Rafenamide triphenylacetate and inhalation aerosol thereof

Abstract

The application discloses a rafenamine triphenylacetic acid salt and an inhalation powder aerosol thereof. The rafenamine triphenylacetic acid salt can be prepared into the inhalation powder aerosol, has good preparation stability, high deposition proportion at an effective site in the body, good curative effect and low side effect, and provides a new drug selection for the treatment of COPD patients.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine and chemical industry, and particularly relates to a ralfinamide triphenylacetic acid salt and an inhalation powder aerosol thereof. BACKGROUND

[0002] Chronic Obstructive Pulmonary Disease (COPD) is a common chronic disease characterized by airflow obstruction, chronic bronchitis and / or emphysema, which can further develop into pulmonary heart disease and respiratory failure. With the aggravation of environmental pollution and population aging, the number of COPD patients is increasing 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 every year. The incidence of respiratory diseases in China is about 6.9%.

[0003] The pathogenesis of COPD is complex, and is generally considered to be related to the following mechanisms: 1. Inflammation mechanism: chronic inflammation of airways, lung parenchyma and pulmonary vessels is a characteristic change of COPD, and inflammatory cells such as neutrophils, macrophages and T lymphocytes participate in the pathogenesis of COPD; 2. Proteinase-antiproteinase imbalance mechanism: proteolytic enzymes have damage and destruction to tissues; antiproteinases have inhibitory function on various proteinases, among which α1 antitrypsin (α1-AT) is the most active one. Excessive proteinases or insufficient antiproteinases can lead to tissue destruction and emphysema; 3. Oxidative stress mechanism: oxidants such as superoxide anion, hydroxyl radical, 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, and can also destroy extracellular matrix, causing proteinase-antiproteinase imbalance and promoting inflammatory response. 4. Other mechanisms: including autonomic nervous dysfunction, malnutrition, temperature change, etc.

[0004] The above mechanisms act together, and ultimately produce two important lesions: 1. Small airway lesions, including small airway inflammation, small airway fibrous tissue formation, small airway lumen mucus plug, etc., which significantly increase the resistance of small airways; 2. Emphysema lesions make the normal pulling force of alveoli on small airways decrease, and small airways are more prone to collapse. At the same time, emphysema makes the elastic recoil force of alveoli decrease significantly. The combination of small airway lesions and emphysema lesions causes the characteristic persistent airflow limitation of COPD.

[0005] Inhalation is the preferred administration route for the treatment of COPD. Commonly used inhaled drugs can be divided into two categories according to their pharmacological effects: (1) bronchodilators: bronchodilators are the first-line treatment for COPD, which can relax airway smooth muscle, dilate bronchi and improve airflow limitation, thereby reducing the symptoms of COPD. The main bronchodilators include β2 receptor agonists, anticholinergic drugs and methylxanthines, which can be selected according to the drug effect and the patient's treatment response. (2) Inhaled corticosteroids: long-term single use of ICS in stable COPD cannot prevent the decrease of FEV1, and has no significant improvement on mortality, so single ICS treatment is not recommended for stable COPD patients.

[0006] Roflumilast is a long-acting anticholinergic drug that binds to M3 muscarinic receptors on bronchial smooth muscle, inhibiting bronchial contraction caused by acetylcholine released at the end of the parasympathetic nerve. It is mainly used for the maintenance treatment of chronic obstructive pulmonary disease, including chronic bronchitis, emphysema with dyspnea, and prevention of acute exacerbations. The existing roflumilast marketed preparation is roflumilast solution for inhalation, which is developed by Theravance Biopharma of Ireland and Mylan Pharmaceuticals of the United States, and was approved for marketing by the FDA of the United States in November 2018, with the trade name Yupelri.

[0007] The deposition rate of inhalation solution in the lungs after atomization is very low, only 10% to 20%, and most patients can only be treated with atomization in the hospital. The equipment is large in size and not convenient to carry, which greatly reduces the convenience of drug administration and affects the treatment effect. The lung deposition rate of inhalation powder is significantly higher than that of inhalation solution, which can reach more than 50%, and it is convenient to carry, which can well meet the clinical drug administration needs.

[0008] The original research company has two crystal form patents authorized in China, CN101163677B and CN102470130B. CN101163677B discloses diphosphate, monosulfate, oxalate hydrogen salt and other salt types, as well as free base crystal form I and crystal form II, which protects diphosphate. CN102470130B discloses crystal form III and crystal form IV, and the two crystal forms have acceptable moisture absorption, which protects crystal form III.

[0009] There is no report on the triphenylacetate salt of roflumilast. SUMMARY

[0010] The application studies rafenamine triphenylacetate, and prepares an inhalation powder spray, determines the rafenamine triphenylacetate crystal form with the best preparation performance through the comparison of the preparation performance and stability among different crystal forms. In addition, through the animal pharmacokinetic test and tissue distribution test, it is found that the inhalation powder spray prepared by using rafenamine triphenylacetate has lower blood peak concentration and systemic exposure, and the deposition in the effective part is higher, which indicates that the rafenamine triphenylacetate crystal form inhalation powder spray has better drug efficacy and lower drug side effects.

[0011] The specific technical scheme of the application is as follows:

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

[0013]

[0014] The application further provides an inhalation preparation of rafenamine, which uses the rafenamine triphenylacetate as the main active ingredient of the drug.

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

[0016] The inhalation powder spray further comprises one or more of a carrier and a dispersion aid.

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

[0018] The dispersion 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 dispersion aid is magnesium stearate.

[0021] In the inhalation preparation, the particle size distribution of the rafenamine triphenylacetate raw material compound is D 10 : 0.4-1.2 μm; D 50 : 1.5-4 μm; D 90 : 2.5-8 μm. 10 : 0.5-0.8 μm; D 50 : 2-3.5 μm; D 90 : 3-7 μm.

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

[0023] 1) After mixing the part of magnesium stearate and raloxifene triphenylacetate raw materials, transfer to jet mill to make raloxifene compound with particle size distribution.

[0024] 2) Put the rest of the prescription amount of magnesium stearate and all prescription amount of lactose into TRV high shear mixing equipment, set the mixing speed and mixing time, and prepare lactose premix.

[0025] 3) Put about 1 / 2 of the lactose premix, all of the raloxifene compound and the remaining about 1 / 2 of the lactose premix into the TRV mixing equipment in turn, set the mixing speed and mixing time, and prepare the raloxifene total mixture.

[0026] 4) Take the raloxifene total mixture powder, fill the capsules with a filling amount of 25mg±1mg, and prepare raloxifene inhalation powder capsules that can be delivered to the lungs by dry powder inhalation device.

[0027] 5) Double aluminum package the above drug-loaded capsules, and the product is obtained.

[0028] The raloxifene triphenylacetate described in the application can be used to prepare a drug for treating COPD.

[0029] Advantages of the application:

[0030] 1) The inhalation powder prepared from the raloxifene triphenylacetate described in the application has a higher fine particle fraction compared with the commercially available raloxifene inhalation solution.

[0031] 2) The inhalation powder prepared from the raloxifene triphenylacetate described in the application has a higher fine particle fraction and formulation stability compared with the inhalation powder prepared from other crystal forms (such as diphosphate, crystal form III).

[0032] 3) Through animal pharmacokinetic tests and tissue distribution tests, it is found that the inhalation powder prepared from the raloxifene triphenylacetate has a lower peak blood drug concentration and systemic exposure, and its deposition in the effective site is higher, which indicates that the raloxifene triphenylacetate inhalation powder has better drug efficacy and lower drug side effects. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 NMR hydrogen spectrum of raloxifene triphenylacetate.

[0034] Figure 2 NMR carbon spectrum of raloxifene triphenylacetate.

[0035] Figure 3 Mass spectrum of raloxifene triphenylacetate.

[0036] Figure 4 Infrared test diagram of raloxifene triphenylacetate.

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

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

[0039] The present application will be described in detail below with specific reference to specific embodiments and examples, but these descriptions are not to be understood as limiting the present application in any way. It will be appreciated by persons skilled in the art that many modifications can be made to the technology schemes and embodiments of the present application without departing from the spirit and scope of the present application, and these modifications are also within the scope of the present application. The scope of protection of the present application is defined by the appended claims. The specific embodiments are described as follows:

[0040] Example 1 Preparation of ralfinamide triphenylacetate

[0041] Into a round bottom flask was added 10.0 g of ralfinamide free base followed by 10 ml of acetone and 7.24 g of triphenylacetic acid. The mixture was stirred and warmed until dissolved. The mixture was then cooled to induce crystallization. The crystals were filtered and dried under vacuum to yield ralfinamide triphenylacetate.

[0042] Example 2 Preparation of ralfinamide diphosphate (Refer to Chinese patent CN101163677B)

[0043] 5.0 g of ralfinamide free base was dissolved in 50 ml of water and 15 ml of 1 M phosphoric acid. The pH was adjusted to about 5.3 with 2.5 ml of 1 M phosphoric acid. The solution was filtered and lyophilized to yield amorphous diphosphate salt. The amorphous diphosphate salt was dissolved in 20 ml of isopropanol:acetonitrile (1 : 1). 1 ml of water was added and the solution was warmed to 60 °C and then cooled to 20-25 °C. The solution was stirred for about 12 h, filtered and dried under vacuum to yield ralfinamide diphosphate.

[0044] Example 3 Preparation of ralfinamide Form III (Refer to Chinese patent CN102470130B)

[0045] 3.07 g of ralfinamide free base was dissolved in 15 ml of acetonitrile and stirred at room temperature for about 80 min. The mixture was placed in a shaker block to undergo thermal cycling (0 °C to 40 °C in 1 h blocks) for 48 h. 15 ml of acetonitrile was added and the mixture was then placed back in the shaker block for 2 h. The crystals were filtered and dried under vacuum to yield ralfinamide Form III.

[0046] Example 4 Preparation of ralfinamide monosulfate (Refer to Chinese patent CN101163677B)

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

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

[0049] Example 5 Preparation of refenamide monooxalate salt (Refer to Chinese patent CN101163677B)

[0050] Dissolve 51.0 g of refenamide free base in 500 ml of H2O:ACN (1:1), slowly add about 170 ml of 1 M aqueous oxalic acid, adjust pH to about 3.0. Filter through a 0.2 micron filter, freeze-dry to obtain the hydrogen oxalate salt.

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

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

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

[0054] Table 1 Screening results of refenamide salt formation

[0055] Serial No. Type of acid Salt formation 1 2-chlorobenzoic acid Clear, no solid precipitated 2 2-naphthalenesulfonic acid Clear, no solid precipitated 3 6M hydrochloric acid Clear, no solid precipitated 4 DL-lactic acid Clear, no solid precipitated 5 sulfamic acid Clear, no solid precipitated 6 benzoic acid Clear, no solid precipitated 7 glacial acetic acid Clear, no solid precipitated 8 propanetricarboxylic acid Clear, no solid precipitated 9 succinic acid Clear, no solid precipitated 10 p-toluenesulfonic acid Clear, no solid precipitated 11 trans-cinnamic acid Clear, no solid precipitated 12 fumaric acid Clear, no solid precipitated 13 α-cyclopentyl mandelic acid Clear, no solid precipitated 14 ascorbic acid Clear, no solid precipitated 15 trifluoroacetic acid Clear, no solid precipitated 16 salicylic acid Clear, no solid precipitated 17 glutaric acid Clear, no solid precipitated 18 ethylsulfonic acid Clear, no solid precipitated 19 oleic acid Clear, no solid precipitated 20 palmitic acid Clear, no solid precipitated 21 maleic acid Oily 22 naphthalenesulfonic acid Hazy on addition, then clear 23 hydroxyethanesulfonic acid Hazy on addition, then clear 24 benzenesulfonic acid Hazy on addition, then clear 25 phenylacetic acid Hazy on addition, then clear 26 1-hydroxy-2-naphthoic acid Hazy on addition, then oily 27 citric acid Solid precipitated on addition, then oily 28 gluconic acid Hazy on addition, then sticky solid 29 DL-malic acid Hazy on addition, then sticky solid 30 D-malic acid Hazy on addition, then sticky solid 31 hydrobromic acid Hazy on addition, then sticky solid 32 tricarballylic acid Solid precipitated on addition, then sticky solid 33 tartaric acid Gummy spheres 34 5-nitroisophthalic acid Yellow powder and lumps, then sticky solid on standing 35 L-malic acid White sticky solid 36 terephthalic acid White powder, unsolubilized acid, no salt 37 glutamic acid White powder, unsolubilized acid, no salt 38 diphenylacetic acid White powder, rufinacine, no salt 39 trifenacine White powder, trifenacine rufinacine

[0056] Example 7 Preparation of refenamide triphenylacetate inhalation powder

[0057] 1) Weigh 0.087 g of magnesium stearate and 2.446 g of refenamide triphenylacetate raw material, mix for 20 min, then transfer to an air jet mill and pulverize at a pressure of 5 bar to obtain a refenamide compound with D 10 : 0.6 μm; D 50 : 2.7 μm; D 90 : 5.0 μm.

[0058] 2) Take the remaining amount of magnesium stearate 0.313 g and all the amount of lactose 327.154 g of the prescription into the TRV high shear mixing equipment, mix at a speed of 500.0 r / min for 6 min, discharge, and obtain the lactose premix.

[0059] 3) Add about 1 / 2 of the lactose premix, all the rilpateride compound, and the remaining about 1 / 2 of the lactose premix into the TRV mixing equipment in turn, set the mixing speed to 1350 r / min, mix for 3 min, discharge, and obtain the rilpateride total mix.

[0060] 4) Take the rilpateride total mix powder, fill the capsules with a filling amount of 25 mg ± 1 mg, and prepare the rilpateride inhalation powder capsule that can be delivered to the lungs for administration by a dry powder inhalation device.

[0061] 5) Double aluminum package the above drug-loaded capsules, and the rilpateride inhalation powder (rilpateride triphenylacetate) is obtained.

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

[0063] Ingredient Prescribed amount Action lactose 327.154g Carrier magnesium stearate 0.40g Dispersing aid rufinacine (trifenatate) 2.446g Active ingredient

[0064] Preparation of rilpateride diphosphate inhalation powder

[0065] 1) Take 0.087 g of magnesium stearate and 2.191 g of rilpateride diphosphate raw material, mix for 20 min, and then transfer to an air jet mill to be micronized at a micronizing pressure of 5 bar to obtain a rilpateride compound with D 10 : 0.6 μm; D 50 : 2.5 μm; D 90 : 4.9 μm.

[0066] 2) Take the remaining amount of magnesium stearate 0.313 g and all the amount of lactose 327.409 g of the prescription into the TRV high shear mixing equipment, mix at a speed of 500.0 r / min for 6 min, discharge, and obtain the lactose premix.

[0067] 3) Add about 1 / 2 of the lactose premix, all the rilpateride compound, and the remaining about 1 / 2 of the lactose premix into the TRV mixing equipment in turn, set the mixing speed to 1350 r / min, mix for 3 min, discharge, and obtain the rilpateride total mix.

[0068] 4) Take the rilpateride total mix powder, fill the capsules with a filling amount of 25 mg ± 1 mg, and prepare the rilpateride inhalation powder capsule that can be delivered to the lungs for administration by a dry powder inhalation device.

[0069] 5) Double aluminum package the above drug-loaded capsules, and the rilpateride inhalation powder (rilpateride triphenylacetate) is obtained.

[0070] Table 3 Formulation list of rilmenidine inhalation powder (rilmenidine diphosphate)

[0071] Ingredient Prescribed amount Action lactose 327.409g Carrier magnesium stearate 0.40g Dispersing aid rufinacine (diphosphate) 2.191g Active ingredient

[0072] Example 9 Preparation of rilmenidine inhalation powder of Form III

[0073] 1) 0.087 g of magnesium stearate and 1.650 g of rilmenidine Form III raw material were weighed and mixed for 20 min, then transferred to a jet mill for micronization at a micronization pressure of 5 bar to obtain a rilmenidine compound with D 10 : 0.5 μm; D 50 : 2.3 μm; D 90 : 4.5 μm.

[0074] 2) The remaining amount of magnesium stearate 0.313 g and the total amount of lactose 327.950 g were weighed and mixed in a TRV high-shear mixing device at a mixing speed of 500.0 r / min for 6 min, and the mixture was discharged to obtain a lactose premix.

[0075] 3) About 1 / 2 of the lactose premix, the total amount of the rilmenidine compound and the remaining about 1 / 2 of the lactose premix were sequentially laid flat in the TRV mixing device, and the mixing speed was set to 1350 r / min, mixed for 3 min, and the mixture was discharged to obtain a rilmenidine total mixture.

[0076] 4) The rilmenidine total mixture powder was filled into capsules at a filling amount of 25 mg ± 1 mg to prepare rilmenidine inhalation powder capsules that can be delivered to the lungs by a dry powder inhalation device.

[0077] 5) The above drug-loaded capsules were double-aluminum packaged, and the rilmenidine inhalation powder capsules were obtained.

[0078] Table 4 Formulation list of rilmenidine inhalation powder (rilmenidine Form III)

[0079] Ingredient Prescribed amount Action lactose 327.95g Carrier magnesium stearate 0.40g Dispersing aid rufinacine (Form III) 1.650g Active ingredient

[0080] Example 10 Preparation of rilmenidine monosulfate and rilmenidine mono-oxalate inhalation powders

[0081] 0.087 g of magnesium stearate and 1.921 g of rilmenidine monosulfate raw material were weighed and mixed for 20 min, then transferred to a jet mill for micronization at a micronization pressure of 5 bar to obtain a rilmenidine compound with D 10 : 0.7 μm; D 50 : 2.7 μm; D 90 : 5.5 μm. The rilmenidine monosulfate inhalation powder was prepared according to the method of Example 8.

[0082] Take 0.087 g of magnesium stearate and 1.899 g of rufinamide monooxalate raw materials, mix for 20 min, then transfer to an air jet mill and micronize at a grinding pressure of 5 bar to obtain a D 10 : 0.6 μm; D 50 : 2.4 μm; D 90 : 4.8 μm, to obtain a rufinamide complex. The rufinamide crystal monooxalate inhalation powder was prepared according to the method of Reference Example 8.

[0083] Example 11 Stability study of different rufinamide inhalation powder formulations

[0084] The different rufinamide inhalation powders prepared in Examples 8-10 were placed in an environment of 40℃±2℃, RH 75%±5%, respectively, and the changes in fine particle dose, fine particle fraction, content and related substances of the product were measured at intervals, and the results are shown in Table 5.

[0085] The related substance test method is as follows:

[0086] Method based on: high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four chapters 0512).

[0087] Chromatographic conditions:

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

[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 the product, transfer the contents to a 25ml volumetric flask, wash the capsule shells with 10ml of mobile phase A in portions, and add the wash to the volumetric flask, shake to dissolve, dilute to the mark with mobile phase A, and shake well.

[0094] (3) Control solution: accurately take 1ml of the test solution in a 100ml volumetric flask, and dilute to the mark with diluent.

[0095] Table 5 Stability study conditions

[0096] Investigation condition Specific condition Accelerated Temperature: 40°C ± 2°C, relative humidity 75% ± 5%

[0097] Table 6 Stability study results

[0098]

[0099] Table 6 Stability study results (continued)

[0100]

[0101] The inhalation powders prepared using rufinamide triphenylacetate had significantly higher fine particle dose and fine particle fraction than the inhalation powders prepared using rufinamide diphosphate and Form III. In the stability study, the fine particle dose and fine particle fraction of the inhalation powder prepared using rufinamide triphenylacetate remained stable for 3 months of accelerated testing, while the fine particle dose and fine particle fraction of the inhalation powders prepared using rufinamide diphosphate and Form III showed a downward trend for 3 months of accelerated testing. The related substances of the inhalation powder prepared using rufinamide triphenylacetate increased slowly for 3 months of accelerated testing, while the related substances of the inhalation powders prepared using rufinamide diphosphate and Form III increased significantly for 3 months of accelerated testing. The inhalation powders prepared using rufinamide monosulfate and rufinamide oxalate had the worst fine particle dose and fine particle fraction, and the related substances of the two increased most significantly in the stability study.

[0102] In summary, the inhalation powder prepared using rufinamide triphenylacetate had the best performance in the stability study. Example 8 Performance of different rufinamide inhalation powders in pharmacokinetics in rats

[0103] The male SD rats (SPF level) used in this example were 9 months old and weighed 180-220 g. During the entire experiment, the rats were allowed to eat and drink freely. The SD rats were grouped using a randomized block design, and were divided into three groups: rufinamide triphenylacetate Form III inhalation powder group, rufinamide diphosphate inhalation powder group, and rufinamide Form III inhalation powder group. The rats were administered the drug by oral inhalation, and the dose was set at 375 μg / kg (based on rufinamide).

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

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

[0106]

[0107] The results of rat in vivo pharmacokinetics showed that the peak blood drug concentration C max and AUC 0-∞ of ralfinamide triphenylacetate inhalation powder were the lowest, indicating that ralfinamide triphenylacetate inhalation powder was significantly superior to ralfinamide diphosphate inhalation powder and ralfinamide crystal form III inhalation powder in terms of safety.

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

[0109] Formulation selection: three different crystal / salt forms of ralfinamide inhalation powder prepared in Examples 4-6

[0110] Dosing frequency: single dose

[0111] Dosing route: oral nasal inhalation

[0112] Test animals: SD rats

[0113] Grouping: A total of 108 SD rats were divided into ralfinamide triphenylacetate inhalation powder 375 μg / kg (based on ralfinamide) dose group, ralfinamide diphosphate inhalation powder 375 μg / kg (based on ralfinamide) dose group and ralfinamide crystal form III inhalation powder 375 μg / kg (based on ralfinamide) dose group, 36 rats in each group. The drug concentration in the lung alveolar lavage fluid, lung tissue, main trachea and bronchus, bladder, heart, liver and kidney of the animals was collected at 0.5 h after administration.

[0114] Table 8 Distribution of ralfinamide in main organs and tissues in rats after 0.5 h of inhalation of two formulations

[0115]

[0116] Refenitin is a long-acting anticholinergic drug, which has similar affinity to M1-M5 subtypes of muscarinic receptors. In the airway, it shows pharmacological effects by inhibiting M3 receptors of smooth muscle to cause bronchodilation. M3 receptors of smooth muscle are mainly located in the trachea and bronchus, which are the main pharmacodynamic sites of refenitin. From the above animal tissue distribution test, it can be seen that after 0.5 h of inhalation administration, the concentration of refenitin triphenylacetate inhalation powder in the lung tissue, main trachea and bronchus, which are the pharmacodynamic sites, is significantly higher than that of refenitin diphosphate inhalation powder and refenitin Form III inhalation powder, while the concentration of refenitin triphenylacetate inhalation powder in the bladder, heart and other places that may cause clinical side effects (such as urinary retention) is significantly lower than that of the other two crystal forms of refenitin inhalation powder, indicating that refenitin triphenylacetate inhalation powder can produce higher bronchodilation effect than refenitin diphosphate inhalation powder and refenitin Form III inhalation powder and produce lower clinical side effects.

Claims

1. A ralfinamide triphenylacetate characterized in that The compound has the following structural formula: 。 2. An inhalation formulation of rafensine, characterized in that The rafenamide salt of claim 1 is used as the main active ingredient of the medicine.

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

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

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

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

7. The inhalation formulation according to claim 6, characterized in that The carrier is lactose, and the dispersion aid is magnesium stearate.

8. The inhalation formulation according to claim 2, characterized in that The ralfinamide triphenylacetate has a particle size distribution D 10 : 0.4-1.2 μm; D 50 : 1.5-4 μm; D 90 : 2.5-8 μm.

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

10. The inhalation formulation according to any one of claims 2-7, wherein The inhalation preparation has the following components by weight: Rafenamide salt 0.2-20 parts; Lactose 972-999.3 parts; Magnesium stearate 0.5-8 parts.

11. Use of the rafenamide salt of claim 1 in the preparation of a medicine for treating COPD.

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