Florfenicol injection and preparation method thereof

Abstract

The invention relates to a florfenicol injection preparation method, which comprises: 1) dissolving a polymer carrier in ethanol, adding a bulk drug florfenicol, uniformly mixing, steaming to remove ethanol, and drying to obtain a loading micro-capsule; and 2) dissolving or dispersing the loading microcapsule in a solvent for injection, adding an osmotic pressure regulator sodium chloride, then adjusting the pH value to 7.0-7.5, fixing the volume, and filtering to obtain the injection. The florfenicol injection is high in drug stability, and the drug content is kept at 95% or above after the florfenicol injection is placed for 6 months under the conditions that the temperature is 40 + / -2 DEG C and the relative humidity is 75% + / -5%. In addition, the preparation also has the characteristics of high bioavailability, high safety and the like, and has great application prospects.

Description

Technical Field

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

[0002] Florfenicol plays an important role in the veterinary clinical treatment of bacterial infectious diseases in animals. However, traditional florfenicol injection has many defects. For example, its drug stability is poor. Under light, temperature changes and long-term storage, florfenicol is prone to chemical structure changes and degradation, resulting in a reduction in the active ingredients of the drug and a decrease in efficacy. In terms of bioavailability, it is difficult for ordinary preparations to fully absorb and utilize florfenicol by the animal body. A larger dosage is often required to achieve the expected therapeutic effect, and the blood drug concentration fluctuates greatly, affecting the stability and reliability of the treatment. In terms of safety, high-dose use can easily cause adverse reactions in animals, such as gastrointestinal irritation, liver and kidney damage, etc.

[0003] In addition, traditional preparation processes may involve expensive raw materials or complicated operating steps, resulting in high production costs and limiting its widespread application in the veterinary field.

[0004] Based on this, this application was developed. Summary of the invention

[0005] The present invention aims to overcome the defects of the prior art and provide a florfenicol injection. The injection solves the problems of poor stability, low bioavailability, insufficient safety and high cost of the existing products, and improves the effectiveness and feasibility of florfenicol in veterinary clinical applications.

[0006] The present invention also provides a method for preparing the florfenicol injection.

[0007] To achieve the above object, the present invention adopts the following technical solution: A method for preparing florfenicol injection comprises the following steps: 1) Dissolve the polymer carrier in ethanol, add the raw material florfenicol and stir to mix (stirring can be continued at 30-45°C for 3-5 hours to mix), evaporate to remove the ethanol, and dry (drying can be done at 40-60°C for 12-36 hours) to obtain the loaded microcapsules; 2) Dissolve or disperse the loaded microcapsules in an injection solvent (eg, water for injection, etc.), add the osmotic pressure regulator sodium chloride, then adjust the pH value to 7.0-7.5, make up to the required volume, filter, and package to obtain florfenicol injection.

[0008] Specifically, in step 1), the mass ratio of florfenicol to the polymer carrier may be 1:0.8-1, and the polymer carrier may be cucurbitacin [6] uril, or a mixture of cucurbitacin [6] uril and cyclodextrin.

[0009] Furthermore, in step 1), the amount of ethanol added may be 10-20% (g / ml) of the florfenicol injection. For example, 10 g, 12 g, 15 g, or 18 g of ethanol may be added to 100 ml of florfenicol injection.

[0010] Specifically, in step 2), the concentration of the loaded microcapsules in the florfenicol injection can be 1-5% (g / ml, w / v). The sodium chloride content in the florfenicol injection is preferably 0.9% (g / ml, w / v). The osmotic pressure regulator is sodium chloride, and its concentration is 0.9% (g / ml, w / v) to maintain the isotonicity of the injection and the animal body fluid.

[0011] Furthermore, sodium hydroxide or hydrochloric acid can be used to adjust the pH value to 7.0-7.5 to ensure the stability of the drug and the comfort during injection. A 0.22 μm microporous filter membrane can be used for filtration and sterilization.

[0012] The present invention provides a florfenicol injection prepared by the above preparation method. The florfenicol injection of the present invention uses specific excipients to form drug-loaded microcapsules, preferably using a polymer carrier and florfenicol to form microcapsules.

[0013] The present invention also provides the use of the florfenicol injection in the preparation of a drug for treating bacterial infectious diseases in animals, including but not limited to pigs, chickens, ducks, cattle, sheep and the like.

[0014] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: 1) High drug stability: The raw material drug is made into drug-loaded microcapsules through a polymer carrier. After accelerated stability testing (placed at 40℃±2℃ and 75%±5% relative humidity for 6 months), the drug content in the florfenicol injection of the present invention was maintained at more than 95%, while the drug residue in the traditional preparation during the same period was only about 91.33%.

[0015] 2) High bioavailability: The drug-loaded microcapsules change the physical and chemical properties of florfenicol and promote its absorption in animals. Pharmacokinetic studies were conducted on chickens as experimental subjects. Comparing the injection of the present invention with the traditional florfenicol injection, the peak blood concentration (Cmax) of the product of the present invention can be increased to about 12 μg / ml (8 μg / ml for the traditional preparation), the time to peak (Tmax) is shortened to about 1.5 hours (2.2 hours for the traditional preparation), and the area under the drug-time curve (AUC) is increased to 55-57 μg・h / ml (about 45 μg・h / ml for the traditional preparation), indicating that the bioavailability is significantly improved.

[0016] 3) High safety: Due to the improvement of stability and bioavailability, the dosage and frequency of medication can be optimized, reducing the risk of drug accumulation and the incidence of adverse reactions. In clinical trials on various animals such as pigs, chickens, and cattle, the incidence of adverse reactions of the injection of the present invention was reduced by about 30% compared with traditional preparations. For example, when traditional preparations are used at high doses, about 40% of pigs will have adverse reactions, while at the same dose, only about 10% of pigs will have such adverse reactions.

[0017] 4) Low cost: The polymer carrier is relatively cheap and widely available, and the preparation process does not require special expensive equipment and complicated steps. Compared with some traditional technologies that use complex synthesis processes or expensive excipients to improve the performance of florfenicol, the production cost of the present invention can be reduced by about 40%. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0019] In the following examples, unless otherwise specified, the raw materials used are all common commercial products that can be directly purchased, or can be prepared using conventional techniques in the art. In subsequent experiments, operations or parameters that are not described in detail can be prepared using conventional techniques in the art, and are not the innovation of the present invention, so they are not described in detail.

[0020] Room temperature refers to 25±5°C.

[0021] Example 1 A method for preparing florfenicol injection comprises the following steps: 1) Preparation of Florfenicol Drug-Loaded Microcapsules 10 g of florfenicol and 8 g of cucurbitacin [6] uril were weighed and placed in a 50 ml three-necked flask. Cucurbitacin [6] uril was first dissolved in 150 g of ethanol, and the original drug florfenicol was added and stirred continuously at 40°C for 4 hours. The ethanol was evaporated by heating, and the obtained solid was dried in a vacuum drying oven at 50°C for 24 hours to obtain florfenicol drug-loaded microcapsules.

[0022] 2) Preparation of Florfenicol Injection Take 20 g of the Florfenicol drug-loaded microcapsules prepared above, add an appropriate amount of water for injection, stir to dissolve, add sodium chloride to adjust the concentration to 0.9% (g / ml, w / v) to adjust the osmotic pressure, adjust the pH to 7.0-7.5 with sodium hydroxide solution, and finally make up to 1000 ml, filter through a 0.22μm microporous filter membrane for sterilization, and package to obtain Florfenicol Injection.

[0023] Example 2 A method for preparing florfenicol injection comprises the following steps: 1) Preparation of Florfenicol Drug-Loaded Microcapsules 8 g of florfenicol and 6.4 g of cucurbitacin [6] uril were weighed and placed in a 50 ml three-necked flask. Cucurbitacin [6] uril was first dissolved in 120 g of ethanol, and the original drug florfenicol was added and stirred continuously at 40°C for 4 hours. The ethanol was evaporated by heating, and the obtained solid was dried in a vacuum drying oven at 50°C for 24 hours to obtain florfenicol drug-loaded microcapsules.

[0024] 2) Preparation of Florfenicol Injection Take 18 g of the Florfenicol drug-loaded microcapsules and dissolve them in an appropriate amount of water for injection. Add sodium chloride to a concentration of 0.9% (g / ml, w / v) to adjust the osmotic pressure. Use hydrochloric acid to adjust the pH to 7.0-7.5. Make up to 1000 ml. Filter through a 0.22 μm microporous filter membrane for sterilization and package to obtain Florfenicol Injection.

[0025] Example 3 A method for preparing florfenicol injection comprises the following steps: 1) Preparation of Florfenicol Drug-Loaded Microcapsules 12 g of florfenicol and 9.6 g of cucurbitacin [6] uril were placed in a 50 ml three-necked flask. Cucurbitacin [6] uril was first dissolved in 180 g of ethanol. The original drug florfenicol was added and stirred continuously at 40°C for 4 hours. The ethanol was evaporated by heating. The obtained solid was dried in a vacuum drying oven at 50°C for 24 hours to obtain florfenicol drug-loaded microcapsules.

[0026] 2) Preparation of Florfenicol Injection: Dissolve 22g of Florfenicol drug-loaded microcapsules in an appropriate amount of water for injection, add sodium chloride to 0.9% (g / ml, w / v) to adjust the osmotic pressure, adjust the pH to 7.0-7.5 with sodium hydroxide, make the volume to 1000ml, sterilize and filter through a 0.22μm microporous filter membrane, and package to obtain Florfenicol Injection.

[0027] Comparative Example 1 The preparation method of traditional florfenicol injection is as follows: 1) Add florfenicol to ethanol and stir to mix; 2) Add propylene glycol to make up to the required volume, filter, and divide into packages to obtain florfenicol injection.

[0028] Experimental data comparison 1. Stability comparison experiment The florfenicol injection prepared in Examples 1-3 of the present invention and the traditional florfenicol injection were placed under the same accelerated stability test conditions (placed at 40°C ± 2°C and relative humidity of 75% ± 5% for 6 months), and samples were taken at different time points (0, 1, 2, 3, and 6 months). The drug content was determined by high performance liquid chromatography, and the results are shown in Table 1 below.

[0029] Table 1 Stability comparison experiment of different florfenicol injection samples It can be clearly seen from the data in Table 1 that the florfenicol injection of the present invention has a significant advantage in stability, with the drug content being above 95% after 6 months of storage, which is better than the 91.33% of the traditional florfenicol injection.

[0030] 2. Bioavailability comparison experiment A number of healthy chickens were selected and randomly divided into 4 groups. The florfenicol injection prepared in Examples 1-3 of the present invention and the commercially available traditional florfenicol injection (at the same dosage, such as 20 mg / kg) were respectively administered. Blood samples were collected at different time points after administration (such as 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours). The blood drug concentration was determined by ultra-high performance liquid chromatography-tandem mass spectrometry, and the drug-time curve was drawn. The pharmacokinetic parameters Cmax (peak concentration refers to the time required for the drug to reach the highest blood drug concentration, which is usually used to reflect the absorption rate of the drug. Drugs that reach the peak quickly usually have higher bioavailability because they are absorbed quickly and the drug quickly enters the systemic circulation.), Tmax (peak time refers to the time required for the drug to reach the highest blood drug concentration in the body, which reflects the speed of drug absorption), T1 / 2 (half-life refers to the time required for the drug concentration to decrease by half, which is an important parameter for measuring the elimination rate of the drug in the body), AUC (area under the drug-time curve, AUC The larger the value, the more drug is absorbed into the systemic circulation and the higher the bioavailability), MRT (mean residence time refers to the average time the drug stays in the body), etc. The results are shown in Table 2 below.

[0031] Table 2 Comparative experiment on bioavailability of different florfenicol injection samples The experimental results in Table 2 above show that the pharmacokinetic parameters Cmax and AUC of the florfenicol injection of the present invention are greater than those of the traditional florfenicol injection, while Tmax, T1 / 2 and MRT are all less than those of the traditional florfenicol injection, indicating that the bioavailability of the florfenicol injection of the present invention is significantly higher than that of the traditional florfenicol injection preparation.

[0032] 3. Safety comparison experiment 50 adult pigs were selected and intramuscularly injected with the florfenicol injection prepared in Examples 1-3 of the present invention and the commercially available traditional florfenicol injection (administered at 1, 3, and 5 times the recommended clinical dose (single dose, 0.06 ml per kg body weight for pigs)), respectively. The animals were observed for 14 consecutive days, and the adverse reactions of the animals (such as loss of appetite, mental depression, redness and swelling at the injection site, etc.) were recorded. The incidence of adverse reactions was statistically analyzed, and the results are shown in Table 3 below.

[0033] Table 3 Safety comparison experiment of different florfenicol injection samples The data in the above table show that the injection of the present invention performs better in terms of safety, with the incidence of adverse reactions at 3 times and 5 times the dose not exceeding 10% and 32% respectively, which is significantly better than the 40% of the traditional florfenicol injection.

[0034] In summary, the florfenicol injection of the present invention has high drug stability: when placed at 40°C ± 2°C and 75% ± 5% relative humidity for 6 months, the drug content remains above 95%. In addition, it has the characteristics of high bioavailability and high safety, and has great application prospects.

Claims

1. A method for preparing florfenicol injection, characterized in that: The steps include: 1) Dissolve the polymer carrier in ethanol, add the raw material florfenicol, mix well, evaporate the ethanol, and dry to obtain the loaded microcapsules; 2) Dissolve or disperse the loaded microcapsules in an injection solvent, add sodium chloride as an osmotic pressure regulator, and then adjust the pH value to 7.0 - 7.5, fix the volume, and filter to obtain.

2. The method for preparing florfenicol injection according to claim 1, characterized in that: In step 1), the mass ratio of florfenicol to the polymer carrier is 1:0.8-1, and the polymer carrier is cucurbitacin [6] uril, or a mixture of cucurbitacin [6] uril and cyclodextrin.

3. The method for preparing florfenicol injection according to claim 1, characterized in that: In step 1), the amount of ethanol added is 10-20% (g / ml) of the florfenicol injection.

4. The method for preparing florfenicol injection according to claim 1, characterized in that: In step 2), the concentration of the loaded microcapsules in the florfenicol injection is 1-5% (g / ml).

5. The method for preparing florfenicol injection according to claim 1, characterized in that: In step 2), the sodium chloride content in the florfenicol injection is 0.9% (g / ml).

6. The method for preparing florfenicol injection according to claim 1, characterized in that: In step 2), sodium hydroxide or hydrochloric acid is used to adjust the pH value to 7.0-7.

5.

7. The method for preparing florfenicol injection according to claim 1, characterized in that: In step 2), a 0.22 μm microporous filter membrane is used for filtration.

8. Florfenicol injection prepared by the preparation method according to any one of claims 1 to 7.

9. Use of the florfenicol injection according to claim 8 in the preparation of drugs for treating bacterial infectious diseases in animals.

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