Nanostructured lipid carriers for enhancing oral bioavailability of small molecules by evading intestinal efflux transporters
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Tiivistelmä
Oral delivery remains to this date as the most convenient, cheapest, and preferred noninvasive drug delivery route. However, certain physiochemical characteristics of active pharmaceutical ingredients (APIs) present significant challenges for effective oral delivery, one of which being their affinity for efflux transporters in the intestinal enterocytes. This active transport in the small intestine can limit the absorption of efflux transporter substrate APIs. Nanostructured lipid carriers (NLCs) have shown potential as drug carrier systems for oral delivery due to their capacity for active loading, protection against the harsh gastrointestinal environment, and cell membrane permeability. The objective of this study was to study the capability of NLC drug delivery systems in evading intestinal efflux transporters in vitro.
Two model compounds, ritonavir (RTV) and Bayer molecule A (BayA), both of which have shown notable efflux in vitro, were encapsulated in NLCs formulated from glyceryl distearate and oleic acid or propylene glycol monocaprylate. The manufacturing process consisted of pre-emulsifying lipids, APIs, surfactant, and aqueous phase at elevated temperatures through mixing, followed by ultrasonication to form nanoscale particles. The permeability of the loaded NLCs (Papp A→B and Papp B→A) and efflux ratio (ER) were measured in human colorectal adenocarcinoma cell line (caco-2) assay and compared with permeability of free API. RTV-loaded NLCs were tested in 2 µM and 10 µM RTV concentrations and BayA-loaded NLCs in 10 µM BayA concentrations in the caco-2 assay.
The results showed a clear increase in permeability (Papp A→B) and a decrease in ER for BayA-loaded NLCs compared to the free API, whereas the NLC formulation for RTV only showed mild evidence of increased Papp A→B and reduced ER at 2 µM, but inconclusive results at 10 µM. This preliminary proof-of-concept study suggests that NLC formulations can have an effect on permeability in vitro, though the effect is likely to vary based on the API and its properties. More comprehensive studies are needed for establishing a better understanding of the underlying mechanisms.