Phase 1 clinical trial evaluating safety, bioavailability, and gut microbiome with a combination of curcumin and ursolic acid in lipid enhanced capsules




Liss, Michael Andre

Journal Title

Journal ISSN

Volume Title



A natural product library screen identified a synergistic combination of curcumin and ursolic acid as a nutraceutical option for treating prostate cancer. Subsequent in vitro and in vivo testing showed substantial promise in the combination which deemed it ready for human translation. However, poor bioavailability has prevented this combination from impacting cancer therapy. A novel formulation for ursolic acid and curcumin was developed by (1) attempting to increase dissolution rates with a reduced particle size and (2) enhancing solubility with lipid-based formulations. A hot-melt rotating disk process prepared the active compounds in the lipid-based microsphere formulations. The formulations were then optimized based on both solubility and process yield with available excipients. Our target was 1200mg/day of curcumin and 300mg/day of ursolic acid. A phase 1 clinical trial design was performed by sequentially enrolling three groups (curcumin, ursolic acid, and combination). Healthy patients were recruited without a history of prostate cancer. Blood was collected for bioavailability measurements and rectal swabs for gut microbiome analysis at baseline, 6 hours, 24 hours, and two weeks post supplementation intake. The primary outcome was safety using Common Terminology Criteria for Adverse Events (CTCAE v.4.03). Mass spectroscopy measured the bioavailability of the active parent compounds in blood. Lastly, we used 16s V1-2/3-4 RNA sequencing to measure the effects on the human gut microbiome. The results indicate that lipid-enhanced ursolic acid and curcumin are safe and well-tolerated. However, renal function was identified as a laboratory value that should be monitored with future studies evaluating this combination. Curcumin improved the bioavailability of ursolic acid when given in combination. The presence of ursolic acid did not appear to alter blood levels of curcumin or its metabolites. Thus, a potential mechanism for synergistic effects of the combination may involve increased bioavailability of ursolic acid. The combination also altered the microbiome favoring the production of the B vitamin biotin, a cofactor in immune regulation and a feature associated with lower prostate cancer risk. In conclusion, a combination of ursolic acid and curcumin is safe and should be evaluated in Phase II clinical trials for possible treatment of prostate cancer.


LCSH Subject Headings