Intranasal Mucoadhesive Microemulsions of Clonazepam: Preliminary Studies on Brain Targeting

The aim of this investigation was to prepare clonazepam microemulsions (CME) for rapid drug delivery to the brain to treat acute status epileptic patients and to characterize and evaluate the performance of CME in vitro and in vivo in rats. The CME were prepared by the titration method and were characterized for globule size and size distribution, zeta potential, and drug content. CME was radiolabeled with 99mTc (technetium) and biodistribution of drug in the brain was studied in Swiss albino rats after intranasal and intravenous administrations. Brain scintigraphy imaging in rabbits was also performed to ascertain the uptake of the drug into the brain. Pre and postCME formulation treated human nasal mucosa was subjected to transmission electron microscopy to investigate the mechanism of drug uptake across the nasal mucosa. CME were transparent and stable with mean globule size of 15 ± 10 nm and zeta potential of −30 mV to −40 mV. 99mTc-labeled clonazepam solution (99mTc CS)/ clonazepam microemulsion (CME)/clonazepam mucoadhesive microemulsion (CMME) were found to be stable and suitable for in vivo studies. Brain/blood uptake ratios at 0.50 hour (h) following intranasal CMME, CME, clonazepam solution (CS), and intravenous CME administrations were found to be 0.67, 0.50, 0.48, and 0.13, respectively indicating more effective targeting with intranasal administration and best targeting of the brain with intranasal CMME. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of CMME compared to intravenous was found to be twofold higher indicating larger extent of distribution of the drug in brain. Rabbit brain scintigraphy also showed higher intranasal uptake of the drug into the brain. Transmission electron microscopy revealed significant accretion of CMME within interstitial spaces and paracellular mode of transport due to stretching of the tight junctions present in the nasal mucosa. This investigation demonstrates a more rapid and larger extent of transport of clonazepam into the rat brain with intranasal CMME, which may prove useful in treating acute status epileptics. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association.