Prasher Alka, Shrivastava Roopali, Dahl Denali, Sharma-Huynh Preetika, Maturavongsadit Panita, Pridgen Tiffany, Schorzman Allison, Zamboni William, Ban Jisun, Blikslager Anthony, Dellon Evan S, Benhabbour Soumya Rahima
Department of Biomedical Engineering, UNC Chapel Hill & North Carolina State University, Chapel Hill, NC 27599-3290, USA.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA.
Polymers (Basel). 2021 Feb 13;13(4):557. doi: 10.3390/polym13040557.
Eosinophilic esophagitis (EoE) is a chronic atopic disease that has become increasingly prevalent over the past 20 years. A first-line pharmacologic option is topical/swallowed corticosteroids, but these are adapted from asthma preparations such as fluticasone from an inhaler and yield suboptimal response rates. There are no FDA-approved medications for the treatment of EoE, and esophageal-specific drug formulations are lacking. We report the development of two novel esophageal-specific drug delivery platforms. The first is a fluticasone-eluting string that could be swallowed similar to the string test "entero-test" and used for overnight treatment, allowing for a rapid release along the entire length of esophagus. In vitro drug release studies showed a target release of 1 mg/day of fluticasone. In vivo pharmacokinetic studies were carried out after deploying the string in a porcine model, and our results showed a high local level of fluticasone in esophageal tissue persisting over 1 and 3 days, and a minimal systemic absorption in plasma. The second device is a fluticasone-eluting 3D printed ring for local and sustained release of fluticasone in the esophagus. We designed and fabricated biocompatible fluticasone-loaded rings using a top-down, Digital Light Processing (DLP) Gizmo 3D printer. We explored various strategies of drug loading into 3D printed rings, involving incorporation of drug during the print process (pre-loading) or after printing (post-loading). In vitro drug release studies of fluticasone-loaded rings (pre and post-loaded) showed that fluticasone elutes at a constant rate over a period of one month. Ex vivo pharmacokinetic studies in the porcine model also showed high tissue levels of fluticasone and both rings and strings were successfully deployed into the porcine esophagus in vivo. Given these preliminary proof-of-concept data, these devices now merit study in animal models of disease and ultimately subsequent translation to testing in humans.
嗜酸性食管炎（EoE）是一种慢性特应性疾病，在过去20年中日益普遍。一线药物选择是局部/吞咽皮质类固醇，但这些药物是从哮喘制剂改编而来，如吸入器中的氟替卡松，其有效率欠佳。目前尚无美国食品药品监督管理局（FDA）批准的用于治疗EoE的药物，且缺乏食管特异性药物制剂。我们报告了两种新型食管特异性药物递送平台的研发情况。第一种是氟替卡松洗脱绳，其吞咽方式类似于“肠内试验”的绳试验，可用于夜间治疗，能沿食管全长实现快速释放。体外药物释放研究显示氟替卡松的目标释放量为每日1毫克。在猪模型中部署该绳后进行了体内药代动力学研究，结果显示食管组织中氟替卡松的局部水平较高，在1天和3天后仍持续存在，且血浆中的全身吸收极少。第二种装置是用于在食管中局部和持续释放氟替卡松的3D打印氟替卡松洗脱环。我们使用自上而下的数字光处理（DLP）Gizmo 3D打印机设计并制造了生物相容性的载氟替卡松环。我们探索了将药物加载到3D打印环中的各种策略，包括在打印过程中（预加载）或打印后（后加载）加入药物。载氟替卡松环（预加载和后加载）的体外药物释放研究表明，氟替卡松在一个月的时间内以恒定速率洗脱。在猪模型中的体外药代动力学研究也显示氟替卡松在组织中的水平较高，并且环和绳均已成功在猪食管中进行了体内部署。鉴于这些初步的概念验证数据，这些装置现在值得在疾病动物模型中进行研究，并最终进行后续的人体试验转化。
