Budesonide suspension for inhalation and preparation method thereof

Abstract

The invention belongs to the technical field of preparation of budesonide inhalation preparations, and particularly relates to budesonide suspension for inhalation and a preparation method of the budesonide suspension. Mixing and sterilizing the micronized budesonide and the dispersion liquid containing polysorbate 80 / soybean lecithin; preparing an auxiliary material solution containing sodium carboxymethyl cellulose, acetylcysteine ammonia and a citric acid buffer pair; performing pulse ultrasonic pretreatment in a low-temperature environment, and performing three-stage gradient microjet homogenization to obtain a suspension; the Span value of the obtained preparation is 1.10-1.30, the proportion of submicron particles is smaller than or equal to 3.4%, and the D50 amplification lt of a 3-month acceleration experiment is achieved; the sedimentation volume ratio is greater than or equal to 0.95, and the delta D50 after shaking is less than or equal to 1.78%. According to the process, particle aggregation is inhibited through a dual stabilization mechanism, particle size distribution is progressively homogenized and optimized, physical stability is enhanced through an auxiliary material network, and the process is particularly suitable for respiratory disease treatment of children and elderly patients.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of budesonide inhalation preparations, and particularly relates to an inhalation budesonide suspension and a preparation method thereof. Background Art

[0002] Budesonide is a glucocorticoid with high local anti-inflammatory effects, and is widely used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Budesonide has low solubility, is almost insoluble in water, freely soluble only in dichloromethane, and slightly soluble in ethanol. Currently, the marketed budesonide dosage forms mainly include inhalation aerosols, inhalation powder aerosols, and inhalation suspensions. Among them, the inhalation budesonide suspension is particularly suitable for children, the elderly, and other patients who cannot use inhalation aerosols and inhalation powder aerosols well because it does not require the patient to initiate the synchronous coordination of atomization and inhalation actions during use.

[0003] The quality of the budesonide inhalation suspension dosage form directly affects the efficacy of the drug and patient compliance. An ideal inhalation preparation needs to achieve efficient drug deposition and uniform distribution in the lungs, and at the same time have good physical stability and redispersibility to ensure the effectiveness and convenience of the drug in clinical use. As one of the key indicators, too large a particle size will cause drug deposition in the upper respiratory tract, while too small a particle size may cause Ostwald ripening, affecting drug stability. In terms of stability, the suspension needs to maintain the uniform dispersion of particles during storage and use, avoiding aggregation and sedimentation. Redispersibility requires that the suspension can quickly return to a uniform state after shaking to ensure the accuracy of each drug dosage.

[0004] Although the clinical demand and technical research of inhalation preparations are constantly advancing, there are still many bottlenecks in the preparation process of existing budesonide suspension preparations. For example, micronization and sterilization processes are both prone to cause particle aggregation, affecting particle size distribution and preparation performance. Although the homogenization process can improve the particle size distribution, it is difficult to achieve precise control with a single homogenization pressure, which is likely to cause the generation of submicron particles and accelerate the Ostwald ripening process. In addition, the surfactant-based stabilizer system has a reduced stability under high-temperature conditions and is difficult to completely inhibit particle aggregation. Summary of the Invention

[0005] Aiming at the deficiencies of the existing technology, the present invention provides an inhalation budesonide suspension and a preparation method thereof, aiming to provide a budesonide suspension that is easy to prepare industrially and use clinically, and solve the problems of uneven particle size distribution, insufficient physical stability and redispersibility of the existing budesonide suspension.

[0006] The first aspect of the present invention is to provide a preparation method of an inhalation budesonide suspension, comprising the following steps:

[0007] Step S1. Preparation and sterilization of raw drug solution: air flow pulverize the budesonide raw drug to D90 <3.5 μm and D50 <1.2 μm, mix with a dispersion containing polysorbate 80 and soybean lecithin, and then sterilize;

[0008] Step S2. Preparation and sterilization of auxiliary material solution: prepare an auxiliary material solution containing disodium edetate, sodium chloride, sodium carboxymethyl cellulose, acetylcysteine ​​and citric acid buffer, sterilize and filter, and precool for standby use;

[0009] Step S3. Low-temperature mixing and gradient homogenization: The sterilized raw material drug solution and the auxiliary material solution are mixed at low temperature, and after magnetic stirring and pulse ultrasonic treatment, a three-level gradient microfluidization homogenization process is used to treat the mixture until D50 is ≤1.3 μm.

[0010] As a further optimization scheme of the above-mentioned method for preparing budesonide suspension for inhalation, the process parameters of the air flow pulverization in step S1 are: feed pressure 120-160 kPa, pulverization pressure 80-100 kPa, feed speed 4.5-6.5 g / min, and the span value of the particles after pulverization is ≤2.3.

[0011] As a further optimization scheme of the above-mentioned method for preparing the budesonide suspension for inhalation, the preparation of the composite dispersion in step S1 includes: adding polysorbate 80 to a final concentration of 0.5%-1.0% w / v and soybean lecithin to a final concentration of 0.05%-0.4% w / v to purified water accounting for 15-20% of the volume of the final suspension, dissolving with magnetic stirring at 250-350 rpm for 15-30 minutes, then adding micronized budesonide at a budesonide: water mass ratio of 1:20-30, and pre-dispersing with a high shear emulsifier at 7000-10000 rpm for 8-15 minutes.

[0012] As a further optimization scheme of the above-mentioned method for preparing budesonide suspension for inhalation, the sterilization process of step S1 is programmed temperature-controlled moist heat sterilization: heating to 118-123°C at 1.5-2.5°C / min and maintaining for 8-15 minutes, then cooling to 55-65°C at 1.0-2.0°C / min. During the sterilization process, the pressure in the tank is ≤0.15MPa and the temperature fluctuation is ≤±1.5°C.

[0013] As a further optimized solution for the preparation method of the above-mentioned budesonide suspension for inhalation, the composition of the auxiliary material solution in step S2 includes: purified water accounting for 65-75% of the total liquid preparation volume, disodium edetate 0.005%-0.15% w / v, sodium chloride 0.4%-0.6% w / v, sodium carboxymethylcellulose 0.03%-0.15% w / v, acetylcysteine ammonia 0.015%-0.025% w / v, and a buffer pair composed of anhydrous citric acid 0.15% w / v and sodium citrate 0.35% w / v, adjusting the pH to the range of 4.8-5.2; the dissolution order of the auxiliary materials is: first dissolve disodium edetate and sodium chloride, then add sodium carboxymethylcellulose, and finally introduce the citric acid buffer pair to adjust the pH.

[0014] As a further optimized solution for the preparation method of the above-mentioned budesonide suspension for inhalation, the sterilizing filtration in step S2 adopts a series filtration of 0.22μm double-layer polyethersulfone filters, and the filtrate is stored in an 8-10°C stainless steel storage tank.

[0015] As a further optimized solution for the preparation method of the above-mentioned budesonide suspension for inhalation, the conditions for low-temperature mixing in step S3 are: cooling the raw material liquid medicine to 10-25°C, mixing it with the pre-cooled auxiliary material solution at 8-10°C, and using magnetic stirring at 400-600 rpm combined with 35-45 kHz pulsed ultrasonic treatment for 15-30 minutes; working for 3-8 seconds / interval for 5-15 seconds.

[0016] As a further optimized solution for the preparation method of the above-mentioned budesonide suspension for inhalation, the three-stage gradient microfluidization homogenization process in step S3 includes: the first stage at 700-900 bar for 2 cycles, the second stage at 1000-1400 bar for 2 cycles, and the third stage at 1500-1700 bar for 1 cycle; controlling the temperature ≤30°C during the homogenization process; monitoring the D50 value after gradient homogenization, if D50>1.3μm, repeat the three-stage gradient treatment until it meets the standard.

[0017] The second aspect of the present invention is to provide a budesonide suspension for inhalation, which is prepared by the above-mentioned preparation method. The Span value of the prepared budesonide suspension for inhalation is 1.10-1.30, and the proportion of submicron particles is ≤3.4%.

[0018] Beneficial effects

[0019] The present invention significantly improves the formulation performance of budesonide suspension through the synergistic effect of a composite stabilizer system, a gradient microfluidic homogenization process, and functional excipients. By adopting a dual stabilization mechanism of polysorbate 80 and soybean phospholipid, a complementary adsorption layer is formed during the high-temperature sterilization process, effectively inhibiting particle aggregation, and controlling the increase in D50 within 3.2%-4.1% in the accelerated stability experiment; the three-stage gradient microfluidic homogenization technology realizes narrow particle size distribution control (Span value 1.10-1.30) through progressive pressure regulation, while reducing the proportion of submicron particles to ≤3.4%, significantly delaying the Ostwald ripening process; combined with the three-dimensional network support of sodium carboxymethylcellulose and the potential regulation function of acetylcysteine ammonia, the sedimentation volume ratio of the suspension is ≥0.95, the redispersibility ΔD50≤1.78%, and the uniform dispersion state is restored within 1 minute after shaking. This process can maintain particle size stability (increase <5%) for 3 months under the accelerated conditions of 40°C / 75%RH, and has excellent physical stability and clinical usability. Detailed implementation mode

[0020] Step S1: Preparation and sterilization of the raw material liquid medicine

[0021] Micronization treatment: Use a jet mill to crush the budesonide raw material medicine until D90 is less than 3.5μm and D50 is less than 1.2μm. The equipment crushing parameters are a feed pressure of 120-160 kPa, a crushing pressure of 80-100 kPa, and a feed rate of 4.5-6.5 g / min. During the crushing process, the span value is monitored in real time by a laser particle size analyzer to ensure ≤2.3.

[0022] Preparation of the composite dispersion liquid: Add purified water (accounting for 15-20% of the final suspension volume) to a clean liquid preparation tank, and sequentially add polysorbate 80 (final concentration 0.5%-1.0% w / v) and soybean phospholipid (final concentration 0.05%-0.4% w / v), and dissolve with magnetic stirring (250-350 rpm) for 15-30 minutes to form a transparent solution. Slowly add the micronized budesonide powder, with a budesonide:water mass ratio of 1:20-30, and pre-disperse it with a high-shear emulsifier (7000-10000 rpm) for 8-15 minutes to avoid agglomeration.

[0023] Sterilization treatment: Transfer the prepared raw material liquid medicine to a sterilization tank, and use programmed temperature-controlled moist heat sterilization. Heat it to 118-123°C at a rate of 1.5-2.5°C / min, maintain it for 8-15 minutes, and then cool it to 55-65°C at a rate of 1.0-2.0°C / min. During the sterilization process, the pressure in the tank is monitored in real time to ensure ≤0.15 MPa, and the temperature fluctuation does not exceed ±1.5°C to avoid phospholipid degradation or particle aggregation caused by high temperature.

[0024] Step S2: Preparation and sterilization of the excipient solution

[0025] Auxiliary material dissolution: Add purified water (accounting for 65 - 75% of the total liquid preparation volume) into another liquid preparation tank, and sequentially dissolve disodium edetate (0.005% - 0.015% w / v), sodium chloride (0.4% - 0.6% w / v), sodium carboxymethylcellulose (0.03% - 0.15% w / v), and ammonium acetylcysteine (0.015% - 0.025% w / v). After stirring and dissolving, add citric acid buffer pair (anhydrous citric acid 0.15% w / v, sodium citrate 0.35% w / v), and adjust the pH to 4.8 - 5.2.

[0026] Sterilization filtration: Make up purified water to the total weight, and filter and sterilize through a 0.22μm double - layer polyethersulfone filter element in series. The filtrate is temporarily stored in a pre - cooled stainless - steel storage tank at 8 - 10°C for standby. The addition sequence of auxiliary materials is: first dissolve ionic auxiliary materials (disodium edetate, sodium chloride), then add high - molecular suspending agent (CMC - Na), and finally introduce pH regulator to avoid flocculation caused by too high local concentration.

[0027] Step S3: Low - temperature mixing and gradient homogenization

[0028] Mixing: Cool the sterilized raw material liquid medicine to 10 - 25°C and mix it with the pre - cooled auxiliary material solution. During the mixing process, use magnetic stirring (400 - 600 rpm) combined with pulsed ultrasonic treatment (35 - 45 kHz, working for 3 - 8 seconds / interval of 5 - 15 seconds) for 15 - 30 minutes.

[0029] Gradient homogenization: Then transfer the mixed liquid into a micro - jet homogenizer (Nano micro - jet homogenizer of Nozo Fluid Technology, equipped with a dynamic cooling jacket, temperature control ≤ 30°C), and perform three - stage pressure gradient treatment: the first stage is 700 - 900 bar for 2 cycles, the second stage is 1000 - 1400 bar for 2 cycles, and the third stage is 1500 - 1700 bar for 1 cycle. After the three - stage pressure gradient treatment, monitor the D50 value through a laser particle size analyzer (sampling frequency 1 time / minute). If the detected D50 exceeds > 1.3μm, perform the three - stage pressure gradient treatment again until the D50 meets the detection requirements.

[0030] The following further clarifies the present invention through specific embodiments. These embodiments are exemplary, aiming to illustrate the problem and explain the present invention, and are not a kind of limitation.

[0031] Example 1

[0032] Step S1:

[0033] Micronization treatment: Feed pressure 120 kPa, crushing pressure 80 kPa, feed rate 4.5 g / min. After crushing, D90 = 3.2μm, D50 = 1.1μm, span value 2.2.

[0034] Composite dispersion: Purified water 15% (v / v), final concentration of polysorbate 80 0.5% (w / v), soybean phospholipid 0.05% (w / v), dissolved by magnetic stirring at 250 rpm for 15 minutes. Budesonide: water = 1:20, pre-dispersed by high-shear emulsifier at 7000 rpm for 8 minutes.

[0035] Sterilization: Heating rate 1.5 °C / min to 118 °C and maintained for 8 minutes, cooling rate 1.0 °C / min to 55 °C, tank pressure ≤ 0.12 MPa.

[0036] Step S2:

[0037] Auxiliary material solution: Purified water 65% (v / v), disodium edetate 0.005% (w / v), sodium chloride 0.4% (w / v), CMC-Na 0.03% (w / v), acetylcysteine ammonia 0.015% (w / v). Temperature of filtrate storage tank 8 °C.

[0038] Step S3:

[0039] Mixing: The raw material liquid medicine is cooled to 10 °C, magnetic stirring at 400 rpm, ultrasonic treatment at 35 kHz (working for 3 seconds / interval of 5 seconds) for 15 minutes.

[0040] Homogenization: The first stage is 700 bar × 2 times, the second stage is 1000 bar × 2 times, and the third stage is 1500 bar × 1 time. D50 = 1.2 μm, meeting the requirements.

[0041] Example 2

[0042] Step S1:

[0043] Micronization treatment: Feed pressure 140 kPa, crushing pressure 90 kPa, feed rate 5.5 g / min, D90 = 3.0 μm, D50 = 1.0 μm, span value 2.0.

[0044] Composite dispersion: Purified water 17.5% (v / v), final concentration of polysorbate 80 0.75% (w / v), soybean phospholipid 0.2% (w / v), dissolved by magnetic stirring at 300 rpm for 22 minutes. Budesonide: water = 1:25, pre-dispersed by high-shear emulsifier at 8500 rpm for 11 minutes.

[0045] Sterilization: Heating rate 2.0 °C / min to 120 °C and maintained for 11 minutes, cooling rate 1.5 °C / min to 60 °C, tank pressure ≤ 0.13 MPa.

[0046] Step S2:

[0047] Adjuvant solution: Purified water 70% (v / v), disodium edetate 0.01% (w / v), sodium chloride 0.5% (w / v), CMC-Na 0.09% (w / v), acetylcysteine ammonia 0.02% (w / v). The temperature of the filtrate storage tank is 9°C.

[0048] Step S3:

[0049] Mixing: Cool the raw material liquid medicine to 17°C, stir magnetically at 500 rpm, and treat it with ultrasound at 40 kHz (working for 5 seconds / interval of 10 seconds) for 22 minutes.

[0050] Homogenization: The first stage is 800 bar × 2 times, the second stage is 1200 bar × 2 times, and the third stage is 1600 bar × 1 time. D50 = 1.1 μm.

[0051] Example 3

[0052] Step S1:

[0053] Micronization treatment: Feed pressure 160 kPa, crushing pressure 100 kPa, feed rate 6.5 g / min, D90 = 3.4 μm, D50 = 1.2 μm, span value 2.3.

[0054] Compound dispersion liquid: Purified water 20% (v / v), final concentration of polysorbate 80 1.0% (w / v), soybean phospholipid 0.4% (w / v), stir magnetically at 350 rpm for 30 minutes to dissolve. Budesonide: water = 1:30, pre-disperse with a high-shear emulsifier at 10000 rpm for 15 minutes.

[0055] Sterilization: Heating rate 2.5°C / min to 123°C and maintain for 15 minutes, cooling rate 2.0°C / min to 65°C, tank pressure ≤ 0.15 MPa.

[0056] Step S2:

[0057] Adjuvant solution: Purified water 75% (v / v), disodium edetate 0.015% (w / v), sodium chloride 0.6% (w / v), CMC-Na 0.15% (w / v), acetylcysteine ammonia 0.025% (w / v). The temperature of the filtrate storage tank is 10°C.

[0058] Step S3:

[0059] Mixing: Cool the raw material liquid medicine to 25°C, stir magnetically at 600 rpm, and treat it with ultrasound at 45 kHz (working for 8 seconds / interval of 15 seconds) for 30 minutes.

[0060] Homogenization: The first stage is 900 bar × 2 times, the second stage is 1400 bar × 2 times, and the third stage is 1700 bar × 1 time. D50 = 1.3 μm, and it needs to be repeatedly treated once to meet the standard.

[0061] Example 4

[0062] Step S1:

[0063] Micronization treatment: Feed pressure 130 kPa, crushing pressure 85 kPa, feed rate 5.0 g / min, D90 = 2.8 μm, D50 = 0.9 μm, span value 1.8.

[0064] Compound dispersion: Purified water 16% (v / v), final concentration of polysorbate 80 0.6% (w / v), soybean phospholipid 0.1% (w / v), dissolved by magnetic stirring at 280 rpm for 18 minutes. Budesonide: water = 1:22, pre-dispersed by high-shear emulsifier at 7500 rpm for 9 minutes.

[0065] Sterilization: Heating rate 1.8 °C / min to 119 °C and maintained for 9 minutes, cooling rate 1.2 °C / min to 58 °C, tank pressure ≤ 0.12 MPa.

[0066] Step S2:

[0067] Auxiliary material solution: Purified water 68% (v / v), disodium edetate 0.008% (w / v), sodium chloride 0.45% (w / v), CMC-Na 0.06% (w / v), acetylcysteine ammonia 0.018% (w / v). Temperature of filtrate storage tank 8.5 °C.

[0068] Step S3:

[0069] Mixing: The raw material liquid medicine is cooled to 12 °C, magnetic stirring at 450 rpm, ultrasonic treatment at 38 kHz (working for 4 seconds / interval for 8 seconds) for 18 minutes.

[0070] Homogenization: The first stage is 750 bar × 2 times, the second stage is 1100 bar × 2 times, and the third stage is 1550 bar × 1 time. D50 = 1.25 μm.

[0071] Example 5

[0072] Step S1:

[0073] Micronization treatment: Feed pressure 150 kPa, crushing pressure 95 kPa, feed rate 6.0 g / min, D90 = 3.1 μm, D50 = 1.05 μm, span value 2.1.

[0074] Compound dispersion: Purified water 18% (v / v), final concentration of polysorbate 80 0.9% (w / v), soybean phospholipid 0.3% (w / v), dissolved by magnetic stirring at 320 rpm for 25 minutes. Budesonide: water = 1:28, pre-dispersed by high-shear emulsifier at 9500 rpm for 13 minutes.

[0075] Sterilization: The heating rate is 2.2 °C / min to 121 °C and maintained for 12 minutes, the cooling rate is 1.8 °C / min to 62 °C, and the tank pressure is ≤ 0.14 MPa.

[0076] Step S2:

[0077] Adjuvant solution: Purified water 72% (v / v), disodium edetate 0.012% (w / v), sodium chloride 0.55% (w / v), CMC-Na 0.12% (w / v), acetylcysteine ammonia 0.022% (w / v). The temperature of the filtrate storage tank is 9.5 °C.

[0078] Step S3:

[0079] Mixing: The raw material liquid medicine is cooled to 20 °C, magnetically stirred at 550 rpm, and ultrasonically treated at 42 kHz (working for 6 seconds / interval of 12 seconds) for 25 minutes.

[0080] Homogenization: The first stage is 850 bar × 2 times, the second stage is 1300 bar × 2 times, and the third stage is 1650 bar × 1 time. After secondary homogenization, it reaches 1.2 μm.

[0081] Comparative Example 1

[0082] Step S1:

[0083] Micronization treatment: The feeding pressure is 140 kPa, the crushing pressure is 90 kPa, the feeding speed is 5.5 g / min, D90 = 3.0 μm, D50 = 1.0 μm, and the span value is 2.0.

[0084] Composite dispersion liquid: Purified water 17.5% (v / v), the final concentration of polysorbate 80 is 0.75% (w / v), and it is magnetically stirred at 300 rpm for 22 minutes to dissolve. Budesonide: water = 1:25, and it is pre-dispersed at 8500 rpm by a high-shear emulsifier for 11 minutes.

[0085] Sterilization: The heating rate is 2.0 °C / min to 120 °C and maintained for 11 minutes, the cooling rate is 1.5 °C / min to 60 °C, and the tank pressure is ≤ 0.13 MPa.

[0086] Step S2:

[0087] Adjuvant solution: Purified water 70% (v / v), disodium edetate 0.01% (w / v), sodium chloride 0.5% (w / v), CMC-Na 0.09% (w / v), acetylcysteine ammonia 0.02% (w / v). The temperature of the filtrate storage tank is 9 °C.

[0088] Step S3:

[0089] Mixing: Cool the raw material liquid medicine to 17°C, stir magnetically at 500 rpm, and treat it with ultrasound at 40 kHz (working for 5 seconds / interval of 10 seconds) for 22 minutes.

[0090] Homogenization: The first stage is 800 bar × 2 times, the second stage is 1200 bar × 2 times, and the third stage is 1600 bar × 1 time. After an additional three homogenizations, the D50 only drops to 1.5 μm.

[0091] The main difference between this comparative example and Example 2 lies in changing the stabilization system. The composite system with a final concentration of 0.5% (w / v) of polysorbate 80 and 0.05% (w / v) of soybean phospholipid is adjusted to use only polysorbate 80.

[0092] Comparative Example 2

[0093] Step S1:

[0094] Micronization treatment: Feed pressure is 140 kPa, crushing pressure is 90 kPa, feed rate is 5.5 g / min, D90 = 3.0 μm, D50 = 1.0 μm, and span value is 2.0.

[0095] Composite dispersion: 17.5% (v / v) of purified water, 0.05% (w / v) of soybean phospholipid, stir magnetically at 300 rpm for 22 minutes to dissolve. Budesonide: water = 1:25, pre-disperse with a high-shear emulsifier at 8500 rpm for 11 minutes.

[0096] Sterilization: Heating rate is 2.0°C / min to 120°C and maintain for 11 minutes, cooling rate is 1.5°C / min to 60°C, tank pressure ≤ 0.13 MPa.

[0097] Step S2:

[0098] Auxiliary material solution: 70% (v / v) of purified water, 0.01% (w / v) of disodium edetate, 0.5% (w / v) of sodium chloride, 0.09% (w / v) of CMC-Na, 0.02% (w / v) of acetylcysteine ammonia. The temperature of the filtrate storage tank is 9°C.

[0099] Step S3:

[0100] Mixing: Cool the raw material liquid medicine to 17°C, stir magnetically at 500 rpm, and treat it with ultrasound at 40 kHz (working for 5 seconds / interval of 10 seconds) for 22 minutes.

[0101] Homogenization: The first stage is 800 bar × 2 times, the second stage is 1200 bar × 2 times, and the third stage is 1600 bar × 1 time. After an additional three homogenizations, the D50 only drops to 1.8 μm.

[0102] The main difference between this comparative example and Example 2 lies in changing the stabilization system. The composite system with a final concentration of 0.5% (w / v) of polysorbate 80 and 0.05% (w / v) of soybean phospholipid was adjusted to use only 0.05% (w / v) of soybean phospholipid.

[0103] Comparative Example 3

[0104] Step S1:

[0105] Micronization treatment: Feed pressure 140 kPa, crushing pressure 90 kPa, feed rate 5.5 g / min, D90 = 3.0 μm, D50 = 1.0 μm, span value 2.0.

[0106] Composite dispersion: Purified water 17.5% (v / v), final concentration of polysorbate 80 0.75% (w / v), soybean phospholipid 0.2% (w / v), dissolved by magnetic stirring at 300 rpm for 22 minutes. Budesonide: water = 1:25, pre-dispersed by high-shear emulsifier at 8500 rpm for 11 minutes.

[0107] Sterilization: Heating rate 2.0 °C / min to 120 °C and maintained for 11 minutes, cooling rate 1.5 °C / min to 60 °C, tank pressure ≤ 0.13 MPa.

[0108] Step S2:

[0109] Auxiliary material solution: Purified water 70% (v / v), disodium edetate 0.01% (w / v), sodium chloride 0.5% (w / v), CMC-Na 0.09% (w / v), acetylcysteine ammonia 0.02% (w / v). Temperature of the filtrate storage tank 9 °C.

[0110] Step S3:

[0111] Mixing: The raw material liquid medicine was cooled to 17 °C, magnetic stirring at 500 rpm, ultrasonic treatment at 40 kHz (working for 5 seconds / interval of 10 seconds) for 22 minutes.

[0112] Homogenization: 1200 bar × 5 times. D50 = 1.6 μm.

[0113] The main difference between this comparative example and Example 2 lies in changing the homogenization process. The homogenization process was changed to single-stage high-pressure homogenization: only the second stage was used for 1200 bar circulation 5 times (the total treatment pressure and time are similar to those in Example 2).

[0114] Comparative Example 4

[0115] Step S1:

[0116] Micronization treatment: Feed pressure 140 kPa, crushing pressure 90 kPa, feed rate 5.5 g / min, D90 = 3.0 μm, D50 = 1.0 μm, span value 2.0.

[0117] Composite dispersion: Purified water 17.5% (v / v), final concentration of polysorbate 80 0.75% (w / v), soybean phospholipid 0.2% (w / v), dissolved by magnetic stirring at 300 rpm for 22 minutes. Budesonide: water = 1:25, pre-dispersed by high-shear emulsifier at 8500 rpm for 11 minutes.

[0118] Sterilization: Heating rate 2.0 °C / min to 120 °C and maintained for 11 minutes, cooling rate 1.5 °C / min to 60 °C, tank pressure ≤ 0.13 MPa.

[0119] Step S2:

[0120] Excipient solution: Purified water 70% (v / v), disodium edetate 0.01% (w / v), sodium chloride 0.5% (w / v), CMC-Na 0.09% (w / v), acetylcysteine ammonia 0.02% (w / v). Temperature of filtrate storage tank 9 °C.

[0121] Step S3:

[0122] Mixing: The raw material liquid medicine is cooled to 17 °C, magnetic stirring at 500 rpm, and treated by ultrasound at 40 kHz (working for 5 seconds / interval of 10 seconds) for 22 minutes.

[0123] Homogenization: 1600 bar × 5 times. D50 = 1.5 μm.

[0124] The main difference between this comparative example and Example 2 lies in changing the homogenization process. The homogenization process is changed to single-stage high-pressure homogenization: only the third stage of 1600 bar is circulated 5 times.

[0125] Comparative Example 5

[0126] Step S1:

[0127] Micronization treatment: Feed pressure 140 kPa, crushing pressure 90 kPa, feed rate 5.5 g / min, D90 = 3.0 μm, D50 = 1.0 μm, span value 2.0.

[0128] Composite dispersion: Purified water 17.5% (v / v), final concentration of polysorbate 80 0.75% (w / v), soybean phospholipid 0.2% (w / v), dissolved by magnetic stirring at 300 rpm for 22 minutes. Budesonide: water = 1:25, pre-dispersed by high-shear emulsifier at 8500 rpm for 11 minutes.

[0129] Sterilization: The heating rate is 2.0 °C / min to 120 °C and maintained for 11 minutes, the cooling rate is 1.5 °C / min to 60 °C, and the tank pressure ≤ 0.13 MPa.

[0130] Step S2:

[0131] Auxiliary material solution: Purified water 70% (v / v), disodium edetate 0.01% (w / v), sodium chloride 0.5% (w / v); CMC-Na and acetylcysteine ammonia are cancelled, and then additional sodium chloride is added to 0.8% w / v to maintain the osmotic pressure; the temperature of the filtrate storage tank is 9 °C.

[0132] Step S3:

[0133] Mixing: The raw material liquid medicine is cooled to 17 °C, magnetically stirred at 500 rpm, and treated with ultrasound at 40 kHz (working for 5 seconds / interval of 10 seconds) for 22 minutes.

[0134] Homogenization: The first stage is 800 bar × 2 times, the second stage is 1200 bar × 2 times, and the third stage is 1600 bar × 1 time. D50 = 1.1 μm.

[0135] The main difference between this comparative example and Example 2 is that the combination of functional excipients is changed, CMC-Na and acetylcysteine ammonia in the functional excipients are cancelled, and the osmotic pressure is maintained at a similar level by adding additional sodium chloride.

[0136] Experimental Example 1: Particle size and distribution determination

[0137] After thoroughly shaking three batches of samples, they are detected using a wet laser diffraction particle size analyzer (Malvern Mastersizer3000). The samples are diluted with purified water to a light obscuration of 10% - 15%, the circulating pump speed is set at 2000 rpm, and the ultrasonic dispersion module (power 50 W, acting for 60 seconds) is turned on to eliminate bubbles and then measured continuously three times. Record the D10, D50, D90 values and calculate the Span value (Span = (D90 - D10) / D50). Further, using a nanoparticle tracking analyzer (NanoSight NS300), the samples are diluted to a concentration range of 10^6 - 10^8 particles / mL, and the proportion of submicron particles is analyzed at 25 °C under the conditions of a camera exposure time of 20 ms and a detection duration of 60 seconds.

[0138] Experimental Example 2: Redispersibility test

[0139] Simulate the clinical use scenario. Take the suspension sample and place it in a 25 mL transparent glass bottle. Use a vertical oscillator (amplitude 3 cm, frequency 120 times per minute) for 5 complete oscillation cycles. Immediately take a sample after the oscillation ends, measure the D50 value according to the method in Experimental Example 1, and calculate the change rate compared with the data before oscillation (ΔD50 = |D50 after oscillation - D50 before oscillation| / D50 before oscillation × 100%). Each group of samples is measured in parallel three times, and the arithmetic mean of the change rate is taken as the final result.

[0140] Experimental Example 3: Accelerated stability investigation

[0141] Place the filled and sealed samples in a constant temperature and humidity chamber (40°C ± 2°C, relative humidity 75% ± 5% RH) for storage. Take samples at the 0th, 1st, 2nd, and 3rd months respectively. Detect the particle size growth according to the method in Experimental Example 1, and calculate the growth amplitude of D50. Synchronously conduct the determination of the sedimentation volume ratio: Take 10 mL of the sample and inject it into a graduated centrifuge tube. After centrifuging at 3000 rpm for 10 minutes, read the volume of the sedimentation layer and calculate the sedimentation volume ratio. The sedimentation volume ratio = volume of the sedimentation layer / initial volume (the qualified standard is that the sedimentation volume ratio ≥ 0.95). After sedimentation, shake it again, and observe and record the state of the dispersion liquid. All detections are completed in an environment of 25°C.

[0142] Table 1 Quality inspection results of the examples and comparative examples

[0143]

[0144]

[0145] It can be seen from the data in Table 1 that the example group is significantly superior to all comparative examples in key indicators such as the Span value (1.10 - 1.30), redispersibility ΔD50 (1.65% - 1.78%), and D50 increase amplitude at 3 months (3.2% - 4.1%). The formation mechanism of the synergistic optimization effect of the present invention in three dimensions of particle size control, stability, and sedimentation redispersibility mainly includes the following three aspects:

[0146] The first aspect is the dual stabilization mechanism of the composite stabilization system. The D50 increase amplitudes of Comparative Example 1 (using only polysorbate 80) and Comparative Example 2 (using only soybean phospholipid) reached 8.7% and 11.2% respectively, which were significantly higher than 3.2% - 4.1% of the example group. Polysorbate 80 forms steric hindrance by adsorbing on the particle surface, while the phosphate group of soybean phospholipid can provide electrostatic repulsion. The complementary effect of the two is particularly crucial at the high temperature stage of sterilization - the particle aggregation rate after sterilization of Comparative Example 1 was significantly higher than that of Example 2, indicating that the thermal stability of soybean phospholipid can compensate for the dissociation tendency of the adsorption layer of polysorbate 80 at high temperature. This dual stabilization mechanism shows a lower proportion of submicron particles in the accelerated stability experiment, effectively inhibiting the Ostwald ripening phenomenon.

[0147] The second aspect is the progressive energy regulation of gradient microfluidization homogenization. The Span values ​​of Comparative Example 3 (single-stage 1200bar) and Comparative Example 4 (single-stage 1600bar) reached 1.60 and 1.50, respectively, which are significantly higher than 1.10 of Example 2. The gradient homogenization process achieves precise control of particle size distribution by gradually increasing the shear energy: the first stage 700-900bar breaks the primary agglomerates, the second stage 1000-1400bar refines the main particle size, and the third stage 1500-1700bar further eliminates submicron crystallites. Although the single-stage high-pressure treatment obtains a large total energy input, the excessive initial shear force will cause uneven particle breakage and produce a large number of submicron fragments. These fragments accelerate Ostwald ripening through Brownian motion, ultimately resulting in a 3-month D50 increase of 7.9%.

[0148] The third aspect is the three-dimensional network construction of functional excipients. The redispersibility ΔD50 of Comparative Example 5 (CMC-Na and acetylcysteine ​​amine are eliminated) reaches 5.82%, which is 3.5 times that of Example 2, revealing the synergistic mechanism of functional excipients: CMC-Na delays sedimentation by forming a three-dimensional network structure, while the thiol group of acetylcysteine ​​amine can modify the zeta potential of the particle surface. This "spatial barrier-electrostatic stabilization" synergistic effect is significantly reflected in the sedimentation experiment-the sedimentation volume ratio of the embodiment group is ≥0.95, while Comparative Example 5 can only maintain a uniform state for <5 minutes. In addition, the D50 increase (9.3%) of Comparative Example 5 is significantly higher than that of Example 2 (3.2%), indicating that simple osmotic pressure regulation cannot replace the inhibitory effect of the polymer network on particle movement.

[0149] In summary, the above three elements of the present invention interact and support each other, wherein the composite stabilization system ensures the dispersion integrity of the primary particles, providing an ideal raw material basis for gradient homogenization; the narrow distribution particles produced by gradient homogenization reduce the polydispersity index of the system, allowing the functional excipients to build a more uniform three-dimensional network; and this network in turn protects the integrity of the adsorption layer of the composite stabilization system by inhibiting particle migration. Through the adsorption synergy of a specific composite stabilization system, the energy optimization of gradient homogenization, and the three-dimensional stability of functional excipients, the "particle size-stability-redispersibility" triangle problem in the development of suspensions is solved. This process can maintain a D50 increase of less than 5% and a redispersibility change rate of less than 2% under accelerated stability conditions, and the Span value is stabilized in the range of 1.10-1.30, which has good prospects for industrial production.

[0150] The above embodiments are exemplary, and their purpose is to illustrate the technical concept and features of the present invention so that people familiar with the technology in this field can understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of budesonide suspension for inhalation, characterized in that, The following steps are involved: Step S1. Preparation and sterilization of the raw drug solution: air flow pulverize the budesonide raw drug to D90 <3.5 μm, D50 <1.2 μm, mix with a dispersion containing polysorbate 80 and soybean lecithin, and then sterilize; Step S2. Preparation and sterilization of auxiliary material solution: prepare an auxiliary material solution containing disodium edetate, sodium chloride, sodium carboxymethyl cellulose, acetylcysteine ​​ammonia and citric acid buffer, sterilize and filter, and precool for standby use; Step S3. Low-temperature mixing and gradient homogenization: The sterilized API solution and the auxiliary material solution are mixed at low temperature, and after magnetic stirring and pulse ultrasonic treatment, a three-stage gradient microfluidization homogenization process is used to treat the mixture until D50 is ≤1.3 μm.

2. The preparation method of the budesonide suspension for inhalation according to claim 1, wherein, The process parameters of the air flow pulverization in step S1 are: feed pressure 120-160 kPa, pulverization pressure 80-100 kPa, feed speed 4.5-6.5 g / min, and particle span value after pulverization ≤2.

3.

3. The preparation method of the budesonide suspension for inhalation according to claim 1, wherein, The preparation of the composite dispersion in step S1 includes: adding polysorbate 80 to a final concentration of 0.5%-1.0% w / v and soybean lecithin to a final concentration of 0.05%-0.4% w / v to purified water accounting for 15-20% of the volume of the final suspension, dissolving with magnetic stirring at 250-350 rpm for 15-30 minutes, then adding micronized budesonide at a budesonide: water mass ratio of 1:20-30, and pre-dispersing with a high shear emulsifier at 7000-10000 rpm for 8-15 minutes.

4. The preparation method of the budesonide suspension for inhalation according to claim 1, wherein, The sterilization process of step S1 is programmed temperature-controlled moist heat sterilization: heating to 118-123°C at 1.5-2.5°C / min and maintaining for 8-15 minutes, then cooling to 55-65°C at 1.0-2.0°C / min. During the sterilization process, the pressure in the tank is ≤0.15 MPa and the temperature fluctuation is ≤±1.5°C.

5. The preparation method of the budesonide suspension for inhalation according to claim 1, wherein, The composition of the auxiliary material solution in step S2 includes: purified water accounting for 65-75% of the total liquid volume, 0.005%-0.015% w / v of disodium edetate, 0.4%-0.6% w / v of sodium chloride, 0.03%-0.15% w / v of sodium carboxymethyl cellulose, 0.015%-0.025% w / v of acetylcysteine, and a buffer pair consisting of 0.15% w / v of anhydrous citric acid and 0.35% w / v of sodium citrate, and the pH is adjusted to within the range of 4.8-5.2; the order of dissolving the auxiliary materials is: first dissolving disodium edetate and sodium chloride, then adding sodium carboxymethyl cellulose, and finally introducing the citric acid buffer pair to adjust the pH.

6. The preparation method of the budesonide suspension for inhalation according to claim 1, characterized in that, The sterilization filtration in step S2 uses a 0.22 μm double-layer polyethersulfone filter element in series, and the filtrate is stored in a stainless steel storage tank at 8-10°C.

7. The preparation method of the budesonide suspension for inhalation according to claim 1, characterized in that, The low-temperature mixing conditions in step S3 are: the raw material solution is cooled to 10-25°C, mixed with the auxiliary material solution pre-cooled at 8-10°C, and treated with magnetic stirring at 400-600 rpm combined with 35-45 kHz pulse ultrasound for 15-30 minutes; working for 3-8 seconds / interval of 5-15 seconds.

8. The preparation method of the budesonide suspension for inhalation according to claim 1, wherein, The three-stage gradient micro-jet homogenization process in step S3 includes: the first stage is 700-900 bar for 2 cycles, the second stage is 1000-1400 bar for 2 cycles, and the third stage is 1500-1700 bar for 1 cycle; during the homogenization process, the temperature is controlled ≤ 30°C; after gradient homogenization, the D50 value is monitored. If D50 > 1.3 μm, the three-stage gradient treatment is repeated until it meets the standard.

9. A budesonide suspension for inhalation, characterized in that, It is prepared by using the preparation method described in any one of claims 1-8.

10. The budesonide suspension for inhalation according to claim 9, wherein The Span value of the suspension is 1.10-1.30, and the proportion of submicron particles is ≤ 3.4%.

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