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.

Background and Purpose: The activation of 5-HT₄ receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C₁₈/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies.

Tegaserod is a serotonin receptor agonist with potential neuroprotective properties for Alzheimer's disease. Due to its low druggability profile and to avoid detrimental side effects, a brain-targeted formulation is required. Nanocarriers targeting the blood-brain barrier (BBB) with a shuttle peptide, such as peptide-22, or enabling direct nose-to-brain delivery were considered as valuable approaches. This study aimed to compare two types of lipid-based nanocarriers and determine the best formulation for intravenous (IV) or intranasal (IN) administration. Tegaserod-loaded nanoemulsions and liposomes were successfully developed, improving the solubilization of tegaserod in injectable formulations. Their properties were optimized for the IV route, and the two formulations were compared in terms of granulometric properties, stability, stealth properties, and transport across a human model of the human BBB. Based on these evaluations, peptide-22-decorated tegaserod-loaded nanoemulsions were the most promising for IV administration. In addition, tegaserod-loaded nanoemulsions or liposomes were incorporated in a gelling formulation with properties optimized for the IN route, focusing on gelation temperature, osmolarity, and pH. Due to its rheological profile and behavior at room temperature, gel-embedded liposomes emerged as the most suitable formulation for the IN route. The successful development of these nanocarriers will facilitate further preclinical evaluation of tegaserod in Alzheimer's disease.