Particle size grading budigegfu inhalation powder inhalation and preparation method thereof

Abstract

The invention discloses a budeagfor inhalation dry powder inhalation which comprises active ingredients, a carrier and a dispersing aid, and the active ingredients are budesonide, glycopyrronium bromide and formoterol fumarate dihydrate which are subjected to particle size grading. According to the invention, different drugs can be delivered to respective target sites of the lung through a particle size grading process of micronized active ingredients. The budigegfu inhalation dry powder inhalation is good in delivery dose uniformity and stable in delivery efficiency, and animal test results show that the product prepared by adopting the active component size grading method has obvious advantages in the aspects of safety and effectiveness.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology and relates to pharmaceutical preparations, in particular to a capsule-type inhalation powder aerosol composition and a preparation method 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. The pathogenesis of COPD is complex. Inhalation of harmful particles or gases such as tobacco smoke can cause airway oxidative stress, inflammatory response, and protease / antiprotease imbalance, which are involved in the pathogenesis of COPD. A variety of inflammatory cells are involved in the airway inflammation of COPD, including macrophages, neutrophils, and Tc1, Th1, Th17, and ILC3 lymphocytes. In addition, autoimmune regulatory mechanisms, genetic risk factors, and lung development-related factors may also play an important role in the occurrence and development of COPD.

[0003] Inhaled drug therapy can reduce or eliminate patients' symptoms, improve activity tolerance, reduce the number and severity of acute attacks, and improve health status. 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 muscle to dilate the bronchi, improve airflow limitation, and thus alleviate the symptoms of COPD. The main bronchodilators include β2 receptor agonists, M cholinergic receptor antagonists, and methylxanthines, which can be selected according to 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, nor does it significantly improve the mortality rate. Therefore, it is not recommended to use a single ICS treatment for patients with stable COPD. Combination ICS treatment can be considered on the basis of using one or two long-acting bronchodilators. The combined use of drugs with different mechanisms of action and duration of action can enhance the bronchial dilation effect and better improve the patient's lung function and health status.

[0004] Glycopyrrolate is a long-acting acetylcholine receptor antagonist (LAMA) that has similar affinity to human acetylcholine M1-M5 subtype receptors and can inhibit the M3 acetylcholine receptors of bronchial smooth muscle to dilate the airways. Formoterol is a long-acting β2 adrenergic receptor agonist (LABA) that relaxes bronchial smooth muscle and relieves bronchospasm. The bronchodilator effect is dose-related, takes effect within 1 to 3 minutes, and a single dose can last at least 12 hours. Budesonide is a glucocorticoid that has a dose-dependent anti-inflammatory effect after inhalation through the airways, can relieve COPD symptoms, and reduce acute exacerbations of COPD.

[0005] The drug combination compositions currently on the market mainly include budesonide formoterol powder inhaler (Symbicort), glycopyrrolate formoterol inhalation aerosol, and budegol aerosol. The combination of the three drugs is the budegol inhalation aerosol (trade name Breztri Aerosphere) developed by AstraZeneca, which is a fixed-dose triple therapy drug administered by a single inhaler. However, aerosols have certain limitations. The amount of drug delivered per inhalation is not large, the lung deposition is low, and the patient's correct use of the device is required. The powder inhaler has a large drug load, a high lung deposition rate, and the inhalation device is easy for patients to use. At present, there is still no powder inhaler for the combination of three drugs on the market. The powder inhaler dosage form of the three drugs is urgently needed in clinical practice to meet unmet clinical needs. The active ingredients in dry powder inhalation preparations require an aerodynamic diameter of less than 5μm. Generally, the active ingredients need to be micronized. However, the specific surface area of ​​the micronized drug particles increases, the surface energy increases, the cohesion and adhesion also increase, and the electrostatic force, van der Waals force, friction between particles and other effects hinder the free flow of particles, making it difficult to mix evenly, resulting in poor uniformity of delivered doses. On the other hand, the combination of the three drugs will affect each other due to their different physical and chemical properties, which will in turn affect FPF and FPF stability.

[0006] The combined use of three drugs with different mechanisms of action can increase the efficacy. However, the combined use of the three drugs also brings local and systemic adverse reactions of the drugs, such as palpitations, dysphonia, cough, anxiety, insomnia, depression, headache, dizziness, etc. The incidence of adverse reactions of inhaled drugs is closely related to the deposition of drugs in non-drug effect sites and the systemic exposure of drugs. Literature reports that β2 receptors with bronchodilator effects are widely distributed in the peripheral airways, and M cholinergic receptors, which also have bronchodilator effects, are located on airway smooth muscles and are most distributed in the central large airways. ICS mainly acts on the deep lungs. According to the above-mentioned drug delivery theory, delivering budesonide to deep lung sites such as the alveolar region is conducive to the anti-inflammatory effect of ICS drugs and improves drug efficacy; delivering formoterol and glycopyrrolate to sites such as the trachea, bronchi and secondary bronchi is conducive to the bronchodilator effect of LAMA and LABA drugs, which is beneficial to drug efficacy. However, if too much is delivered to non-drug-effective sites such as the terminal bronchi, alveolar ducts and alveoli, the drug is easy to quickly enter the blood, thereby increasing C max How to efficiently deliver drugs to the optimal target site in the lungs, improve drug efficacy, and reduce adverse drug reactions are issues that need to be addressed in the development of inhaled preparations. Summary of the invention

[0007] The present invention develops a powder inhaler with good delivery uniformity and stable delivery efficiency through the development of prescription process. Different drugs can be delivered to the target parts of the lungs through the particle size classification process of micronized active ingredients. The animal test results show that the product prepared by the method of active ingredient particle size classification has obvious advantages in safety and effectiveness.

[0008] The present invention provides a composition with fewer adverse reactions and better clinical effects. The composition is graded by a special process to achieve targeted delivery of different drugs, and has stable and reliable quality.

[0009] The specific technical solutions of the present invention are as follows:

[0010] A budesonide inhalation powder comprises an active ingredient, a carrier and a dispersing aid, wherein the active ingredient is budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle size, and has the following particle size distribution characteristics:

[0011] d10=0.5-0.9μm, d50=1.5-2.5μm, d90=3.0-5.0μm, span=1.6-1.8; glycopyrrolate d10=0.6-0.9μm, d50=1.6-2.6μm, d90=3.5-5.5μm, span=1.6-1.8; formoterol fumarate dihydrate d10=0.7-1.1μm, d50=1.8-3.0μm, d90=4.0-6.0μm, span=1.6-1.8; the mass ratio of budesonide, glycopyrrolate and formoterol fumarate dihydrate is 200-500:10-30:5-15.

[0012] The above-mentioned budegol inhalation powder has the following particle size distribution characteristics of the carrier: d10 = 3.0 μm to 25.0 μm, d50 = 40 μm to 120 μm, d90 = 100 μm to 180 μm. The dispersing aid has the following particle size distribution characteristics:

[0013] d10=2.0~5.0μm, d50=7.0~12.0μm, d90=18~30μm.

[0014] Furthermore, the budegol inhalation powder of the present invention contains 0.03% to 3.68% by mass of active ingredients, 95.6% to 98.1% by mass of carriers and 0.40% to 0.60% by mass of dispersing aids.

[0015] In a specific example of the present invention, the carrier is lactose monohydrate and the dispersing aid is magnesium stearate.

[0016] A specific example of the budesonide inhalation powder of the present invention is a capsule-type inhalation powder, each capsule containing 200-500 μg of budesonide, 10-30 μg of glycopyrrolate and 5-15 μg of formoterol fumarate dihydrate.

[0017] The budegol inhalation powder of the present invention uses Copley Citdas software to calculate the mass percentage of the particle size of the active ingredients as follows: in the particle size range of 0-2.1 μm, the mass percentage of budesonide in the total amount of budesonide is 25%-35%, the mass percentage of glycopyrrolate in the total amount of glycopyrrolate is 12%-18%, and the mass percentage of formoterol fumarate dihydrate in the total amount of formoterol fumarate dihydrate is 15%-20%; in the particle size range of 2.1-4.7 μm, the mass percentage of budesonide in the total amount of budesonide is 24%-28%, the mass percentage of glycopyrrolate in the total amount of glycopyrrolate is 37%-45%, the mass percentage of formoterol fumarate in the total amount of formoterol fumarate dihydrate is 37%-43%, and the portion of each active ingredient with a particle size larger than 4.7 μm accounts for the remainder.

[0018] The budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle size of the present invention are prepared by the following method:

[0019] 1) Micronization of active ingredients: budesonide, glycopyrrolate, and formoterol fumarate dihydrate were added to the feed hopper of a jet mill respectively, and the crushing pressure was set to 3.0 to 7.0 bar, the feed pressure was set to 4.0 to 8.0 bar, and the feed speed was set to 4.0 to 10.0 rpm for crushing;

[0020] 2) Conditioning: placing the micronized budesonide, glycopyrrolate, and formoterol in an environment at 30° C. and 75% RH for 0 to 72 hours;

[0021] 3) respectively adding the conditioned budesonide, glycopyrrolate and formoterol fumarate dihydrate into the grinding chamber of a classifying airflow mill, setting the grinding pressure to 0.6-1.0 bar and the classifying wheel speed to 45000-55000 rpm, and performing classification to obtain budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle sizes.

[0022] The budegol inhalation powder of the present invention is prepared by the following method:

[0023] 1) Add the carrier and the dispersing aid into a high shear mixer, set the mixing speed to 3-7 m / s, and mix for 3-9 minutes to prepare a premix;

[0024] 2) Add the budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle size and the premix of step 1) to a high shear mixer in proportion, set the mixing speed to 1350-1750 r / min, mix for 4-8 minutes, and obtain a total mixture.

[0025] 3) Fill the total mixture into No. 3 HPMC capsules and double aluminum packaging.

[0026] Another object of the present invention is to disclose the use of the budegol inhalation powder in the preparation of a drug for treating chronic obstructive pulmonary disease.

[0027] Advantages of the present invention:

[0028] The present invention studies the micronization preparation process of budesonide, glycopyrrolate and formoterol fumarate, and obtains active ingredients with graded particle sizes that can achieve effective deposition of different drugs at corresponding target sites. Animal experiments show that by adopting the technical solution of the present invention, the budegone inhalation powder spray not only improves the efficacy, but also significantly reduces systemic adverse reactions. DETAILED DESCRIPTION

[0029] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0030] It should be noted that the terms used herein are for describing specific embodiments only and are not intended to be limiting of exemplary embodiments according to the present invention.

[0031] Example 1 Preparation of micronized raw materials

[0032] 1. Airflow milling: Add budesonide, glycopyrrolate and formoterol fumarate into the feed hopper of Microm JEMILL Pilot respectively, and grind them according to the grinding parameters in the following table to obtain micronized raw material budesonide samples 1-3, glycopyrrolate samples 1-3, and formoterol fumarate samples 1-3 with different particle size distributions.

[0033] Table 1 Airflow milling parameters

[0034] Crushing pressure (bar) Feed pressure (bar) Feed speed (rpm) 3.0 4.0 4.0 5.0 6.0 7.0 7.0 8.0 10.0

[0035] 2. Conditioning: Place budesonide, glycopyrrolate, and formoterol in a drug stability test chamber at 30°C / 75%RH for 72 hours.

[0036] 3. Determine the particle size of each micronized API after conditioning. Use Sympatec HELOS / RODOS laser particle size analyzer to test the particle size of the conditioned active ingredients. The results are as follows:

[0037] Table 2 Particle size and particle size distribution of micronized API

[0038]

[0039]

[0040] Example 2 Classification and Particle Size Distribution Determination of Micronized API

[0041] 1. Classification: The conditioned budesonide sample 1, glycopyrrolate sample 1 and formoterol fumarate sample 1 were respectively added into the grading chamber of the HOSOKAWAALPINE (Hosokawa Alpine) Picoline Picosplit module, the crushing pressure was set to 0.6 bar, the classification wheel speed was 45000 rpm, and classification was performed to obtain the classified budesonide sample 4, glycopyrrolate sample 4 and formoterol fumarate sample 4.

[0042] The conditioned budesonide sample 2, glycopyrrolate sample 2 and formoterol fumarate sample 2 were respectively added into the grading chamber of the HOSOKAWAALPINE (Hosokawa Alpine) Picoline Picosplit module, the crushing pressure was set to 0.8 bar, the grading wheel speed was 50000 rpm, and classification was performed to obtain the classified budesonide sample 5, glycopyrrolate sample 5 and formoterol fumarate sample 5.

[0043] The conditioned budesonide sample 3, glycopyrrolate sample 3 and formoterol fumarate sample 3 were respectively added into the grading chamber of the HOSOKAWAALPINE (Hosokawa Alpine) Picoline Picosplit module, the crushing pressure was set to 1.0 bar, the grading wheel speed was 55000 rpm, and classification was performed to obtain the classified budesonide sample 6, glycopyrrolate sample 6 and formoterol fumarate sample 6.

[0044] The particle size of the classified active ingredients was measured using a Sympatec HELOS / RODOS laser particle size analyzer. The results are as follows:

[0045] Table 3 Particle size and particle size distribution of API after classification

[0046]

[0047]

[0048] Comparison of the results in Table 1 and Table 2 shows that after the API is airflow-pulverized, the particle size distribution is relatively wide, and there are many extremely fine particles. After being prepared into a powder inhaler and inhaled, a large amount of fine particle active ingredients will be deposited in the alveoli, causing an increase in blood drug concentration, which will not achieve the desired therapeutic effect and will also increase adverse reactions. The micronized active ingredients were graded using specific classification parameters (crushing pressure 0.6-1.0 bar, classification wheel speed 45000-55000 rpm) to remove the extremely fine particle active ingredients. The particle size results after classification showed that the particle size of the active ingredients increased slightly after classification, and the span of each active ingredient was reduced from 1.9-2.4 to 1.6-1.8, and the particle size distribution of each active ingredient was narrowed, and the particle size was more concentrated.

[0049] Example 3 Preparation of different formulations

[0050] The fractionated budesonide sample 5, glycopyrrolate sample 5, and formoterol fumarate sample 5 were prepared according to the following formula table.

[0051] Table 4 Recipe

[0052] Material Name Formulation 1 (μg) Formulation 2 (μg) Formulation 3 (μg) Formulation 4 (μg) Budesonide 421 421 421 421 Glycopyrrolate 24.1 24.1 24.1 24.1 Formoterol 12.7 12.7 12.7 12.7 lactose 13000 -- 13000 -- Chitosan -- 13000 -- 13000 Magnesium Stearate -- -- 60 -- Leucine -- -- -- 60

[0053] Preparation: 1. Mixing: According to the formula in the above table, the carrier, budesonide, glycopyrrolate, and formoterol in the formula are added to the GEA high-speed stirring mixer in sequence for mixing at a mixing speed of 1350 m / s for a mixing time of 6 min to obtain a total mixture. 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain preparations 1-4.

[0054] The mixing method was changed according to Formulation 3. Lactose and magnesium stearate were added to a GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s for a mixing time of 6 min. Budesonide, glycopyrrolate and formoterol were added in sequence at a mixing speed of 1350 m / s for a mixing time of 6 min to obtain a total mixture, which was then filled into No. 3 HPMC capsules to obtain Preparation 5.

[0055] The mixing method was changed according to Formulation 4. Chitosan and leucine were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s and a mixing time of 6 min. Budesonide, glycopyrrolate and formoterol were added in sequence at a mixing speed of 1350 m / s and a mixing time of 6 min to obtain a total mixture, which was filled into No. 3 HPMC capsules to obtain Preparation 6.

[0056] Example 4

[0057] According to the 2020 edition of the Chinese Pharmacopoeia, the delivery dose uniformity of the inhaled powder was studied and measured using the delivery dose uniformity measurement device (DUSA tube); according to the general provisions of the Chinese Pharmacopoeia <0951> The method for measuring the aerodynamic characteristics of fine particles of inhalation preparations is used to measure the fine particle dose of inhaled powder aerosols and calculate the FPF.

[0058] Table 5 DDU value and FPF value of each active ingredient

[0059]

[0060]

[0061] The results in Table 5 show that when direct mixing is adopted without adding a dispersing agent, the DDU value and FPF value are both low and unstable (preparations 1 and 2); when direct mixing is carried out after adding a dispersing agent, the DDU value, FPF value and stability are all improved to a certain extent (preparations 3 and 4); after the dispersing agent is mixed with the carrier and then mixed with the active ingredient to prepare an inhalation powder preparation (preparations 5 and 6), the DDU value and FPF value are higher than those of direct mixing of the dispersing agent, the carrier and the active ingredient and mixing only the carrier and the active ingredient without adding a dispersing agent, and the FPF stability of the preparation is also significantly improved.

[0062] Example 4

[0063] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate

[0064] Preparation steps:

[0065] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 3 m / s and a mixing time of 3 min. The graded budesonide sample 4, glycopyrrolate sample 4 and formoterol sample 4 were added in sequence at a mixing speed of 1350 r / min and a mixing time of 8 min to obtain a total mixture.

[0066] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain Preparation 7.

[0067] Example 5

[0068] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate

[0069] Preparation steps:

[0070] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s and a mixing time of 6 min. The graded budesonide sample 5, glycopyrrolate sample 5 and formoterol sample 5 were added in sequence at a mixing speed of 1550 r / min and a mixing time of 6 min to obtain a total mixture.

[0071] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain Preparation 8.

[0072] Example 6

[0073] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate

[0074] Preparation steps:

[0075] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 7 m / s and a mixing time of 9 min. The graded budesonide sample 6, glycopyrrolate sample 6 and formoterol sample 6 were added in sequence at a mixing speed of 1750 r / min and a mixing time of 4 min to obtain a total mixture.

[0076] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain Preparation 9.

[0077] Comparative Example 1

[0078] The conditioned budesonide sample 1, glycopyrrolate sample 1 and formoterol fumarate sample 1 in Example 1 were taken and added into the grading chamber of the HOSOKAWAALPINE (Hosokawa Alpine) Picoline Picosplit module, respectively. The crushing pressure was set to 0.5 bar and the classifying wheel speed was 45000 rpm for classification to obtain the classified budesonide sample 7, glycopyrrolate sample 7 and formoterol fumarate sample 7.

[0079] The conditioned budesonide sample 1, glycopyrrolate sample 1 and formoterol fumarate sample 1 in Example 1 were taken and added into the grading chamber of the HOSOKAWAALPINE (Hosokawa Alpine) Picoline Picosplit module, respectively, and the crushing pressure was set to 1.0 bar and the classifying wheel speed was 60000 rpm for classification to obtain the classified budesonide sample 8, glycopyrrolate sample 8 and formoterol fumarate sample 8.

[0080] The particle size of the classified active ingredients was measured using a Sympatec HELOS / RODOS laser particle size analyzer. The results are as follows:

[0081]

[0082] Based on the classification parameters in Example 2, the classification parameters were further adjusted. It was found that after the crushing pressure was reduced and the classification wheel speed was increased, the span of each active ingredient decreased from 2.2-2.4 to about 2.0, and the decrease became narrower, indicating that the effect of classification on particle size and particle size distribution was weakened.

[0083] Comparative Example 2

[0084] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate Preparation steps:

[0085] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s and a mixing time of 6 min. Unfractionated budesonide sample 1, glycopyrrolate sample 1 and formoterol sample 1 were added in sequence at a mixing speed of 1550 r / min and a mixing time of 6 min to obtain a total mixture.

[0086] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain preparation 10.

[0087] Comparative Example 3

[0088] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate Preparation steps:

[0089] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s and a mixing time of 6 min. Unfractionated budesonide sample 2, glycopyrrolate sample 2 and formoterol sample 2 were added in sequence at a mixing speed of 1550 r / min and a mixing time of 6 min to obtain a total mixture.

[0090] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain preparation 11.

[0091] Comparative Example 4

[0092] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate

[0093] Preparation steps:

[0094] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s and a mixing time of 6 min. Unfractionated budesonide sample 3, glycopyrrolate sample 3 and formoterol sample 3 were added in sequence at a mixing speed of 1550 r / min and a mixing time of 6 min to obtain a total mixture.

[0095] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain preparation 12.

[0096] Comparative Example 5

[0097] Formula: budesonide 320μg + glycopyrrolate 18μg + formoterol fumarate 10μg + lactose 13000μg + 60μg magnesium stearate

[0098] Preparation steps:

[0099] 1. Mixing: According to the formula, the carrier lactose and magnesium stearate were added to the GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s and a mixing time of 6 min. The graded budesonide sample 7, glycopyrrolate sample 7 and formoterol sample 7 were added in sequence at a mixing speed of 1550 r / min and a mixing time of 6 min to obtain a total mixture.

[0100] 2. Filling: Fill the total mixture into No. 3 HPMC capsules to obtain preparation 13.

[0101] Example 7 Aerodynamic Particle Size Distribution Segment Comparison

[0102] The APSD of preparations 7, 8 and 9 in the examples is compared with preparations 10, 11, 12 and 13 in the comparative examples and the marketed preparation Budigefu aerosol (trade name: Bei Ze Rui Ling Chang, specification: 160 μg / 9.0 μg / 5.0 μg). Since the marketed preparation is an aerosol, the method used in detecting APSD is different from that of the powder aerosol. For better evaluation, COPLEY inhalation test data analysis software (referred to as CITDAS) is used for statistical analysis. This software can calculate the deposition distribution of the drug in each particle size segment of NGI to calculate the cumulative mass proportion in a certain set particle size segment. Studies have shown that particles with an aerodynamic diameter of 2 to 5 μm are more likely to be deposited in the upper conducting airways (such as trachea, bronchi, bronchioles, etc.) due to inertial collision, and particles of 0.5 μm to 2 μm are more likely to be deposited in the respiratory area (such as respiratory bronchioles, alveoli, etc.) due to gravity sedimentation. Therefore, the CITDAS statistical calculation of the mass proportion of the drug in the particle size range of 0-2.1μm, 2.10-4.70μm, and above 4.70μm is used to compare the aerodynamic properties, which can also eliminate the differences in the cut-off particle sizes of each level of NGI caused by different detection flow rates, and evaluate the lung deposition sites of active ingredients in vivo and in vitro. The experimental results are shown in the table below:

[0103] Table 6 Comparison of CITDAS distribution of different preparations

[0104]

[0105] The experimental results in Table 6 show that the product preparations 10-12 prepared from the unclassified active ingredients and the classified preparation 13, compared with the marketed preparation, have more budesonide, glycopyrrolate, and formoterol deposited in the range of 0-2.1 μm, less in the range of 2.1 μm-4.7 μm, and more fine particles deposited in the alveoli, suggesting that the products prepared from the unclassified active ingredients may produce higher C max The amount of systemic exposure was lower than that of the marketed preparation. The product preparations 7-9 prepared with the fractionated active ingredients showed more budesonide deposition at 0-2.1 μm, and more glycopyrrolate and formoterol deposition at 2.1 μm-4.7 μm compared with the marketed preparation, indicating that more budesonide, glycopyrrolate, and formoterol acted on the target site, which may have a better therapeutic effect than the reference preparation.

[0106] Example 8 Animal lung function experiment

[0107] Inhalation test was carried out on COPD model rats using Preparation 7, Preparation 8, Preparation 9 in the examples and Preparation 10, Preparation 11, Preparation 12 and Preparation 13 in the comparative examples. After the test, lung function was measured and compared with the effects on animal lung function by inhalation of blank excipient group, control group and positive control group reference preparation.

[0108] 1) Rat COPD model

[0109] The COPD model was established by CSE method. 90 SD rats, aged 6-8 weeks and weighing 160±20g, were selected to establish the COPD model.

[0110] Rats were placed in a fumigation box and exposed to smoke from 10 lit cigarettes for 1 hour, once in the morning and once in the afternoon every day, with an interval of 6 hours in between; the fumigation was performed 6 days a week for a total of 24 weeks.

[0111] 2) Grouped medication

[0112] The experimental animals were randomly divided into 9 groups, namely, test group A (preparation 7), test group B (preparation 8), test group C (preparation 9), test group D (preparation 10), test group E (preparation 11), test group F (preparation 12), test group G (preparation 13), blank group (inhalation of blank excipients), and control group (inhalation of marketed preparation Budeglove aerosol 160μg / 9.0μg / 5.0μg, 2 inhalations), with 10 animals in each group.

[0113] The rats were placed in an animal ventilator-confined device for controlled ventilation. Nine groups of rats inhaled the corresponding drugs twice a day for a total of 12 weeks.

[0114] 3) Test results

[0115] After 12 weeks of inhalation administration, the COPD rats were anesthetized with 3% sodium pentobarbital according to their body weight, fixed in the supine position, and intubated. The rats were connected to an invasive pulmonary function instrument for small animals to measure the invasive pulmonary function indicators of the rats, including forced expiratory volume in 50ms (FEV 50 ) and forced vital capacity (FVC) and other parameters.

[0116] Table 7 Rat lung function test results

[0117] Group <![CDATA[FEV 50 (ml)]]> FVC (ml) Blank Group 0.75±0.05 4.56±0.28 Control group <![CDATA[0.91±0.06 a ]]> <![CDATA[5.93±0.32 a ]]> Experimental Group A <![CDATA[0.95±0.06 ab ]]> <![CDATA[6.36±0.34 ab ]]> Test Group B <![CDATA[0.98±0.05 ab ]]> <![CDATA[6.58±0.38 ab ]]> Test Group C <![CDATA[0.96±0.07 ab ]]> <![CDATA[6.42±0.41 ab ]]> Test Group D <![CDATA[0.80±0.09 ab ]]> <![CDATA[5.45±0.43 ab ]]> Experimental Group E <![CDATA[0.82±0.07 ab ]]> <![CDATA[5.60±0.40 ab ]]> Experimental Group F <![CDATA[0.83±0.08 ab ]]> <![CDATA[5.66±0.45 ab ]]> Experimental Group G <![CDATA[0.82±0.04 ab ]]> <![CDATA[5.62±0.38 ab ]]>

[0118] Note a p is compared with the blank group, p < 0.05; b p is compared with the control group p < 0.05

[0119] From the results in the table, it can be seen that compared with the blank group (inhalation of blank excipients), the FEV of rats in the control group, test A, test B, test C, test D, test E, test F, and test G were 50 , FVC, were significantly increased (p < 0.05). Compared with the control group, FEV50 , FVC were significantly increased (p<0.05), and there were no significant differences in test D, test E, test F, and test G.

[0120] The test results showed that the rats inhaled the control group, test A, test B, test C, test D, test E, test F, and test G preparations, which could improve their pulmonary ventilation function, and test A, test B, and test C were better than the control group, while test D, test E, test F, and test G were worse than the control group. This further confirmed that by controlling the particle size of the active ingredient through specific classification parameters, the drug can be delivered to different parts of the lungs to achieve better therapeutic effects.

[0121] Example 9 Animal Pharmacokinetic Experiment

[0122] Preparation selection: Preparation 7, Preparation 8, Preparation 9 in the examples and Preparation 10, Preparation 11, Preparation 12, Preparation 13 in the comparative examples and the marketed preparation (Budegol aerosol 160 μg / 9.0 μg / 5.0 μg) were used.

[0123] Dosing frequency: Single dose

[0124] Route of administration: Inhalation through the mouth and nose

[0125] Experimental animals: Male SD rats

[0126] Grouping: A total of 64 male rats were divided into 8 groups, with 8 rats in each group.

[0127] Table 8 Animal pharmacokinetic data

[0128]

[0129]

[0130] Animal pharmacokinetic test data show that when rats inhaled the same dose of the marketed preparation, the self-developed preparation after classification (preparation 7-9) and the self-developed preparation after classification (preparation 13), and the unclassified self-developed preparation (preparation 10-12), the Cmax and AUC of the self-developed preparation after classification (preparation 7-9) were 0～∞ Significantly lower than the marketed preparation, the Cmax and AUC of the self-made preparation after classification (preparation 13) and the unclassified self-made preparation 0～∞All of them are significantly higher than the marketed preparations. Combined with CITDAS data analysis, the mass proportion of budesonide in the 0-2.1μm particle size segment is 25%-35%, and the mass proportion in the 2.1-4.7μm particle size segment is 24%-28%; the mass proportion of glycopyrrolate in the 0-2.1μm particle size segment is 12%-18%, and the mass proportion in the 2.1-4.7μm particle size segment is 37%-45%; the mass proportion of formoterol fumarate in the 0-2.1μm particle size segment is 15%-20%, and the mass proportion in the 2.1-4.7μm particle size segment is 37%-43%. After classification, the drug can reach the target site, produce higher efficacy and lower adverse reactions.

[0131] Example 10 Preparation of different formulations

[0132] The fractionated budesonide sample 5, glycopyrrolate sample 5, and formoterol fumarate sample 5 were prepared according to the following formula table.

[0133] Table 9 Recipe

[0134] Material Name Formula 5 (μg) Formulation 6 (μg) Formula 7 (μg) Formulation 8 (μg) Formulation 9 (μg) Formula 10 (μg) Budesonide 200 350 350 500 500 500 Glycopyrrolate 10 10 20 20 25 30 Formoterol 5 10 10 12.5 15 15 lactose 16000 13000 13000 16000 13000 10000 Magnesium Stearate 90 60 60 90 60 30

[0135] Preparation: Mixing: Add the carrier lactose and magnesium stearate to a GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s for a mixing time of 6 min. After sufficient mixing, add budesonide, glycopyrrolate and formoterol in the formula in sequence at a mixing speed of 1550 r / min for a mixing time of 6 min to obtain a total mixture.

[0136] Filling: The total mixture was filled into No. 3 HPMC capsules to obtain preparations 14-19.

[0137] Example 11 In vitro lung deposition rate experiment

[0138] Take the capsules in Example 9 and <0951> The aerodynamic characteristics of fine particles of inhaled preparations were measured to determine the fine particle dose of inhaled powder aerosols and calculate the lung deposition rate. The average value of each group of experimental results was taken. The measurement conditions were a new generation cascade impactor (NCI), a pump flow rate of 60L / min, 4s; and a breatherhaler was used as the inhalation device.

[0139] The contents of budesonide, glycopyrrolate and formoterol were determined by liquid chromatography, and the liquid phase conditions were as follows:

[0140] Column: Poroshell 120EC-C18 100mm×4.6mm, 2.7μm

[0141] Mobile phase A: 10mmol / L phosphate buffer (pH2.5)

[0142] Mobile phase B: acetonitrile

[0143] Detection wavelength: 214nm Flow rate: 1.5ml / min Injection volume: 20μl

[0144] Column temperature: 40°C Injector temperature: 8°C

[0145] Gradient elution program

[0146] Time (min) Mobile phase A (%) Mobile phase B (%) 0 78 22 6 25 75 7 78 22 9 82 18

[0147] The results are shown in the table below:

[0148] Table 10 In vitro lung deposition rate

[0149]

[0150]

[0151] Table 11 CITDAS distribution of different preparations

[0152]

[0153] The results showed that the FPF of samples with different formulations prepared using graded APIs was high and had no significant difference. The CITDAS results showed that the mass proportion of each particle size segment was basically the same, with no significant change.

[0154] Example 12 Testing the stability of capsules

[0155] The capsules obtained in Example 4 were packaged into aluminum blisters and placed in a constant temperature and humidity chamber at 40°C and 75%RH. The contents of budesonide, glycopyrrolate, and formoterol and the stability of aerodynamic particle size distribution at different time points were investigated. The results are as follows:

[0156] Table 12 Content stability of different formulations

[0157]

[0158]

[0159] Table 13 FPF stability of different formulations

[0160]

[0161] The stability results show that the content and FPF of preparations 14-19 do not change significantly over time under high temperature and high humidity conditions, and the product quality is stable.

[0162] Embodiment 13

[0163] The fractionated budesonide sample 5, glycopyrrolate sample 5, and formoterol sample 5 were prepared according to the following formula.

[0164] Table 14 Investigation of lactose and magnesium stearate of different particle sizes

[0165]

[0166]

[0167] The preparation was prepared according to the following steps: 1) Mixing: The carrier lactose and magnesium stearate were placed in a GEA high-speed stirring mixer for mixing at a mixing speed of 5 m / s for a mixing time of 6 min. After sufficient mixing, the graded budesonide, glycopyrrolate and formoterol were added in sequence at a mixing speed of 1550 r / min for a mixing time of 6 min to obtain a total mixture. 2) Filling: The total mixture was filled into No. 3 HPMC capsules to obtain preparations 20-22.

[0168] Embodiment 14

[0169] APSD was measured for the preparations 20, 21 and 22 in the examples, and statistical analysis was performed using CITDAS. The results are shown in the table below.

[0170] Table 15 Mass proportion of each active ingredient in each particle size range

[0171]

[0172] Conclusion: The CITDAS results of preparations prepared with lactose of different particle sizes and magnesium stearate of different particle sizes were within the range.

Claims

1. A budegol inhalation powder, characterized in that The invention comprises an active ingredient, a carrier and a dispersing aid, wherein the active ingredient is budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle size, and has the following particle size distribution characteristics: budesonide d10=0.5-0.9 μm, d50=1.5-2.5 μm, d90=3.0-5.0 μm, span=1.6-1.8; glycopyrrolate d10=0.6-0.9 μm, d50=1.6 ~2.6μm, d90=3.5~5.5μm, span=1.6~1.8; formoterol fumarate dihydrate d10=0.7~1.1μm, d50=1.8~3.0μm, d90=4.0~6.0μm, span=1.6~1.8, the mass ratio of budesonide, glycopyrrolate and formoterol fumarate dihydrate is 200~500:10~30:5~15.

2. The budegol inhalation powder according to claim 1, characterized in that The carrier has the following particle size distribution characteristics: d10=3.0 μm-25.0 μm, d50=40 μm-120 μm, d90=100 μm-180 μm.

3. The budegol inhalation powder according to claim 1, characterized in that The dispersing aid has the following particle size distribution characteristics: d10=2.0-5.0 μm, d50=7.0-12.0 μm, d90=18-30 μm.

4. The budegol inhalation powder according to claim 1, characterized in that The budegol inhalation powder contains 0.03% to 3.68% by mass of active ingredients, 95.6% to 98.1% of carriers and 0.40% to 0.60% of dispersing aids.

5. The budegol inhalation powder according to claim 1, characterized in that The carrier is lactose monohydrate, and the dispersing aid is magnesium stearate.

6. The budegol inhalation powder according to any one of claims 1 to 5, characterized in that It is a capsule-type inhalation powder, each capsule contains 200-500 μg budesonide, 10-30 μg glycopyrrolate and 5-15 μg formoterol fumarate dihydrate.

7. The budegol inhalation powder according to any one of claims 1 to 5, characterized in that The mass percentage of the active ingredient particle size was calculated using CopleyCitdas software as follows: in the particle size range of 0-2.1 μm, the mass percentage of budesonide in the total amount of budesonide was 25%-35%, the mass percentage of glycopyrrolate in the total amount of glycopyrrolate was 12%-18%, and the mass percentage of formoterol fumarate dihydrate in the total amount of formoterol fumarate dihydrate was 15%-20%; in the particle size range of 2.1-4.7 μm, the mass percentage of budesonide in the total amount of budesonide was 24%-28%, the mass percentage of glycopyrrolate in the total amount of glycopyrrolate was 37%-45%, and the mass percentage of formoterol fumarate dihydrate in the total amount of formoterol fumarate dihydrate was 37%-43%.

8. The budegol inhalation powder according to any one of claims 1 to 5, characterized in that The budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle size are prepared by the following method: 1) Micronization of active ingredients: budesonide, glycopyrrolate, and formoterol fumarate dihydrate were added to the feed hopper of a jet mill respectively, and the crushing pressure was set to 3.0 to 7.0 bar, the feed pressure was set to 4.0 to 8.0 bar, and the feed speed was set to 4.0 to 10.0 rpm for crushing; 2) Conditioning: placing the micronized budesonide, glycopyrrolate, and formoterol in an environment at 30° C. and 75% RH for 0 to 72 hours; 3) respectively adding the conditioned micronized budesonide, glycopyrrolate and formoterol fumarate dihydrate into the grinding chamber of a classifying airflow mill, setting the grinding pressure to 0.6-1.0 bar and the classifying wheel speed to 45000-55000 rpm, and performing classification to obtain budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle sizes.

9. The budegol inhalation powder according to claim 8, characterized in that It is prepared by the following method: 1) Add the carrier and the dispersing aid into a high shear mixer, set the mixing speed to 3-7 m / s, and mix for 3-9 min to prepare a premix; 2) Add the budesonide, glycopyrrolate and formoterol fumarate dihydrate with graded particle size and the premix of step 1) to a high shear mixer in proportion, set the mixing speed to 1350-1750 r / min, mix for 4-8 minutes, and obtain a total mixture. 3) Filling and packaging the total mixture.

10. Use of the budegol inhalation powder according to any one of claims 1 to 9 in the preparation of a medicament for treating chronic obstructive pulmonary disease.

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