健康成年志愿者中安慰剂微丸制剂与吞咽凝胶联合给药的安全性和可接受性：迈向吞咽困难患者易吞咽替代方案的第一步

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中文摘要

吞咽口服固体剂型（OSDFs），如片剂和胶囊，对吞咽困难个体可能具有挑战性，常导致治疗依从性降低和未经许可的剂型改造。替代口服剂型仍然有限。多微粒微丸制剂可能因其相对较小的尺寸和球形度而改善吞咽可接受性，并提供治疗优势，包括高载药量、均匀的胃肠道分布、适合控释或矫味（若包衣）以及灵活给药。本研究在34名健康成人中评估了安慰剂微丸与吞咽凝胶联合给药的安全性和可接受性。评估了八种制剂，其微丸大小（500 µm vs 1000 µm）、微丸总质量（250 mg vs 750 mg）和吞咽凝胶类型（Gloup Zero vs Gloup Forte）各不相同。吞咽安全性作为主要终点，在软式内镜吞咽评估期间使用渗透-误吸量表（PAS）评估。次要结局包括研究者报告的可接受性（使用改良Yale咽部残留严重程度评定量表测量）和参与者报告的可接受性（使用八项视觉模拟量表）。基于研究者报告的评分：1）在健康成人中未观察到临床相关的 airway compromise，尽管发生了一例PAS 3事件；2）较小的微丸尺寸与健康成人中较高的咽部残留评分相关。吞咽和冲洗后残留减少；然而，对于较小微丸尺寸，并未始终实现完全清除。参与者报告较小微丸质量时吞咽性改善，尽管较小微丸尺寸时残留仍然较高。虽然当前研究结果证明了在健康成人中的安全性和可接受性，但仍需要在吞咽困难患者中开展专门的临床研究，以确认多微粒微丸制剂与通用吞咽凝胶联合给药用于药物递送的适用性。

英文摘要

Swallowing oral solid dosage forms (OSDFs), such as tablets and capsules, can be challenging for individuals with dysphagia, often leading to reduced therapy adherence and unauthorized dosage form modification. Alternative oral dosage forms remain limited. Multiparticulate pellet formulations may improve swallowing acceptability due to their relatively small size and sphericity as well as offer therapeutic advantages including high drug loading, uniform gastrointestinal distribution, suitability for controlled release or taste masking if coated, and flexible dosing. This study evaluated the safety and acceptability of placebo pellets administered with swallowing gels in 34 healthy adults. Eight formulations were evaluated, varying in pellet size (500 µm versus 1000 µm), total pellet mass (250 mg versus 750 mg), and type of swallowing gel (Gloup Zero versus Gloup Forte). Swallowing safety was assessed as the primary endpoint using the Penetration Aspiration Scale (PAS) during Flexible Endoscopic Evaluation of Swallowing. Secondary outcomes included investigator-reported acceptability, measured using a modified Yale Pharyngeal Residue Severity Rating Scale, and participant-reported acceptability using an eight-item Visual Analogue Scale. Based on the investigator-reported scores 1) no clinically relevant airway compromise was observed in healthy adults, although one PAS 3 event occurred and 2) smaller pellet size was associated with higher pharyngeal residue scores in healthy adults. Residue was reduced after swallowing and rinsing; however, complete clearance was not consistently achieved for smaller pellet sizes. Participants reported improved swallowability with smaller pellet masses, although residue remained higher with smaller pellet sizes. While the present findings demonstrate safety and acceptability in healthy adults, dedicated clinical studies in patients with dysphagia are required to confirm the applicability of multiparticulate pellet formulations co-administered with a generically applicable swallowing gel for drug delivery.