| The objective of this study is to mask the extremely bitter taste of tilmicosin, and the tilmicosin-resin complex(DRC) microspheres were prepared by entrapping tilmicosin into resins(Tulsion? 339 and Eudragit? RS/ RL 100) for further pharmacokinetics study in rat. Currently, soluble tilmicosin phosphate is used in clinics with its injectable form and Tilmicosin phosphate premix is used in veterinary medicine for the treatment of infections in poultry and livestock at a dose of 10 mg/kg inje cted subcutaneously. However, the drug has a narrow therapeutic index and rapidly achieves the maximum serum concentration in vivo, and it may be fatal to swine and horses by intramuscular injection and intravenous administration and thus affect the growth of animals because of its extremely bitter taste.The HPLC was selected to analyze tilmicosin. The ratio of 1: 1, 45°C and 3 mg/m L(initial concentration) were selected as the optimum further microspheres studies. The DRC was characterized by FTIR, DSC a nd X-ray diffraction, Based on the results of IR, DSC and XRD.The liquid paraffin, span 80 and acetone at the ratio of 8: 1: 3 was used for the preparation according to the three ternary phase diagram. Other conditions were optimized by orthogonal experiment. 3% RS/RL, 5% PEG 400 and 20% DEP were used after optimization.The microspheres containing DRC and Eudragit? RS/RL 100 were characterized by scanning electron microscopy(SEM), and these microspheres do not taste bitter. The kinetics study suggests that the drug released from microspheres meet the first order kinetics(r = 0.9911). The microspheres were evenly distributed and the diameter was in the range of 50–250 μm. The median particle size is between 125μm and 150μm. The cumulative release of the microspheres was 30.53%±0.67%, 60.10%±1.32% and 81.23%±1.88%. In the PBS at p H 6.8, the cumulative releases were 33.93%±0.78%, 61.86% ±1.22% and 85.23%±1.43% in the 900 m L HC l(0.1N) solution at 2, 6 and 8 h. The drug content of microspheres is 36.69% ± 1.24%.To analyze the mechanism of drug release from microspheres, data obtained from the drug-release studies were analyzed according to equations of the zero order model(k0 = 6.33, r = 0.88), the first order model(k1 = 0.21, r = 0.99) and the Higuchi model(k H = 25.18, r = 0.97). The correlation(r) was used as an indicator of the best fitting for each of the model considered. It suggests that the first order kinetics model performed best among the models, indicating that the results are in accordance with the commonly used description of a membrane-controlled process.The mice were orally administrated with tilmicosin phosphate(10mg/kg) and the microspheres containing the same dose of tilmicosin, respectively, and the experimental results showed that T? and Tmax of microspheres were much longer than those of tilmicosin phosphate, which indicates that the oral microspheres can be a promising long-active formulation for taste masking of tilmicosin. Pharmacokinetic parameters(Tmax, Cmax, AUC0-∞T?, MRT) in rats were 1h, 1.26μg/m L, 5.55 h*μg/m L, 0.44 h, 2.06 h and 6h, 0.99μg/m L, 33.67h*μg/m L, 25.23 h, 33.44 h, respectively. Finally, AUC of drug following administration of microspheres formulation is six times as much as that of the drug tilmicosin. So the results can be conclusion that the range is 1– 42 h up to the minimum concentration. |
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