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目的:为了促进难溶性药物西罗莫司(sirolimus,SRL)的口服吸收,制备西罗莫司自微乳化微丸(SRL-SMEDDS pellets,SSP),并对其进行体内外评价。方法:通过考察液态SRL-SMEDDS制成微丸前后所形成微乳的粒径和粒径分布变化、SSP的溶出度和物相结构特征,对制剂进行体外评价。采用高效液相色谱-串联质谱法(HPLC-MS/MS)测定全血样品中SRL浓度,以市售西罗莫司片(commercial sirolimus tablets,CST)为参比制剂,考察SSP在比格犬体内的药动学特征。结果:液态SRL-SMEDDS固体化前后形成微乳的粒径和粒径分布变化不大;SSP与CST在水中30 min的溶出度分别为94.2%和10.4%,在0.4%SDS溶液中2制剂溶出度相当,SRL在SSP中以非结晶态存在;SSP与CST在Beagle犬体内的Cmax分别为(18.44±1.97)和(12.72±0.36)ng·m L-1;Tmax分别为(0.875±0.209)和(1.042±0.246)h;AUC0~48h分别为(131.65±7.81)和(96.17±8.45)ng·m L-1·h;SSP的相对生物利用度F0→48h为136.9%。结论:SMEDDS能显著提高SRL在水中的溶出度和比格犬体内的口服生物利用度。
OBJECTIVE: To promote the oral absorption of sirolimus (SRL), the SRL-SMEDDS pellets (SSP) were prepared and evaluated in vitro and in vivo. Methods: The preparation was evaluated in vitro by investigating the changes of the particle size and particle size distribution of the microemulsion formed before and after the pellets made from liquid SRL-SMEDDS, the dissolution and the phase structure of SSP. The concentrations of SRL in whole blood samples were determined by HPLC-MS / MS. Commercial sirolimus tablets (CST) In vivo pharmacokinetic characteristics. Results: The particle size and particle size distribution of microemulsion before and after solidification of liquid SRL-SMEDDS did not change much. The dissolution rates of SSP and CST in water for 30 min were 94.2% and 10.4%, respectively. The dissolution rate of 2 in 0.4% SDS solution The SRL was in the amorphous state in SSP. The Cmax of SSP and CST in Beagle dogs were (18.44 ± 1.97) and (12.72 ± 0.36) ng · m L-1, respectively; the Tmax were (0.875 ± 0.209) And (1.042 ± 0.246) h respectively. The relative bioavailability of SSP at F0 → 48h was 136.9% for AUC0 ~ 48h, (131.65 ± 7.81) and (96.17 ± 8.45) ng · m L-1 · h, respectively. Conclusion: SMEDDS can significantly improve SRL dissolution in water and oral bioavailability in Beagle dogs.