Florfenicol preparation with high water solubility and antibacterial effect and preparation method of florfenicol preparation

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a florfenicol preparation with high water solubility and antibacterial effect and a preparation method of the florfenicol preparation. The florfenicol preparation with high water solubility and antibacterial effect is prepared from the following raw materials in parts by mass: 20 to 30 parts of florfenicol, 30 to 50 parts of beta-cyclodextrin, 30 to 50 parts of solid polyethylene glycol, 2 to 5 parts of lauryl sodium sulfate, 100 to 200 parts of dopamine aqueous solution and 1 to 5 parts of dextran sulfate aqueous solution. 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 preparation method is relatively wide in application, is commonly used for granulating heat-sensitive materials and medicines which are easy to decompose when encountering water, and is convenient for subsequent re-tabletting or encapsulation; and compared with wet granulation, the method has the advantages of simple process, low energy consumption, low filler consumption and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a florfenicol preparation with high water solubility and bacteriostatic effect and a preparation method thereof. Background Art

[0002] Florfenicol is a 3-fluoro derivative of thiamphenicol and belongs to a new type of broad-spectrum antibiotic of the amide alcohol class. This drug was first developed successfully by the American Schering-Plough Corporation in the late 1980s and is a new type of chemically synthesized broad-spectrum antibacterial drug for animals. Florfenicol was first marketed in Japan in 1990, and China approved this drug in 2000 and it belongs to the second-class new veterinary drugs in China. Compared with other chloramphenicol drugs, florfenicol has better antibacterial activity, and has the advantages of good absorption, wide distribution in the body, long half-life, no residue or low residue in the body, and no potential aplastic anemia, etc., and also has no disadvantages such as teratogenicity, carcinogenicity, and mutagenicity.

[0003] Currently in veterinary clinics, 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 from being used in food animals of animal origin, the market demand for florfenicol has been further expanded. So far, in various countries, florfenicol is widely used as the main force of anti-infective drugs, and tens of thousands of tons are used annually worldwide.

[0004] Florfenicol belongs to class II drugs in the biopharmaceutics classification system (BCS), that is, low solubility / high permeability drugs. This property can enable it to be rapidly absorbed and utilized in the body, but the problems of its 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] Currently, in addition to the commonly used clinical florfenicol injections (30%, 10%, and 5%), solution agents (2%), soluble powders (10%), and premixes (5%) in the market, there are also florfenicol ultramicro powder, florfenicol nanoemulsion, in-situ gel, solid dispersion, and water-soluble complex, etc. Although the above methods have improved the solubility of florfenicol to a certain extent, they all have their own different disadvantages and are not conducive to clinical use. Therefore, how to improve the solubility of florfenicol by means of preparations is of great significance for the clinical application of this product. Summary of the Invention

[0006] The purpose of the present invention is to solve the deficiencies existing in the prior art and to provide 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, the raw materials of which include, by mass: 20-30 parts of florfenicol, 30-50 parts of β-cyclodextrin, 30-50 parts of solid polyethylene glycol, 2-5 parts of sodium dodecyl sulfate, 100-200 parts of dopamine aqueous solution, 1-5 parts of dextran sulfate aqueous solution; 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 preparation method of the above-mentioned florfenicol preparation with high water solubility and bacteriostatic effect includes the following steps:

[0011] S1. Add florfenicol to the dopamine solution, stir for 5-10 min, adjust the pH value of the system to 9-10, perform ultrasonic treatment for 1-2 h, and spray dry to obtain pretreated florfenicol.

[0012] S2. Add β-cyclodextrin to the acetic acid solution, stir evenly, adjust the pH value of the system to 5-6, add the pretreated florfenicol thereto and mix evenly, dropwise add the dextran sulfate solution thereto under stirring, continue to stir for 30-40 min after complete dropping, centrifuge, wash, and vacuum dry to obtain coated florfenicol.

[0013] S3. Mix the coated florfenicol, β-cyclodextrin, and sodium dodecyl sulfate evenly, and add the crushed solid polyethylene glycol and mix evenly to obtain a premix.

[0014] S4. Granulate the premix by dry granulation, size the granules, sieve, and collect the materials between 30-80 meshes.

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

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

[0017] Preferably, the mass ratio of β-cyclodextrin used in S2 to β-cyclodextrin 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 using a dry granulator, with the roller spacing set at 0.5 - 1.0 mm, the horizontal screw speed at 8 - 12 rpm, the vertical screw speed at 250 - 350 rpm, the pressure wheel speed at 2.0 - 4.0 rpm, the temperature controlled at 25 - 30 °C, the sizing speed at 1500 - 2000 rpm, and the sizing screen at 1.0 mm.

[0020] Preferably, in S4, sizing is carried out using a sizing machine, with the screen in the sizing machine at 0.8 mm and the sizing speed at 800 - 1500 rpm.

[0021] Beneficial effects:

[0022] 1. The present invention utilizes the compounding of florfenicol and dopamine. Dopamine self - polymerizes and forms a hydrophilic polydopamine layer in combination with florfenicol, improving the dispersibility of florfenicol, effectively increasing the solubility, and enhancing the structural stability and delaying drug release through host - guest inclusion (cyclodextrin) and polyelectrolyte complexation (electrostatic interaction between dextran sulfate and polydopamine).

[0023] 2. The present invention uses β - cyclodextrin to coat the pretreated florfenicol in a weakly acidic (pH = 5 - 6) environment. The inclusion ability of β - cyclodextrin is enhanced under weakly acidic conditions. Subsequently, a stable polyelectrolyte complex is formed using negatively charged sulfuric acid polysaccharide and positively charged polydopamine, effectively reducing drug hydrolysis or aggregation. At the same time, dextran sulfate can also be combined with florfenicol to expand the antibacterial spectrum, which can not only effectively enhance bacterial membrane permeability but also greatly extend the antibacterial time.

[0024] 3. The present invention relies on the principle of mechanical extrusion to directly compress, form, and coarsely crush the raw material powder to produce granular finished products. After granulation, the bulk density increases significantly, improving the appearance and fluidity of the material, facilitating storage and transportation, and also controlling solubility, porosity, specific surface area, etc.

[0025] 4. The present invention has a relatively wide application and is commonly used for granulation of heat - sensitive materials and drugs that are easily decomposed by water, facilitating subsequent re - tabletting or encapsulation. Moreover, compared with wet granulation, it has the advantages of simple process, low energy consumption, and less filler usage. Description of the drawings

[0026] Figure 1 It is a graph showing the change in the content of active substances in the florfenicol preparation solutions obtained in Example 5 and Comparative Examples 1 - 4 at different time points.

[0027] Figure 2 It is a comparison graph of the minimum inhibitory concentrations of the florfenicol preparations obtained in Example 5 and Comparative Examples 1 - 4 against Escherichia coli, Staphylococcus aureus, and Pasteurella.

[0028] Figure 3Comparison chart of the maximum concentration and the area under the plasma concentration-time curve in the body after intragastric administration of the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 to miniature pigs.

[0029] Figure 4 Comparison chart of the peak time and half-life after intragastric administration of the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 to miniature pigs. Detailed implementation manners

[0030] The present invention will be further illustrated below in conjunction with specific embodiments.

[0031] Example 1

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

[0033] The preparation method of the above-mentioned florfenicol preparation with high water solubility and bacteriostatic effect comprises 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, perform ultrasonic treatment for 1 h, the ultrasonic frequency is 20 kHz, the ultrasonic power is 100 W, and spray drying is performed to obtain pretreated florfenicol;

[0035] S2. Add 6 g of β-cyclodextrin to 50 g of an acetic acid solution with a mass fraction of 0.6%, stir evenly, adjust the pH value of the system to 5, add the pretreated florfenicol thereto and mix evenly, dropwise add the dextran sulfate solution thereto under stirring, continue stirring for 30 min after complete dropping, centrifuge, wash, and vacuum dry to obtain coated florfenicol;

[0036] S3. Feed PEG-4000 into a mechanical pulverizer, set the stirring speed to 10 hz and the stirring time to 2 min;

[0037] Feed the coated florfenicol, 34 g of β-cyclodextrin, and sodium dodecyl sulfate into a multi-directional motion mixer and mix evenly, add the pulverized PEG-4000 and mix evenly to obtain a premix;

[0038] S4. Add the premix to the dry granulator for dry granulation, set the roller spacing to 0.5 mm, the horizontal screw speed to 8 rpm, the vertical screw speed to 250 rpm, the pressure wheel speed to 2.0 rpm, the temperature to 25 ° C, the granulation speed to 1500 rpm, the granulation screen to 1.0 mm, collect the material discharged from the dry granulator discharge port, and then transfer it to the granulator, the granulation screen to 0.8 mm, the granulation speed to 800 rpm, sieve, and collect the material between the 30 mesh sieve.

[0039] Example 2

[0040] A florfenicol preparation with high water solubility and antibacterial effect, wherein the raw materials include: 30 g of florfenicol, 50 g of beta-cyclodextrin, 50 g of PEG-4000, 5 g of sodium lauryl sulfate, 200 g of a 3 g / L dopamine aqueous solution, and 5 g of a 0.5 mol / L dextran sulfate (molecular weight 22 kDa) aqueous solution.

[0041] The method for preparing the above-mentioned florfenicol preparation with high water solubility and antibacterial effect comprises the following steps:

[0042] S1, adding florfenicol to the dopamine solution, stirring at a speed of 200r / min for 10min, adjusting the pH value of the system to 10 with a 3mol / L sodium hydroxide solution, ultrasonically treating for 2h, the ultrasonic frequency is 30kHz, the ultrasonic power is 150W, and spray drying to obtain pretreated florfenicol;

[0043] S2, adding 8g of β-cyclodextrin to 100g of 1% acetic acid solution and stirring evenly, adjusting the pH value of the system to 6, adding the pretreated florfenicol and mixing evenly, adding the dextran sulfate solution dropwise thereto under stirring, stirring for 40min after the addition is complete, centrifuging, washing, and vacuum drying to obtain coated florfenicol;

[0044] S3, feeding PEG-4000 into a mechanical pulverizer, setting the stirring speed to 20 Hz and the stirring time to 3 min;

[0045] The coated florfenicol, 42 g of β-cyclodextrin, and sodium lauryl sulfate were fed into a multi-directional motion mixer and mixed evenly, and the crushed PEG-4000 was added and mixed evenly to obtain a premix;

[0046] S4. Add the premix to a dry granulator for dry granulation. Set the roller spacing at 1.0 mm, the horizontal screw speed at 12 rpm, the vertical screw speed at 350 rpm, the pressure roller speed at 4.0 rpm, control the temperature at 30 °C, the screening speed at 2000 rpm, the screening mesh at 1.0 mm. Collect the material discharged from the outlet of the dry granulator, then transfer it to a screening machine, with the screening mesh at 0.8 mm and the screening speed at 1500 rpm. Screen it and collect the material between 80-mesh sieves.

[0047] Example 3

[0048] A florfenicol preparation with high water solubility and antibacterial effect, the raw materials of which include: 22 g of florfenicol, 45 g of β-cyclodextrin, 45 g of PEG-4000, 3 g of sodium dodecyl sulfate, 120 g of dopamine aqueous solution with a concentration of 2.5 g / L, and 2 g of dextran sulfate (molecular weight 20 kDa) aqueous solution with a concentration of 0.4 mol / L.

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

[0050] S1. Add florfenicol to the dopamine solution, stir at a speed of 180 r / min for 7 min, adjust the pH value of the system to 9.5 with a 2.5 mol / L sodium hydroxide solution, perform ultrasonic treatment for 80 min, with an ultrasonic frequency of 27 kHz and an ultrasonic power of 110 W, and obtain pretreated florfenicol by spray drying;

[0051] S2. Add 7 g of β-cyclodextrin to 70 g of acetic acid solution with a mass fraction of 0.9%, stir evenly, adjust the pH value of the system to 5.5, add the pretreated florfenicol and mix evenly, dropwise add the dextran sulfate solution under stirring, continue to stir for 33 min after complete dropping, centrifuge, wash, and vacuum dry to obtain coated florfenicol;

[0052] S3. Feed PEG-4000 into a mechanical crusher, set the stirring speed at 18 hz and the stirring time at 1.5 min;

[0053] Feed the coated florfenicol, 38 g of β-cyclodextrin, and sodium dodecyl sulfate into a multi-directional motion mixer and mix evenly, then add the crushed PEG-4000 and mix evenly to obtain a premix;

[0054] S4. Add the premix to a dry granulator for dry granulation. Set the roller spacing at 0.7 mm, the horizontal screw speed at 11 rpm, the vertical screw speed at 280 rpm, the pressure roller speed at 3.5 rpm, control the temperature at 27 °C, the screening speed at 1900 rpm, and the screening mesh at 1.0 mm. Collect the material discharged from the outlet of the dry granulator, then transfer it to a screening machine, with a screening mesh of 0.8 mm and a screening speed of 1000 rpm. Screen and collect the material between 70-mesh sieves.

[0055] Example 4

[0056] A florfenicol preparation with high water solubility and antibacterial effect, the raw materials of which include: 28 g of florfenicol, 35 g of β-cyclodextrin, 35 g of PEG-4000, 4 g of sodium dodecyl sulfate, 180 g of dopamine aqueous solution with a concentration of 1.5 g / L, and 4 g of dextran sulfate (molecular weight 20 kDa) aqueous solution with a concentration of 0.2 mol / L.

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

[0058] S1. Add florfenicol to the dopamine solution, stir at a speed of 120 r / min for 9 min, adjust the pH value of the system to 9.5 with a 1.5 mol / L sodium hydroxide solution, perform ultrasonic treatment for 100 min, with an ultrasonic frequency of 21 kHz and an ultrasonic power of 130 W, and obtain pretreated florfenicol by spray drying;

[0059] S2. Add 5 g of β-cyclodextrin to 90 g of acetic acid solution with a mass fraction of 0.7%, stir evenly, adjust the pH value of the system to 5.5, add the pretreated florfenicol to it and mix evenly, dropwise add the dextran sulfate solution under stirring, continue to stir for 37 min after complete addition, centrifuge, wash, and vacuum dry to obtain coated florfenicol;

[0060] S3. Feed PEG-4000 into a mechanical grinder, set the stirring speed at 12 hz and the stirring time at 2.5 min;

[0061] Feed the coated florfenicol, 30 g of β-cyclodextrin, and sodium dodecyl sulfate into a multi-directional motion mixer and mix evenly, then add the pulverized PEG-4000 and mix evenly to obtain a premix;

[0062] S4. Add the premix to a dry granulator for dry granulation. Set the roller spacing to 0.9 mm, the horizontal screw speed to 9 rpm, the vertical screw speed to 320 rpm, the pressure roller speed to 2.5 rpm, control the temperature at 29 °C, the screening speed to 1700 rpm, the screening mesh to 1.0 mm, collect the material discharged from the dry granulator discharge port, then transfer it to a granulator, with a screening mesh of 0.8 mm, a screening speed of 1400 rpm, sieve, and collect the material between 40-mesh sieves.

[0063] Example 5

[0064] A florfenicol preparation with high water solubility and antibacterial effect, the raw materials of which include: 20 g of florfenicol, 30 g of β-cyclodextrin, 48 g of PEG-4000, 2 g of sodium dodecyl sulfate, 150 g of dopamine aqueous solution with a concentration of 2 g / L, and 3 g of dextran sulfate (molecular weight 20 kDa) aqueous solution with a concentration of 0.3 mol / L.

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

[0066] S1. Add florfenicol to the dopamine solution, stir at a speed of 150 r / min for 8 min, adjust the pH value of the system to 9.5 with a 2 mol / L sodium hydroxide solution, perform ultrasonic treatment for 90 min, with an ultrasonic frequency of 24 kHz and an ultrasonic power of 120 W, and obtain pretreated florfenicol by spray drying;

[0067] S2. Add 4 g of β-cyclodextrin to 80 g of acetic acid solution with a mass fraction of 0.8%, stir evenly, adjust the pH value of the system to 5.5, add the pretreated florfenicol to it and mix evenly, dropwise add the dextran sulfate solution under stirring, continue to stir for 35 min after complete dropping, centrifuge, wash, and vacuum dry to obtain coated florfenicol;

[0068] S3. Feed PEG-4000 into a mechanical pulverizer, set the stirring speed to 15 hz, and the stirring time to 1 min;

[0069] Put the coated florfenicol, 26 g of β-cyclodextrin, and sodium dodecyl sulfate into a multi-directional motion mixer and mix evenly, add the pulverized PEG-4000 and mix evenly to obtain a premix;

[0070] S4. Add the premix to the dry granulator for dry granulation, set the roller spacing to 0.8 mm, the horizontal screw speed to 10 rpm, the vertical screw speed to 300 rpm, the pressure wheel speed to 3 rpm, the temperature to 28 ° C, the granulation speed to 1800 rpm, the granulation screen to 1.0 mm, collect the material discharged from the dry granulator discharge port, and then transfer it to the granulator, the granulation screen to 0.8 mm, the granulation speed to 1200 rpm, sieve, and collect the material between the 50 mesh sieve.

[0071] Comparative Example 1

[0072] A florfenicol preparation with high water solubility and antibacterial effect, the raw materials of which include: 17g of florfenicol, 30g of beta-cyclodextrin, 48g of PEG-4000, and 2g of sodium dodecyl sulfate.

[0073] The method for preparing the above-mentioned florfenicol preparation with high water solubility and antibacterial effect comprises the following steps:

[0074] S1. Feed PEG-4000 into a mechanical pulverizer, set the stirring speed to 15 Hz, and the stirring time to 1 min;

[0075] Put florfenicol, β-cyclodextrin and sodium lauryl sulfate into a multi-directional motion mixer and mix them evenly, add the crushed PEG-4000 and mix them evenly to obtain a premix;

[0076] S2. Add the premix to the dry granulator for dry granulation, set the roller spacing to 0.8 mm, the horizontal screw speed to 10 rpm, the vertical screw speed to 300 rpm, the pressure wheel speed to 3 rpm, the temperature to 28 ° C, the granulation speed to 1800 rpm, the granulation screen to 1.0 mm, collect the material discharged from the dry granulator discharge port, and then transfer it to the granulator, the granulation screen to 0.8 mm, the granulation speed to 1200 rpm, sieve, and collect the material between the 50 mesh sieve.

[0077] Comparative Example 2

[0078] A florfenicol preparation with high water solubility and antibacterial effect, the raw materials of which include: 17g of florfenicol, 30g of beta-cyclodextrin, 48g of PEG-4000, and 2g of sodium dodecyl sulfate.

[0079] The method for preparing the above-mentioned florfenicol preparation with high water solubility and antibacterial effect comprises the following steps:

[0080] PEG-4000 was fed into a mechanical pulverizer, and the stirring speed was set to 15 Hz and the stirring time was 1 min;

[0081] Put florfenicol, β-cyclodextrin and sodium lauryl sulfate into a multi-directional motion mixer and mix them evenly, then add the crushed PEG-4000 and mix them evenly.

[0082] Comparative Example 3

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

[0084] The preparation method of the above-mentioned florfenicol preparation with high water solubility and bacteriostatic effect includes the following steps:

[0085] S1. Feed PEG-4000 into a mechanical pulverizer, set the stirring speed to 15 hz, and the stirring time to 1 min;

[0086] Mix florfenicol, β-cyclodextrin, and sodium dodecyl sulfate evenly, add them to a wet granulator, set the stirring speed to 9 Hz, the cutter speed to 3 Hz, and run for 5 min; after mixing, add the pulverized PEG-4000 and mix evenly, and then keep running at the same speed for 5 min to obtain a premix.

[0087] S2. After the operation is completed, set the stirring speed to 13 Hz and the cutter speed to 5 Hz, add a certain amount of purified water, and perform granulation operation. After the addition of purified water is completed, stir and granulate for an additional 1 min. Transfer the collected soft material to a granulating machine for wet granulation operation. Transfer the wet granulated particles to a fluidized bed for drying, with the material temperature at 40 - 45 °C. Transfer the dried material to a granulating machine for dry granulation operation; sieve the dry granulated material, and collect the particles passing through a 30 - 80 mesh sieve, which are the finished florfenicol particles.

[0088] Comparative Example 4

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

[0090] The preparation method of the above-mentioned florfenicol preparation with high water solubility and bacteriostatic effect includes the following steps:

[0091] S1. Add florfenicol to the dopamine solution, stir at a speed of 150 r / min for 8 min, adjust the pH value of the system to 9.5 with a 2 mol / L sodium hydroxide solution, perform ultrasonic treatment for 90 min, with an ultrasonic frequency of 24 kHz and an ultrasonic power of 120 W, and spray dry to obtain pretreated florfenicol;

[0092] S2. Feed PEG-4000 into a mechanical pulverizer, set the stirring speed at 15 hz and the stirring time at 1 min;

[0093] Feed the pretreated florfenicol, β-cyclodextrin, sodium dodecyl sulfate and dextran sulfate solution into a multi-directional motion mixer to mix evenly, add the pulverized PEG-4000 and mix evenly to obtain a premix;

[0094] S3. Add the premix into a dry granulator for dry granulation. Set the roller spacing at 0.8 mm, the horizontal screw speed at 10 rpm, the vertical screw speed at 300 rpm, the pressure roller speed at 3 rpm, control the temperature at 28 °C, the screening speed at 1800 rpm, and the screening mesh at 1.0 mm. Collect the material discharged from the discharge port of the dry granulator, then transfer it to a granulator, with the screening mesh at 0.8 mm and the screening speed at 1200 rpm. Screen and collect the material between 50-mesh sieves.

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

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

[0097] Group Solubility Dissolution phenomenon Example 5 ≤30000 ppm The solution is clear and transparent Comparative Example 1 ≤20000 ppm The solution is clear and transparent Comparative Example 2 ≤10000 ppm The solution is slightly turbid with floating substances Comparative Example 3 ≤12000 ppm The solution is slightly turbid Comparative Example 4 ≤24000 ppm The solution is clear and transparent

[0098] It can be seen from Table 1 that the solubility of the florfenicol preparation obtained in Comparative Example 1 increased by 100% compared with that in Comparative Example 2, and increased by 66% compared with that in Comparative Example 3; while the solubilities of the florfenicol preparations obtained in Example 5 and Comparative Example 4 are much better than that in 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 and suitability for drinking use are beneficial for customers to feed materials. In the pharmaceutical industry, for poorly soluble drugs, the solubility of their products is improved through formulation processes, thereby improving the bioavailability of the products in clinical applications. The solubility of the product in Example 5 has been greatly improved, which can effectively solve the long-term problem of low bioavailability of florfenicol in clinical applications.

[0100] Referring to the solution preparation method in the Veterinary Pharmacopoeia, the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 were formulated into corresponding solutions, stored in a qualified environment, and at regular time points, samples were taken to detect the content of the active substance in the solution. The sampling time points were 0, 2, 4, 6, 8, 12, and 24 h.

[0101] As Figure 1 shown, the florfenicol preparations obtained in Example 5, Comparative Example 1, and Comparative Example 4 had good stability in aqueous solution and the content was stable and controllable; among them, the florfenicol preparation obtained in Example 5 had the best stability.

[0102] The minimum inhibitory concentrations (MIC) (μg / mL) of the florfenicol preparations obtained in Example 5 and Comparative Examples 1-4 against Escherichia coli (standard strain 25922), Staphylococcus aureus ATCC25923, and Pasteurella multocida ATCC11859 were tested in vitro for antibacterial activity.

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

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

[0105] As Figure 3 and Figure 4 shown, the florfenicol preparation obtained in Example 5 was released rapidly in vivo, and the peak time T max was the shortest (P < 0.05). Moreover, due to its good solubility, its stability in vivo was also better, and C max was the highest (P < 0.05); that is, the florfenicol preparation obtained in Example 5 played a better drug role in vivo and was more effective in the treatment and prevention of animal diseases.

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

[0107] The applicant believes that: This is because the present invention utilizes the compounding of florfenicol and dopamine. Dopamine self-polymerizes and complexes with florfenicol to form a hydrophilic polydopamine layer, improving the dispersibility of florfenicol and effectively increasing its solubility. Through host-guest inclusion (cyclodextrin) and polyelectrolyte complexation (electrostatic interaction between dextran sulfate and polydopamine), the structural stability is enhanced and the drug release is delayed. At the same time, the present invention uses β-cyclodextrin to coat the pretreated florfenicol in a weakly acidic (pH = 5-6) environment, and the inclusion ability of β-cyclodextrin is enhanced under weakly acidic conditions; subsequently, a stable polyelectrolyte complex is formed by the negatively charged sulfated polysaccharide and the positively charged polydopamine, effectively reducing drug hydrolysis or aggregation. At the same time, dextran sulfate can also be used in combination with florfenicol to expand the antibacterial spectrum, which can not only effectively enhance bacterial membrane permeability but also greatly extend the antibacterial time effect.

[0108] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes should be covered within the protection scope of the present invention.

Claims

1. A florfenicol preparation with high water solubility and antibacterial effect, characterized in that: The raw materials include, by mass: 20-30 parts of florfenicol, 30-50 parts of beta-cyclodextrin, 30-50 parts of solid polyethylene glycol, 2-5 parts of sodium lauryl sulfate, 100-200 parts of dopamine aqueous solution, and 1-5 parts of dextran sulfate aqueous solution; 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.

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 dextran sulfate is 15-22 kDa.

4. A method for preparing a florfenicol preparation with high water solubility and antibacterial effect as claimed in any one of claims 1 to 3, characterized in that: The steps include: S1, adding florfenicol to the dopamine solution and stirring for 5-10 minutes, adjusting the pH value of the system to 9-10, ultrasonically treating for 1-2 hours, and spray drying to obtain pretreated florfenicol; S2, adding β-cyclodextrin to the acetic acid solution and stirring evenly, adjusting the pH value of the system to 5-6, adding the pretreated florfenicol thereto and mixing evenly, adding the dextran sulfate solution dropwise thereto under stirring, continuing to stir for 30-40 minutes after the addition is complete, centrifuging, washing, and vacuum drying to obtain coated florfenicol; S3, mixing the coated florfenicol, β-cyclodextrin, and sodium lauryl sulfate evenly, adding the crushed solid polyethylene glycol and mixing evenly to obtain a premix; S4. Dry granulate the premix, size the particles, sieve, and collect the material between 30-80 mesh.

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

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: The mass ratio of β-cyclodextrin used in S2 to β-cyclodextrin used in S3 is 4-8:26-42.

8. 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%.

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 dry granulator is used for dry granulation, and 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 wheel speed is 2.0-4.0 rpm, the temperature is controlled at 25-30 ° C, the granulation speed is 1500-2000 rpm, and the granulation screen is 1.0 mm.

10. 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 screen in the granulator is 0.8 mm, and the granulation speed is 800-1500 rpm.

Images