Bromochlorohydantoin sustained-release tablet and preparation method thereof

Abstract

The invention relates to the technical field of bromochlorohydantoin tablets, and particularly discloses a bromochlorohydantoin sustained-release tablet and a preparation method thereof. The preparation method of the bromochlorohydantoin sustained-release tablet comprises the following steps: preparing the modified hydroxypropyl methylcellulose; preparing a mesoporous silica-polydopamine nano carrier; preparing a medicine carrying mesoporous silica-polydopamine; preparing an outer sheet layer; preparing an inner-layer tablet core; and wrapping the inner-layer tablet core with the outer-layer tablet layer, tabletting by a double-layer tablet press, putting into a coating machine, and carrying out spray coating and drying to obtain the bromochlorohydantoin sustained-release tablet. The prepared bromochlorohydantoin sustained-release tablet has the functions of dynamic release regulation, water quality purification and substrate improvement, is high and lasting in sterilization efficiency, and is suitable for large-scale popularization and application.

Description

Technical Field

[0001] The present invention relates to the technical field of bromochlorohydantoin tablets, and particularly to a sustained-release bromochlorohydantoin tablet and a preparation method thereof. Background Art

[0002] China is the world's largest aquaculture country, with its output accounting for over 60% of the world's total for a long time. In 2023, the national aquaculture output of aquatic products reached 58.0961 million tons (Statistical Yearbook of Fisheries in China 2024), with an output value exceeding 1.3 trillion yuan, making it the core of the global aquatic food supply. In the field of aquaculture, the use of disinfectants is crucial for preventing and controlling the spread of pathogens. As a common disinfectant, bromochlorohydantoin is widely used in the disinfection of aquaculture water bodies due to its broad-spectrum bactericidal ability and relatively low toxicity. However, the existing bromochlorohydantoin tablets still have some limitations in practical applications, especially in three key performance aspects: bactericidal efficiency and persistence, dynamic release regulation ability, and water quality purification ability.

[0003] Bactericidal efficiency and persistence are important indicators for measuring the performance of disinfectants. The existing bromochlorohydantoin tablets show acceptable bactericidal efficiency but lack persistence. In practical applications, the disinfectant needs to maintain an effective bactericidal concentration for a long time to ensure the continuous cleanliness of the aquaculture water body. However, after the traditional bromochlorohydantoin tablets are put into the water body, the drug release rate is relatively fast, making it difficult to maintain a long-term bactericidal effect, resulting in a gradual weakening of the disinfection effect and an inability to effectively inhibit the regeneration and spread of pathogens.

[0004] The dynamic release regulation ability is crucial for the adaptability of disinfectants under different environmental conditions. In aquaculture, factors such as the pH value, temperature, and organic matter content of the water body will significantly affect the release and bactericidal effect of disinfectants. The existing bromochlorohydantoin tablets lack an effective dynamic release regulation mechanism and cannot adjust the drug release rate according to changes in environmental conditions. This leads to the situation that in some environments, the drug is released too fast, causing waste of resources and water pollution, while in other environments, the drug release is insufficient and the expected bactericidal effect cannot be achieved.

[0005] The ability to purify water quality and improve the bottom substrate is another important performance of disinfectants in aquaculture. An ideal disinfectant should not only have a bactericidal function but also be able to effectively remove organic pollutants and harmful substances in the water body, improving water quality and the bottom substrate. However, the existing bromochlorohydantoin tablets do not perform well in this regard. Traditional bromochlorohydantoin tablets mainly focus on sterilization and lack consideration for water quality purification and bottom substrate improvement, and cannot effectively reduce the content of harmful substances such as ammonia nitrogen and nitrite in the water body, resulting in the deterioration of water quality and the bottom substrate and affecting the healthy growth of aquaculture organisms.

[0006] In summary, the existing bromochlorohydantoin tablets have obvious limitations in three key performance aspects: bactericidal efficiency and persistence, dynamic release regulation ability, and water quality and sediment purification ability. These limitations not only affect the actual application effect of the disinfectant but also restrict its wide application in the aquaculture field. Therefore, developing a new type of bromochlorohydantoin sustained-release tablet to overcome these limitations and improve the comprehensive performance of the disinfectant is of great significance for the healthy development of the aquaculture industry. Summary of the Invention

[0007] The purpose of the present invention is to solve the disadvantages existing in the prior art, and a preparation method of a bromochlorohydantoin sustained-release tablet is proposed.

[0008] A preparation method of a bromochlorohydantoin sustained-release tablet is characterized by including the following steps:

[0009] S1. Disperse hydroxypropyl methylcellulose, maleic anhydride, DCC, and DMAP in tetrahydrofuran, stir in a constant-temperature water bath, cool, filter, pour the filtrate into ethanol, collect the precipitate, and dry it under vacuum to obtain modified hydroxypropyl methylcellulose;

[0010] S2. Disperse mesoporous silica in Tris buffer solution, add dopamine hydrochloride, ultrasonicate, stir, centrifuge, wash, and dry it under vacuum to obtain a mesoporous silica-poly dopamine nanocarrier;

[0011] S3. Dissolve bromochlorohydantoin in ethanol, add the mesoporous silica-poly dopamine nanocarrier, ultrasonicate, stir, and dry it under vacuum to obtain a drug-loaded mesoporous silica-poly dopamine;

[0012] S4. (1) Disperse the modified hydroxypropyl methylcellulose and ethyl cellulose in ethanol and water, and freeze-dry to obtain an outer layer;

[0013] (2) Mix the drug-loaded mesoporous silica-poly dopamine with ethyl cellulose and press into tablets to obtain an inner core;

[0014] S5. Wrap the outer layer around the inner core, press the tablets with a double-layer tablet press, place them in a coating machine, carry out spray coating, and dry to obtain the bromochlorohydantoin sustained-release tablet.

[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°C, the constant-temperature water bath stirring time is 8-9 h, and the stirring speed is 200-300 rpm.

[0017] Preferably, in the step S1, the vacuum drying temperature is 45 - 55°C.

[0018] Preferably, in the step S2, the weight ratio of mesoporous silica, Tris buffer solution, and dopamine hydrochloride is 8 - 12: 180 - 220: 2 - 3.

[0019] Preferably, in the step S2, perform ultrasonic treatment with an ultrasonic time of 0.5 - 1 h and an ultrasonic frequency of 40 - 60 kHz.

[0020] Preferably, in the step S2, perform stirring with a stirring time of 16 - 20 h and a stirring speed of 200 - 300 rpm.

[0021] Preferably, in the step S2, the vacuum drying temperature is 55 - 65°C.

[0022] Preferably, in the step S3, the weight ratio of bromochlorohydantoin, ethanol, and mesoporous silica - polydopamine nanocarrier is 10 - 14: 15 - 25: 10 - 12.

[0023] Preferably, in the step S3, perform ultrasonic treatment for 0.5 - 1.5 h with an ultrasonic frequency of 40 - 60 kHz.

[0024] Preferably, in the step S3, perform stirring with a stirring time of 5 - 6 h and a stirring speed of 100 - 200 rpm. Preferably, in the step S3, the vacuum drying temperature is 55 - 65°C.

[0025] Preferably, in the 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 the step S4(1), the freeze - drying temperature is - 75 - - 85°C and the freeze - drying time is 34 - 38 h to obtain an outer layer lamella with a porosity > 75%.

[0027] Preferably, in the step S4(2), the weight ratio of drug - loaded mesoporous silica - polydopamine and ethylcellulose is 20 - 24: 0.5 - 1.5.

[0028] Preferably, in the step S2(2), perform tabletting with a pressure of 18 - 22 kN.

[0029] Preferably, in the step S5, perform tabletting with a double - layer tabletting machine, with an outer layer pressure of 8 - 12 kN and an inner layer pressure of 18 - 22 kN.

[0030] Preferably, in the step S5, it is placed in a coating machine and spray-coated with an Eudragit S100 acetone solution 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 °C, the outlet air temperature is 35-45 °C, and the coating weight gain is controlled at 3-5%.

[0031] Preferably, in the step S5, it is dried at 55-65 °C.

[0032] A bromochlorohydantoin sustained-release tablet is prepared by using the preparation method of the bromochlorohydantoin sustained-release tablet described in any one of the above.

[0033] Beneficial effects:

[0034] Through the combination of molecular functionalization, structural stratification and nano synergy, the comprehensive performance of the bromochlorohydantoin sustained-release tablet is significantly improved. Compared with the traditional technology that relies on a single polymer or a simple composite system, the present invention constructs a logical closed loop of "dynamic release regulation - gradient structure optimization - carrier synergistic purification" from the dimensions of microscopic molecular design and functional integration. First, hydroxypropyl methylcellulose is modified with carboxylic acid groups to endow the substrate with pH responsiveness, so that the carboxylic acid groups dissociate in alkaline sediment to enhance hydrophilicity and accelerate drug release for rapid sterilization, while the groups are protonated in acidic water bodies to slow down release for extended action time, realizing the adaptive regulation of the release rate. Secondly, the freeze-drying technology is used to construct a porous structure on the outer layer to accelerate the initial drug dissolution to meet the rapid disinfection requirements; the inner layer is designed by the composite of mesoporous silica-poly dopamine nano carrier and ethyl cellulose. The high specific surface area of mesoporous silica is used to improve the drug loading efficiency, while the poly dopamine layer reduces the ammonia nitrogen and organic pollutants in the sediment through adsorption, synchronously realizing the functions of drug loading, slow release and water quality purification. The double-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-term slow release of the inner layer synergistically optimize the release kinetics, forming a technical closed loop of "rapid sterilization - long-term maintenance - ecological restoration".

[0035] The present invention progresses step by step: the pH-responsive substrate realizes dynamic release regulation through molecular modification, the gradient structure balances the release efficiency through pore design and functional stratification, and the nano carrier expands the performance boundary through high drug loading and adsorption functions. The bromochlorohydantoin sustained-release tablet of the present invention has the characteristics of high efficiency, long term and environmental protection, providing an innovative solution for the disinfection and ecological management of aquaculture water bodies. Specific embodiments

[0036] The present invention will be further explained below with reference to specific embodiments.

[0037] Example 1

[0038] A preparation method of a bromochlorohydantoin sustained-release tablet includes the following steps:

[0039] S1. Disperse 6 g of hypromellose, 1 g of maleic anhydride, 0.05 g of DCC, and 0.03 g of DMAP in 25 g of tetrahydrofuran, stir in a constant temperature water bath at 75 °C for 8 h, with a stirring speed of 200 rpm. Cool, filter, pour the filtrate into ethanol, collect the precipitate, and dry it in vacuo at 45 °C to obtain modified hypromellose;

[0040] S2. Disperse 8 g of mesoporous silica in 180 g of Tris buffer solution, add 2 g of dopamine hydrochloride, perform ultrasonic treatment for 0.5 h with an ultrasonic frequency of 40 kHz, stir for 16 h with a stirring speed of 200 rpm, centrifuge, wash, and dry in vacuo at 55 °C to obtain mesoporous silica-poly(dopamine) nanocarriers;

[0041] S3. Dissolve 10 g of bromochlorohydantoin in 15 g of ethanol, add 10 g of mesoporous silica-poly(dopamine) nanocarriers, perform ultrasonic treatment for 0.5 h with an ultrasonic frequency of 40 kHz, stir for 5 h with a stirring speed of 100 rpm, and dry in vacuo at 55 °C to obtain drug-loaded mesoporous silica-poly(dopamine);

[0042] S4. (1) Disperse 8 g of modified hypromellose and 2 g of ethyl cellulose in 12 g of ethanol and 4 g of water, and perform freeze-drying at -75 °C for 34 h to obtain an outer layer lamella;

[0043] (2) Mix 20 g of drug-loaded mesoporous silica-poly(dopamine) with 0.5 g of ethyl cellulose, and the tableting pressure is 18 kN to obtain an inner layer tablet core;

[0044] S5. Wrap the outer layer lamella around the inner layer tablet core, perform tableting with a double-layer tableting machine, with an outer layer pressure of 8 kN and an inner layer pressure of 18 kN. Place it in a coating machine, use a 10% (mass fraction) acetone solution of Eudragit S100, with a coating solution spraying speed of 8 mL / min, an inlet air temperature of 55 °C, an outlet air temperature of 35 °C, control the coating weight gain to 3%, and dry at 55 °C to obtain bromochlorohydantoin sustained-release tablets.

[0045] Example 2

[0046] A preparation method of bromochlorohydantoin sustained-release tablets, comprising the following steps:

[0047] S1. Disperse 10 g of hypromellose, 1.5 g of maleic anhydride, 0.15 g of DCC, and 0.07 g of DMAP in 35 g of tetrahydrofuran, stir in a constant temperature water bath at 85 °C for 9 h, with a stirring speed of 300 rpm. Cool, filter, pour the filtrate into ethanol, collect the precipitate, and dry it in vacuo at 55 °C to obtain modified hypromellose;

[0048] S2. Disperse 12 g of mesoporous silica in 220 g of Tris buffer solution, add 3 g of dopamine hydrochloride, perform ultrasonic treatment for 1 h at an ultrasonic frequency of 60 kHz, stir for 20 h at a stirring speed of 300 rpm, centrifuge, wash, and dry in vacuum at 65 °C to obtain a mesoporous silica-poly(dopamine) nanocarrier;

[0049] S3. Dissolve 14 g of bromochlorohydantoin in 25 g of ethanol, add 12 g of the mesoporous silica-poly(dopamine) nanocarrier, perform ultrasonic treatment for 1.5 h at an ultrasonic frequency of 60 kHz, stir for 6 h at a stirring speed of 200 rpm, and dry in vacuum at 65 °C to obtain a drug-loaded mesoporous silica-poly(dopamine);

[0050] S4. (1) Disperse 10 g of modified hydroxypropyl methylcellulose and 4 g of ethylcellulose in 16 g of ethanol and 8 g of water, and perform freeze-drying at -85 °C for 38 h to obtain an outer layer sheet;

[0051] (2) Mix 24 g of the drug-loaded mesoporous silica-poly(dopamine) with 1.5 g of ethylcellulose, press into tablets at a pressure of 22 kN to obtain an inner layer tablet core;

[0052] S5. Wrap the outer layer sheet around the inner layer tablet core, press the tablets with a double-layer tablet press, with an outer layer pressure of 12 kN and an inner layer pressure of 22 kN, place them in a coating machine, and perform spray coating with a 12% (mass fraction) acetone solution of Eudragit S100. The spraying speed of the coating solution is 12 mL / min, the inlet air temperature is 65 °C, the outlet air temperature is 45 °C, control the coating weight gain to be 5%, and dry at 65 °C to obtain a bromochlorohydantoin sustained-release tablet.

[0053] Example 3

[0054] A preparation method of a bromochlorohydantoin sustained-release tablet, comprising the following steps:

[0055] S1. Disperse 8 g of hydroxypropyl methylcellulose, 1.2 g of maleic anhydride, 0.1 g of DCC, and 0.05 g of DMAP in 30 g of tetrahydrofuran, stir in a constant temperature water bath at 80 °C for 8.5 h at a stirring speed of 250 rpm, cool, filter, pour the filtrate into ethanol, collect the precipitate, and dry in vacuum at 50 °C to obtain modified hydroxypropyl methylcellulose;

[0056] S2. Disperse 10 g of mesoporous silica in 200 g of Tris buffer solution, add 2.5 g of dopamine hydrochloride, perform ultrasonic treatment for 0.7 h at an ultrasonic frequency of 50 kHz, stir for 18 h at a stirring speed of 250 rpm, centrifuge, wash, and dry in vacuum at 60 °C to obtain a mesoporous silica-poly(dopamine) nanocarrier;

[0057] S3. Dissolve 12 g of bromochlorohydantoin in 20 g of ethanol, add 11 g of mesoporous silica-polydopamine nanocarrier, ultrasonically treat for 1 h with an ultrasonic frequency of 50 kHz, stir for 5.5 h at a stirring speed of 150 rpm, and vacuum dry at 60 °C to obtain the drug-loaded mesoporous silica-polydopamine;

[0058] S4. (1) Disperse 9 g of modified hypromellose and 3 g of ethylcellulose in 14 g of ethanol and 6 g of water, and freeze-dry at -80 °C for 36 h to obtain the outer lamella;

[0059] (2) Mix 22 g of the drug-loaded mesoporous silica-polydopamine with 1 g of ethylcellulose, and the tableting pressure is 20 kN to obtain the inner tablet core;

[0060] S5. Wrap the outer lamella around the inner tablet core, tablet with a double-layer tablet press, the outer pressure is 10 kN and the inner pressure is 20 kN, place it in a coating machine, and perform spray coating with a 10% (mass fraction) acetone solution of Eudragit S100. The spraying speed of the coating solution is 10 mL / min, the inlet air temperature is 60 °C, the outlet air temperature is 40 °C, control the coating weight gain to be 4%, and dry at 60 °C to obtain the bromochlorohydantoin sustained-release tablets.

[0061] Comparative Example 1

[0062] The difference between Comparative Example 1 and Example 3 is that in step S1, maleic anhydride-modified hypromellose is not used, and the original hypromellose is directly used.

[0063] A preparation method of bromochlorohydantoin tablets comprises the following steps:

[0064] S1. Disperse 10 g of mesoporous silica in 200 g of Tris buffer solution, add 2.5 g of dopamine hydrochloride, ultrasonically treat for 0.7 h with an ultrasonic frequency of 50 kHz, stir for 18 h at a stirring speed of 250 rpm, centrifuge, wash, and vacuum dry at 60 °C to obtain the mesoporous silica-polydopamine nanocarrier;

[0065] S2. Dissolve 12 g of bromochlorohydantoin in 20 g of ethanol, add 11 g of mesoporous silica-polydopamine nanocarrier, ultrasonically treat for 1 h with an ultrasonic frequency of 50 kHz, stir for 5.5 h at a stirring speed of 150 rpm, and vacuum dry at 60 °C to obtain the drug-loaded mesoporous silica-polydopamine;

[0066] S3. (1) Disperse 9 g of hypromellose and 3 g of ethylcellulose in 14 g of ethanol and 6 g of water, and freeze-dry at -80 °C for 36 h to obtain the outer lamella;

[0067] (2) Mix 22 g of drug-loaded mesoporous silica-polydopamine with 1 g of ethyl cellulose, and the tabletting pressure is 20 kN to obtain the inner tablet core;

[0068] S4. Wrap the outer tablet layer around the inner tablet core, and tablet it with a double-layer tabletting machine. The outer pressure is 10 kN and the inner pressure is 20 kN. Place it in a coating machine and perform spray coating with a 10% (mass fraction) acetone solution of Eudragit S100. The spraying speed of the coating solution is 10 mL / min, the inlet air temperature is 60 °C, the outlet air temperature is 40 °C, control the coating weight gain to 4%, and dry at 60 °C to obtain the bromochlorohydantoin sustained-release tablets.

[0069] Comparative Example 2

[0070] The difference between Comparative Example 2 and Example 3 is that in step S4, no layering is performed, direct mixing and tabletting are carried out, and freeze-drying is not performed.

[0071] A preparation method of bromochlorohydantoin sustained-release tablets comprises the following steps:

[0072] S1. Disperse 8 g of hydroxypropyl methylcellulose, 1.2 g of maleic anhydride, 0.1 g of DCC, and 0.05 g of DMAP in 30 g of tetrahydrofuran, stir in a constant temperature water bath at 80 °C for 8.5 h, the stirring speed is 250 rpm, cool, filter, pour the filtrate into ethanol, collect the precipitate, and dry it in vacuum at 50 °C to obtain modified hydroxypropyl methylcellulose;

[0073] S2. Disperse 10 g of mesoporous silica in 200 g of Tris buffer solution, add 2.5 g of dopamine hydrochloride, perform ultrasonic treatment for 0.7 h, the ultrasonic frequency is 50 kHz, stir for 18 h, the stirring speed is 250 rpm, centrifuge, wash, and dry in vacuum at 60 °C to obtain the mesoporous silica-polydopamine nanocarrier;

[0074] S3. Dissolve 12 g of bromochlorohydantoin in 20 g of ethanol, add 11 g of the mesoporous silica-polydopamine nanocarrier, perform ultrasonic treatment for 1 h, the ultrasonic frequency is 50 kHz, stir for 5.5 h, the stirring speed is 150 rpm, and dry in vacuum at 60 °C to obtain the drug-loaded mesoporous silica-polydopamine;

[0075] S4. Mix 9 g of modified hydroxypropyl methylcellulose, 4 g of ethyl cellulose, and 22 g of the drug-loaded mesoporous silica-polydopamine, the tabletting pressure is 10 kN, place it in a coating machine, and perform spray coating with a 10% (mass fraction) acetone solution of Eudragit S100. The spraying speed of the coating solution is 10 mL / min, the inlet air temperature is 60 °C, the outlet air temperature is 40 °C, control the coating weight gain to 4%, and dry at 60 °C to obtain the bromochlorohydantoin sustained-release tablets.

[0076] Comparative Example 3

[0077] The difference between Comparative Example 3 and Example 3 lies in that freeze-drying is not carried out in step S4(1).

[0078] A preparation method of a bromochlorohydantoin sustained-release tablet comprises the following steps:

[0079] S1. Disperse 8 g of hypromellose, 1.2 g of maleic anhydride, 0.1 g of DCC, and 0.05 g of DMAP in 30 g of tetrahydrofuran, stir in a constant-temperature water bath at 80 °C for 8.5 h, with a stirring speed of 250 rpm, cool, filter, pour the filtrate into ethanol, collect the precipitate, and dry it in vacuo at 50 °C to obtain modified hypromellose;

[0080] S2. Disperse 10 g of mesoporous silica in 200 g of Tris buffer solution, add 2.5 g of dopamine hydrochloride, perform ultrasonic treatment for 0.7 h with an ultrasonic frequency of 50 kHz, stir for 18 h with a stirring speed of 250 rpm, centrifuge, wash, and dry in vacuo at 60 °C to obtain a mesoporous silica-polydopamine nanocarrier;

[0081] S3. Dissolve 12 g of bromochlorohydantoin in 20 g of ethanol, add 11 g of the mesoporous silica-polydopamine nanocarrier, perform ultrasonic treatment for 1 h with an ultrasonic frequency of 50 kHz, stir for 5.5 h with a stirring speed of 150 rpm, and dry in vacuo at 60 °C to obtain a drug-loaded mesoporous silica-polydopamine;

[0082] S4. (1) Tableting 9 g of modified hypromellose and 3 g of ethyl cellulose under a pressure of 20 kN to obtain an outer layer tablet layer;

[0083] (2) Mix 22 g of the drug-loaded mesoporous silica-polydopamine with 1 g of ethyl cellulose and tableting under a pressure of 20 kN to obtain an inner layer tablet core;

[0084] S5. Wrap the outer layer tablet layer around the inner layer tablet core, tablet with a double-layer tablet press, with an outer layer pressure of 10 kN and an inner layer pressure of 20 kN, place it in a coating machine, and perform spray coating with a 10% (mass fraction) acetone solution of Eudragit S100. The spraying speed of the coating solution is 10 mL / min, the inlet air temperature is 60 °C, the outlet air temperature is 40 °C, control the coating weight gain to be 4%, and dry at 60 °C to obtain the bromochlorohydantoin sustained-release tablet.

[0085] Comparative Example 4

[0086] The difference between Comparative Example 4 and Example 3 lies in that mesoporous silica is not modified with dopamine hydrochloride.

[0087] A preparation method of a bromochlorohydantoin sustained-release tablet comprises the following steps:

[0088] S1. Disperse 8 g of hydroxypropyl methylcellulose, 1.2 g of maleic anhydride, 0.1 g of DCC, and 0.05 g of DMAP in 30 g of tetrahydrofuran, stir in a constant temperature water bath at 80 °C for 8.5 h, with a stirring speed of 250 rpm. Cool, filter, and pour the filtrate into ethanol. Collect the precipitate and dry it in a vacuum at 50 °C to obtain modified hydroxypropyl methylcellulose;

[0089] S2. Dissolve 12 g of bromochlorohydantoin in 20 g of ethanol, add 11 g of mesoporous silica, perform ultrasonic treatment for 1 h with an ultrasonic frequency of 50 kHz, stir for 5.5 h with a stirring speed of 150 rpm, and dry in a vacuum at 60 °C to obtain drug-loaded mesoporous silica;

[0090] S3. (1) Disperse 9 g of modified hydroxypropyl methylcellulose and 3 g of ethyl cellulose in 14 g of ethanol and 6 g of water, and perform freeze-drying at -80 °C for 36 h to obtain the outer layer sheet;

[0091] (2) Mix 22 g of drug-loaded mesoporous silica-polydopamine with 1 g of ethyl cellulose, and press into tablets with a pressure of 20 kN to obtain the inner layer tablet core;

[0092] S4. Wrap the outer layer sheet around the inner layer tablet core, press the tablets with a double-layer tablet press, with an outer layer pressure of 10 kN and an inner layer pressure of 20 kN. Place them in a coating machine and perform spray coating with a 10% (mass fraction) acetone solution of Eudragit S100. The spraying speed of the coating solution is 10 mL / min, the inlet air temperature is 60 °C, the outlet air temperature is 40 °C, control the coating weight gain to 4%, and dry at 60 °C to obtain bromochlorohydantoin sustained-release tablets.

[0093] Performance Test

[0094] Preparation of aqueous solution: NaCl: 3.5%, CaCl2: 0.1%, MgCl2: 0.05%, pH: 6.5 (adjusted with HCl / NaOH).

[0095] Preparation of sediment: Formula: Diatomite: 70%, Humus: 30%, add NH4Cl to an ammonia nitrogen concentration of 10 mg / L, pH: 8.5.

[0096] Bacteria and culture medium: Aeromonas veronii (ATCC 35624), LB culture medium (Tryptone: 10 g / L, Yeast extract: 5 g / L, NaCl: 10 g / L), culture until 10 6 CFU / mL.

[0097] Dynamic release regulation ability: According to the guiding principles for sustained-release preparations in the Chinese Veterinary Pharmacopoeia 2020 edition and the quality standards for bromochlorohydantoin powder (for aquatic use), the bromochlorohydantoin tablets prepared in Examples 1-3 and Comparative Examples 1-4 were respectively placed in sediment (alkaline) and water body (acidic), and shaken 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 detected by titration; the data were recorded; the results are shown in Table 1.

[0098] Calculation formula:

[0099] pH response difference (%) = release rate in alkaline environment - release rate in acidic environment.

[0100] Bactericidal efficiency: According to the standard of GB / T 38502-2020, the bromochlorohydantoin sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-4 were respectively added to the water body containing Aeromonas veronii (pH 7.0), and kept at a constant temperature of 25°C; samples were taken after 60 min and 48 h respectively, and spread on agar plates for culturing for 24 h; the data were recorded; the results are shown in Table 1.

[0101] Calculation formula: Water quality purification: According to the standard of GB17378.4-2007, the bromochlorohydantoin sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-4 were put into the sediment, left standing at 25°C for 48 h, and the supernatant was taken by centrifugation; the ammonia nitrogen concentration was measured by the spectrophotometric method with Nessler's reagent; 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] From the data of Examples 1-3 in Table 1, it can be seen that the comprehensive performance of the bromochlorohydantoin sustained-release tablets prepared by the present invention is excellent. Specifically, the average value of the cumulative release rate at 48 h is 98.4%, and the highest can reach 98.6%; the average value of the pH response difference is 41.5%, and the highest can reach 41.8%; the initial bactericidal rate is ≥99.9, the average value of the bactericidal maintenance rate at 48 h is 95.6%, and the highest can reach 95.8%; the average value of the ammonia nitrogen adsorption rate is 38.8%, and the highest can reach 39.1%.

[0108] From the data of Example 3 and Comparative Example 1 in Table 1, it can be seen that in terms of the dynamic release regulation, bactericidal efficiency and water quality purification function of bromochlorohydantoin sustained-release tablets, Example 3 is significantly superior to Comparative Example 1. This is mainly because in Comparative Example 1, hydroxypropyl methylcellulose was not modified with carboxylic acid groups, resulting in the lack of pH responsiveness of the tablets and the inability to dynamically regulate the release rate according to the acid-base differences between the sediment and the water body. Although Comparative Example 1 retained the water quality purification function of the drug-loaded mesoporous silica-polydopamine, the shortcomings in its core release and bactericidal performance limited its comprehensive application value. In contrast, Example 3 endows the substrate with dynamic response ability through carboxylic acid group modification, and combines gradient structure design to achieve the balance between efficient release and long-term maintenance.

[0109] From the data of Example 3 and Comparative Example 2 in Table 1, it can be seen that in terms of the release kinetics and bactericidal efficiency of bromochlorohydantoin sustained-release tablets, Example 3 is significantly superior to Comparative Example 2. This is mainly because in Comparative Example 2, the layered tableting process was not adopted, and the modified hydroxypropyl methylcellulose, ethyl cellulose and drug-loaded mesoporous silica-polydopamine were directly mixed and tabletted, resulting in the absence of the outer porous structure and the inner sustained-release functional layer. In addition, the mechanical strength of the single-structure tablets is relatively low, and they are prone to premature disintegration in water. Example 3 constructs an outer porous layer and an inner drug-loaded sustained-release layer through freeze-drying, realizing the precise regulation of "rapid release-long-term maintenance", protecting the structural stability of the tablets, and significantly improving the actual application effect.

[0110] From the data of Example 3 and Comparative Example 3 in Table 1, it can be seen that in terms of the initial release rate and bactericidal efficiency of bromochlorohydantoin sustained-release tablets, Example 3 is significantly superior to Comparative Example 3. This is mainly because in Comparative Example 3, freeze-drying was not carried out in step S4, and the porosity of the outer layer tablets decreased significantly, unable to quickly dissolve and release the drug. Although the sustained-release function of the inner drug-loaded mesoporous silica-polydopamine was retained, the too low initial release resulted in the ineffective inhibition of pathogenic bacteria during the critical period, and the overall disinfection effect was limited. Example 3 forms a high-porosity outer layer through the -80 °C freeze-drying process to accelerate drug dissolution, and combines the sustained-release effect of the inner drug-loaded mesoporous silica-polydopamine to achieve the dual optimization of bactericidal efficiency and persistence.

[0111] From the data of Example 3 and Comparative Example 4 in Table 1, it can be seen that in terms of the water quality purification function and drug-loading efficiency of bromochlorohydantoin sustained-release tablets, Example 3 is significantly superior to Comparative Example 4. This is mainly because in Comparative Example 4, mesoporous silica was not modified with dopamine hydrochloride, and the original mesoporous silica was directly used for drug loading, resulting in a decrease in its specific surface area and adsorption function. In addition, the surface of the unmodified mesoporous silica lacks the action of polydopamine, and the drug release regulation ability is weakened. Example 3 not only improves the drug-loading efficiency by modifying mesoporous silica, but also endows it with the ability to adsorb pollutants, realizing disinfection and ecological restoration simultaneously, with significant technical advantages.

[0112] Those of ordinary skill in the art should understand that any discussion of the above embodiments is merely exemplary and is not intended to imply that the scope of the present invention is limited to these examples; under the concept of the present invention, the technical features in the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations in different aspects of the present invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. A method for preparing bromochlorohydantoin sustained-release tablets, characterized in that: The steps include: S1. Disperse hydroxypropyl methylcellulose, maleic anhydride, DCC and DMAP in tetrahydrofuran, stir in a constant temperature water bath, cool, filter and pour the filtrate into ethanol, collect the precipitate, and vacuum dry to obtain modified hydroxypropyl methylcellulose; S2, dispersing mesoporous silica in Tris buffer, adding dopamine hydrochloride, ultrasonicating, stirring, centrifuging, washing, and vacuum drying to obtain a mesoporous silica-polydopamine nanocarrier; S3, dissolving bromochlorohydantoin in ethanol, adding mesoporous silica-polydopamine nanocarrier, ultrasonicating, stirring, and vacuum drying to obtain drug-loaded mesoporous silica-polydopamine; S4, (1) dispersing modified hydroxypropyl methylcellulose and ethyl cellulose in ethanol and water, and freeze-drying to obtain an outer sheet; (2) mixing the drug-loaded mesoporous silica-polydopamine with ethyl cellulose and tableting to obtain an inner layer tablet core; S5, wrapping the inner layer tablet core with the outer layer tablet, pressing the tablets with a double-layer tablet press, placing the tablets in a coating machine, spray coating, and drying to obtain bromochlorohydantoin sustained-release tablets.

2. The method for preparing the bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In the 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. The method for preparing bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In the step S2, the weight ratio of mesoporous silica, Tris buffer and dopamine hydrochloride is 8-12:180-220:2-3.

4. The method for preparing the bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In the step S3, the weight ratio of bromochlorohydantoin, ethanol, and mesoporous silica-polydopamine nanocarrier is 10-14:15-25:10-12.

5. The method for preparing bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In step S4(1), the weight ratio of modified hydroxypropyl methylcellulose, ethyl cellulose, ethanol and water is 8-10:2-4:12-16:4-8.

6. The method for preparing the bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In step S4(1), the freeze-drying temperature is -75--85°C, and the freeze-drying time is 34-38 hours.

7. The method for preparing the bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In step S4(2), the weight ratio of drug-loaded mesoporous silica-polydopamine to ethyl cellulose is 20-24: 0.5-1.5。 8. The method for preparing the bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In step S4(2), the tabletting pressure is 18-22 kN.

9. The method for preparing bromochlorohydantoin sustained-release tablets according to claim 1, characterized in that: In step S5, tablets are pressed using 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 bromochlorohydantoin sustained-release tablet, characterized in that: The bromochlorohydrin sustained-release tablets are prepared by the preparation method of any one of claims 1 to 9.

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