Brain targeting of zolmitriptan via transdermal terpesomes: statistical optimization and in vivo biodistribution study by 99mTc radiolabeling technique

Abstract

Zolmitriptan (ZT) is a potent second generation triptan, commonly administered to alleviate migraine attacks. ZT suffers various limitations; massive hepatic first pass metabolism, P-gp efflux transporters susceptibility, and limited (≈40%) oral bioavailability. Transdermal route of administration could be explored to enhance its bioavailability. A 2³.3¹ full factorial design was constructed to developed twenty-four ZT loaded terpesomes via thin film hydration technique. The influence of drug: phosphatidylcholine ratio, terpene type, terpene concentration and sodium deoxycholate concentration on the characterization of the developed ZT-loaded terpesomes was assessed. Particle size (PS), zeta potential (ZP), ZT entrapment efficiency (EE%), drug loading (DL%) and drug released percentages after 6 h (Q_6h) were the selected dependent variables. Further morphological, crystallinity, and in-vivo histopathological studies were conducted for the optimum terpesomes (T6). ^99mTc-ZT and ^99mTc-ZT-T6 gel were radio-formulated for in-vivo biodistribution studies in mice following transdermal application of ^99mTc-ZT-T6 gel, relative to ^99mTc-ZT oral solution. T6 terpesomes [comprising ZT and phosphatidylcholine (1:15), cineole (1% w/v) and sodium deoxycholate (0.1% w/v)] were optimum with respect to spherical PS (290.2 nm), ZP (-48.9 mV), EE% (83%), DL% (3.9%) and Q_6h (92.2%) with desirability value of 0.85. The safety of the developed T6 terpesomes was verified by the in-vivo histopathological studies. ^99mTc-ZT-T6 gel showed maximum brain concentration (5 ± 0.1%ID/ g) with highest brain to blood ratio of 1.92 ± 0.1 at 4 h post transdermal application. Significant improvement of ZT brain relative bioavailability (529%) and high brain targeting efficiency (315%) were revealed with ^99mTc-ZT-T6 gel, which confirmed successful ZT delivery to the brain. Terpesomes could be safe, successful systems capable of improving ZT bioavailability with high brain targeting efficiency.

Keywords: Brain Targeting; Radiolabeling; Terpesomes; Transdermal; Zolmitriptan.