Preparation method of budesonide and formoterol inhalation powder inhalation spheroidized particles

Abstract

The invention relates to preparation of pharmaceutical preparations, in particular to a preparation method of spherical particles of budesonide and formoterol inhalation powder. The preparation method comprises the following steps: respectively preparing the lactose, the formoterol and the budesonide into micronized powder, and dividing the micronized lactose into three parts; performing first spheroidization treatment on the first part of micronized lactose to prepare a spheroidized lactose core; uniformly mixing the second part of micronized lactose, micronized formoterol and micronized budesonide to obtain a budesonide and formoterol mixture; carrying out second spheroidization treatment on the spheroidized lactose core and the budesonide formoterol mixture to prepare a spheroidized intermediate; and carrying out third spheroidization treatment on the spheroidized intermediate and a third part of micronized lactose to obtain spheroidized particles. The spheroidized particles prepared by the method are good in roundness, and the uniformity of the delivery dose of the product is remarkably improved; in addition, the key quality attribute of the product can be improved and kept stable.

Description

TECHNICAL FIELD

[0001] The present application relates to the preparation of pharmaceutical formulations, in particular to a method for preparing budesonide formoterol inhalation powder. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing the understanding of the general background of the application and does not necessarily constitute an admission by the patent applicant or the patent owner that this information constitutes prior art.

[0003] Budesonide formoterol inhalation powder (trade name: symbicort) is developed by AstraZeneca pharmaceutical company, and since its launch, symbicort has become the first choice for the treatment of asthma and chronic obstructive pulmonary disease (COPD). According to the research of the inventors, the current preparation method of symbicort is as follows: first, lactose and formoterol fumarate are co-micronized into powder below 10 μm, the powder is treated by equilibration, then mixed with another micronized raw material budesonide to prepare budesonide formoterol mixture, then the budesonide formoterol mixture is prepared into spheroidized particles with a bulk density of 0.28-0.38 g / ml on a spheroidization equipment, and finally the spheroidized particles are filled into a reservoir device to obtain the preparation product. There is a strong interaction force between the micronized powders, such as van der waals force, electrostatic force, capillary force, etc. Due to the existence of powder force, the flowability of the powder becomes very poor, which will adversely affect the filling of the powder. Therefore, the above preparation method of symbicort agglomerates the micronized powder into a ball and then fills it into a reservoir device, which can effectively solve the filling problem of the drug powder.

[0004] However, the inventors have found that symbicort has poor delivery dose uniformity, which will adversely affect the safety and effectiveness of patient medication; in addition, patients are easy to forget to screw the shell after using symbicort, which can easily cause the product to have low atomization efficiency in high humidity environment, affecting the drug efficacy. SUMMARY

[0005] The factors affecting the delivery dose uniformity of inhalation powder include product prescription, process and inhalation device characteristics, etc. Specifically, the properties of the raw drug (cohesion / adsorption), the properties of the carrier (surface topography, particle size distribution, surface energy, etc.), the preparation process, the material and structure of the dry powder inhaler. The present application has found that the main reason for the poor delivery dose uniformity of budesonide formoterol inhalation powder is that the spheroidized particles have poor roundness. The poor roundness of the spheroidized particles leads to differences in weight when filling a single dose, which in turn leads to large differences in drug delivery dose.

[0006] Further research in this invention revealed that budesonide possesses extremely strong adhesive properties. During the preparation of spherical particles, budesonide readily adheres to the inner wall of the spheroidizing equipment. Even the addition of coatings such as polytetrafluoroethylene to the inner wall of the spheroidizing equipment cannot improve the adhesion of budesonide. Once budesonide adheres to the inner wall of the spheroidizing equipment, the entire spheroidizing process is affected. This manifests as the powder being unable to move in an orderly relative manner within the spheroidizing equipment, resulting in poor sphericity of the final spherical particles and consequently, poor uniformity in product delivery dosage.

[0007] This product requires the use of an inhaler. When using the product, the patient must unscrew the device casing and then inhale the medication through their mouth. Research has found that a significant proportion of product usage errors occurred when patients forgot to tighten the device casing after inhalation. This error makes the drug powder highly susceptible to environmental humidity. Studies have shown that when the ambient humidity exceeds the material's relative critical humidity, moisture will rapidly adhere to the drug surface, leading to sample dissolution or the formation of liquid bridges between particles, causing sample clumping. This significantly reduces the drug's atomization ability and the amount deposited at the effective site, thus reducing the drug's efficacy.

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing spherical particles of budesonide / formoterol inhalation powder. This invention effectively solves the problem of budesonide sticking to the wall during the spherification process, and the prepared spherical particles have good roundness, significantly improving the uniformity of product delivery dosage. In addition, when the product prepared using this patent is exposed to an environment with a temperature of 25±2℃ and a relative humidity of 75±5% for 7 days, the key quality attributes of the product remain stable.

[0009] To achieve the above objectives, the technical solution of the present invention is as follows: In a first aspect, a method for preparing spherical particles of budesonide / formoterol inhalation powder includes the following steps: Lactose, formoterol, and budesonide were respectively formulated into particles with particle size distributions D. 90 Micronized powder with a particle size of <10μm, and the micronized lactose is divided into three parts; The first part of micronized lactose is subjected to a first spheroidization process to form a spherical lactose core; The micronized lactose, micronized formoterol, and micronized budesonide in the second part are mixed evenly to obtain a budesonide-formoterol mixture; A spheroidized intermediate was prepared by subjecting a mixture of spheroidized lactose kernels and budesonide formoterol to a second spheroidization process. The spheroidized intermediate and the third part of micronized lactose are subjected to a third spheroidization process to obtain spheroidized particles.

[0010] This invention has found that micronized lactose has low adhesion. When micronized lactose is used alone for spheroidization, the resulting spheroidized particles have excellent roundness and no lactose adheres to the inner wall of the equipment. Therefore, this invention first prepares spheroidized lactose cores from a portion of the micronized lactose, then spheroidizes a mixture of the spheroidized lactose cores and budesonide / formoterol, and finally adds the remaining micronized lactose for spheroidization. This avoids budesonide adhering to the inner wall of the spheroidization equipment, thereby improving the roundness of the spheroidized particles.

[0011] Simultaneously, this invention involves a third spheroidization treatment of the spheroidized intermediate and the remaining micronized lactose. This not only further improves the roundness of the spheroidized particles, but also, during this third spheroidization process, the micronized lactose coats the surface of the spheroidized intermediate, completely encapsulating budesonide and formoterol within the lactose. This prevents the active ingredients from directly contacting the external environment, improving their physical stability under high humidity conditions. Specifically, it minimizes the risk of budesonide and formoterol particles clumping due to high humidity, ensuring that budesonide and formoterol do not experience a decrease in atomization efficiency due to clumping. Furthermore, the micronized lactose coating further reduces the likelihood of budesonide and formoterol coming into contact with high humidity, improving the chemical stability of both raw materials. Specifically, the coating reduces the risk of hydrolysis of the active pharmaceutical ingredients, which is particularly important for formoterol.

[0012] Secondly, a budesonide-formoterol inhalation powder comprising spherical particles obtained by the above-described preparation method.

[0013] The beneficial effects of this invention are as follows: 1. This invention first forms a spherical lactose core from a portion of micronized lactose, then spheroidizes the spheroidized lactose core with a mixture of budesonide and formoterol, and then further spheroidizes it with the remaining micronized lactose. This avoids the phenomenon of budesonide sticking to the wall during the spheroidization process, solves the problem of poor spheroidization particle roundness, improves the spheroidization particle roundness, and thus improves the uniformity of budesonide formoterol inhaled powder delivery.

[0014] 2. The present invention uses a third spheroidization process to place the remaining micronized lactose on the surface of the formed spheroidized particles, thereby completely encapsulating budesonide formoterol inside the spheroidized particles, thus increasing the stability of budesonide formoterol inhalation powder in high humidity environments. Attached Figure Description

[0015] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0016] Fig. 1 Here is a scanning electron microscope image of the budesonide-formoterol spheroidized composition prepared in Comparative Example 1 of this invention; Fig. 2 Scanning electron microscope (SEM) image of spherical particles of budesonide / formoterol inhalation powder prepared in Example 1 of this invention. Detailed Implementation

[0017] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0018] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0019] In view of the problems of poor delivery uniformity and reduced atomization efficiency under high humidity in existing budesonide formoterol inhalation powder, this invention proposes a method for preparing spherical particles of budesonide formoterol inhalation powder.

[0020] A typical embodiment of the present invention provides a method for preparing spherical particles of budesonide / formoterol inhalation powder, comprising the following steps: Lactose, formoterol, and budesonide were respectively formulated into particles with particle size distributions D. 90 Micronized powder with a particle size of <10μm, and the micronized lactose is divided into three parts; The first part of micronized lactose is subjected to a first spheroidization process to form a spherical lactose core; The micronized lactose, micronized formoterol, and micronized budesonide in the second part are mixed evenly to obtain a budesonide-formoterol mixture; A spheroidized intermediate was prepared by subjecting a mixture of spheroidized lactose kernels and budesonide formoterol to a second spheroidization process. The spheroidized intermediate and the third part of micronized lactose are subjected to a third spheroidization process to obtain spheroidized particles.

[0021] In some embodiments, lactose, formoterol, and budesonide are respectively formulated to have a particle size distribution D. 90 Micronized powder with a particle size of <7μm.

[0022] In some embodiments, the mass ratio of lactose, formoterol, and budesonide in the spherical particles is (796.5~833.5): (4.5~5.5): (162~198).

[0023] In some embodiments, the micronized lactose is subjected to a powder equilibration treatment. Specifically, the micronized lactose is placed in an environment with a temperature of 25℃±5℃ and a humidity of 60%RH±10%RH for equilibration treatment for 24h~120h.

[0024] In some embodiments, micronized formoterol is subjected to powder equilibration treatment. Specifically, micronized formoterol is placed in an environment with a temperature of 30°C ± 5°C and a humidity of 60%RH ± 10%RH for equilibration treatment for 48h to 96h.

[0025] In some embodiments, the micronized budesonide is subjected to powder equilibration treatment. Specifically, the micronized budesonide is fumigated in a 60%~90% ethanol gas atmosphere at 25℃±2℃ for 2h~24h.

[0026] The material after balancing has a more stable particle size that will not increase or decrease over time; secondly, the material after balancing has a relatively smooth surface, especially the edges, which is more conducive to subsequent spheroidization.

[0027] In some embodiments, the diameter of the spherical lactose core is between 100 μm and 350 μm. Studies have shown that under these conditions, the delivery dose of the final product is closer to that of the original drug. When the diameter of the spherical lactose core is between 150 μm and 250 μm, the delivery dose of the final product is closer to that of the original drug and the fine particle dose.

[0028] In some embodiments, the mass of the first portion of micronized lactose is 10% to 40% of the total mass of the spherical particles.

[0029] In some embodiments, the mass of the second portion of micronized lactose is 21.5% to 51.5% of the total mass of the spherical particles.

[0030] In some embodiments, the method for uniformly mixing the second portion of micronized lactose, micronized formoterol, and micronized budesonide is air jet milling. Air jet milling allows for more uniform mixing of the second portion of micronized lactose, micronized formoterol, and micronized budesonide. Specifically, during air jet milling, the feed pressure is 5 bar to 9 bar, and the feed rate is 0.3 kg / h to 3 kg / h.

[0031] In some embodiments, in the first spheroidization process, the rotation angle is 20°~60°, the rotation speed is 10rpm~50rpm, and the processing time is 3min~10min.

[0032] In some embodiments, in the second spheroidization process, the rotation angle is 20°~60°, the rotation speed is 10rpm~50rpm, and the processing time is 3min~10min.

[0033] In some embodiments, in the third spheroidization process, the rotation angle is 20°~60°, the rotation speed is 10rpm~50rpm, and the processing time is 3min~10min.

[0034] Specifically, it includes the following steps: Use the following materials: Lactose (D) 90 <200μm) Formoterol fumarate (D) 90 <30μm) Budina (D) 90 <200μm) 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <10μm.

[0035] 2. Powder equilibration treatment: The micronized powders were placed in a specific temperature and humidity environment for equilibration treatment.

[0036] 3. Preparation of spherical lactose core: Place a portion of the prescribed amount of micronized lactose in a spheroidizing device and perform spheroidizing treatment for 3 to 10 minutes at a rotation angle of 20° to 60° and a rotation speed of 10 rpm to 50 rpm to prepare spherical lactose core.

[0037] 4. Preparation of budesonide and formoterol mixture: Take a portion of the prescribed amount of lactose, the whole amount of the prescribed amount of budesonide and formoterol, and mix them evenly by air jet milling to obtain the budesonide and formoterol mixture.

[0038] 5. Preparation of spheroidized intermediate: Place the spheroidized lactose kernel and budesonide-formoterol mixture into a spheroidization device and perform spheroidization treatment for 3 min to 10 min at a rotation angle of 20° to 60° and a rotation speed of 10 rpm to 50 rpm to prepare the spheroidized intermediate.

[0039] 6. Preparation of spheroidized particles: Take the spheroidizing intermediate and the remaining lactose in the prescription, place them in the spheroidizing equipment, and perform spheroidizing treatment for 3 min to 10 min at a rotation angle of 20° to 60° and a rotation speed of 10 rpm to 50 rpm to prepare spheroidized particles. Sieve the particles to obtain spheroidized particles of the target particle size.

[0040] Another embodiment of the present invention provides a budesonide-formoterol inhalation powder, comprising spherical particles obtained by the above preparation method.

[0041] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0042] Comparative example: A method for preparing a budesonide-formoterol spheroidized composition, comprising the following steps: 1. Take 6.5g of formoterol fumarate and 1000g of lactose monohydrate and place them in a TRV mixer. Set the mixing linear speed to 6.0m / s and mix for 3min to prepare the formoterol premix.

[0043] 2. The formoterol premix was pulverized to D using an air jet mill at a pulverizing pressure of 5.0 bar, a feed pressure of 6.0 bar, and a feed rate of 1 kg / h. 90 <7μm, to obtain a formoterol mixture.

[0044] 3. Place the formoterol mixture in an environment with a temperature of 35℃ and a humidity of 60%RH for 72 hours to equilibrate and obtain the conditioned formoterol mixture.

[0045] 4. Prepare micronized budesonide and prepare a budesonide-formoterol mixture according to the formulation ratio of budesonide, formoterol, and lactose of 180:5:815.

[0046] 5. Place the budesonide-formoterol mixture on a spheroidizing device to spheroidize it, and obtain spheroidized particles with a bulk density of 0.35 g / ml.

[0047] Example 1: A method for preparing spherical particles of budesonide / formoterol inhalation powder includes the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0048] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0049] 3. Preparation of spherical lactose core: Take 200g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 40° and a rotation speed of 30rpm for 5 minutes to prepare spherical lactose core.

[0050] 4. Preparation of budesonide-formoterol mixture: Take 415g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0051] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0052] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm~0.8mm.

[0053] The appearance, delivery dose uniformity, fine particle dose, and quality stability in high humidity environments of the example products and the comparative products were compared respectively.

[0054] 1. Appearance and morphology The appearance and morphology of the example products and comparative products were observed using a ZEISS Sigma300 high-resolution field emission scanning electron microscope.

[0055] The results are as follows Figs. 1-2 As shown, the spherical product prepared in the example has a smooth, round surface without protruding edges; the spherical product prepared in the comparative example has an uneven surface with slightly angular edges. This indicates that the spherical product prepared in the example has a higher degree of roundness than the spherical product prepared in the comparative example.

[0056] 2. Uniformity of delivery dosage According to the method for determining the delivery dose uniformity of inhaled powder formulations under General Chapter 0111 of the 2020 edition of the Chinese Pharmacopoeia, the delivery dose uniformity of the example products and comparative products was determined. The results are shown in Table 1.

[0057] Table 1. Delivery Dosage Uniformity of Example Products and Comparative Product

[0058] The delivery dose fluctuation range of the product prepared in the example (60 inhalations per vial, with 3 inhalations at the beginning, 4 inhalations at the middle, and 3 inhalations at the end of the course, totaling 10 inhalations) was as follows: budesonide 152.6 μg ~ 170.4 μg, RSD 3.5%; formoterol 4.18 μg ~ 4.67 μg, RSD 5.0%. The delivery dose fluctuation range of the product prepared in the comparative example (10 inhalations) was as follows: budesonide 125.9 μg ~ 182.7 μg, RSD 14.1%; formoterol 3.57 μg ~ 5.20 μg, RSD 14.2%.

[0059] This demonstrates that the delivery dose uniformity of the product prepared in the embodiments of the present invention is significantly better than that of the product prepared in the comparative example.

[0060] 3. Microparticle dosage According to the method for determining the aerodynamic properties of fine particles in inhaled formulations (General Chapter 0951, Part IV, Chinese Pharmacopoeia 2020 Edition), the fine particle dose (FPD) of the example products and comparative products was determined using device 3 (Next Generation Impactor, NGI). The test results are shown in the table below.

[0061]

[0062] The fine particle dose of the product prepared in the embodiments of the present invention is significantly higher than that of the product prepared in the comparative example, indicating that the product prepared in the embodiments of the present invention is beneficial to deliver more drugs to the target site and better exert its therapeutic effect on asthma and COPD.

[0063] 4. Product quality stability under high humidity conditions The spherical products of the examples and comparative examples were filled into inhalation devices, and the outer shell of the inhalation device was unscrewed to allow the drug powder to communicate with the external environment. The products of the examples and comparative examples were placed in an environment with a temperature of 25±2℃ and a relative humidity of 75±5% for 7 days, and the key quality attributes of the products, such as fine particle dosage and related substances, were tested at three time points: 0 time, 3 days, and 7 days. The results are shown in Table 2.

[0064] Table 2 Key quality attributes of products prepared in the examples and comparative examples

[0065] After unscrewing the inhalation device shell and keeping the drug in contact with the external environment for 7 days, the key quality attributes of the product, namely the fine particle dose and related substances, remained consistent with those at 0, indicating that even after being placed in an environment with a temperature of 25±2℃ and a relative humidity of 75±5% for 7 days, the quality of the product of the example did not change significantly. After unscrewing the inhalation device shell and keeping the drug in contact with the external environment for 7 days, the fine particle dose of the two active ingredients of the comparative product showed a significant decreasing trend with the number of days of placement, while the related substances of formoterol fumarate in the product showed a significant increasing trend with the increase of the number of days of placement, indicating that the quality of the comparative product had changed significantly after being placed in an environment with a temperature of 25±2℃ and a relative humidity of 75±5% for 7 days.

[0066] Example 2: Screening of the diameter range of spherical lactose kernels The formulation products were prepared using spherical lactose kernels of different diameters to investigate the effect of the spherical lactose kernel diameter on the uniformity of dosage delivery and the dosage of fine particles.

[0067] (1) A method for preparing spherical particles (with a diameter of 100 μm for the spherical lactose core) of budesonide / formoterol inhalation powder, comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0068] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0069] 3. Preparation of spherical lactose core: Take 200g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 20° and a rotation speed of 10rpm for 3 minutes to prepare spherical lactose core.

[0070] 4. Preparation of budesonide-formoterol mixture: Take 415g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0071] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0072] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0073] (2) A method for preparing spherical particles (with a diameter of 150 μm for the spherical lactose core) of budesonide / formoterol inhalation powder, comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0074] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0075] 3. Preparation of spherical lactose core: Take 200g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 40° and a rotation speed of 30rpm for 5 minutes to prepare spherical lactose core.

[0076] 4. Preparation of budesonide-formoterol mixture: Take 415g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0077] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0078] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0079] (3) A method for preparing spherical particles (with a diameter of 250 μm for the spherical lactose core) of budesonide / formoterol inhalation powder, comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0080] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0081] 3. Preparation of spherical lactose core: Take 200g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 50° and a rotation speed of 40rpm for 8 minutes to prepare spherical lactose core.

[0082] 4. Preparation of budesonide-formoterol mixture: Take 415g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0083] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0084] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0085] (4) A method for preparing spherical particles (with a spherical lactose core diameter of 350 μm) of budesonide / formoterol inhalation powder, comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0086] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0087] 3. Preparation of spherical lactose core: Take 200g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 60° and a rotation speed of 50rpm for 10min to prepare spherical lactose core.

[0088] 4. Preparation of budesonide-formoterol mixture: Take 415g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0089] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0090] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0091]

[0092] When the diameter of the spherical lactose core in the example product is between 100 μm and 350 μm, the delivery dose of the product in the example and the delivery dose of the comparative product are comparable and close to the target delivery dose (budesonide: 160 μg; formoterol: 4.5 μg). The fine particle dose of the product in the example is slightly higher than that of the comparative product and closer to the target fine particle dose (budesonide: 81 μg / inhalation; formoterol: 2.3 μg / inhalation). When the diameter of the spherical lactose core in the example product is between 150 μm and 250 μm, the delivery dose and fine particle dose of the product are closer to the target values.

[0093] Example 3: Investigation of the mass proportion of spherical lactose kernels in spherical products (1) A method for preparing spherical particles of budesonide / formoterol inhalation powder (with a spherical lactose core comprising 10% by mass), comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0094] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0095] 3. Preparation of spherical lactose core: Take 100g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 40° and a rotation speed of 30rpm for 5min to prepare spherical lactose core.

[0096] 4. Preparation of budesonide-formoterol mixture: Take 515g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0097] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0098] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0099] (2) A method for preparing spherical particles of budesonide / formoterol inhalation powder (the mass percentage of the spherical lactose core is 20%), comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0100] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0101] 3. Preparation of spherical lactose core: Take 200g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 40° and a rotation speed of 30rpm for 5 minutes to prepare spherical lactose core.

[0102] 4. Preparation of budesonide-formoterol mixture: Take 415g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0103] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0104] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0105] (3) A method for preparing spherical particles of budesonide / formoterol inhalation powder (the mass percentage of the spherical lactose core is 30%), comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0106] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0107] 3. Preparation of spherical lactose core: Take 300g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 40° and a rotation speed of 30rpm for 5min to prepare spherical lactose core.

[0108] 4. Preparation of budesonide-formoterol mixture: Take 315g micronized lactose, 180g micronized budesonide and 5g micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0109] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0110] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0111] (4) A method for preparing spherical particles of budesonide / formoterol inhalation powder (the mass percentage of the spherical lactose core is 40%), comprising the following steps: 1. Grinding: Lactose, formoterol fumarate, and budesonide were separately ground using an air jet mill to prepare a particle size distribution D. 90 Micronized powder with a diameter of <7μm.

[0112] 2. Powder equilibration treatment: Micronized lactose was equilibrated in an environment with a temperature of 25℃ and a humidity of 60%RH for 72 hours, micronized formoterol was equilibrated in an environment with a temperature of 30℃ and a humidity of 60%RH for 72 hours, and budesonide was fumigated in a 75% ethanol gas atmosphere at 25℃ for 10 hours.

[0113] 3. Preparation of spherical lactose core: Take 400g of micronized lactose and place it in a spheroidizing device. Perform spheroidizing treatment at a rotation angle of 40° and a rotation speed of 30rpm for 5min to prepare spherical lactose core.

[0114] 4. Preparation of budesonide-formoterol mixture: Take 215g of micronized lactose, 180g of micronized budesonide and 5g of micronized formoterol and mix them in an air jet mill at a grinding pressure of 0.5 bar, a feed pressure of 7 bar and a feed rate of 1 kg / h until uniform to obtain budesonide-formoterol mixture.

[0115] 5. Preparation of spheroidized intermediate: The spheroidized lactose kernel prepared in step 3 and the budesonide-formoterol mixture prepared in step 4 were placed in a spheroidization device and spheroidized for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm to prepare the spheroidized intermediate.

[0116] 6. Preparation of spheroidized particles: Take 200g of the spheroidized intermediate from step 5 and the remaining micronized lactose from the prescription, place them in a spheroidizing device, and spheroidize them for 5 minutes at a rotation angle of 40° and a rotation speed of 30 rpm. Then, sieve to obtain spheroidized particles with a diameter of 0.3mm to 0.8mm.

[0117]

[0118] When the mass percentage of the spherical lactose kernel in the spherical product is 10% to 40%, the fine particle dosage of the example product is better than that of the comparative product, especially when the mass percentage is 20% to 30%.

[0119] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing spherical particles of budesonide / formoterol inhalation powder, characterized in that, Includes the following steps: Lactose, formoterol, and budesonide were each prepared into micronized powders with a particle size distribution D90 < 10 μm, and the micronized lactose was divided into three parts; The first part of micronized lactose is subjected to a first spheroidization process to form a spherical lactose core; The micronized lactose, micronized formoterol, and micronized budesonide in the second part are mixed evenly to obtain a budesonide-formoterol mixture; A spheroidized intermediate was prepared by subjecting a mixture of spheroidized lactose kernels and budesonide formoterol to a second spheroidization process. The spheroidized intermediate and the third part of micronized lactose are subjected to a third spheroidization process to obtain spheroidized particles.

2. The preparation method according to claim 1, characterized in that, Lactose, formoterol, and budesonide were formulated to produce particle size distributions D. 90 Micronized powder with a particle size of <7μm.

3. The preparation method according to claim 1, characterized in that, The mass ratio of lactose, formoterol, and budesonide was (796.5~833.5): (4.5~5.5): (162~198).

4. The preparation method according to claim 1, characterized in that, Micronized lactose was placed in an environment with a temperature of 25℃±5℃ and a humidity of 60%RH±10%RH for 24h~120h to equilibrate. Alternatively, micronized formoterol can be placed in an environment with a temperature of 30℃±5℃ and a humidity of 60%RH±10%RH for 48h~96h to equilibrate. Alternatively, micronized budesonide can be fumigated in a 60%~90% ethanol gas atmosphere at 25℃±2℃ for 2h~24h.

5. The preparation method according to claim 1, characterized in that, The diameter of the spherical lactose core is between 100 μm and 350 μm, or between 150 μm and 250 μm.

6. The preparation method according to claim 1, characterized in that, The first part consists of micronized lactose, which accounts for 10% to 40% of the total mass of the spherical particles.

7. The preparation method according to claim 1, characterized in that, The second part consists of micronized lactose, which accounts for 21.5% to 51.5% of the total mass of the spherical particles.

8. The preparation method according to claim 1, characterized in that, The method for uniformly mixing the micronized lactose, micronized formoterol, and micronized budesonide in the second part is air jet milling.

9. The preparation method according to claim 1, characterized in that, In the first spheroidization process, the rotation angle is 20°~60°, the rotation speed is 10rpm~50rpm, and the processing time is 3min~10min; Alternatively, in the second spheroidization process, the rotation angle is 20°~60°, the rotation speed is 10rpm~50rpm, and the processing time is 3min~10min; Alternatively, in the third spheroidization process, the rotation angle is 20°~60°, the rotation speed is 10rpm~50rpm, and the processing time is 3min~10min.

10. A budesonide / formoterol inhalation powder, characterized in that, Includes spherical particles obtained by the preparation method according to any one of claims 1 to 9.

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