用于乳腺癌预防的稳定化Z-endoxifen局部外用制剂的开发

Purpose: The primary objective of this work was to develop a pharmaceutically stable, transdermal delivery strategy for Z-endoxifen, the highly potent and bioactive metabolite of tamoxifen. Methods: Four distinct topical formulation types were prepared. Each formulation type was evaluated with a control and four different antioxidants, allowing for the assessment of both water-soluble and lipid-soluble antioxidant effects across various bases. Each prepared formulation was stored at both refrigerated conditions and ambient temperature for a period of up to 6 months. Formulations were evaluated for visual appearance and isomeric purity over time. Isomeric purity was determined by high-performance liquid chromatography. Results: Our study identified specific antioxidant combinations that mitigated Z-endoxifen isomerization. Combined with reduced temperature storage, these strategies led to the successful development of a stable topical formulation of Z-endoxifen. Conclusion: Instability challenges of Z-endoxifen in a topical formulation were overcome by adding specific antioxidants into varied formulation bases and controlling storage temperature. This advancement enables the development of a more potent and potentially safer localized breast cancer prevention therapy by delivering the highly bioactive Z-isomer and minimizing systemic exposure. Future work will involve in vivo pharmacokinetic/pharmacodynamic studies to confirm localized breast tissue delivery and minimal systemic absorption, paving the way for advanced clinical trials aimed at providing an improved preventative treatment for women at high risk for breast cancer.