Kapourani Afroditi, Proaki Lemonia-Eleni, Anagnostaki Maria-Emmanouela, Gkougkourelas Ioannis, Barmpalexis Panagiotis
Laboratory of Pharmaceutical Technology, Division of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece.
Laboratory of Pharmaceutical Technology, Division of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece; Natural Products Research Centre of Excellence-AUTH (NatPro-AUTH), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Thessaloniki 57001, Greece.
J Pharm Sci. 2025 Sep 19;114(11):104000. doi: 10.1016/j.xphs.2025.104000.
This study aims to elucidate the role of amphiphilic polymer combinations in the formation and performance of ternary amorphous solid dispersions (ASDs) of griseofulvin (GRF), a poorly water-soluble BCS Class II drug with high recrystallization tendency. Although ASDs are widely used to enhance solubility and oral bioavailability, achieving long-term physical stability and sustained supersaturation (especially at high drug loadings) remains a major formulation challenge. In this context, we systematically investigated the synergistic potential of combining amphiphilic polymers with differing hydrophilicity, namely hydroxypropyl cellulose/SL (HPC/SL), Soluplus® (SOL), copovidone (PVPVA), and hypromellose acetate succinate (HPMCAS), to form stable and effective binary and ternary GRF ASDs. The study employed a comprehensive experimental design, including thermal and solid-state characterization (TGA, DSC, pXRD, PLM), miscibility screening, molecular interaction analyses at the solid (via ATR-FTIR) and the solution (via ¹H-NMR) state. Dissolution studies were also conducted under non-sink conditions to evaluate supersaturation behavior and precipitation inhibition. Results revealed that ternary ASDs, particularly the HPMCAS-HPC/SL system, provided superior stabilization of amorphous GRF at both low (30% w/w) and high (50% w/w) drug loadings. Solid- and solution- state spectroscopic data confirmed the presence of strong and specific intermolecular interactions only in this ternary system, correlating with enhanced physical stability and prolonged supersaturation. Solution-state dynamics using T relaxation time measurements indicated restricted molecular mobility, supporting the hypothesis of cooperative polymer-drug interactions. Overall, this work advances the understanding of how amphiphilic polymer combinations influence the physical and biopharmaceutical performance of ternary GRF ASDs. The findings provide a rational framework for designing synergistic polymer matrices that enable high drug loading while ensuring stability and dissolution enhancement, critical factors for next-generation oral dosage forms of challenging active pharmaceutical ingredients (APIs) like GRF.
本研究旨在阐明两亲性聚合物组合在灰黄霉素（GRF）三元无定形固体分散体（ASD）形成及性能方面的作用，GRF是一种水溶性差的BCS II类药物，具有较高的重结晶倾向。尽管ASD被广泛用于提高溶解度和口服生物利用度，但实现长期物理稳定性和持续过饱和（尤其是在高载药量时）仍然是一个主要的制剂挑战。在此背景下，我们系统地研究了将具有不同亲水性的两亲性聚合物（即羟丙基纤维素/SL（HPC/SL）、尤特奇®（SOL）、共聚维酮（PVPVA）和醋酸羟丙甲纤维素琥珀酸酯（HPMCAS））组合形成稳定且有效的二元和三元GRF ASD的协同潜力。该研究采用了全面的实验设计，包括热分析和固态表征（热重分析（TGA）、差示扫描量热法（DSC）、粉末X射线衍射（pXRD）、偏光显微镜（PLM））、混溶性筛选、在固体状态（通过衰减全反射傅里叶变换红外光谱（ATR-FTIR））和溶液状态（通过氢核磁共振（¹H-NMR））下的分子相互作用分析。还在非漏槽条件下进行了溶出度研究，以评估过饱和行为和沉淀抑制。结果表明，三元ASD，特别是HPMCAS-HPC/SL体系，在低载药量（30% w/w）和高载药量（50% w/w）时均能提供对无定形GRF的卓越稳定性。固态和溶液状态的光谱数据证实仅在该三元体系中存在强烈且特定的分子间相互作用，这与增强的物理稳定性和延长的过饱和相关。使用T弛豫时间测量的溶液状态动力学表明分子迁移受限，支持了聚合物 - 药物协同相互作用的假设。总体而言，这项工作推进了对两亲性聚合物组合如何影响三元GRF ASD的物理和生物药剂学性能的理解。这些发现为设计协同聚合物基质提供了一个合理的框架，该基质能够实现高载药量，同时确保稳定性和溶出度提高，这是像GRF这样具有挑战性的活性药物成分（API）下一代口服剂型的关键因素。
