D'Hondt Matthias, Verbeke Frederick, Wuytens Pieter, Skirtach Andre, De Spiegeleer Bart, Wynendaele Evelien
Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Department of Molecular Biotechnology, Centre for Nano-Biophotonics, Ghent University, Ghent, Belgium.
Protein Pept Lett. 2019;26(9):691-701. doi: 10.2174/0929866526666190619113724.
Both biodegradable and non-biodegradable peptide-loaded implants are already developed for the long-term treatment of patients, thereby reducing the frequency of drug administration. To further improve peptide formulation, extending the scope of implant-based drug delivery systems towards other polymers and processing techniques is highly interesting.
In this study, as a proof-of-principle, the feasibility of hot-melt processing of a peptide active pharmaceutical ingredient was assessed by developing a non-biodegradable poly(ethylenevinyl acetate) (33% VA) implant loaded with 20% (w/w) buserelin acetate.
Cross-sectional implant characterization was performed by Raman microscopy. The stability of buserelin acetate in the polymeric matrix was evaluated for 3 months under ICH stability conditions and the quantity as well as the degradation products analyzed using LC-UV methods. An in vitro dissolution study was performed as well and buserelin acetate and its degradants analyzed using the same chromatographic methods.
No significant quantities of buserelin acetate-related degradation products were formed during the hot-melt preparation as well as during the stability study. Together with the consistent buserelin acetate assay values over time, chemical peptide stability was thus demonstrated. The in vitro buserelin acetate release from the implant was found to be diffusion-controlled after an initial burst release, with stable release profiles in the stability study, demonstrating the functional stability of the peptide implant.
These results indicate the feasibility of preparing non-biodegradable peptide-loaded implants using the hot-melt production method and may act as a proof of principle concept for further innovation in peptide medicinal formulations.
可生物降解和不可生物降解的载肽植入物均已开发用于患者的长期治疗，从而减少给药频率。为了进一步改进肽制剂，将基于植入物的药物递送系统的范围扩展到其他聚合物和加工技术非常有意义。
在本研究中，作为原理验证，通过开发一种载有20%（w/w）醋酸布舍瑞林的不可生物降解聚（乙烯-醋酸乙烯酯）（33%VA）植入物，评估了肽活性药物成分热熔加工的可行性。
通过拉曼显微镜对植入物进行横截面表征。在ICH稳定性条件下，对醋酸布舍瑞林在聚合物基质中的稳定性进行了3个月的评估，并使用LC-UV方法分析了其含量和降解产物。还进行了体外溶出研究，并使用相同的色谱方法分析了醋酸布舍瑞林及其降解产物。
在热熔制备过程以及稳定性研究过程中，均未形成大量与醋酸布舍瑞林相关的降解产物。随着时间推移，醋酸布舍瑞林的测定值保持一致，从而证明了肽的化学稳定性。发现植入物中醋酸布舍瑞林的体外释放最初有一个突释，之后为扩散控制，在稳定性研究中释放曲线稳定，证明了肽植入物的功能稳定性。
这些结果表明了使用热熔生产方法制备不可生物降解载肽植入物的可行性，并可为肽药物制剂的进一步创新提供原理概念证明。
