Purpose: 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, X_A (the molar ratio of surfactant mixture to cholesterol) at a ratio of 1:1 or 2:1; X_B (the molar ratio of Span™ 60 to Peceol™) at a ratio of 1:1 or 2:1; and X_C (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.
Conclusion: 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.

Keywords: candesartan cilexetil, glyceryl monooleate, chitosan, niosomes, PROSOLV®


中文翻译：

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用于坎地沙坦西酯的新型 Peceol™/Span™ 60 Niosomes 包被壳聚糖：有望提高大鼠的绝对生物利用度


目的：坎地沙坦酯 (CC) 是坎地沙坦 (CDT) 的前药，是一种 II 类 BCS 药物，由于水溶性低、P-gp 外排和首过代谢，口服生物利用度较差。据报道，CC 的绝对生物利用度仅为 15%，而提高其的方法仍然难以捉摸，因此我们工作的目的是制备新的 CC 负载的脂质体，首次包含单油酸甘油酯转基因生物 (Peceol™)，如 P -gp 外排抑制剂和淋巴运输促进剂，使用 Span™ 60 作为生物增强剂。制备的囊泡进一步涂有壳聚糖以增强 CC 口服吸收。

方法：通过薄膜水合法通过质量设计方法制备囊泡，使用三个关键工艺参数 (CPP) 中每一个的两个水平，即 X _A （表面活性剂混合物与胆固醇的摩尔比），比例为 1 :1 或 2:1; X _B （Span™ 60 与 Peceol™ 的摩尔比），比例为 1:1 或 2:1； _XC （药物量）为15mg或30mg。所研究的关键质量属性 (CQA) 包括包封效率百分比、粒径和多分散指数。对优化的未包衣和壳聚糖包衣制剂进行了 DSC 和稳定性研究。评估了体外药物释放、与 Caco-2 细胞的生物相容性以及最后在大鼠中的绝对生物利用度评估。

结果：优化后的稳定的纳米囊体物理性能令人满意。这些成分彼此相容，并且与 Caco-2 细胞具有生物相容性。 Peceol™ 和 Span™ 60 的协同组合可能超越了 P-gp 外流，使 niosomes 的口服绝对生物利用度增加至 CC 悬浮液的五倍。

结论：含有 Peceol™ 和 Span™ 60 以及未包被或包被壳聚糖的胆固醇的新型 CC 类脂质体制剂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。


关键词：坎地沙坦西酯、单油酸甘油酯、壳聚糖、niosomes、PROSOLV®