Controlling the gastrointestinal fate of nutraceutical and pharmaceutical-enriched lipid nanoparticles: From mixed micelles to chylomicrons

Abstract

The oral bioavailability of lipophilic nutraceuticals can be greatly enhanced by lipid nanoparticle‐based delivery systems. These lipid nanoparticles are dissembled in the gastrointestinal tract to form mixed micelles that are then reassembled into chylomicrons within enterocytes and secreted into the lymph. In this study, we examined the influence of fatty acid type on the properties of mixed micelles and chylomicrons, and on the uptake of a highly lipophilic nutraceutical 5‐demethylnobiletin (5‐DN, found in citrus fruits). There were distinct differences in the structural properties of chylomicrons formed depending on fatty acid unsaturation. Oleic acid (C18:1) was most effective at enhancing transport of 5‐DN and led to the formation of the largest chylomicrons. Linoleic acid (C18:2) and linolenic acid (C18:3) also promoted 5‐DN incorporation into chylomicrons, but they were less efficient than oleic acid. The metabolism of 5‐DN within the epithelium cells was greatly reduced when they were incorporated into chylomicrons, presumably because they were isolated from metabolic enzymes in the cytoplasm. These results have important implications for the design of lipid nanoparticle‐based delivery systems for lipophilic nutraceuticals by targeting them to the lymphatic circulation.

Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical Aspects

“…Shangguan et al (2015) evaluated the BA of silymarin in Beagle dogs, comparing the administration as intact drug-loaded SLN/NLC and as a lipolysate produced by the enzymatic action of pancreatic lipase over the lipid NP. The lower BA obtained with the lipolysate was in agreement with the loss of drug in the formulation, since the micelles formed in the GI to facilitate the uptake of lipophilic compounds (known as "mixed micelles, " and mainly composed by phospholipids, bile salts, and cholesterol, Yao et al, 2017) cannot keep all silymarin in suspension, and drug precipitation occurs. In other words, when the BA values are corrected by a factor that accounts for the true dose administered (i.e., amount of drug remaining in suspension), it may be concluded that the lipolysis pathway is the predominant mechanism underlying the enhanced oral BA of a drug formulated as lipid NPs, whereas the absorption of intact NPs only plays a minor role.…”

An integrated methodology for assessing the impact of food matrix and gastrointestinal effects on the biokinetics and cellular toxicity of ingested engineered nanomaterials

“…Most importantly, these methodologies must reproduce and account for the physicochemical transformations of iENMs that occur when they are incorporated into food products (food matrix effects) and as they pass through the GIT (gastrointestinal effects). While evidence continues to grow and show that such transformations can greatly impact the biokinetics and nano-biointeractions of iENMs, and alter the bioavailability and bioaccessibility of nutrients [ 31 , 32 ], until recently they have been largely overlooked [ 3 , 5 ]. In in vitro cellular studies, pristine iENMs are often mixed with culture media containing serum proteins and applied to cells to assess their bioactivity [ 31 , 33 ].…”

Nanoparticulate Drug Delivery Strategies to Address Intestinal Cytochrome P450 CYP3A4 Metabolism towards Personalized Medicine

“…In Table 3 , select LNS examples and their delivered drugs based on BDDCS class are presented to demonstrate their mechanistic strategies of improving oral bioavailability [ 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. By taking advantage of existing physiological characteristics of the small intestines, the following six strategies have the potential to use nanoparticle (NPs) formulations to address intestinal CYP3A4 metabolism and to enhance the absorption of drugs and NPs across enterocytes: (1) incorporating mucoadhesive polymers or lipids that are attracted to the unstirred water layer adjacent to the intestinal epithelia, allowing drugs to be in close proximity which increases the flux into epithelial cells to overwhelm CYP3A4 metabolism; (2) CYP3A4 inhibitor-containing LNS locally inhibits intestinal CYP3A4 during transcytosis; (3) using highly lipophilic lipid NPs to traverse enterocytes straight into lymphatic vessels; (4) formulating LNS targeting M cell integrins for endocytosis that carries the drug to lymphatic vessels; (5) pH-sensitive formulation that selectively releases drug in the ileum where there is a lower expression of intestinal CYP3A4; (6) vitamin B12 targeting cubilin in the terminal ileum for absorption via receptor mediated endocytosis.…”