Design of Non-Haemolytic Nanoemulsions for Intravenous Administration of Hydrophobic APIs

Abstract

Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems allowing to improve the solubility and the bioavailability of lipophilic drugs. To select safe excipients for nanoemulsion formulation and to discard any haemolytic potential, an in vitro miniaturized test was performed on human whole blood. From haemolysis results obtained on eighteen of the most commonly used excipients, a medium chain triglyceride, a surfactant, and a solubilizer were selected for formulation assays. Based on a design of experiments and a ternary diagram, the feasibility of nanoemulsions was determined. The composition was defined to produce monodisperse nanodroplets with a diameter of either 50 or 120 nm, and their physicochemical properties were optimized to be suitable for intravenous administration. These nanoemulsions, stable over 21 days in storage conditions, were shown to be able to encapsulate with high encapsulation efficiency and high drug loading, up to 16% (w/w), two water practically insoluble drug models: ibuprofen and fenofibrate. Both drugs may be released according to a modulable profile in sink conditions. Such nanoemulsions appear as a very promising and attractive strategy for the efficient early preclinical development of hydrophobic drugs.

Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer’s Disease Treatment

“…Nanoemulsions were obtained according to the formulation process recently developed in our laboratory [38], based on spontaneous nanoemulsification. Briefly, Labrafac ® WL 1349, Kolliphor ® HS 15 and Transcutol ® HP were mixed under gentle magnetic stirring (250 rpm), heated to 70 • C and then cooled down to 25 • C. At this temperature, the magnetic stirring was increased from 250 to 750 rpm, and the aqueous phase (60 mM phosphate buffer, pH 7.2, 25 • C) was suddenly added to the anhydrous phase.…”

“…Hemolysis tests were realized according to the protocol previously described by our team [38]. Briefly, whole human blood samples from three healthy compatible volunteers were collected in Li-heparin tubes (Etablissement Français du Sang, EFS Hauts-de-France-Normandie, France), pooled and diluted in DPBS to adjust the total hemoglobin concentration at 10 mg/mL.…”

“…They permit to obtain high loading efficiency. Thanks to well-adapted excipients, they may be also non-toxic, highly stable and easily produced, particularly by low energy processes [38,68].…”

“…The nanoemulsion formulation, and the same spontaneous emulsification process, previously described by our team [38], was transposed to tegaserod. After formulation, the obtained tegaserod-loaded nanoemulsions (Tg-NEs) had a clear appearance with a slight greenish coloration attributable to tegaserod (Figure 3).…”

“…On the basis of our previous formulation studies, the development and the pharmaceutical characterization of tegaserod-loaded lipid nanoemulsions will be realized [38]. Considering that the LDL-Rs is a relevant target to shuttle therapeutics into the CNS after receptor-mediated transcytosis, functionalization of the nanoemulsions will be attempted by a peptide ligand having an improved binding affinity for this receptor [39].…”