(596r) Delivery Systems for Controlled and Sustained Release of Malarial Inhibitors

Drug delivery systems are engineered-materials that dispense a constant supply of drugs to a patient for a desired dosage period at a level below the minimum toxic concentration (MTC) and above the minimum effective concentration (MEC). Since each molecule possesses unique hydrophobicity and size, which can alter overall drug retention or in vivo release kinetics, a known challenge is the adaptability of therapeutic molecules to the desired system. In this study, we develop a process to effectively incorporate slightly hydrophilic drugs into poly(lactic-co-glycolic acid) (PLGA) particles. 

The model drug is a malaria transmission blocking inhibitor, BKI-1.  Malaria is a mosquito-borne disease caused by a Plasmodium parasite, with 216 million reported cases world-wide and close to one million deaths per year according to the Center for Disease Control.  Current treatments for malaria are becoming ineffective and allow gametocytes to infect mosquitoes for up to 3 weeks after successful therapy.  A possible strategy through collaborative efforts is to develop compounds that break the malaria transmission circle. These compounds are predicted to inhibit malaria sexual stage in mosquitoes without noticeable toxic effects to mammals, potentially resulting in a decrease in the transmission and spread of malaria. In mouse PK studies, BKI-1 has a high blood clearance rate and is slightly hydrophilic. However, the extended presence of viable gametocytes in the mammalian host will require a prolonged drug bioavailability at a level between the MTC and MEC for effective transmission blocking to occur. To overcome this challenge, we have commenced the development of a low-cost, easy to fabricate, and easy to administer subcutaneous particulate injection formulated with PLGA to ensure slow release of BKIs into the blood stream over an extended period.

The main challenge of incorporating slightly hydrophilic drugs in PLGA particles by either single emulsion or double emulsion is that the loading efficiency is low. We hypothesized that the partition of drug in aqueous and organic phases during the fabrication process would be critical for the effective incorporation of drug into PLGA particles. To test our hypothesis, we varied the overall drug level, pH in aqueous phase and the composition of organic phase. We measured the loading of BKI-1 in PLGA particles. It was found that there existed an optimal overall drug level, pH and the composition of organic phase. We will then correlate the efficiency of drug loading with the partition coefficient.