• Analysis of Surfactant-mediated Dissolution Effects in Biorelevant Media

      Raman, Siddarth; Polli, James E. (2016)
      Food is known to impact drug bioavailability through a variety of mechanisms, including drug solubilization and prolonged gastric residence time. In vitro dissolution media that aim to mimic in vivo gastrointestinal (GI) conditions have been developed to lessen the need for fed human bioequivalence studies. The first aim of this work was to develop an in vitro lipolysis model to predict positive food effect of three BCS Class II drugs (i.e. danazol, amiodarone and ivermectin) in previously developed lipolysis media. The in vitro lipolysis model accurately predicted the in vivo positive food effect for three model BCS class II drugs. The in vitro lipolysis model has potential use as a screening test of drug candidates in early development to assess positive food effect. In vitro lipolysis is an in vitro approach to simulate drug dissolution under fed conditions, in an effort to anticipate when food increases the absorption of poorly water soluble drugs in vivo due to increased drug solubilization. Imaging techniques have promise to aid in understanding such positive food effects. The second aim of this work was to employ cryogenic transmission electron microscopy (cryo-TEM) to characterize the colloidal changes in Fe-Lipolysis during drug dissolution, and correlate food-enhanced dissolution with colloid structures. Danazol was selected as a model BCS Class II drug with a positive food effect. Danazol samples from fed and fasted state dissolution experiments were subjected to cryo-TEM. Compared to the fed state observations, no major changes were observed in the fasted state. These findings concur with in vivo observations and previously developed hypothetical models of lipolysis and drug solubilization. The third aim of the work was to develop a better understanding of surfactant-mediated dissolution effects in biorelevant media. Three poorly soluble drugs, ciprofloxacin HCl, ivermectin and fexofenadine HCl, that differed in their lipophilicity were analyzed using biorelevant dissolution in human as well as canine fasted state intestinal media. The main objective was to compare the rate and extent of dissolution between these drugs and further elucidate the surfactant-mediated enhancements they experienced. Ivermectin displayed significantly slower dissolution than ciprofloxacin HCl and fexofenadine HCl. Using previously derived models of surfactant-mediated dissolution enhancement, it was determined that ivermectin was heavily dependent on the presence of surfactant, while ciprofloxacin and fexofenadine dissolution showed no dependence on the presence of surfactant as a result of being heavily surfactant-independent.