Cyclodextrin complexation as a fruitful strategy for improving the performance of nebivolol delivery from solid lipid nanoparticles
Abstract
Oral bioavailability of nebivolol (NEB), a highly-selective β1-adrenergic receptor antagonist specially used in hypertension treatment, is limited by its low aqueous solubility. In this work we investigated the possibility of developing a new effective oral formulation of NEB by exploiting a combined strategy based on NEB complexation with hydroxypropyl-βCyclodextrin (HPβCD) and complex incorporation into solid lipid nanoparticles (SLNs). Solubility studies enabled to choose Imwitor 491 and 988 as solid lipids for SLN preparation. The effect of their separated or combined use, at different amounts, and of different surfactants on nanoparticles dimensions, homogeneity and surface charge was examined.
The best formulations were selected for drug loading, as such or as complex with HPβCD, and evaluated for physicochemical properties, morphology, entrapment efficiency and drug release. A comparison of the two kinds of formulations revealed that the presence of HPβCD improved SLNs quality in terms of reduced dimensions, higher homogeneity and greater physicochemical stability, avoiding the sharp Zeta Potential reduction observed when loading the plain drug; moreover, it allowed a marked increase in entrapment efficiency and better control of drug release. Furthermore, the use of HPβCD gave the opportunity of doubling drug loading without noticeable variations in SLNs physicochemical properties and maintaining excellent entrapment efficiency.
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Materials
Nebivolol.HCl (NEB) (2,2′-Azanediylbis(1-(6-fluorochroman-2-yl) ethanol) hydrochloride) was a kind gift of Menarini S.p.a. (L’Aquila, Italy). Hydroxypropyl-βCD (HPβCD), loss on drying 10 % max, total impurities (on D.S.) 1 % max, Molar substitution (MS) 0.81–0.99, was kindly supplied by Roquette (Lestrem, France) (Roquette, 2022). Glyceryl palmitostearate (Precirol® ATO5), Glyceryl behenate (Compritol® 888 ATO), Glycerol monostearate (Geleol®) and Polyoxyl-32 Stearate (Gelucire® 48/16) were kindly gifted by Gattefossé (Saint-Priest, Cedex, France). Cetyl palmitate and glyceryl tripalmitate were from Sigma Aldrich (St. Louis, MO, USA). Glyceryl monostearate (Imwitor® 491) and glycerol monocaprylate Type 1 (Imwitor® 988) were kindly provided by IOI Oleo GmbH (Witten, Germany). Polyoxyethylene sorbitan monooleate (Tween® 80) was from Merck (Hohenbrunn, Germany) and Poloxamer 188 (Pluronic® F68) from BASF (Ludwigshafen, Germany). All other chemicals and solvents were of analytical reagent grade.
P. Mura, F. Maestrelli, L.M.D. Gonçalves, M. Cirri, N. Mennini, A.J. Almeida, Cyclodextrin complexation as a fruitful strategy for improving the performance of nebivolol delivery from solid lipid nanoparticles, International Journal of Pharmaceutics, 2024, 124972, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124972.
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