Liposomal Delivery of Hydrophobic Weak Acids: Enhancement of Drug Retention Using a High Intraliposomal pH

ABSTRACTClinical development of highly potent lipophilic neutral camptothecins has been impeded by the poor solubility, stability, and nonspecific toxicity of these compounds. Liposomal encapsulation offers a promising formulation route for tumor site‐specific delivery of these novel drug candidates. However, the development of formulation strategies for liposomal loading and retention of hydrophobic drugs such as the neutral camptothecins has been lacking. In the studies presented here, we explored the potential of a trans‐bilayer pH gradient strategy for prolonging the liposome retention of DB‐67, a novel lipophilic camptothecin that can undergo lactone ring‐opening to form a hydrophobic weak acid. The liposome membrane permeability of DB‐67 was obtained as a function of pH in aqueous buffers. A permeability model was developed and liposome membrane permeability was shown to be controlled by the fraction of unbound neutral lactone entrapped in the vesicles. Liposome membrane permeability of DB‐67 was also studied under physiological conditions. The high membrane partitioning of DB‐67 in the intraliposomal microenvironment was found to shift the equilibrium between lactone and carboxylate towards the lactone species resulting in a faster than desired drug release under physiological conditions. The effectiveness of the pH gradient strategy was further reduced under physiological conditions by the rapid loss of trans‐membrane pH gradients due to CO2 uptake. Simulations were conducted to explore the role of membrane binding, intravesicular pH, and carbonate buffer concentration in successful utilization of the pH gradient strategy for hydrophobic weak acids. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:433–454, 2008