A budesonide suspension and its preparation method

Abstract

The present invention discloses a budesonide suspension and a preparation method thereof, comprising: dissolving a prescription amount of the surfactant polysorbate 80 in a part of purified water, then adding a prescription amount of micronized budesonide, stirring and dispersing to obtain a raw material liquid medicine, and then performing moist heat sterilization; sequentially adding other excipients in a prescription amount to purified water, dissolving and adding water to a preset weight value to obtain an excipient solution, and then performing sterile filtration; stirring and mixing the sterile filtered excipient solution with the raw material liquid medicine after moist heat sterilization to obtain a mixed solution; subjecting the mixed solution to high-speed shearing and high-pressure homogenization to obtain the budesonide suspension. The present invention simplifies the operation steps and reduces the risk of abnormal increase in particle size. The particle size of the budesonide suspension prepared by the present invention is basically the same as that of the original research preparation and the particle size distribution.

Description

Technical Field

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

[0002] Budesonide is a highly effective local anti-inflammatory glucocorticoid and one of the commonly used glucocorticoids in clinical practice, which can effectively control airway inflammation. The administration routes of budesonide include inhalation, oral administration, intravenous administration, etc. Among them, inhalation administration is the preferred administration route. Through this route, the local anti-inflammatory effect is stronger, which can effectively control airway inflammation, reduce the frequency of asthma attacks and alleviate the severity of attacks, and reduce the mortality rate.

[0003] There are significant differences between budesonide suspension for inhalation and budesonide nasal spray. The requirements for the particle size of the active ingredient in budesonide nasal spray are relatively loose, and larger particle sizes are more conducive to the adsorption of the active ingredient on the nasal mucosa, thereby improving the therapeutic effect. Compared with budesonide nasal spray, the requirements for the particle size of the active ingredient in budesonide suspension for inhalation (for nebulization therapy) are smaller and more stringent. Excessively large particles will deposit in the oral cavity and upper respiratory tract and cannot be effectively deposited in the lungs. Moreover, the particle size increases significantly after sterilization, and it is difficult to restore to the size before sterilization through homogeneous dispersion. Especially in the large-scale production of budesonide suspension, there will be a problem that the active ingredient is prone to agglomeration and caking during the heat and moisture sterilization process, resulting in an increase in particle size, which is more difficult to solve than in small-scale experiments.

[0004] The original research process of budesonide suspension for inhalation (Patent CN1173702C) is as follows: After micronized budesonide is sterilized by dry heat, it is added to a sterile-filtered auxiliary solution, and after mixing, it is filled into a container through a blow-fill-seal system. The process described in this patent has relatively high requirements for the sterilization process of the active ingredient, and there are relatively large risks during batch scale-up.

[0005] A known preparation method of a budesonide suspension is to mix budesonide with a part of surfactant and a part of water to obtain a raw material liquid medicine, and mix the remaining auxiliary materials to obtain an auxiliary solution; after the raw material liquid medicine is sterilized by heat and moisture and mixed with the sterile-filtered auxiliary solution, a budesonide suspension is obtained. However, the surfactant is fed in two parts, and the operation is relatively complex. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies and defects in the background art, and provide an inhalation budesonide suspension and a preparation method thereof, which simplify the process and at the same time meet the requirements of the particle size of the budesonide suspension.

[0007] The study found that: after mixing budesonide with part of the surfactant and part of the water to obtain the raw drug solution, after wet heat sterilization, it was mixed with other auxiliary material solutions (including the remaining surfactant and the remaining water) that were sterilized by filtration to obtain the budesonide suspension. During the production and scale-up process of this method, if the surfactant concentration in the raw drug solution is too low, adding too much water will lead to an increase in the particle size of the raw drug. It was also found that during the operation of this method, budesonide was not easy to disperse, and the fine particle dose (FPD) was lower than that of the reference preparation.

[0008] During the research process of production scale-up, the inventors tried to add the surfactant polysorbate 80 in one step to simplify the process. The research found that if polysorbate 80 is added at one time during the preparation of the raw material liquid, more water needs to be added, and the ratio of budesonide, polysorbate 80 and water in the raw material liquid needs to be within a certain range. Otherwise, the raw material will inevitably agglomerate and clump during the wet heat sterilization process, and the particle size will increase.

[0009] To this end, the technical solution proposed by the present invention is:

[0010] A method for preparing a budesonide suspension comprises the following steps:

[0011] (1) dissolving a prescribed amount of surfactant polysorbate 80 in partially purified water, then adding a prescribed amount of micronized budesonide, stirring and dispersing to obtain a raw material drug solution, and then sterilizing with wet heat;

[0012] The amount of the partially purified water is 0.5% to 1% of the suspension preparation volume, the mass ratio of budesonide to water in the raw material liquid is 1: (10 to 15), and the mass ratio of polysorbate 80 to water is 1: (25 to 37.5);

[0013] The particle size D90 of the micronized budesonide is less than 5 μm, and the D50 is less than 2 μm;

[0014] (2) adding the prescribed amount of other excipients to purified water in sequence, dissolving them, and then adding water to weigh them to a preset value to obtain an excipient solution, which is then sterilized and filtered;

[0015] (3) stirring and mixing the filtered and sterilized auxiliary material solution with the wet heat sterilized raw material drug solution to obtain a mixed solution;

[0016] (4) subjecting the mixed solution to high-speed shearing and high-pressure homogenization to obtain the budesonide suspension;

[0017] The high-speed shearing speed is 30-45 Hz, and the high-pressure homogenization pressure is 250-350 bar.

[0018] As a further improvement, the particle size D90 of the micronized budesonide is less than 4 μm, D50 is less than 1.5 μm, and the span is no greater than 2.5.

[0019] As a further improvement, the budesonide content in the budesonide suspension prescription is 0.25-0.5 g / L, and the polysorbate 80 content is 0.15-0.25 g / L.

[0020] As a further improvement, the other auxiliary materials include disodium edetate, sodium chloride, anhydrous citric acid and sodium citrate.

[0021] As a further improvement, the contents of disodium edetate, sodium chloride, anhydrous citric acid and sodium citrate in the budesonide suspension prescription are:

[0022]

[0023] As a further improvement, the moist heat sterilization temperature is above 121° C. and the time is not less than 12 minutes.

[0024] As a further improvement, the high-speed shearing time is not less than 30 minutes.

[0025] As a further improvement, the amount of the budesonide suspension prepared at one time is 15 to 30 L.

[0026] The present invention also provides a budesonide suspension, which is prepared by adopting the method.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention is dedicated to simplifying the operation steps and reducing the risk of abnormal increase in particle size during the production and amplification process of budesonide suspension for inhalation (up to 20 kg level). Factors affecting the particle size and particle size distribution of budesonide suspension include: the particle size of budesonide raw material, the type of surfactant, the dosage ratio of budesonide, surfactant and water in the raw material liquid, preparation parameters such as mixing shear and homogenization parameters, and each factor affects each other. The present invention simplifies the process operation by adding the surfactant once in the process of preparing the raw material liquid, but this will bring difficulties in particle size control. The present invention selects a specific surfactant polysorbate 80, strictly controls the polysorbate 80 content and the water addition ratio in the raw material liquid, and controls the shear speed and homogenization pressure within the scope of the present invention at the same time. Multiple process parameters are controlled together, so that the problem of abnormal increase in particle size is avoided during the mass production process of the present invention, and the content uniformity in the tank and the blow-fill-seal process is improved.

[0029] Secondly, the present invention increases the control range of the D50 value of the particle size of the active pharmaceutical ingredient, resulting in a smaller particle size distribution span, thereby ensuring a narrow particle size distribution of the active pharmaceutical ingredient in the budesonide suspension and further improving the quality control of the product particle size. At the same time, during storage and use, it ensures that the budesonide suspension is easy to mix evenly and the dosing dose is accurate.

[0030] The particle size and particle size distribution of the budesonide suspension prepared by the present invention are basically the same as those of the original developed preparation. The results of the aerodynamic particle size distribution show that the Fine Particle Dose (FPD) and Fine Particle Fraction (FPF) values are the same as those of the original developed product, and the results of the Population Bioequivalence (PBE) analysis show "PASS". This indicates that the preparation of the present invention is highly consistent with the original developed product in vitro research results, thereby providing a definite basis for in vivo bioequivalence. Detailed implementation manners

[0031] For the convenience of understanding the present invention, the following will describe the present invention more comprehensively and meticulously in combination with preferred embodiments, but the protection scope of the present invention is not limited to the following specific embodiments.

[0032] Unless otherwise defined, all professional terms used hereinafter have the same meaning as commonly understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the protection scope of the present invention.

[0033] Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the present invention can be obtained through market purchase or can be prepared by existing methods.

[0034] The content of each component in the prescription of the budesonide suspension for inhalation in some specific embodiments of the present invention is as follows:

[0035]

[0036] The preparation method of the budesonide suspension for inhalation in some specific embodiments of the present invention includes the following steps:

[0037] (1) Preparation and sterilization of the raw material liquid medicine

[0038] In some specific embodiments, the budesonide active pharmaceutical ingredient is first micronized, for example, by using a jet mill for pulverization. Preferably, after micronization of the budesonide active pharmaceutical ingredient, the particle size requirement is that D90 is less than 5 μm, D50 is less than 2 μm, and at the same time, the span (span value) is not greater than 2.5. More preferably, the particle size D90 is less than 4 μm, D50 is less than 1.5 μm, and D10 is less than 1 μm.

[0039] In some specific embodiments, dissolve the prescribed amount of polysorbate 80 (surfactant) with partially purified water, and then add the prescribed amount of budesonide, stirring until completely dispersed without obvious aggregates to obtain the raw material liquid medicine. In some specific embodiments, the amount of partially purified water used is 0.5% - 1% of the volume of the suspension preparation, and the mass ratio of budesonide to water in the raw material liquid medicine is 1:(10 - 15), and the mass ratio of polysorbate 80 to water is 1:(25 - 37.5). Beyond the above range, it will cause an increase in the particle size of the active pharmaceutical ingredient, affecting the fine particle dose (FPD) and the proportion of fine particles (FPF). The value range above is also closely related to the selection of polysorbate 80 as the surfactant.

[0040] In some specific embodiments, subject the raw material liquid medicine to moist heat sterilization. Since budesonide is poorly soluble in water, filtration sterilization cannot be carried out. In some specific embodiments, place it in a sterilization tank and perform moist heat sterilization at a temperature above 121°C for not less than 12 minutes.

[0041] (2) Preparation and sterilization of the excipient solution

[0042] In some specific embodiments, sequentially add the prescribed amounts of disodium edetate, sodium chloride, anhydrous citric acid, and sodium citrate to purified water, dissolve completely and then add water to a preset weight to obtain the excipient solution, and then filter and sterilize it.

[0043] (3) Mixing

[0044] In some specific embodiments, stir and mix the excipient solution with the raw material liquid medicine cooled to room temperature to obtain a mixed solution.

[0045] (4) Shearing and homogenization

[0046] In some specific embodiments, subject the mixed solution to high-speed shearing and high-pressure homogenization to obtain a suspension. In some specific embodiments, the shearing speed is 3000 - 4500 rpm (30 - 45 Hz). In some specific embodiments, the homogenization pressure is 250 - 350 bar. If the high-speed shearing speed and high-pressure homogenization pressure are too low, the particle size will be too large, while if they are too high, the particle size will be too small. At the same time, when the shearing speed and homogenization pressure are within the above range, they match the contents of budesonide and polysorbate 80 in the prescription, making the particle size and particle size distribution of the final suspension within a suitable range.

[0047] In some specific embodiments, fill it through a blow-fill-seal system after homogenization.

[0048] Example 1

[0049] This embodiment provides a method for preparing budesonide suspension, and the composition of various raw and auxiliary materials is shown in Table 1 (where the particle size and particle size distribution of budesonide raw material medicine: D10 = 0.573μm; D50 = 1.473μm; D90 = 4.641μm; span value = 2.21):

[0050] Table 1

[0051]

[0052]

[0053] Preparation and sterilization of raw material liquid medicine: Weigh the prescribed amount of polysorbate in a clean container, add 100 g of purified water thereto, and stir to dissolve; weigh the prescribed amount of budesonide and add it thereto, and stir to disperse evenly; seal the container, place it in a high-pressure steam sterilizer, set the sterilization time to not less than 12 min, and the sterilization temperature to not less than 121 °C for sterilization.

[0054] Preparation and filtration sterilization of auxiliary material solution: Add 19.24 kg of purified water to a clean stainless steel barrel, then sequentially weigh and add sodium chloride, disodium edetate, anhydrous citric acid, and sodium citrate thereto according to the weighing table, and stir until completely dissolved; weigh to 19.90 kg; filter the auxiliary material solution through a 0.22 μm sterilizing filter.

[0055] Mixing: Mix the filtrate after filtration sterilization with the raw material liquid medicine after moist heat sterilization, and stir and mix evenly for not less than 30 min;

[0056] Shearing: The suspension is sheared online at high speed into buffer tank 1, the rotation speed of the high-speed shearing machine is 30 Hz, and the shearing time is not less than 30 min;

[0057] Homogenization: Homogenize the suspension after shearing treatment under high pressure, and the homogenization pressure is 300 bar;

[0058] Blow-filling-sealing: Transfer the homogenized suspension to storage tank 2, and then press it into the blow-filling-sealing system by sterile plugging air for filling and forming.

[0059] Other embodiments and comparative examples

[0060] The prescription composition is the same as that of Example 1, and the particle size of the budesonide raw material medicine used and the preparation process parameters are shown in Table 2 (other parameters are the same as those of Example 1):

[0061] Table 2

[0062]

[0063] Comparative Example 4

[0064] This comparative example provides a preparation method of budesonide suspension, which adopts the method of first mixing the excipient solution and the budesonide raw material liquid and then performing moist heat sterilization. The particle size of the budesonide used is the same as that in Example 1, and the compositions of various raw and auxiliary materials are shown in Table 3:

[0065] Table 3

[0066] Name Prescription Composition (g) Budesonide 10.0 Polysorbate 80 4.0 Disodium Edetate 2.0 Sodium Chloride 170.0 Anhydrous Citric Acid 5.6 Sodium Citrate 10.0 Purified Water Up to 20 L

[0067] Suspension preparation: Add 19.24 kg of purified water to a clean stainless steel bucket, and then sequentially weigh and add sodium chloride, disodium edetate, anhydrous citric acid, and sodium citrate according to the weighing table, and stir until completely dissolved; Weigh the prescribed amount of polysorbate in a clean container, add 100 g of purified water to it, stir to dissolve, weigh the prescribed amount of budesonide and add it to it, stir to disperse evenly, and then transfer it to the excipient solution and stir to mix evenly.

[0068] Sterilization: Set the sterilization time to not less than 12 min and the sterilization temperature to not less than 121 °C for sterilization.

[0069] Shearing: The suspension is sheared online at high speed into buffer tank 1, the rotation speed of the high-speed shearing machine is between 30 Hz, and the shearing time is not less than 30 min;

[0070] Homogenization: The suspension after shearing treatment is homogenized under high pressure, and the homogenization pressure is 350 bar;

[0071] Blow-filling-sealing: The homogenized suspension is transferred to storage tank 2, and then pressed into the blow-filling-sealing system by sterile plug-pressing air for filling and forming.

[0072] Comparative Example 5

[0073] This comparative example reduces the batch size to 2 L on the basis of Comparative Example 1, and the prescription compositions of various raw and auxiliary materials are shown in Table 4:

[0074] Table 4

[0075] Name Prescription Composition (g) Budesonide 1.0 Polysorbate 80 0.4 Disodium Edetate 0.2 Sodium Chloride 17.0 Anhydrous Citric Acid 0.56 Sodium Citrate 1.0 Purified Water Up to 2 L

[0076] The liquid preparation process and process parameters are the same as those in Comparative Example 1.

[0077] Testing experiment:

[0078] Measure the particle sizes of Examples 1 to 4 and Comparative Examples 1 to 5, and the results are shown in Table 5.

[0079] Particle size measurement method: Wet method detection is carried out according to the method for the determination of particle size and particle size distribution (Method 3 Light Scattering Method in General Rules 0982, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0080] Table 5

[0081]

[0082]

[0083] It can be seen that in Examples 1 to 4, the particle size and particle size distribution are comparable to the reference preparation, and D90 is even smaller, avoiding the problem of increased particle size. By comparing Example 2 with Example 4, it can be seen that the D90 and D50 of the raw material medicine become smaller, and the particle size D90 of the suspension becomes significantly smaller. Comparative Examples 1 to 4 have the problem of increased particle size. It can be seen from Example 1 and Comparative Examples 1 to 2 that the mass ratio of budesonide to water in the raw material drug solution exceeds the scope of the present invention, which will significantly increase the particle size of the suspension. Through Example 1 and Comparative Example 3, it can be seen that as the shear speed and homogenization pressure increase, the particle size decreases significantly. Through Comparative Examples 1 and Comparative Example 5, it can be seen that after the preparation amount is enlarged from 2L to 20L, the particle size of the suspension increases significantly, indicating that the particle size control is more difficult after enlargement, and the condition parameters required for enlarged production and small batch experiments are different.

[0084] The fine particle dose (FPD) and fine particle fraction (FPF) of Examples 1 to 4 and Comparative Examples 1 to 5 were measured. The results are shown in Table 6.

[0085] The fine particle dose is determined using device 3 in accordance with the method for determining the aerodynamic characteristics of fine particles of inhalation preparations (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0951).

[0086] Table 6

[0087] Example FPD (μg) FPF (%) Example 1 159.190 37.394 Example 2 164.653 35.319 Control Example 1 120.955 34.145 Control Example 2 144.014 34.745 Control Example 3 147.903 35.184 Example 3 164.759 35.972 Example 4 170.218 36.680 Control Example 4 120.955 34.145 Control Example 5 157.105 35.184 Reference Preparation 166.007 36.695

[0088] The results of implementation 1 to 4 show that the ratio of budesonide to water in the raw material liquid is in the range of 1:10 to 1:15, the shear speed is in the range of 30 to 40 Hz, the homogenization pressure is between 300 and 350 bar, and the fine particle dosage and the proportion of fine particles of the preparation of the present invention are not significantly different from those of the reference preparation.

[0089] However, the fine particle dosage and the ratio of fine particles in Comparative Examples 1 to 4 are relatively low. Combined with the particle size results, the budesonide suspension in Comparative Example 4 is sterilized by wet heat after mixing the excipient solution with the raw material liquid, and the particle size is significantly increased, which leads to a significant decrease in the fine particle dosage and the ratio of fine particles, and the amount of drug entering the lungs will be less, affecting the efficacy of the drug. After batch expansion of Comparative Example 5 (Comparative Example 1), the fine particle dosage and the ratio of fine particles in the preparation are significantly reduced, and the risk is greater after batch expansion.

[0090] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. A preparation method of budesonide suspension, characterized in that, it comprises the following steps: (1) Dissolve the prescribed amount of the surfactant polysorbate 80 with partial purified water, then add the prescribed amount of micronized budesonide, stir and disperse to obtain the raw material liquid medicine, and then carry out moist heat sterilization; The amount of the partial purified water used is 0.5% - 1% of the volume of the suspension preparation, and the mass ratio of budesonide to water in the raw material liquid medicine is 1:10 - 1:15, and the mass ratio of polysorbate 80 to water is 1:25 - 1:37.5; The particle size D90 of the micronized budesonide is less than 5 μm and D50 is less than 2 μm; (2) Sequentially add the prescribed amount of disodium edetate, sodium chloride, anhydrous citric acid and sodium citrate into purified water, dissolve and then add water to a preset weight value to obtain the auxiliary material solution, and then carry out sterile filtration; (3) Stir and mix the sterile filtered auxiliary material solution with the moist heat sterilized raw material liquid medicine to obtain a mixed solution; (4) Subject the mixed solution to high - speed shearing and high - pressure homogenization to obtain the budesonide suspension; The high - speed shearing speed is 30 - 45 Hz, and the high - pressure homogenization pressure is 250 - 350 bar.

2. The preparation method of budesonide suspension according to claim 1, characterized in that, the particle size D90 of the micronized budesonide is less than 4 μm, D50 is less than 1.5 μm, and the span value is not more than 2.

5.

3. The preparation method of budesonide suspension according to claim 1 or 2, characterized in that, the content of budesonide in the budesonide suspension is 0.25 - 0.5 g / L, and the content of polysorbate 80 is 0.15 - 0.25 g / L.

4. The preparation method of budesonide suspension according to claim 1, characterized in that, the contents of disodium edetate, sodium chloride, anhydrous citric acid and sodium citrate in the budesonide suspension are: Disodium edetate 0.08 - 0.12 g / L Sodium chloride 8 - 10 g / L Anhydrous citric acid 0.2 - 0.3 g / L Sodium citrate 0.35 - 0.65 g / L.

5. The preparation method of budesonide suspension according to claim 1 or 2, characterized in that, the moist heat sterilization temperature is above 121 °C and the time is not less than 12 min.

6. The preparation method of budesonide suspension according to claim 1 or 2, characterized in that, the high - speed shearing time is not less than 30 min.

7. The preparation method of budesonide suspension according to claim 1 or 2, characterized in that, the amount of the budesonide suspension prepared at one time is 15 - 30 L.

8. A budesonide suspension, characterized in that, the budesonide suspension is prepared by the method according to any one of claims 1 - 7.

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