Regenthal Ralf, Voskanian Margarita, Baumann Frank, Teichert Jens, Brätter Christian, Aigner Achim, Abraham Getu
Rudolf-Boehm-Institute of Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Leipzig, Germany,
Department of Pharmaceutical Development, Formula GmbH, Pharmaceutical and Chemical Development Company, Berlin, Germany.
Drug Des Devel Ther. 2018 Nov 1;12:3653-3664. doi: 10.2147/DDDT.S170764. eCollection 2018.
Anastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions.
Anastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography- mass spectrometry method using fragment ion detection was developed and validated.
After efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration-time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h.
These results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects.
阿那曲唑是一种成熟的活性药物成分（API），用于治疗绝经后女性的激素敏感性乳腺癌（BC）。然而，使用唯一可用的口服制剂进行治疗时，常常会出现浓度依赖性的严重副作用，如潮热、疲劳、肌肉和关节疼痛、恶心、腹泻、头痛等。相比之下，用于局部应用阿那曲唑的缓释系统应能将这些严重的药物不良反应降至最低。
开发了含阿那曲唑的贴剂透皮给药系统（TDDS），该系统具有高效载药能力，可避免药物的不均匀性或结晶，具备所需的控释动力学、储存稳定性、易于操作、机械稳定性以及对皮肤足够的粘性。在Franz扩散池中研究了阿那曲唑在体外的持续释放曲线。在体内，对最终的阿那曲唑透皮系统在比格犬中进行了连续的药物血浆动力学测试。为进行药物分析，开发并验证了一种使用碎片离子检测的特定的经过验证的液相色谱 - 质谱方法。
在高效载药后，TDDS在48小时内实现了65%的线性持续药物释放。体内数据显示阿那曲唑的血浆浓度 - 时间过程良好，避免了口服给药后出现的与副作用相关的峰值浓度，但在长达72小时内与治疗性血浆水平相匹配。
这些结果为确立阿那曲唑的透皮应用提供了依据，其具有改善的药代动力学和药物安全性，作为一种新的治疗方法和有前景的选择，可通过减轻不必要副作用的高负担来治疗人类乳腺癌。
