Abstract
Zoonotic intestinal pathogens threaten human health and cause huge economic losses in farming. Enrofloxacin (ENR) shows high antibacterial activity against common intestinal bacteria. However, its poor palatability and low aqueous solubility limit the clinical application of ENR. To obtain an ENR oral preparation with good palatability and high solubility, a granule containing an amorphous ENR solid dispersion (ENR-SD) was prepared. Meanwhile, a PBPK model of ENR in pigs was built based on the physiological parameters of pigs and the chemical-specific parameters of ENR to simulate the pharmacokinetics (PK) of ENR-SD granules in the intestinal contents. According to the results of parameter sensitivity analysis (PSA) and the predicted PK parameters at different doses of the model, formulation strategies and potential dose regimens against common intestinal infections were provided. The DSC and XRD results showed that no specific interactions existed between the excipients and ENR during the compatibility tests, and ENR presented as an amorphous form in ENR-SD. Based on the similar PK performance of ENR-SD granules and the commercial ENR soluble powder suggesting continued enhancement of the solubility of ENR, a higher drug concentration in intestinal contents could not be obtained. Therefore, a 1:5 ratio of ENR and stearic acid possessing a saturated aqueous solubility of 1190 ± 7.71 µg/mL was selected. The predictive AUC24h/MIC90 ratios against Campylobacter jejuni, Salmonella, and Escherichia coli were 133, 266 and 8520 (>100), respectively, suggesting that satisfactory efficacy against common intestinal infections would be achieved at a dose of 10 mg/kg b.w. once daily. The PSA results indicated that the intestinal absorption rate constant (Ka) was negatively correlated with the Cmax of ENR in the intestine, suggesting that we could obtain higher intestinal Cmax using P-gp inducers to reduce Ka, thus obtaining a higher Cmax. Our studies suggested that the PBPK model is an excellent tool for formulation and dose design.
Highlights
Intestinal bacterial infections caused by zoonotic pathogens, including Campylobacter jejuni (Camp. jejuni), Salmonella spp. and Escherichia coli (E. coli), have resulted in serious threats to human health and enormous economic losses in farming [1,2,3,4]
We emphasized that the PK curves of ENR solid dispersion (ENR-solid dispersion (SD)) granules in the intestinal contents at different doses were predicted by the physiologically based pharmacokinetics (PBPK) model directly rather than animal experiments; potential dose regimens against common intestinal infections and further formulation strategies of ENR-SD granules were provided by the PBPK model without animal use
The XRD results indicated that the most intense peaks in the XRD of the ENR powder were visible at 9.7 2-theta degrees, which agreed with previous studies [44]
Summary
Intestinal bacterial infections caused by zoonotic pathogens, including Campylobacter jejuni (Camp. jejuni), Salmonella spp. and Escherichia coli (E. coli), have resulted in serious threats to human health and enormous economic losses in farming [1,2,3,4]. This paper attempts to apply amorphous SD technology to improve the palatability and solubility of ENR, achieving its higher efficacy against infections caused by common intestinal bacteria. The AUC24h /MIC method was adopted in this study to predict the potential dose of ENR-SD granules for common zoonotic intestinal pathogens. We emphasized that the PK curves of ENR-SD granules in the intestinal contents at different doses were predicted by the PBPK model directly rather than animal experiments; potential dose regimens against common intestinal infections and further formulation strategies of ENR-SD granules were provided by the PBPK model without animal use This is the first study to apply the PBPK model to the field of new veterinary drug development, which will be beneficial for simplifying the regulation and development processes of new veterinary drugs
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