Mechanistic and modeling studies of lipid nanoemulsions impact on oral lapatinib absorption
Mentor: Rebecca Carrier, PhD (Northeastern University)
Today many oral drugs, including oral chemotherapeutics, have poor water solubility and poor drug absorption. Studies have shown that when taken in the presence of lipid-containing food, or with a lipid-based drug delivery system, drug dosages can sometimes be decreased significantly, thus alleviating possible side effects. Orally dosed lipids form nanoemulsions in the GI tract, which alter drug dissolution, solubility, and absorption. To date, however, the effect of lipid nanoemulsions on overall oral drug absorption is not quantitatively predictable, making the development of lipid based drug formulations an experimentally and financially exhaustive process. The Carrier lab is conducting mechanistic studies and developing a mathematical model that predicts the impact of lipid nanoemulsions on overall drug absorption. Given the significance and particularly harsh side effects of oral chemotherapeutics, this study will be evaluating the impact of lipid nanoemulsions on oral delivery of Lapatinib. Lapatinib is a chemotherapeutic drug used in the treatment of advanced stages of breast cancer that is known to have improved bioavailability when taken with a high fat meal, yet is dosed in the fasted state. As a conclusion of this study we will utilize experimental results from studying lapatinib in vitro together with modeling to predict the impact of orally dosed nanoemulsions on lapatinib absorption. Drug solubility and dissolution experiments will be performed in vitro in simulated gastric and intestinal fluids, and with concurrent digestion of lipids. The extent of lipid digestion, drug solubility and dissolution will be analyzed using high performance liquid chromatograph (HPLC) and an emitted light scattering detector (ELSD). Human cancerous colon cells (Caco-2 cells) will be used to study the impact of lipid nanoemulsions on intestinal permeation of Lapatinib.
A schematic representation of the lipid system being studied: solid drug dosed with food associated lipid. Where CD, water: free drug concentration, CD, aqueous: free and micelle-associated drug concentration, CD,em: drug concentration in food-associated oil emulsions; h: static layer around the dissolving drug particles. Source: Buyukozturk, et al. Pharm. Res. 2013;30:3131-44 Source: