Method for adjusting state of micronized raw material medicine

Abstract

The invention belongs to the technical field of pharmaceutical engineering, and provides a method for adjusting the state of a micronized bulk drug, according to the provided method, a propellant is used as a system main body to adjust the state of the micronized bulk drug, the particle size is basically kept unchanged before and after treatment, and the particle size of the treated powder drug is stable and controllable; the particle size of the treated powder medicine does not change drastically even if the powder medicine is stored for a long time, good particle stability is kept, and the powder medicine is particularly suitable for immediate treatment of micronized raw material medicines of inhalation preparations. The method provided by the invention also has the unique advantages of high yield, simplicity and convenience in use, low input cost and capability of realizing green, circulating and clean production, and is suitable for industrial production and use.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical engineering, and in particular relates to a method for regulating the state of a micronized raw material drug. Background Art

[0002] Inhalation preparations are a special dosage form that is administered through the lungs. They can quickly and directly enter the lungs to exert their efficacy through local administration, and are especially of great clinical value for the symptomatic treatment of COPD, lung infections, etc. Inhalation preparations include inhalation aerosols, inhalation powders, and liquid preparations (solutions, suspensions) for atomized inhalation. Due to the special structure of the human respiratory tract, the particle size that can usually enter the lungs must not exceed 10μm. Therefore, micronized drug technology can obtain uniform drug particles with a specific required particle size range, thereby ensuring that the inhalation preparation obtains appropriate delivery efficiency and a stable delivery dose at a specific site. It is a key technology to ensure the physical and chemical stability and absorption stability of the inhalation preparation.

[0003] The technology used for micronized drugs in industrial production usually uses high-energy grinding, shearing, grinding and other methods to make particles collide with each other or with the wall of the equipment to reduce the size of the particles, such as commonly used wet media grinding technology, air flow crushing technology, high-pressure homogenization technology, etc. Some micronized drugs can also be spray-dried, freeze-spray-dried, and supercritical fluid technology to obtain controllable sizes. For inhalation preparations, the above-mentioned pulverization technology can only provide temporary uniformity and temporary uniformity to control the particle size of the raw material. This is because after the above-mentioned pulverization technology is processed, the surface of the drug particles absorbs a large amount of energy in an amorphous state, and the amorphous state undergoes a crystal transformation phenomenon during storage, resulting in adsorption and aggregation between drug particles, changes in particle morphology and particle size distribution, and these changes will affect the delivery dose, delivery efficiency and delivery uniformity of the inhalation preparations for inhalation preparations, leading to serious consequences, so these changes are usually unfavorable and hope to be avoided.

[0004] In the early days, the industry adopted harsh storage conditions to deal with such thorny problems. After micronization, the production of subsequent preparations was completed within a short change time. Or such micronized materials were stored at room temperature until they were completely stable (amorphous form was completely converted to stable crystalline form), but the disadvantages of such technology were obvious, and the final result of the change was usually impossible to predict or control. With the advancement of basic research and industrial technology, such common problems have gradually been solved to a certain extent, but many problems still exist.

[0005] For example:

[0006] The CN101896165B Chinese patent of Novartis of Switzerland pointed out that there is amorphous on the surface of particles after micronization, which leads to the problem of agglomeration, and provides a method for preparing a stable dry powder of particles by an acetone homogenization process. As shown in its embodiment, the glycopyrrolate after micronization is suspended in acetone for homogenization, then spray-dried at a temperature higher than the boiling point of acetone, and the dry powder is collected with a cyclone separator. The method still needs to use spray drying in the final step, and under the high-energy particle collision of spray drying, there is still amorphous on the surface of the particles after high energy, and by this method, a higher yield will be lost.

[0007] AstraZeneca's Chinese patent number CN105188679B also points out the problem of the use of heat and mechanical energy in the micronization process leading to the production of non-crystalline and amorphous particles. It provides a system of equipment for processing these amorphous particles - a fluidized bed airflow mill and method to try to solve this problem. Figure 2 As shown in the embodiment, the system equipment-fluidized bed air flow mill is in the form of a pipeline, including a micronization zone, a state adjustment gas supply zone, a mixing zone, a state adjustment zone, a separation zone and a collector. The micropowder to be processed is provided in the micronization zone, and the airflow is provided in the state adjustment gas supply zone. The airflow is mixed with the micropowder in the mixing zone. After mixing, it continues to enter the state adjustment zone to adjust the state of the micropowder in the airflow. After the state adjustment is completed, the micropowder is separated from the separation zone and collected in the next step. The micronized amorphous problem processing technology provided in the patent requires special complex equipment, especially the equipment needs to be modified, and the equipment investment cost is high. Due to the pipeline structure of the processing equipment, the micropowder cannot stay in the state adjustment zone for a long time, and the state adjustment processing time is very limited (such as the 3 seconds residence time shown in its embodiment). The device structure designed in this way and the short residence processing time are difficult to complete the amorphous conversion processing in the micropowder. Some raw materials need to be repeatedly processed to achieve the required stability, which reduces the processing efficiency, and with the increase of the micropowder processing time, the powder particle size continues to increase and is unpredictable. On the other hand, the micropowder of inhalation preparations has a smaller particle size and a larger specific surface area. During the processing of this patented technology, the micropowder needs to pass through many processing chambers in sequence with the air flow. When the micropowder collides with the wall of the chamber, it will adhere to the chamber, resulting in a significant reduction in the processing yield.

[0008] In addition, many patents such as CN114129545A, CN100548277C, WO00 / 32165A1, US7041318B2, and US7309707B2 also attempt to use temperature and humidity control methods to deal with problems in the micronization process. However, even if temperature and humidity are controlled, it is still impossible to completely avoid problems such as aggregation caused by amorphous transformation. Summary of the invention

[0009] In order to solve the above problems existing in the prior art, the present invention aims to provide a new method for regulating the state of micronized APIs, which can stably and efficiently handle the problem of amorphous particles caused by heat or mechanical energy in the micronization process. The micronized drug treated by the new method is stable in state and remains in a stable physical state after long-term storage, which is convenient for providing sufficient time for subsequent preparation processes. In addition, the new method also has the advantages of high yield, environmental protection or simple operation.

[0010] The object to be processed by the method provided by the present invention is "micronized API", which is obtained by crushing the API through a micronization process, and the API after micronization and crushing absorbs energy such as heat or mechanical energy, resulting in amorphous surface of all or part of the micropowder particles. The micronization treatment in the described micronization process can use any method in the industry that can crush the API into micropowder, including but not limited to common methods such as air flow milling, high pressure homogenization, spray drying, freeze spray drying, ultrasonic milling or grinding, and grinding includes but is not limited to ball milling or wet medium grinding.

[0011] The novel method for regulating the state of micronized API provided by the present invention comprises the following steps:

[0012] S1. Take the micronized API and add it to a pressure-resistant container. S2. Add propellant to the pressure-resistant container. S3. Keep the API in a suspended state in the propellant and perform a stabilization state adjustment process. S4. Drain the propellant and collect the powdered drug.

[0013] Among them, S1 especially recommends that the raw material drug after micronization be immediately added to a pressure-resistant container for subsequent treatment by the method of the present invention. This will avoid the aggregation of particles of the micronized raw material drug after long-term storage, and help to adjust the amorphous state of the particle surface as much as possible through the method of the present invention before crystallization occurs and causes particle aggregation.

[0014] Wherein, the propellant is in a gaseous state at normal temperature and pressure, and is pressurized in the pressure-resistant container in steps S2 and S3 to maintain a liquid state. Depending on the type of the bulk drug, the selected propellant should be a poor solvent for the bulk drug. The propellant can be selected from alkanes, halogenated alkanes or ethers with a carbon number less than 6. In some embodiments, the propellant is a liquefied gas propellant, and the liquefied gas propellant can be selected from one or more mixtures of fluorochloroalkanes (Freon), propane, n-butane, isobutane, dimethyl ether and fluoroalkanes. Fluorochloroalkanes, also known as Freon, abbreviated CFC, are a kind of propellants widely used in the early days, but due to the presence of Cl therein, ozone decomposition will occur, which harms the environment. Fluoroalkanes, abbreviated HFA or HFC, are a new generation of propellants developed based on environmental protection, which avoids the use of Cl, does not damage the atmospheric ozone layer, and is more environmentally friendly. In some more specific embodiments, the fluorochloroalkane (Freon) includes but is not limited to trichloromonofluoromethane (Freon 11), dichlorodifluoromethane (Freon 12), dichloromonofluoromethane (Freon 21), monochlorodifluoromethane (Freon 22), monochlorodifluoroethane (Freon 142b), dichlorotetrafluoroethane (Freon 114) and trichlorotrifluoroethane (Freon 113), and the fluoroalkane includes but is not limited to octafluorocyclobutane (C-318), tetrafluoroethane (HFA-134a) and heptafluoropropane (HFA-227). In other more specific embodiments, considering environmental protection factors, the liquefied gas propellant can be selected as tetrafluoroethane (HFA-134a), heptafluoropropane (HFA-227) or a mixture of the two.

[0015] In the method provided by the present invention, the concentration of the API in the propellant is based on the basic condition that the API micropowder particles can be divided and evenly dispersed in the propellant in a uniform suspension state. Based on the specific embodiment of the present invention, the concentration of the API in the propellant in the new method provided by the present invention is 3.2 to 160 mg / mL, and can be 36 to 160 mg / mL.

[0016] In some embodiments, the organic solvent of the API in liquid state at room temperature and pressure is added to the pressurized container along with the propellant. The organic solvent in liquid state at room temperature and pressure (hereinafter referred to as liquid organic solvent) can be added to the pressurized container before, at the same time or after the propellant. The liquid organic solvent includes but is not limited to halogenated alkanes, alcohols, ethers, acetone or esters containing or not containing water, and can be specifically selected as dichloromethane, methanol, ethanol, ether, methyl tert-butyl ether, acetone, ethyl acetate or methyl acetate containing or not containing water. The liquid organic solvent can be taken away by the propellant when it is vaporized when the propellant is drained in step S4, so the liquid organic solvent is usually selected from solvents with lower boiling points, such as boiling points less than 60°C, such as acetone with a boiling point of 56.5°C, and the amount of the liquid organic solvent added should not be too much, such as not more than 5% of the weight of the propellant. The addition of a small amount of the liquid organic solvent increases wettability, especially for highly hydrophobic APIs, which can quickly disperse the API particles through wetting, thereby shortening the aging treatment time.

[0017] In the new method provided by the present invention, step S3 is a step of adjusting the micronized state, in which the micronized API is suspended in the propellant for stabilization state adjustment until aging is completed. In some embodiments, the specific time for stabilization state adjustment can be selected according to the type, property, crushing method, and micropowder particle size of the API. Generally, a relatively short stabilization state adjustment time can be selected for APIs that are easy to crystallize quickly, the crushing method is not violent, and the micropowder crushing particle size is large and absorbs less energy. For APIs that are not easy to crystallize, the amorphous to stable crystal form is slow to crystallize, the crushing method is violent, and the micropowder crushing particle size is small and absorbs more energy, a relatively long stabilization state adjustment time can be selected. According to a specific embodiment of the present invention, the time for stabilization state adjustment can be selected from more than 1 minute, more than 5 minutes, more than 30 minutes, more than 2 hours, or 30 minutes to 2 hours.

[0018] In some embodiments, in order to make the micro powder API in a better and more evenly dispersed suspension state in the propellant, stirring can be used and the suspension state can be controlled by controlling the stirring speed. The ideal optional suspension state is to adjust the stirring speed to control the API propellant suspension system to be vortex-shaped. In particular, the stirring speed is close to or the same as the rotation speed of the suspension system vortex. At this time, stirring can maintain the suspension state of the system, the micro powder can be evenly dispersed in the system and is in a relatively stable state of the spacing between the particles, and the stirring paddle and the suspension system have less relative movement, and the collision between the stirring paddle and the particles is also less. This state is more conducive to the independent aging of the micro powder particles.

[0019] In some embodiments, ultrasonic dispersion pretreatment is performed simultaneously in S3. Through ultrasonic predispersion treatment, the particles temporarily gathered together due to weight extrusion and other reasons in the micronized bulk drug can be quickly dispersed, and further each particle is isolated from each other and independently suspended in the propellant under stirring. Therefore, the ultrasonic predispersion treatment is preferably performed immediately when the suspension treatment starts in S3. The specific order steps are, for example, adding the micronized bulk drug, adding the propellant, and starting the ultrasonic treatment synchronously while turning on the stirring. Of course, according to the selection, it is also possible to firstly perform ultrasonic treatment before turning on the stirring, and then stir and suspend to adjust the state, or to perform ultrasonic dispersion treatment after turning on the stirring for a period of time. The time of ultrasonic dispersion can be selected to be within 5min.

[0020] In some embodiments, the pressure-resistant container should be able to bear at least the pressure provided by the propellant in the liquid state. According to the material classification, the pressure-resistant container can be selected as a glass container, a metal container or a plastic container, and metal containers, especially steel tank containers, are the most common for large-scale batch production in workshop production. The selected pressure-resistant container should generally be a material that has been tested to have good compatibility with the API. In some cases, according to the different types and forms of the API, an isolation coating, such as polyethylene or epoxy resin coating, can also be optionally applied to the inside of the pressure-resistant container. A pressure relief valve should be provided on the pressure-resistant container, and the pressure relief valve is generally arranged in the upper middle part of the pressure-resistant container. By opening the pressure relief valve in S4, the propellant can be emptied to obtain a stabilized powder drug after the propellant is discharged and the state is adjusted. The powder drug can generally be collected from the bottom of the pressure-resistant container.

[0021] In some embodiments, when the stabilization state adjustment treatment is performed in S3 and the propellant is dried in S4, the system temperature is maintained by a heat preservation medium at room temperature or 18-21°C.

[0022] The particle size of the drug delivered by pulmonary inhalation is lower, and the raw material drug also needs to be crushed finer in the micronization process, and the required crushing heat energy or mechanical energy is also higher. The obtained micronized raw material drug has a larger particle surface area, higher energy absorption, and the surface amorphization is usually more serious. Therefore, the micronized raw material drug for inhalation delivery also needs state adjustment treatment, and it has been verified by the present invention that it is more suitable for the new method provided by the present invention to be state-adjusted. The Dv90 of this type of micronized raw material drug for pulmonary inhalation is less than 10μm, 0.5-10μm or 0.5-5μm. This type of drug delivered by pulmonary inhalation includes but is not limited to glycopyrrolate, budesonide, formoterol, tiotropium bromide, fluticasone, beclomethasone, salmeterol, indacaterol, mometasone, umeclidinium bromide or vilanterol (it should be noted that in the enumeration of drug types in the present invention, the listed drug names mean their free form, any pharmaceutically acceptable salt form and any crystalline form).

[0023] The powder medicine obtained by the new method provided by the present invention has unique advantages, which are reflected in: the particle size of the micronized raw material drug remains basically unchanged before and after the treatment by the method of the present invention, the particle size of the powder medicine after treatment is stable and controllable, and the particle size of the powder medicine after treatment does not change drastically even if it is stored for a long time, thereby maintaining good particle stability.

[0024] Based on the unique good performance of the powdered medicine prepared by the new method provided by the present invention, the present invention further provides a pharmaceutical composition, comprising a powdered medicine obtained by any of the above methods for regulating the state of micronized raw materials provided by the present invention and a pharmaceutically acceptable excipient.

[0025] In addition to being able to prepare powdered drugs with unique properties, the method for adjusting the state of micronized APIs provided in the present invention also has the technical advantage of high product yield. At the same time, the entire preparation process is simple, the required equipment is simple, and there is no need to make complex changes to the structure of traditional pharmaceutical equipment. The product powdered drug can be collected by naturally releasing the pressure and drying the propellant. The entire preparation process is simple and easy to industrialize, and the production input cost is low. After the propellant is vaporized, it can be further collected and recycled after liquefaction, realizing green circulation and clean production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the X-ray powder diffraction pattern of the glycopyrrolate measured immediately after the air flow pulverization in Comparative Example 1.

[0027] Figure 2 This is the X-ray powder diffraction pattern of the glycopyrrolate in Comparative Example 1, which was sampled and measured after being placed for 12 hours after air flow pulverization.

[0028] Figure 3 This is a SEM scan of glycopyrrolate immediately after air flow pulverization in Comparative Example 1.

[0029] Figure 4 This is a SEM scan of the glycopyrrolate in Comparative Example 1 after airflow crushing and leaving for 12 hours.

[0030] Figure 5 This is a SEM scan of the glycopyrrolate in Comparative Example 2 immediately after homogenization and spray drying.

[0031] Figure 6 This is a SEM scan of the glycopyrrolate in Comparative Example 2 immediately after homogenization and vacuum drying.

[0032] Figure 7 This is a SEM scan of the glycopyrrolate in Comparative Example 2 immediately after homogenization, vacuum drying, and air flow pulverization.

[0033] Figure 8This is a SEM scan of the glycopyrrolate in Comparative Example 2 after homogenization, vacuum drying, air flow pulverization and then standing for 24 hours.

[0034] Fig. 9 This is a SEM scan of the micronized glycopyrrolate in Example 1 immediately after aging with the propellant HFA-134a.

[0035] Fig.10 This is a SEM scan of the micronized glycopyrrolate in Example 1 after being aged with the propellant HFA-134a for 3 days.

[0036] Fig.11 This is a SEM scan of the micronized glycopyrrolate in Example 1 after being aged with the propellant HFA-134a for 17 days.

[0037] Fig.12 This is a SEM scan of the micronized glycopyrrolate in Example 1 after being aged with the propellant HFA-134a for 90 days.

[0038] Fig.13 This is a SEM scan of the micronized glycopyrrolate in Example 2 immediately after aging with the propellant HFA-227.

[0039] Fig.14 This is a SEM scan of the micronized glycopyrrolate in Example 2 after being aged with the propellant HFA-227 for 90 days.

[0040] Fig.15 This is a SEM scan of the micronized glycopyrrolate in Example 3 immediately after aging with the propellant HFA-134a and acetone.

[0041] Fig.16 This is a SEM scan of the micronized glycopyrrolate in Example 3 after being aged with the propellant HFA-134a and acetone for 90 days.

[0042] Fig.17 This is a SEM scan of the micronized fluticasone propionate in Example 4 immediately after air flow grinding.

[0043] Fig.18 This is a SEM scan of the micronized fluticasone propionate in Example 4 immediately after being air flow-ground and aged with the propellant HFA-134a and ethanol.

[0044] Fig.19 This is a SEM scan of the micronized fluticasone propionate in Example 4 after air flow grinding, aging with propellant HFA-134a and ethanol, and then standing for 30 days. DETAILED DESCRIPTION

[0045] The industry terms involved in the present invention may be understood in accordance with their commonly understood meanings in the industry. In order to explain the present invention more clearly, the present invention further explains the following terms in detail.

[0046] The term "conditioning" generally refers to methods and processes that can be used to improve the physicochemical stability of particulate crystalline materials. More specifically, in the present invention, the term "conditioning" refers to a method that allows the particulate material to be aged in a controlled manner, and the term "conditioning completed" refers to the particulate material having been aged under controlled conditions.

[0047] The term "aging" generally refers to a method and process that can control the transformation of a particulate material from a physicochemically unstable state to a physicochemically stable state. More specifically, in the present invention, the term "aging" refers to a process that reduces or eliminates the amorphous content in the micronized particulate material, and the term "completed aging" means that the amorphous content in the micronized particulate material has been substantially eliminated or at least substantially eliminated to the extent that it does not affect the particle size stability of the particulate material particles during long-term storage.

[0048] The present invention will be further explained below in conjunction with the accompanying drawings and specific embodiments.

[0049] Comparative Example 1: Glycopyrrolate Airflow Grinding Process

[0050] Take glycopyrrolate raw material, perform air flow pulverization, control the environmental humidity at 30-40% RH, pulverization pressure at 6.8 bar, feed pressure at 7.4 bar, finish feeding, pulverize for more than 1 minute, collect the material, immediately take samples to measure the particle size, and characterize by electron microscope scanning and X-ray powder diffraction, and take another sample of aluminum plastic bag sealed at -20℃ for 12 hours, measure the particle size, and characterize by electron microscope scanning and X-ray powder diffraction. The results are shown in Table 1. Figures 1 to 4 shown.

[0051] Table 1 Glycopyrrolate air flow milling process particle size determination results

[0052] Treatment process Placement time D10(μm) D50(μm) D90(μm) Yield (%) Air flow crushing 0h 0.75 1.52 2.79 69 Air flow crushing 12h 1.37 3.98 7.45 Same as above

[0053] Summary of Comparative Example 1:

[0054] Figure 1 The XRPD shown shows that the micronized glycopyrrolate product just crushed contains amorphous components. Figure 2 The XRPD displayed shows that after the crushed micronized glycopyrrolate is left for 12 hours, the amorphous form gradually transforms into a crystalline form.

[0055] Table 1 shows that after 12 hours of storage, the particle size of micronized glycopyrrolate increased significantly and was completely inconsistent with the powder particle size expected by crushing. Figure 3 and Figure 4By comparison, it can also be clearly confirmed that the micropowder particles have obvious local aggregation in the electron microscope scanning image after 12 hours of storage.

[0056] Comparative Example 2: Glycopyrronium bromide acetone homogenization process

[0057] Take the glycopyrrolate raw material, disperse it in acetone to form a suspension, add it to the material cup of the high-pressure homogenizer, turn on the high-pressure homogenizer, control the pressure at more than 600 bar, homogenize until the particle size D50 is 1.30-1.70 μm, collect the material, immediately take samples to determine the particle size, and divide the remaining samples into 2 equal parts for standby use.

[0058] The first sample was spray dried, and the dry powder was collected and immediately sampled for particle size determination and characterization by electron microscopy.

[0059] The second sample was vacuum dried, and the dry powder was collected. Samples were immediately taken to determine the particle size and characterized by scanning electron microscopy. The vacuum dried powder was further subjected to air flow pulverization. The material was collected and immediately sampled to determine the particle size and characterized by scanning electron microscopy. After air flow pulverization, the micropowder was sealed in an aluminum-plastic bag and placed for 24 hours. Samples were taken to determine the particle size and characterized by scanning electron microscopy.

[0060] The results are shown in Table 2. Figures 5 to 8 shown.

[0061] Table 2 Glycopyrronium bromide acetone homogenization process particle size determination results

[0062] Treatment process Placement time D10(μm) D50(μm) D90(μm) Overall yield (%) Homogenization 0h 0.97 1.43 2.80 63.5 Homogenization + spray drying 0h 1.98 13.09 78.6 21.3 Homogenization + vacuum drying 0h 2.51 22.36 66.89 55.1 Homogenization + vacuum drying + air flow crushing 0h 1.01 1.56 2.76 19.6 Homogenization + vacuum drying + air flow crushing 24h 1.37 3.98 7.5 /

[0063] Summary of Comparative Example 2:

[0064] Table 2 shows that after homogenization and micronization, the particles of glycopyrrolate can be broken to the expected small size, but after the traditional spray drying to remove the solvent acetone, the particle size of the micropowder increases significantly, even if the solvent removal method of vacuum drying is replaced, a large particle size increase is still obtained. Continue to apply the airflow milling micronization process to the dried glycopyrrolate to obtain a small-sized particle size micropowder, but consistent with Comparative Example 1, the micropowder after airflow milling can reach the expected small size state immediately, but with the storage time of the micropowder, its particle size gradually increases significantly, and the particle size stability is difficult to meet the requirements. Figures 5 to 8 The SEM scans of each stage also confirm the particle size test results in Table 2. Figure 5 and Figure 6 It was shown that after homogenization, the particle size of glycopyrrolate increased significantly regardless of spray drying or vacuum drying. Figure 7 and Figure 8 Compared with each other, it shows Figure 7 Although the air flow can continue to break the powder into smaller particle size, Figure 8As shown in the figure, after a period of storage, the glycopyrrolate micropowder particles began to aggregate again.

[0065] Example 1: New process for regulating the state of micronized API of the present invention (HFA-134a scheme example)

[0066] Take glycopyrrolate raw material and perform air flow crushing. Control the environmental humidity at 30-40% RH, the crushing pressure at 7.0 bar, and the feed pressure at 7.5 bar. Finish the feeding. Crush for more than 1 minute, collect the material, and immediately take samples to measure the particle size.

[0067] The crushed powder was collected into a pressure-resistant container, which was sealed and filled with HFA-134a until the concentration of glycopyrrolate was 80 mg / ml. Stirring was started, ultrasound was started, and the insulation medium (18-21° C.) was started. The stirring speed was adjusted until the liquid surface formed a vortex and the material was in a suspended state. Ultrasound was applied for 5 minutes, and ultrasound was turned off. Stirring was continued for more than 30 minutes. The pressure was released from the top of the pressure-resistant container (the insulation medium was 18-21° C. and was not turned off). The propellant was emptied, and the stabilized glycopyrrolate powder was collected from the bottom of the pressure-resistant container. Samples were immediately taken to determine the particle size and characterized by electron microscopy. Another sample was sealed in an aluminum-plastic bag and placed for 3 days, 17 days, and 90 days, and the particle size was determined and characterized by electron microscopy.

[0068] The results are shown in Table 3. Figures 9 to 12 shown.

[0069] Table 3 Particle size determination results of propellant aging process in Example 1

[0070] Treatment process Placement time D10(μm) D50(μm) D90(μm) Overall yield (%) Air flow crushing 0h 0.59 1.44 2.85 78.7 HFA-134a aging 0h 0.64 1.48 2.90 75.3 HFA-134a aging 3d 0.60 1.46 2.91 / HFA-134a aging 17d 0.61 1.45 2.89 / HFA-134a aging 90d 0.64 1.47 2.88 /

[0071] Example 2: New process for regulating the state of micronized API of the present invention (HFA-227 scheme example)

[0072] Take glycopyrrolate raw material, perform air flow crushing, control the environmental humidity at 30-40% RH, crushing pressure at 6.8 bar, feed pressure at 7.2 bar, finish feeding, crush for more than 1 minute, collect the material, and immediately take samples to measure the particle size.

[0073] The crushed powder was collected into a pressure-resistant container, which was sealed and filled with HFA-227 until the concentration of glycopyrrolate was 36 mg / ml. Stirring was started, ultrasound was started, and the insulation medium was started. The stirring speed was adjusted until a vortex was formed on the liquid surface and the material was in a suspended state. Ultrasound was applied for 5 minutes, and ultrasound was turned off. Stirring was continued for more than 2 hours. The pressure was released from the top of the pressure-resistant container, the propellant was discharged, and the stabilized glycopyrrolate powder was collected from the bottom of the pressure-resistant container. Samples were immediately taken to determine the particle size and characterized by electron microscopy. Another sample was sealed in an aluminum-plastic bag and placed for 90 days, and then the particle size was determined and characterized by electron microscopy.

[0074] The results are shown in Table 4. Figures 13-14 shown.

[0075] Table 4 Example 2 Propellant aging process particle size measurement results

[0076] Treatment process Placement time D10(μm) D50(μm) D90(μm) Overall yield (%) Air flow crushing 0h 0.62 1.41 2.68 77.6 HFA-227 Aging 0h 0.72 1.53 2.89 74.12 HFA-227 Aging 90d 0.73 1.55 2.91 /

[0077] Example 3: New process for regulating the state of micronized API of the present invention (HFA-134a+acetone solution example)

[0078] Take glycopyrrolate raw material and perform air flow crushing. Control the ambient humidity at 30-40% RH, the crushing pressure at 5.8 bar, and the feed pressure at 6.3 bar. Finish the feeding. Crush for more than 1 minute. Collect the material and immediately take samples to measure the particle size.

[0079] The crushed powder is collected in a pressure-resistant container, 2% of the total weight of acetone is added to the liquid preparation tank, most of the HFA-134a is filled in after sealing, and stirred evenly. The crushed raw material is put into the top buffer tank, and the raw material is flushed into the liquid preparation tank with the remaining HFA-134a until the concentration of glycopyrrolate is 160 mg / ml, stirring is turned on, and the insulation medium (18-23° C.) is turned on. The stirring speed is adjusted until the liquid surface forms a vortex and the material is in a suspended state. Ultrasound is applied for 5 minutes, and the ultrasound is turned off. The stirring is continued for more than 2 hours, and the pressure is released from the top of the pressure-resistant container to empty the propellant. The stabilized glycopyrrolate powder is collected from the bottom of the pressure-resistant container, and the particle size is immediately measured and characterized by electron microscopy. Another sample is sealed in an aluminum-plastic bag and placed for 90 days, and the particle size is measured and characterized by electron microscopy.

[0080] The results are shown in Table 5. Figures 15-16 shown.

[0081] Table 5 Example 3 Propellant aging process particle size measurement results

[0082] Treatment process Placement time D10(μm) D50(μm) D90(μm) Overall yield (%) Air flow crushing 0h 0.68 1.55 3.00 72.9 HFA-134a+acetone aging 0h 0.71 1.63 3.19 71.1 HFA-134a+acetone aging 90d 0.73 1.63 3.11 /

[0083] Example 4: New process for regulating the state of micronized API of the present invention (Example of fluticasone propionate solution)

[0084] Fluticasone propionate API was taken and subjected to air flow pulverization. The ambient humidity was controlled at 30-40% RH, the pulverization pressure was 6.3 bar, the feed pressure was 6.8 bar, and after the feeding was completed, the pulverization was continued for 5 minutes. The material was collected and samples were taken immediately to determine the particle size.

[0085] The crushed powder is collected in a pressure-resistant container, 1.0% of anhydrous ethanol is added to the liquid preparation tank by total weight, and most of the HFA-134a is filled in after sealing, and stirred evenly. The crushed raw material is put into the top buffer tank, and the raw material is flushed into the liquid preparation tank with the remaining HFA-134a until the concentration of fluticasone propionate is 40 mg / ml. Stirring is turned on, and the heat preservation medium (18-23° C.) is turned on. The stirring speed is adjusted until the liquid surface forms a vortex and the material is in a suspended state. Ultrasound is applied for 2 minutes, and the ultrasound is turned off. The stirring is continued for 4 hours, and the pressure is released from the top of the pressure-resistant container to empty the propellant. The stabilized glycopyrrolate powder is collected from the bottom of the pressure-resistant container, and a sample is immediately taken to determine the particle size and characterized by electron microscopy. Another sample is sealed in an aluminum-plastic bag and placed for 30 days, and the particle size is determined and characterized by electron microscopy.

[0086] The results are shown in Table 6. Figures 17 to 19 shown.

[0087] Table 6 Example 4 Propellant aging process particle size measurement results

[0088] Treatment process Placement time D10(μm) D50(μm) D90(μm) Overall yield (%) Air flow crushing 0h 0.824 2.79 14.0 36.8 HFA-134a+ethanol aging 0h 0.839 2.88 14.9 35.1 HFA-134a+ethanol aging 30d 0.835 2.85 14.6 /

[0089] Summary of Examples 1, 2, 3, and 4:

[0090] Tables 3, 4, 5, and 6 of the four embodiments show that after airflow pulverization, the particles of glycopyrrolate and fluticasone propionate can be broken to the expected small size. Further, the new process for adjusting the state of the micronized API provided by the present invention is then used, and the propellant is used as the main part for suspension aging treatment. The collected glycopyrrolate and fluticasone propionate powders after aging treatment maintain the same particle size distribution as the glycopyrrolate and fluticasone propionate just after micronization, whether the particle size is immediately detected or stored for a certain period of time (such as 3 days, 17 days, 30 days, and 90 days). This also shows that the new method for processing micronized APIs provided by the present invention can stably and controllably obtain the target drug particle size distribution, and the obtained drug powder maintains good particle stability. Figures 9 to 19The electron microscope scanning diagram shows that after the aging of the method of the present invention is completed, there is no obvious change in the particle distribution before and after long-term storage, and no obvious particle aggregation occurs. Such results can also be verified with the particle size distribution detected in Tables 3 to 6. From the perspective of yield, the new process provided by the present invention has a higher overall yield after state airflow crushing and state-adjusted aging. Taking glycopyrrolate as an example, the present invention is 71.1-75.3%, which is significantly improved compared to 19.6-55.1% of Comparative Example 2. Considering the yield of the state-adjusted aging step of the new process provided by the present invention alone, it can be calculated by the overall yield and the yield of the airflow crushing in the previous step. The yields of the state-adjusted aging steps of Examples 1 to 4 are 95.7%, 95.5%, 97.5%, and 95.4%, respectively, which are suitable for a variety of raw materials. The novel state-adjusted aging treatment method of the new process provided by the present invention has a very high yield.

[0091] The present invention is not limited to the above optional implementations, and anyone can derive other various forms of products under the enlightenment of the present invention. The above specific implementations should not be understood as limiting the scope of protection of the present invention. The scope of protection of the present invention should be based on the definition in the claims, and the description can be used to interpret the claims.

Claims

1. A method for regulating the state of a micronized bulk drug, characterized in that: The steps include: S1. Take the micronized API and add it into a pressure-resistant container; S2. Adding a propellant into the pressure container; S3. Keep the API in a suspended state in the propellant and perform a stabilization state adjustment process; S4. Release the propellant and collect the powdered drug.

2. The method according to claim 1, characterized in that The method used for the micronization treatment is selected from air flow pulverization, high pressure homogenization, spray drying, freeze spray drying, ultrasonic pulverization or grinding, and the grinding can be selected from ball milling or wet medium grinding.

3. The method according to claim 1, characterized in that The propellant is in a gaseous state at normal temperature and pressure. The propellant is pressurized into a liquid state in the pressure-resistant container in steps S2 and S3. The propellant is a poor solvent for the drug substance. The propellant can be selected from alkanes, halogenated alkanes or ethers having a carbon number of less than 6.

4. The method according to claim 3, characterized in that The propellant is a liquefied gas propellant, and the liquefied gas propellant can be selected from one or a mixture of two or more of fluorochloroalkanes (Freon), propane, n-butane, isobutane, dimethyl ether and fluoroalkanes; The fluorochloroalkanes (Freon) may optionally include trichloromonofluoromethane (Freon 11), dichlorodifluoromethane (Freon 12), dichloromonofluoromethane (Freon 21), monochlorodifluoromethane (Freon 22), monochlorodifluoroethane (Freon 142b), dichlorotetrafluoroethane (Freon 114) and trichlorotrifluoroethane (Freon 113), and the fluorinated alkanes may optionally include octafluorocyclobutane (C-318), tetrafluoroethane (HFA-134a) and heptafluoropropane (HFA-227).

5. The method according to claim 4, characterized in that The liquefied gas propellant is tetrafluoroethane (HFA-134a), heptafluoropropane (HFA-227) or a mixture of the two.

6. The method according to claim 1, characterized in that After the propellant is added to S2, the concentration of the API in the propellant is 3.2 to 160 mg / mL, and can be optionally 36 to 160 mg / mL.

7. The method according to claim 1, characterized in that Before S3, there is also a step of adding an organic solvent in a liquid state at normal temperature and pressure into the pressure-resistant container, wherein the amount of the organic solvent in the liquid state added is less than 5% of the weight of the propellant, and the organic solvent in the liquid state includes halogenated alkanes, alcohols, ethers, acetone or esters containing or not containing water. The organic solvent in the liquid state can be selected from dichloromethane, methanol, ethanol, ether, methyl tert-butyl ether, acetone, ethyl acetate or methyl acetate containing or not containing water.

8. The method according to claim 1, characterized in that: The suspension stabilization state in S3 is adjusted until the aging of the raw material is complete. The time for adjusting the stabilization state can be selected to be more than 1 minute, more than 5 minutes, more than 30 minutes, more than 2 hours, or 30 minutes to 2 hours.

9. The method according to claim 1, characterized in that: In S3, the API is suspended in the propellant by stirring, and the stirring speed can be optionally adjusted to control the API-propellant suspension system to be in a vortex shape.

10. The method according to claim 1, characterized in that In S3, ultrasonic dispersion pretreatment is performed simultaneously. The ultrasonic dispersion pretreatment can be performed immediately when the suspension treatment is started in S3. The ultrasonic dispersion time can be selected to be within 5 minutes.

11. The method according to claim 1, characterized in that: The pressure-resistant container is a glass container, a metal container or a plastic container. The inner wall of the pressure-resistant container may be provided with an isolation coating, and the isolation coating may be polyethylene or epoxy resin. In S4, a valve may be opened at the top of the pressure-resistant container to release pressure and discharge the propellant. After the propellant is discharged, the powdered medicine may be collected from the bottom of the pressure-resistant container.

12. The method according to claim 1, characterized in that When S3 is carrying out the stabilization state adjustment treatment and S4 is draining the propellant, the system temperature is maintained by a heat preservation medium at room temperature or 18-21°C.

13. The method according to claim 1, characterized in that The raw material drug is a drug for delivery via pulmonary inhalation, and the Dv90 of the raw material drug after micronization is 0.5-10 μm or 0.5-5 μm. The raw material drug can be selected from glycopyrrolate, budesonide, formoterol, tiotropium bromide, fluticasone, beclomethasone, salmeterol, indacaterol, mometasone, umeclidinium bromide or vilanterol.

14. A pharmaceutical composition comprising the powdered drug obtained by the method of any one of claims 1 to 13 and pharmaceutically acceptable excipients.

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