Veterinary water-soluble florfenicol powder and preparation method thereof

Abstract

The invention relates to the field of veterinary drugs, in particular to veterinary water-soluble florfenicol powder and a preparation method thereof. Comprising florfenicol, an inclusion agent and a dispersing agent, the inclusion agent is selected from beta-cyclodextrin, hydroxypropyl beta-cyclodextrin and a water-soluble cyclodextrin polymer, the water-soluble cyclodextrin polymer is water-soluble epoxypropane cross-linked cyclodextrin, and the molecular weight of the water-soluble cyclodextrin polymer is 1t; 100,000, 20,000, 20,000, 20,000; the dispersing agent is selected from povidone K30, polyethylene glycol, poloxamer 188 or sodium carboxymethyl cellulose. The preparation process is simplified, and the preparation method is suitable for large-scale industrial production; the production cost is greatly reduced; meanwhile, the water solubility of florfenicol is improved, the water solubility reaches up to 10000 ppm, and the prepared product is good in water solubility, safe and reliable and does not affect the health of animals.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of veterinary medicine, and particularly relates to a veterinary water-soluble florfenicol powder and a preparation method thereof. BACKGROUND

[0002] Florfenicol (FFC) is also called fluoromethanesulfone, and its chemical name is: D-(+)-threo-1-p-methylsulfonylphenyl-2-dichloroacetylamino-3-fluoropropanol, molecular formula is C 12 H 14 C l2 FNO4S, and its relative molecular weight is 358.2. It is an amido alcohol broad-spectrum antibacterial drug. The drug was first developed by the American Schering-Plough Corporation in the late 1980s, and was first marketed in Japan in 1990. China approved the drug in 2000, and it is a national new veterinary drug of type II. Compared with other chloramphenicol drugs, florfenicol has more advantages such as better antibacterial activity, good absorption, wide distribution in vivo, long half-life, no residual or low residual in vivo, no potential aplastic anemia, no teratogenicity, carcinogenicity, and mutagenicity, and the like. It has been widely used in the treatment of bacterial diseases of aquatic fish and livestock and poultry such as cattle, pigs, dogs, and chickens. The solubility of florfenicol in pure water at room temperature is about 1.25 mg / ml, and the solubility is poor, the bioavailability is low, the absorption effect after animals eat is not very good, the drug is not easy to absorb in the animal body, the drug residue is increased, and the bacterial drug resistance is increased. Therefore, it is urgent to improve the water solubility of florfenicol.

[0003] The existing technology for improving the water solubility of florfenicol mainly includes physical methods and chemical methods. The chemical method has low yield and many by-products, and is not suitable for industrial production. The physical method includes adding a cosolvent, micronization, cyclodextrin inclusion, and solid dispersion. The publication No. 102160854A discloses a kind of inclusion florfenicol powder preparation of cyclodextrin and its preparation method, which is prepared by uniformly stirring florfenicol, cyclodextrin and water by using inclusion technology. The preparation process includes inclusion reaction, drying and subsequent treatment steps. The problems are that the prepared water-soluble powder preparation has poor water solubility and poor stability, and the preparation process is complex. SUMMARY

[0004] The present application provides a veterinary water-soluble florfenicol powder and a preparation method thereof, so as to overcome the problems of the existing technology, such as poor water solubility of the prepared water-soluble powder preparation, poor stability, and complex preparation process.

[0005] In order to achieve the above object, the technical scheme of the present application is: a veterinary water-soluble florfenicol powder, comprising florfenicol, a clathration agent and a dispersing agent; the clathration agent is selected from betadex, hydroxypropyl betadex and water-soluble cyclodextrin polymer, the water-soluble cyclodextrin polymer is water-soluble propylene oxide cross-linked cyclodextrin with a molecular weight <100000; the dispersing agent is selected from povidone K30, polyethylene glycol, poloxamer 188 or sodium carboxymethyl cellulose.

[0006] Further, the mass fraction of the above raw materials is 10-20 parts of florfenicol, 10-40 parts of betadex, 10-40 parts of hydroxypropyl betadex, 20-55 parts of water-soluble cyclodextrin polymer and 1-2 parts of dispersing agent.

[0007] Further, the mass fraction of the above raw materials is 10 parts of florfenicol powder, 18 parts of betadex, 36 parts of hydroxypropyl betadex, 34.5 parts of water-soluble propylene oxide cross-linked cyclodextrin and 1.5 parts of dispersing agent.

[0008] Further, the dispersing agent is povidone K30.

[0009] The preparation method of the above-mentioned veterinary water-soluble florfenicol powder comprises the following steps:

[0010] Step one, dissolve hydroxypropyl betadex in water, and the mass concentration of hydroxypropyl betadex is 10%-40%;

[0011] Step two, take betadex and water-soluble betadex polymer according to the proportion, add the hydroxypropyl betadex solution prepared in step one, heat and stir to dissolve, and prepare a solution for standby use;

[0012] Step three, take the dispersing agent according to the proportion, add the mixture solution prepared in step two, heat and stir to dissolve for standby use;

[0013] Step four, take florfenicol according to the proportion, add the mixture solution prepared in step three, heat and stir to dissolve for standby use;

[0014] Step five, powder the solution, and the preparation is completed.

[0015] Further, in steps two-four, the heating temperature is 50-70°C.

[0016] Further, in step four, the stirring time is 2-4h.

[0017] Further, in step five, the powdering mode is rotary evaporation or spray drying.

[0018] Compared with the prior art, the present application has the following advantages:

[0019] 1. The application realizes green preparation of the inclusion process by screening different cyclodextrin types for inclusion with florfenicol, and the process does not use organic solvents, and the problem of poor water solubility and poor stability of the inclusion compound is solved by selecting appropriate dispersant types, simplifies the preparation process, and is suitable for large-scale industrial production.

[0020] 2. The water-soluble florfenicol powder prepared by the application effectively reduces the use amount of water-soluble cyclodextrin polymer and hydroxypropyl betadex by adjusting the mixing ratio of betadex, hydroxypropyl betadex and water-soluble cyclodextrin polymer, thereby greatly reducing the production cost. At the same time, the water solubility of florfenicol is improved to 10000ppm, and the prepared product is safe and reliable, and does not affect the health of animals. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 Infrared spectrograms of florfenicol, betadex, hydroxypropyl betadex, physical mixture and inclusion compound;

[0022] Figure 2 X-ray powder diffraction patterns of florfenicol, betadex, hydroxypropyl betadex, physical mixture and inclusion compound;

[0023] Figure 3 Differential scanning calorimetric analysis patterns of florfenicol, betadex, hydroxypropyl betadex, physical mixture and inclusion compound;

[0024] Figure 4 Scanning electron microscope analysis patterns of florfenicol, betadex, hydroxypropyl betadex, physical mixture and inclusion compound. DETAILED DESCRIPTION

[0025] The technical solutions and technical effects of the application are further described and explained in combination with specific embodiments and the accompanying drawings. Unless otherwise specified, the test methods used in the embodiments are conventional methods, and the materials, reagents, etc. used are commercially available unless otherwise specified.

[0026] Example 1, 100g of water-soluble florfenicol powder is prepared, and the raw materials used include:

[0027] Florfenicol powder 10.0g, betadex 18.0g, hydroxypropyl betadex 36.0g, water-soluble propylene oxide cross-linked cyclodextrin 34.5g, povidone K30 1.5g.

[0028] The preparation method comprises the following steps:

[0029] Step one, 36.0g of hydroxypropyl betadex is dissolved in 100g of water;

[0030] Step two, take the ratio of betadex 18.0 g and water-soluble betadex polymer 34.5 g, add the hydroxypropyl betadex solution prepared in step one, heated to 70 °C stirring to dissolve, ready for use when the solution is clear;

[0031] Step three, add 1.5 g of dispersant povidone K30 to step one, 70 °C stirring;

[0032] Step four, after adding 10.0 g of florfenicol to step three, 70 °C constant temperature stirring for 4 hours;

[0033] Step five, then use the pressure type spray dryer for spray drying treatment, the inlet temperature is set to 190 °C, the spray pressure is adjusted to 11 MPa, the particle size of the prepared powder is controlled in 100 μm-180 μm, the finished product is obtained.

[0034] Example 2, making 100 g of water-soluble florfenicol powder, the raw materials include:

[0035] Florfenicol powder 10.0 g, betadex 36.0 g, hydroxypropyl betadex 18.0 g, water-soluble propylene oxide cross-linked cyclodextrin 34.5 g, povidone K30 1.5 g.

[0036] The preparation method comprises the following steps:

[0037] Step one, 18.0 g of hydroxypropyl betadex is dissolved in 100 g of water;

[0038] Step two, take the ratio of betadex 36.0 g and water-soluble propylene oxide cross-linked cyclodextrin 34.5 g, add the hydroxypropyl betadex solution prepared in step one, heated to 70 °C stirring to dissolve, ready for use when the solution is clear;

[0039] Step three, add 1.5 g of dispersant povidone K30 to step two, 70 °C stirring;

[0040] Step four, after adding 10.0 g of florfenicol to step three, 70 °C constant temperature stirring for 4 hours;

[0041] Step five, then use the pressure type spray dryer for spray drying treatment, the inlet temperature is set to 190 °C, the spray pressure is adjusted to 11 MPa, the particle size of the prepared powder is controlled in 100 μm-180 μm, the finished product is obtained.

[0042] Example 3, making 100 g of water-soluble florfenicol powder, the raw materials include:

[0043] Florfenicol powder 15.0g, betadex 18.0g, hydroxypropyl betadex 35.0g, water-soluble propylene oxide cross-linked cyclodextrin 30.0g, sodium carboxymethyl cellulose 2.0g.

[0044] The preparation method comprises the following steps:

[0045] Step one, 35.0g hydroxypropyl betadex is dissolved in 100g water;

[0046] Step two, betadex 18.0g and water-soluble propylene oxide cross-linked cyclodextrin 30.0g are added to the hydroxypropyl betadex solution prepared in step one according to the proportion, and heated to 70°C for stirring and dissolution, and the solution is ready for use after clarification;

[0047] Step three, 2.0g of sodium carboxymethyl cellulose is added to step two, and stirring is continued at 70°C;

[0048] Step four, after adding 15.0g of florfenicol to step three, constant temperature stirring is carried out at 70°C for 4 hours;

[0049] Step five, then a pressure type spray dryer is used for spray drying treatment, the inlet temperature is set to 190°C, and the spray pressure is adjusted to 11MPa, so that the particle size of the prepared powder is controlled to be 100μm-180μm, and the finished product is obtained.

[0050] Example 4, 100g of water-soluble florfenicol powder is prepared, and the raw materials used include:

[0051] Florfenicol powder 20.0g, betadex 18.0g, hydroxypropyl betadex 30.0g, water-soluble propylene oxide cross-linked cyclodextrin 30.0g, sodium carboxymethyl cellulose 2.0g.

[0052] The preparation method comprises the following steps:

[0053] Step one, 30.0g hydroxypropyl betadex is dissolved in 100g water;

[0054] Step two, betadex 18.0g and water-soluble propylene oxide cross-linked cyclodextrin 30.0g are added to the hydroxypropyl betadex solution prepared in step one according to the proportion, and heated to 60°C for stirring and dissolution, and the solution is ready for use after clarification;

[0055] Step three, 2.0g of sodium carboxymethyl cellulose is added to step two, and stirring is continued at 60°C;

[0056] Step four, after adding 20.0g of florfenicol to step three, constant temperature stirring is carried out at 60°C for 4 hours;

[0057] Step five, then a rotary evaporator is used for rotary evaporation drying treatment, and the finished product is obtained.

[0058] Example 5, making 100 g of water-soluble florfenicol powder, the raw materials used include:

[0059] Florfenicol powder 15.0 g, betadex 20.0 g, hydroxypropyl betadex 40.0 g, water-soluble propylene oxide cross-linked betadex 23.0 g, poloxamer 188 2.0 g.

[0060] The preparation method includes the following steps:

[0061] Step one, 40.0 g of hydroxypropyl betadex is dissolved in 100 g of water;

[0062] Step two, according to the ratio, 20.0 g of betadex and 23.0 g of water-soluble propylene oxide cross-linked betadex are added to the hydroxypropyl betadex solution prepared in step one, heated to 70°C and stirred to dissolve, and the solution is ready for use after clarification;

[0063] Step three, 2.0 g of poloxamer 188 is added to step two, and stirring is continued at 70°C;

[0064] Step four, 15.0 g of florfenicol is added to step three, and stirring is continued at 70°C for 3 hours;

[0065] Step five, then use a pressure type spray dryer to spray dry it, set the inlet temperature to 190°C, and adjust the spray pressure to 11 MPa, so that the particle size of the prepared powder is controlled within 100 μm-180 μm, and the finished product is obtained.

[0066] Through experiments, example 1 is the best embodiment:

[0067] The water-soluble florfenicol powder inclusion prepared in example 1 is characterized, and the specific content is as follows; 1) Fourier infrared spectroscopy (FTIR):

[0068] The infrared spectra of florfenicol, betadex, hydroxypropyl betadex, physical mixture and inclusion are determined by NICOLET 6700 Fourier infrared spectrometer. The sample and KBr are mixed and ground at a ratio of about 1:100, and the infrared absorption spectrum of each sample is tested. The scanning wavelength is 400-4000 cm -1

[0069] As shown in Figure 1 , florfenicol has an -OH stretching vibration absorption peak at 3451 cm -1 , a -C=O stretching vibration absorption peak at 1684 cm -1 , a -NH bending vibration and -CN stretching vibration absorption peak at 1535 cm -1 , and a -NH bending vibration and -CN stretching vibration absorption peak at 1274 cm-1 bend vibration and -NH stretching vibration absorption peak of -CN, β-CD and HP-β-CD are about 3400 cm -1 -OH stretching vibration absorption peak, in the infrared spectrum of the physical mixture, due to the presence of β-CD and HP-β-CD, the original peak of FF is slightly shifted, as a whole, the spectrum of the physical mixture is the superposition of the infrared spectrum of FF and the infrared spectrum of β-CD / HP-β-CD, the inclusion complex has -OH stretching vibration absorption peak at 3406 cm -1 -OH stretching vibration absorption peak, which is not significantly different from β-CD / HP-β-CD, the characteristic peak of FF disappears or weakens, indicating that hydrogen bonding occurs between florfenicol and β-CD / HP-β-CD in the inclusion complex, thereby indicating that the benzene ring structure of florfenicol is included in the cavity of β-CD / HP-β-CD to form a new phase.

[0070] (2) X-ray powder diffraction method

[0071] The morphological structure of florfenicol, betadex, hydroxypropyl betadex, physical mixture and inclusion complex was analyzed by using a German Bruker D8 Advanced diffractometer. An appropriate amount of powder sample was placed on a glass slide and pressed flat, then tested by using Cu-Kα ray with a wavelength of 0.154 nm, a power of 40 kV, and 40 mA, sampling by using a step scanning mode with a step size of 0.02°, a test range of 5-55°C, and a scanning rate of 6° / min.

[0072] As shown in Figure 2 , florfenicol has strong diffraction peaks at 8.07°, 16.20°, 21.08°, 24.42°, 26.85°, 26.88°, and 31.94°, indicating that florfenicol has a specific crystal structure. β-CD has diffraction peaks at 8.94°, 10.63°, 12.64°, and 15.36°, indicating that β-CD is a crystalline substance, HP-β-CD has no obvious diffraction peak and is in an amorphous state. In the diffraction pattern of the physical mixture, there is an overlay of the diffraction peaks of florfenicol and β-CD / HP-β-CD, indicating that after direct mixing of FF and β-CD / HP-β-CD, the crystal form does not change and still maintains its own crystal characteristics. In the inclusion complex, the characteristic absorption peak of florfenicol completely disappears and is in an amorphous state, indicating that the inclusion complex is formed.

[0073] (3) Differential scanning calorimetry analysis

[0074] DSC3500 was used to analyze the relationship between florfenicol, betacyclodextrin, hydroxypropyl betacyclodextrin, physical mixture and inclusion compound and temperature. Appropriate amount of sample was weighed in empty crucible, then was clamped on sample table with tweezers for testing, setting program RT24-350℃, temperature rising speed 10° / min, collecting temperature rising curve under nitrogen atmosphere

[0075] As shown in Figure 3 , the differential thermal curves of FF, β-CD / HP-β-CD, physical mixture and inclusion compound are shown in the figure. It can be seen from the figure that the differential thermal curve of FF raw material has a strong endothermic peak at about 156℃, which is the melting point peak of florfenicol. The differential thermal curve of β-CD has wide endothermic peaks at 82-130℃ and 304-340℃, wherein 82-130℃ is the melting point peak of crystal water in β-CD, and 304-340℃ is the melting point peak of β-CD. The differential thermal curve of HP-β-CD has wide endothermic peaks at 50-130℃ and 300-350℃, wherein 50-130℃ is the melting point peak of crystal water in HP-β-CD, and 300-350℃ is the melting point peak of HP-β-CD. The physical mixture shows the common characteristics of FF and β-CD / HP-β-CD, having FF and β-CD / HP-β-CD melting point peaks, indicating that the mixture is a simple physical mixture without mutual action. The differential thermal curve of the inclusion compound has a strong endothermic peak of FF at about 156℃, and a crystal water endothermic peak at about 100℃ disappears, only having a characteristic endothermic peak at 262℃, indicating that FF is successfully embedded in the cavity of cyclodextrin during the inclusion process, the inclusion compound is formed, the melting point of the inclusion compound is lower than that of cyclodextrin parent body, and a new structure system is formed by inclusion.

[0076] (4) Scanning electron microscope analysis

[0077] A small amount of sample was evenly coated on the conductive tape with white protective paper by Hitachi SU8020. Vacuum sputtering method was used. The instrument used was vacuum sputtering instrument, the sample was placed on the sample table about 10-15 cm away from the evaporation source, the sample was rotated, gold was sprayed (10KV / 60s), the sputtering should be uniform, and the sample was observed under the microscope after completion.

[0078] As shown in Figure 4 , the scanning electron microscope analysis of florfenicol and β-CD / HP-β-CD is shown in figures a-f. As can be seen from figures a and b, there is obvious difference between FF and β-CD, figure c shows that HP-β-CD is spherical, figure d shows that the physical mixture shows the comprehensive characteristics of florfenicol and β-CD / HP-β-CD, figures e and f are completely different from the inclusion compound, the shape and morphology of which have changed significantly, indicating that a new phase is formed.

[0079] Although the present application has been described in detail with regard to the embodiments thereof, it should be apparent that various modifications, changes, and substitutions can be made by one skilled in the art without departing from the spirit and scope of the present application.

Claims

1. A water-soluble florfenicol powder for veterinary use, characterized in that: Including florfenicol, inclusion agents, and dispersants; The inclusion agent is selected from: beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and water-soluble cyclodextrin polymers; The water-soluble cyclodextrin polymer is a water-soluble propylene oxide cross-linked cyclodextrin with a molecular weight of [missing information]. <100000; The dispersant is selected from: povidone K30, polyethylene glycol, poloxamer 188 or sodium carboxymethyl cellulose.

2. The veterinary water-soluble florfenicol powder according to claim 1, characterized in that: The raw materials are in the following proportions by weight: 10-20 parts florfenicol, 10-40 parts beta-cyclodextrin, 10-40 parts hydroxypropyl beta-cyclodextrin, 20-55 parts water-soluble cyclodextrin polymer, and 1-2 parts dispersant.

3. The water-soluble florfenicol powder for veterinary use according to claim 1, characterized in that: The raw materials are in the following proportions by weight: 10 parts florfenicol powder, 18 parts beta-cyclodextrin, 36 parts hydroxypropyl beta-cyclodextrin, 34.5 parts water-soluble propylene oxide cross-linked cyclodextrin, and 1.5 parts dispersant.

4. The water-soluble florfenicol powder for veterinary use according to claim 1, characterized in that: The dispersant is polyvinylpyrrolidone K30.

5. The method for preparing a water-soluble florfenicol powder for veterinary use according to claim 1, characterized in that: Includes the following steps: Step 1: Dissolve hydroxypropyl beta-cyclodextrin in water, with a mass concentration of 10%-40%. Step 2: Weigh out beta-cyclodextrin and water-soluble beta-cyclodextrin polymer according to the ratio, add them to the hydroxypropyl beta-cyclodextrin solution prepared in Step 1, heat and stir to dissolve, and wait for the solution to become clear for later use. Step 3: Weigh the dispersant according to the ratio, add it to the mixture solution obtained in Step 2, heat and stir to dissolve, and set aside for later use; Step 4: Weigh out florfenicol according to the ratio, add it to the mixture solution obtained in Step 3, heat and stir to dissolve and set aside; Step 5: Powder the solution to obtain the final product.

6. The method for preparing a water-soluble florfenicol powder for veterinary use according to claim 5, characterized in that: In steps two through four, the heating temperature is 50-70℃.

7. The method for preparing a water-soluble florfenicol powder for veterinary use according to claim 5, characterized in that: In step four, the stirring time is 2-4 hours.

8. The method for preparing a water-soluble florfenicol powder for veterinary use according to claim 5, characterized in that: In step five, the powder preparation method is rotary evaporation or spray drying.

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