Water-soluble florfenicol powder and preparation method thereof

Abstract

The invention provides water-soluble florfenicol powder and a preparation method thereof, and belongs to the technical field of veterinary drugs. The water-soluble florfenicol powder is prepared from the following components in percentage by weight: 20 to 30 percent of florfenicol, 40 to 60 percent of inclusion agent, 5 to 20 percent of dispersing agent and 6 to 10 percent of cosolvent, the inclusion agent is beta-cyclodextrin-hyaluronic acid, and the dispersing agent is a mixture of sucrose fatty acid ester, sodium lignin sulfonate and chitin; by controlling the mass ratio of the inclusion agent to the dispersing agent to be (2-6): 1, the florfenicol powder has relatively strong inclusion and dispersion effects on florfenicol, the stability of the florfenicol powder during storage is remarkably improved on the basis of not additionally adding a stabilizer, and the water solubility is kept.

Description

Technical Field

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

[0002] Florfenicol, also known as fluorometholone, is an excellent broad-spectrum antibiotic for animals. It is mainly used for bacterial diseases of pigs, chickens and fish caused by sensitive bacteria, especially for respiratory infections and intestinal infections. Florfenicol belongs to Class II drugs in the biopharmaceutics classification system, that is, low solubility / high permeability drugs. Due to its extremely low solubility in water, less than 1 mg / mL at room temperature, its bioavailability is seriously affected. When the drug is administered in drinking water, it is very easy to block the water line. Therefore, improving the solubility of florfenicol in water has become a hot spot and difficulty in research.

[0003] At present, the main technologies and forms of rapid-release florfenicol prepared in my country include: adding cosolvents, micronization, β-cyclodextrin inclusion, hydroxypropyl-β-cyclodextrin inclusion, PVPK dispersion, PEG6000 dispersion, ultrafine grinding, etc. However, the effect is not ideal. The existing florfenicol preparations are not easy to dissolve in water and have low oral bioavailability. Liquid preparations made by adding solubilizers and cosolvents often have poor stability, high toxicity and irritation, which will lead to problems such as poor bioavailability after medication or damage to the body.

[0004] For example, Chinese patent CN112121016A discloses a water-soluble florfenicol powder and a preparation method thereof. The raw materials of the water-soluble florfenicol powder include: florfenicol; at least one inclusion agent is selected from: β-cyclodextrin and hydroxypropyl-β-cyclodextrin; at least one dispersant is selected from: hydroxypropyl methylcellulose, sodium alginate and sodium carboxymethyl cellulose; at least one cosolvent is selected from: sodium citrate, sodium succinate and acetamide; and a pressure spray drying treatment method is adopted. The solubility of the water-soluble florfenicol powder of the invention in 15°C water reaches 6mg / mL, which is much higher than the 3mg / mL (25°C) of the prior art, and is more than 12 times the solubility of the raw material drug; although the invention improves the solubility of florfenicol powder, the stability and irritation of florfenicol powder are not well improved.

[0005] Another example is a soluble florfenicol powder and a preparation method thereof disclosed in Chinese patent CN104922073A. It is composed of the following components by weight percentage: florfenicol 1-10%, cosolvent 1-15%, attractant 1-5%, and the remaining filler. The soluble florfenicol powder provided by the invention has good solubility in water and can obtain drug treatment by drinking water and feeding when the animal is sick and does not eat, covering up the original bad smell and irritation of florfenicol, and can effectively ensure the feed intake of sick animals to the drug, and has a good therapeutic effect in a short time, reducing the cost of treatment, and is therefore welcomed by the majority of farmers, but the invention still does not solve the stability problem of florfenicol powder.

[0006] Therefore, it is necessary to develop a florfenicol powder with low irritation, good stability and good water solubility and a preparation method thereof. Summary of the invention

[0007] Based on the deficiencies of the prior art, the present invention aims to provide a florfenicol powder with low irritation, good stability and good water solubility and a preparation method thereof.

[0008] In order to achieve the above object, the present invention adopts the following technical solution: A water-soluble florfenicol powder consists of the following components by weight percentage: 20-30% of florfenicol, 40-60% of an inclusion agent, 5-20% of a dispersant and 6-10% of a cosolvent.

[0009] Preferably, the water-soluble florfenicol powder is composed of the following components by weight percentage: 25-30% florfenicol, 45-55% inclusion agent, 10-15% dispersant and 8-10% cosolvent.

[0010] More preferably, the water-soluble florfenicol powder is composed of the following components by weight percentage: 30% florfenicol, 50% inclusion agent, 10% dispersant, and 10% co-solvent.

[0011] As some preferred embodiments, the inclusion agent is β-cyclodextrin-hyaluronic acid.

[0012] Hyaluronic acid is a linear polysaccharide composed of alternating D-glucuronic acid and N-acetylglucosamine units. As the main component of most natural tissues, it has good hydrophilicity and biocompatibility, and the carboxyl and hydroxyl groups on the molecular chain can be modified under mild conditions.

[0013] β-cyclodextrin is a cyclic oligopeptide with a hydrophilic exterior and a hydrophobic interior, which forms inclusion complexes with drugs through reversible non-covalent interactions.

[0014] The preparation method of the β-cyclodextrin-hyaluronic acid is a method disclosed in the prior art, or is obtained by the following preparation method: (1) mixing a sodium hydroxide aqueous solution containing β-cyclodextrin with an acetonitrile solution containing p-toluenesulfonyl chloride, reacting at room temperature, filtering, and drying to obtain mono-6-p-toluenesulfonyl-β-cyclodextrin; (2) dissolving mono-6-p-toluenesulfonyl-β-cyclodextrin and hexadecylamine in dimethylformamide, stirring for reaction, precipitating, washing and drying to obtain β-cyclodextrin-hexadecylamine; (3) β-cyclodextrin-hexadecylamine and hyaluronic acid are mixed and dissolved in a phosphate buffer containing EDC·HCl and NHS, and reacted at room temperature to obtain a reaction solution. The reaction solution is dialyzed in distilled water and then dried to obtain β-cyclodextrin-hyaluronic acid.

[0015] The molar ratio of β-cyclodextrin to p-toluenesulfonyl chloride in the above step (1) is 1:0.9-1.2, preferably 1:1.

[0016] The volume ratio of the sodium hydroxide aqueous solution containing β-cyclodextrin to the acetonitrile solution containing p-toluenesulfonyl chloride in the above step (1) is 14-20:1, preferably 15-18:1.

[0017] The molar concentration of the sodium hydroxide aqueous solution is 0.3-0.5 mol / L.

[0018] The reaction time of the above step (1) is 2-5 hours, preferably 3-4 hours.

[0019] The molar ratio of mono-6-p-toluenesulfonyl-β-cyclodextrin to hexadecylamine in the above step (2) is 1:20-25; The reaction time of the above step (2) is 70-80°C and the reaction time is 3-5 hours.

[0020] The precipitation in the above step (2) is performed by adding a poor solvent, wherein the poor solvent is cold acetone; and the washing is performed by washing with a mixed solution of methanol and water in a volume ratio of 1:1.

[0021] The molar ratio of the β-cyclodextrin-hexadecylamine and the carboxyl group in the hyaluronic acid in the above step (3) is 1:1.

[0022] The molar ratio of EDC·HCl to NHS is 1:1, and the pH value of the phosphate buffer is 7.4.

[0023] The reaction time of the above step (3) is 20-24 hours; the dialysis time is 5-6 days.

[0024] The dispersant is a mixture of sucrose fatty acid ester, sodium lignin sulfonate and chitosan; the mass ratio of the sucrose fatty acid ester, sodium lignin sulfonate and chitosan is 3-6:1:1-3; preferably 5:1:2.

[0025] During the implementation of the present invention, it was found that using β-cyclodextrin-hyaluronic acid as an inclusion agent can not only better include florfenicol, but also improve the solubility of florfenicol powder.

[0026] As some preferred embodiments, the mass ratio of the inclusion agent to the dispersant is 2-6:1; preferably 5:1.

[0027] On the one hand, the water-soluble florfenicol powder of the present invention uses molecular inclusion technology to make most of florfenicol included, increasing the solubility of florfenicol; on the other hand, the present invention selects a mixture of sucrose fatty acid ester, sodium lignin sulfonate and chitosan in a mass ratio of 3-6:1:1-3 as a dispersant, and unexpectedly finds that the three are mixed in the above ratio to make the florfenicol that is not included better and more evenly dispersed, thereby improving the solubility of florfenicol powder. On the other hand, the present invention is 4-6:1 by controlling the mass ratio of inclusion agent and dispersant, not only has a strong dispersion and inclusion effect on florfenicol, but also significantly improves the stability of florfenicol powder during storage without additionally increasing stabilizer, and water solubility is maintained.

[0028] The cosolvent is a mixture of sodium citrate and nicotinamide, and the mass ratio of the two is 1-3:1; preferably 1.5:1.

[0029] The present invention also provides a method for preparing the water-soluble florfenicol powder, comprising the following steps: (1) Weigh the florfenicol and inclusion agent in the formula content, add the florfenicol and inclusion agent to 80° C. water in sequence, use the inclusion technology, stir until most of them are dissolved, and obtain a mixture A; (2) adding the dispersant and the co-solvent in the prescribed amount to the mixture A obtained in step (1), stirring at a temperature maintained until dissolved, to obtain a mixture B; (3) drying the mixture B obtained in step (2), sieving, and mixing to obtain florfenicol powder; The drying air inlet temperature in the above step (3) is 90°C-220°C, and the sieved particle size is 120-150 μm.

[0030] The present invention also provides application of the water-soluble florfenicol powder in preparing veterinary antibacterial drugs.

[0031] Compared with the prior art, the present invention has the following beneficial effects: (1) Hyaluronic acid is a linear polysaccharide composed of alternating D-glucuronic acid and N-acetylglucosamine units. As the main component of most natural tissues, it has good hydrophilicity and biocompatibility, and the carboxyl and hydroxyl groups on the molecular chain can be modified under mild conditions; β-cyclodextrin is a cyclic oligopeptide that is hydrophilic on the outside and hydrophobic on the inside, and forms inclusion complexes with drugs through reversible non-covalent interactions. During the implementation of the present invention, it was found that using β-cyclodextrin-hyaluronic acid as an inclusion agent can not only better include florfenicol, but also improve the solubility of florfenicol powder.

[0032] (2) On the one hand, the water-soluble florfenicol powder of the present invention adopts molecular inclusion technology to make most of the florfenicol included, thereby increasing the solubility of florfenicol; on the other hand, the present invention selects a mixture of sucrose fatty acid ester, sodium lignin sulfonate and chitosan in a mass ratio of 3-6:1:1-3 as a dispersant, and unexpectedly finds that mixing the three in the above ratio can make the unincluded florfenicol better and more evenly dispersed, thereby improving the solubility of florfenicol powder. On the other hand, the present invention controls the mass ratio of the inclusion agent and the dispersant to 2-6:1, which not only has a strong dispersing and inclusion effect on florfenicol, but also significantly improves the stability of florfenicol powder during storage without adding additional stabilizers, and maintains water solubility.

[0033] (3) The present invention uses a mixture of sucrose fatty acid ester, sodium lignin sulfonate and chitosan as a dispersant and a mixture of sodium citrate and nicotinamide as a cosolvent, which can significantly improve the irritation of florfenicol and effectively ensure the drug intake of sick animals. DETAILED DESCRIPTION

[0034] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0035] Basic Example: Preparation Method of β-cyclodextrin-hyaluronic acid: (1) mixing a sodium hydroxide aqueous solution containing β-cyclodextrin with an acetonitrile solution containing p-toluenesulfonyl chloride, reacting at room temperature for 4 hours, filtering, and drying to obtain mono-6-p-toluenesulfonyl-β-cyclodextrin; The molar ratio of the β-cyclodextrin to p-toluenesulfonyl chloride is 1:1; the volume ratio of the sodium hydroxide aqueous solution containing β-cyclodextrin to the acetonitrile solution containing p-toluenesulfonyl chloride is 16:1; the molar concentration of the sodium hydroxide aqueous solution is 0.4 mol / L; (2) dissolving mono-6-p-toluenesulfonyl-β-cyclodextrin and hexadecylamine in dimethylformamide, stirring and reacting at 80° C. for 5 hours, adding cold acetone for precipitation, then washing with a mixed solution of methanol and water in a volume ratio of 1:1 and drying to obtain β-cyclodextrin-hexadecylamine; The molar ratio of mono-6-p-toluenesulfonyl-β-cyclodextrin to hexadecylamine is 1:22; (3) mixing β-cyclodextrin-hexadecylamine and hyaluronic acid in a phosphate buffer containing EDC·HCl and NHS, reacting at room temperature for 20 hours to obtain a reaction solution, dialyzing the reaction solution in distilled water for 5 days and then drying to obtain β-cyclodextrin-hyaluronic acid; The molar ratio of the beta-cyclodextrin-hexadecylamine to the carboxyl group in the hyaluronic acid is 1:1.

[0036] The molar ratio of EDC·HCl to NHS is 1:1, and the pH value of the phosphate buffer is 7.4.

[0037] Example 1 A water-soluble florfenicol powder comprises, by weight percentage, 20% of florfenicol, 60% of beta-cyclodextrin-hyaluronic acid prepared in a basic embodiment, 10% of a dispersant and 10% of a cosolvent.

[0038] The dispersant is sucrose fatty acid ester, sodium lignin sulfonate and chitosan in a mass ratio of 3:1:1; The cosolvent is sodium citrate and niacinamide in a mass ratio of 1:1; The preparation method is: (1) Weigh the florfenicol and inclusion agent in the formula content, add the florfenicol and inclusion agent to 80° C. water in sequence, use the inclusion technology, stir until most of them are dissolved, and obtain a mixture A; (2) adding the dispersant and the co-solvent in the prescribed amount to the mixture A obtained in step (1), stirring at a temperature maintained until dissolved, to obtain a mixture B; (3) drying the mixture B obtained in step (2) at an inlet air temperature of 200° C., passing through a 120-150 μm sieve, and mixing to obtain florfenicol powder; Example 2 A water-soluble florfenicol powder comprises, by weight percentage, 30% of florfenicol, 40% of beta-cyclodextrin-hyaluronic acid prepared in a basic embodiment, 20% of a dispersant and 10% of a cosolvent.

[0039] The dispersant is sucrose fatty acid ester, sodium lignin sulfonate and chitosan in a mass ratio of 6:1:3; The cosolvent is sodium citrate and niacinamide in a mass ratio of 3:1; The preparation method is: (1) Weigh the florfenicol and inclusion agent in the formula content, add the florfenicol and inclusion agent to 80° C. water in sequence, use the inclusion technology, stir until most of them are dissolved, and obtain a mixture A; (2) adding the dispersant and the co-solvent in the prescribed amount to the mixture A obtained in step (1), stirring at a temperature maintained until dissolved, to obtain a mixture B; (3) drying the mixture B obtained in step (2) at an inlet air temperature of 200° C., passing through a 120-150 μm sieve, and mixing to obtain florfenicol powder; Example 3 A water-soluble florfenicol powder comprises, by weight percentage, 30% of florfenicol, 50% of beta-cyclodextrin-hyaluronic acid prepared in a basic embodiment, 10% of a dispersant, and 10% of a cosolvent.

[0040] The dispersant is sucrose fatty acid ester, sodium lignin sulfonate and chitosan in a mass ratio of 5:1:2; The cosolvent is sodium citrate and niacinamide in a mass ratio of 1.5:1; The preparation method is: (1) Weigh the florfenicol and inclusion agent in the formula content, add the florfenicol and inclusion agent to 80° C. water in sequence, use the inclusion technology, stir until most of them are dissolved, and obtain a mixture A; (2) adding the dispersant and the co-solvent in the prescribed amount to the mixture A obtained in step (1), stirring at a temperature maintained until dissolved, to obtain a mixture B; (3) drying the mixture B obtained in step (2) at an inlet air temperature of 200° C., passing through a 120-150 μm sieve, and mixing to obtain florfenicol powder; Comparative Example 1 The difference from Example 3 is that the mass ratio of the inclusion agent to the dispersant is 1:1, that is, 30% inclusion agent and 30% dispersant, and the rest is the same as Example 3.

[0041] Comparative Example 2 The difference from Example 3 is that the mass ratio of the inclusion agent to the dispersant is 19:1, that is, 57% of the inclusion agent and 3% of the dispersant, and the rest is the same as Example 3.

[0042] Comparative Example 3 The difference from Example 3 is that the dispersant is only a mixture of sucrose fatty acid ester and sodium lignin sulfonate, with a mass ratio of 4:1, and the rest is the same as Example 3.

[0043] Comparative Example 4 The difference from Example 3 is that the dispersant is a mixture of sodium lignin sulfonate and chitosan, with a mass ratio of 1:4, and the rest is the same as Example 3.

[0044] Comparative Example 5 The difference from Example 3 is that the mass ratio of sucrose fatty acid ester, sodium lignin sulfonate and chitosan is 1:1:6, and the rest is the same as Example 3.

[0045] Performance Test: 1. Accelerated stability test Detection method: According to the "Pharmacopoeia of the People's Republic of China on Veterinary Medicine" (2020), the detection temperature was 40°C ± 2°C, and the humidity was 75% ± 5%. The samples prepared in Example 3 and Comparative Examples 1-5 were tested to detect the florfenicol content in the prepared florfenicol powder. The test results are shown in Table 1 below.

[0046] Table 1 Accelerated stability test results According to the test results of Table 1 above, it can be seen that the florfenicol powder prepared in Examples 1-3 of the present invention has high stability, and the content of florfenicol in the florfenicol powder after accelerated placement for 6 months is still above 98%; while in Comparative Examples 1-2, changing the mass ratio of the inclusion agent and the dispersant will significantly affect the stability of the florfenicol powder, because the change in the mass ratio of the inclusion agent and the dispersant will affect the inclusion and dispersing effects of the inclusion agent and the dispersant on florfenicol, thereby affecting the stability of the florfenicol powder; in Comparative Examples 3-4, changing the specific composition or mass ratio of the dispersant will also affect the stability of the florfenicol powder to a certain extent, that is, only the dispersant with a specific ratio disclosed in the present invention is used to make the obtained florfenicol powder have better stability.

[0047] 2. Water solubility determination: Weigh 1.0 g of each of the florfenicol powder samples (in terms of florfenicol) prepared in Examples 1-3 and Comparative Examples 1-5 into a stoppered colorimetric tube, record the number of milliliters of water that can dissolve the sample into a clear and transparent solution at 25°C, and convert it into mg / ml. After dissolution, observe for 8 hours to detect the percentage of florfenicol in each test group. The specific data are shown in Table 2 below.

[0048] Table 2 Water solubility test results According to the test results of Table 2 above, the maximum water solubility of the florfenicol powder prepared in Examples 1-3 of the present invention in water is relatively high and can reach more than 6 mg / mL, and the florfenicol content in the solution can still reach more than 99% after being placed for 8 hours; in Comparative Examples 1-2, changing the mass ratio of the inclusion agent and the dispersant will significantly affect the solubility of the florfenicol powder, because the change in the mass ratio of the inclusion agent and the dispersant will affect the inclusion and dispersing effect of the inclusion agent and the dispersant on florfenicol, thereby affecting the solubility of the florfenicol powder; in Comparative Examples 3-4, changing the specific composition or mass ratio of the dispersant will also affect the solubility of the florfenicol powder to a certain extent, that is, only the dispersant with a specific ratio disclosed in the present invention is used to make the obtained florfenicol powder have better solubility.

[0049] The above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A water-soluble florfenicol powder, characterized in that: The composition is composed of the following components by weight percentage: 20-30% of florfenicol, 40-60% of inclusion agent, 5-20% of dispersant and 6-10% of cosolvent; The inclusion agent is β-cyclodextrin-hyaluronic acid, and the dispersant is a mixture of sucrose fatty acid ester, sodium lignin sulfonate and chitosan; The mass ratio of the inclusion agent to the dispersant is 2-6:

1.

2. The water-soluble florfenicol powder according to claim 1, characterized in that: The composition is composed of the following components by weight percentage: 25-30% of florfenicol, 45-55% of inclusion agent, 10-15% of dispersant and 8-10% of co-solvent.

3. The water-soluble florfenicol powder according to claim 1, characterized in that: The composition is composed of the following components by weight percentage: 30% florfenicol, 50% inclusion agent, 10% dispersant and 10% solvent.

4. The water-soluble florfenicol powder according to claim 1, characterized in that: The mass ratio of the sucrose fatty acid ester, sodium lignin sulfonate and chitosan is 3-6:1:1-3.

5. The water-soluble florfenicol powder according to claim 4, characterized in that: The mass ratio of the sucrose fatty acid ester, sodium lignin sulfonate and chitosan is 5:1:

2.

6. The water-soluble florfenicol powder according to claim 1, characterized in that: The mass ratio of the inclusion agent to the dispersant is 5:

1.

7. The water-soluble florfenicol powder according to claim 1, characterized in that: The cosolvent is a mixture of sodium citrate and nicotinamide, and the mass ratio of the two is 1-3:

1.

8. The water-soluble florfenicol powder according to claim 1, characterized in that: The mass ratio of the sodium citrate to niacinamide is 1.5:

1.

9. The method for preparing the water-soluble florfenicol powder according to any one of claims 1 to 8, characterized in that: The steps include: (1) Weigh the florfenicol and inclusion agent in the formula content, add the florfenicol and inclusion agent to 80° C. water in sequence, use the inclusion technology, stir until most of them are dissolved, and obtain a mixture A; (2) adding the dispersant and the co-solvent in the prescribed amount to the mixture A obtained in step (1), stirring at a temperature maintained until dissolved, to obtain a mixture B; (3) drying the mixture B obtained in step (2), sieving, and mixing to obtain florfenicol powder; The drying air inlet temperature in step (3) is 90°C-220°C, and the sieved particle size is 120-150 μm.

10. Use of the water-soluble florfenicol powder according to any one of claims 1 to 8 in the preparation of veterinary antibacterial drugs.

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