Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies

Abstract

Being one of the highly effective drugs in treatment of Alzheimer's disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, À8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels. KeywordsRivastigmine, pegylated liposomes, Tween 80, ex vivo permeation, in vivo pharmacokinetic studies History

Double Optimization of Rivastigmine-Loaded Nanostructured Lipid Carriers (NLC) for Nose-to-Brain Delivery Using the Quality by Design (QbD) Approach: Formulation Variables and Instrumental Parameters

“…Nonetheless, it was reported that rivastigmine hydrogen tartrate undergoes an extensive first-pass effect in the liver, which decreases bioavailability [ 10 , 11 ]. This molecule also has a short half-life and a hydrophilic nature, which makes it difficult for it to pass through the blood brain barrier (BBB) and cerebrospinal fluid (CSF) [ 5 , 9 , 12 ]. In addition, the tight junctions between the BBB capillary endothelial cells restrict the passage, absorption, and permeation of drugs to the brain [ 13 , 14 ].…”

Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model

“…Their surface can be easily modified to provide them with multiple functions [17]. This has already been demonstrated for improvement of intranasal delivery [18] of rivastigmine [19,20], donepezil [21], zolmitriptan [22].…”

A Practical and Efficient Stereoselective Synthesis of (S)‐Rivastigmine and (R)‐Rivastigmine

“…Since the discovery of rivastigmine,, its synthesis has been studied widely in organic chemistry . Over the past three decades, several strategies for the synthesis of rivastigmine have been developed.…”