Enhancing the solubility and in vitro permeability of pyrimethamine

Abstract

ABSTRACT Malaria poses a substantial health problem, with nearly half of the world’s population susceptible to it. Malaria causes an estimated one million deaths per year. People who fall prey to malaria are also burdened with numerous other health issues, such as: an increased burden to HIV/AIDS, respiratory tract infections, malnutrition, and anaemia. Malaria infection during pregnancy furthermore greatly increases the chances of severe complications, such as low birth weight, abortions, and stillbirths. The combination of pyrimethamine and sulfadoxine remains the preferred prevention and treatment of uncomplicated malaria in pregnant women, due to the fact that this combination is safe to use in these patients. However, even though these drugs still appear on the essential list of medicine of the World Health Organization (WHO), pyrimethamine is known for its poor aqueous solubility and low permeability. The purpose of this study is to investigate the enhancement of solubility and in vitro permeability of pyrimethamine. This study will investigate the effect of cyclodextrins, particularly β-hydroxypropyl cyclodextrin, on the enhancement in solubility of the target drug. Furthermore, Aloe vera will be employed to potentially improve the intestinal permeability of the target drug through opening of the tight junctions. In this study the solubility and membrane permeability of pyrimethamine as a single component and in combination with sulfadoxine, A. vera and hydroxypropyl β-cyclodextrin was determined. Different combinations of all the above-mentioned components were prepared. An inclusion complex of pyrimethamine and hydroxypropyl β-cyclodextrin was prepared for solubility enhancement and A. vera was added into some combinations to aid in the permeability enhancement of pyrimethamine. Four sets of solubility studies were performed each in a different media. The different media used were water, 0.1 N HCl at pH 1.2, phosphate buffered solution (PBS) at pH 6.8 and dulbeco`s modified eagles’ media (DMEM) at pH 7.2. Increased solubility was obtained by various combinations compared to pyrimethamine as a single component in all four media. The permeability studies performed on Caco-2 cell monolayers proved that the permeability of pyrimethamine could be enhanced by preparing a combination of pyrimethamine with the above-mentioned components. Increased permeation was observed by various combinations compared to pyrimethamine alone.

It is evident that an inclusion complex between pyrimethamine and hydroxypropyl β-cyclodextrin increased the solubility and that the addition of A. vera to pyrimethamine increased the in vitro permeability.