Preparation, characterization, and in vivo evaluation of albumin-encapsulated primaquine diphosphate

It has been demonstrated by others that encapsulating a drug into microparticles may improve its therapeutic index by targeting the drug to the site of action while maintaining a sustained release of the drug to that site. In this case the site of action is the liver, where plasmodia initiates the disease. Also, the microencapsulation technique may buffer drug toxicity as well as protect the drug from degradation.; The goal of this dissertation was to develop and evaluate various techniques to produce albumin-encapsulated primaquine diphosphate. An in-vivo mouse study was initially performed with glutaraldehyde-crosslinked microspheres containing primaquine disphosphate. The results of this study suggested that glutaraldehyde should not be used when producing microspheres with drugs bearing amine groups (reactive). Therefore considerable effort in testing other microencapsulation methods was made.; During this process a novel nebulization/heat stabilization technique was developed. Microparticles were produced by forcing a nebulized aqueous mixture of albumin and primaquine diphosphate into heated vegetable oil. The microparticles were extracted from the oil with ethyl acetate and dried. The resulting microparticles were five to seven microns and generally followed Higuchi drug release kinetics. An in-vivo evaluation of these microparticles was performed in mice. To determine liver tissue levels of primaquine diphosphate, an HPLC method using derivatization with a fluorogenic reagent (fluorescamine) was developed. Pharmacokinetic profiles of encapsulated primaquine diphosphate showed a ten-fold increase of primaquine in liver tissue relative to mice given an equivalent dose of free primaquine diphosphate in solution. Also the half-life of primaquine in the encapsulated formulation was 2.5 times slower in the liver tissue while the steady state volume of distribution was ten fold less in the liver compartment. These characteristics suggest targeting and sustained release of primaquine in the livers of mice administered the encapsulated formulation. An efficacy study in mice challenged with Plasmodium berghei malaria revealed a moderate reduction in parasitemia when administered the encapsulated formulation of primaquine relative to free primaquine. (Abstract shortened by UMI.)...