Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization.
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 -2.73 mV to 6.52 mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r(2) = 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.
a Department of Pharmaceutics , B. V. Patel PERD Centre , Ahmedabad , Gujarat , India .
Brijesh M
BM
Shah
b Department of Pharmaceutics , NIPER-Ahmedabad, C/O B. V. Patel PERD Centre , Ahmedabad , Gujarat , India , and.
Manju
M
Misra
a Department of Pharmaceutics , B. V. Patel PERD Centre , Ahmedabad , Gujarat , India .
Chamanlal J
CJ
Shishoo
c Vice Chancellor, Sardar Patel University , Vallabh Vidyanagar , Gujarat , India.
Harish
H
Padh
D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D004655:Emulsions; D005079:Excipients / Q000737:chemistry; D006041:Goats; D006863:Hydrogen-Ion Concentration; D009297:Nasal Mucosa / Q000378:metabolism; D010316:Particle Size; D000068836:Rivastigmine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D012995:Solubility; D014018:Tissue Distribution; D014783:Viscosity
D002800:Cholinesterase Inhibitors; D004655:Emulsions; D005079:Excipients; D000068836:Rivastigmine
Alzheimer’s disease; brain targeting; intranasal route; mucoadhesive agents; rivastigmine