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Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-23 , DOI: 10.1021/acs.molpharmaceut.9b00996 Marta F Simões 1, 2 , Alexandra Pereira 1 , Sara Cardoso 1 , Stephanie Cadonau 3 , Karl Werner 3 , Rui M A Pinto 1 , Sérgio Simões 1, 2
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-23 , DOI: 10.1021/acs.molpharmaceut.9b00996 Marta F Simões 1, 2 , Alexandra Pereira 1 , Sara Cardoso 1 , Stephanie Cadonau 3 , Karl Werner 3 , Rui M A Pinto 1 , Sérgio Simões 1, 2
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The aim of this study was to develop a fast, effective, and material sparing screening method to design amorphous solid dispersions (ASDs) of etravirine to drive more effectively the development process, leading to improved bioavailability (BA) and stability. A systematic step-by-step approach was followed by combining theoretical calculations with high-throughput screening (HTS) and software-assisted multivariate statistical analysis. The thermodynamic miscibility and interaction of the drug in several polymers were predicted using Hansen solubility parameters (δ). The selected polymers were evaluated by HTS, using solvent evaporation. Binary compositions were evaluated by their solubilization capacity and physical stability over 2 months. JMP 14.0 was used for multivariate statistical analysis using principal components analysis. Extrusion was performed in Thermo Scientific HAAKE MiniLab II, and extrudates were characterized by assay, related substances, dissolution, and physical state (polarized light microscopy (PLM), Raman spectroscopy, and X-ray powder diffraction (XRPD)). A short stability study was performed where milled extrudates were exposed to 25 °C/60%RH and 40 °C/75%RH for 3 months. Through thermodynamic predictions, five main polymers were selected. The HTS enabled the evaluation of 42 formulations for solubilization capacity and physical stability. The three most promising compositions were selected for hot-melt extrusion (HME) tests. In general, a good correlation was found among the results of theoretical predictions, HTS, and HME. Poly(vinylpyrrolidone) (PVP)-based formulations were shown to be easily extrudable, with low degradation and complete amorphicity, whereas in Soluplus, the drug was not miscible, leading to a high crystalline content. The drug release rate was improved more than two times with PVP, and the manufactured ASD was demonstrated to be stable physically and chemically. A fast and effective screening technique to develop stable ASDs for a poorly soluble drug was successfully developed as applied to etravirine. The given method is easy to use, requires a low amount of drug, and is fairly accurate in predicting the amorphization of the drug when formulated. The success of HME formulation development of etravirine was undoubtedly enhanced with this high-throughput tool, which led to the identification of extrudates with improved biopharmaceutical properties. The structural characterization performed by PLM, XRPD, and Raman spectroscopy demonstrated that the HME prototype was essentially amorphous. The unexpected stability at 40 °C/75%RH was correlated with the presence of molecular interaction characterized by Raman spectroscopy.
中文翻译：
通过热熔挤出系统筛选和开发伊曲霉素无定形固体分散体的五阶段方法。
这项研究的目的是开发一种快速，有效且节省材料的筛选方法，以设计依他韦林的无定形固体分散体（ASD），以更有效地驱动开发过程，从而改善生物利用度（BA）和稳定性。遵循系统的逐步方法，将理论计算与高通量筛选（HTS）和软件辅助的多元统计分析相结合。使用Hansen溶解度参数（δ）可以预测药物在几种聚合物中的热力学混溶性和相互作用。使用溶剂蒸发，通过HTS评估所选的聚合物。通过其在两个月内的增溶能力和物理稳定性来评估二元组合物。JMP 14.0用于使用主成分分析的多元统计分析。在Thermo Scientific HAAKE MiniLab II中进行挤出，并通过测定，相关物质，溶解度和物理状态（偏振光显微镜（PLM），拉曼光谱和X射线粉末衍射（XRPD））对挤出物进行表征。进行了短暂的稳定性研究，其中将研磨的挤出物暴露于25°C / 60％RH和40°C / 75％RH的条件下3个月。通过热力学预测，选择了五种主要聚合物。HTS能够评估42种配方的增溶能力和物理稳定性。选择了三种最有希望的成分进行热熔挤出（HME）测试。通常，在理论预测，HTS和HME的结果之间发现良好的相关性。基于聚乙烯吡咯烷酮（PVP）的配方显示出易于挤出的特性，具有低降解和完全无定形性，而在Soluplus中，该药物不可混溶，导致高结晶含量。PVP使药物释放速率提高了两倍以上，并且所制造的ASD被证明在物理和化学上是稳定的。成功开发了一种快速有效的筛选技术，以开发用于难溶性药物的稳定ASD，并将其应用于Etravirine。给定的方法易于使用，需要的药物量少，并且在配制时预测药物的无定形性是相当准确的。毫无疑问，这种高通量工具提高了依维韦林HME制剂开发的成功，从而鉴定出具有改善的生物制药特性的挤出物。由PLM，XRPD，拉曼光谱表明，HME原型基本上是无定形的。在40°C / 75％RH下的出乎意料的稳定性与通过拉曼光谱表征的分子相互作用的存在相关。
更新日期：2020-01-24
中文翻译：
通过热熔挤出系统筛选和开发伊曲霉素无定形固体分散体的五阶段方法。
这项研究的目的是开发一种快速，有效且节省材料的筛选方法，以设计依他韦林的无定形固体分散体（ASD），以更有效地驱动开发过程，从而改善生物利用度（BA）和稳定性。遵循系统的逐步方法，将理论计算与高通量筛选（HTS）和软件辅助的多元统计分析相结合。使用Hansen溶解度参数（δ）可以预测药物在几种聚合物中的热力学混溶性和相互作用。使用溶剂蒸发，通过HTS评估所选的聚合物。通过其在两个月内的增溶能力和物理稳定性来评估二元组合物。JMP 14.0用于使用主成分分析的多元统计分析。在Thermo Scientific HAAKE MiniLab II中进行挤出，并通过测定，相关物质，溶解度和物理状态（偏振光显微镜（PLM），拉曼光谱和X射线粉末衍射（XRPD））对挤出物进行表征。进行了短暂的稳定性研究，其中将研磨的挤出物暴露于25°C / 60％RH和40°C / 75％RH的条件下3个月。通过热力学预测，选择了五种主要聚合物。HTS能够评估42种配方的增溶能力和物理稳定性。选择了三种最有希望的成分进行热熔挤出（HME）测试。通常，在理论预测，HTS和HME的结果之间发现良好的相关性。基于聚乙烯吡咯烷酮（PVP）的配方显示出易于挤出的特性，具有低降解和完全无定形性，而在Soluplus中，该药物不可混溶，导致高结晶含量。PVP使药物释放速率提高了两倍以上，并且所制造的ASD被证明在物理和化学上是稳定的。成功开发了一种快速有效的筛选技术，以开发用于难溶性药物的稳定ASD，并将其应用于Etravirine。给定的方法易于使用，需要的药物量少，并且在配制时预测药物的无定形性是相当准确的。毫无疑问，这种高通量工具提高了依维韦林HME制剂开发的成功，从而鉴定出具有改善的生物制药特性的挤出物。由PLM，XRPD，拉曼光谱表明，HME原型基本上是无定形的。在40°C / 75％RH下的出乎意料的稳定性与通过拉曼光谱表征的分子相互作用的存在相关。
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