Zero-Order Release of Gossypol Improves Its Antifertility Effect and Reduces Its Side Effects Simultaneously

摘要

Gossypol was considered a promising male contraceptive but finally failed due to two side effects: hypokalemia and the irreversibility of its contraceptive effect. Here we demonstrate that sustained zero-order release could be a solution for these problems. The in vitro release of gossypol from gossypol/PEG layer-by-layer films follows a perfect zero-order kinetics. In vivo tests indicate that the films can maintain the plasma drug concentration constant in male SD rats for similar to 20 days for a 30-bilayer film. The plasma drug concentration is 2 orders of magnitude lower than the peak plasma drug concentration when administered orally and the daily dose is 50-fold lower than the commonly used contraceptive oral dose. However, significant antifertility effects were still observed. Furthermore, hypokalemia was not observed, and the antifertility effects can be reversed after a recovery period. The results suggest that zero-order release can significantly improve the desired antifertility effect of gossypol and, meanwhile, significantly reduce developed to be an effective, safe, and reversible male contraceptive by zero-order its side effects. We envision the drug could be release.