无定形固体分散体的溶出机制：载药量和分子相互作用的作用,Molecular Pharmaceutics

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无定形固体分散体的溶出机制：载药量和分子相互作用的作用
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2022-12-22 , DOI: 10.1021/acs.molpharmaceut.2c00892
Alexandru Deac ₁ , Qingqing Qi ₁ , Anura S Indulkar ₂ , Hitesh S Purohit ₂ , Yi Gao ₂ , Geoff G Z Zhang ₂ , Lynne S Taylor ₁

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高载药量无定形固体分散体 (ASD) 一直是配制部分挑战，因为药物释放在高载药量下受到抑制。抑制释放前的最大载药量被称为一致性极限 (LoC)，并且已针对基于共聚维酮 (PVPVA) 的 ASD 进行了最广泛的研究。该术语来源于以下观察结果：低于 LoC，聚合物控制动力学，药物和聚合物一致释放，而高于 LoC，释放速率不同并受到损害。最近的研究表明 LoC 值与药物-聚合物相互作用强度之间存在相关性，其中对于具有更强相互作用的系统观察到较低的 LoC。本研究的目的是调查药物-PVPVA 相互作用强度与 LoC 之间的因果关系。四种与 PVPVA 具有不同相互作用能力的化学类似物被用作模型药物。使用溶液核磁共振波谱和传统分离技术研究了聚合物在稀水相和含药不溶性纳米颗粒之间的分布，以了解稀环境中系统的热力学。对悬浮在水溶液中的 ASD 颗粒进出的聚合物扩散进行监测，以了解 LoC 以上的药物载量，以研究聚合物释放的热力学驱动力。使用傅立叶变换红外光谱研究了暴露于缓冲液之前和之后 ASD 压块的表面组成，以捕获释放的潜在动力学障碍。结果发现，载药量高于 LoC 的 ASD 压片在表面形成不溶性屏障，与水相处于假平衡状态，并阻止药物和聚合物在溶解过程中进一步释放。不溶性屏障含有大量用于强相互作用药物-聚合物系统的聚合物。相比之下，弱相互作用系统的数量可以忽略不计。这一观察结果解释了强相互作用系统在较低载药量下形成不溶性屏障的能力。该研究强调了热力学和动力学因素对 ASD 溶出行为的重要性，并为最大化 ASD 中的载药量提供了一个潜在框架。

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Dissolution Mechanisms of Amorphous Solid Dispersions: Role of Drug Load and Molecular Interactions

High drug load amorphous solid dispersions (ASDs) have been a challenge to formulate partially because drug release is inhibited at high drug loads. The maximum drug load prior to inhibition of release has been termed the limit of congruency (LoC) and has been most widely studied for copovidone (PVPVA)-based ASDs. The terminology was derived from the observation that below LoC, the polymer controlled the kinetics and the drug and the polymer released congruently, while above LoC, the release rates diverged and were impaired. Recent studies show a correlation between the LoC value and drug–polymer interaction strength, where a lower LoC was observed for systems with stronger interactions. The aim of this study was to investigate the causality between drug–PVPVA interaction strength and LoC. Four chemical analogues with diverse abilities to interact with PVPVA were used as model drugs. The distribution of the polymer between the dilute aqueous phase and the insoluble nanoparticles containing drug was studied with solution nuclear magnetic resonance spectroscopy and traditional separation techniques to understand the thermodynamics of the systems in a dilute environment. Polymer diffusion to and from ASD particles suspended in aqueous solution was monitored for drug loads above the LoC to investigate the thermodynamic driving force for polymer release. The surface composition of ASD compacts before and after exposure to buffer was studied with Fourier transform infrared spectroscopy to capture potential kinetic barriers to release. It was found that ASD compacts with drug loads above the LoC formed an insoluble barrier on the surface that was in pseudo-equilibrium with the aqueous phase and prevented further release of drugs and polymers during dissolution. The insoluble barrier contained a substantial amount of the polymer for the strongly interacting drug–polymer systems. In contrast, a negligible amount was found for the weakly interacting systems. This observation provides an explanation for the ability of strongly interacting systems to form an insoluble barrier at lower drug loads. The study highlights the importance of thermodynamic and kinetic factors on the dissolution behavior of ASDs and provides a potential framework for maximizing the drug load in ASDs.

更新日期：2022-12-22

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