Florfenicol preparation with high water solubility and bacteriostatic effect and preparation method thereof

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a florfenicol preparation with high water solubility and bacteriostatic effect and a preparation method thereof.The raw materials of the florfenicol preparation with high water solubility and bacteriostatic effect include, by mass fraction, florfenicol 20-30 parts, beta-cyclodextrin 30-50 parts, solid polyethylene glycol 30-50 parts, sodium dodecyl sulfate 2-5 parts, dopamine aqueous solution 100-200 parts and dextran sulfate aqueous solution 1-5 parts; wherein the concentration of the dopamine aqueous solution is 1-3 g / L, and the concentration of the dextran sulfate aqueous solution is 0.1-0.5 mol / L.The application has a wide application range, is commonly used for granulation of heat-sensitive materials and drugs which are easily decomposed in water, and is convenient for subsequent re-compression tabletting or encapsulation; and compared with a wet granulation method, the application has the advantages of simple process, low energy consumption, small filler consumption and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a florfenicol preparation with high water solubility and bacteriostatic effect and a preparation method thereof. BACKGROUND

[0002] Florfenicol is a 3-fluorine derivative of thiamphenicol, belonging to a new type of amido alcohol broad-spectrum antibiotic. The drug was first developed by the American Schering-Plough Corporation in the late 1980s, and is a new type of chemically synthesized broad-spectrum antibiotic for animals. Florfenicol was first marketed in Japan in 1990, and was approved in China in 2000, which is a national new Class II veterinary drug. Compared with other chloramphenicol drugs, florfenicol has better antibacterial activity, good absorption, wide distribution in the body, long half-life, no or low residual in the body, no potential aplastic anemia, and no teratogenic, carcinogenic and mutagenic disadvantages.

[0003] At present, in the veterinary clinic, florfenicol is widely used in the treatment of bacterial diseases of aquatic fish and livestock and poultry such as cattle, pigs, dogs and chickens. Since chloramphenicol is prohibited for use in animals, the market demand for florfenicol has further expanded. So far, florfenicol has been widely used as an anti-infective drug in various countries, and the annual consumption is tens of thousands of tons worldwide.

[0004] Florfenicol belongs to Class II drugs in the Biopharmaceutics Classification System (BCS), i.e. low solubility / high permeability drugs, which can be rapidly absorbed and utilized in the body. However, the low solubility in water and slow dissolution in the gastrointestinal tract limit the absorption of the drug, resulting in insufficient drug efficacy and low bioavailability. In recent years, scholars at home and abroad have developed many valuable florfenicol preparations from the perspective of improving the bioavailability of florfenicol.

[0005] At present, in addition to the commonly used florfenicol injections (30%, 10% and 5%), solutions (2%), soluble powders (10%) and premixes (5%) in clinical practice, there are also florfenicol ultrafine powder, florfenicol nanoemulsion, in-situ gel, solid dispersion and water-soluble complex. Although the above methods improve the solubility of florfenicol to some extent, they all have different shortcomings, which are not conducive to clinical use. Therefore, how to improve the solubility of florfenicol through preparation means is of great significance to the clinical application of the product. SUMMARY

[0006] The present application relates to the technical field of pharmaceutical preparation, in particular to a florfenicol preparation with high water solubility and bacteriostatic effect and a preparation method thereof.

[0007] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises, by mass fraction, florfenicol 20-30 parts, beta-cyclodextrin 30-50 parts, solid polyethylene glycol 30-50 parts, sodium dodecyl sulfate 2-5 parts, dopamine aqueous solution 100-200 parts, and dextran sulfate aqueous solution 1-5 parts; wherein the concentration of the dopamine aqueous solution is 1-3 g / L, and the concentration of the dextran sulfate aqueous solution is 0.1-0.5 mol / L.

[0008] Preferably, the average molecular weight of the solid polyethylene glycol is 3600-4400.

[0009] Preferably, the molecular weight of the dextran sulfate is 15-22 kDa.

[0010] The above-mentioned preparation method of the florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0011] S1, adding florfenicol to the dopamine solution and stirring for 5-10 min, adjusting the pH value of the system to 9-10, ultrasonic treatment for 1-2 h, and spray drying to obtain pretreated florfenicol;

[0012] S2, adding beta-cyclodextrin to the acetic acid solution and stirring until uniform, adjusting the pH value of the system to 5-6, adding the pretreated florfenicol thereto and mixing until uniform, adding the dextran sulfate solution dropwise under stirring, continuing to stir for 30-40 min after the dropwise addition is completed, centrifuging, washing, and vacuum drying to obtain coated florfenicol;

[0013] S3, mixing the coated florfenicol, beta-cyclodextrin, and sodium dodecyl sulfate uniformly, and adding the pulverized solid polyethylene glycol to obtain a premix;

[0014] S4, dry granulating the premix, sizing, sieving, and collecting the material between 30-80 mesh sieves.

[0015] Preferably, in S1, the pH value of the system is adjusted to 9-10 using a sodium hydroxide solution with a concentration of 1-3 mol / L.

[0016] Preferably, in S1, the ultrasonic frequency is 20-30 kHz, and the ultrasonic power is 100-150 W.

[0017] Preferably, in S2, the mass ratio of the beta-cyclodextrin used to that used in S3 is 4-8:26-42.

[0018] Preferably, in S2, the mass fraction of the acetic acid solution is 0.6-1%.

[0019] Preferably, in S4, dry granulation is carried out by using a dry granulator, the roller distance is set to 0.5-1.0 mm, the horizontal screw speed is 8-12 rpm, the vertical screw speed is 250-350 rpm, the pressure roller speed is 2.0-4.0 rpm, the temperature is controlled at 25-30 DEG C, the whole granulation speed is 1500-2000 rpm, and the whole granulation screen is 1.0 mm.

[0020] Preferably, in S4, whole granulation is carried out by using a whole granulator, the screen in the whole granulator is 0.8 mm, and the whole granulation speed is 800-1500 rpm.

[0021] Beneficial effects:

[0022] 1. The present application utilizes florfenicol and dopamine to form a hydrophilic polydopamine layer by self-polymerization and complexation, thereby improving the dispersibility of florfenicol, effectively improving the solubility, enhancing the structural stability by host-guest inclusion (cyclodextrin) and polyelectrolyte complexation (electrostatic interaction between dextran sulfate and polydopamine), and delaying drug release.

[0023] 2. The present application utilizes beta-cyclodextrin to coat the pretreated florfenicol in a weak acid (pH = 5-6) environment, and the beta-cyclodextrin has enhanced inclusion capacity under weak acid conditions; subsequently, a stable polyelectrolyte complex is formed by using negatively charged sulfated polysaccharides and positively charged polydopamine, effectively reducing drug hydrolysis or aggregation, and the dextran sulfate can also be used in combination with florfenicol to expand the antibacterial spectrum, effectively enhancing bacterial membrane permeability and greatly prolonging the bacteriostatic time.

[0024] 3. The present application relies on the principle of mechanical extrusion to directly compress, shape, and coarsely crush the raw powder to form granular finished products; after granulation, the bulk density is significantly increased, the appearance and flowability of the material are improved, storage and transportation are facilitated, and the solubility, porosity, and specific surface area can also be controlled.

[0025] 4. The present application has a wide range of applications and is commonly used for granulation of heat-sensitive materials and drugs that are easily decomposed in water, facilitating subsequent re-compression or encapsulation; and compared with wet granulation, the present application has the advantages of simple process, low energy consumption, and less filler usage. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The figure is the active substance content change graph at different time points in the florfenicol preparation solution obtained from Example 5 and Comparative Examples 1-4.

[0027] Figure 2 The figure is the minimum inhibitory concentration comparison chart of the florfenicol preparation obtained from Example 5 and Comparative Examples 1-4 against Escherichia coli, Staphylococcus aureus, and Pasteurella multocida.

[0028] Figure 3The maximum concentration in the body and the area under the blood concentration-time curve of the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 are compared after the preparations are administered to small pigs by gavage.

[0029] Figure 4 The time to peak and the half-life of the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 are compared after the preparations are administered to small pigs by gavage. DETAILED DESCRIPTION

[0030] The application is further described below in conjunction with specific examples.

[0031] Example 1

[0032] A florfenicol preparation having high water solubility and bacteriostatic effect, which raw materials include: florfenicol 25 g, β-cyclodextrin 40 g, PEG-4000 30 g, sodium dodecyl sulfate 3.5 g, dopamine aqueous solution with a concentration of 1 g / L 100 g, dextran sulfate aqueous solution with a concentration of 0.1 mol / L 1 g (molecular weight 15 kDa).

[0033] The preparation method of the above-mentioned florfenicol preparation having high water solubility and bacteriostatic effect includes the following steps:

[0034] S1, add florfenicol to the dopamine solution, stir at a speed of 100 r / min for 5 min, adjust the pH value of the system to 9 with a 1 mol / L sodium hydroxide solution, ultrasonic treatment for 1 h, ultrasonic frequency 20 kHz, ultrasonic power 100 W, spray drying to obtain pretreated florfenicol;

[0035] S2, add 6 g of β-cyclodextrin to 50 g of 0.6% acetic acid solution and stir until uniform, adjust the pH value of the system to 5, add the pretreated florfenicol and mix well, add the dextran sulfate solution dropwise under stirring, continue stirring for 30 min after the dropwise addition is complete, centrifuge, wash, and vacuum dry to obtain coated florfenicol;

[0036] S3, send PEG-4000 to a mechanical crusher, set the stirring speed to 10 hz, and stir for 2 min;

[0037] Add the coated florfenicol, 34 g of β-cyclodextrin, and sodium dodecyl sulfate to a multi-directional motion mixer and mix until uniform, add the crushed PEG-4000 and mix until uniform to obtain a premix;

[0038] S4, the premix is added into the dry granulator, the roller distance is set to 0.5mm, the horizontal screw speed is 8rpm, the vertical screw speed is 250rpm, the pressure roller speed is 2.0rpm, the temperature is controlled at 25℃, the granulation speed is 1500rpm, the granulation screen is 1.0mm, the material discharged from the dry granulator is collected and then transferred to the granulator, the granulation screen is 0.8mm, the granulation speed is 800rpm, the material between the 30-mesh screens is collected.

[0039] Example 2

[0040] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises: florfenicol 30g, β-cyclodextrin 50g, PEG-4000 50g, sodium dodecyl sulfate 5g, dopamine aqueous solution with a concentration of 3g / L 200g, dextran sulfate aqueous solution with a concentration of 0.5mol / L 5g.

[0041] The preparation method of the above florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0042] S1, the florfenicol is added into the dopamine solution, stirred at a speed of 200r / min for 10min, the pH value of the system is adjusted to 10 by using a sodium hydroxide solution with a concentration of 3mol / L, ultrasonic treatment is performed for 2h, the ultrasonic frequency is 30kHz, the ultrasonic power is 150W, and spray drying is performed to obtain pretreated florfenicol;

[0043] S2, 8g of β-cyclodextrin is added into 100g of acetic acid solution with a mass fraction of 1% and stirred uniformly, the pH value of the system is adjusted to 6, the pretreated florfenicol is added and mixed uniformly, the dextran sulfate solution is added dropwise under stirring, stirring is continued for 40min after the dropwise addition is completed, centrifugation, washing and vacuum drying are performed to obtain coated florfenicol;

[0044] S3, the PEG-4000 is sent into the mechanical crusher, the stirring speed is set to 20hz, and the stirring time is 3min;

[0045] The coated florfenicol, 42g of β-cyclodextrin and sodium dodecyl sulfate are sent into the multi-motion mixer and mixed uniformly, the crushed PEG-4000 is added and mixed uniformly to obtain a premix;

[0046] S4, the premix is added into the dry granulator, the roller distance is set to 1.0 mm, the horizontal screw speed is 12 rpm, the vertical screw speed is 350 rpm, the pressure roller speed is 4.0 rpm, the temperature is controlled at 30°C, the granulation speed is 2000 rpm, the granulation screen is 1.0 mm, the material discharged from the dry granulator is collected and then transferred to the granulator, the granulation screen is 0.8 mm, the granulation speed is 1500 rpm, the material between the 80 mesh screens is collected.

[0047] Example 3

[0048] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises: florfenicol 22 g, β-cyclodextrin 45 g, PEG-4000 45 g, sodium dodecyl sulfate 3 g, dopamine aqueous solution with a concentration of 2.5 g / L 120 g, dextran sulfate aqueous solution with a concentration of 0.4 mol / L 2 g.

[0049] The preparation method of the above florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0050] S1, florfenicol is added to the dopamine solution, stirred at a speed of 180 r / min for 7 min, the pH value of the system is adjusted to 9.5 with a sodium hydroxide solution with a concentration of 2.5 mol / L, ultrasonic treatment is performed for 80 min, the ultrasonic frequency is 27 kHz, the ultrasonic power is 110 W, and spray drying is performed to obtain pretreated florfenicol;

[0051] S2, 7 g of β-cyclodextrin is added to 70 g of acetic acid solution with a mass fraction of 0.9% and stirred uniformly, the pH value of the system is adjusted to 5.5, the pretreated florfenicol is added and mixed uniformly, the dextran sulfate solution is added dropwise under stirring, stirring is continued for 33 min after the dropwise addition is completed, centrifugation, washing, and vacuum drying are performed to obtain coated florfenicol;

[0052] S3, PEG-4000 is sent into a mechanical crusher, the stirring speed is set to 18 hz, and the stirring time is 1.5 min;

[0053] The coated florfenicol, 38 g of β-cyclodextrin, and sodium dodecyl sulfate are sent into a multi-directional motion mixer and mixed uniformly, the crushed PEG-4000 is added and mixed uniformly to obtain a premix;

[0054] S4, the premix is added to the dry granulator, the roller distance is set to 0.7mm, the horizontal screw speed is 11rpm, the vertical screw speed is 280rpm, the pressure roller speed is 3.5rpm, the temperature is controlled at 27℃, the granulation speed is 1900rpm, the granulation screen is 1.0mm, the material discharged from the dry granulator is collected and then transferred to the granulator, the granulation screen is 0.8mm, the granulation speed is 1000rpm, the material between the 70-mesh screens is collected.

[0055] Example 4

[0056] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises: florfenicol 28g, β-cyclodextrin 35g, PEG-4000 35g, sodium dodecyl sulfate 4g, dopamine aqueous solution with a concentration of 1.5g / L 180g, dextran sulfate aqueous solution with a concentration of 0.2mol / L 4g.

[0057] The preparation method of the above florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0058] S1, florfenicol is added to the dopamine solution, stirred at a speed of 120r / min for 9min, the pH value of the system is adjusted to 9.5 with a sodium hydroxide solution with a concentration of 1.5mol / L, ultrasonic treatment is performed for 100min, the ultrasonic frequency is 21kHz and the ultrasonic power is 130W, and spray drying is performed to obtain pretreated florfenicol;

[0059] S2, 5g of β-cyclodextrin is added to 90g of acetic acid solution with a mass fraction of 0.7% and stirred uniformly, the pH value of the system is adjusted to 5.5, the pretreated florfenicol is added and mixed uniformly, the dextran sulfate solution is added dropwise under stirring, stirring is continued for 37min after the dropwise addition is completed, centrifugation, washing and vacuum drying are performed to obtain coated florfenicol;

[0060] S3, PEG-4000 is sent to a mechanical crusher, the stirring speed is set to 12hz and the stirring time is 2.5min;

[0061] The coated florfenicol, 30g of β-cyclodextrin and sodium dodecyl sulfate are sent to a multi-directional motion mixer and mixed uniformly, the crushed PEG-4000 is added and mixed uniformly to obtain a premix;

[0062] S4, the premix is added into the dry granulator, the roller distance is set to 0.9mm, the horizontal screw speed is 9rpm, the vertical screw speed is 320rpm, the pressure roller speed is 2.5rpm, the temperature is controlled at 29℃, the granulation speed is 1700rpm, the granulation screen is 1.0mm, the material discharged from the dry granulator is collected and then transferred to the granulator, the granulation screen is 0.8mm, the granulation speed is 1400rpm, the material between the 40-mesh screens is collected.

[0063] Example 5

[0064] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises: florfenicol 20g, β-cyclodextrin 30g, PEG-4000 48g, sodium dodecyl sulfate 2g, dopamine aqueous solution with a concentration of 2g / L 150g, dextran sulfate aqueous solution with a concentration of 0.3mol / L 3g.

[0065] The preparation method of the above florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0066] S1, the florfenicol is added into the dopamine solution, stirred at a speed of 150r / min for 8min, the pH value of the system is adjusted to 9.5 by using a sodium hydroxide solution with a concentration of 2mol / L, ultrasonic treatment is performed for 90min, the ultrasonic frequency is 24kHz, the ultrasonic power is 120W, and spray drying is performed to obtain pretreated florfenicol;

[0067] S2, 4g of β-cyclodextrin is added into 80g of acetic acid solution with a mass fraction of 0.8% and stirred uniformly, the pH value of the system is adjusted to 5.5, the pretreated florfenicol is added and mixed uniformly, the dextran sulfate solution is added dropwise under stirring, stirring is continued for 35min after the dropwise addition is completed, centrifugation, washing and vacuum drying are performed to obtain coated florfenicol;

[0068] S3, the PEG-4000 is sent into the mechanical crusher, the stirring speed is set to 15hz, and the stirring time is 1min;

[0069] The coated florfenicol, 26g of β-cyclodextrin and sodium dodecyl sulfate are sent into the multi-directional motion mixer and mixed uniformly, the crushed PEG-4000 is added and mixed uniformly to obtain a premix;

[0070] S4, the premix is added into the dry granulator, the roller distance is set to 0.8mm, the horizontal screw speed is 10rpm, the vertical screw speed is 300rpm, the pressure roller speed is 3rpm, the temperature is controlled at 28℃, the granulation speed is 1800rpm, the granulation screen is 1.0mm, the material discharged from the dry granulator is collected and then transferred to the granulator, the granulation screen is 0.8mm, the granulation speed is 1200rpm, the material between the 50-mesh screens is collected.

[0071] Comparative Example 1

[0072] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises: florfenicol 17g, β-cyclodextrin 30g, PEG-4000 48g, and sodium dodecyl sulfate 2g.

[0073] The preparation method of the florfenicol preparation with high water solubility and bacteriostatic effect, comprising the following steps:

[0074] S1, the PEG-4000 is sent into a mechanical crusher, the stirring speed is set to 15hz, and the stirring time is 1min;

[0075] The florfenicol, β-cyclodextrin and sodium dodecyl sulfate are sent into a multi-directional motion mixer and uniformly mixed, and the crushed PEG-4000 is added and uniformly mixed to obtain a premix;

[0076] S2, the premix is added into the dry granulator, the roller distance is set to 0.8mm, the horizontal screw speed is 10rpm, the vertical screw speed is 300rpm, the pressure roller speed is 3rpm, the temperature is controlled at 28℃, the granulation speed is 1800rpm, the granulation screen is 1.0mm, the material discharged from the dry granulator is collected and then transferred to the granulator, the granulation screen is 0.8mm, the granulation speed is 1200rpm, the material between the 50-mesh screens is collected.

[0077] Comparative Example 2

[0078] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises: florfenicol 17g, β-cyclodextrin 30g, PEG-4000 48g, and sodium dodecyl sulfate 2g.

[0079] The preparation method of the florfenicol preparation with high water solubility and bacteriostatic effect, comprising the following steps:

[0080] The PEG-4000 is sent into a mechanical crusher, the stirring speed is set to 15hz, and the stirring time is 1min;

[0081] The florfenicol, β-cyclodextrin and sodium dodecyl sulfate are sent into a multi-directional motion mixer and uniformly mixed, and the crushed PEG-4000 is added and uniformly mixed.

[0082] Comparative Example 3

[0083] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises florfenicol 20 g, β-cyclodextrin 30 g, PEG-4000 48 g, and sodium dodecyl sulfate 2 g.

[0084] The preparation method of the florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0085] S1, the PEG-4000 is sent into a mechanical crusher, the stirring speed is set to 15 Hz, and the stirring time is 1 min;

[0086] The florfenicol, β-cyclodextrin and sodium dodecyl sulfate are uniformly mixed and added into a wet granulator, the stirring speed is set to 9 Hz, the cutter speed is set to 3 Hz, and the operation is performed for 5 min; after the mixing is completed, the crushed PEG-4000 is uniformly added and mixed again, and the speed is maintained for 5 min to obtain a premix;

[0087] S2, after the operation is completed, the stirring speed is set to 13 Hz, the cutter speed is set to 5 Hz, a certain amount of purified water is added, and granulation is performed. After the purified water is added, the granulation is additionally stirred for 1 min. The collected soft material is transferred to a whole granulator for wet whole granulation. The granules after wet whole granulation are transferred to a fluidized bed for drying, the material temperature is 40-45℃, the material after drying is transferred to a whole granulator for dry whole granulation; the material after dry whole granulation is sieved, and the granules with a mesh size of 30-80 are collected, which are the finished florfenicol granules.

[0088] Comparative Example 4

[0089] A florfenicol preparation with high water solubility and bacteriostatic effect, which comprises florfenicol 20 g, β-cyclodextrin 30 g, PEG-4000 48 g, sodium dodecyl sulfate 2 g, dopamine aqueous solution with a concentration of 2 g / L 150 g, and dextran sulfate aqueous solution with a concentration of 0.3 mol / L and a molecular weight of 20 kDa 3 g.

[0090] The preparation method of the florfenicol preparation with high water solubility and bacteriostatic effect comprises the following steps:

[0091] S1, the florfenicol is added into a dopamine solution, stirred at a speed of 150 r / min for 8 min, the pH value of the system is adjusted to 9.5 by using a sodium hydroxide solution with a concentration of 2 mol / L, ultrasonic treatment is performed for 90 min, the ultrasonic frequency is 24 kHz, the ultrasonic power is 120 W, and spray drying is performed to obtain pretreated florfenicol;

[0092] S2, send PEG-4000 into the mechanical crusher, set the stirring speed to 15 hz, and the stirring time to 1 min;

[0093] Send the pretreated florfenicol, β-cyclodextrin, sodium dodecyl sulfate and dextran sulfate solution into the multi-way motion mixer and mix uniformly, add the crushed PEG-4000 and mix uniformly to obtain a premix;

[0094] S3, add the premix into the dry granulator, set the roller distance to 0.8 mm, the horizontal screw speed to 10 rpm, the vertical screw speed to 300 rpm, the pressure roller speed to 3 rpm, the temperature to 28℃, the granulating speed to 1800 rpm, the granulating screen to 1.0 mm, collect the material discharged from the dry granulator, then transfer it to the granulator, set the granulating screen to 0.8 mm and the granulating speed to 1200 rpm, sieve, and collect the material between the 50 mesh screens.

[0095] Take the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 for solubility comparison, and the specific detection method is as follows: add 100 mL of purified water into a beaker, place the beaker on a magnetic stirrer, and start the stirring function; while stirring, add a certain amount of experimental sample, observe the sample dissolution phenomenon, if it is dissolved and clear, continue to add a certain amount of experimental sample, until it cannot be dissolved, the amount of sample added is the maximum solubility of the experimental sample under the condition. The results are shown in Table 1.

[0096] Table 1 Solubility of florfenicol preparations obtained in Example 5 and Comparative Examples 1-4

[0097] Group Solubility Dissolution phenomenon Example 5 ≤ 30,000 ppm Solution clear and transparent Comparative Example 1 ≤ 20,000 ppm Solution clear and transparent Comparative Example 2 ≤ 10,000 ppm Solution slightly turbid with floating matter Comparative Example 3 ≤ 12,000 ppm Solution slightly turbid Comparative Example 4 ≤ 24,000 ppm Solution clear and transparent

[0098] As can be seen from Table 1, the solubility of the florfenicol preparation obtained in Comparative Example 1 is increased by 100% compared with Comparative Example 2, and by 66% compared with Comparative Example 3; while the solubility of the florfenicol preparations obtained in Example 5 and Comparative Example 4 is much better than that of Comparative Example 1, and the solubility of the florfenicol preparation obtained in Example 5 is the highest. At the same time, the florfenicol preparations obtained in Example 5, Comparative Example 1 and Comparative Example 4 are clear and transparent after dissolution.

[0099] Good water solubility can be used for drinking water, which is beneficial for customers to use. In the pharmaceutical industry, for poorly soluble drugs, the solubility of the product is improved through the preparation process, thereby improving the bioavailability of the product in clinical application. The solubility of the product of Example 5 is greatly improved, which can effectively improve the difficulty of low bioavailability of florfenicol in clinical application for a long time.

[0100] The florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 were prepared into corresponding solutions according to the solution preparation method in the Veterinary Pharmacopoeia, and stored in qualified environment. The active substance content in the solution was detected by sampling at certain time points. The sampling time points were 0, 2, 4, 6, 8, 12, 24 h.

[0101] As shown in Table 1, the florfenicol preparations obtained in Example 5, Comparative Example 1 and Comparative Example 4 have good stability in aqueous solution, and the content is stable and controllable; and the stability of the florfenicol preparation obtained in Example 5 is the best. Figure 1

[0102] The minimum inhibitory concentration (MIC) (μg / mL) of the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 on Escherichia coli (standard strain 25922), Staphylococcus aureus ATCC25923 and Pasteurella multocida ATCC11859 was determined by in vitro inhibitory test.

[0103] As shown in Table 2, the minimum inhibitory concentration of the florfenicol preparation obtained in Example 5 on each bacterium is the smallest, which is better than that of Comparative Examples 1-4 (P<0.05). Figure 2

[0104] Twenty healthy Wuzhishan small pigs (body weight 27±2 kg) were selected and randomly divided into 5 groups, 4 pigs in each group. The 5 groups were administered with the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 respectively, and the administration mode was according to the recommended dose of 30 mg / kg by gavage according to the Veterinary Pharmacopoeia. Blood sampling was performed at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 12 h, and the drug concentration was detected to compare the main pharmacokinetic parameters of the samples in vivo.

[0105] As shown in Table 3 and Table 4, the florfenicol preparation obtained in Example 5 is released quickly in vivo, and the time to peak T max is the smallest (P<0.05), and because of its good solubility, the in vivo stability is also good, and the C max is the highest (P<0.05); that is, the florfenicol preparation obtained in Example 5 can better play a drug role in vivo, and has a better effect on the treatment and prevention of animal diseases. Figure 3 Figure 4 In summary, the florfenicol preparation obtained by the present application has high water solubility, is easy to feed, and has good stability in aqueous solution, and the content is stable and controllable; the granulation particles are stable, and the finished product has good inhibitory effect; the in vivo pharmacokinetic parameters have more advantages.

[0106] In summary, the florfenicol preparation obtained by the present application has high water solubility, is easy to feed, and has good stability in aqueous solution, and the content is stable and controllable; the granulation particles are stable, and the finished product has good inhibitory effect; the in vivo pharmacokinetic parameters have more advantages.

[0107] ​​​The applicant believes that: this is due to the present application utilizes florfenicol and dopamine complex, dopamine self-polymerization and florfenicol complex forms a hydrophilic polydopamine layer, improves the dispersibility of florfenicol, effectively improves the solubility, through host-guest inclusion (cyclodextrin) and polyelectrolyte complex (electrostatic interaction of dextran sulfate and polydopamine), enhances the structural stability, delays drug release. Meanwhile, the present application adopts β-cyclodextrin to coat the pretreated florfenicol in weak acid (pH=5-6) environment, the β-cyclodextrin inclusion capacity is enhanced under weak acid condition; then the negative charge sulfated polysaccharide and the positive charge polydopamine form a stable polyelectrolyte complex, effectively reduces drug hydrolysis or aggregation, and the dextran sulfate can also be combined with florfenicol to expand the antibacterial spectrum, which can effectively enhance the bacterial membrane permeability and greatly prolong the bacteriostatic time.

[0108] The above is only the preferred specific embodiment of the present application, but the protection scope of the present application is not limited to this, any person skilled in the art in the technical range disclosed by the present application, according to the technical scheme and the inventive concept of the present application, equivalent replacement or change, should be covered in the protection scope of the present application.

Claims

1. A florfenicol preparation with high water solubility and antibacterial effect, characterized in that, The raw materials, by weight, include: 20-30 parts florfenicol, 30-50 parts β-cyclodextrin, 30-50 parts solid polyethylene glycol, 2-5 parts sodium dodecyl sulfate, 100-200 parts dopamine aqueous solution, and 1-5 parts sulfated dextran aqueous solution. The concentration of dopamine aqueous solution is 1-3 g / L, and the concentration of dextran sulfate aqueous solution is 0.1-0.5 mol / L; The following steps are used to prepare it: S1. Add florfenicol to the dopamine solution and stir for 5-10 min. Adjust the pH of the system to 9-10, sonicate for 1-2 h, and spray dry to obtain pretreated florfenicol. S2. Add β-cyclodextrin to the acetic acid solution and stir until homogeneous. Adjust the pH of the system to 5-6. Add pretreated florfenicol and mix until homogeneous. While stirring, add sulfated dextran solution dropwise. After the addition is complete, continue stirring for 30-40 minutes. Centrifuge, wash, and vacuum dry to obtain coated florfenicol. S3. Mix the coated florfenicol, β-cyclodextrin and sodium dodecyl sulfate evenly, then add the pulverized solid polyethylene glycol and mix evenly to obtain a premix. S4. Dry granulate the premixed material, sizing it, sieving it, and collecting the material between 30-80 mesh sieves. The mass ratio of β-cyclodextrin used in S2 to that used in S3 is 4-8:26-42.

2. The florfenicol preparation with high water solubility and antibacterial effect according to claim 1, characterized in that, The average molecular weight of solid polyethylene glycol is 3600-4400.

3. The florfenicol preparation with high water solubility and antibacterial effect according to claim 1, characterized in that, The molecular weight of sulfated dextran is 15-22 kDa.

4. A method for preparing a florfenicol preparation with high water solubility and antibacterial effect as described in any one of claims 1-3, characterized in that, Includes the following steps: S1. Add florfenicol to the dopamine solution and stir for 5-10 min. Adjust the pH of the system to 9-10, sonicate for 1-2 h, and spray dry to obtain pretreated florfenicol. S2. Add β-cyclodextrin to the acetic acid solution and stir until homogeneous. Adjust the pH of the system to 5-6. Add pretreated florfenicol and mix until homogeneous. While stirring, add sulfated dextran solution dropwise. After the addition is complete, continue stirring for 30-40 minutes. Centrifuge, wash, and vacuum dry to obtain coated florfenicol. S3. Mix the coated florfenicol, β-cyclodextrin and sodium dodecyl sulfate evenly, then add the pulverized solid polyethylene glycol and mix evenly to obtain a premix. S4. Dry granulate the premixed material, sizing it, sieving it, and collecting the material between 30-80 mesh sieves. The mass ratio of β-cyclodextrin used in S2 to that used in S3 is 4-8:26-42.

5. The method for preparing the florfenicol preparation with high water solubility and antibacterial effect according to claim 4, characterized in that, In S1, the pH of the system is adjusted to 9-10 using a sodium hydroxide solution with a concentration of 1-3 mol / L.

6. The method for preparing the florfenicol preparation with high water solubility and antibacterial effect according to claim 4, characterized in that, In S1, the ultrasonic frequency is 20-30kHz and the ultrasonic power is 100-150W.

7. The method for preparing the florfenicol preparation with high water solubility and antibacterial effect according to claim 4, characterized in that, In S2, the mass fraction of the acetic acid solution is 0.6-1%.

8. The method for preparing the florfenicol preparation with high water solubility and antibacterial effect according to claim 4, characterized in that, In S4, a dry granulation machine is used for dry granulation. The roller spacing is set to 0.5-1.0 mm, the horizontal screw speed is 8-12 rpm, the vertical screw speed is 250-350 rpm, the pressure roller speed is 2.0-4.0 rpm, the temperature is controlled at 25-30℃, the granulation speed is 1500-2000 rpm, and the granulation screen is 1.0 mm.

9. The method for preparing the florfenicol preparation with high water solubility and antibacterial effect according to claim 4, characterized in that, In S4, a granulator is used for granulation. The granulator has a screen size of 0.8mm and a granulation speed of 800-1500rpm.

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