Preparation method of inhalation budesonide superfine crystal with adjustable particle size

Abstract

The application discloses a preparation method of inhalation budesonide superfine crystal with adjustable particle size; the preparation method comprises the following steps: (1) dispersing and dropping budesonide solution A into a deep cold environment with a temperature of-100 to-200 DEG C, and rapidly solidifying the liquid drops into spherical composite particles; (2) under the action of stirring, adding the solidified spherical composite particles in the step (1) into an aqueous solution containing an emulsifier with a temperature of-5 DEG C to 15 DEG C, and obtaining budesonide superfine crystal. The particle size of the budesonide superfine crystal can be effectively adjusted by changing the concentration of the solution A; the obtained superfine crystal product is an ellipsoid with uniform particle size, a roundness value of 0.6 to 1.0, a CV value of 20% to 30%, an average particle size range of 1 to 10 microns, and a unique crystal form; the product is suitable for being developed into an inhalation administration dosage form, especially a dry powder inhalation agent; the process is stable, does not need a post-granulation process such as airflow crushing, is energy-saving and environment-friendly, and can realize large-scale preparation and production.

Description

Technical Field

[0001] This invention relates to the field of drug microparticles, specifically to a method for preparing inhaled budesonide ultrafine crystals with adjustable particle size. Technical Background

[0002] According to data from the "my country Chronic Disease Report 2021" released by the Chinese Center for Disease Control and Prevention, the prevalence of chronic obstructive pulmonary disease (COPD) in my country is 13.9%. Respiratory diseases are a leading cause of death and disability, with COPD being the third leading cause of death and disability. Asthma is a chronic inflammatory disease of the airways involving multiple inflammatory cells. Anti-inflammatory treatment is key to asthma maintenance therapy, and glucocorticoids are one of the first-line drugs for long-term maintenance therapy of asthma.

[0003] Budesonide, molecular formula C 25 H 34 O6, with a molecular weight of 430.534 and CAS NO: 51333-22-3, is a glucocorticoid with highly effective local anti-inflammatory effects. Compared with other glucocorticoids, its systemic side effects, such as weight loss and atrophy of lymphoid tissue and adrenal cortex, are relatively weaker. It is widely used in the treatment of asthma and COPD and is currently the first-line drug for these conditions. In addition, budesonide is also the first-line drug for treating moderate to severe segmental enteritis, ulcerative colitis, and other locally inflammatory bowel diseases. CN 115721734 A proposes a method for preparing a budesonide-loaded solid lipid nanoparticle complex, which can reduce the release of budesonide in the upper gastrointestinal tract and rapidly release it in the colonic environment, increasing the amount of budesonide at the site of colonic inflammation, thereby improving the oral bioavailability of budesonide.

[0004] For treating lung diseases such as asthma or chronic obstructive pulmonary disease, inhalation delivery allows for direct delivery of the active pharmaceutical ingredient to the bronchi and lungs compared to oral administration. This avoids degradation of the active drug by the gastrointestinal environment and the first-pass effect in the liver, significantly reducing the oral dosage and systemic side effects. Furthermore, the large surface area of ​​the lung absorption membrane (~100m²) further enhances the therapeutic benefits. 2It is thin (0.1–0.2 μm) and has a fast blood flow rate (5 L / min), thus providing rapid onset of action for pulmonary inhalation. Currently, commercially available budesonide inhalation delivery formulations include nebulized suspensions, inhaled powders, and inhaled suspensions. However, the developed formulations are limited in their application for pulmonary delivery due to low efficiency, environmental unfriendliness, or difficulty in maintaining the stability of the suspension over a long period. Dry powder inhalers are considered the most promising formulations for inhalation therapy. Dry powder inhalers offer advantages such as portability, ease of use, rapid product development, low equipment costs, and improved drug stability (the drug exists in a solid, dry state).

[0005] The deposition (action) site of inhaled drugs largely depends on the particle size. When the particle size is >10 μm, almost all particles settle in the oropharynx; when the particle size is 5–10 μm, the particles mainly settle in the upper respiratory tract; when the particle size is 0.5–5 μm, the particles mainly settle in the lower respiratory tract and lungs; while particles with a diameter <0.5 μm, after being inhaled into the lungs, remain suspended in the air, and most of the particles are exhaled. Dry powder inhalers require an active drug particle size of 1–5 μm. The particle morphology also affects the deposition efficiency of the inhaler in the lungs; some literature indicates that spherical particles have a better deposition effect than elongated particles. Furthermore, due to the small particle size of the active pharmaceutical ingredient, it has high surface activity and is prone to aggregation or adhesion to the surface of other substances, often resulting in poor dispersion and flow properties. Additionally, when the particle size is reduced to the micrometer level, the crystallinity of the product often decreases, or even transforms into an amorphous state, leading to reduced drug stability. Therefore, obtaining ultrafine crystals with a target particle size range, good particle sphericity, and stable crystal form is a key challenge in preparing budesonide into a dry powder inhaler.

[0006] Currently, high-pressure homogenization, spray drying, or air jet milling are commonly used to obtain budesonide powder with small particle sizes. CN105534925A proposes a method based on spray drying to modify the surface of dry powder inhaler carrier particles into a surface nanoscale rough structure to improve the dispersibility and deposition efficiency of dry powder inhalers, but it has not yet been confirmed whether the drug is a stable crystalline form. CN101961320A uses high-pressure homogenization technology to prepare sinetide nanocrystals, and then cold-cools the nano-suspension to prepare aerosol, oral, or injectable formulations, which are below the particle size requirements for dry powder inhalers. Dissolution crystallization is a commonly used method for preparing ultrafine crystals, but it is prone to producing local high supersaturation, resulting in an excessively wide particle size distribution. CN200610165255.9 uses dissolution crystallization to prepare budesonide ultrafine powder suitable for inhalation formulations, but the product morphology is slender and spindle-shaped with poor particle size uniformity.

[0007] Therefore, finding a method for preparing budesonide ultrafine crystals with adjustable particle size, good flowability, high sphericity, and particle size suitable for inhalation administration, and achieving industrial-scale production with low economic investment, remains an unsolved problem in the existing technology. Summary of the Invention

[0008] To overcome the shortcomings of existing methods for preparing inhaled budesonide products, this invention provides a method for preparing budesonide ultrafine crystals with adjustable particle size by utilizing the freeze-thaw principle. The resulting ultrafine crystal product consists of uniformly sized ellipsoids with a roundness between 0.6 and 1.0, a CV value between 20% and 30%, an average particle size range of 1 to 10 μm, and a unique crystal form. This method is suitable for developing inhaled drug delivery formulations, especially dry powder inhalers. The process is robust, eliminates the need for post-granulation processes such as airflow milling, is energy-saving and environmentally friendly, and is suitable for large-scale industrial production.

[0009] The technical solution of the present invention is as follows:

[0010] (1) Prepare budesonide solution A at room temperature, and then disperse solution A dropwise into a cryogenic environment of -100 to -200℃, such as -100℃, -120℃, -140℃, -160℃, -180℃ or -200℃. The droplets quickly solidify into spherical composite particles.

[0011] (2) Add the solidified spherical composite particles described in step (1) to an aqueous solution containing an emulsifier at a temperature of -5℃ to 15℃, for example, -5℃, -1℃, 3℃, 4℃, 8℃, 12℃ or 15℃, and stir for 0.5 to 5 hours, for example, 0.5, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours or 5 hours, to obtain budesonide ultrafine crystals.

[0012] In step (1), solvent A is selected from one or a combination of two of the following solvents: low-carbon hydroxyl alcohols such as methanol, ethanol, n-propanol, isopropanol, ethylene glycol, or propylene glycol; acetonitrile; carbon tetrachloride; methyl acetate; ethyl acetate; DMSO; N-methylpyrrolidone; N,N-dimethylformamide; 1,4-dioxane; acetone; formic acid; acetic acid; or diethylene glycol ethyl ether. The concentration of budesonide is 10–130 mg / mL, for example, 10 mg / mL, 30 mg / mL, 50 mg / mL, 70 mg / mL, 90 mg / mL, 110 mg / mL, or 130 mg / mL. When the concentration of budesonide is outside the range specified in this invention, a large number of fine particles and agglomerates will appear during the subsequent stirring process, resulting in a final product with an excessively wide particle size distribution and an excessively large average particle size, which cannot meet the particle size and shape requirements for inhalation administration.

[0013] In step (1), solution A is dispersed and dropped into a cryogenic environment. When the average volume of the droplets is controlled between 10 and 60 μL, for example, it can be 10 μL, 15 μL, 20 μL, 25 μL, 30 μL, 35 μL, 40 μL, 45 μL, 50 μL, 55 μL, or 60 μL. When the droplet volume of solution A is not within the range specified in this invention, the microcrystalline particle size distribution is wider, the average particle size is larger, and the crystal aggregation behavior is aggravated, which cannot meet the particle size and shape requirements for inhalation administration.

[0014] In step (2), the volume ratio of water to solution A in step (1) is (1-25):1, for example, it can be 1:1, 3:1, 5:1, 7:1, 9:1, 11:1, 13:1, 15:1, 17:1, 19:1, 21:1, 23:1, or 25:1. When the volume ratio of the antisolvent to solvent A in step (1) is not within the range specified in this invention, the budesonide crystal nuclei will agglomerate into large-particle-size aggregates with a wide particle size distribution due to Oswald ripening during subsequent stirring, which cannot meet the particle size and shape requirements for inhalation administration.

[0015] In step (2), the emulsifier is selected from one or more of the following: sodium octadecyl sulfate, sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, sodium cholate, sodium citrate, sodium alginate, sodium dodecyl cellulose sulfate, phospholipids, dipalmitoyl lecithin, soybean lecithin, hydrogenated soybean lecithin, tylosap, Tween 80, Span 20, poloxamer F68, and poloxamer F127, mixed in any proportion. When the type of emulsifier is not within the scope defined by this invention, the resulting product is an agglomerate with poor sphericity and uneven particle size distribution, which cannot meet the particle size requirements for inhalation administration.

[0016] In step (2), the mass ratio of emulsifier to water in the emulsifier aqueous solution is 0.05% to 0.5%, for example, it can be 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5%. When the amount of emulsifier added is not within the range specified in this invention, it will cause budesonide microcrystals dispersed in the mixed solution to agglomerate, and the product will be irregular nano- or micron-sized agglomerates with an excessively wide particle size distribution and an excessively large average particle size. This cannot meet the particle size requirements for inhalation administration.

[0017] In step (2), the stirring power per unit volume is maintained between 0.157 and 1.325 kW / m³. 3 Between, for example, could be 0.157 kW / m 3 0.314kW / m 3 0.471kW / m 3 0.628kW / m 3 0.785kW / m3 0.942kW / m 3 ,

[0018] 1.099kW / m 3 1.256kW / m 3 Or 1.325kW / m 3 When the stirring power per unit volume is not within the range defined by this invention, it will result in the average particle size of budesonide microcrystals dispersed in the mixed solution being too large and the particle size distribution being uneven.

[0019] In step (2), the particle size of the ultrafine budesonide crystals can be effectively adjusted by changing the concentration of solution A in step (1). To achieve rapid cooling and solidification of the droplets within seconds, the volume of the dispersed droplets in step (1) is relatively small, and the cryogenic temperature is sufficiently low. The quasi-spherical particles obtained by rapid cooling and solidification of the droplets are a composite of the solvent solid and the dispersed and uniformly sized nanoscale budesonide particles. During the suspension of the obtained quasi-spherical composite particles in an aqueous solution containing an emulsifier, the emulsifier combines the nanoscale budesonide particle group dispersed in the suspension through charge interaction. At the same time, the emulsifier accelerates the Oswald ripening process of the nanoscale particle group, ultimately forming micron-sized budesonide particles in a relatively short time.

[0020] Within a certain range, as the concentration of solution A increases, the budesonide microparticles in the composite particles formed by the rapid cooling and solidification of the droplets maintain their nanoscale size with no significant change in particle size. The number of nano-budesonide particles per unit volume of suspension increases, and the charge of the particle swarm increases. To achieve charge balance, the nano-sized budesonide particles dispersed in the suspension combine into larger particle swarms, which subsequently mature to form larger ultrafine crystals. Simultaneously, with increasing concentration, the time required for the Oswald maturation process of the suspension also increases accordingly. When the concentration of solution A continues to increase, the diameter of the budesonide microparticles in the near-spherical composite particles formed by rapid cooling and solidification increases, but the number of nano-budesonide particles per unit volume of suspension decreases, the charge of the particle swarm decreases accordingly, the amount of budesonide microparticles bound in the suspension decreases, and the size of the microcrystals formed during the subsequent maturation process decreases.

[0021] The preparation method further includes sequentially performing solid-liquid separation, washing, and drying on the substance obtained by stirring in step (2).

[0022] The solid-liquid separation method is centrifugal filtration.

[0023] The cleaning process involves rinsing with water 3-5 times.

[0024] The drying conditions are freeze-drying, with a freezing temperature of -85 to -105°C, for example, -85°C, -90°C, -95°C, -100°C, or -105°C, and a drying time of 12 to 48 hours, for example, 12 hours, 20 hours, 24 hours, 36 hours, 40 hours, or 48 hours. The budesonide ultrafine crystal product is a uniformly sized ellipsoid with a roundness value between 0.6 and 1, for example, products with roundness values ​​of 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0 can be obtained, and a CV value between 20% and 30%, for example, products with a CV value between 20% and 30%.

[0025] Products with 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% particle size ranging from 1 to 10 μm, such as 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm, have a unique crystal form and are suitable for development into inhaled drug delivery formulations, especially dry powder inhalers. The process is robust, requiring no post-granulation processes such as airflow milling, and is energy-saving and environmentally friendly, making it suitable for large-scale industrial production.

[0026] The above method has the following beneficial effects:

[0027] a) This method yields budesonide ultrafine crystals with a high sphericity ellipsoidal morphology, with a roundness value between 0.6 and 1.0. Compared with other morphologies (e.g., fibrous, flake, powder), this method greatly improves the product powder properties such as morphology and flowability, which is beneficial for its development into an inhalation formulation.

[0028] b) The crystal product obtained by this method is a thermodynamically stable crystal form, which ensures the thermodynamic stability of the product. The product particle size ranges from 1 to 10 μm, the CV value is between 20% and 30%, and it can realize the "customization" of ultrafine crystals in different particle size ranges. It has high bioavailability and is suitable for developing into an inhaled drug delivery formulation, especially suitable for developing into a dry powder inhaler.

[0029] c) This method has a simple preparation process, high preparation efficiency, robust process and easy control. It can produce budesonide ultrafine crystals with particle size, shape and diameter that meet the requirements for inhalation administration in one step. It does not require post-processing such as airflow pulverization, is energy-saving and environmentally friendly, and can realize large-scale preparation and production. Attached Figure Description

[0030] Figure 1 XRD powder diffraction pattern of budesonide ultrafine crystals prepared in the embodiments of the present invention;

[0031] Figure 2 SEM image of budesonide ultrafine crystals in Example 1 of this invention (scale bar is 20 μm);

[0032] Figure 3 SEM image of budesonide ultrafine crystals in Example 2 of this invention (scale bar is 20 μm);

[0033] Figure 4 SEM image of budesonide ultrafine crystals in Example 3 of this invention (scale bar is 20 μm);

[0034] Figure 5 SEM image of budesonide ultrafine crystals in Example 4 of this invention (scale bar is 20 μm);

[0035] Figure 6 : Roundness distribution diagrams of budesonide ultrafine crystals in Examples 1, 2, 3, and 4 of the present invention;

[0036] Figure 7 : Particle size distribution diagram of budesonide ultrafine crystals in Examples 1, 2, 3, and 4 of the present invention. Detailed Implementation

[0037] Example 1:

[0038] (1) Prepare a budesonide-diethylene glycol ethyl ether solution with a concentration of 10 mg / mL and a Tween 80 aqueous solution with a concentration of 0.05% (w / v), wherein the amount of water used is 1 times the amount of diethylene glycol ethyl ether (v / v); the budesonide-diethylene glycol ethyl ether solution is stored at room temperature, and the Tween 80 aqueous solution is maintained at -5℃;

[0039] (2) Budesonide-diethylene glycol ethyl ether solution was dispersed and dropped into a cryogenic environment at -100°C, and the droplets quickly solidified into spherical composite particles;

[0040] (3) Under stirring, the solidified spherical composite particles described in step (1) are added to a Tween 80 aqueous solution at -5℃, maintaining a stirring power of 1.325 kW / m³ per unit volume. 3 The stirring time was 0.5 h to obtain budesonide ultrafine crystals.

[0041] The product's XRD pattern (XRD model R-AXIS-RAPID, Rigaku, Japan) can be found here. Figure 1 In the 2θ range of 5–40°, the peak spectra of budesonide ultrafine crystals and raw materials are... Figure 1 The consistency indicates that both the product and the raw materials are in the Form I crystal form (stable crystal form), ensuring the product's stability; the scanning electron microscope image of the product is shown below. Figure 2 The budesonide ultrafine crystals are uniform ellipsoids; size analysis of the particle group based on ImageJ shows that the average roundness of the product is 0.889 (see...). Figure 6 The particle size ranges from 2 to 4 μm, with an average particle size of 2.662 μm (see...). Figure 7The CV value is 23.6%, and 100% of the product particles have a diameter of 1-5 μm, which meets the particle size requirements for inhalation administration.

[0042] Example 2:

[0043] (1) Prepare a budesonide-ethylene glycol solution with a concentration of 50 mg / mL and a poloxamer F127 aqueous solution with a concentration of 0.2% (w / v), wherein the amount of water used is 11 times (v / v) the amount of ethylene glycol used; the budesonide-ethylene glycol solution is stored at room temperature, and the poloxamer F127 aqueous solution is maintained at 0℃;

[0044] (2) Budesonide-ethylene glycol solution was dispersed and dropped into a cryogenic environment at -130°C, and the droplets quickly solidified into spherical composite particles;

[0045] (3) Under stirring, the solidified near-spherical composite particles described in step (1) are added to a 0°C poloxamer F127 aqueous solution, maintaining a stirring power of 0.936 kW / m³ per unit volume. 3 Stirring time was 2 hours to obtain budesonide ultrafine crystals.

[0046] XRD testing of the product confirmed that it is a stable crystalline product; the scanning electron microscope image of the product is shown below. Figure 3 The budesonide ultrafine crystals are uniform ellipsoids; Figure 6 The average roundness of the displayed products is 0.877; Figure 7 The product particle size range is 3–5 μm, with an average particle size of 3.691 μm and a CV value of 24.2%. 100% of the product particles fall within the 1–5 μm range, meeting the particle size requirements for inhalation administration.

[0047] Example 3:

[0048] (1) Prepare budesonide-N-methylpyrrolidone solutions with a concentration of 90 mg / mL and 0.35% respectively.

[0049] A (w / v) aqueous solution of soybean lecithin, wherein the amount of water is 18 times (v / v) of the amount of N-methylpyrrolidone; the budesonide-N-methylpyrrolidone solution is stored at room temperature, while the soybean lecithin aqueous solution is maintained at 8°C;

[0050] (2) Budesonide-N-methylpyrrolidone solution was dispersed and dropped into a cryogenic environment at -160°C, and the droplets quickly solidified into spherical composite particles;

[0051] (3) Under stirring, the solidified spherical composite particles described in step (1) are added to a soybean lecithin aqueous solution maintained at 8°C, with a stirring power of 0.546 kW / m³ per unit volume. 3The stirring time was 3.5 h to obtain budesonide ultrafine crystals.

[0052] XRD testing of the product confirmed that it is a stable crystalline product; the scanning electron microscope image of the product is shown below. Figure 4 The budesonide ultrafine crystals are uniform ellipsoids; Figure 6 The average roundness of the displayed products is 0.823; Figure 7 The product particle size range is 4.5–11.5 μm, with an average particle size of 7.87 μm and a CV value of 27.8%. 93% of the product particles have a particle size within 10 μm.

[0053] Example 4:

[0054] (1) Prepare a budesonide-acetone solution with a concentration of 130 mg / mL and a sodium dodecyl sulfate aqueous solution with a concentration of 0.5% (w / v), wherein the amount of water used is 25 times (v / v) the amount of acetone used; the budesonide-acetone solution is stored at room temperature, and the sodium dodecyl sulfate aqueous solution is maintained at 8℃.

[0055] (2) Budesonide-acetone solution was dispersed and dropped into a cryogenic environment at -200°C, and the droplets quickly solidified into spherical composite particles;

[0056] (3) Under stirring, the solidified spherical composite particles described in step (1) are added to a sodium dodecyl sulfate aqueous solution maintained at 15°C, with a stirring power of 0.157 kW / m³ per unit volume. 3 The stirring time was 5 hours to obtain budesonide ultrafine crystals.

[0057] XRD testing of the product confirmed that it is a stable crystalline product; the scanning electron microscope image of the product is shown below. Figure 5 The budesonide ultrafine crystals are uniform ellipsoids; Figure 6 The average roundness of the displayed products is 0.822. Figure 7 The product particle size range is 3.5–6.25 μm, with an average particle size of 4.801 μm and a CV value of 24.5%. 100% of the product particles have a particle size of 1–10 μm, and 82% of the product particles have a particle size of less than 5 μm, which meets the particle size requirements for inhalation administration.

[0058] Comparative Example 1:

[0059] The only difference from Example 1 is that the cryogenic environment temperature is -80°C.

[0060] Based on the PXRD pattern of the product, it was determined that the budesonide product exists in crystalline form with a thin, flaky crystal habit. The final product is an aggregate with a roundness of 0.535. The average particle size ranges from 10 to 100 μm, and the CV value is 40%. No ultrafine product with a particle size of less than 5 μm was obtained, so it cannot be directly used for inhalation administration. The test method is the same as in Example 1.

[0061] Comparative Example 2:

[0062] The only difference from Example 1 is that the concentration of budesonide in the solution is 150 mg / mL.

[0063] Based on the PXRD pattern of the product, it was determined that the budesonide product exists in crystalline form. The product is an irregular ellipsoid with a sphericity of 0.589. The average particle size ranges from 7 to 55 μm, and the CV value is 37%. No ultrafine product with a particle size of less than 5 μm was obtained, so it cannot be directly used for inhalation administration. The test method is the same as in Example 1.

[0064] Comparative Example 3:

[0065] The only difference from Example 1 is that the concentration of the Tween 80 aqueous solution in the solution is 0.65% (w / v).

[0066] Based on the PXRD pattern of the product, it was determined that the budesonide product exists in crystalline form. The product is an irregular ellipsoid with a sphericity of 0.603. The average particle size ranges from 3 to 37 μm, and the CV value is 35%. The ultrafine budesonide crystals with a particle size of less than 5 μm account for less than 10%, and cannot be directly used for inhalation administration. The test method is the same as in Example 1.

[0067] Comparative Example 4:

[0068] The only difference from Example 1 is that the amount of water used is 30 times (v / v) that of diethylene glycol ethyl ether.

[0069] Based on the PXRD pattern of the product, it was determined that the budesonide product exists in crystalline form. The product is an aggregate of irregular ellipsoids with a roundness of 0.488. The average particle size ranges from 1 to 88 μm, and the CV value is 42%. It has poor dispersibility, with less than 5% of the budesonide ultrafine crystals having a particle size of less than 5 μm. Therefore, it cannot be used directly for inhalation administration. The test method is the same as in Example 1.

[0070] A comparison of Example 1 and Comparative Example 1 shows that when the cryogenic environment temperature is outside the range defined by this invention, the crystal morphology of the product changes from regular ellipsoids to plate-like aggregates, resulting in a wider particle size distribution and a larger average particle size. This is because when the quenching temperature is too high, the driving force for budesonide crystal nucleus precipitation decreases during the solidification of the budesonide diethylene glycol ethyl ether solution into spherical composite particles, leading to a slower crystal nucleus precipitation rate. The crystal nuclei then rapidly grow to form large plate-like microcrystals. These microcrystals penetrate the solid solvent layer and interconnect, ultimately forming plate-like microcrystalline aggregates.

[0071] A comparison of Example 1 and Comparative Example 2 shows that when the solution concentration is outside the limits defined in this invention, the product exhibits micro-irregular ellipsoids, a wider particle size distribution, and a larger average particle size. This is because when the concentration of budesonide exceeds the critical concentration, as the concentration increases, the increased contact area between microcrystals during the cryogenic freezing and solidification process leads to the formation of aggregates of several microcrystals in the composite particles. Furthermore, the increased concentration leads to an overall increase in the size of the budesonide microcrystals, resulting in a wider particle size distribution and a larger average particle size during the subsequent Oswald curing process.

[0072] A comparison of Example 1 and Comparative Example 3 shows that when the emulsifier concentration is outside the limits defined in this invention, the product exhibits micro-irregular ellipsoids, a wider particle size distribution, and a larger average particle size. This is because when the emulsifier concentration exceeds the critical micelle concentration, budesonide microcrystals tend to aggregate during suspension, resulting in an increase in the average particle size and a wider particle size distribution of the final product.

[0073] The comparison between Example 1 and Comparative Example 4 shows that when the volume ratio of water to solvent A is not within the limits of this invention, the budesonide crystal nuclei agglomerate into larger aggregates with a wider particle size distribution due to Oswald ripening during the subsequent stirring process, which cannot meet the particle size and shape requirements for inhalation administration.

[0074] This invention discloses and proposes a method for preparing inhaled budesonide ultrafine crystals with adjustable particle size. Those skilled in the art can refer to the content of this article and appropriately change the budesonide solution concentration, cryogenic ambient temperature, ratio of solvent A to water, type of emulsifier, stirring power per unit volume, or type of solvent A to obtain budesonide ultrafine crystal products with more concentrated particle size distribution, smaller average particle size, and greater roundness. Furthermore, by controlling the key parameter of budesonide solution concentration, budesonide ultrafine crystals of different particle sizes suitable for inhalation administration can be obtained.

[0075] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A method for preparing inhaled budesonide ultrafine crystals with adjustable particle size, characterized in that, The preparation method includes the following steps: (1) Budesonide solution A was dispersed and dropped into a cryogenic environment of -100 to -200°C, and the droplets quickly solidified into spherical composite particles; (2) Under the action of stirring, the solidified spherical composite particles described in step (1) are added to an aqueous solution containing emulsifier at -5 to 15°C to obtain budesonide ultrafine crystals; In step (1), solution A has a solute of budinard and a solvent of any one or at least two of the following: low-carbon chain alcohol, acetonitrile, carbon tetrachloride, methyl acetate, ethyl acetate, DMSO, N-methylpyrrolidone, N,N-dimethylformamide, 1,4-dioxane, acetone, formic acid, acetic acid, or diethylene glycol ethyl ether. In step (1), the concentration of budesonide in solution A is 10 mg / mL to 130 mg / mL; In step (2), the emulsifier is selected from any one or a combination of at least two of the following: sodium octadecyl sulfate, sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, sodium cholate, sodium citrate, sodium alginate, sodium dodecyl cellulose sulfate, phospholipid, tyrosab, Tween 80, Span 20, poloxamer F68, and poloxamer F127. In step (2), the mass ratio of emulsifier to water in the emulsifier aqueous solution is 0.05% to 0.5%. In step (2), the volume ratio of the aqueous solution containing the emulsifier to the budesonide solution A is (1-25):

1. The average particle size of the inhaled budesonide ultrafine crystals is 1–10 μm; The low-carbon chain alcohols include any one or a combination of at least two of methanol, ethanol, n-propanol, isopropanol, ethylene glycol, or propylene glycol; In step (1), the average volume of the droplets of solution A is 10 μL to 60 μL.

2. The preparation method according to claim 1, characterized in that, The phospholipids include any one or a combination of at least two of dipalmitoyl lecithin, soy lecithin, and hydrogenated soy lecithin.

3. The preparation method according to claim 1, characterized in that, The stirring power in step (2) is 0.157~1.325kW / m 3 The stirring time is 0.5 to 5 hours.

4. The preparation method according to claim 1, characterized in that, The preparation method further includes sequentially performing solid-liquid separation, washing, and drying on the substance obtained by stirring in step (2).

5. The preparation method according to claim 4, characterized in that, The solid-liquid separation method is centrifugal filtration.

6. The preparation method according to claim 4, characterized in that, The cleaning process involves rinsing with water 3-5 times.

7. The preparation method according to claim 4, characterized in that, The drying conditions are freeze drying, with a freezing temperature of -85 to -105°C and a drying time of 12 to 48 hours.

8. The preparation method according to any one of claims 1-7 yields inhaled budesonide ultrafine crystals with adjustable particle size; The inhaled budesonide ultrafine crystals are uniformly sized ellipsoids with a roundness of 0.6 to 1.

0. The coefficient of variation (CV) of the particle size of the inhaled budesonide ultrafine crystals is 20% to 30%. The average particle size of the inhaled budesonide ultrafine crystals is 1–10 μm.

9. The application of the particle size-adjustable inhaled budesonide ultrafine crystals according to claim 8 in the preparation of anti-asthmatic drugs.

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