Bromochlorohydrin sustained release tablet and its preparation method
By using molecular functionalization and structural hierarchical design, combined with nanocarrier technology, the limitations of bromochlorohydantoin tablets in terms of bactericidal efficiency, persistence, and water purification capabilities have been overcome. This has enabled dynamic regulation of drug release and water purification, thereby improving the disinfection effect and ecological management capabilities of aquaculture water bodies.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- YELLOW SEA FISHERIES RES INST CHINESE ACAD OF FISHERIES SCI
- Filing Date
- 2025-03-27
- Publication Date
- 2026-06-19
AI Technical Summary
Existing bromochlorohydantoin tablets have significant limitations in terms of bactericidal efficiency and persistence, dynamic release regulation capabilities, and water purification capabilities. They cannot effectively maintain long-term bactericidal effects, cannot adjust the drug release rate according to environmental conditions, and lack the ability to purify water and improve sediment.
By employing molecular functionalization, structural layering, and nanosynergistic methods, pH-responsive release is achieved through modification of the carboxylic acid groups of hydroxypropyl methylcellulose. Combined with the composite design of mesoporous silica-polydopamine nanocarrier and ethyl cellulose, an outer porous structure and an inner drug-carrying and purification functional layer are constructed, forming a technical closed loop of "rapid sterilization-long-term maintenance-ecological restoration".
It significantly improves the overall performance of bromochlorohydantoin sustained-release tablets, achieves adaptive regulation of drug release, improves sterilization efficiency and durability, and also has the ability to purify water and improve sediment, forming an efficient, long-lasting and environmentally friendly disinfection and ecological management solution.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of bromochlorohydantoin tablet technology, and more particularly to a bromochlorohydantoin sustained-release tablet and its preparation method. Background Technology
[0002] China is the world's largest aquaculture nation, consistently accounting for over 60% of global production. In 2023, China's aquaculture output reached 58.0961 million tons (2024 China Fisheries Statistical Yearbook), with a value exceeding 1.3 trillion yuan, making it a core player in global aquatic food supply. In the aquaculture sector, the use of disinfectants is crucial for preventing and controlling the spread of pathogens. Bromochlorohydantoin, a common disinfectant, is widely used for disinfecting aquaculture waters due to its broad-spectrum bactericidal ability and relatively low toxicity. However, existing bromochlorohydantoin tablets still have some limitations in practical applications, particularly in three key performance areas: bactericidal efficiency and persistence, dynamic release regulation, and water purification capabilities.
[0003] Bactericidal efficiency and persistence are important indicators for evaluating disinfectant performance. Existing bromochlorohydantoin tablets show acceptable bactericidal efficiency, but their persistence is insufficient. In practical applications, disinfectants need to maintain an effective bactericidal concentration for a relatively long period to ensure the continuous cleanliness of aquaculture water. However, traditional bromochlorohydantoin tablets release the drug rapidly after being added to the water, making it difficult to maintain a long-term bactericidal effect. This leads to a gradual weakening of the disinfection effect, failing to effectively inhibit the regeneration and spread of pathogens.
[0004] Dynamic release regulation is crucial for the adaptability of disinfectants under different environmental conditions. In aquaculture, factors such as water pH, temperature, and organic matter content significantly affect the release and bactericidal effect of disinfectants. Existing bromochlorohydantoin tablets lack an effective dynamic release regulation mechanism, failing to adjust the drug release rate according to changes in environmental conditions. This leads to excessively rapid drug release in some environments, resulting in resource waste and water pollution, while insufficient drug release in others fails to achieve the expected bactericidal effect.
[0005] Water purification and bottom sediment improvement capabilities are another crucial performance characteristic of disinfectants in aquaculture. An ideal disinfectant should not only possess bactericidal properties but also effectively remove organic pollutants and harmful substances from the water, improving both water quality and bottom sediment. However, existing bromochlorohydantoin tablets do not perform ideally in this regard. Traditional bromochlorohydantoin tablets primarily focus on bactericidal action, lacking consideration for water purification and bottom sediment improvement. They are unable to effectively reduce the levels of harmful substances such as ammonia nitrogen and nitrite in the water, leading to deterioration of water and bottom sediment and negatively impacting the healthy growth of farmed organisms.
[0006] In summary, existing bromochlorohydantoin tablets have significant limitations in three key performance aspects: bactericidal efficiency and persistence, dynamic release regulation capability, and water and sediment purification ability. These limitations not only affect the practical application effect of the disinfectant but also restrict its widespread use in aquaculture. Therefore, developing a novel bromochlorohydantoin sustained-release tablet to overcome these limitations and improve the overall performance of the disinfectant is of great significance for the healthy development of the aquaculture industry. Summary of the Invention
[0007] The purpose of this invention is to address the shortcomings of existing technologies by proposing a method for preparing bromochlorohydantoin sustained-release tablets.
[0008] A method for preparing bromochlorohydantoin sustained-release tablets, characterized by comprising the following steps:
[0009] S1. Hydroxypropyl methylcellulose, maleic anhydride, DCC, and DMAP are dispersed in tetrahydrofuran, stirred in a constant temperature water bath, cooled, filtered, and the filtrate is poured into ethanol. The precipitate is collected and dried under vacuum to obtain modified hydroxypropyl methylcellulose.
[0010] S2. Disperse mesoporous silica in Tris buffer, add dopamine hydrochloride, sonicate, stir, centrifuge, wash, and vacuum dry to obtain mesoporous silica-polydopamine nanocarrier.
[0011] S3. Dissolve bromochlorohydantoin in ethanol, add mesoporous silica-polydopamine nanocarrier, sonicate, stir, and vacuum dry to obtain drug-loaded mesoporous silica-polydopamine;
[0012] S4、(1) Disperse modified hydroxypropyl methylcellulose and ethylcellulose in ethanol and water, freeze dry to obtain outer sheet;
[0013] (2) Mix drug-loaded mesoporous silica-polydopamine with ethyl cellulose, compress the mixture into tablets, and obtain the inner core.
[0014] S5. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press, place it in a coating machine for spray coating, and dry it to obtain bromochlorohydantoin sustained-release tablets.
[0015] Preferably, in step S1, the weight ratio of hydroxypropyl methylcellulose, maleic anhydride, DCC, DMAP, and tetrahydrofuran is 6-10:1-1.5:0.05-0.15:0.03-0.07:25-35.
[0016] Preferably, in step S1, the water bath temperature is 75-85℃, the constant temperature water bath stirring time is 8-9h, and the stirring speed is 200-300rpm.
[0017] Preferably, in step S1, the vacuum drying temperature is 45-55℃.
[0018] Preferably, in step S2, the weight ratio of mesoporous silica, Tris buffer, and dopamine hydrochloride is 8-12:180-220:2-3.
[0019] Preferably, in step S2, ultrasound is performed for 0.5-1 hour at a frequency of 40-60 kHz.
[0020] Preferably, in step S2, the stirring is carried out for 16-20 hours at a speed of 200-300 rpm.
[0021] Preferably, in step S2, the vacuum drying temperature is 55-65℃.
[0022] Preferably, in step S3, the weight ratio of bromochlorohydantoin, ethanol, and mesoporous silica-polydopamine nanocarrier is 10-14:15-25:10-12.
[0023] Preferably, in step S3, ultrasound is used for 0.5-1.5 hours, and the ultrasound frequency is 40-60 kHz.
[0024] Preferably, in step S3, the stirring time is 5-6 hours and the stirring speed is 100-200 rpm. Preferably, in step S3, the vacuum drying temperature is 55-65℃.
[0025] Preferably, in step S4(1), the weight ratio of modified hydroxypropyl methylcellulose, ethylcellulose, ethanol, and water is 8-10:2-4:12-16:4-8.
[0026] Preferably, in step S4(1), the freeze-drying temperature is -75 to -85°C and the freeze-drying time is 34 to 38 hours to obtain an outer layer with a porosity > 75%.
[0027] Preferably, in step S4(2), the weight ratio of drug-loaded mesoporous silica-polydopamine and ethyl cellulose is 20-24:0.5-1.5.
[0028] Preferably, in step S2(2), the tablet is compressed at a pressure of 18-22 kN.
[0029] Preferably, in step S5, the tablet is pressed by a double-layer tablet press, with the outer layer pressure being 8-12 kN and the inner layer pressure being 18-22 kN.
[0030] Preferably, in step S5, the coating is placed in a coating machine and spray-coated with an acetone solution of Eudragit S100 with a mass fraction of 8-12%. The spraying speed of the coating solution is 8-12 mL / min, the inlet air temperature is 55-65℃, the outlet air temperature is 35-45℃, and the coating weight gain is controlled at 3-5%.
[0031] Preferably, in step S5, drying is performed at 55-65°C.
[0032] A bromochlorohydantoin sustained-release tablet, prepared using any one of the above-described methods for preparing bromochlorohydantoin sustained-release tablets.
[0033] Beneficial effects:
[0034] This invention significantly improves the overall performance of bromochlorohydantoin sustained-release tablets through a combination of molecular functionalization, structural layering, and nano-synergistic effects. Compared to traditional technologies that rely on single polymers or simple composite systems, this invention constructs a logical closed loop of "dynamic release regulation - gradient structure optimization - carrier synergistic purification" from the perspective of microscopic molecular design and functional integration. First, by modifying hydroxypropyl methylcellulose with carboxylic acid groups, the substrate is given pH responsiveness. In alkaline sediment, the carboxylic acid groups dissociate, enhancing hydrophilicity and accelerating drug release for rapid sterilization. Simultaneously, in acidic water, the groups are protonated to slow down release and prolong the action time, achieving adaptive regulation of the release rate. Second, a porous outer layer is constructed using freeze-drying technology to accelerate initial drug dissolution to meet the requirements of rapid disinfection. The inner layer, through a composite design of mesoporous silica-polydopamine nanocarrier and ethyl cellulose, utilizes the high specific surface area of mesoporous silica to improve drug loading efficiency. At the same time, the polydopamine layer reduces ammonia nitrogen and organic pollutants in the sediment through adsorption, simultaneously achieving drug loading, sustained release, and water purification. The dual-layer tableting process tightly combines the outer porous structure with the inner drug-loading and purification functional layer. The rapid release of the outer layer and the long-acting sustained release of the inner layer synergistically optimize the release kinetics, forming a three-in-one technical closed loop of "rapid sterilization - long-acting maintenance - ecological restoration".
[0035] This invention features a progressive approach: pH-responsive substrates achieve dynamic release regulation through molecular modification; gradient structures balance release efficiency through pore design and functional stratification; and nanocarriers expand performance boundaries through high drug loading and adsorption capabilities. The bromochlorohydantoin sustained-release tablets of this invention combine high efficiency, long-lasting effect, and environmental friendliness, providing an innovative solution for disinfection and ecological management of aquaculture water bodies. Detailed Implementation
[0036] The present invention will be further explained below with reference to specific embodiments.
[0037] Example 1
[0038] A method for preparing bromochlorohydantoin sustained-release tablets includes the following steps:
[0039] S1. Disperse 6g of hydroxypropyl methylcellulose, 1g of maleic anhydride, 0.05g of DCC, and 0.03g of DMAP in 25g of tetrahydrofuran. Stir in a constant temperature water bath at 75℃ for 8h at a stirring speed of 200rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it under vacuum at 45℃ to obtain modified hydroxypropyl methylcellulose.
[0040] S2. Disperse 8g of mesoporous silica in 180g of Tris buffer, add 2g of dopamine hydrochloride, sonicate for 0.5h at a frequency of 40kHz, stir for 16h at a stirring speed of 200rpm, centrifuge, wash, and vacuum dry at 55℃ to obtain mesoporous silica-polydopamine nanocarrier.
[0041] S3. Dissolve 10g of bromochlorohydantoin in 15g of ethanol, add 10g of mesoporous silica-polydopamine nanocarrier, sonicate for 0.5h at a frequency of 40kHz, stir for 5h at a stirring speed of 100rpm, and vacuum dry at 55℃ to obtain drug-loaded mesoporous silica-polydopamine.
[0042] S4、(1) Disperse 8g of modified hydroxypropyl methylcellulose and 2g of ethylcellulose in 12g of ethanol and 4g of water, and freeze-dry at -75℃ for 34h to obtain the outer sheet;
[0043] (2) Mix 20g of drug-loaded mesoporous silica-polydopamine with 0.5g of ethyl cellulose and compress the tablets at a pressure of 18kN to obtain the inner core.
[0044] S5. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press with an outer layer pressure of 8 kN and an inner layer pressure of 18 kN. Place the tablet in a coating machine and use a 10% Eudragit S100 acetone solution. The coating solution spray rate is 8 mL / min, the inlet air temperature is 55℃, and the outlet air temperature is 35℃. Control the coating weight gain to 3%. Dry at 55℃ to obtain bromochlorohydantoin sustained-release tablets.
[0045] Example 2
[0046] A method for preparing bromochlorohydantoin sustained-release tablets includes the following steps:
[0047] S1. Disperse 10g of hydroxypropyl methylcellulose, 1.5g of maleic anhydride, 0.15g of DCC, and 0.07g of DMAP in 35g of tetrahydrofuran. Stir in a constant temperature water bath at 85℃ for 9h at a stirring speed of 300rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it under vacuum at 55℃ to obtain modified hydroxypropyl methylcellulose.
[0048] S2. Disperse 12g of mesoporous silica in 220g of Tris buffer, add 3g of dopamine hydrochloride, sonicate for 1h at a frequency of 60kHz, stir for 20h at a stirring speed of 300rpm, centrifuge, wash, and vacuum dry at 65℃ to obtain mesoporous silica-polydopamine nanocarrier.
[0049] S3. Dissolve 14g of bromochlorohydantoin in 25g of ethanol, add 12g of mesoporous silica-polydopamine nanocarrier, sonicate for 1.5h at a frequency of 60kHz, stir for 6h at a stirring speed of 200rpm, and vacuum dry at 65℃ to obtain drug-loaded mesoporous silica-polydopamine.
[0050] S4、(1) Disperse 10g of modified hydroxypropyl methylcellulose and 4g of ethylcellulose in 16g of ethanol and 8g of water, and freeze-dry at -85℃ for 38h to obtain the outer sheet;
[0051] (2) Mix 24g of drug-loaded mesoporous silica-polydopamine with 1.5g of ethyl cellulose, compress the mixture into tablets at a pressure of 22kN to obtain the inner core.
[0052] S5. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press with an outer layer pressure of 12 kN and an inner layer pressure of 22 kN. Place the tablet in a coating machine and spray it with a 12% Eudragit S100 acetone solution at a spray rate of 12 mL / min. The inlet air temperature is 65°C and the outlet air temperature is 45°C. Control the coating weight gain to 5%. Dry the tablet at 65°C to obtain bromochlorohydantoin sustained-release tablets.
[0053] Example 3
[0054] A method for preparing bromochlorohydantoin sustained-release tablets includes the following steps:
[0055] S1. Disperse 8g of hydroxypropyl methylcellulose, 1.2g of maleic anhydride, 0.1g of DCC, and 0.05g of DMAP in 30g of tetrahydrofuran. Stir in a constant temperature water bath at 80℃ for 8.5h at a stirring speed of 250rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it under vacuum at 50℃ to obtain modified hydroxypropyl methylcellulose.
[0056] S2. Disperse 10g of mesoporous silica in 200g of Tris buffer, add 2.5g of dopamine hydrochloride, sonicate for 0.7h at a frequency of 50kHz, stir for 18h at a stirring speed of 250rpm, centrifuge, wash, and vacuum dry at 60℃ to obtain mesoporous silica-polydopamine nanocarrier.
[0057] S3. Dissolve 12g of bromochlorohydantoin in 20g of ethanol, add 11g of mesoporous silica-polydopamine nanocarrier, sonicate for 1h at a frequency of 50kHz, stir for 5.5h at a stirring speed of 150rpm, and vacuum dry at 60℃ to obtain drug-loaded mesoporous silica-polydopamine.
[0058] S4、(1) Disperse 9g of modified hydroxypropyl methylcellulose and 3g of ethylcellulose in 14g of ethanol and 6g of water, and freeze-dry at -80℃ for 36h to obtain the outer sheet;
[0059] (2) Mix 22g of drug-loaded mesoporous silica-polydopamine with 1g of ethyl cellulose, and compress the tablet at a pressure of 20kN to obtain the inner core.
[0060] S5. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press with an outer layer pressure of 10 kN and an inner layer pressure of 20 kN. Place the tablet in a coating machine and spray it with a 10% Eudragit S100 acetone solution at a spray rate of 10 mL / min, an inlet air temperature of 60°C, and an outlet air temperature of 40°C. Control the coating weight gain to 4% and dry at 60°C to obtain bromochlorohydantoin sustained-release tablets.
[0061] Comparative Example 1
[0062] The difference between Comparative Example 1 and Example 3 is that maleic anhydride-modified hydroxypropyl methylcellulose is not used in step S1; instead, raw hydroxypropyl methylcellulose is used directly.
[0063] A method for preparing bromochlorohydantoin tablets includes the following steps:
[0064] S1. Disperse 10g of mesoporous silica in 200g of Tris buffer, add 2.5g of dopamine hydrochloride, sonicate for 0.7h at a frequency of 50kHz, stir for 18h at a stirring speed of 250rpm, centrifuge, wash, and vacuum dry at 60℃ to obtain mesoporous silica-polydopamine nanocarrier.
[0065] S2. Dissolve 12g of bromochlorohydantoin in 20g of ethanol, add 11g of mesoporous silica-polydopamine nanocarrier, sonicate for 1h at a frequency of 50kHz, stir for 5.5h at a stirring speed of 150rpm, and vacuum dry at 60℃ to obtain drug-loaded mesoporous silica-polydopamine.
[0066] S3, (1) Disperse 9g of hydroxypropyl methylcellulose and 3g of ethylcellulose in 14g of ethanol and 6g of water, and freeze-dry at -80℃ for 36h to obtain the outer sheet;
[0067] (2) Mix 22g of drug-loaded mesoporous silica-polydopamine with 1g of ethyl cellulose, and compress the tablet at a pressure of 20kN to obtain the inner core.
[0068] S4. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press with an outer layer pressure of 10 kN and an inner layer pressure of 20 kN. Place the tablet in a coating machine and spray it with a 10% Eudragit S100 acetone solution at a spray rate of 10 mL / min, an inlet air temperature of 60°C, and an outlet air temperature of 40°C. Control the coating weight gain to 4% and dry at 60°C to obtain bromochlorohydantoin sustained-release tablets.
[0069] Comparative Example 2
[0070] The difference between Comparative Example 2 and Example 3 is that step S4 does not involve stratification, but is directly mixed and compressed into tablets, and is not freeze-dried.
[0071] A method for preparing bromochlorohydantoin sustained-release tablets includes the following steps:
[0072] S1. Disperse 8g of hydroxypropyl methylcellulose, 1.2g of maleic anhydride, 0.1g of DCC, and 0.05g of DMAP in 30g of tetrahydrofuran. Stir in a constant temperature water bath at 80℃ for 8.5h at a stirring speed of 250rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it under vacuum at 50℃ to obtain modified hydroxypropyl methylcellulose.
[0073] S2. Disperse 10g of mesoporous silica in 200g of Tris buffer, add 2.5g of dopamine hydrochloride, sonicate for 0.7h at a frequency of 50kHz, stir for 18h at a stirring speed of 250rpm, centrifuge, wash, and vacuum dry at 60℃ to obtain mesoporous silica-polydopamine nanocarrier.
[0074] S3. Dissolve 12g of bromochlorohydantoin in 20g of ethanol, add 11g of mesoporous silica-polydopamine nanocarrier, sonicate for 1h at a frequency of 50kHz, stir for 5.5h at a stirring speed of 150rpm, and vacuum dry at 60℃ to obtain drug-loaded mesoporous silica-polydopamine.
[0075] S4. Mix 9g of modified hydroxypropyl methylcellulose, 4g of ethylcellulose, and 22g of drug-loaded mesoporous silica-polydopamine. Compress the mixture at a pressure of 10kN and place it in a coating machine. Spray coating is performed using a 10% Eudragit S100 acetone solution. The spraying speed of the coating solution is 10mL / min, the inlet air temperature is 60℃, the outlet air temperature is 40℃, and the coating weight gain is controlled at 4%. Dry at 60℃ to obtain bromochlorohydantoin sustained-release tablets.
[0076] Comparative Example 3
[0077] The difference between Comparative Example 3 and Example 3 is that freeze drying is not performed in step S4(1).
[0078] A method for preparing bromochlorohydantoin sustained-release tablets includes the following steps:
[0079] S1. Disperse 8g of hydroxypropyl methylcellulose, 1.2g of maleic anhydride, 0.1g of DCC, and 0.05g of DMAP in 30g of tetrahydrofuran. Stir in a constant temperature water bath at 80℃ for 8.5h at a stirring speed of 250rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it under vacuum at 50℃ to obtain modified hydroxypropyl methylcellulose.
[0080] S2. Disperse 10g of mesoporous silica in 200g of Tris buffer, add 2.5g of dopamine hydrochloride, sonicate for 0.7h at a frequency of 50kHz, stir for 18h at a stirring speed of 250rpm, centrifuge, wash, and vacuum dry at 60℃ to obtain mesoporous silica-polydopamine nanocarrier.
[0081] S3. Dissolve 12g of bromochlorohydantoin in 20g of ethanol, add 11g of mesoporous silica-polydopamine nanocarrier, sonicate for 1h at a frequency of 50kHz, stir for 5.5h at a stirring speed of 150rpm, and vacuum dry at 60℃ to obtain drug-loaded mesoporous silica-polydopamine.
[0082] S4、(1) Compress 9g of modified hydroxypropyl methylcellulose and 3g of ethylcellulose into tablets at a pressure of 20kN to obtain the outer layer;
[0083] (2) Mix 22g of drug-loaded mesoporous silica-polydopamine with 1g of ethyl cellulose, and compress the tablet at a pressure of 20kN to obtain the inner core.
[0084] S5. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press with an outer layer pressure of 10 kN and an inner layer pressure of 20 kN. Place the tablet in a coating machine and spray it with a 10% Eudragit S100 acetone solution at a spray rate of 10 mL / min, an inlet air temperature of 60°C, and an outlet air temperature of 40°C. Control the coating weight gain to 4% and dry at 60°C to obtain bromochlorohydantoin sustained-release tablets.
[0085] Comparative Example 4
[0086] The difference between Comparative Example 4 and Example 3 is that dopamine hydrochloride is not used to modify the mesoporous silica.
[0087] A method for preparing bromochlorohydantoin sustained-release tablets includes the following steps:
[0088] S1. Disperse 8g of hydroxypropyl methylcellulose, 1.2g of maleic anhydride, 0.1g of DCC, and 0.05g of DMAP in 30g of tetrahydrofuran. Stir in a constant temperature water bath at 80℃ for 8.5h at a stirring speed of 250rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it under vacuum at 50℃ to obtain modified hydroxypropyl methylcellulose.
[0089] S2. Dissolve 12g of bromochlorohydantoin in 20g of ethanol, add 11g of mesoporous silica, sonicate for 1h at a frequency of 50kHz, stir for 5.5h at a stirring speed of 150rpm, and dry under vacuum at 60℃ to obtain drug-loaded mesoporous silica.
[0090] S3、(1) Disperse 9g of modified hydroxypropyl methylcellulose and 3g of ethylcellulose in 14g of ethanol and 6g of water, and freeze-dry at -80℃ for 36h to obtain the outer sheet;
[0091] (2) Mix 22g of drug-loaded mesoporous silica-polydopamine with 1g of ethyl cellulose, compress the tablets at a pressure of 20kN, and obtain the inner core.
[0092] S4. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press with an outer layer pressure of 10 kN and an inner layer pressure of 20 kN. Place the tablet in a coating machine and spray it with a 10% Eudragit S100 acetone solution at a spray rate of 10 mL / min, an inlet air temperature of 60°C, and an outlet air temperature of 40°C. Control the coating weight gain to 4% and dry at 60°C to obtain bromochlorohydantoin sustained-release tablets.
[0093] Performance testing
[0094] Water preparation: NaCl: 3.5%, CaCl2: 0.1%, MgCl2: 0.05%, pH: 6.5 (adjusted with HCl / NaOH).
[0095] Substrate preparation: Formula: Diatomaceous earth: 70%, Humus: 30%, NH4Cl added to ammonia nitrogen concentration of 10mg / L, pH: 8.5.
[0096] Bacterial strain and culture medium: Aeromonas verrucosa (ATCC 35624), LB medium (tryptone: 10 g / L, yeast extract: 5 g / L, NaCl: 10 g / L), cultured to 100 μL. 6 CFU / mL.
[0097] Dynamic release regulation: In accordance with the guidelines for sustained-release preparations in the 2020 edition of the Chinese Veterinary Pharmacopoeia and the quality standard for bromochlorohydantoin powder (for aquaculture), the bromochlorohydantoin tablets prepared in Examples 1-3 and Comparative Examples 1-4 were placed in sediment (alkaline) and water (acidic), respectively, and oscillated at a constant temperature of 25°C (100 rpm). Samples were taken at regular intervals (0.5 h, 2 h, 6 h, 24 h, 48 h), and the drug concentration was determined by titration. The data were recorded. The results are shown in Table 1.
[0098] Calculation formula:
[0099] pH response difference (%) = alkaline environment release rate - acidic environment release rate.
[0100] Sterilization efficiency: According to GB / T 38502-2020 standard, the bromochlorohydantoin sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-4 were added to water containing Aeromonas villus (pH 7.0) and kept at a constant temperature of 25℃; samples were taken after 60 min and 48 h, respectively, and spread on agar plates for 24 h; data were recorded; the results are shown in Table 1.
[0101] Calculation formula: Water purification: According to GB17378.4-2007 standard, the bromochlorohydantoin sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-4 were added to the bottom sediment, allowed to stand at 25°C for 48 hours, and the supernatant was collected by centrifugation; the ammonia nitrogen concentration was determined by Nessler's reagent spectrophotometry; the data were recorded; the results are shown in Table 1.
[0102] Calculation formula:
[0103] Table 1 Performance Test Results
[0104]
[0105]
[0106] Data Analysis:
[0107] As can be seen from the data in Examples 1-3 in Table 1, the bromochlorohydantoin sustained-release tablets prepared by this invention have excellent comprehensive performance. Specifically, the average cumulative release rate over 48 hours is 98.4%, with a maximum of 98.6%; the average pH response difference is 41.5%, with a maximum of 41.8%; the initial sterilization rate is ≥99.9%, the average sterilization maintenance rate over 48 hours is 95.6%, with a maximum of 95.8%; and the average ammonia nitrogen adsorption rate is 38.8%, with a maximum of 39.1%.
[0108] As can be seen from the data in Table 1 for Example 3 and Comparative Example 1, Example 3 is significantly superior to Comparative Example 1 in terms of dynamic release regulation, bactericidal efficiency, and water purification function of the bromochlorohydantoin sustained-release tablets. This is mainly because Comparative Example 1 did not modify the hydroxypropyl methylcellulose with carboxylic acid groups, resulting in a lack of pH responsiveness in the tablets, making it impossible to dynamically regulate the release rate based on the acid-base differences between the sediment and the water. Although Comparative Example 1 retained the water purification function of drug-loaded mesoporous silica-polydopamine, its shortcomings in core release and bactericidal performance limited its overall application value. In contrast, Example 3, by modifying the substrate with carboxylic acid groups, endowed it with dynamic responsiveness, and combined with a gradient structure design, achieved a balance between efficient release and long-lasting effect.
[0109] As can be seen from the data in Table 1 for Example 3 and Comparative Example 2, Example 3 is significantly superior to Comparative Example 2 in terms of release kinetics and bactericidal efficiency of bromochlorohydantoin sustained-release tablets. This is mainly because Comparative Example 2 did not use a layered tableting process, but directly mixed modified hydroxypropyl methylcellulose, ethyl cellulose, and drug-loaded mesoporous silica-polydopamine for tableting, resulting in the absence of an outer porous structure and an inner sustained-release functional layer. In addition, single-structure tablets have low mechanical strength and are prone to premature disintegration in water. Example 3, by freeze-drying to construct an outer porous layer and an inner drug-loaded sustained-release layer, achieved precise control of "rapid release-long-lasting maintenance," while protecting the structural stability of the tablet and significantly improving the practical application effect.
[0110] As can be seen from the data in Table 1 for Example 3 and Comparative Example 3, Example 3 is significantly superior to Comparative Example 3 in terms of initial release rate and bactericidal efficiency of the bromochlorohydantoin sustained-release tablets. This is mainly because Comparative Example 3 did not undergo freeze-drying in step S4, resulting in a significant decrease in the porosity of the outer layer and an inability to rapidly dissolve and release the drug. Although the sustained-release function of its inner drug-loaded mesoporous silica-polydopamine was retained, the excessively low initial release meant that pathogens were not effectively inhibited during the critical period, limiting the overall disinfection effect. Example 3, through a -80℃ freeze-drying process, forms a high-porosity outer layer, accelerating drug dissolution. Combined with the sustained-release effect of the inner drug-loaded mesoporous silica-polydopamine, it achieves a dual optimization of bactericidal efficiency and durability.
[0111] As shown in Table 1, the data from Example 3 and Comparative Example 4 indicate that Example 3 significantly outperforms Comparative Example 4 in terms of water purification function and drug loading efficiency of the bromochlorohydantoin sustained-release tablets. This is mainly because Comparative Example 4 did not use dopamine hydrochloride to modify the mesoporous silica, directly using the original mesoporous silica for drug loading, resulting in a decrease in its specific surface area and adsorption capacity. Furthermore, the unmodified mesoporous silica surface lacks the effect of polydopamine, weakening its drug release regulation ability. Example 3, by modifying the mesoporous silica, not only improves drug loading efficiency but also endows it with pollutant adsorption capacity, simultaneously achieving disinfection and ecological restoration, demonstrating significant technical advantages.
[0112] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
Claims
1. A process for the preparation of a sustained release tablet of bromochlorohydantoin characterized in that, Includes the following steps: S1. Hydroxypropyl methylcellulose, maleic anhydride, DCC, and DMAP are dispersed in tetrahydrofuran, stirred in a constant temperature water bath, cooled, filtered, and the filtrate is poured into ethanol. The precipitate is collected and dried under vacuum to obtain modified hydroxypropyl methylcellulose. S2. Disperse mesoporous silica in Tris buffer, add dopamine hydrochloride, sonicate, stir, centrifuge, wash, and vacuum dry to obtain mesoporous silica-polydopamine nanocarrier. S3. Dissolve bromochlorohydantoin in ethanol, add mesoporous silica-polydopamine nanocarrier, sonicate, stir, and vacuum dry to obtain drug-loaded mesoporous silica-polydopamine; S4、(1) Disperse modified hydroxypropyl methylcellulose and ethylcellulose in ethanol and water, freeze dry to obtain outer sheet; (2) Mix drug-loaded mesoporous silica-polydopamine with ethyl cellulose, compress the mixture into tablets, and obtain the inner core. S5. Wrap the inner core with the outer tablet layer, compress the tablet using a double-layer tablet press, place it in a coating machine for spray coating, and dry it to obtain bromochlorohydantoin sustained-release tablets.
2. A process for the preparation of sustained release tablets of bromochlorohydantoin as claimed in claim 1, wherein, In step S1, the weight ratio of hydroxypropyl methylcellulose, maleic anhydride, DCC, DMAP, and tetrahydrofuran is 6-10:1-1.5:0.05-0.15:0.03-0.07:25-35.
3. A process for the preparation of sustained release tablets of bromochlorohydantoin as claimed in claim 1, wherein, In step S2, the weight ratio of mesoporous silica, Tris buffer, and dopamine hydrochloride is 8-12:180-220:2-3.
4. The process for the preparation of sustained release tablets of bromochlorohydramine according to claim 1, characterized in that, In step S3, the weight ratio of bromochlorohydantoin, ethanol, and mesoporous silica-polydopamine nanocarrier is 10-14:15-25:10-12.
5. The process for the preparation of sustained release tablets of bromochlorohydantoin as claimed in claim 1 wherein, In step S4(1), the weight ratio of modified hydroxypropyl methylcellulose, ethylcellulose, ethanol, and water is 8-10:2-4:12-16:4-8.
6. The process for the preparation of sustained release tablets of bromochlorohydramine according to claim 1, wherein, In step S4(1), the freeze-drying temperature is -75 to -85°C and the freeze-drying time is 34 to 38 hours.
7. A process for the preparation of sustained release tablets of bromochlorohydantoin as claimed in claim 1, wherein, In step S4(2), the weight ratio of drug-loaded mesoporous silica-polydopamine to ethyl cellulose is 20-24: 0.5-1.5。 8. A process for the preparation of sustained release tablets of bromochlorohydantoin as claimed in claim 1, wherein, In step S4(2), the pressure of the tablet is 18-22kN.
9. A process for the preparation of sustained release tablets of bromochlorohydantoin as claimed in claim 1, wherein, In step S5, the tablet is pressed by a double-layer tablet press, with an outer layer pressure of 8-12 kN and an inner layer pressure of 18-22 kN.
10. A sustained release tablet of bromochlorohydantoin characterized in that, It is prepared using the method for preparing bromochlorohydantoin sustained-release tablets according to any one of claims 1-9.