Ceftiofur Injection

Ceftiofur injection is a broad-spectrum antibiotic with strong antibacterial activity against both Gram positive and Gram negative bacteria. Sensitive bacteria mainly include Pasteurella multocida, hemolytic Pasteurella, Actinobacillus pleuropneumoniae, Salmonella, Escherichia coli, Streptococcus, Staphylococcus, etc. However, some Pseudomonas aeruginosa and Enterococcus are resistant to them. Its antibacterial activity is stronger than ampicillin, and its activity against streptococcus is also stronger than quinolone antibiotics. Pathogens have been isolated from bovine respiratory disease samples, and their MIC90 values have been tested as follows: hemolytic Pasteurella ≤ 0.06 (0.03-0.13), multi killing Pasteurella ≤ 0.06 (0.03-0.25), and Haemophilus influenzae ≤ 0.06 (0.03-0.13), indicating high sensitivity. The MIC90 values for porcine pathogens are Actinobacillus pleuropneumoniae ≤ 0.03, Pasteurella multocida ≤ 0.03, Salmonella cholerae ≤ 0.1, Salmonella typhimurium 2.0, and Escherichia coli 1.0.

Cefotaxime acts on transcriptional peptidases to block the synthesis of mucins, leading to the loss of bacterial cell walls and achieving bactericidal effects. It is a cell wall synthesis inhibitor targeting bacterial penicillin binding proteins (PBPs), which exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycans, leading to bacterial cell lysis. At the same time, it also inhibits the activation of NF - κ B and MAPKs, thereby reducing the secretion of pro-inflammatory cytokines such as TNF - α, IL-1 β, and IL-6. For example, Ceftiofur (1, 5, 10 mg/L; pre-treatment for 1 h+LPS stimulation for 12 h) significantly inhibited the secretion of TNF - α, IL-1 β, and IL-6 in RAW 264.7 cells, but had no significant effect on IL-10 secretion; Ceftiofur (1, 5, 10 mg/L; pre-treatment for 1 hour+LPS stimulation for 30 minutes) significantly inhibited the phosphorylation of ERK, JNK, p38 and nuclear translocation of NF - κ Bp65 in RAW 264.7 cells.

Cefotaxime is rapidly absorbed after intramuscular and subcutaneous injection, with a peak time of 0.5-3.0 hours. The drug concentration is high in the blood and tissues, and the effective blood drug concentration is maintained for a long time, with slow elimination and a long half-life. Within 15 minutes after intramuscular injection of this product into animals, it is rapidly absorbed and produces the primary metabolite Desfuroyl cefidofur (DFC) in the plasma. Due to the intact β - lactam ring, its antibacterial activity is basically the same as that of cefotaxime. DFC can further form inactive DFC cysteine disulfide in tissues, and the apparent distribution volume of this product is less than 1L/Kg. Multiple doses of intramuscular injection in pigs, cows, and sheep have the highest concentration in the kidneys, followed by the lungs, liver, fat, and muscles, and can generally maintain concentrations higher than MIC. Cefotaxime is excreted slowly, and there are significant species differences in its half-life among animals. The half lives of horses, cows, sheep, pigs, dogs, chickens, and turkeys are 3.15, 7.12, 2.83, 4.12, 6.77, and 7.45 hours, respectively. However, most of it can be excreted from urine and feces within 24 hours after intramuscular injection, and DFC rapidly degrades into inactive compounds in pig and chicken feces. For example, intramuscular injection of 2.2mg/kg in cattle resulted in a Cmax of 9.79-15.3ug/ml, a tmax of 1-4 hours, and a t1/2B of 9.68-13.3h; intramuscular injection of 3mg/kg in pigs resulted in a Cmax of 14.22ug/ml, a tmax of 0.625h, and a t1/2B of 13.46h.

The purpose of this experiment is to provide a theoretical basis for the optimization of the development process and rational clinical use of cefotaxime injection through the evaluation of process optimization and pharmacokinetic studies of target animals.

Comparative analysis was conducted on the viscosity test, simulated injection effect test, settling volume ratio test, dispersibility test, and other tests of cefotaxime hydrochloride injection before and after process optimization of Hunan Agricultural University Animal Pharmaceutical Co., Ltd. compared with popular products on the market. At the same time, 18 healthy hybrid long white pigs were selected and randomly divided into three groups. Three types of cefotaxime hydrochloride suspension injections were injected into the muscle at a dose of 5mg/kg body weight, including the optimized product, the product from Qilu Animal Health Products Co., Ltd., and the product before process optimization. 3ml of cefotaxime hydrochloride suspension injection was collected from the vena cava before 1, 4, 8, 11, 24, 48, 72, 96, 120, and 144 hours, and the content of cefotaxime hydrochloride in the plasma was determined by HPLC.

The viscosity of the sample decreased from (269.5 ± 21.5mPa · s) before optimization to (204.0 ± 16.7mPa · s) (P<0.05), and there was no difference compared to the products of Pharmaceutical Co., Ltd. A and Animal Health Products Co., Ltd. B (P<0.05); The injection time of the product after process optimization is shorter than that before process optimization (P<0.05), and there is no significant difference in sedimentation between the optimized product and before optimization (P<0.05). However, the sedimentation volume ratio of the optimized product is larger than that of the product produced by Qilu Pharmaceutical at 72 hours (P<0.05). Compared with before optimization, there is no agglomeration, sedimentation, or wall hanging phenomenon in the optimized product. The results showed that the properties of viscosity, settling ratio, and needle penetration of the finished product were significantly improved after process optimization compared to before optimization. When injecting the old and new process products of Nongda Pharmaceutical into the muscle, effective blood drug concentration can be achieved in a short period of time. Among the 6 pigs injected with the old process products, 2 pigs can only maintain an effective blood drug concentration for 3 days, while the other 4 pigs can maintain an effective blood drug concentration for 5 days. However, when injecting the new process products into the muscle, all 6 pigs can maintain an effective blood drug concentration for 4 days, and 4 pigs can maintain an effective blood drug concentration for 5 days. This indicates that the products produced by the new and old processes can prolong the effective blood concentration maintenance time of cefotaxime hydrochloride, and scientifically and intuitively evaluate the sustained release effect of the products before and after process optimization. From the pharmacological effect, ceftiofur injection shows that the new process products are better than those produced by other processes. Old craft products.