bm7b01648_si_001.pdf (695.86 kB)
Zero-Order Release of Gossypol Improves Its Antifertility Effect and Reduces Its Side Effects Simultaneously
journal contribution
posted on 2018-01-20, 17:04 authored by Na Wen, Yansheng Dong, Rui Song, Wenpeng Zhang, Chao Sun, Xiaomei Zhuang, Ying Guan, Qingbin Meng, Yongjun ZhangGossypol
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 ∼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 its side effects. We envision the drug could be developed to
be an effective, safe, and reversible male contraceptive by zero-order
release.