State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing , 100850 , China.
State Key Laboratory of Medicinal Chemical Biology and Key Laboratory of Functional Polymer Materials, Institute of Polymer Chemistry, College of Chemistry , Nankai University and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) , Tianjin 300071 , China.
Biomacromolecules. 2018 Jun 11;19(6):1918-1925. doi: 10.1021/acs.biomac.7b01648. Epub 2018 Jan 22.
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 ∼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.
棉酚作为一种有前景的男性避孕药，但最终由于两个副作用而失败：低钾血症和避孕效果的不可逆性。在这里，我们证明持续的零级释放可以解决这些问题。从棉酚/PEG 层层膜中棉酚的体外释放遵循完美的零级动力学。体内实验表明，对于 30 层膜，该膜可以将雄性 SD 大鼠的血浆药物浓度在约 20 天内保持恒定。血浆药物浓度比口服给药时的峰值血浆药物浓度低 2 个数量级，每日剂量比常用的避孕口服剂量低 50 多倍。然而，仍然观察到显著的抗生育作用。此外，未观察到低钾血症，并且在恢复期后抗生育作用可以逆转。结果表明，零级释放可以显著提高棉酚的理想抗生育效果，同时显著降低其副作用。我们设想通过零级释放可以将该药物开发为一种有效、安全和可逆的男性避孕药。
