WO2021109771A1

WO2021109771A1 - Method for preparing micropowder mixture of active pharmaceutical ingredients of glycopyrronium bromide and indacaterol

Info

Publication number: WO2021109771A1
Application number: PCT/CN2020/125810
Authority: WO
Inventors: 李猛; 陶红富; 马永浩; 高成林; 李励; 林坛
Original assignee: 长风药业股份有限公司
Priority date: 2019-12-02
Filing date: 2020-11-02
Publication date: 2021-06-10
Also published as: CN112972384A; CN112972384B

Abstract

Chronic obstructive pulmonary disease is a type of chronic bronchitis and (or) emphysema having the characteristic of airflow obstruction, which is debilitating and has a high mortality rate. On the basis of a synergistic effect, compound drugs have been widely applied to treat said disease. In order to achieve the best therapeutic effect, two active ingredients should exhibit similar deposition behavior in the human lungs and should be delivered to an affected area to have a medicinal effect. Compared with the inhalation dosage forms of dry powder and atomization, the convenience and safety of patients when using a medicine is considered, and a method for preparing a micropowder of the active pharmaceutical ingredients of a compound inhalation aerosol is provided. The glycopyrronium bromide and indacaterol compound inhalation aerosol obtained by using the present preparation method can effectively increase the effective site deposition rate of glycopyrronium bromide, and can improve the degree of co-deposition between the two active ingredients. Processing is simple for the micropowder mixture of the active pharmaceutical ingredients of glycopyrronium bromide and indacaterol prepared by using the present preparation method as well as for a compound inhalation aerosol thereof, and the FPF of the active ingredients is significantly increased.

Description

Preparation method of glycopyrrolate and indacaterol crude drug micropowder mixture

Technical field

The invention relates to a preparation method of a compound inhalation aerosol raw material medicine micropowder mixture. In particular, a method for preparing a mixture of glycopyrrolate and indacaterol crude drug micropowder.

Background technique

Inhaled aerosols use propellants as the power source for drug delivery. This is based on the fact that the propellant exists as a liquid in the container (mainly aluminum cans). When the valve is pressed, the drug formulation with the propellant as the solvent is ejected from the nozzle. Drug particles can be delivered to human bronchial and lung lesions to play a therapeutic role. Among them, solution-type aerosols need to pay attention to the problem of chemical stability. The suspension aerosol needs to be concerned about the dispersion behavior of the bulk drug in the propellant. In order to improve the dispersion and delivery efficiency of suspension aerosols, the following auxiliary materials are often added to suspension aerosols, including cromolyn sodium (co-dispersant), oleic acid (surfactant), ethanol (solubilizer) ), Sorbitan trioleate (surfactant), PVP K25 (suspending agent), PEG1000 (valve lubricant). Of course, by studying the physical and chemical properties of the bulk drug, the morphology, particle size, surface roughness, crystal form, etc. of the bulk drug can also be changed to improve the performance of the preparation.

US8143239 discloses a new formulation of budesonide and formoterol inhalation aerosol, which contains 0.001% PVP K25 and 0.3% PEG1000. PVP K25 as a suspending agent can fully improve the physical stability of the formulation. After shaking, the active ingredients were evenly dispersed in the propellant. The experimental results showed that most of the drug particles were still in suspension after 1 minute of shaking. Experiments have found that the effective site deposition rate (FPF) of the two active ingredients determined by the long-term stability study is maintained in the range of 55-60%, and the physical stability is good. In order to solve this problem, Astrazene uses PVP K25 with an appropriate concentration (0.001%) as a suspending agent. After PVP is dissolved in the propellant, the viscosity of the propellant is enhanced and the sedimentation rate of the two active ingredients is reduced.

CN1150890 discloses a new type of metered dose inhaler (Metered dose inhaler, MDI) prescription, in which an unconventional excipient sodium cromoglycate or nadocromil is added. Sodium Cromolyn or Nadocromil is clinically a mast cell stabilizer, which inhibits inflammatory cells from releasing inflammatory mediators and treats asthma. However, in this prescription, the trace amount of cromolyn sodium or nadocromil is not used for treatment but as a functional adjuvant to inhibit the adhesion and agglomeration of the active ingredients in the suspension and improve its dispersibility. The active ingredients in this patent are fluticasone propionate and formoterol fumarate. The addition of cromolyn sodium or nadocromil inhibits the agglomeration of the two active ingredients. The principle is that after cromolyn sodium and formoterol are mixed uniformly and added to the propellant, the cromolyn sodium forms a stable association with formoterol in the form of a salt.

Patent US8808713 discloses a new MDI formulation, which uses long-acting muscarinic antagonists (LAMA) such as glycopyrrolate, tiotropium and umebromide and long-acting β ₂ adrenergic receptor agonists (LABA) Such as indacaterol, formoterol, salmeterol and odacaterol as the main active ingredients, and lecithin as the suspension particle. After the company spray-dried the lecithin, the lecithin became porous. The density of this porous lecithin is much lower than that of the propellant, so the buoyancy of the porous lecithin in the propellant is very large, and the active ingredient LABA or LAMA can be well absorbed in the porous lecithin suspended in the propellant surface. Even if it is shaken, centrifuged, or temperature fluctuates, LABA or LAMA is still adsorbed on the surface of the porous lecithin particles without significant sedimentation or agglomeration.

WO2013/021199 (CN103930095) uses a method to first dissolve two active ingredients (glycopyrrolate and indacaterol), and then spray dry the spray-dried mixture, ultrasonically process the spray-dried mixture, and finally filter to obtain the eutectic product. Compared with a single crystalline product, the melting point of one component in the eutectic product may decrease, and the melting point of the other component may increase or decrease. Therefore, the melting point of at least one active ingredient in the eutectic is lowered, and the chemical stability and solubility will be changed. Although this co-crystal has achieved the fusion of the two active ingredients, it can be expected that the co-deposition degree after being prepared into an inhalation preparation is very high, but the FPF is not necessarily high, and the physical and chemical properties of the co-crystal have changed, and there may still be stability. Sexual issues.

US 2015/0352077 discloses that glycopyrronium bromide, salmeterol, formoterol and other LABAs are first dissolved, and then the solution is added to an anti-solvent, ultrasound, crystallization, and recovery and filtration of the co-crystal. The results provided in the examples show that the stability is good and the degree of co-deposition is high, but the FPF of the inhalation preparation prepared by the co-crystal is not high (up to only 40%). The solubility and dissolution rate may change, and the dissolution rate of the active ingredient deposited on the surface of the lung after the administration of the inhaled preparation directly affects the rate and degree of absorption of the drug in the lung. The solubility of the two active ingredients in the co-crystal in this patent On the one hand, the change in dissolution rate may be difficult to control stably through the process, on the other hand, it may affect the absorption in the lungs, and then affect the onset speed.

In the development of suspension MDI compound products, it is not only necessary to consider the problem that the active ingredient is easier to settle because its density is higher than that of the propellant, and the poor dispersion results in the low deposition rate of the effective part, but also the two active ingredients are projected due to the difference in density. The difference in sedimentation behavior in the agent ultimately leads to the problem of low co-deposition of the two active ingredients in the product. The low degree of co-deposition is manifested in in vitro studies as a significant difference in the deposition rate of the drug on each level of the Anderson Cascade Impactor (Anderson Cascade Impactor, ACI) (the amount of deposition on each level of the plate/the total collected volume of the Anderson Cascade Impactor). Subsequently, the deposition rate of active ingredients in the lesion site is different in clinical practice, which will seriously affect the efficacy and safety of the drug.

Glycopyrrolate/indacaterol inhalation powder mist (trade name: Ultibro Breezhaler; capsule type) has been on the market. The inherent shortcomings of capsule powders mainly include: the use of acupuncture to puncture the capsule may cause capsule fragments to fall into the powder, and the capsule fragments will enter the human respiratory tract after inhalation, causing dry cough and foreign body sensation, while inhaled aerosols have no effect. This risk; dry powder inhaler (DPI) product development, especially device design, is very costly, so the price is higher than inhaled aerosol; DPI product storage temperature is lower than 25 ℃, and need to be moisture-proof, capsules Once the medicinal powder in Chinese medicine absorbs water, the product cannot be effectively delivered to the human lungs, and most aerosols do not need to be moisture-proof, and storage conditions do not need to be so strict.

Therefore, the applicant in the present invention has developed glycopyrrolate/indacaterol inhalation aerosol products. Glycopyrronium bromide is an anticholinergic drug that can dilate the bronchus, and indacaterol is a β ₂ receptor agonist. The compound preparation composed of the two can effectively treat COPD. In the formulation development, glycopyrrolate mono-MDI and indacaterol mono-MDI were prepared in parallel. Studies have found that the aerodynamic behavior of micronized indacaterol in single or compound preparations is very good, and the effective part (lung) deposition rate is as high as 40-50%; however, whether micronized glycopyrrolate is in single prescription The deposition rate of the effective parts in the compound preparation is very low, only reaching 15-20%, and most of the drugs are deposited in the throat. Obviously, glycopyrrolate is easy to agglomerate, has poor dispersion performance, and has a low deposition rate of effective parts.

As mentioned above, during the development of glycopyrrolate/indacaterol inhalation aerosol, the difference in the sedimentation behavior of the two active ingredients in the propellant resulted in a low degree of co-deposition.

In order to solve these two problems, the applicant first tried the adjustment prescription and the micronization process after individual crystallization in the above-mentioned patent. However, the results show that the above-mentioned prior art does not change the problem of low FPF and poor co-deposition degree.

Summary of the invention

In the present invention, fine powder refers to powder with D90≤5μm, and coarse powder refers to powder with D90≥10μm.

In the present invention, D90 is described as the volume of particles smaller than a certain size (x) accounts for 90% of the total volume of the particles; D50 is described as the volume of particles smaller than a certain size (x) accounts for 50% of the total volume of the particles; D10 description The volume of particles smaller than a certain particle size (x) accounts for 10% of the total volume of the particles.

The technical problem to be solved by the present invention is to improve the FPF of glycopyrrolate and indacaterol compound inhalation aerosol and the co-deposition degree of glycopyrrolate and indacaterol.

In order to solve the above technical problems, the technical solution adopted by the present invention is:

A method for preparing a mixture of micronized raw materials of a compound inhalation aerosol, comprising the following steps:

(1) Dissolving glycopyrrolate and indacaterol in a solvent to obtain glycopyrrolate indacaterol solution;

(2) After pumping the anti-solvent into the glycopyrrolate indacaterol solution obtained in step (1), continue stirring to obtain the glycopyrrolate indacaterol suspension;

(3) The glycopyrrolate indacaterol suspension obtained in step (2) is aged in a dry environment and then suction filtered, the filtered solid is collected, and dried to obtain glycopyrrolate indacaterol Tero crystal mixture;

(4) The glycopyrrolate indacaterol crystal mixture obtained in step (3) can be micronized.

In step (1), the solvent is selected from methanol or ethanol, and the mass ratio of glycopyrrolate and indacaterol is 1:5 to 5:1, preferably 1:5 to 1:1, glycopyrrolate The concentration of ammonium and indacaterol is 4.28-12 mg/ml.

In step (2), the anti-solvent is selected from one or more of isopropyl ether, methyl tert-butyl ether or ethyl acetate, preferably isopropyl ether.

In step (2), the volume of the anti-solvent is 7.5-15 times that of the solvent in step (1).

In step (2), the anti-solvent pumping rate is 15-65 ml/min; preferably, the anti-solvent pumping rate is 45-50 ml/min.

In step (2), the duration of the continuous stirring is at least 1 hour, preferably 2 hours.

In step (3), the time of the aging treatment is 12-24 hours, and the temperature of the aging treatment is 25-30°C.

In step (4), the pressure of the micronization treatment is 4-10 bar, preferably 6-8 bar.

In step (4), the micronization feed rate is 0.5 g-1.0 g/min.

The mixture of glycopyrronium bromide and indacaterol crude drug micropowder prepared according to the above method.

The D90 distribution range of the glycopyrrolate and indacaterol crude drug micropowder mixture is 3.53 μm to 3.90 μm, the D50 distribution range is 1.57 μm to 2.13 μm, and the D10 distribution range is 0.61 μm to 0.74 μm.

The mass ratio of glycopyrrolate and indacaterol in the micropowder is 1:5 to 5:1, and the preferred mass ratio is 1:1.

A compound inhalation aerosol is prepared by placing the mixture of glycopyrrolate and indacaterol raw materials in a fluoride-coated aluminum can, sealing the valve, filling a propellant, and ultrasonic processing. The propellant is one or more of HFA 134a, HFA 227, and HFA 152.

The FPF range of glycopyrrolate in the compound inhalation aerosol is 43%-52%, and the FPF range of indacaterol is 46%-54%.

In the course of research, the inventor found that when glycopyrrolate and indacaterol were directly micronized without any pretreatment, the prepared inhalation aerosols had lower FPF and poor co-deposition degree after ACI detection.

When glycopyrrolate and indacaterol were crystallized separately by antisolvent forward recrystallization, micronized, and then mixed to prepare a suspension type inhalation aerosol, although the FPF of indacaterol was significantly increased, However, the FPF of glycopyrrolate was reduced, and the degree of co-deposition was still very poor.

However, when the inventors used the anti-solvent forward recrystallization method to dissolve glycopyrrolate and indacaterol in the same solvent-antisolvent system, first complete the dissolution-precipitation-crystallization, and then micronize the precipitated crystal mixture When processed and prepared into a suspension type inhalation aerosol, we found that the FPF of glycopyrrolate and indacaterol were significantly increased, and the codeposition degree was good.

The crushing equipment used in the present invention is a ball mill, a jet mill, a high-pressure homogenizer or a spray dryer. Preferably, the pulverizing equipment is a jet pulverizer.

Add the prepared glycopyrrolate and indacaterol micropowder mixture into the aluminum can coated with fluorocarbon coating, then seal the valve, fill the propellant HFA134a, ultrasonically treat for 10 minutes, leave the sample for 2 days and then perform the Anderson cascade impact器Detection.

When performing ACI detection, the FPF range of glycopyrrolate is 43%-52%, and the FPF range of indacaterol is 48%-54%. The deposition rate difference of 0-2 grade board is ±10%, the difference of 3-4 grade board deposition rate is ±20%, the difference of 5 grade board deposition rate is ±30%, and the difference of 6-7 grade board deposition rate is ±50%.

As shown in Figure 5-9, the SEM scan shows that glycopyrrolate and indacaterol are compared with the morphology of glycopyrrolate and indacaterol without crystallization treatment and the morphology of the two after crystallization alone. The morphology and particle size of Luo co-crystal changed significantly.

When glycopyrrolate and indacaterol were crystallized separately, scanning electron microscopy (SEM) showed that the morphological features of glycopyrrolate changed from the initial round or oval (Figure 6) to smooth polygons. The flaky structure has a larger particle size; while indacaterol has changed from the initial rough round or oval (Figure 7) to a flaky and striped structure, and the particle size has become larger. After the glycopyrrolate indacaterol is crystallized in the same solvent-antisolvent system, the glycopyrrolate also changes from the initial round or oval to a smooth polygonal sheet structure, while the indacaterol from the initial The round or oval shape is transformed into a block and strip structure.

However, when crystallization in the same solvent-antisolvent (Figure 10) compares with separate crystallization (Figure 8-9), the area of the flaky crystals of glycopyrrolate is reduced, and the strip crystals of indacaterol do not change significantly. Glycopyrronium bromide flake crystals have strips of indacaterol adhered to the surface. We believe that the morphological changes and adhesion of glycopyrrolate and indacaterol caused by crystallization in the same solvent-antisolvent system may be the two activities in the prepared glycopyrrolate indacaterol inhalation aerosol. The increase in composition FPF is the direct cause of the good co-deposition degree.

The comparison of the deposition rate of each ACI plate of the suspension type inhalation aerosol prepared after simple mixing of glycopyrrolate and indacaterol after micronization is shown in Table 1 below. The ACI of the suspension type inhalation aerosol prepared after the recrystallization of glycopyrrolate and the indacaterol respectively after micronization and co-micronization, and the suspension type inhalation aerosol prepared after the co-crystallization and micronization The comparison of the deposition ratio of the grade plate is shown in Table 2 below.

Table 1: Comparison of the deposition rate of each ACI plate of the suspension type inhalation aerosol prepared after simple mixing and micronization of glycopyrrolate and indacaterol

Table 2: Glycopyrronium bromide recrystallization and indacaterol recrystallization, respectively, after micronization and co-micronization, and the suspension type inhalation aerosol prepared after co-crystallization and micronization Comparison of the deposition rate of each level of ACI

Beneficial effects:

The present invention adopts a new raw material drug pretreatment process to solve the problem of low glycopyrrolate bromide FPF in the glycopyrrolate indacaterol compound inhalation aerosol and the low degree of co-deposition of glycopyrrolate and indacaterol The problem.

The process method of the present invention is only a physical process, which is simple and fast.

Description of the drawings

Figure 1: Glycopyrronium bromide and indacaterol maleate in a mass ratio of 1:1 by anti-solvent forward recrystallization method. After recrystallization, micronized (8bar), a compound inhalation aerosol is prepared According to the Anderson Cascade Impactor test results, the volume ratio of solvent-antisolvent is 1:7.5.

Figure 2: Glycopyrronium bromide and indacaterol maleate in a mass ratio of 1:1 by anti-solvent forward recrystallization method, after recrystallization, micronized (8bar), a compound inhalation aerosol prepared In the Anderson Cascade Impactor test results, the volume ratio of solvent-antisolvent is 1:15.

Figure 3: Anderson cascade impactor detection of compound inhalation aerosol prepared by separate micronization (8bar) after recrystallization of glycopyrrolate and indacaterol maleate at a mass ratio of 1:1 result.

Figure 4: The Anderson cascade impactor test results of the compound inhalation aerosol prepared after glycopyrrolate and indacaterol maleate were recrystallized separately and co-micronized (8 bar) at a mass ratio of 1:1 .

Figure 5: The Anderson cascade impactor test of the compound inhalation aerosol prepared by the mass ratio of glycopyrrolate and indacaterol maleate powder at a mass ratio of 5:1. result.

Figure 6: SEM image of glycopyrrolate raw material.

Figure 7: SEM image of indacaterol maleate raw material.

Figure 8: SEM image of glycopyrrolate after crystallization alone.

Figure 9: SEM scan of indacaterol alone crystal.

Figure 10: SEM image of glycopyrrolate and indacaterol recrystallized in the same solvent-antisolvent system.

Detailed ways

Experimental equipment: The jet mill is a Micron JETMILL Lab ultrafine powder jet mill, the model of the high performance liquid phase (HPLC) instrument is Waters 2695, and the model of the peristaltic pump is BT100-1F.

Reagent sources: glycopyrronium bromide was purchased from Harman Finochem Ltd, India, indacaterol maleate was purchased from Inke, Italy, and HFA 134a was purchased from Meixi Chemical Company (Japan).

The indacaterol used in the present invention is indacaterol maleate. Add the prescription amount of glycopyrrolate and indacaterol maleate to the aluminum can. Then the valve is closed and the propellant HFA-134a is filled. After being inverted for 2 days, it was tested in accordance with the Chinese Pharmacopoeia 2015 edition of the four general rules 0951. The sum of the deposition from the third-level plate to the filter membrane is the effective part deposition (Fine Particle Dose, FPD), the effective part deposition (under 5 microns) divided by the total amount collected by the Anderson Cascade Impactor (Total Dose, TD) ) Obtain the effective part deposition rate (Fine Particle Fraction, FPF).

In the present invention, the abbreviations have the following meanings:

HV: High Voltage

WD: Work Distance, refers to the distance between the sample and the pole shoe

Mag: Magnification magnification, refers to the magnification of the sample

Det: Detector, detector

ETD: Electron Detector, refers to the secondary electron probe

SEM: Scanning electron microscope.

experimental method:

The precision weighed micropowder is placed in a 14mL fluorocarbon polymer (FCP) coated aluminum can, the valve is sealed, filled, and subjected to ultrasonic treatment for 10 minutes. The sample is left for 2 days and then tested by the Anderson cascade impactor. According to the Chinese Pharmacopoeia 2015 Edition Four General Rules 0951 Device 2, the relative humidity of the test environment should be 45% to 55%. Adjust the flow rate to 28.3±1.5 liters per minute. Take 1 bottle of this product separately, after fully shaken, discard 4 sprays, wipe the mouth of the sleeve with ethanol, fully dry, turn on the vacuum pump, shake for 5 seconds (note that each spray shakes for 5 seconds with 30 seconds interval), Insert the product into the adapter, spray once, remove the aluminum can and the driver, shake for 5 seconds, reinsert the adapter, spray the second time immediately, repeat this process until the completion of 10 sprays, the last spray After that, wait for 1 minute. After removing the aluminum can and the driver, turn off the vacuum pump and remove the device. Wash each ACI plate with a specific ratio of methanol aqueous solution, and use HPLC to determine the content of the deposited drug on each plate.

Example 1:

Weigh 0.6058g glycopyrrolate and 0.6004g indacaterol maleate in a 100ml beaker, add 55ml methanol, dissolve it ultrasonically, transfer to a 1000ml beaker, rinse with 5ml methanol; use a peristaltic pump at 45ml/min Pump in 450ml of isopropyl ether at a rate, and after the addition is complete, continue to stir for 2h; divide into 3 conical flasks and age in a drying oven at 30°C overnight; filter with suction and vacuum at 50°C; dry; Just collect it. Weigh 1.0105 g glycopyrronium bromide indacaterol maleate crystal mixture, add it to a jet mill, and perform micronization treatment under a pressure of 8 bar. The micronized API is sealed and stored for later use. Weigh 16 mg glycopyrrolate bromide and indacaterol maleate fine powder mixture in a 14mL FCP-coated aluminum can, seal the valve, fill it, ultrasonically treat it for 10 minutes, leave the sample for 2 days for testing. The ACI test result is shown in Figure 1.

Example 2

Weigh 0.3030g glycopyrrolate and 0.3025g indacaterol maleate in a 100ml beaker, add 40ml methanol, dissolve it ultrasonically, transfer to a 1000ml beaker, rinse with 5ml methanol; use a peristaltic pump at 45ml/min Pump in 675ml of isopropyl ether at a rate. After the addition is complete, continue to stir for 2h; divide into 3 conical flasks and age in a drying oven at 30°C overnight; filter with suction and dry in an oven at 50°C; collect it immediately can. Weigh 0.5 g glycopyrrolate bromide indacaterol maleate crystal mixture, add it to a jet mill, and perform micronization treatment under a pressure of 8 bar. The micronized API is sealed and stored for later use. Weigh 16 mg glycopyrrolate bromide and indacaterol maleate fine powder mixture in a 14mL FCP-coated aluminum can, seal the valve, fill it, ultrasonically treat it for 10 minutes, leave the sample for 2 days for testing. The ACI test result is shown in Figure 2.

Comparative example 1:

Weigh 0.8065g glycopyrrolate in a 100ml beaker, add 45ml methanol, dissolve it ultrasonically, transfer to a 1000ml beaker, rinse with 5ml methanol; use a peristaltic pump to pump 500ml (10 times the volume of methanol) at a rate of 45ml/min Isopropyl ether, after the addition is complete, continue to stir for 2h; divide into 3 conical flasks and age in a drying oven at 30°C overnight; use a suction filtration device and vacuum dry at 50°C; dry and collect.

Weigh 0.8040g indacaterol maleate into a 150ml beaker, add 105ml methanol, dissolve it ultrasonically, transfer to a 2000ml beaker, rinse with 5ml methanol; use a peristaltic pump to pump 1100ml isopropyl ether at a rate of 45ml/min After the addition is complete, continue to stir for 2h; divide into 3 conical flasks and age in a drying oven at 30°C overnight; filter with suction and vacuum dry at 50°C; dry and collect.

Weigh 0.5 g glycopyrronium bromide crystals and 0.5 g indacaterol maleate crystals to micronize under a pressure of 8 bar. The micronized API is sealed and stored for later use.

Weigh 8mg glycopyrronium bromide fine powder and 8mg indacaterol maleate fine powder, mix them, place them in a 14mL FCP-coated aluminum can, seal the valve, fill, ultrasonically treat for 10 minutes, leave the sample for 2 days for testing .

The ACI test result is shown in Figure 3.

Comparative example 2:

Weigh 0.6069g glycopyrronium bromide into a 100ml beaker, add 50ml methanol, dissolve it ultrasonically, transfer to a 2000ml beaker, rinse with 5ml methanol; use a peristaltic pump to pump in 825ml isopropyl ether at a rate of 45ml/min to complete the addition After that, continue to stir for 2 hours; divide into 3 conical flasks and age in a drying oven at 30°C overnight; use a suction filter to filter and dry in vacuum at 50°C; just dry and collect.

Weigh 0.6005g of indacaterol maleate in a 100ml beaker, add 80ml of methanol, dissolve it ultrasonically, transfer to a 2000ml beaker, rinse with 5ml of methanol; use a peristaltic pump to pump in 825ml of isopropyl ether at a rate of 45ml/min After the addition is complete, continue to stir for 2h; divide into 3 conical flasks and age in a drying oven at 30°C overnight; filter with suction and vacuum dry at 50°C; dry to collect the crystals.

Weigh 0.37 g glycopyrronium bromide crystals and 0.37 g indacaterol maleate crystals to co-micronize under a pressure of 8 bar. The micronized API is sealed and stored for later use.

Place 16 mg glycopyrrolate and indacaterol powder mixture in a 14mL FCP-coated aluminum can, seal the valve, fill, ultrasonically treat for 10 minutes, and leave the sample for 2 days for testing. The ACI test result is shown in Figure 4.

Table 3. ACI test results of inhalation aerosols prepared with glycopyrrolate and indacaterol raw materials prepared by three different treatment processes

As shown in Table 3, compared with the separate crystallization-single micronization and separate crystallization-co-micronization processes, the glycopyrrolate and indacaterol maleate mixture prepared by the same solvent-antisolvent system crystallization process is micronized The FPFs of glycopyrrolate and indacaterol maleate in the prepared inhalation aerosol were significantly increased.

The ACI test results in Figure 1-3 show that compared with the single crystallization-single micronization process and the single crystallization-co-micronization process, glycopyrrolate maleate prepared by the same solvent-antisolvent system crystallization-micronization process The co-deposition degree of glycopyrrolate and indacaterol maleate in the inhalation aerosol prepared from the mixture of indacaterol acid was significantly improved.

Comparative example 3:

Weigh 20 mg of micronized glycopyrrolate bromide and 4 mg of micronized indacaterol maleate in a 14mL FCP-coated aluminum can, seal the valve, fill, ultrasonically treat for 10 minutes, leave the sample for 2 days for testing. The ACI detection method is as described above. The test result of the Anderson cascade impactor is shown in Figure 5.

Table 4. FPF of inhalation aerosol prepared by directly mixing glycopyrrolate powder and indacaterol maleate powder (5:1)

The above are only the preferred embodiments of the present application, so that those skilled in the art can understand or implement the invention of the present application. Various modifications and combinations of these embodiments will be obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the application. . Therefore, this application will not be limited to the embodiments shown in this document, but should conform to the widest scope consistent with the principles and novel features disclosed in this document.

Claims

A method for preparing a mixture of micronized raw materials of a compound inhalation aerosol, which is characterized in that it comprises the following steps:

(1) Dissolving glycopyrrolate and indacaterol in a solvent to obtain glycopyrrolate indacaterol solution;

(2) Pump the anti-solvent into the glycopyrrolate indacaterol solution obtained in step (1) and continue to stir to obtain the glycopyrrolate indacaterol suspension;

(3) The glycopyrrolate indacaterol suspension obtained in step (2) is aged in a dry environment and then suction filtered, the filtered solids are collected, and dried to obtain glycopyrrolate and indene Datrol crystal mixture;

(4) The glycopyrrolate indacaterol crystal mixture obtained in step (3) can be micronized.
The method according to claim 1, wherein in step (1), the solvent is selected from methanol or ethanol, and the mass ratio of glycopyrrolate and indacaterol is 1:5 to 5:1, The concentration of glycopyrrolate and indacaterol is 4.28-12 mg/ml.
The method according to claim 2, wherein the mass ratio of glycopyrrolate and indacaterol in step (1) is 1:5 to 1:1.
The method according to claim 1, wherein in step (2), the anti-solvent is selected from one or more of isopropyl ether, methyl tert-butyl ether or ethyl acetate.
The method according to claim 1, wherein in step (2), the volume of the anti-solvent is 7.5-15 times that of the solvent in step (1).
The method according to claim 1, wherein in step (2), the anti-solvent pumping rate is 15-65 ml/min.
The method according to claim 6, wherein in step (2), the anti-solvent pumping rate is 45-50 ml/min.
The method according to claim 1, wherein in step (2), the duration of the continuous stirring is at least 1 hour.
The method according to claim 1, wherein in step (3), the time of the aging treatment is 12-24 hours, and the temperature of the aging treatment is 25-30°C.
A mixture of glycopyrrolate and indacaterol crude drug micropowder prepared according to any one of the methods of claims 1-9.
The mixture of glycopyrrolate and indacaterol crude drug micropowder according to claim 10, wherein the D90 distribution range of the micropowder is 3.53 μm to 3.90 μm, and the D50 distribution range is 1.57 μm to 2.13 μm, and The distribution range of D10 is 0.61μm～0.74μm.
A compound inhalation aerosol, characterized in that the micropowder mixture of glycopyrrolate and indacaterol raw materials according to any one of claims 1-9 is placed in a fluorocarbon polymer coated aluminum can, and the valve is sealed, It is prepared by filling propellant and ultrasonic treatment.
The compound inhalation aerosol according to claim 12, characterized in that when the received inhalation aerosol is tested by the Anderson cascade impactor, the FPF range of glycopyrrolate is 43% to 52%, and the FPF of indacaterol The range is 48% to 54%.