PDF(Pubmed)
Abstract：
OBJECTIVE: Candesartan cilexetil (CC), a prodrug of candesartan (CDT), is a class II BCS drug that suffers from poor oral bioavailability because of low aqueous solubility, P-gp efflux and first-pass metabolism. The absolute bioavailability reported for CC was only 15% and the methods to increase it remain elusive, thus the aim of our work was to prepare new CC-loaded niosomes encompassing, for the first time, glycerol monooleate GMO (Peceol™), as P-gp efflux inhibitor and promoter of lymphatic transport with Span™ 60 as bioenhancer. The prepared niosomes were further coated with chitosan for augmenting the CC oral absorption.
METHODS: The niosomes were prepared by thin film hydration method through quality by design approach, using two levels of each of three critical process parameters (CPPs), namely, XA (the molar ratio of surfactant mixture to cholesterol) at a ratio of 1:1 or 2:1; XB (the molar ratio of Span™ 60 to Peceol™) at a ratio of 1:1 or 2:1; and XC (the drug amount) at 15 mg or 30 mg. The investigated critical quality attributes (CQAs) were entrapment efficiency percent, particle size, and polydispersity index. The optimized uncoated and chitosan coated formulations were subjected to DSC and stability study. In vitro drug release, biocompatibility with Caco-2 cells and lastly the absolute bioavailability evaluation in rats were assessed.
RESULTS: The physical properties of the optimized and stable niosomes were satisfactory. The ingredients were compatible with each other and biocompatible with Caco-2 cells. The synergistic combination of Peceol™ and Span™ 60 probably surmounted the P-gp efflux with an increase in oral absolute bioavailability of niosomes to five times that of CC suspension.
CONCLUSIONS: The new niosomal formulations of CC containing Peceol™ with Span™ 60 and cholesterol either uncoated or coated with chitosan were a successful paradigm in achieving high oral absolute bioavailability and increased Caco-2 cells biocompatibility.
METHODS: The niosomes were prepared by thin film hydration method through quality by design approach, using two levels of each of three critical process parameters (CPPs), namely, XA (the molar ratio of surfactant mixture to cholesterol) at a ratio of 1:1 or 2:1; XB (the molar ratio of Span™ 60 to Peceol™) at a ratio of 1:1 or 2:1; and XC (the drug amount) at 15 mg or 30 mg. The investigated critical quality attributes (CQAs) were entrapment efficiency percent, particle size, and polydispersity index. The optimized uncoated and chitosan coated formulations were subjected to DSC and stability study. In vitro drug release, biocompatibility with Caco-2 cells and lastly the absolute bioavailability evaluation in rats were assessed.
RESULTS: The physical properties of the optimized and stable niosomes were satisfactory. The ingredients were compatible with each other and biocompatible with Caco-2 cells. The synergistic combination of Peceol™ and Span™ 60 probably surmounted the P-gp efflux with an increase in oral absolute bioavailability of niosomes to five times that of CC suspension.
CONCLUSIONS: The new niosomal formulations of CC containing Peceol™ with Span™ 60 and cholesterol either uncoated or coated with chitosan were a successful paradigm in achieving high oral absolute bioavailability and increased Caco-2 cells biocompatibility.
摘要：
目标：坎地沙坦酯（CC），坎地沙坦（CDT）的前药，是一种II类BCS药物，由于水溶性低，口服生物利用度差，P-gp流出和首过代谢。CC报告的绝对生物利用度仅为15％，增加它的方法仍然难以捉摸，因此，我们工作的目的是准备新的CC加载的niosome，第一次,甘油单油酸酯GMO（Peceol™），作为P-gp外排抑制剂和淋巴运输促进剂，Span™60作为生物增强剂。制备的囊泡进一步用壳聚糖包被以增强CC口服吸收。
方法：通过设计方法，通过质量，通过薄膜水化法制备囊泡，使用三个关键工艺参数(CPP)中的每一个的两个级别，即,XA(表面活性剂混合物与胆固醇的摩尔比)为1:1或2:1;XB(Span™60与Peceol™的摩尔比)为1:1或2:1;XC(药物量)为15mg或30mg。调查的关键质量属性(CQA)是截留效率百分比，颗粒大小,和多分散指数。对优化的未包衣和壳聚糖包衣的制剂进行DSC和稳定性研究。体外药物释放，与Caco-2细胞的生物相容性，最后评估大鼠的绝对生物利用度评估。
结果：优化和稳定的囊泡的物理性质令人满意。这些成分彼此相容并且与Caco-2细胞生物相容。Peceol™和Span™60的协同组合可能超过P-gp外排，使囊体的口服绝对生物利用度增加到CC悬浮液的五倍。
结论：含有Peceol™和Span™60和胆固醇的CC的新的脂质体制剂未包衣或用壳聚糖包衣是实现高口服绝对生物利用度和增加Caco-2细胞生物相容性的成功范例。
方法：通过设计方法，通过质量，通过薄膜水化法制备囊泡，使用三个关键工艺参数(CPP)中的每一个的两个级别，即,XA(表面活性剂混合物与胆固醇的摩尔比)为1:1或2:1;XB(Span™60与Peceol™的摩尔比)为1:1或2:1;XC(药物量)为15mg或30mg。调查的关键质量属性(CQA)是截留效率百分比，颗粒大小,和多分散指数。对优化的未包衣和壳聚糖包衣的制剂进行DSC和稳定性研究。体外药物释放，与Caco-2细胞的生物相容性，最后评估大鼠的绝对生物利用度评估。
结果：优化和稳定的囊泡的物理性质令人满意。这些成分彼此相容并且与Caco-2细胞生物相容。Peceol™和Span™60的协同组合可能超过P-gp外排，使囊体的口服绝对生物利用度增加到CC悬浮液的五倍。
结论：含有Peceol™和Span™60和胆固醇的CC的新的脂质体制剂未包衣或用壳聚糖包衣是实现高口服绝对生物利用度和增加Caco-2细胞生物相容性的成功范例。
