Quinine: Redesigned and Rerouted

Abstract

Quinine hydrochloride (QHCl) has remained a very relevant antimalarial drug 400 years after its effectiveness was discovered. Unlike other antimalarials, the development of resistance to quinine has been slow. Hence, this drug is to date still used for the treatment of severe and cerebral malaria, for malaria treatment in all trimesters of pregnancy, and in combination with doxycycline against multidrug-resistant malaria parasites. The decline in its administration over the years is mainly associated with poor tolerability due to its gastrointestinal (GIT) side effects such as cinchonism, complex dosing regimen and bitter taste, all of which result in poor compliance. Hence, our research was aimed at redesigning quinine using nanotechnology and investigating an alternative route for its administration for the treatment of malaria. QHCl nanosuspension (QHCl-NS) for intranasal administration was prepared using lipid matrices made up of solidified reverse micellar solutions (SRMS) comprising Phospholipon® 90H and lipids (Softisan® 154 or Compritol®) in a 1:2 ratio, while Poloxamer® 188 (P188) and Tween® 80 (T80) were used as a stabilizer and a surfactant, respectively. The QHCl-NS formulated were in the nanosize range (68.60 ± 0.86 to 300.80 ± 10.11 nm), and highly stable during storage, though zeta potential was low (≤6.95 ± 0.416). QHCl-NS achieved above 80% in vitro drug release in 6 h. Ex vivo permeation studies revealed that formulating QHCl as NS resulted in a 5-fold and 56-fold increase in the flux and permeation coefficient, respectively, thereby enhancing permeation through pig nasal mucosa better than plain drug solutions. This implies that the rate of absorption as well as ease of drug permeation through porcine nasal mucosa was impressively enhanced by formulating QHCl as NS. Most importantly, reduction in parasitaemia in mice infected with Plasmodium berghei ANKA by QHCl-NS administered through the intranasal route (51.16%) was comparable to oral administration (52.12%). Therefore, redesigning QHCl as NS for intranasal administration has great potential to serve as a more tolerable option for the treatment of malaria in endemic areas.