminum packaging is performed on the above-mentioned drug-loaded capsules to obtain the product.

[0062] Table 2 Prescription list of revenacin inhalation powder (revenacin triphenylacetate)

[0063] Element Prescription dosage effect lactose 327.154g Carrier Magnesium Stearate 0.40g Dispersing aids Refenacin (triphenylacetate) 2.446g Active ingredients

[0064] Example 8 Preparation of revenacin diphosphate inhalation powder

[0065] 1) Weigh 0.087g of magnesium stearate and 2.191g of revenacin diphosphate and stir and mix for 20min, then transfer to a jet mill and grind to a fine powder at 5 bar pressure. 10 :0.6μm; D 50 :2.5μm; D 90 : 4.9 μm, and the refenacin complex was obtained.

[0066] 2) Weigh the remaining amount of magnesium stearate (0.313 g) and the total amount of lactose (327.409 g) and place them in a TRV high shear mixer, mix them at a mixing speed of 500.0 r / min for 6 min, and discharge the mixture to obtain a lactose premix.

[0067] 3) Add about 1 / 2 of the lactose premix, all of the refenacin complex and the remaining about 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, discharge, and obtain the refenacin total mixture.

[0068] 4) Take the revenacin total mixture powder and fill it into capsules according to the filling amount of 25 mg±1 mg to prepare revenacin inhalation powder capsules that can be delivered to the lungs for administration through a dry powder inhalation device.

[0069] 5) Double-aluminum packaging is performed on the above-mentioned drug-loaded capsules to obtain the product.

[0070] Table 3 Prescription list of revenacin inhalation powder (revenacin diphosphate)

[0071] Element Prescription dosage effect lactose 327.409g Carrier Magnesium Stearate 0.40g Dispersing aids Revenacin (bisphosphonate) 2.191g Active ingredients

[0072] Example 9 Preparation of Revenacin Form III Inhalation Powder

[0073] 1) Weigh 0.087g of magnesium stearate and 1.650g of refenacin crystal form III raw materials, stir and mix for 20 minutes, transfer to a jet mill and grind to a fine powder at a pressure of 5 bar to D 10 :0.5μm; D 50 :2.3μm; D 90 : 4.5 μm, and the refenacin complex was obtained.

[0074] 2) Weigh the remaining amount of magnesium stearate (0.313 g) and the total amount of lactose (327.950 g) and place them in a TRV high shear mixer, mix them at a mixing speed of 500.0 r / min for 6 min, and discharge the mixture to obtain a lactose premix.

[0075] 3) Add about 1 / 2 of the lactose premix, all of the refenacin complex and the remaining about 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, discharge, and obtain the refenacin total mixture.

[0076] 4) Take the revenacin total mixture powder and fill it into capsules according to the filling amount of 25 mg±1 mg to prepare revenacin inhalation powder capsules that can be delivered to the lungs for administration through a dry powder inhalation device.

[0077] 5) Double-aluminum packaging is performed on the above-mentioned drug-loaded capsules to obtain the product.

[0078] Table 4 Prescription list of refenacin inhalation powder (refenacin crystal form III)

[0079] Element Prescription dosage effect lactose 327.95g Carrier Magnesium Stearate 0.40g Dispersing aids Revenacin (Crystal Form III) 1.650g Active ingredients

[0080] Example 10 Preparation of revenacin monosulfate and revenacin monooxalate inhalation powder

[0081] Weigh 0.087g of magnesium stearate and 1.921g of refenacin monosulfate, stir and mix for 20min, transfer to a jet mill and grind to powder D at 5 bar pressure. 10 :0.7μm; D 50 :2.7μm; D 90 : 5.5 μm, and the revenacin complex was obtained. The revenacin monosulfate inhalation powder was prepared by referring to the method of Example 8.

[0082] Weigh 0.087g of magnesium stearate and 1.899g of revenacin monooxalate, stir and mix for 20min, transfer to a jet mill and grind to powder D at 5 bar pressure. 10 :0.6μm; D 50 :2.4μm; D 90 : 4.8 μm, and the revenacin complex was obtained. Referring to the method of Example 8, the revenacin monooxalate inhalation powder was prepared.

[0083] Example 11 Study on the stability of different revenacin inhalation powder preparations

[0084] The different revenacin inhalation powders prepared in Examples 8 to 10 were placed in an environment of 40°C ± 2°C and RH 75% ± 5%, and the changes in the fine particle dosage, fine particle fraction, content and related substances of the products were measured at regular intervals. The results are shown in Table 5.

[0085] The testing methods for the relevant substances are as follows:

[0086] Method basis: High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0087] Chromatographic conditions:

[0088] High performance liquid chromatography (HPLC): model waters e2695, mobile phase: 0.01 mol / L ammonium dihydrogen phosphate buffer (pH adjusted to 2.9 with phosphoric acid)-acetonitrile (95:5) as mobile phase A, acetonitrile as mobile phase B, column temperature: 40°C, detection wavelength: 220 nm, chromatographic column: YMC Triart C18 column (4.6 mm×150 mm, 3 μm).

[0089] Gradient elution:

[0090] Time (min) Mobile phase A% Mobile phase B% 0 85 15 3 85 15 30 35 65 35 35 65 37 85 15 45 85 15

[0091] Solution preparation:

[0092] (1) Diluent: mobile phase A.

[0093] (2) Test solution: Take 10 capsules of this product and transfer the contents to a 25 ml volumetric flask. Wash the capsule shells with 10 ml of mobile phase A in batches. Add the washing solution to the volumetric flask and shake to dissolve. Dilute to the mark with mobile phase A and shake well.

[0094] (3) Control solution: Accurately measure 1 ml of the test solution and place it in a 100 ml volumetric flask. Add diluent to dilute to the mark.

[0095] Table 5 Stability test conditions

[0096] Inspection conditions specific conditions accelerate Temperature: 40℃±2℃, relative humidity 75%±5%

[0097] Table 6 Stability test results

[0098]

[0099] Table 6: Stability test results

[0100]

[0101] The fine particle dose and fine particle fraction of the inhalation powder prepared with refenacin triphenylacetate were significantly higher than those of the inhalation powder prepared with refenacin diphosphate and crystalline form III. In the stability study, the fine particle dose and fine particle fraction of refenacin triphenylacetate inhalation powder remained stable within 3 months of acceleration, while the fine particle dose and fine particle fraction of refenacin diphosphate and crystalline form III inhalation powder showed a downward trend within 3 months of acceleration. The related substances of refenacin triphenylacetate inhalation powder increased slowly within 3 months of acceleration, while the related substances of refenacin diphosphate and crystalline form III inhalation powder increased significantly within 3 months of acceleration. The inhalation powder prepared with refenacin monosulfate and refenacin oxalate had the worst fine particle dose and fine particle fraction, and the related substances of both increased most significantly in the stability study.

[0102] In summary, the inhalation powder prepared using refenacin triphenylacetate has the best performance in the stability study. Example 8 Pharmacokinetic performance of different refenacin inhalation powders in rats

[0103] Male SD rats (SPF grade) were used in this embodiment, aged 9 months and weighing 180-220g. During the whole experiment, the rats were free to eat and drink. The SD rats for the experiment were grouped by randomized block design and divided into three groups: refenacin triphenylacetate crystalline inhalation powder group, refenacin diphosphate inhalation powder group and refenacin crystalline III inhalation powder group. The drug was administered by oral and nasal inhalation in rats, and the dosage was set to 375μg / kg (in terms of refenacin).

[0104] 0.5 ml of venous blood 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 after administration and placed in a pre-labeled EDTA (4 mM) anticoagulated EP tube. After whole blood collection, it was placed on ice and then centrifuged at 4 ° C, 8000 rpm, 5 min to collect plasma, transferred to a 96-well plate, and stored at -20 ° C until LC-MS / MS detection. The drug concentration in EDTA (4 mM) anticoagulated SD rat plasma was determined using the LC / MS / MS (Agilent 6460) method. WinNonlin 5.2 software was used to calculate the relevant pharmacokinetic parameters of the concentration at each time point after administration of each group according to the statistical distance theory. See Table 7 for details.

[0105] Table 7 Pharmacokinetic performance of different crystal / salt forms of revenacin inhalation powder in rats

[0106]

[0107] The pharmacokinetic results in rats showed that revenacin triphenylacetate inhalation powder had the lowest peak blood concentration C max and AUC 0-∞ , indicating that the safety of revifenacin triphenylacetate inhalation powder is significantly better than that of revifenacin diphosphate inhalation powder and revifenacin form III inhalation powder.

[0108] Example 9 Tissue distribution of different crystalline / salt forms of revenacin inhalation powder in rats

[0109] Preparation selection: three different crystal forms / salt forms of revenacin inhalation powder prepared in Examples 4 to 6

[0110] Dosing frequency: Single dose

[0111] Route of administration: Inhalation through the mouth and nose

[0112] Experimental animals: SD rats

[0113] Grouping: A total of 108 SD rats were divided into 375 μg / kg (calculated as refenacin) dose group of refenacin triphenylacetate inhalation powder, 375 μg / kg (calculated as refenacin) dose group of refenacin diphosphate inhalation powder and 375 μg / kg (calculated as refenacin) dose group of refenacin crystal form III inhalation powder, 36 rats in each group. The drug concentrations of animal bronchoalveolar lavage fluid, lung tissue, main trachea and bronchus, bladder, heart, liver and kidney were collected at 0.5 h after administration.

[0114] Table 8 Distribution of revenacin in major organs and tissues in rats 0.5h after inhalation of two preparations

[0115]

[0116] Revenacin is a long-acting anticholinergic drug that has similar affinity to the subtypes of sarcosine receptors M1-M5. In the airway, it exhibits pharmacological effects by inhibiting smooth muscle M3 receptors to cause bronchial dilation. Smooth muscle M3 receptors are mainly located in the trachea and bronchi and are the main pharmacodynamic site of Revenacin. The above-mentioned animal tissue distribution test shows that 0.5h after inhalation administration, the concentration of refenacin triphenylacetate inhalation powder in the lung tissue, main trachea and bronchus at the drug effect site is significantly higher than that of refenacin diphosphate inhalation powder and refenacin crystal form III inhalation powder, while in the bladder, heart and other places where clinical side effects (such as urinary retention) may occur, the concentration of refenacin triphenylacetate inhalation powder is significantly lower than that of the other two crystal forms of refenacin inhalation powder, indicating that refenacin triphenylacetate inhalation powder can produce a higher bronchodilator effect than refenacin diphosphate inhalation powder and refenacin crystal form III inhalation powder and produce lower clinical side effects.

Claims

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

2. An inhalation preparation of revenacin, characterized in that The revenacin triphenylacetate described in claim 1 is used as the main active ingredient of the drug.

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

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

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

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

7. The inhalation preparation according to claim 6, characterized in that The carrier is lactose; the dispersing aid is magnesium stearate.

8. The inhalation preparation according to claim 1, characterized in that The particle size distribution of refenacin triphenylacetate is D 10 :0.4~1.2μm;D 50 :1.5~4μm;D 90 :2.5~8μm.

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

10. The inhalation preparation according to claims 1-7, characterized in that The inhalation preparation has the following components in parts by weight: 0.2-20 parts of revenacin triphenylacetate; Lactose 972-999.3 parts; 0.5-8 parts of magnesium stearate.

11. Use of the revenacin triphenylacetate according to claim 1 in the preparation of a drug for treating COPD.

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