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目的研究自制磷酸川芎嗪(TMPP)缓释微丸及TMPP冰片复方缓释微丸与市售TMPP普通片在比格犬体内的单剂量和多剂量的药动学和生物等效性。方法利用高效液相-紫外检测6只比格犬单剂量与多剂量分别口服TMPP缓释微丸及TMPP冰片复方缓释微丸与市售TMPP普通片后的血药浓度,应用3P97程序计算药动学参数,对AUC0～∞、AUC0-24 h的对数值进行方差分析、双单侧t检验等统计学处理,以80%～125%为等效标准,评价缓释制剂与普通制剂的生物等效性。结果单剂量时TMPP缓释微丸的tmax、ρmax、AUC0～24 h和MRT分别为(2.50±0.29)h、(213.06±32.44)ng.mL-1、(2 722.25±369.42)ng.h.mL-1和(9.43±1.05)h,TMPP冰片复方缓释微丸的上述参数分别为(2±0.76)h、(252.09±28.96)ng.mL-1、(3 613.51±974.16)ng.h.mL-1和(9.14±2.56)h,市售普通片的上述参数分别为(0.33±0.09)h、(3 402.13±584.97)ng.mL-1、(2 801.24±560.17)ng.h.mL-1和(1.52±0.35)h。多剂量达稳态时TMPP缓释微丸的tmax、ρmax、ρmin、AUC0～24 h、ρav和FI分别为(2±0.12)h、(340.36±28.91)ng.mL-1、(60.39±11.18)ng.mL-1、(3 161.82±314.68)ng.h.mL-1、(145.94±15.68)ng.mL-1和(191.84±11.58)%,TMPP冰片复方缓释微丸的上述参数分别为(2±0.31)h、(402.21±29.48)ng.mL-1、(80.13±21.65)ng.mL-1、(4 025.17±954.76)ng.h.mL-1、(167.87±29.37)ng.mL-1和(191.87±13.29)%,市售普通片的上述参数分别为(0.5±0.011)h、(376.79±44.6)ng.mL-1、0 ng.mL-1、(2 550.27±154.88)ng.h.mL-1、(114.93±13.68)ng.mL-1和(327.84±22.37)%。结论经方差分析和双单侧t检验,不论是单剂量口服还是多剂量口服,TMPP缓释微丸和普通片均具有生物等效性,而TMPP复方缓释微丸与普通片均生物不等效。缓释制剂均表现出良好的缓释效果,且波动系数均优于普通片。
Objective To study the pharmacokinetics and bioequivalence of homemade tetramethylphosphate (TMPP) sustained-release pellets and TMPP borneol-coated sustained-release pellets with commercially available TMPP tablets in Beagle dogs. Methods The plasma concentrations of TMPP sustained-release pellets, TMPP borneol-coated sustained-release pellets and the commercially available TMPP tablets were measured by high performance liquid chromatography-ultraviolet spectrophotometry in 6 beagle dogs. The drug was calculated by 3P97 program Kinetic parameters of the AUC0 ~ ∞, AUC0-24 h logarithmic analysis of variance, double unilateral t-test and other statistical analysis, 80% ~ 125% for the equivalent standard, evaluation of sustained-release preparations and general preparation of biological Equivalence. Results The tmax, ρmax, AUC0 ~ 24 h and MRT of TMPP sustained-release pellets were (2.50 ± 0.29) h and (213.06 ± 32.44) ng.mL-1 and (2 722.25 ± 369.42) ng.h, respectively. mL and (9.43 ± 1.05) h, respectively. The above parameters of TMPP borneol sustained-release pellets were (2 ± 0.76) h, (252.09 ± 28.96) ng.mL-1 and (3613.51 ± 974.16) ng.h mL and 1 (9.14 ± 2.56) h, respectively. The above parameters of commercial tablets were (0.33 ± 0.09) h, (3 402.13 ± 584.97) ng.mL-1 and (2 801.24 ± 560.17) ng.h, respectively. mL-1 and (1.52 ± 0.35) h. The tmax, ρmax, ρmin, AUC0-24h, ρav and FI of TMPP sustained-release pellets reached (2 ± 0.12) h and (340.36 ± 28.91) ng.mL-1 and (60.39 ± 11.18 (145.16 ± 15.68) ng.mL-1 and (191.84 ± 11.58)%, respectively. The above parameters of TMPP borneol sustained-release pellets were (402 ± 21 ± 29.48) ng.mL-1, (80.13 ± 21.65) ng.mL-1, (4025.17 ± 954.76) ng.h.mL-1, (167.87 ± 29.37) ng mL, and (191.87 ± 13.29)%, respectively. The above parameters of the commercially available common tablets were (0.5 ± 0.011) h, 376.79 ± 44.6 ng.mL-1, 154.88) ng.h.mL-1, (114.93 ± 13.68) ng.mL-1, and (327.84 ± 22.37)%. Conclusion Both ANOVA and TMPP sustained-release pellets were bioequivalent, both by ANOVA and two-sided one-tailed t test. TMPP and conventional pellets were not bioequivalent . Sustained release formulations showed good sustained release effect, and the volatility coefficient are better than ordinary tablets.