A suspension type budesonide inhalation aerosol and preparation method thereof

Abstract

The present invention relates to a pharmaceutical preparation, and in particular to a suspension type budesonide inhalation aerosol and a preparation method thereof. The budesonide inhalation aerosol comprises budesonide, phospholipids and calcium chloride; the budesonide micropowder particles are prepared by high pressure homogenization combined with spray drying technology, and perfluorooctane bromide is not used. The budesonide inhalation aerosol has a high fine particle fraction (FPF), and the delivery dose uniformity RSD is less than or equal to 15%. The suspension type budesonide inhalation aerosol prepared by the method of the present invention has a high fine particle dose and good delivery dose uniformity.

Description

Technical Field

[0001] The invention relates to a pharmaceutical preparation, in particular to a suspension type budesonide inhalation aerosol and a preparation method thereof. Background Art

[0002] The active ingredient, bodenolone, is a highly selective inhaled glucocorticoid with anti-inflammatory, antispasmodic and antiasthmatic effects. It has become the first choice drug for the clinical treatment of bronchial asthma due to its high efficiency and safety.

[0003] Inhalation preparations are currently the best way to treat asthma. Drugs inhaled into the lungs avoid the first-pass effect and degradation of the gastrointestinal tract, quickly reach the target site at a higher concentration, and take effect quickly. The medicinal dose is much lower than systemic administration, avoiding the side effects that may be caused by systemic administration. Currently, inhalation preparations mainly include inhalation aerosols (solution type and suspension type), powder inhalers, nebulizer inhalers, etc. Inhalation aerosols are the most convenient to carry, use, and relatively low-cost inhalation preparations.

[0004] For aerosols, particle size is the key factor that determines whether the drug can reach the lungs. Drugs with particle sizes between 0.5μm and 5μm mainly settle in the bronchi and bronchioles of the lungs, particles larger than 10μm mainly settle in the oropharynx, and particles of 0.5μm are easily exhaled with the airflow. Therefore, drugs with particle sizes between 0.5μm and 5μm are most suitable for pulmonary administration. The particle size of the drug can be directly reduced to the ideal particle size by airflow pulverization. Reducing the particle size of the drug can increase lung deposition, but there are many common problems with suspension aerosols with only APIs and propellants, such as fast sedimentation rate, wide particle size distribution, poor delivery uniformity, etc. Adding a certain amount of suspending agent can improve the uniformity of its delivery dose, but at the same time increase the particle size, resulting in reduced lung deposition.

[0005] Some people use co-suspension drug delivery technology to adsorb drug crystals of different densities on porous low-density phospholipid microsphere carriers, and add them to the bottle together with the propellant to prepare an aerosol, thereby improving the uniformity of drug delivery and the dose of fine particles. The aerosol uses distearoylphosphatidylcholine (DSPC), perfluorooctyl bromide, calcium chloride and other excipients, but the cost of excipients such as perfluorooctyl bromide is relatively high, the preparation process is complicated, and a solvent recovery device is required. Summary of the invention

[0006] The present invention aims to solve at least one of the problems in the prior art or at least provide a commercial option.

[0007] The present invention provides a suspension type budesonide inhalation aerosol and a preparation method thereof, which can at least solve the problem of uneven delivery dose of the inhalation aerosol, and can obtain an inhalation aerosol with a high fine particle dose, and the production cost is relatively low.

[0008] A budesonide inhalation aerosol comprises: budesonide, phospholipid and propellant; the mass median aerodynamic diameter (MMAD) of the budesonide inhalation aerosol is 1-8 μm, the fine particle percentage (FPF) is 20%-70%, and the delivery dose uniformity (RSD) is less than or equal to 15%.

[0009] Furthermore, the delivery dose uniformity of the budesonide inhalation aerosol is less than or equal to 5%, such as 2-5%.

[0010] In some embodiments, the budesonide inhalation aerosol has a delivered dose uniformity of 1%, 2%, 3%, 3.4%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%.

[0011] In some embodiments, the mass median aerodynamic diameter of the budesonide inhalation aerosol is 2.8-3.2 μm, the percentage of fine particles is 45%-50%, and the delivery dose uniformity is less than or equal to 5%.

[0012] In some embodiments, the budesonide inhalation aerosol has a mass median aerodynamic diameter of 3 μm, a percentage of fine particles of 48%, and a delivered dose uniformity of 3-3.4%.

[0013] In some embodiments, the geometric standard deviation (GSD) of the budesonide inhalation aerosol is 1-2, such as 1.50-1.67.

[0014] In some embodiments, the mass percentage of budesonide in the budesonide inhalation aerosol is 0.05%-2%, for example, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.328%, 0.33%, 0.35%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%.

[0015] In some embodiments, the mass percentage of calcium chloride in the budesonide inhalation aerosol is 0.001%-0.1% or 0.01%-0.05%; for example, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%.

[0016] In some embodiments, the mass percentage of phospholipids in the budesonide inhalation aerosol is 0.02%-0.15%, or 0.03%-0.1%; for example, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%.

[0017] In some embodiments, in the budesonide inhalation aerosol, the molar ratio of phospholipid to calcium chloride is (1-6):1, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1.

[0018] Furthermore, in the budesonide inhalation aerosol, the mass ratio of budesonide to phospholipid (such as hydrogenated phospholipid (HSPC)) is 10:(0.5-3.5), or 10:(1-3); specifically, for example, 10:0.5, 10:1, 10:2, 10:3, 10:3.5.

[0019] In some embodiments, the propellant is specifically HFA134a (tetrafluoroethane).

[0020] In some embodiments, the entire preparation process of the budesonide inhalation aerosol does not use any organic solvent such as perfluorooctyl bromide.

[0021] In some embodiments, the budesonide inhalation aerosol does not include perfluorooctyl bromide.

[0022] The present invention also provides a method for preparing the budesonide inhalation aerosol, comprising:

[0023] 1) providing a phospholipid emulsion containing calcium chloride;

[0024] 2) adding budesonide powder to the phospholipid emulsion to prepare a budesonide suspension;

[0025] 3) high pressure homogenizing the budesonide suspension;

[0026] 4) spray drying the budesonide suspension after high pressure homogenization to obtain budesonide micropowder;

[0027] 5) preparing the budesonide micropowder into budesonide inhalation aerosol.

[0028] According to an embodiment of the present invention, the phospholipid emulsion containing calcium chloride uses purified water as a medium.

[0029] According to an embodiment of the present invention, in the phospholipid emulsion containing calcium chloride, the molar ratio of phospholipid to calcium chloride is (1-6): 1. The inventors have found that the addition of calcium chloride can significantly reduce the particle size of the budesonide micropowder particles after spray drying, and calcium chloride can increase the phase transition temperature of phospholipids, thereby improving the stability of the aerosol.

[0030] According to an embodiment of the present invention, in the phospholipid emulsion containing calcium chloride, the mass percentage of the phospholipid is 0.05%-5%, and can be optionally 0.05%-1%; according to an embodiment of the present invention, the phospholipid can be selected from one or more of HSPC, soybean lecithin, dipalmitoylphosphatidylcholine molecule (DPPC), and distearoylphosphatidylcholine (DSPC).

[0031] Hydrogenated phospholipids are phospholipids that have been hydrogenated to convert unsaturated bonds in phospholipids into saturated bonds. The melting point of hydrogenated phospholipids is increased, the solid shape is maintained, the plasticity is enhanced, and the problem of easy oxidation of unsaturated groups in phospholipids is avoided. The stability, emulsification, permeability, and dispersibility are more advantageous than those of unhydrogenated phospholipids. The anionic phosphate group in phospholipids combines with calcium ions to significantly increase the phase transition temperature of phospholipids, making the preparation more stable.

[0032] According to an embodiment of the present invention, the specific preparation method of the phospholipid emulsion containing calcium chloride includes: using purified water as a medium, adding phospholipids and calcium chloride, and emulsifying. The emulsification temperature can be selected from 40°C to 95°C, preferably 50-80°C. The emulsification process also includes a high-speed dispersion step, usually high-speed dispersion for 10-30 minutes to fully emulsify it. The speed of the high-speed dispersion is generally 1000-15000rpm, for example 9000rpm.

[0033] According to an embodiment of the present invention, in the budesonide suspension, the mass percentage of budesonide is 0.1%-10%, and can be optionally 0.5%-3%.

[0034] According to an embodiment of the present invention, the specific preparation method of the budesonide suspension includes: adding budesonide powder to the emulsion for pre-dispersion (10-30 minutes), the dispersion temperature is 40°C-95°C, optionally 50°C-90°C, for example 80°C.

[0035] According to an embodiment of the present invention, the pressure of the high-pressure homogenization is 10000psi-30000psi, and can be optionally 15000psi-30000psi; the number of cycles is 5-80 times, for example 20-70 times; specifically, for example, 5 times, 6 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, and 80 times.

[0036] According to an embodiment of the present invention, the pressure of the high-pressure homogenization is 15000psi-30000psi, and the number of cycles is 60-80 times.

[0037] According to an embodiment of the present invention, during the high pressure homogenization, the number of cycles is at least 60 times under the pressure condition of 10000psi-30000psi.

[0038] The present invention has found that high pressure homogenization is an effective method for reducing the size of particles and droplets, processing particles or droplets into micron or nanometer sizes, and using them as stable dispersions or emulsions for further processing, and high-quality particles can be obtained by spray drying.

[0039] Generally, conventional spray drying methods in the art may be used, and the present invention is not particularly limited thereto.

[0040] According to some specific embodiments of the present invention, the inlet temperature of the spray drying is 80-170°C, and can be optionally 90-150°C; for example, 80°C, 85°C, 90°C, 95°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, and 170°C.

[0041] In some specific embodiments, a B290 spray dryer (BUCHI, Switzerland) is used for drying. Specifically, the suction rate is 20-40m 3 ·h -1 ; Optional: 25-38m 3 ·h -1 ; Atomization flow rate 335-2293L·h -1 ; Atomizer flow meter height 25-65mm; Feed rate 1-30ml·min -1 , optional: 2-10ml·min -1 .

[0042] In the present invention, a high-pressure homogenization process combined with a spray drying technology can be used to prepare budesonide micropowder particles coated with phospholipids (such as hydrogenated phospholipids), and the structure and crystal form of budesonide are not significantly changed.

[0043] According to an embodiment of the present invention, the budesonide micropowder has an X10 of 0.45-0.62 μm, an X50 of 1.70-2.16 μm, an X90 of 3.19-4.40 μm, a volume mean particle size (VMD) of 1.83-2.45 μm, and a particle size distribution width (SPAN) of 1.60-1.75.

[0044] According to a specific embodiment of the present invention, the X10 of the budesonide micropowder is 0.45 μm, the X50 is 1.70 μm, the X90 is 3.19 μm, the mean volume particle size (VMD) is 1.83 μm, and the particle size distribution width (SPAN) is 1.61.

[0045] According to an embodiment of the present invention, the budesonide micropowder can be made into a budesonide inhalation aerosol according to a conventional method in the art, and the present invention is not particularly limited. According to an embodiment of the present invention, the budesonide micropowder is specifically added into a tank, a valve is covered, a seal is applied, and a propellant (HFA134a) is poured into the tank to prepare the budesonide inhalation aerosol.

[0046] According to an embodiment of the present invention, no perfluorooctyl bromide is added during the preparation of the budesonide inhalation aerosol.

[0047] The present invention also provides the above-mentioned budesonide micropowder, which is made of calcium chloride, phospholipids and budesonide powder. Specifically, the preparation method thereof comprises: providing a phospholipid emulsion containing calcium chloride; adding budesonide powder to the phospholipid emulsion to prepare a budesonide suspension; high-pressure homogenizing the budesonide suspension; spray drying the high-pressure homogenized budesonide suspension to obtain budesonide micropowder. The detailed preparation method is as described above.

[0048] Specifically, in the budesonide micropowder, the molar ratio of phospholipid to calcium chloride is (1-6):1; and / or, in the budesonide micropowder, the mass ratio of budesonide to phospholipid is 10:(0.5-3.5).

[0049] The budesonide micropowder of the present invention can be used to prepare budesonide inhalation aerosol.

[0050] The present invention also provides a budesonide inhalation aerosol prepared by the method, which is prepared from the budesonide micropowder.

[0051] Aerosols containing only micronized APIs have fast settling speed, wide particle size distribution, and poor delivery uniformity. The present invention adds a certain amount of phospholipids, coats budesonide through a high-pressure homogenization process and a spray drying process, and changes its surface properties. The phospholipids are first emulsified at high temperature, and the micronized budesonide powder is put into the emulsion at high temperature to fully wet it, and then subjected to high-speed dispersion pretreatment, and then high-pressure homogenization, and then spray drying to obtain mixed micropowders, and finally prepared into an inhalation aerosol with high fine particle dosage and good delivery uniformity.

[0052] Compared with the sample without calcium chloride, the HSPC emulsion with calcium chloride is more stable, the particle size of the budesonide micropowder after spray drying is smaller, and the prepared aerosol has a better suspension state. Compared with the aerosol prepared by the co-suspension technology, the aerosol prepared by the present invention has a higher lung deposition amount, a lower proportion of auxiliary materials, and does not use any organic solvents such as perfluorooctane bromide in the preparation process.

[0053] The suspension type budesonide inhalation aerosol prepared by the method of the present invention has high fine particle dosage and good delivery dosage uniformity. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 is the particle size distribution of different samples in Experiment 1 (n=3).

[0055] Figure 2 SEM images of different samples in Experiment 1 (×40 000).

[0056] Figure 3 Infrared spectra of different samples in Experiment 1.

[0057] Figure 4 X-ray diffraction patterns of different samples in Experiment 1.

[0058] Figure 5 DSC curves of different samples in Experiment 1.

[0059] Figure 6 The suspension states of (a)-aerosol and (h)-aerosol in Experiment 1 after standing for different time periods; A. comparison after standing for 3 seconds; B. comparison after standing for 10 seconds; C. comparison after standing for 30 seconds; D. comparison after standing for 60 seconds; Figure 6 The sample on the left in A, B, C, and D is (a)-aerosol, and the sample on the right is (h)-aerosol.

[0060] Figure 7 (a) shows the uniformity of the delivered dose of the aerosol after standing for 3s, 10s, and 60s in Experiment 1.

[0061] Figure 8 It shows the delivery dose uniformity of (h)-aerosol in Experiment 1 after standing for 3s, 10s, and 60s.

[0062] Fig. 9 The deposition data of different budesonide aerosols in the new generation pharmaceutical impactor (NGI) of Experiment 1 (n=3).

[0063] Fig.10 The comparison results of different emulsions in Experiment 2; the left side of the figure is hydrogenated phospholipid emulsion I; the right side of the figure is hydrogenated phospholipid emulsion II.

[0064] Fig.11 This is the comparison result of different budesonide aerosol suspension states in Experiment 2. Fig.11 The sample on the left is aerosol I, and the sample on the right is aerosol II.

[0065] Fig.12 This is the particle size distribution of different budesonide micropowder particles in Experiment 4.

[0066] Fig.13 The uniformity of delivered dose of different budesonide aerosols in Experiment 4. DETAILED DESCRIPTION

[0067] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0068] Unless otherwise specified, the particle sizes of budesonide powder (i.e., raw material) are: X10=0.51 μm, X50=1.53 μm, X90=3.15 μm.

[0069] Example 1

[0070] Weigh 0.3g of hydrogenated phospholipid and calcium chloride (the molar ratio of hydrogenated phospholipid to calcium chloride is 2:1), use 100g of 80℃ purified water as a medium to prepare hydrogenated phospholipid emulsion, keep a constant temperature of 80℃, and stir for 10min accompanied by magnetic stirring mode, and hydrogenated phospholipid is completely emulsified; weigh 1g of budesonide powder in hydrogenated phospholipid emulsion, disperse at high speed for 10min, the speed is 9000rpm, and the constant temperature of 80℃ is maintained during dispersion; after pretreatment, the budesonide suspension is subjected to high-pressure homogenization, the pressure is 30000psi, and the number of cycles is 60 times; the budesonide suspension is spray-dried to obtain budesonide micropowder. Add the budesonide micropowder into the tank, cover the valve, grab the seal, and inject the propellant HFA134a to prepare a budesonide inhalation aerosol. Among them, the mass proportion of budesonide in the aerosol is 0.3%, and each press contains 200μg of budesonide.

[0071] Example 2

[0072] The only difference between this embodiment and embodiment 1 is that the number of cycles of high pressure homogenization of the budesonide suspension is 20 times.

[0073] Example 3

[0074] The only difference between this embodiment and embodiment 1 is that the number of cycles of high pressure homogenization of the budesonide suspension is 40 times.

[0075] Example 4

[0076] The difference between this embodiment and embodiment 1 is that the budesonide suspension is not subjected to high pressure homogenization; and the budesonide micropowder is obtained by spray drying.

[0077] Example 5

[0078] The difference between this embodiment and embodiment 1 is that: 100g purified water and 0.1g hydrogenated phospholipid are used in the preparation of hydrogenated phospholipid emulsion; high pressure homogenization is not performed on the budesonide suspension; and budesonide micropowder is obtained by spray drying. In the budesonide inhalation aerosol, the mass proportion of budesonide is 0.1%.

[0079] Example 6

[0080] The difference between this embodiment and embodiment 1 is that: 100g purified water and 0.2g hydrogenated phospholipid are used in the preparation of hydrogenated phospholipid emulsion; high pressure homogenization is not performed on the budesonide suspension; and budesonide micropowder is obtained by spray drying. In the budesonide inhalation aerosol, the mass proportion of budesonide is 0.16%.

[0081] Experiment 1

[0082] The samples used in this experiment are shown in Table 1 below.

[0083] Table 1 Samples

[0084] serial number sample (a) Budesonide API (b) Hydrogenated phospholipids (HSPC) (c) Calcium chloride anhydrous (d) Hydrogenated phospholipids-anhydrous calcium chloride micropowder (e) Budesonide micropowder prepared in Example 4 (f) Budesonide micropowder prepared in Example 2 (g) Budesonide micropowder prepared in Example 3 (h) Budesonide micropowder prepared in Example 1

[0085] Sample (a) and samples (e) to (h) use the same budesonide raw material.

[0086] Preparation of sample (d): A hydrogenated phospholipid emulsion was prepared in the same manner as in Example 1 and spray-dried to obtain sample (d).

[0087] Particle size distribution

[0088] Laser diffraction was used to detect the particle size distribution of budesonide API and each sample micropowder. R1 lens was used, the detection pressure was 2.0 bar, and the injection speed was 40 mm min. -1 The test results are as follows: Figure 1As shown in Table 2 below (the test results of budesonide micropowder prepared in Examples 5 and 6 are also listed in Table 2). It was found that the particle size of the budesonide micropowder particles of sample (e) obtained by directly spray drying the budesonide suspension without homogenization increased significantly relative to the particle size of the raw material drug, with X50 increasing from 1.53 μm to 2.21 μm and X90 increasing from 3.15 μm to 4.68 μm. This is mainly due to the increase in the overall particle size of the particles due to the coating of hydrogenated phospholipids. With the increase in the number of high-pressure homogenization times, the particle size of the obtained budesonide micropowder particles gradually decreased, and the X10, X50 and X90 of the budesonide micropowder particles of sample (h) homogenized 60 times were close to the particle size of the raw material drug.

[0089] Table 2

[0090]

[0091] Morphology

[0092] The morphology of the particles may directly affect the quality characteristics of the final aerosol, so the morphology of the micropowder particles was observed using a scanning electron microscope (SEM), and the morphology of each sample at different time points was imaged at a beam acceleration voltage of 1 kV. Figure 2 As shown, sample (a) budesonide raw material was irregular in shape, sample (e) budesonide micropowder particles obtained by direct spray drying of budesonide suspension without homogenization showed obvious particle aggregation, and budesonide micropowder particles obtained by high-pressure homogenization combined with spray drying, such as sample (f), sample (g), and sample (h), showed spherical agglomerates formed by multiple particles. The spherical agglomerates in the micropowder particles homogenized 60 times were smaller, and the individual particles forming the spherical agglomerates were also smaller.

[0093] Structural characterization

[0094] In order to study whether the substances in each micropowder particle after spray drying are simply physically mixed or have other interactions with each other, infrared spectroscopy (FT-IR) was used to detect the structure of each sample. The test method is: KBr tablets are used at 400-4000cm -1 Scan. Figure 3 As shown, samples (e), (f), (g), and (h) are at a wavelength of 3492 cm -1 、2956cm -1 、2933cm -1 、1723cm -1 、1667cm -1 、1098cm -1There are obvious characteristic peaks, which are consistent with the peak shape and peak position of the raw material drug, indicating that high-pressure homogenization combined with spray drying and phospholipid coating have not changed the structure of budesonide particles. In samples (d) and (e), (f), (g), and (h), anhydrous calcium chloride 1614 cm -1 The characteristic peaks of phospholipids disappear because the phosphate groups in phospholipids interact with calcium ions to form a complex.

[0095] Crystal form

[0096] The crystal properties of the samples were tested by powder X-ray diffraction (PXRD) to explore whether the crystal form of the API changed during high-pressure homogenization and spray drying. The Cu K target beam was scanned in the range of 3° to 50° at a scanning speed of 10 min. -1 The scanning step was 0.02°, the tube voltage was 40kV, and the tube current was 100mA to analyze the crystal changes. Figure 4 .

[0097] The four budesonide micropowder particles after spray drying, namely sample (e), sample (f), sample (g), and sample (h), showed obvious diffraction peaks at 2θ of 6.1°, 10.1°, 11.4°, 12.0°, 13.8°, 14.5°, 15.4°, 16.0°, 16.9°, 18.5°, 21.1°, 21.4°, 22.8°, and 23.2°, which were consistent with the peak positions of the budesonide raw material, showing high crystallinity, indicating that high pressure homogenization combined with spray drying and phospholipid coating did not change the crystal form of budesonide. Sample (d) showed diffraction peaks at 5.4° and 21.5°, which had little effect on the diffraction peaks of budesonide.

[0098] Phase transition temperature

[0099] Phospholipids exist in the product. Increasing the phase transition temperature of phospholipids can improve the stability of aerosols. The phase transition temperature is detected by differential scanning calorimetry (DSC). Parameters: The lower limit of temperature is 35°C, the upper limit of temperature is 270°C, and the temperature is 20°C·min -1 The temperature was raised from 30°C to 270°C at a rate of 1.04°C. Under nitrogen protection, about 10 mg of sample was placed in an aluminum pan. Figure 5The DSC curves of different micropowder particles are shown in Figure 2. The DSC curves of the four spray-dried budesonide micropowder particles, i.e., samples (e), (f), (g), and (h), and the DSC curve of the budesonide API, i.e., sample (a), all have only one endothermic peak. The endothermic peak temperature of the four spray-dried budesonide micropowder particles is relatively low, about 249°C, while that of the API (a) is about 260°C, which may be related to the reduction in particle size and the fluxing effect of HSPC on budesonide at high temperature. In sample (b), there is an obvious phospholipid endothermic phase transition peak at 125°C, while the phospholipid phase transition peak disappears in sample (d) and sample (e)-sample (h) obtained by spray drying after adding anhydrous calcium chloride, which is consistent with the characteristics shown by FT-IR. The anionic phosphate group in phospholipid combines with calcium ions, which can significantly increase the phase transition temperature of phospholipid in micropowder.

[0100] In vitro evaluation of aerosols

[0101] Suspension state

[0102] Suspension aerosols require a good suspension state to ensure good quality characteristics such as uniformity of delivered dose. Transparent PET bottles were used as tanks to prepare (a)-aerosols and (h)-aerosols.

[0103] (a)-Aerosol preparation method: Add budesonide API into a tank, cover the valve, seal it, and pour in propellant HFA134a to prepare budesonide inhalation aerosol. The mass ratio of budesonide API to propellant HFA134a is 1:304.

[0104] (h)-Aerosol: the budesonide inhalation aerosol prepared in Example 1.

[0105] After shaking the aerosol for 5 seconds, let it stand and observe the suspension state at 3 seconds, 10 seconds, 30 seconds, and 60 seconds and take photos. Figure 6 As shown, (a)-aerosol flocculated at 3 seconds, flocculation became more obvious at 10 seconds, and there was obvious sedimentation, and most of it had settled at 60 seconds; while (h)-aerosol could maintain a good suspension state from the beginning to 60 seconds, without flocculation and sedimentation.

[0106] Delivered dose uniformity

[0107] Detection Methods

[0108] The DUSA tube method was used to evaluate the uniformity of delivered dose, that is, to detect the difference between the delivered dose measured multiple times and the average value. Take a can of aerosol, shake it for 5 seconds, discard the first 5 presses, assemble the adapter and DUSA tube, and set the gas flow rate to 28.3L·min -1(±2%), insert the inhalation device into the adapter, let it stand for 3s and then spray (the same applies to spray after standing for 10s and 60s), evacuate for 5s, and remove the inhalation device. Wash the filter paper, adapter and the inside of the DUSA tube with methanol, combine the washing liquid and dilute it into a 50mL volumetric flask, shake well, filter through a 0.45μm PTFE membrane, and take the filtrate as the test solution for the uniformity of the delivered dose. Use HPLC to determine the delivered dose of the 1st, 2nd, 3rd, 50th, 51st, 52nd, 53rd, 98th, 99th, and 100th presses in sequence, for a total of 10 presses.

[0109] like Figure 7 As shown, the relative average percentages of the 10 presses of the drug before, during and after the (a)-aerosol sprayed after standing for 3 seconds were all within the specified values ​​of 75% to 125% in the Chinese Pharmacopoeia, but the relative average percentages of the multiple presses of the drug before, during and after the aerosol after standing for 10 seconds and 60 seconds were significantly higher than the specified values. The RSD values ​​(relative standard deviation) of the uniformity of the delivered dose of the aerosol after standing for 3 seconds, 10 seconds and 60 seconds were 14.4%, 35.1% and 46.4%, respectively, indicating poor uniformity of the delivered dose.

[0110] like Figure 8 As shown, the relative average percentages of the drugs in the front, middle and last 10 presses of the (h)-aerosol after standing for 3s, 10s and 60s are all within the specified value range, and the relative average percentage after standing for 3s is even within the range of 94% to 106%, and the RSD value is 3.4%, reflecting good delivery dose uniformity.

[0111] Aerodynamic particle size distribution

[0112] The particle size of the particles has an impact on FPF. The smaller the particle size, the higher the FPF value.

[0113] Test method: The APSD of inhaled aerosol determines the location of drug particle deposition in the respiratory tract and is the most important quality characteristic of inhaled aerosol. According to the four general rules of the 2020 edition of the Pharmacopoeia of the People's Republic of China <0951> For detection, the outlet of the Next Generation Impactor (NGI) was connected to a vacuum pump, and the gas flow rate was adjusted so that the gas flow rate at the inlet of the L-shaped connecting pipe was 30 L min -1(±2%). Turn on the vacuum pump, shake the inhalation device for 5s and then immediately press once; remove the inhalation device and shake for 5s, reinsert it into the nozzle adapter, and spray for the second time until 10 presses are completed. After the last press, remove the inhalation device and turn off the vacuum pump. Wash the recovery throat with methanol to a 100mL volumetric flask, wash the driver, adapter, 4th collection layer, 5th collection layer with methanol to the corresponding 50mL volumetric flask, wash and recover the 1st, 2nd, 3rd, 6th and moc collection layers to a 25mL volumetric flask, wash and recover the 7th collection layer to a 10mL volumetric flask, continue to dilute to the scale with methanol, shake well, and use it as the test solution. The moc collection layer is filtered through a 0.45μm PTFE membrane, and the filtrate is taken as the test solution. HPLC is used for content detection, and the drug deposition amount of each distribution layer is calculated by peak area according to the external standard method. The drug deposition amount of each level is input into the dedicated software to obtain relevant evaluation parameters, such as FPF, MMAD and GSD.

[0114] This experiment uses NGI (new generation pharmaceutical impactor) to compare APSD (aerodynamic particle size distribution) experimental data with (a)-aerosol and (h)-aerosol. As shown in Table 3, Fig. 9 As shown, both (a)-aerosol and (h)-aerosol obtained nearly consistent high FPF values, which were 51.91% and 48.39%, respectively; the MMAD value (mass median aerodynamic diameter) of (h)-aerosol was slightly larger than that of (a)-aerosol, and the GSD was nearly consistent.

[0115] Table 3 FPF, MMAD, GSD results of different aerosols (x±s, n=3)

[0116] Sample name FPF(%) MMAD(μm) GSD (a)-Aerosol 51.91±0.02 2.66±0.1 1.68±0.03 (h)-Aerosol 48.39±0.01 3.09±0.02 1.67±0.01

[0117] Using the same method to detect, the budesonide inhalation aerosols of Examples 2-3 all had a good suspension state.

[0118] Results

[0119] Depend on Figures 6 to 9 It can be shown that the advantages of the budesonide inhalation aerosol of the present invention are high FPF, standing for 60 seconds after shaking and spraying, good suspension state, and good delivery dose uniformity data.

[0120] Through the description of the above embodiments and specific experimental data, a budesonide inhalation aerosol with good delivery uniformity and high fine particle dose can be obtained. Visually observing the aerosol suspension state, it can be found that it is milky, evenly distributed, does not settle for a long time, and has good dispersion function.

[0121] Experiment 2

[0122] The budesonide raw material used in this experiment (batch number: BD190301): X10 = 0.49 μm, X50 = 1.66 μm, X90 = 4.75 μm.

[0123] Sample preparation

[0124] (1) Weigh 0.3 g of hydrogenated phospholipid and calcium chloride (the molar ratio of hydrogenated phospholipid to calcium chloride is 2:1), use 100 g of 80°C purified water as a medium to prepare a hydrogenated phospholipid emulsion, maintain a constant temperature of 80°C, and stir continuously for 10 minutes in a magnetic stirring mode until the hydrogenated phospholipid is completely emulsified to obtain a hydrogenated phospholipid emulsion I; weigh 1 g of budesonide API in the hydrogenated phospholipid emulsion I, and disperse at high speed for 10 minutes; spray dry the budesonide suspension to obtain budesonide micropowder I. Add the budesonide micropowder I into a tank, cover the valve, seal it, and inject the propellant HFA134a to prepare a budesonide inhalation aerosol I. In the aerosol, The mass proportion of budesonide is 0.3%.

[0125] (2) Weigh 0.3 g of hydrogenated phospholipids, use 100 g of 80°C purified water as a medium to prepare a hydrogenated phospholipid emulsion, maintain a constant temperature of 80°C, and stir continuously for 10 minutes in a magnetic stirring mode until the hydrogenated phospholipids are completely emulsified to obtain a hydrogenated phospholipid emulsion II; weigh 1 g of budesonide API in the hydrogenated phospholipid emulsion II, and disperse at high speed for 10 minutes; spray dry the budesonide suspension to obtain budesonide micropowder II. Add the budesonide micropowder II to the tank, cover the valve, seal it, and inject the propellant HFA134a to prepare a budesonide inhalation aerosol. Among them, the mass proportion of budesonide in the aerosol is 0.3%.

[0126] Particle size distribution

[0127] The particle size distribution of budesonide API and each sample micropowder was tested by the same method as in Experiment 1. The test results are shown in Table 4 below.

[0128] Table 4

[0129] X10(μm) X50(μm) X90(μm) VMD(μm) SPAN API 0.49 1.66 4.75 2.23 2.56 Budesonide Micro Powder I 0.72 3.11 6.87 3.54 1.98 Budesonide Micro Powder II 1.12 3.57 7.42 4.03 1.76

[0130] The results showed that compared with budesonide micropowder I with added calcium chloride, budesonide micropowder II without added calcium chloride had a larger particle size.

[0131] Stability of hydrogenated phospholipid emulsion

[0132] The comparison results of hydrogenated phospholipid emulsion are shown in Fig.10Compared with hydrogenated phospholipid emulsion I with added calcium chloride, hydrogenated phospholipid emulsion II without added calcium chloride will show obvious sedimentation within a few hours; hydrogenated phospholipid emulsion I with added calcium chloride can maintain a stable emulsion for several hours or even several days.

[0133] Aerosol suspension state

[0134] The results of the comparison of aerosol suspension state are shown in Fig.11 Aerosol II was shaken and then left to stand. After 3 seconds, obvious flocculation had occurred, which was more obvious after 10 seconds. After 1 minute, it had floated up and obvious suspension occurred. Aerosol I was shaken and then left to stand. It could maintain a good suspension state from the beginning to 1 minute.

[0135] Experiment 3

[0136] A suspension containing 50% (w / w) budesonide was prepared by high shear homogenization of a dispersion containing 1.785 g HSPC and calcium chloride (HSPC to calcium chloride molar ratio of 2:1) in 200 mL hot water (75°C) using a high shear mixer at 9000 rpm while slowly adding 28.3 g perfluorooctyl bromide. 1.785 g micronized BUD (1:1 mass ratio with HSPC) was added to the resulting crude emulsion and further homogenized 10 times using a high pressure homogenizer at a pressure of up to 1000 bar. The emulsion was spray dried using the following spray drying conditions: inlet temperature 95°C; outlet temperature 64°C; emulsion feed rate 2.4 ml / min; total drying nitrogen flow rate 667 L / min; pumping rate 35 m 2 / h. The particle size distribution of the obtained powder (Budesonide porous particles) was measured by laser diffraction, and 50% of the volume of the micropowder particles was less than 2.44 μm. The results are shown in Table 5 below.

[0137] Table 5

[0138] X10(μm) X50(μm) X90(μm) VMD(μm) SPAN 0.71 2.44 8.10 3.59 3.02

[0139] The budesonide inhalation aerosol is prepared as follows: the prepared budesonide porous particles are added into a can, a valve is covered, the can is sealed, and the propellant HFA134a is poured into the can to prepare the budesonide inhalation aerosol, wherein the mass ratio of budesonide to the propellant HFA134a is 1:304.

[0140] The aerodynamic particle size distribution results are shown in Table 6 below:

[0141] Table 6 FPF, MMAD, GSD results of aerosol (x±s, n=3)

[0142] FPF(%) MMAD(μm) GSD 31.95 3.85 1.99

[0143] The result shows that the FPF is 31.95%, and the FPF value obtained in Example 1 of the present invention is 48.39%. The FPF value is significantly improved, indicating that after omitting "perfluorooctyl bromide" and changing the process of the present invention, the lung deposition amount is higher.

[0144] Experiment 4: Delivery dose uniformity of aerosols with different budesonide / hydrogenated phospholipid (BUD / HSPC) mass ratios.

[0145] Experimental samples: budesonide powder (i.e., raw material, BUD) and (a)-aerosol prepared according to the method of Experiment 1; budesonide micropowder and budesonide inhalation aerosol prepared in Examples 4, 5, and 6.

[0146] The particle size distribution of budesonide powder and different budesonide micropowder particles is shown in Fig.12 Wherein, BUD is budesonide powder, (BUD:HSPC=10:3) is the budesonide aerosol of Example 4, (BUD:HSPC=10:1) is the budesonide aerosol of Example 5, and (BUD:HSPC=10:2) is the budesonide aerosol of Example 6.

[0147] Insert the inhaler into the adapter, let it sit for 3 seconds, then spray and test according to the delivery dose uniformity analysis conditions. Fig.13 As shown, BUD is (a)-aerosol, (BUD:HSPC=10:3) is the budesonide aerosol of Example 4, (BUD:HSPC=10:1) is the budesonide aerosol of Example 5, and (BUD:HSPC=10:2) is the budesonide aerosol of Example 6.

[0148] The aerosols with different BUD / HSPC mass ratios were sprayed after standing for 3 seconds. The relative average percentages of the first, middle and last 10 presses of the drug were all within the 75% to 125% specified in the Chinese Pharmacopoeia, reflecting the uniformity of the compliant delivery dose. The RSD values ​​of (a)-aerosol and budesonide inhalation aerosols of Examples 4, 5 and 6 were 35.3%, 5.6%, 12.7% and 8.9%, respectively. When the mass ratio of budesonide (BUD) to HSPC was 10:3 (Example 4), the RSD value was the smallest, indicating that the aerosol delivery dose uniformity under this mass ratio was the best.

[0149] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing a budesonide inhalation aerosol, characterized in that: The method comprises the following steps: weighing 0.3 g of hydrogenated phospholipid and calcium chloride, wherein the molar ratio of hydrogenated phospholipid to calcium chloride is 2:1, and using 100 g of 80℃ purified water is used as a medium to prepare a hydrogenated phospholipid emulsion, and the constant temperature of 80℃ is maintained, accompanied by a magnetic stirring mode, and the stirring is continued for 10 minutes, and the hydrogenated phospholipid is completely emulsified; 1g of budesonide powder is weighed into the hydrogenated phospholipid emulsion, and high-speed dispersion is performed for 10 minutes at a speed of 9000rpm, and a constant temperature of 80℃ is maintained during dispersion; after pretreatment, the budesonide suspension is subjected to high-pressure homogenization at a pressure of 30000psi and a cycle number of 60 times; the budesonide suspension is spray-dried to obtain budesonide micropowder; the budesonide micropowder is added to a tank body, the valve is covered, the tank body is sealed, and the propellant HFA134a is poured in to prepare a budesonide inhalation aerosol; wherein, the mass proportion of budesonide in the aerosol is 0.3%, and each press contains 200μg of budesonide.

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