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目的深层次评价四种盐酸氨溴索注射剂在生理环境p H条件下的稳定性及体内药物动力学。方法以p H 7.4磷酸缓冲液模拟血液的生理p H环境,考察四种制剂不同剂量下与其混合后的含量和p H变化;采用随机、自身交叉试验设计,应用HPLC-MS/MS测定盐酸氨溴索血浆浓度,考察四种盐酸氨溴索制剂在比格犬体内的药物动力学。结果 A与B两种盐酸氨溴索注射水针剂在p H 7.4磷酸缓冲液中相对比较稳定;C和D两种注射用盐酸氨溴索粉针剂在低剂量时含量呈现下降趋势,高剂量时含量降低大于10%。四种制剂的缓冲能力具有明显的差别,水针剂的缓冲能力明显强于粉针剂。中、高剂量C、D制剂的生物利用度均明显低于A制剂,提示盐酸氨溴索注射剂配方的差异可能影响药物的生物利用度。四种制剂的药物生物半衰期t1/2随剂量的增加而改变,AUC(0-∞)随剂量增加呈现非线性增加的趋势,表明该药物体内动力学可能为非线性药物动力学过程。结论盐酸氨溴索水针剂配方中的缓冲盐体系增强了盐酸氨溴索对于PBS的稳定性,有利于提高药物在体内的稳定性。
Objective To evaluate the stability and in vivo pharmacokinetics of ambroxol hydrochloride injection under the physiological environment of p H level. Methods The physiological p H environment of blood was simulated with p H 7.4 phosphate buffer. The contents and p H changes of the four formulations at different dosages were investigated. By the randomized, self-designed crossover design, Pharmacokinetics of ambroxol hydrochloride preparations in Beagle dogs were investigated. Results Ambroxol hydrochloride injection aqueous solution A and B were relatively stable in p H 7.4 phosphate buffer solution. Ambroxol hydrochloride injection injection C and D showed a decreasing trend at low dose, The content is reduced by more than 10%. The buffering capacity of the four preparations has obvious difference, and the buffering capacity of the water injection is obviously stronger than that of the powder injection. The bioavailability of middle and high dosage of C and D preparations were significantly lower than that of A preparation, suggesting that the differences of formulations of ambroxol hydrochloride injection may affect the bioavailability of the drug. The biological half-life t1 / 2 of the four formulations changed with the increase of the dose, and the AUC (0-∞) tended to increase nonlinearly with the increase of the dose, indicating that the in vivo pharmacokinetics of the four formulations may be nonlinear pharmacokinetic. CONCLUSION: The buffer salt system in ambroxol hydrochloride injection enhances the stability of ambroxol hydrochloride in PBS, which is beneficial to improve the stability of drug in vivo.