Mechanistic studies of self emulsifying drug delivery systems for the oral delivery of lipophilic drugs

Introduction Oral drug delivery is a $35 billion dollar industry [1] and the most preferred way of drug administration. However, the oral route is not possible for 50% of currently marketed drug compounds due to their low solubility in water. Forty percent of prospective drugs coming out of discovery pipelines are lipophilic compounds, which leads to difficulty in achieving acceptable oral bioavailability. Lipid based drug delivery systems, and in particular self-emulsifying drug delivery systems (SEDDS), show great potential for enhancing oral bioavailability of lipophilic drugs, as well as offering the advantage of minimal processing and inherent stability, but have not been broadly applied, largely due to lack of general formulation guidance and lack of knowledge of how these systems function to enhance bioavailability [2, 3]. SEDDS are oil in water emulsions that typically have droplet sizes ranging from tens of nanometers to hundreds of nanometers and consist minimally of oil, surfactant, and the drug to be delivered dissolved in oil (Figure 1). SEDDS are spontaneously formed in the gently mixed aqueous gastrointestinal (GI) environment [4]. To gain a better understanding of the dependence of emulsion drug delivery function in the GI tract on formulation composition, a quantitative study of properties central to emulsion function was conducted utilizing representative self-emulsifying formulations based on a 3 factorial experimental design. Formulations have been studied as follows. Oils from three different structural classes (long chain triglyceride (Soybean oil), medium chain trigylcerides (Neobee M5), propylene glycol dicaprylate/dicaprate (Captex 200)) and surfactants with hydrophilic-lipophilic balance (HLB) values ranging from 10-15 (Cremophor EL, Tween 80, a mixture of Capmul MCM and Labrasol) were combined at three different oil-to-surfactant weight ratios (9:1, 5:1, 1:1).. A major reason why SEDDS influence oral bioavailability of a hydrophobic drug is the increased overall solubility in intestinal fluid upon oral administration. Mechanism by which SEDDS are believed to increase drug solubility is by digestion of lipid component of SEDDS formulation in the intestine and consequently solubilization of formulation lipid component digestion products into endogenous bile salt micelles leading to formation of complex colloidal structures which alter the overall drug solubility in the intestine. In this study, kinetics of formulation digestion was studied using an in vitro lipolyis set up and digestion profiles were expressed using a mathematical expression that relates digestion rate to droplet surface area. Secondly, partitioning of model drug Tempol Benzoate from emulsion droplets into aqueous phase (including mixed micelles) during in vitro lipid digestion was monitored using Electron Paramagnetic Resonance (EPR). Multi-component analysis of EPR spectra will give quantitative information on drug relase and partitioning processes during in vitro digestion. This information will be used together with mathematical expressions on digestion and absorption kinetics which will allow building an overall kinetic model to predict oral drug absorption.