Sweeney Gerard, Liu Dijia, Hatahet Taher, Jones David S, Li Shu, Andrews Gavin P
Pharmaceutical Engineering Group, School of Pharmacy, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
North Wales Medical School, Bangor University, Briganita Building, Sackville Road, Gwynedd, Bangor LL57 2DG, UK.
Pharmaceutics. 2025 Jul 24;17(8):955. doi: 10.3390/pharmaceutics17080955.
Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% / ethanol) to assess AIDD risk. MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5-1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% / ethanol, with only high concentrations (40% /) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine.
热熔挤出（HME）在制造缓释口服剂型方面已备受关注，但蜡基基质的应用及其对酒精诱导剂量倾泻（AIDD）的耐受性仍未得到充分研究。本研究旨在开发并表征蜡基缓释非洛地平制剂，特别关注辅料功能以及对AIDD的抗性。通过HME使用Syncrowax HGLC作为可热加工的蜡基质制备非洛地平缓释制剂。加入微晶纤维素（MCC）和一水乳糖作为功能性填充剂和加工助剂。系统评估了蜡含量和填充剂类型对机械性能、润湿性和药物释放行为的影响。在模拟同时摄入的条件下（4%、20%和40%乙醇）进行乙醇敏感性测试，以评估AIDD风险。含MCC的片剂在24小时内表现出优异的缓释特性，具有更好的润湿性和崩解性。相比之下，用一水乳糖配制的片剂在溶解过程中结构保持完整，过度限制了药物释放。通过制粒有效解决了这一限制，减小粒径显著提高了表面可及性，0.5 - 1毫米的颗粒实现了令人满意的释放曲线。乙醇敏感性测试揭示了两种填充剂系统之间的不同行为。出乎意料的是，含MCC的片剂在乙醇介质中药物释放受到抑制，这可能是由于乙醇对填充剂溶胀和崩解的抑制作用。相反，含一水乳糖的制剂在高达20%乙醇的情况下仍保持其释放性能，只有高浓度（40%）会损害基质药物保留功能并导致药物释放显著增加。本研究强调了辅料类型和组成比例在设计蜡基缓释制剂中的关键作用。它还通过体外评估有助于理解AIDD风险，并为非洛地平的坚固、抗酒精口服给药系统提供了合理的设计策略。
