Intranasal artesunate-loaded nanostructured lipid carriers: A convenient alternative to parenteral formulations for the treatment of severe and cerebral malaria

Abstract

Early treatment with parenteral antimalarials is key in preventing deaths and complications associated with severe and cerebral malaria. This can be challenging in 'hard-to-reach' areas in Africa where transit time to hospitals with facilities to administer drugs parenterally can be more than 6 h. Consequently, the World Health Organization has recommended the use of artesunate (ATS) suppositories for emergency treatment of patients, however, this treatment is only for children under 6 years. The intranasal route (INR) can provide a safe and effective alternative to parenteral and rectal routes for patients of all ages; thus, reducing delays to the initiation of treatment. Hence, we designed ATS-loaded nanostructured lipid carriers (NLCs) for intranasal administration. ATS-NLCs were formulated using varying concentrations of lipid matrices made up of solidified reverse micellar solutions (SRMS) comprising a 1:2 ratio of Phospholipon ® 90H and lipids (Softisan ® 154 or Compritol ®). ATS-NLCs were spherical, and the small sizes of ATS-NLCs obtained for some formulations (76.56 ± 1.04 nm) is an indication that ATS-NLCs can pass through the nasal mucosa and reach the brain or systemic circulation. Encapsulation efficiency of ATS in NLCs was ≥70% for all formulations. ATS-NLCs achieved up to 40% in vitro drug release in 1 h, while ex vivo permeation studies revealed that formulating ATS as NLCs enhanced permeation through pig nasal mucosa better than drug solution. Most importantly, the activity and reduction in parasitaemia [in mice infected with Plasmodium berghei ANKA in a murine cerebral malaria model] by ATS-NLCs administered through the INR (54.70%, 33.28%) was comparable to intramuscular administration (58.80%, 42.18%), respectively. Therefore, intranasal administration of NLCs of ATS has great potentials to serve as a satisfactory alternative to parenteral administration for the treatment of severe and cerebral malaria in both adults and children in remote areas of sub-Saharan Africa.

Keywords: Artesunate; Cerebral malaria; Intranasal route; Nanostructured lipid carriers; Severe malaria; Solidified reverse micellar solutions.