Process for the preparation of ibuprofen sustained release capsules

Abstract

The application discloses a preparation process of ibuprofen sustained-release capsules and relates to the technical field of sustained-release preparation, which comprises the following steps: adding ibuprofen, stearic acid and polyvinylpyrrolidone into medicinal ethanol to obtain ethanol medicine liquid; spraying the ethanol medicine liquid onto blank pellet cores in a fluidized bed; pre-drying and dissolving to retain residual ethanol to obtain pre-dried medicine-loaded pellets; introducing humid hot air to perform controllable humid hot treatment, so that the surface layer material of the pellets is softened and appears temporary agglomeration; performing fluidized collision to promote the softened material to be evenly spread on the surface of the pellets again; and drying and solidifying the ibuprofen sustained-release pellets by low-humidity air flow to fill capsules; and the application controls the controllable softening and even re-spreading of the surface layer material of the pellets by the cooperation of residual ethanol and humid heat, significantly improves the uniformity of the drug release rate of the pellets in the same batch, and guarantees the stability of the sustained-release effect.

Description

Technical Field

[0001] This invention relates to the field of sustained-release formulation preparation technology, and in particular to a process for preparing ibuprofen sustained-release capsules. Background Technology

[0002] Ibuprofen is a nonsteroidal anti-inflammatory drug that reduces prostaglandin synthesis by inhibiting cyclooxygenase, thereby alleviating tissue congestion and swelling, reducing peripheral nerve pain sensitivity, and acting on the hypothalamic thermoregulatory center to exert an antipyretic effect. Clinically, it is used to relieve chronic joint inflammation such as rheumatoid arthritis and osteoarthritis, as well as various acute mild to moderate pains such as toothache, headache, and postoperative pain.

[0003] Most commercially available products are prepared in the form of sustained-release microcapsules, while traditional ibuprofen sustained-release microcapsules are mostly prepared by centrifugal granulation. Centrifugal granulation involves alternating powder deposition and coating liquid spraying to directly construct the drug-containing layer and sustained-release layer on the core of the capsule. It is widely used because of its simple equipment and fast pelleting.

[0004] However, when preparing ibuprofen sustained-release microspheres using centrifugal granulation, the lamination process relies on multiple cycles of spraying liquid and sprinkling powder. The growth of microspheres is highly random, which easily leads to a wide particle size distribution, discontinuous and poorly compact sustained-release coating on the surface. This inherent defect results in significant differences in drug release rates among microspheres in the same batch, making it difficult to stably control the smooth release of the drug. Summary of the Invention

[0005] This invention provides a process for preparing ibuprofen sustained-release capsules, comprising the following steps: Ibuprofen, stearic acid and polyvinylpyrrolidone were added to pharmaceutical ethanol and stirred to obtain the ethanol-based drug solution. A blank pellet core is placed in a fluidized bed, and the ethanol-based drug-coated solution is sprayed into the blank pellet core in a fluidized state. After spraying, wet drug-loaded micro pellets are obtained. The wet drug-loaded microspheres were pre-dried and desolventized to obtain pre-dried drug-loaded microspheres with an ethanol content of 0.3% to 1.5%. A hot and humid airflow with a temperature of 42–52°C and a relative humidity of 60%–78% is introduced into the pre-dried drug-loaded microspheres in a fluidized state. The pressure difference P0 of the fluidized bed before the hot and humid airflow is introduced is recorded. The hot and humid treatment continues until the pressure difference of the bed increases to 108%–120% of P0, and a brief agglomeration occurs between the pre-dried drug-loaded microspheres. Continue to maintain the fluidized collision of the pre-dried drug-loaded microspheres. The briefly agglomerated pre-dried drug-loaded microspheres are dispersed by fluidized collision, and the bed pressure difference drops back to 95% to 110% of P0, thus obtaining the wet heat-treated microspheres. The wet heat-treated microspheres are kept in a fluidized state, and through collision and tumbling between the microspheres, the softened material on the surface of the microspheres is dispersed on the surface of the microspheres to obtain fluidized dispersed microspheres. The fluidized dispersed microspheres were dried and solidified by passing a low-humidity airflow with a relative humidity of 5% to 15% to obtain ibuprofen sustained-release microspheres. The ibuprofen sustained-release microspheres are filled into capsules to obtain ibuprofen sustained-release capsules.

[0006] Specifically, in the ethanol-based drug solution, the mass ratio of ibuprofen, stearic acid, and polyvinylpyrrolidone is 100:5 to 10:3 to 6, and the mass of pharmaceutical ethanol is 1.8 to 2.8 times the mass of ibuprofen.

[0007] Specifically, the blank pellet core is a sucrose pellet core with a particle size of 0.60–0.85 mm; The ethanol-based drug solution is sprayed from the bottom of the fluidized bed. During the spraying process, the material temperature is 30-36°C and the atomization pressure is 0.12-0.20 MPa.

[0008] Specifically, the pre-drying and desolventizing treatment is carried out under hot air at 65-69°C for 2-4 hours, and the endpoint of the pre-drying and desolventizing treatment is defined as the residual ethanol content in the drug-loaded microspheres reaching 0.3%-1.5%.

[0009] Specifically, the pre-drying and solvent removal treatment is carried out under hot air at 67°C for 3 hours.

[0010] Specifically, the hot and humid airflow is introduced into the fluidized bed in segments. After each segment of hot and humid airflow is introduced, the pre-dried drug-loaded microparticles are kept in fluidized collision. The number of hot and humid airflow segments is 2 to 5, and the introduction time of each segment is 3 to 6 minutes. A dry airflow with a relative humidity of 20% to 35% is introduced between two adjacent hot and humid airflow segments for 1 to 3 minutes.

[0011] Specifically, the bed pressure difference P0 is the average value obtained by continuously recording for 60 seconds before the hot and humid airflow is introduced; The bed pressure difference was collected at intervals of 5 to 10 seconds, and the bed pressure difference drop value was the average value obtained by continuously recording for 60 seconds before the end of fluidization collision. The brief reunion is specifically described as follows: During the hot and humid airflow treatment process, there are agglomerates formed by temporary contact of 2 to 10 microspheres. After continuous fluidization and collision for 1 to 10 minutes, the bed pressure difference can drop back to 95% to 110% of P0, and the proportion of agglomerates on the sieve after treatment is not higher than 2.0%.

[0012] Specifically, after obtaining the wet heat-treated microparticles, the air volume of the fluidized bed is increased to 1.15 to 1.45 times that of the wet heat treatment stage, and maintained for 4 to 10 minutes to obtain the fluidized dispersed microparticles.

[0013] Specifically, the temperature of the low-humidity airflow is 50-62℃, the drying and curing time is 25-45 min, and the residual ethanol content in the dried and cured ibuprofen sustained-release microspheres is no higher than 0.2%, and the water activity is 0.20-0.35.

[0014] Specifically, the ibuprofen sustained-release microspheres are granulated through a 20-30 mesh sieve and equilibrated for 10-20 minutes in an environment of 25-30°C and 35%-45% relative humidity before being directly fed into a capsule filling machine to fill capsules.

[0015] The beneficial effects of this invention are: By combining fluidized bed spraying with controlled humid heat, fluidized impact, and drying curing processes, the ibuprofen drug-loaded layer containing stearic acid and polyvinylpyrrolidone retains an appropriate amount of residual ethanol after pre-drying. During humid heat treatment, the surface material softens appropriately and undergoes brief agglomeration. Then, fluidized impact promotes the softened material to spread evenly on the surface of the microspheres again. After drying, a continuous and dense sustained-release layer is spontaneously formed. This method effectively overcomes the inherent defects of traditional centrifugal granulation methods, such as wide particle size distribution, discontinuous sustained-release coating, and poor density caused by repeated powder layering. It significantly improves the uniformity of drug release rate within the same batch of microspheres and ensures the stable and controllable sustained-release effect. Attached Figure Description

[0016] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is a process flow diagram for preparing ibuprofen sustained-release capsules according to the present invention; Figure 2 This is a schematic diagram of the transient aggregation and fluidized dispersion process of the drug-loaded microspheres of the present invention. Detailed Implementation

[0018] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0019] This invention relates to a process for preparing ibuprofen sustained-release capsules, which mainly includes ethanol loading solution preparation, fluidized bed spray loading, pre-drying and solvent removal, hot and humid airflow treatment, fluidized collision dispersion, low-humidity airflow drying and curing, and capsule filling; The hot and humid airflow treatment is a process in which drug-loaded microspheres are made to form a dispersible, transient aggregate state in a fluidized state before being filled into capsules, and this transient aggregate state is dispersed through fluidized collision.

[0020] In this embodiment, the blank pellet core is made of sucrose with a particle size of 0.60 mm to 0.85 mm; the fluidized bed is a bottom-spray fluidized bed, which includes an air inlet system, a humidification and temperature control system, a bottom spray gun, a material container, an exhaust system, and a bed pressure differential detection device; the ethanol loading solution is sprayed into the material zone from the bottom of the fluidized bed, and the blank pellet core forms a fluidized state under the action of the air inlet, and the loading solution is deposited on the surface of the blank pellet core after atomization.

[0021] In this embodiment, the temperature and relative humidity of the hot and humid airflow are the inlet air parameters before entering the fluidized bed material zone; the temperature and relative humidity of the low-humidity airflow are also the inlet air parameters before entering the fluidized bed material zone. The bed pressure difference is the pressure difference between the upstream and downstream of the material zone, and its value is continuously recorded by the pressure difference sensor configured in the fluidized bed.

[0022] In this embodiment, pre-dried drug-loaded microspheres refer to drug-loaded microspheres whose residual ethanol content is in the range of 0.3% to 1.5% after being pre-dried and desolventized by hot air; the residual ethanol content is calculated as a percentage of the total mass of the drug-loaded microspheres.

[0023] The transient agglomeration state refers to the state in which, during the treatment of hot and humid airflow, the bed pressure difference rises to 108% to 120% of P0, and the observation window or sampling sieve shows the presence of agglomerates formed by temporary contact of 2 to 10 microspheres. After 1 to 10 minutes of continued fluidization and collision, the bed pressure difference can drop back to 95% to 110% of P0, and the proportion of agglomerates on the sieve after treatment is not higher than 2.0%. The aforementioned transient aggregation state is different from irreversible agglomeration; if the bed pressure difference is still higher than 110% of P0 after continued fluidization and collision, or the proportion of agglomerates on the sieve is higher than 2.0%, then it is not determined to be the transient aggregation state described in this embodiment.

[0024] In this embodiment, fluidized impact dispersion refers to the process of stopping humidification or switching to low humidity airflow after the bed pressure difference is increased to a set range during the humidification treatment, while keeping the microparticles in a fluidized state, so that the temporarily agglomerated microparticles are dispersed by collision, tumbling and airflow shearing. The endpoint of fluidized impact dispersion was determined by the primary criterion that the bed pressure differential returned to 95% to 110% of P0, and by the secondary criterion that the proportion of agglomerates on the screen after treatment was no higher than 2.0%.

[0025] In this embodiment, low-humidity airflow drying and solidification refers to the process of introducing an airflow with a relative humidity of 5% to 15% into the fluidized and dispersed microspheres and continuing to dry them at 50°C to 62°C, so that the residual ethanol content in the microspheres is no higher than 0.2% and the water activity is 0.20 to 0.35. Low-humidity airflow drying and curing is used to reduce the risk of adhesion and changes in the release profile during subsequent storage of microcapsules.

[0026] Reference Figure 2 In this invention, the drug-loaded microparticles undergo different state changes sequentially during the processes of hot and humid airflow treatment, fluidized collision dispersion, and low-humidity airflow drying and solidification. The first stage involves pre-drying the drug-loaded microspheres. After spraying the drug, the wet drug-loaded microspheres are pre-dried and desolventized, maintaining a generally dispersed state between the microspheres. The residual ethanol content in the drug-loaded microspheres is controlled within the range of 0.3% to 1.5%, so that the microspheres have the necessary state for subsequent hot and humid airflow treatment.

[0027] The second stage is the hot and humid airflow treatment stage. After hot and humid airflow is introduced into the pre-dried drug-loaded microspheres in the fluidized state, the surface state of the microspheres undergoes a temporary change, and transient agglomerates formed by temporary contact between 2 to 10 microspheres appear between adjacent microspheres; As the hydrothermal treatment proceeds, the bed pressure differential gradually increases relative to the baseline pressure differential P0 under stable fluidization conditions before the introduction of hydrothermal gas. When the bed pressure differential increases to 108% to 120% of P0, it indicates that a temporary agglomeration state suitable for subsequent fluidization collision dispersion has been formed in the bed; although the microparticles in this state are in temporary contact, irreversible agglomerates that are difficult to disperse have not yet formed.

[0028] The third stage is the fluidization collision dispersion stage; when the bed pressure difference reaches the above-mentioned set range, humidification is stopped or switched to a lower humidity airflow, while maintaining the microparticles in a fluidized state. The temporarily agglomerated microparticles continue to collide, tumble, and shear under the impetus of the airflow, gradually dispersing the contacting microparticles. As the agglomerates are dispersed, the bed pressure difference gradually decreases. When the average bed pressure difference obtained from continuous recording before the end of fluidization collision falls back to 95% to 110% of P0, it can be determined that the temporary aggregation state has been effectively dispersed.

[0029] The fourth stage is the low-humidity airflow drying and solidification stage. After fluidized collision dispersion, the microparticles are further dried and solidified by a low-humidity airflow, so that the microparticles can be restored and maintain a stable state of mutual dispersion. After drying and solidification, the residual ethanol content of the microparticles is controlled to be no higher than 0.2%, the water activity is controlled to be between 0.20 and 0.35, and the proportion of agglomerates on the sieve obtained by sieving is no higher than 2.0%.

[0030] therefore, Figure 2 The illustration shows the process of the drug-loaded microspheres of the present invention changing from a pre-dried dispersed state to a dispersible, transiently aggregated state after hydrothermal treatment, and then redispersed by fluidized collision and dried and solidified by low-humidity airflow to obtain stable dispersed microspheres. The transient agglomeration state is different from irreversible agglomeration; if the bed pressure difference is still higher than 110% of P0 after continued fluidization and collision, or the proportion of agglomerates on the sieve after treatment is higher than 2.0%, it indicates that the microparticles have failed to achieve the effective dispersion state described in this invention.

[0031] The ibuprofen, stearic acid, polyvinylpyrrolidone, pharmaceutical ethanol, and sucrose core used in the examples are all pharmaceutical materials; the polyvinylpyrrolidone used is PVP K30; and the volume fraction of pharmaceutical ethanol is 95%.

[0032] The residual ethanol content was determined by gas chromatography. Take about 0.500g of drug-loaded microspheres, place them in a 20mL headspace vial, add 5mL of purified water and seal, equilibrate at 80℃ for 30min, and then inject the headspace gas for analysis. A standard curve was established using ethanol standard solution, and the residual ethanol content in the sample was calculated. The results were expressed as a percentage of the total mass of the drug-loaded microcapsules.

[0033] Water activity was measured using a water activity meter. Approximately 2.0 g of dried and cured ibuprofen sustained-release microspheres were placed in the sample cup of the water activity meter, and the water activity value was read after equilibration at 25°C.

[0034] The bed pressure difference P0 is the average value obtained by continuously recording for 60 seconds under the stable fluidized state of the drug-loaded microspheres before the introduction of hot and humid airflow. During the hydrothermal treatment, the bed pressure difference was collected at intervals of 5 to 10 seconds; the pressure difference drop value was the average value obtained by continuously recording for 60 seconds before the end of fluidization collision.

[0035] The proportion of agglomerates on the sieve was determined using the following method: Take 50.0g of the processed microspheres, place them on a 20-mesh sieve and shake them gently for 1 minute. Weigh the mass of the agglomerates formed by the adhesion of multiple microspheres on the sieve that cannot pass through the sieve after slight shaking. Calculate the mass based on the percentage of the mass of the agglomerates on the sieve to the total mass of the sampled microspheres.

[0036] The adhesion rate of the microspheres was determined as follows: Take capsule samples after accelerated stability testing, open the capsule shell, take out the microspheres, observe and separate the adhered microspheres; the microsphere adhesion rate is calculated as the percentage of the mass of the adhered microspheres to the total mass of the sampled microspheres.

[0037] The capsule deformability was determined using the following method: 100 capsules were taken from each group. After accelerated stability testing, the appearance of the capsule shells was observed. Capsules that softened, shrank, dented, or adhered were counted as deformed capsules. The capsule deformation rate was calculated as the percentage of deformed capsules to the total number of capsules tested.

[0038] Release rate testing was conducted according to the release rate testing conditions under the ibuprofen sustained-release capsules section; the release medium was 900 mL of pH 6.0 ± 0.05 phosphate buffer, the temperature was 37℃ ± 0.5℃, and the rotation speed was 30 r / min. Samples were taken at 1 h, 2 h, 4 h, and 7 h, respectively, and the ibuprofen content was determined by high performance liquid chromatography, and the release rate was calculated cumulatively.

[0039] To further evaluate the changes in release curves before and after the accelerated stability test, samples were taken at 1h, 2h, 4h and 7h after the accelerated stability test, using 900mL of pH 7.2 phosphate buffer as the release medium, at a temperature of 37℃±0.5℃ and a rotation speed of 50r / min. The ibuprofen content was determined by high performance liquid chromatography. Calculate the changes in release rate at 1h, 2h, 4h, and 7h based on the absolute difference between the release rate at the corresponding time point after the accelerated stability test and the release rate at the corresponding time point before the test. The f2 similarity factor is calculated based on the average release rate of samples before and after the accelerated stability test at 1h, 2h, 4h and 7h. At each time point, 12 capsules are taken for release rate detection, and the average release rate of all capsules at the corresponding time point is taken as the release rate at the corresponding time point.

[0040] The maximum release rate change refers to the maximum change in release rate at each sampling time point of 1h, 2h, 4h and 7h before and after the accelerated stability test.

[0041] When filling the capsules, the target fill weight of each capsule is calculated based on the ibuprofen content in the ibuprofen sustained-release microspheres, with each capsule containing 0.3g of ibuprofen, and hard capsule shells are used for filling. The difference in capsule content is evaluated according to the routine inspection methods for capsules. Capsules with content differences that meet the preset quality standards and with intact appearance are considered to be qualified capsules.

[0042] The accelerated stability test conditions are 40℃ and 75%RH; unless otherwise specified, the accelerated stability test time is 30 days; this accelerated stability test is used to evaluate the effects of different processing techniques on microsphere adhesion, capsule deformation and release curve changes under high humidity conditions.

[0043] It should be noted that the test data is the average of the test results of 3 batches of samples.

[0044] Example 1 Reference Figure 1 This embodiment illustrates the complete process for preparing ibuprofen sustained-release capsules under median process conditions and verifies the effects of hot and humid airflow treatment, fluidized impact dispersion, and low-humidity airflow drying and curing on the high-humidity storage stability and release curve stability of the microparticles.

[0045] Weigh 1000g of ibuprofen, 75g of stearic acid and 45g of polyvinylpyrrolidone, add them to 2300g of pharmaceutical ethanol, and stir at 25℃ to 30℃ for 40 minutes to obtain the ethanol solution. Keep the liquid uniform during stirring, and continue stirring at a low speed before spraying to reduce the impact of solid sedimentation on the uniformity of spraying.

[0046] Take 1500g of sucrose pellet cores with a particle size of 0.70mm to 0.80mm and place them in a bottom-spray fluidized bed material container; Start the air intake to keep the sucrose pellet cores in a continuously agitated fluidized state. Adjust the material temperature to 33℃ and the atomization pressure to 0.16MPa, and spray the ethanol-based drug solution from the bottom of the fluidized bed.

[0047] During the spraying process, the spraying speed of the medicine should be matched with the drying capacity of the air intake to prevent wet clumps from forming in the material zone. After the spraying is completed, hot air is continued to be introduced so that there is no free liquid on the surface of the drug-loaded microspheres, resulting in wet drug-loaded microspheres.

[0048] The wet drug-loaded microspheres were pre-dried and desolventized under hot air at 67°C for 3 hours. During the pre-drying and desolventizing process, samples were taken every 30 minutes to detect the residual ethanol content. Upon testing, the residual ethanol content in the microspheres obtained at the processing endpoint was 0.90%, yielding pre-dried drug-loaded microspheres.

[0049] The pre-dried drug-loaded pellets were placed in the fluidized bed, and the air intake was adjusted to maintain a stable fluidization state. Before the hot and humid gas flow was introduced, the bed pressure difference was continuously recorded for 60 seconds, and the calculated P0 was 1.00 kPa. Subsequently, a hot and humid gas flow with a temperature of 47°C and a relative humidity of 69% was introduced into the material zone.

[0050] The humid and hot airflow is introduced in three sections, each section for 4 minutes, and a dry airflow with a relative humidity of 28% is introduced for 2 minutes between adjacent sections. During the hydrothermal treatment stage, the bed pressure difference was continuously recorded. When the bed pressure difference increased to 1.14 kPa, which is 114% of P0, a transient agglomeration state was observed between the pellets.

[0051] After reaching the above pressure difference, humidification was stopped, and the airflow was switched to a dry airflow with a relative humidity of 28%, and the microparticles were kept in fluidized collision for 5 minutes. The airflow during the fluidized collision stage was 1.10 times that during the wet heat treatment stage. The bed pressure difference was continuously recorded for 60 seconds before the fluidized collision dispersion ended. The average value obtained was 1.03 kPa, which is 103% of P0, and the wet heat treated microparticles were obtained.

[0052] After obtaining the wet heat treated micro pellets, the air volume of the fluidized bed was increased to 1.30 times that of the wet heat treatment stage and maintained for 7 minutes. During this process, the micro pellets continuously collided and turned over, which further dispersed and redistributed the surface material that was prone to agglomeration after wet heat treatment. After sieving, the proportion of agglomerates on the sieve was 0.6%, resulting in fluidized dispersed microspheres.

[0053] A low-humidity airflow at 56℃ and 10% relative humidity was introduced into the fluidized dispersed microspheres for drying and solidification for 35 minutes. The residual ethanol content of the dried and solidified microspheres was found to be 0.12%, and the water activity was 0.28, thus obtaining ibuprofen sustained-release microspheres.

[0054] The obtained ibuprofen sustained-release microspheres were granulated through 20-mesh and 30-mesh sieves. Microspheres that passed through the 20-mesh sieve and passed through the 30-mesh sieve were placed in an environment of 28°C and 40% relative humidity for 15 minutes to equilibrate. After balancing, each capsule contains 0.3g of ibuprofen. The fill weight is calculated based on the ibuprofen content in the ibuprofen sustained-release microcapsules, and the capsules are directly fed into the capsule filling machine to obtain ibuprofen sustained-release capsules.

[0055] To evaluate the impact of each step on the effectiveness of this embodiment, comparative examples 1-1 to 1-6 were set up; Except for the differences listed in Table 1, the comparative examples were identical to those in Example 1 in terms of ibuprofen, stearic acid, polyvinylpyrrolidone, pharmaceutical ethanol, sucrose core, spray application conditions, detection methods, and capsule filling methods.

[0056] Comparative Example 1-1: No humid heat airflow treatment was performed. The pre-dried drug-loaded microspheres were dried with low humidity airflow and then directly granulated and filled into capsules. This comparative example was used to evaluate the adhesion and release curve changes of the microspheres under high humidity conditions when only pre-drying and low humidity drying were used.

[0057] Comparative Examples 1-2 were subjected to humid heat treatment, but the air intake was reduced to 0.40 times that of the humid heat treatment stage in Example 1, so that the microparticles were in a weak fluidized state; after humid heat treatment, subsequent drying and curing were carried out in the manner of Example 1; this comparative example was used to evaluate the effect of insufficient fluidization collision during the humid heat treatment stage.

[0058] Comparative Examples 1-3 show that the time for introducing humid heat gas is shortened, and the humid heat treatment only makes the bed pressure difference reach 105% of P0; these comparative examples are used to evaluate the impact when the humid heat treatment is insufficient and does not reach the pressure difference increase range specified in this invention.

[0059] Comparative Examples 1-4A extended the treatment time of the hot and humid airflow, increasing the bed pressure difference to 126% of P0, and then immediately performed fluidization collision dispersion in the same manner as in Example 1; this comparative example was used to evaluate the effect when the peak pressure difference exceeded the specified upper limit.

[0060] Comparative Examples 1-4B were subjected to hydrothermal treatment until the bed pressure difference reached 114% of P0, but this state was maintained for 10 minutes before fluidized collision dispersion was performed; this comparative example was used to evaluate the impact of not performing fluidized collision dispersion in time after reaching a brief agglomeration state.

[0061] After the wet heat treatment of Comparative Examples 1-5 reached 114% of P0, the air intake was not increased to 1.30 times the air intake during the wet heat treatment stage; the original air intake was maintained for subsequent treatment. This comparative example was used to evaluate the effect of insufficient fluidization dispersion intensity on the state and stability of the microparticles.

[0062] After humid heat treatment and fluidized impact dispersion, Comparative Examples 1-6 were not dried and cured by passing a low-humidity airflow with a relative humidity of 10%, but by using room temperature ventilation treatment; the final residual ethanol was made close to that of Example 1 by extending the ventilation time; this comparative example was used to evaluate the effect of low-humidity airflow drying and curing conditions on high humidity stability.

[0063] Table 1: Performance Comparison of Example 1 and Univariate Comparative Example Residual ethanol / % 0.9 0.91 0.9 0.89 0.91 0.9 0.9 0.13 water activity 0.28 0.29 0.31 0.29 0.34 0.33 0.3 0.36 Peak pressure difference during damp heat treatment / P0 114% — 116% 105% 126% 114% 114% 114% Pressure differential drop value / P0 103% — 118% 101% 116% 115% 116% 103% Percentage of agglomerates on the sieve / % 0.6 1.8 7.4 2.6 10.8 8.6 4.7 1.4 Capsule filling pass rate / % 99.6 98.7 93.8 97.9 90.2 92.6 95.1 98.2 Microsphere adhesion rate after 30 days at 40℃ and 75%RH / % 2.8 16.7 24.6 12.5 31.4 27.2 18.9 14.6 Capsule deformation rate / % 0.5 6.8 12.8 5.6 16.3 13.7 8.7 6.2 Release curve f2 before and after acceleration 78 52 46 57 40 43 50 55 Change in maximum release rate / % 3.1 10.8 14.7 9.4 17.6 16.2 12.6 10.1 As shown in Table 1, in Example 1, the bed pressure difference increased to 114% of P0 during the wet heat treatment stage, and then dropped back to 103% of P0 after fluidized collision. The proportion of agglomerates on the sieve was 0.6%, indicating that the transient agglomeration state in Example 1 could be dispersed under the action of fluidized collision.

[0064] Comparative Example 1-1, without wet heat treatment, showed that after accelerated stabilization, the microparticle adhesion rate increased to 16.7%, and the maximum release rate changed by 10.8%, indicating that ordinary pre-drying and low-humidity drying cannot sufficiently reduce microparticle adhesion and release curve changes during subsequent high-humidity storage.

[0065] Comparative Examples 1-2 were subjected to weak fluidized hydrothermal treatment, and the pressure drop value was still 118% of P0, while the proportion of agglomerates on the sieve was 7.4%, indicating that insufficient fluidization collision during the hydrothermal treatment stage makes it difficult to fully disperse the temporary agglomerates.

[0066] The peak pressure difference of Comparative Examples 1-3 was less than 108% of P0, and the micro-particle adhesion rate after high humidity was 12.5%, indicating that when the wet heat treatment was insufficient, there was still a significant risk of adhesion during subsequent high humidity storage. Comparative Examples 1-4A and 1-4B respectively demonstrate that both exceeding the upper limit of peak pressure difference and delayed dispersion after reaching a brief agglomeration state will cause an increase in the proportion of agglomerates on the sieve and a greater change in the release curve.

[0067] Comparative Examples 1-5 and 1-6 lacked sufficient fluidization dispersion intensity and low-humidity airflow drying and curing conditions, respectively. Although the final residual ethanol in Comparative Examples 1-6 was close to that in Example 1, the water activity was higher, and the changes in microparticle adhesion rate and release rate were still higher than those in Example 1. This indicates that low-humidity airflow drying and curing is not simply about reducing residual ethanol, but is also related to the subsequent high-humidity stability of the microparticles.

[0068] Example 2 This embodiment is used to verify that ibuprofen sustained-release capsules with low microparticle adhesion rate and small release curve changes can still be prepared under process conditions close to the lower limit.

[0069] Except for the parameter adjustments described below, the equipment structure, spray application method, residual ethanol detection method, bed pressure difference recording method, release rate detection method, accelerated stability test conditions, and capsule filling method in this embodiment are all the same as in Example 1.

[0070] In this embodiment, 1000g of ibuprofen, 50g of stearic acid and 30g of polyvinylpyrrolidone were weighed and added to 1800g of pharmaceutical ethanol, and stirred to obtain the ethanol-based drug solution. The ethanol-based drug solution is sprayed into the bottom of the bottom-spray fluidized bed. During the spraying process, the material temperature is controlled at 30℃ and the atomization pressure is 0.12MPa.

[0071] After pre-drying and solvent removal, gas chromatography analysis showed that the residual ethanol content in the drug-loaded microcapsules was 0.30%, thus obtaining pre-dried drug-loaded microcapsules. The temperature of the humid airflow is 42℃ and the relative humidity is 60%. The humid airflow is introduced in two sections, each for 3 minutes, and a dry airflow with a relative humidity of 20% is introduced for 1 minute between the two adjacent sections.

[0072] Record the bed pressure difference P0 before introducing the hot and humid airflow. When the bed pressure difference increases to 109% of P0 during hot and humid treatment, a brief aggregation occurs between the pellets. Humidification was then stopped while fluidized collision was maintained, and the bed pressure difference dropped back to 99% of P0, resulting in wet-heat treated microspheres.

[0073] After obtaining the hydrothermally treated microspheres, the airflow rate in the fluidized bed was increased to 1.15 times that of the hydrothermal treatment stage and maintained for 4 minutes to obtain fluidized dispersed microspheres. Subsequently, a low-humidity airflow at a temperature of 62℃ and a relative humidity of 15% was introduced, and the microspheres were dried and solidified for 25 minutes. Testing showed that the residual ethanol content of the dried and solidified microspheres was 0.18%, and the water activity was 0.35.

[0074] The obtained ibuprofen sustained-release microspheres were sized by sieving through a 20-30 mesh sieve and then equilibrated for 10 minutes in an environment of 25°C and 35% relative humidity before being directly fed into a capsule filling machine to fill capsules.

[0075] To evaluate the rationality of the lower limit process conditions, comparative examples 2-1 to 2-5 were set up. Except for the differences listed in Table 2, the conditions for each comparative example were the same as those for Example 2.

[0076] Comparative Example 2-1 controlled the pre-drying and solvent removal endpoint to 0.20% residual ethanol; this comparative example was used to evaluate whether the bed pressure difference change and high humidity stability were affected when the residual ethanol was below the lower limit during the hydrothermal treatment.

[0077] Comparative Example 2-2 adjusts the relative humidity of the hot and humid airflow to 55%; this comparative example is used to evaluate the treatment effect when the humidity of the hot and humid airflow is insufficient.

[0078] Comparative Examples 2-3 shortened the damp heat treatment time, so that the peak bed pressure difference only reached 105% of P0; this comparative example was used to evaluate the treatment effect when the bed pressure difference did not reach the specified lower limit.

[0079] Comparative Examples 2-4 involved a continuous flow of hot and humid air for 6 minutes without any drying airflow between adjacent hot and humid airflows; these comparative examples were used to evaluate the effect of segmented hot and humid treatment on controlling the transient aggregation state.

[0080] Comparative Examples 2-5 adjust the relative humidity of the low-humidity airflow to 25%; these comparative examples are used to evaluate whether the drying and curing endpoint and accelerated stability are affected when the humidity of the low-humidity airflow is too high.

[0081] Table 2: Performance Comparison of Example 2 and Comparative Example under Conditions Approaching the Lower Limit of Process Range Residual ethanol / % 0.3 0.2 0.31 0.3 0.3 0.3 Water activity after low humidity drying 0.35 0.34 0.35 0.35 0.36 0.42 relative humidity of hot and humid airflow / % 60 60 55 60 60 60 Peak pressure difference during damp heat treatment / P0 109% 104% 105% 105% 113% 109% Pressure differential drop value / P0 99% 98% 98% 99% 111% 100% Percentage of agglomerates on the sieve / % 0.9 1.7 1.9 2.2 3.8 1.1 Microsphere adhesion rate after 30 days at 40℃ and 75%RH / % 4.5 13.8 14.6 15.1 12.9 10.7 Capsule deformation rate / % 1.2 5.9 6.4 6.8 5.2 4.6 Release curve f2 before and after acceleration 72 56 54 53 58 60 Change in maximum release rate / % 4.8 9.9 10.4 10.8 8.7 8.1 As shown in Table 2, under conditions close to the lower limit of the process range, the bed pressure difference in Example 2 can still be increased to 109% of P0, and after fluidization collision, it drops back to 99% of P0. After accelerated stabilization, the microparticle adhesion rate is 4.5%, and the f2 similarity factor is 72.

[0082] In Comparative Example 2-1, when the residual ethanol content was less than 0.3%, the peak pressure difference during hydrothermal treatment only reached 104% of P0, and the adhesion rate of the microparticles increased to 13.8% after subsequent accelerated stabilization. This result indicates that when the residual ethanol content is too low, the state change of the drug-loaded microparticles during hydrothermal treatment is insufficient.

[0083] Comparative Examples 2-2 and 2-3 showed insufficient humidity and insufficient peak pressure difference in the hot and humid airflow, respectively. After acceleration, the microparticle adhesion rates were 14.6% and 15.1%, respectively. This result indicates that the high humidity stability of Example 2 cannot be achieved when the intensity of the hot and humid treatment is insufficient.

[0084] Comparative Examples 2-4, which did not employ segmented hydrothermal treatment, showed a pressure drop of 111% of P0 and an oversize agglomerate ratio of 3.8%. This result indicates that segmented hydrothermal treatment, even under conditions close to the lower limit, is beneficial for controlling transient agglomeration and reducing the risk of sustained agglomeration. Comparative Examples 2-5 showed higher relative humidity in the low-humidity airflow, with higher water activity and high-humidity adhesion rate than Example 2, indicating that the humidity of the low-humidity airflow affects the drying and curing effect.

[0085] Example 3 This embodiment is used to verify that even under process conditions close to the upper limit, the state of microparticles can still be controlled by bed pressure difference and fluidized collision dispersion to avoid the formation of irreversible agglomeration.

[0086] Except for the parameter adjustments described below, the equipment structure, spray application method, detection method, release rate evaluation method, and accelerated stability test conditions in this embodiment are the same as in Example 1.

[0087] In this embodiment, 1000g of ibuprofen, 100g of stearic acid, and 60g of polyvinylpyrrolidone were weighed and added to 2800g of pharmaceutical ethanol. The mixture was stirred at 25°C to 30°C for 45 minutes to obtain an ethanol-based drug-coated solution. The sucrose pellet core had a particle size of 0.60mm to 0.85mm. The material temperature during the spray application process was 36°C, and the atomization pressure was 0.20MPa.

[0088] After the spray application is completed, the obtained wet drug-loaded microspheres are pre-dried and desolventized. The residual ethanol content of the pre-dried drug-loaded microspheres was found to be 1.50%. The pre-dried drug-loaded microspheres were then placed in a fluidized bed, and the bed pressure difference P0 before the inflow of hot and humid air was recorded.

[0089] The temperature of the humid airflow is 52℃ and the relative humidity is 78%. The humid airflow is introduced in 5 sections, each section is introduced for 6 minutes, and a dry airflow with a relative humidity of 35% is introduced for 3 minutes between adjacent sections; When the bed pressure difference increases to 119% of P0, humidification is stopped and the fluidized impact of the microspheres is maintained.

[0090] Before the fluidized collision dispersion ends, the bed pressure difference drops back to 108% of P0. Then, the fluidized bed airflow is increased to 1.45 times that of the wet heat treatment stage and maintained for 10 minutes to allow the wet heat treatment pellets to continue to collide and tumble, thus obtaining fluidized dispersed pellets.

[0091] A low-humidity airflow at a temperature of 50℃ and a relative humidity of 5% was introduced into the fluidized dispersed microparticles, and the mixture was dried and solidified for 45 minutes. Testing revealed that the residual ethanol content of the dried and solidified microspheres was 0.10%, and the water activity was 0.20. The resulting ibuprofen sustained-release microspheres were then granulated and equilibrated before being filled into capsules.

[0092] To evaluate the rationality of the high-limit process conditions, comparative examples 3-1 to 3-5 were set up; Except for the differences listed in Table 3, the conditions for each comparative example were the same as those for Example 3.

[0093] Comparative Example 3-1 controlled the residual ethanol content of pre-dried drug-loaded pellets to 1.80%; this comparative example was used to evaluate the effect of residual ethanol exceeding the upper limit on hydrothermal treatment and fluidized dispersion.

[0094] Comparative Example 3-2 adjusted the relative humidity of the hot and humid airflow to 85%; this comparative example was used to evaluate the changes in microparticle aggregation and capsule stability when the humidity of the hot and humid airflow exceeded the specified range.

[0095] Comparative Example 3-3 extends the wet heat treatment time to make the bed pressure difference reach 126% of P0; this comparative example is used to evaluate whether the microparticles enter a difficult-to-disperse agglomerate state after the peak pressure difference exceeds the specified range.

[0096] Comparative Examples 3-4 were not increased after wet heat treatment; the air intake was maintained at the same air intake during the wet heat treatment stage. This comparative example was used to evaluate the effect of insufficient fluidization dispersion intensity on agglomerates on the sieve and the release curve.

[0097] Comparative Examples 3-5 had their low-humidity airflow temperature adjusted to 45°C and their drying time extended to 60 min, so that the residual ethanol was close to that of Example 3; these comparative examples were used to evaluate the effect of insufficient low-humidity drying temperature on water activity and accelerated stability.

[0098] Table 3: Performance Comparison of Example 3 and Comparative Example under Conditions Approaching the Upper Limit of Process Range Residual ethanol / % 1.5 1.8 1.51 1.5 1.49 0.13 Water activity after low humidity drying 0.2 0.31 0.35 0.34 0.29 0.39 relative humidity of hot and humid airflow / % 78 78 85 78 78 78 Peak pressure difference during damp heat treatment / P0 119% 123% 128% 126% 119% 119% Pressure differential drop value / P0 108% 119% 125% 123% 116% 108% Percentage of agglomerates on the sieve / % 1.3 9.8 15.6 14.1 6.7 2.4 Capsule filling pass rate / % 98.9 93.4 86.7 88.1 94.6 97.5 Microsphere adhesion rate after 30 days at 40℃ and 75%RH / % 3.6 25.8 38.4 34.7 19.5 13.2 Capsule deformation rate / % 0.9 12.4 20.6 18.9 8.6 5.7 Release curve f2 before and after acceleration 76 47 36 39 51 58 Change in maximum release rate / % 3.8 14.9 21.5 19.8 12.7 9.4 As shown in Table 3, under conditions close to the upper limit of the process range, the peak pressure difference of the wet heat treatment in Example 3 is 119% of P0, the pressure difference drop value is 108% of P0, and the proportion of agglomerates on the sieve is 1.3%, indicating that Example 3 can still keep the temporary agglomeration state within the dispersible range.

[0099] Comparative Example 3-1 had a residual ethanol content of 1.80%, Comparative Example 3-2 had a relative humidity of 85% for the hot and humid airflow, and Comparative Example 3-3 had a peak pressure difference of 126% of P0. All three groups showed insufficient pressure difference reduction, a significant increase in the proportion of agglomerates on the sieve, and an increase in the microsphere adhesion rate and capsule deformation rate after accelerated stabilization. These results indicate that it is still necessary to control residual ethanol, hot and humid airflow humidity, and peak bed pressure difference even under conditions close to the upper limit.

[0100] Comparative Examples 3-4 did not increase the air intake volume, and the proportion of agglomerates on the sieve was 6.7%, with a microparticle adhesion rate of 19.5% after acceleration. This result indicates that continuing to perform fluidized impact dispersion with sufficient intensity after hydrothermal treatment is beneficial to reducing subsequent adhesion. Although the residual ethanol in Comparative Examples 3-5 was close to that in Example 3, the water activity was higher than that in Example 3, and the maximum release rate changed more, indicating that the high humidity stability of microparticles was affected when the low humidity airflow temperature was insufficient.

[0101] Example 4 This embodiment is used to verify the feasibility of the process of the present invention under scale-up conditions, and to verify the feasibility of directly filling capsules with the obtained ibuprofen sustained-release microspheres after granulation and equilibration.

[0102] This embodiment uses a batch size of 10 kg microspheres for preparation; The mass ratio of ibuprofen, stearic acid, and polyvinylpyrrolidone is 100:7.5:4.5, and the amount of pharmaceutical ethanol is 2.3 times the mass of ibuprofen; the sucrose core particle size is 0.70 mm to 0.80 mm.

[0103] The preparation of the ethanol-based drug solution, the fluidized bed bottom spray application, and the pre-drying and solvent removal treatment were carried out in accordance with Example 1; After pre-drying and solvent removal treatment, the residual ethanol content was tested at three locations, and the measured values ​​were 0.86%, 0.94% and 1.02%, respectively, with an average value of 0.94%.

[0104] The pre-dried drug-loaded pellets were placed in an enlarged bottom-jet fluidized bed, and a humid heat gas flow with a temperature of 47°C and a relative humidity of 68% to 70% was introduced. The bed pressure difference P0 was recorded before the humid heat treatment. During the humid heat treatment, the bed pressure difference increased to 112% to 116% of P0.

[0105] After maintaining fluidized collision, the bed pressure difference dropped back to 100% to 106% of P0. Then, the fluidized bed airflow was increased to 1.30 times that of the wet heat treatment stage and maintained for 7 minutes to obtain fluidized dispersed microparticles.

[0106] A low-humidity airflow at 56℃ and 10% relative humidity is introduced into the fluidized dispersed microspheres, and the microspheres are dried and solidified for 35 minutes. After drying and solidification, the microspheres are granulated through a 20-30 mesh sieve and equilibrated in an environment of 25℃-30℃ and 35%-45% relative humidity for 10-20 minutes before being directly fed into a capsule filling machine to fill capsules.

[0107] To evaluate the impact of critical steps under scaled-up production, comparative examples 4-1 to 4-4 were set up. Except for the differences listed in Table 4, the prescriptions, batch sizes, spray application conditions, and testing methods for each comparative example are the same as those in Example 4.

[0108] Comparative Example 4-1 uses a conventional drying process. After spraying and pre-drying, no hot and humid airflow treatment or fluidized collision dispersion is performed. Instead, the product is directly dried at low humidity, granulated, and equilibrated before being filled into capsules.

[0109] Comparative Example 4-2 uses a reference process with an independent anti-stick protective layer. The anti-stick protective layer is composed of hydroxypropyl methylcellulose, talc and polyethylene glycol in a mass ratio of 10:5:1, and is prepared into a coating solution with purified water. After ordinary drying, the drug-loaded microspheres were placed in a fluidized bed for protective coating. The coating weight gain was 2.0% of the microsphere mass. During the coating process, the material temperature was 40℃ to 45℃ and the atomization pressure was 0.15MPa. After coating, continue drying until the residual ethanol is no higher than 0.2%, and then fill the capsules; this comparative example is used to compare the process time and stability with the direct filling process of the present invention.

[0110] Comparative Examples 4-3 were subjected to wet heat treatment, fluidized dispersion and low-humidity airflow drying and curing according to Example 4, but without granulation through a 20-30 mesh sieve, and were directly subjected to environmental equilibration and capsule filling.

[0111] Comparative Examples 4-4 were subjected to wet heat treatment, fluidized dispersion, low-humidity airflow drying and curing, and granulation according to Example 4. However, after granulation, they were not equilibrated in an environment of 25°C to 30°C and relative humidity of 35% to 45%, but were directly fed into a capsule filling machine to fill capsules.

[0112] Table 4: Performance Comparison of Example 4 and Comparative Example under Large-Scale Batch Batch size / kg 10 10 10 10 10 Should an additional non-stick protective layer be applied? no no yes no no Total process time / h 5.8 4.6 8.9 5.5 5.6 Micro pellet yield / % 99.4 98.6 96.8 98.1 99 Capsule content variation RSD / % 2.1 3.8 2.5 4.6 3.2 Capsule filling pass rate / % 99.2 96.1 98.7 94.9 97.4 Microsphere adhesion rate after 30 days at 40℃ and 75%RH / % 3.1 18.4 4.2 9.7 8.5 Capsule deformation rate / % 0.7 7.6 1 3.8 3.2 Release curve f2 before and after acceleration 77 50 75 63 65 As shown in Table 4, in Example 4, the micro-pellet yield was 99.4% and the capsule filling qualification rate was 99.2% under a batch size of 10kg. The RSD of the capsule filling weight difference was 2.1%, indicating that the process of the present invention can maintain good flowability and filling stability under scaled-up production.

[0113] Comparative Example 4-1, without humid heat airflow treatment and fluidized collision dispersion, showed a microparticle adhesion rate of 18.4% after acceleration, with an f2 similarity factor of 50, indicating that direct filling with ordinary drying is insufficient in terms of high humidity stability.

[0114] In Comparative Example 4-2, after adding an independent anti-sticking protective layer, the adhesion rate of the micro-pellets after acceleration was 4.2%, and the f2 similarity factor was 75. However, the total process time increased to 8.9 h, and the yield of micro-pellets decreased to 96.8%. This result shows that the coating protective layer can reduce the risk of adhesion, but it will increase the process time and material loss. The present invention can still obtain a lower adhesion rate and a higher f2 similarity factor without separately coating an independent anti-sticking protective layer.

[0115] Compared with Comparative Example 4-3, which did not undergo whole-capsule processing, the RSD of capsule weight variation increased to 4.6%, and the capsule filling qualification rate decreased to 94.9%.

[0116] Comparative Example 4-4, without prior environmental equilibration, showed increased pellet adhesion and capsule deformation rates after acceleration. These results indicate that granulation and equilibration steps contribute to capsule filling consistency and storage stability in scaled-up production.

[0117] Verification Example 1 This validation example is used to verify the correspondence between changes in bed pressure differential and transient agglomeration and dispersion states, and to confirm that the bed pressure differential rising to 108% to 120% of P0 and falling back to 95% to 110% of P0 after fluidization collision are used as process control indicators for hydrothermal treatment and fluidized dispersion.

[0118] This verification example selects the processing procedures of Example 1, Example 2, Example 3, Comparative Example 2-3, Comparative Example 3-3 and Comparative Example 1-2 for recording; Apart from the process differences between the selected groups, the methods for recording bed pressure difference, detecting agglomerates on the sieve, and detecting particle size are all the same.

[0119] The change in particle size D90 was determined using the following method: Microsphere samples were taken before and after treatment, and the particle size distribution was determined by sieving or laser particle size distribution method. The particle size distribution was calculated as the percentage change of D90 after treatment relative to D90 before treatment. The greater the change in D90, the more obvious the aggregation or particle size shift.

[0120] Image recognition clustering rate is determined as follows: Images were continuously acquired at the fluidized bed observation window. Images near the peak pressure difference of the wet heat treatment were analyzed. Aggregates formed by temporary contact of 2 to 10 microspheres were included in the agglomerated particle region and calculated as a percentage of the number of agglomerated particle regions to the total number of particle regions.

[0121] Table 5: Relationship between bed pressure difference and the proportion of agglomerates on the sieve Example 1 114% 103% 5.8 0.6 3.2 Example 2 109% 99% 4.2 0.9 4.1 Example 3 119% 108% 8.6 1.3 4.8 Comparative Examples 2-3 105% 99% 1.6 2.2 5.5 Comparative Example 3-3 126% 123% 18.9 14.1 22.6 Comparative Examples 1-2 116% 118% 13.4 7.4 16.2 As shown in Table 5, the peak pressure difference of Examples 1 to 3 is within the range of 108% to 120% of P0, the pressure difference drop value is within the range of 95% to 110% of P0, the proportion of agglomerates on the sieve is not higher than 1.3%, and the change in particle size D90 is not higher than 4.8%.

[0122] The peak pressure difference of Comparative Examples 2-3 was only 105% of P0, and the image recognition agglomeration rate was 1.6%, indicating that insufficient wet heat treatment did not form a sufficient transient agglomeration state between the microparticles, and the subsequent improvement in high humidity stability was limited.

[0123] Comparative Example 3-3 showed a peak pressure difference of 126% of P0, a pressure difference reduction of 123% of P0, an oversize agglomerate ratio of 14.1%, and a particle size change of 22.6%. These results indicate that when the pressure difference exceeds the specified upper limit and cannot be reduced, the microparticles have formed a large number of difficult-to-disperse agglomerates.

[0124] The peak pressure difference in Comparative Examples 1-2 was 116% of P0, but due to insufficient fluidization intensity during the wet heat treatment stage, the pressure difference drop was still 118% of P0, and the proportion of agglomerates on the sieve was 7.4%. This result shows that simply reaching the peak pressure difference range is not enough; fluidization collision is also needed to bring the pressure difference back to the specified range.

[0125] This verification example shows that the peak pressure difference of the bed and the pressure difference drop-off value after fluidization dispersion together constitute the process criteria for hydrothermal treatment and fluidization dispersion, which are used to determine whether the microparticles are in a dispersible, transient agglomeration state.

[0126] Verification Example 2 This verification example is used to verify the microparticle adhesion rate, capsule deformation rate, and release curve stability of the ibuprofen sustained-release capsules obtained in this invention under high temperature and high humidity conditions.

[0127] This verification example selects samples from Examples 1 to 4 and the main comparative examples, and places them at 40°C and 75%RH for 30 days. After the experiment, the changes in release rate, f2 similarity factor, microsphere adhesion rate and capsule deformation rate were measured at 1h, 2h, 4h and 7h.

[0128] The change in release rate was calculated as the absolute difference between the release rate at the corresponding time point after the accelerated stability test and the release rate at the corresponding time point before the test; the f2 similarity factor was used to evaluate the similarity between the release curves before and after acceleration.

[0129] Table 6: Comparison of release curves after accelerated stability Example 1 2.5 2.8 3 3.1 78 2.8 0.5 Example 2 3.8 4.2 4.5 4.8 72 4.5 1.2 Example 3 3.1 3.4 3.6 3.8 76 3.6 0.9 Example 4 2.9 3.1 3.3 3.5 77 3.1 0.7 Comparative Example 1-1 8.6 9.4 10.2 10.8 52 16.7 6.8 Comparative Examples 1-2 11.4 12.7 13.8 14.7 46 24.6 12.8 Comparative Example 3-3 15.8 17 18.6 19.8 39 34.7 18.9 Comparative Example 4-2 3.2 3.5 3.8 4 75 4.2 1 As shown in Table 6, after the accelerated stability test, the maximum release rate of Examples 1 to 4 did not exceed 4.8%, the f2 similarity factor was not lower than 72, the microparticle adhesion rate was not higher than 4.5%, and the capsule deformation rate was not higher than 1.2%.

[0130] Comparative Example 1-1 was not subjected to humid heat airflow treatment, Comparative Example 1-2 had insufficient fluidization intensity during the humid heat treatment stage, and Comparative Example 3-3 exceeded the upper limit of pressure difference during humid heat treatment. All of the above samples showed obvious changes in microparticle adhesion rate, capsule deformation rate and release rate, indicating that humid heat treatment, fluidization collision dispersion and pressure difference control jointly affect the storage stability of microparticles.

[0131] Comparative Example 4-2 is a reference sample with a separate anti-sticking protective layer. Its microparticle adhesion rate after acceleration is 4.2%, and the f2 similarity factor is 75. Example 4 did not have a separate anti-sticking protective layer, but the microparticle adhesion rate was 3.1%, and the f2 similarity factor was 77. These results show that the present invention can maintain the stability of microparticles by using humid heat treatment, fluidized dispersion, and low-humidity airflow drying and curing before capsule filling.

Claims

1. A process for preparing ibuprofen sustained-release capsules, characterized in that, Includes the following steps: Ibuprofen, stearic acid and polyvinylpyrrolidone were added to pharmaceutical ethanol and stirred to obtain the ethanol-based drug solution. A blank pellet core is placed in a fluidized bed, and the ethanol-based drug-coated solution is sprayed into the blank pellet core in a fluidized state. After spraying, wet drug-loaded micro pellets are obtained. The wet drug-loaded microspheres were pre-dried and desolventized to obtain pre-dried drug-loaded microspheres with an ethanol content of 0.3% to 1.5%. A hot and humid airflow with a temperature of 42–52°C and a relative humidity of 60%–78% is introduced into the pre-dried drug-loaded microspheres in a fluidized state. The pressure difference P0 of the fluidized bed before the hot and humid airflow is introduced is recorded. The hot and humid treatment continues until the pressure difference of the bed increases to 108%–120% of P0, and a brief agglomeration occurs between the pre-dried drug-loaded microspheres. Continue to maintain the fluidized collision of the pre-dried drug-loaded microspheres. The briefly agglomerated pre-dried drug-loaded microspheres are dispersed by fluidized collision, and the bed pressure difference drops back to 95% to 110% of P0, thus obtaining the wet heat-treated microspheres. The wet heat-treated microspheres are kept in a fluidized state, and through collision and tumbling between the microspheres, the softened material on the surface of the microspheres is dispersed on the surface of the microspheres to obtain fluidized dispersed microspheres. The fluidized dispersed microspheres were dried and solidified by passing a low-humidity airflow with a relative humidity of 5% to 15% to obtain ibuprofen sustained-release microspheres. The ibuprofen sustained-release microspheres are filled into capsules to obtain ibuprofen sustained-release capsules.

2. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, In the ethanol-based drug solution, the mass ratio of ibuprofen, stearic acid, and polyvinylpyrrolidone is 100:5 to 10:3 to 6, and the mass of pharmaceutical ethanol is 1.8 to 2.8 times the mass of ibuprofen.

3. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, The blank pellet core is a sucrose pellet core with a particle size of 0.60–0.85 mm; The ethanol-based drug solution is sprayed from the bottom of the fluidized bed. During the spraying process, the material temperature is 30-36°C and the atomization pressure is 0.12-0.20 MPa.

4. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, The pre-drying and solvent removal process was carried out under hot air at 65-69°C for 2-4 hours, and the endpoint of the pre-drying and solvent removal process was defined as the residual ethanol content in the drug-loaded microspheres reaching 0.3%-1.5%.

5. The ibuprofen sustained-release capsule preparation process according to claim 4, characterized in that, The pre-drying and solvent removal process was carried out under hot air at 67°C for 3 hours.

6. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, The hot and humid airflow is introduced into the fluidized bed in segments. After each segment of hot and humid airflow is introduced, the pre-dried drug-loaded microparticles are kept in fluidized collision. The number of hot and humid airflow segments is 2 to 5, and the introduction time of each segment is 3 to 6 minutes. A dry airflow with a relative humidity of 20% to 35% is introduced between two adjacent hot and humid airflow segments for 1 to 3 minutes.

7. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, The bed pressure difference P0 is the average value obtained by continuously recording for 60 seconds before the hot and humid airflow is introduced; The bed pressure difference was collected at intervals of 5 to 10 seconds, and the bed pressure difference drop value was the average value obtained by continuously recording for 60 seconds before the end of fluidization collision. The brief reunion is specifically described as follows: During the hot and humid airflow treatment process, there are agglomerates formed by temporary contact of 2 to 10 microspheres. After continuous fluidization and collision for 1 to 10 minutes, the bed pressure difference can drop back to 95% to 110% of P0, and the proportion of agglomerates on the sieve after treatment is not higher than 2.0%.

8. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, After obtaining the hydrothermal treated microspheres, the air inlet volume of the fluidized bed is increased to 1.15 to 1.45 times that of the hydrothermal treatment stage, and maintained for 4 to 10 minutes to obtain the fluidized dispersed microspheres.

9. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, The low-humidity airflow temperature is 50-62℃, the drying and curing time is 25-45 min, and the residual ethanol content in the dried and cured ibuprofen sustained-release microspheres is no higher than 0.2%, and the water activity is 0.20-0.

35.

10. The ibuprofen sustained-release capsule preparation process according to claim 1, characterized in that, The ibuprofen sustained-release microspheres are granulated through a 20-30 mesh sieve and equilibrated for 10-20 minutes in an environment of 25-30°C and 35%-45% relative humidity before being directly fed into a capsule filling machine to fill capsules.

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