目的:评估载有大麻二酚(CBD)的自乳化药物递送系统(SEDDS)的表面装饰对制剂跨越口服药物所面临的各种障碍的功效的影响。
方法:不含聚乙二醇(PEG)的聚甘油(PG)基SEDDS,混合的两性离子磷脂酰胆碱(PC)/含PEG的SEDDS和基于PEG的SEDDS在对脂质降解酶的稳定性方面进行了比较,表面属性,通过猪粘液渗透,细胞摄取和细胞相容性。
结果:开发了具有窄尺寸分布的约200nm尺寸的SEDDS,并负载了20-21%的CBD。对于含PG的无PEG的SEDDS,与含PEG的制剂相比,观察到脂质降解酶的降解增加。安慰剂SEDDS的表面疏水性以基于PG至基于混合的PC/PEG至基于PEG的SEDDS的顺序增加。还观察到该表面疏水性对SEDDS穿过粘液凝胶层的能力的影响,其中对于大多数疏水性基于PEG的SEDDS实现最高粘液渗透。对于基于PEG的LumogenYellow(LY)负载的SEDDS,在Caco-2细胞中观察到最高的细胞内化,而混合的基于PC/PEG的SEDDS仅为30%,基于PG的SEDDS仅为1%。导致具有最高表面疏水性的SEDDS的细胞摄取提高100倍。对于细胞相容性,所有开发的安慰剂SEDDS在Caco-2细胞上显示出相似的结果,对于低于0.05%的浓度,细胞存活率高于75%。
结论:SEDDS口服递送亲脂性药物的较高表面疏水性,因为CBD似乎是通过增强通过粘液层的渗透和细胞内化来增加细胞内药物浓度的有希望的方法。
OBJECTIVE: To evaluate the impact of the surface decoration of cannabidiol (CBD) loaded self-emulsifying drug delivery systems (SEDDS) on the efficacy of the formulations to cross the various barriers faced by orally administered drugs.
METHODS: Polyethylene glycol (PEG)-free polyglycerol (PG)-based SEDDS, mixed zwitterionic phosphatidyl choline (PC)/PEG-containing SEDDS and PEG-based SEDDS were compared regarding stability against lipid degrading enzymes, surface properties, permeation across porcine mucus, cellular uptake and cytocompatibility.
RESULTS: SEDDS with a size of about 200 nm with narrow size distributions were developed and loaded with 20-21 % of CBD. For PG containing PEG-free SEDDS increased degradation by lipid degrading enzymes was observed compared to PEG-containing formulations. The surface hydrophobicity of placebo SEDDS increased in the order of PG-based to mixed PC/PEG-based to PEG-based SEDDS. The influence of this surface hydrophobicity was also observed on the ability of the SEDDS to cross the mucus gel layer where highest mucus permeation was achieved for most hydrophobic PEG-based SEDDS. Highest cellular internalization was observed for PEG-based Lumogen Yellow (LY) loaded SEDDS with 92 % in Caco-2 cells compared to only 30 % for mixed PC/PEG-based SEDDS and 1 % for PG-based SEDDS, leading to a 100-fold improvement in cellular uptake for SEDDS having highest surface hydrophobicity. For cytocompatibility all developed placebo SEDDS showed similar results with a cell survival of above 75 % for concentrations below 0.05 % on Caco-2 cells.
CONCLUSIONS: Higher surface hydrophobicity of SEDDS to orally deliver lipophilic drugs as CBD seems to be a promising approach to increase the intracellular drug concentration by an enhanced permeation through the mucus layer and cellular internalization.