Innovation that Enables the Encapsulation of Sparingly Soluble Drugs for Delivery in Liposomes

F.C. Szoka, C.O. Noble, M.E. Hayes
University of California, San Francisco,
United States

Keywords: cancer, drug delivery


There is a continuing expansion of materials and approaches used to create new nanodrug carriers. However, after 40 years nanodrug carriers satisfy only a nano-portion of the drug delivery market, mainly in the oncology sector. The one carrier that has multiple FDA approved products is the liposome. I will describe recent developments concerning a new packaging methodology for encapsulation of sparingly soluble drugs. This class of compounds account for most drugs in early discovery and approximately 50% of the molecules that advance to potential drug products. Sparingly soluble drugs have proven difficult to formulate in liposomes. Although they may have hydrophobic elements, such molecules often do not accommodate into a liposome bilayer. If they do, the drug may quickly transfer into biomembranes and serum proteins when the liposome-drug is injected into an animal. Methods to load such compounds include: high ethanol concentrations or the use of solubility enhancing cyclodextrins. We have devised an alternative approach to load sparingly soluble compounds from precipitates formed outside of the liposome. The ZIP technology enables high efficiency encapsulation of sparingly soluble drugs in liposomes. The ppt loading method can be implemented in current liposome production processes, results in a high efficiency of encapsulation >90%, in which the compounds inside the liposome are usually in a ppt form. Because the compounds are often in a ppt inside the liposome, they are retained in the liposome for a significant time post-injection into an animal. This can extend the exposure of the target tissue to the drug and enable enhanced deposition of the drug into tumors and the reticuloendothelial system. Using carfilzomib (CFZ) as a model sparingly soluble API, we demonstrate high efficiency encapsulation, altered CFZ pharmacokinetics, increased tolerability compared to the commercial cyclodextrin formulation and improved anti-tumor activity in a stable, scalable liposome formulation.