Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. This investigation was aimed to formulate microemulsion (ME) and mucoadhesive microemulsions (MMEs) of rivastigmine for nose to brain delivery and to compare percentage drug diffused for both systems using in-vitro and ex-vivo study. Rivastigmine-loaded ME and MMEs were prepared by titration method and characterized for drug content, globule size distribution, zeta potential, pH, viscosity and nasal ciliotoxicity study. Rivastigmine-loaded ME system containing 8% w/w Capmul MCM EP, 44% w/w Labrasol:Transcutol-P (1:1) and 48% w/w distilled water was formulated, whereas 0.3% w/ w chitosan (CH) and cetyl trimethyl ammonium bromide (as mucoadhesive agents) were used to formulate MMEs, respectively. ME and MMEs formulations were transparent with drug content, globule size and zeta potential in the range of 98.59% to 99.43%, 53.8 nm to 55.4 nm and À2.73 mV to 6.52 mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r 2 ¼ 0.9773) and showed highest diffusion coefficient. It was free from nasal ciliotoxicity and stable for three months. However, the potential of developed CH-based MME for nose to brain delivery of rivastigmine can only be established after in-vivo and biodistribution study.

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Alzheimer’s disease therapies: Selected advances and future perspectives

“…Indeed, some current therapeutic approaches include reversible cholinesterase inhibitor like rivastigmine. 2 Epidemiological studies have important contributions to presenting new bases for future. For instance, risks of developing Alzheimer's disease can be decreased by smoking tobacco and it was suggested that nicotine inhibits neuronal apoptosis which prevents the Ab25-35-induced neurotoxicity 15 pointing a starting point to new therapeutic approaches.…”

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

“…The mucosa must be oriented with the mucosal side facing the donor chamber. The thickness of the tissue (usually 200 µm) should be measured and mentioned as it is directly linked to the diffusion rate (Tas et al, 2009;Shah et al, 2015;Acharya et al, 2013). The influence of the thickness was investigated in a study that compared the permeation of both hydrophilic (i.e.…”