TY - JOUR
T1 - 'Stealth' lipid-based formulations
T2 - Poly(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly water soluble drug
AU - Feeney, Orlagh
AU - Williams, Hywel David
AU - Pouton, Colin William
AU - Porter, Christopher John
PY - 2014
Y1 - 2014
N2 - For over 20 years, stealth drug delivery has been synonymous with nanoparticulate formulations and intravenous dosing. The putative determinants of stealth in these applications are the molecular weight and packing density of a hydrophilic polymer (commonly poly(ethylene glycol) (PEG)) that forms a steric barrier at the surface of the nanoparticle. The current study examined the potential translation of the concepts learned from stealth technology after intravenous administration to oral drug delivery and specifically, to enhance drug exposure after administration of oral lipid-based formulations (LBFs) containing medium-chain triglycerides (MCT). MCT LBFs are rapidly digested in the gastrointestinal tract, typically resulting in losses in solubilisation capacity, supersaturation and drug precipitation. Here, non-ionic surfactants containing stealth PEG headgroups were incorporated into MCT LBFs in an attempt to attenuate digestion, reduce precipitation risk and enhance drug exposure. Stealth capabilities were assessed by measuring the degree of digestion inhibition that resulted from steric hindrance of enzyme access to the oil-water interface. Drug-loaded LBFs were assessed for maintenance of solubilising capacity during in vitro digestion and evaluated in vivo in rats. The data suggest that the structural determinants of stealth LBFs mirror those of parenteral formulations, i.e., the key factors are the molecular weight of the PEG in the surfactant headgroup and the packing density of the PEG chains at the interface. Interestingly, the data also show that the presence of labile ester bonds within a PEGylated surfactant also impact on the stealth properties of LBFs, with digestible surfactants requiring a PEG Mw of 1800 g/mol and non-digestible ether-based surfactants 800 g/mol to shield the lipidic cargo. In vitro evaluation of drug solubilisation during digestion showed stealth LBFs maintained drug solubilisation at or above 80 of drug load and reduced supersaturation in comparison to digestible counterparts. This trend was also reflected in vivo, where the relative bioavailability of drug after administration in two stealth LBFs increased to 120 and 182 in comparison to analogous digestible (non-stealth) formulations. The results of the current study indicate that self-assembled stealth LBFs have potential as a novel means of improving LBF performance.
AB - For over 20 years, stealth drug delivery has been synonymous with nanoparticulate formulations and intravenous dosing. The putative determinants of stealth in these applications are the molecular weight and packing density of a hydrophilic polymer (commonly poly(ethylene glycol) (PEG)) that forms a steric barrier at the surface of the nanoparticle. The current study examined the potential translation of the concepts learned from stealth technology after intravenous administration to oral drug delivery and specifically, to enhance drug exposure after administration of oral lipid-based formulations (LBFs) containing medium-chain triglycerides (MCT). MCT LBFs are rapidly digested in the gastrointestinal tract, typically resulting in losses in solubilisation capacity, supersaturation and drug precipitation. Here, non-ionic surfactants containing stealth PEG headgroups were incorporated into MCT LBFs in an attempt to attenuate digestion, reduce precipitation risk and enhance drug exposure. Stealth capabilities were assessed by measuring the degree of digestion inhibition that resulted from steric hindrance of enzyme access to the oil-water interface. Drug-loaded LBFs were assessed for maintenance of solubilising capacity during in vitro digestion and evaluated in vivo in rats. The data suggest that the structural determinants of stealth LBFs mirror those of parenteral formulations, i.e., the key factors are the molecular weight of the PEG in the surfactant headgroup and the packing density of the PEG chains at the interface. Interestingly, the data also show that the presence of labile ester bonds within a PEGylated surfactant also impact on the stealth properties of LBFs, with digestible surfactants requiring a PEG Mw of 1800 g/mol and non-digestible ether-based surfactants 800 g/mol to shield the lipidic cargo. In vitro evaluation of drug solubilisation during digestion showed stealth LBFs maintained drug solubilisation at or above 80 of drug load and reduced supersaturation in comparison to digestible counterparts. This trend was also reflected in vivo, where the relative bioavailability of drug after administration in two stealth LBFs increased to 120 and 182 in comparison to analogous digestible (non-stealth) formulations. The results of the current study indicate that self-assembled stealth LBFs have potential as a novel means of improving LBF performance.
U2 - 10.1016/j.jconrel.2014.07.037
DO - 10.1016/j.jconrel.2014.07.037
M3 - Article
VL - 192
SP - 219
EP - 227
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -