Editors' ChoiceDrug Delivery

Bursting bubbles for better bioavailability

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Science Translational Medicine  17 Jun 2020:
Vol. 12, Issue 548, eabc8945
DOI: 10.1126/scitranslmed.abc8945

Abstract

An effervescent formulation increases the oral bioavailability of hard-to-solubilize hydrophobic and hydrophilic chemotherapeutics.

Certain hard-to-solubilize chemotherapeutics require formulations that necessitate intravenous—particularly, central venous—administration. Venous access induces discomfort for patients and logistical challenges for the health care system. An oral formulation of such drugs would be game-changing for many patients with cancer and their oncology teams.

In a recent study in Biomaterials, Chen and colleagues demonstrate a new drug delivery system that can be used to increase the oral bioavailability of both hydrophobic and hydrophilic chemotherapeutic drugs. Importantly, the inactive excipients of this formulation, including capric (decanoic) acid, citric acid, and sodium bicarbonate, are each commonly used and generally safe. The authors exhibit the utility of this system for oral delivery of paclitaxel and gemcitabine to pancreatic tumors in rat models. Paclitaxel is a notoriously hard-to-solubilize and commonly used hydrophobic chemotherapeutic, and gemcitabine is a hydrophilic chemotherapeutic. In their system, the hydrophobic drug is mixed with capric acid, while a hydrophilic drug (if codelivered) is layered between citric acid and bicarbonate, and the whole mix is packed in a gelatin capsule. When exposed to water—and especially to acidic pH, like in the stomach—an effervescent reaction occurs, yielding self-assembly of drug-loaded microbubbles. After outgassing, the microbubbles convert to lipid-coated drug-loaded nanoemulsions that may then cross the enteric mucosal barrier into the vasculature or lymphatics.

The authors previously showed the basic functionality of this system in proof-of-concept papers. This study explicitly validates that this system can yield suitable oral bioavailability and pharmacokinetics of chemotherapeutics to treat a realistic rat model of cancer. Indeed, using this oral formulation they were able to see pancreatic tumor–killing effects without any change in animal body weight (as a marker of toxicity). Notably, their oral formulation yielded a prolonged blood residence time of each chemotherapeutic compared with intravenous administration, which is particularly desirable for cell cycle–selective agents.

There are many steps to be taken between this demonstration in a single rat model and eventual clinical trials. However, many patients will certainly be bubbly over this effervescent oral formulation if it saves them from having to receive intravenous chemotherapy.

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