Editors' ChoiceDrug Delivery

Improving “gut feelings” for poorly water-soluble drugs

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Science Translational Medicine  20 Jun 2018:
Vol. 10, Issue 446, eaau0472
DOI: 10.1126/scitranslmed.aau0472

Abstract

A nanocarrier system self-assembled in the intestine significantly improves oral availability of poorly water-soluble drugs.

Most medicines are taken orally, the most convenient route for patients. However, many clinical small-molecule drugs are poorly water soluble. They often become nonabsorbable aggregates upon contact with bodily fluids in the digestive tract, which compromises their clinical effectiveness. Here, Chuang et al. developed a “Transformers”-like nanocarrier system to improve the bioavailability of poorly water-soluble drugs and demonstrated its use in a rat model of acute pancreatitis.

The system allows the drug molecules to self-assemble into nanoemulsions in the intestinal lumen, with optimal sizes that enhance passive uptake by M cells, a special type of epithelial cells in the small intestine functionally associated with the lymphoid tissue. The drug is then transported through the lymphatic system, which bypasses the presystemic metabolism in the liver and further improves its oral availability. To achieve this, the authors designed a powdered mixture of an acid initiator; a foaming agent; a surfactant; and a poorly water-soluble anti-inflammatory drug, curcumin, into an enteric-coated gelatin capsule (which protects the mixture from the acidic environment in stomach). Upon reaching the small intestine, the acid initiator dissolves and reacts with the foaming agent to generate carbon dioxide bubbles, leading to a self-assembled nanofilm of the surfactant and the drug on the bubble surface. When the bubbles bursts at the water-air interface in the intestine, a drug-surfactant nanoemulsion is formed, with a size range more likely to be taken by M cells. The research team showed that rats taking curcumin in this nanocarrier formulation have more dispersed curcumin distribution along the intestine and greater accumulation in the pancreas. In a rat model of acute pancreatitis, curcumin delivered as nanoemulsion significantly improved the recovery of the pancreas from the acute inflammation, confirmed by the serum level of inflammatory cytokine and protein, histological integrity, and in vivo imaging of inflammatory cells accumulated in pancreas. The authors further validated the route of drug delivery by showing that curcumin colocalized with M cells and lymphatic system upon intestinal absorption.

Overall, the researchers have demonstrated great potential of the system for clinical translation, as all the components in their formulation are biocompatible and/or approved for oral formulations. To facilitate the translation, more studies are needed on how the nanocarrier system delivers the drug to pancreas in such a site-specific manner and whether it would also enhance the delivery of toxic compounds from the intestine.

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