Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, Gifu, Japan.
Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
Int J Pharm. 2021 Jan 25;593:120148. doi: 10.1016/j.ijpharm.2020.120148. Epub 2020 Dec 5.
We investigated the feasibility of densely polyethylene glycol (PEG2000)-modified liposomes as mucus-penetrating particles (MPPs) for oral delivery of systemically absorbed peptides. The oral absorption of MPPs and mucoadhesive liposomes modified with glycol chitosan (GCS) was compared. In an in vitro artificial mucus model, the densely PEGylated liposomes showed mucus permeability. Intracellular uptake of liposomes was evaluated in a Caco-2 and mucus-secreting Caco-2/HT29 co-culture. Intracellular uptake of MPPs was unaffected by mucus in the co-culture system, whereas the cellular uptake of GCS-liposomes was lower with a mucus layer than in Caco-2 alone. Rat in vivo oral absorption of liposomes was evaluated by using fluorescein isothiocyanate dextran (FD) as a model peptide drug. Oral absorption was higher for densely PEGylated than for unmodified liposomes and was PEG-concentration dependent, but excessive PEGylation decreased FD blood concentration. PEGylated liposomes incorporating spermine (SPM) as an absorption enhancer were then designed and showed the highest in vivo absorption of FD of all tested formulations. The pharmacological effects of the oral liposomes were evaluated by using elcatonin and did not correlate with FD oral absorption. The non-PEGylated SPM liposomes showed the highest pharmacological effect, suggesting the need for drug-specific optimization of liposomal components and surface modifiers.
我们研究了高度聚乙二醇（PEG2000）修饰的脂质体作为穿透黏液的颗粒（MPP）用于全身吸收肽类药物的口服给药的可行性。比较了 MPP 和用壳聚糖糖基（GCS）修饰的粘弹性脂质体的口服吸收。在体外人工黏液模型中，高度 PEG 化的脂质体显示出黏液通透性。在 Caco-2 和分泌黏液的 Caco-2/HT29 共培养物中评估了脂质体的细胞内摄取。在共培养系统中，MPP 的细胞内摄取不受黏液的影响，而 GCS-脂质体的细胞内摄取在有黏液层时低于单独的 Caco-2。用荧光素异硫氰酸酯葡聚糖（FD）作为模型肽药物评估了脂质体在大鼠体内的口服吸收。与未修饰的脂质体相比，高度 PEG 化的脂质体的口服吸收更高，且与 PEG 浓度有关，但过度 PEG 化会降低 FD 的血药浓度。然后设计了包含亚精胺（SPM）作为吸收增强剂的 PEG 化脂质体，所有测试配方中 FD 的体内吸收最高。通过使用降钙素评估了口服脂质体的药理作用，但与 FD 的口服吸收无关。非 PEG 化的 SPM 脂质体显示出最高的药理作用，这表明需要针对特定药物优化脂质体成分和表面修饰剂。
