A kind of florfenicol highly dispersible soluble powder and preparation method thereof

Abstract

The present invention relates to the technical field of veterinary drug preparation, discloses a florfenicol highly dispersible soluble powder and a preparation method thereof, a florfenicol highly dispersible soluble powder, composed of florfenicol, glyceryl monostearate, sodium lauryl sulfate, ethyl orthosilicate, cetyl trimethyl ammonium bromide, polyvinyl pyrrolidone, modified hydroxypropyl methylcellulose, polyethylene glycol, glutaraldehyde. The present invention utilizes glyceryl monostearate and sodium lauryl sulfate to encapsulate florfenicol to prepare a drug-lipid mixed solution, forming nano-scale particles, effectively improving its solubility; polyvinyl pyrrolidone and modified hydroxypropyl methylcellulose are used to form a stable drug-carrier network, increase the viscosity of the solution, form a stable colloid system to prevent the aggregation of florfenicol components, and also by forming a protective layer, effectively reduce the direct effect of heat energy on florfenicol, while improving the solubility of the drug preparation and its stability.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drug preparation, and particularly relates to a florfenicol highly dispersible soluble powder and a preparation method thereof. Background Art

[0002] Florfenicol is an important veterinary antibiotic. Since its introduction, it has been widely used in veterinary clinics for its unique antibacterial mechanism and broad-spectrum antibacterial activity. It is a representative drug of the third-generation amide antibiotics, showing strong antibacterial effects on a variety of Gram-positive and Gram-negative bacteria, especially in the treatment of respiratory tract, digestive tract and urogenital tract infections of livestock and poultry.

[0003] Although florfenicol has excellent antibacterial activity, its solubility and stability have become important factors that restrict its efficacy in actual application. The property of florfenicol raw materials being slightly soluble in water will cause it to take a long time and a large amount of energy during the dissolution process, thus affecting its use effect in veterinary clinics. In addition, florfenicol, which is slightly soluble in water, will mix with food and chyme after entering the gastrointestinal tract of animals orally, making it difficult for the drug to be freed from the food, reducing its solubility in the digestive juice. The reduction in solubility means that the amount of florfenicol absorbed in the gastrointestinal tract is reduced, which in turn affects its distribution in the body and the performance of its efficacy. In addition, the stability of florfenicol is also a key factor affecting its application effect. During storage and use, the drug may be degraded or deteriorated due to the influence of environmental factors such as light, temperature, and humidity, thereby affecting its efficacy and safety. In view of the above problems, it is particularly important to develop a highly dispersible soluble powder of florfenicol that is efficient, stable, easy to absorb and safe. Summary of the invention

[0004] In view of the defects of the prior art, the object of the present invention is to provide a highly dispersible soluble powder of florfenicol and a preparation method thereof.

[0005] The technical effect of the present invention is achieved through the following technical scheme: a highly dispersible soluble powder of florfenicol, which is composed of florfenicol, glyceryl monostearate, sodium lauryl sulfate, tetraethyl orthosilicate, cetyltrimethylammonium bromide, polyvinyl pyrrolidone, modified hydroxypropyl methylcellulose, polyethylene glycol, and glutaraldehyde.

[0006] Another aspect of the present invention provides a method for preparing a highly dispersible soluble powder of florfenicol, comprising the following steps:

[0007] S1: Dissolve florfenicol and glyceryl monostearate in isopropanol, heat in a water bath to control the temperature at 40-50°C, stir at 300 rpm for 30-60 min, then slowly add sodium dodecyl sulfate and continue stirring for 10-15 min. After stirring, use ultrasonic treatment for 5-20 min, set the frequency at 20-40 kHz, and the power density at 2-10 W / cm 2 , the temperature was controlled at 10°C in an ice bath, and after the treatment, a drug-lipid mixed solution was obtained;

[0008] S2: Add tetraethyl orthosilicate to anhydrous ethanol, add 1wt% HCl solution to adjust the pH to 3-5 after dissolving evenly, stir at 400-600rpm for 60min at room temperature to obtain a precursor solution; add hexadecyltrimethylammonium bromide to 25wt% ethanol solution, stir at 400-600rpm for 5min at room temperature, then add ammonia water dropwise, and continue stirring for 10min to obtain a template agent solution;

[0009] S3: adding the template solution prepared in step S2 to the precursor solution prepared in step S2 at a rate of 5-10 mL / min, stirring at 400-600 rpm for 10 min at room temperature, and ultrasonically treating at 600 W for 10-20 min to obtain a mixed solution; heating the mixed solution in a water bath at 100° C. for 24 h, cooling naturally to room temperature, centrifuging at 8000 rpm for 5 min, taking a precipitate, washing alternately with deionized water and ethanol, drying at 80° C. for 12 h, and calcining the dried product in air at 550° C. for 3 h to obtain mesoporous silica;

[0010] S4: Mix the drug-lipid mixed solution prepared in step S1 and the mesoporous silica prepared in step S3, control the speed to 100-200 rpm at room temperature for mechanical stirring for 10-15 minutes, heat in a water bath to raise the temperature to 40-50° C., and continue the stirring for 10 minutes to obtain a mixed solution A; add polyvinyl pyrrolidone to the mixed solution A, stir at 500-800 rpm at room temperature for 10 minutes using a magnetic stirrer, and after the stirring is completed, continue to slowly add modified hydroxypropyl methylcellulose and polyethylene glycol, and continue the stirring for 20-30 minutes to obtain a colloidal solution;

[0011] S5: Slowly add glutaraldehyde to the colloidal solution prepared in step S4, and react for 5 to 10 minutes at room temperature with mechanical stirring at a speed of 100 to 200 rpm, and centrifuge at 8000 to 10000 rpm for 5 to 10 minutes. Take the supernatant and filter it through a 0.22 μm microporous filter membrane, wash it with deionized water for multiple times, and vacuum dry it at 50° C. for 12 hours to obtain florfenicol powder.

[0012] Preferably, the ratio of florfenicol, glyceryl monostearate, sodium lauryl sulfate and isopropanol used in step S1 is 0.1 g: 0.9 g: 0.015-0.02 g: 20-30 mL.

[0013] Preferably, in step S2, the volume ratio of tetraethyl orthosilicate to anhydrous ethanol is 1:10; the ratio of the amount of hexadecyltrimethylammonium bromide to the ethanol solution is 1 g:20-30 mL; the ratio of the amount of tetraethyl orthosilicate, hexadecyltrimethylammonium bromide and ammonia water is 1 mL:0.25-0.4 g:0.5 mL.

[0014] Preferably, the method for preparing modified hypromellose in step S4 comprises the following steps:

[0015] A1: Dissolve hydroxypropyl methylcellulose in isopropanol, heat in a water bath to raise the temperature to 40-50°C, stir at 100-200 rpm for 10 min, add 0.1 mol / L NaOH solution to adjust the pH to 10-11, slowly add monochloroacetic acid during the reaction, continue stirring at the above temperature and speed, react for 1-2 h, and adjust the pH to neutral with hydrochloric acid to obtain a modified solution;

[0016] A2: Glutaraldehyde was added slowly and continuously to the modified solution prepared in step A1, and the mixture was stirred at 100-200 rpm for 5-10 min at room temperature, and then centrifuged at 8000 rpm for 10 min, filtered through a 0.22 μm microporous filter membrane, washed three times with deionized water, and vacuum dried at 50° C. for 8-12 h to obtain modified hydroxypropyl methylcellulose.

[0017] Preferably, the ratio of the amount of hydroxypropyl methylcellulose, isopropyl alcohol and monochloroacetic acid used in step A1 is 1 g: 20-30 mL: 0.1-0.2 g.

[0018] Preferably, the ratio of glutaraldehyde to hydroxypropyl methylcellulose in step A2 is 0.25-0.4 mL:1 g.

[0019] Preferably, the mass ratio of the mesoporous silica in step S4 to the florfenicol in step S1 is 1-3:1; the mass ratio of the polyvinyl pyrrolidone, modified hydroxypropyl methylcellulose, polyethylene glycol to the florfenicol in step S1 is 0.1-0.15:0.05-0.1:0.01-0.05:0.1.

[0020] Preferably, the amount of glutaraldehyde used in step S5 is 0.5% of the volume of the colloidal solution.

[0021] The beneficial effects of the present invention are as follows:

[0022] The present invention uses solid lipid nanoparticles (glyceryl monostearate) to wrap florfenicol to form nano-scale particles, which effectively improves the solubility of the florfenicol in water. At the same time, the nano-scale particles show a larger surface area to volume ratio, which accelerates the contact between florfenicol and the solvent and promotes its dissolution and dispersion. In addition, the present invention prepares mesoporous silica through tetraethyl orthosilicate to provide a large number of adsorption sites for florfenicol. When florfenicol is adsorbed in the gaps, this can further effectively increase its concentration in the solution. The nano-scale carrier provided by the solid lipid nanoparticles (glyceryl monostearate) not only increases the solubility, but also protects florfenicol from degradation by the external environment through its stable lipid core. At the same time, the nano-size is conducive to cell uptake, which effectively improves the biological availability.

[0023] The invention utilizes polyvinyl pyrrolidone and modified hypromellose to form a stable drug-carrier network, which not only increases the viscosity of the solution and forms a stable colloidal system to prevent the aggregation of florfenicol components, but also effectively reduces the direct effect of heat energy on florfenicol by forming a protective layer, and also improves the solubility and stability of the preparation; the drug-carrier network can effectively protect the mesoporous silica carrier from being difficult to break, and also increases the overall biocompatibility of the preparation; the high loading capacity of the mesoporous silica and the solubilization effect of polyvinyl pyrrolidone and modified hypromellose work together to increase the dissolution rate of the florfenicol powder in the body, thereby enhancing the bioavailability of the powder. The addition of polyethylene glycol further optimizes the flexibility and stability of the network, and through its interaction with water molecules, helps maintain the uniform dispersion of florfenicol in the solution; at the same time, the presence of polyethylene glycol can adjust the internal environment of the preparation, and through the synergistic dehumidification effect, effectively reduce the influence of humidity on the stability of florfenicol; by using glutaraldehyde to slightly cross-link the powder containing modified hypromellose, the physical stability of the preparation can be effectively further enhanced, the rapid release of florfenicol can be reduced, and biocompatibility can be increased. The present invention disperses florfenicol in auxiliary materials at the molecular level through solid dispersion technology, converts it into a more soluble amorphous form, and significantly increases its dissolution rate in water.

[0024] In addition, the stable drug-carrier network constructed by the present invention can not only help prevent the aggregation and degradation of the florfenicol component, but also ensure the stability of florfenicol during storage and transportation, and provide effective protection to effectively avoid the effects of light, heat and oxidation. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a SEM scanning electron microscope image of the florfenicol powder prepared in Example 3 of the present invention;

[0026] Figure 2 is the XRD diffraction pattern of the florfenicol powder prepared in Example 3 of the present invention;

[0027] Figure 3 FTIR infrared spectra of the florfenicol powder prepared in Example 3 of the present invention and conventional florfenicol;

[0028] Figure 4 It is a comparison diagram of the cumulative dissolution curves of the florfenicol powder prepared in Examples 1 to 4 of the present invention and Comparative Examples 1 to 2;

[0029] Figure 5 It is a graph showing the weight loss of florfenicol powder prepared in Examples 1 to 4 of the present invention and Comparative Examples 1 to 2. DETAILED DESCRIPTION

[0030] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0031] Embodiment 1: A method for preparing a highly dispersible soluble powder of florfenicol, comprising the following steps:

[0032] (1). Preparation of modified hydroxypropyl methylcellulose:

[0033] A1: Dissolve 100g of hydroxypropyl methylcellulose in 2000mL of isopropanol, heat in a water bath to 40°C, stir at 100rpm for 10min, add 0.1mol / L NaOH solution to adjust the pH to 10, slowly add 10g of monochloroacetic acid during the reaction, continue stirring at the above temperature and speed, react for 1h, adjust the pH to neutral with hydrochloric acid, and obtain a modified solution;

[0034] A2: 25 mL of glutaraldehyde was added slowly to the modified solution prepared in step A1, and the mixture was stirred at 100 rpm for 5 min at room temperature, centrifuged at 8000 rpm for 10 min, filtered through a 0.22 μm microporous membrane, washed three times with deionized water, and dried under vacuum at 50° C. for 8 h to obtain modified hydroxypropyl methylcellulose;

[0035] (2) Preparation of Florfenicol Highly Dispersible Soluble Powder:

[0036] S1: Dissolve 10 g of florfenicol and 90 g of glyceryl monostearate in 2000 mL of isopropanol, heat in a water bath to control the temperature to 40 °C, stir at 300 rpm for 30 min, then slowly add 1.5 g of sodium dodecyl sulfate and continue stirring for 10 min. After stirring, use ultrasonic treatment for 5 min, set the frequency to 20 kHz, and the power density to 2 W / cm2 , the temperature was controlled at 10°C in an ice bath, and after the treatment, a drug-lipid mixed solution was obtained;

[0037] S2: 100 mL of tetraethyl orthosilicate was added to 1000 mL of anhydrous ethanol, and after being uniformly dissolved, a 1 wt% HCl solution was added to adjust the pH to 5, and the mixture was stirred at 400 rpm for 60 min at room temperature to obtain a precursor solution; 100 g of hexadecyltrimethylammonium bromide was added to 2000 mL of a 25 wt% ethanol solution, and the mixture was stirred at 400 rpm for 5 min at room temperature, and then 125 mL of ammonia water was added dropwise, and the mixture was stirred for 10 min to obtain a template solution;

[0038] S3: adding 550 mL of the template solution prepared in step S2 to 1100 mL of the precursor solution prepared in step S2 at a rate of 5 mL / min, stirring at 400 rpm for 10 min at room temperature, and ultrasonically treating at 600 W for 10 min to obtain a mixed solution; heating the mixed solution in a water bath at 100° C. for 24 h, cooling naturally to room temperature, centrifuging at 8000 rpm for 5 min, taking a precipitate, washing alternately with deionized water and ethanol, drying at 80° C. for 12 h, and calcining the dried product in air at 550° C. for 3 h to obtain mesoporous silica;

[0039] S4: Mix the drug-lipid mixed solution prepared in step S1 and 10 g of mesoporous silica prepared in step S3, control the speed to 100 rpm at room temperature for 10 min, heat in a water bath to raise the temperature to 40° C., and continue the stirring for 10 min to obtain a mixed solution A; add 10 g of polyvinyl pyrrolidone to the mixed solution A, stir at 500 rpm with a magnetic stirrer at room temperature for 10 min, and after the stirring is completed, slowly add 5 g of modified hydroxypropyl methylcellulose and 1 g of polyethylene glycol during the reaction, and continue the stirring for 20 min to obtain a colloidal solution;

[0040] S5: Slowly add 10 mL of glutaraldehyde to the colloidal solution prepared in step S4, react for 5 min at room temperature with mechanical stirring at a speed of 100 rpm, centrifuge at 8000 rpm for 5 min, take the supernatant and filter it through a 0.22 μm microporous filter membrane, wash it with deionized water several times, and vacuum dry it at 50° C. for 12 h to obtain florfenicol powder.

[0041] Embodiment 2: A method for preparing a highly dispersible soluble powder of florfenicol, comprising the following steps:

[0042] (1). Preparation of modified hydroxypropyl methylcellulose:

[0043] A1: Dissolve 100g of hydroxypropyl methylcellulose in 2500mL of isopropanol, heat in a water bath to 42°C, stir at 140rpm for 10min, add 0.1mol / L NaOH solution to adjust the pH to 10.5, slowly add 15g of monochloroacetic acid during the reaction, continue stirring at the above temperature and speed, react for 1.5h, adjust the pH to neutral with hydrochloric acid to obtain a modified solution;

[0044] A2: 30 mL of glutaraldehyde was added slowly to the modified solution prepared in step A1, and the mixture was stirred at 140 rpm for 7 min at room temperature, centrifuged at 8000 rpm for 10 min, filtered through a 0.22 μm microporous membrane, washed three times with deionized water, and vacuum dried at 50° C. for 9 h to obtain modified hydroxypropyl methylcellulose;

[0045] (2) Preparation of Florfenicol Highly Dispersible Soluble Powder:

[0046] S1: Dissolve 10 g of florfenicol and 90 g of glyceryl monostearate in 2500 mL of isopropanol, heat in a water bath to control the temperature to 42 °C, stir at 300 rpm for 40 min, then slowly add 1.8 g of sodium dodecyl sulfate and continue stirring for 12 min. After stirring, use ultrasonic treatment for 10 min, set the frequency to 30 kHz, and the power density to 5 W / cm 2 , the temperature was controlled at 10°C in an ice bath, and after the treatment, a drug-lipid mixed solution was obtained;

[0047] S2: 100 mL of tetraethyl orthosilicate was added to 1000 mL of anhydrous ethanol, and after being uniformly dissolved, a 1 wt % HCl solution was added to adjust the pH to 4, and the mixture was stirred at 500 rpm for 60 min at room temperature to obtain a precursor solution; 100 g of hexadecyltrimethylammonium bromide was added to 2500 mL of a 25 wt % ethanol solution, and the mixture was stirred at 500 rpm for 5 min at room temperature, and then 150 mL of ammonia water was added dropwise, and the mixture was stirred for 10 min to obtain a template solution;

[0048] S3: adding 750 mL of the template solution prepared in step S2 to 1100 mL of the precursor solution prepared in step S2 at a rate of 7 mL / min, stirring at 500 rpm for 10 min at room temperature, and ultrasonically treating at 600 W for 15 min to obtain a mixed solution; heating the mixed solution in a water bath at 100° C. for 24 h, cooling naturally to room temperature, centrifuging at 8000 rpm for 5 min, taking a precipitate, washing alternately with deionized water and ethanol, drying at 80° C. for 12 h, and calcining the dried product in air at 550° C. for 3 h to obtain mesoporous silica;

[0049] S4: Mix the drug-lipid mixed solution prepared in step S1 and 20 g of mesoporous silica prepared in step S3, control the speed to 150 rpm at room temperature for 12 min, heat in a water bath to raise the temperature to 42° C., and continue the stirring for 10 min to obtain a mixed solution A; add 12 g of polyvinyl pyrrolidone to the mixed solution A, stir at 600 rpm with a magnetic stirrer at room temperature for 10 min, and after the stirring is completed, continue to slowly add 7 g of modified hydroxypropyl methylcellulose and 3 g of polyethylene glycol, and continue the stirring for 25 min to obtain a colloidal solution;

[0050] S5: 12.5 mL of glutaraldehyde was slowly added to the colloidal solution prepared in step S4, and the reaction was carried out at room temperature with mechanical stirring at a speed of 150 rpm for 7 min, and the mixture was centrifuged at 9000 rpm for 7 min. The supernatant was filtered through a 0.22 μm microporous filter membrane, washed with deionized water for multiple times, and vacuum dried at 50° C. for 12 h to obtain florfenicol powder.

[0051] Embodiment 3: A method for preparing a highly dispersible soluble powder of florfenicol, comprising the following steps:

[0052] (1). Preparation of modified hydroxypropyl methylcellulose:

[0053] A1: Dissolve 100g of hydroxypropyl methylcellulose in 2800mL of isopropanol, heat in a water bath to 48°C, stir at 180rpm for 10min, add 0.1mol / L NaOH solution to adjust the pH to 11, slowly add 18g of monochloroacetic acid during the reaction, continue stirring at the above temperature and speed, react for 2h, adjust the pH to neutral with hydrochloric acid, and obtain a modified solution;

[0054] A2: 35 mL of glutaraldehyde was added slowly to the modified solution prepared in step A1, and the mixture was stirred at 180 rpm for 9 min at room temperature, centrifuged at 8000 rpm for 10 min, filtered through a 0.22 μm microporous membrane, washed three times with deionized water, and vacuum dried at 50° C. for 11 h to obtain modified hydroxypropyl methylcellulose;

[0055] (2) Preparation of Florfenicol Highly Dispersible Soluble Powder:

[0056] S1: Dissolve 10 g of florfenicol and 90 g of glyceryl monostearate in 2800 mL of isopropanol, heat in a water bath to control the temperature to 48 °C, stir at 300 rpm for 50 min, then slowly add 1.9 g of sodium dodecyl sulfate and continue stirring for 14 min. After stirring, use ultrasonic treatment for 15 min, set the frequency to 35 kHz, and the power density to 8 W / cm 2 , the temperature was controlled at 10°C in an ice bath, and after the treatment, a drug-lipid mixed solution was obtained;

[0057] S2: 100 mL of tetraethyl orthosilicate was added to 1000 mL of anhydrous ethanol, and after being uniformly dissolved, a 1 wt % HCl solution was added to adjust the pH to 3.5, and the mixture was stirred at 550 rpm for 60 min at room temperature to obtain a precursor solution; 100 g of hexadecyltrimethylammonium bromide was added to 2800 mL of a 25 wt % ethanol solution, and the mixture was stirred at 550 rpm for 5 min at room temperature, and then 180 mL of ammonia water was added dropwise, and the mixture was stirred for 10 min to obtain a template solution;

[0058] S3: adding 1000 mL of the template solution prepared in step S2 to 1100 mL of the precursor solution prepared in step S2 at a rate of 9 mL / min, stirring at 550 rpm for 10 min at room temperature, and ultrasonically treating at 600 W for 18 min to obtain a mixed solution; heating the mixed solution in a water bath at 100° C. for 24 h, naturally cooling to room temperature, centrifuging at 8000 rpm for 5 min, taking a precipitate, washing it alternately with deionized water and ethanol, drying it at 80° C. for 12 h, and calcining the dried product in air at 550° C. for 3 h to obtain mesoporous silica;

[0059] S4: Mix the drug-lipid mixed solution prepared in step S1 and 25g of mesoporous silica prepared in step S3, control the speed to 180rpm at room temperature for 14min, heat in a water bath to raise the temperature to 48°C, and continue the stirring for 10min to obtain a mixed solution A; add 14g of polyvinyl pyrrolidone to the mixed solution A, stir at 700rpm at room temperature for 10min using a magnetic stirrer, and after the stirring is completed, continue to slowly add 9g of modified hydroxypropyl methylcellulose and 4g of polyethylene glycol, and continue the stirring for 28min to obtain a colloidal solution;

[0060] S5: 14 mL of glutaraldehyde was slowly added to the colloidal solution prepared in step S4, and the reaction was carried out at room temperature with mechanical stirring at a speed of 180 rpm for 9 min, and centrifuged at 9500 rpm for 9 min. The supernatant was filtered through a 0.22 μm microporous filter membrane, washed with deionized water for multiple times, and vacuum dried at 50° C. for 12 h to obtain florfenicol powder.

[0061] Example 4: A method for preparing a highly dispersible soluble powder of florfenicol, comprising the following steps:

[0062] (1). Preparation of modified hydroxypropyl methylcellulose:

[0063] A1: Dissolve 100g of hydroxypropyl methylcellulose in 3000mL of isopropanol, heat in a water bath to 50°C, stir at 200rpm for 10min, add 0.1mol / L NaOH solution to adjust the pH to 11, slowly add 20g of monochloroacetic acid during the reaction, continue stirring at the above temperature and speed, react for 2h, adjust the pH to neutral with hydrochloric acid, and obtain a modified solution;

[0064] A2: 40 mL of glutaraldehyde was added slowly to the modified solution prepared in step A1, and the mixture was stirred at 200 rpm for 10 min at room temperature, centrifuged at 8000 rpm for 10 min, filtered through a 0.22 μm microporous membrane, washed three times with deionized water, and vacuum dried at 50° C. for 12 h to obtain modified hydroxypropyl methylcellulose;

[0065] (2) Preparation of Florfenicol Highly Dispersible Soluble Powder:

[0066] S1: Dissolve 10 g of florfenicol and 90 g of glyceryl monostearate in 3000 mL of isopropanol, heat in a water bath to control the temperature to 50 °C, stir at 300 rpm for 60 min, then slowly add 2 g of sodium dodecyl sulfate and continue stirring for 15 min. After stirring, use ultrasonic treatment for 20 min, set the frequency to 40 kHz, and the power density to 10 W / cm 2 , the temperature was controlled at 10°C in an ice bath, and after the treatment, a drug-lipid mixed solution was obtained;

[0067] S2: 100 mL of tetraethyl orthosilicate was added to 1000 mL of anhydrous ethanol, and after being uniformly dissolved, a 1 wt % HCl solution was added to adjust the pH to 3, and the mixture was stirred at 600 rpm for 60 min at room temperature to obtain a precursor solution; 100 g of hexadecyltrimethylammonium bromide was added to 3000 mL of a 25 wt % ethanol solution, and the mixture was stirred at 600 rpm for 5 min at room temperature, and then 200 mL of ammonia water was added dropwise, and the mixture was stirred for 10 min to obtain a template solution;

[0068] S3: adding 1280 mL of the template solution prepared in step S2 to 1100 mL of the precursor solution prepared in step S2 at a rate of 10 mL / min, stirring at 4600 rpm for 10 min at room temperature, and ultrasonically treating at 600 W for 20 min to obtain a mixed solution; heating the mixed solution in a water bath at 100° C. for 24 h, cooling naturally to room temperature, centrifuging at 8000 rpm for 5 min, taking a precipitate, washing alternately with deionized water and ethanol, drying at 80° C. for 12 h, and calcining the dried product in air at 550° C. for 3 h to obtain mesoporous silica;

[0069] S4: 3000 mL of the drug-lipid mixed solution prepared in step S1 and 30 g of the mesoporous silica prepared in step S3 were mixed, the speed was controlled to be 200 rpm at room temperature and mechanically stirred for 15 min, the temperature was raised to 50° C. by heating in a water bath, and the stirring was continued for 10 min to obtain a mixed solution A; 15 g of polyvinyl pyrrolidone was added to the mixed solution A, and the mixture was stirred at 800 rpm at room temperature for 10 min using a magnetic stirrer. After the stirring was completed, 10 g of modified hydroxypropyl methylcellulose and 5 g of polyethylene glycol were slowly added, and the stirring was continued for 30 min to obtain a colloidal solution;

[0070] S5: 15 mL of glutaraldehyde was slowly added to the colloidal solution prepared in step S4, and the mixture was reacted for 10 min at room temperature with mechanical stirring at a speed of 200 rpm, and centrifuged at 10000 rpm for 10 min. The supernatant was filtered through a 0.22 μm microporous filter membrane, washed with deionized water for multiple times, and vacuum dried at 50° C. for 12 h to obtain florfenicol powder.

[0071] Comparative Example 1: is basically the same as Example 2, except that Comparative Example 1 does not use the drug-lipid mixed solution formed by polyvinyl pyrrolidone and modified hydroxypropyl methylcellulose.

[0072] Comparative Example 2: is basically the same as Example 3, except that mesoporous silica is not used in Comparative Example 2.

[0073] Performance Testing:

[0074] Spectrum determination: The florfenicol powder sample prepared in Example 3 of the present invention is placed on a SEM sample tray, fixed with a sticky carbon tape, covered with a layer of carbon by spraying, the voltage is set between 3-10 kV by adjusting the parameters, and the sample surface is scanned by an electron beam; the florfenicol powder prepared in Example 3 is mixed with KBr powder and pressed into a sheet, and the spectrum is measured by an FTIR spectrometer; the florfenicol powder prepared in Example 3 is evenly spread on the XRD sample tray, and the sample diffraction spectrum is measured by an X-ray diffractometer; the SEM scanning electron microscope image is as follows Figure 1 As shown; XRD diffraction pattern as Figure 2 As shown; FTIR spectrum as shown Figure 3 shown.

[0075] Dissolution test: Take 3 samples of florfenicol powder prepared in Examples 1 to 4 of the present invention and Comparative Examples 1 to 2, respectively, for a total of 18 samples, each sample weighing 1 g, and dissolve each sample in 900 mL of pH 6.8 phosphate buffer, sample at 5 min, 10 min, 20 min, 30 min, 40 min, and 60 min, sample 10 mL at each sampling point, and then replenish 10 mL of solution to determine the dissolution (Xn'=Xn+(X1+X2+Xn-1)V2 / V1; wherein Xn is the relative percentage dissolution measured after correction for the nth time, Xn' is the relative percentage dissolution actually measured for the nth time, V1 is the volume of the dissolution medium, and V2 is the volume number supplemented after each sampling). The results are as follows: Figure 4 shown.

[0076] Drying loss test: Take 3 samples of florfenicol powder prepared in Examples 1 to 4 of the present invention and Comparative Examples 1 to 2 and 3 samples of control samples purchased from the market, a total of 15 samples, each sample weighing 1 g, and place each sample at 105 ° C. Dry to constant weight, and calculate the weight before and after weight loss [loss rate (%) = (weight of product after weight loss - weight of product before measurement) / weight of product before measurement × 100%], measure each sample three times, and take the average value. The results are as follows Figure 5 shown.

[0077] Stability test: Stability An accelerated stability test was carried out in accordance with the relevant provisions of the Chinese Veterinary Pharmacopoeia. The florfenicol powder samples prepared in Examples 1 to 4 of the present invention and Comparative Examples 1 to 2 were sealed according to commercially available packaging and placed at a temperature of 40° C. and a relative humidity of 75% for 6 months. Samples were taken once at the 1st, 2nd, 3rd and 6th month of the test period, and the stability was calculated [stability (%) = (sample weight before the test - sample weight on the nth day of the test) / sample weight before the test × 100%]. The results are shown in Table 1:

[0078] Table 1. Stability test results.

[0079]

[0080] Depend on Figure 1 The results show that the florfenicol powder prepared by the present invention has a stable morphology; Figure 2 The results show that due to the addition of porous silica, a broad diffraction peak is shown between 20° and 30°. Figure 3 The results show that the florfenicol powder preparation prepared by the present invention has a large surface area of ​​1100 to 1000 cm due to the addition of mesoporous silica. -1 The Si-O-Si bond stretching vibration is obvious in the range of , which is essentially consistent with the infrared peak of florfenicol. Figure 4The results show that the florfenicol powder prepared by the present invention can reach a dissolution rate of more than 90% in 20 minutes and can be basically dissolved completely within 60 minutes; the solubility effect of the florfenicol powder prepared by the present invention is significantly improved; from Table 1 and Figure 5 The results show that the florfenicol powder prepared by the present invention has significantly improved stability under the synergistic effect of mesoporous silica and the cross-linked network system.

[0081] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a highly dispersible soluble powder of florfenicol, characterized in that: The florfenicol highly dispersible soluble powder is made of florfenicol, glyceryl monostearate, sodium lauryl sulfate, tetraethyl orthosilicate, cetyltrimethylammonium bromide, polyvinyl pyrrolidone, modified hydroxypropyl methylcellulose, polyethylene glycol, and glutaraldehyde; The preparation method of the modified hypromellose comprises the following steps: A1: Dissolve hydroxypropyl methylcellulose in isopropanol, heat in a water bath to raise the temperature to 40-50°C, stir, add 0.1 mol / L NaOH solution to adjust the pH, slowly add monochloroacetic acid during the reaction, continue stirring at the above temperature and speed, react, adjust the pH to neutral with hydrochloric acid, and obtain a modified solution; A2: Glutaraldehyde is added slowly and continuously to the modified solution prepared in step A1, the mixture is stirred for reaction at room temperature, centrifuged, filtered through a microporous filter membrane, washed three times with deionized water, and vacuum dried to obtain modified hydroxypropyl methylcellulose; The ratio of the amount of hydroxypropyl methylcellulose, isopropyl alcohol and monochloroacetic acid used in step A1 is 1g:20-30mL:0.1-0.2g; the ratio of the amount of glutaraldehyde to hydroxypropyl methylcellulose used in step A2 is 0.25-0.4mL:1g; The preparation method of the florfenicol highly dispersible soluble powder comprises the following steps: S1: Dissolve florfenicol and glyceryl monostearate in isopropanol, heat in a water bath to control the temperature, continue stirring, and then slowly add sodium dodecyl sulfate and continue stirring. After stirring, use ultrasonic treatment and control the temperature at 10°C in an ice bath. After treatment, obtain a drug-lipid mixed solution; S2: adding tetraethyl orthosilicate to anhydrous ethanol, and after uniform dissolution, adding 1wt% HCl solution to adjust the pH to 3-5, stirring at room temperature to react, to obtain a precursor solution; adding hexadecyltrimethylammonium bromide to a 25wt% ethanol solution, stirring at room temperature, and then adding ammonia water dropwise, and continuing to stir, to obtain a template agent solution; S3: adding the template solution prepared in step S2 to the precursor solution prepared in step S2, stirring at room temperature, and ultrasonically treating to obtain a mixed solution; heating the mixed solution in a water bath, cooling naturally to room temperature, centrifuging, taking a precipitate, washing alternately with deionized water and ethanol, drying, and calcining the dried product in air to obtain mesoporous silica; S4: Mix the drug-lipid mixed solution prepared in step S1 and the mesoporous silica prepared in step S3, control the speed of mechanical stirring at room temperature, heat in a water bath to increase the temperature, and continue the stirring for 10 minutes to obtain a mixed solution A; add polyvinyl pyrrolidone to the mixed solution A, stir at room temperature, and after the stirring is completed, continue to slowly add modified hydroxypropyl methylcellulose and polyethylene glycol, and continue the stirring to obtain a colloidal solution; S5: slowly adding glutaraldehyde to the colloidal solution prepared in step S4, mechanically stirring the reaction at room temperature, centrifuging, taking the supernatant, filtering with a microporous filter membrane, washing with deionized water for multiple times, and vacuum drying to obtain florfenicol powder; The ratio of florfenicol, glyceryl monostearate, sodium lauryl sulfate and isopropyl alcohol used in step S1 is 0.1 g: 0.9 g: 0.015-0.02 g: 20-30 mL; In step S2, the volume ratio of tetraethyl orthosilicate to anhydrous ethanol is 1:10; the volume ratio of hexadecyltrimethylammonium bromide to ethanol solution is 1 g:20-30 mL; the volume ratio of tetraethyl orthosilicate, hexadecyltrimethylammonium bromide and ammonia water is 1 mL:0.25-0.4 g:0.5 mL; The mass ratio of the mesoporous silica in step S4 to the florfenicol in step S1 is 1-3:1; the mass ratio of the polyvinyl pyrrolidone, modified hydroxypropyl methylcellulose, polyethylene glycol to the florfenicol in step S1 is 0.1-0.15:0.05-0.1:0.01-0.05:0.1; The amount of glutaraldehyde used in step S5 is 0.5% of the volume of the colloidal solution.

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