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

Wen, N (Wen, Na)^{[ 1,2,3,4 ]} ; Dong, YS (Dong, Yansheng)^[ 1 ] ; Song, R (Song, Rui)^[ 1 ] ; Zhang, WP (Zhang, Wenpeng)^[ 1 ] ; Sun, C (Sun, Chao)^[ 1 ] ; Zhuang, XM(Zhuang, Xiaomei)^[ 1 ] ; Guan, Y (Guan, Ying)^[ 2,3,4 ] ; Meng, QB (Meng, Qingbin)^[ 1 ] ; Zhang, YJ (Zhang, Yongjun)^[ 2,3,4 ]

BIOMACROMOLECULES, 2018, 19(6): 1918-1925 特刊: SI

DOI: 10.1021/acs.biomac.7b01648

 WOS:000435226200014

Abstract

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.

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