Kulkarni Radha, Fanse Suraj, Lalla Rajesh V, Morales Daniella, Burgess Diane J
University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA.
University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA.
Int J Pharm. 2025 Aug 20;681:125834. doi: 10.1016/j.ijpharm.2025.125834. Epub 2025 Jun 9.
Thermosensitive mucoadhesive in situ forming gels are sprayable liquids at room temperature, that form hydrogels which can adhere to the mucosal tissue at body temperature. These versatile drug delivery systems can be effectively utilized as localized drug delivery vehicles in the oral cavity. However, conventional methods to assess these products often overlook the influence of physiological factors (such as the presence of saliva and gravitational effects), all of which can potentially result in misleading conclusions about formulation performance. The main objective of the present research is to evaluate the impact of physiological factors on key performance markers (such as gelation temperature, mucoadhesion, rheology, and drug release) of in situ forming oral gels comprising different mucoadhesive polymers. A comprehensive comparison was conducted between traditional evaluation methods and methods that incorporate physiological factors. The physiologically relevant methods demonstrated higher gelation temperatures and reduced mucoadhesion, highlighting the importance of physiological relevance in formulation screening. Small Angle X-ray Spectroscopy (SAXS) and rheological oscillatory temperature sweeps revealed the formation of a hexagonal liquid crystalline micellar arrangement at physiological temperature (35 °C), leading to a sustained in vitro drug release over 4-6 h. Moreover, drug release was shown to be significantly influenced by the presence of salivary amylase, the pH of the release medium, and the chemistry and solubility of the mucoadhesive polymers. Notably, formulations containing chitosan exhibited faster drug release rates at lower pH, attributed to the increased solubility of chitosan in acidic conditions. In contrast, formulation containing sodium alginate demonstrated slower release rates due to ionic crosslinking with components in the artificial saliva, which reduced polymer dissolution and drug diffusion. The current research emphasizes the importance of integrating physiological factors in early-stage formulation evaluation to enable accurate performance prediction, ensuring that suboptimal candidates are identified before advancing to clinical studies. The novel insights obtained can serve to guide formulation design and evaluation approaches for other oral mucoadhesive systems.
热敏性粘膜粘附原位凝胶在室温下为可喷雾液体，在体温下形成可粘附于粘膜组织的水凝胶。这些多功能药物递送系统可有效地用作口腔局部药物递送载体。然而，评估这些产品的传统方法往往忽视生理因素（如唾液的存在和重力作用）的影响，所有这些因素都可能导致关于制剂性能的误导性结论。本研究的主要目的是评估生理因素对包含不同粘膜粘附聚合物的原位形成口腔凝胶的关键性能指标（如凝胶化温度、粘膜粘附性、流变学和药物释放）的影响。对传统评估方法和纳入生理因素的方法进行了全面比较。与生理相关的方法显示出更高的凝胶化温度和降低的粘膜粘附性，突出了生理相关性在制剂筛选中的重要性。小角X射线光谱（SAXS）和流变振荡温度扫描显示在生理温度（35°C）下形成了六方液晶胶束排列，导致体外药物在4-6小时内持续释放。此外，药物释放显示受唾液淀粉酶的存在、释放介质的pH值以及粘膜粘附聚合物的化学性质和溶解性的显著影响。值得注意的是，含有壳聚糖的制剂在较低pH值下表现出更快的药物释放速率，这归因于壳聚糖在酸性条件下溶解度的增加。相反，含有海藻酸钠的制剂由于与人工唾液中的成分发生离子交联而显示出较慢的释放速率，这降低了聚合物的溶解和药物扩散。当前的研究强调在早期制剂评估中纳入生理因素以实现准确性能预测的重要性，确保在推进到临床研究之前识别出次优候选物。获得的新见解可用于指导其他口腔粘膜粘附系统的制剂设计和评估方法。
