Steroid Eluting Esophageal-Targeted Drug Delivery Devices for Treatment of Eosinophilic Esophagitis.

Alka Prasher,Denali Dahl,Soumya Rahima Benhabbour,Panita Maturavongsadit,Allison Schorzman,William Zamboni,Jisun Ban,Evan S Dellon,Roopali Shrivastava,Tiffany Pridgen,Preetika Sharma-Huynh,Anthony Blikslager

doi:10.3390/polym13040557

Abstract

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.

Highlights

Eosinophilic esophagitis (EoE) is an emerging chronic allergic disease characterized by eosinophilic infiltration of the esophageal mucosa [1,2]
The slower release kinetics when hydroxyethyl methacrylate (HEMA) was included as a diluent in the resin was attributed to the presence of hydrogen bonding between the hydroxyl groups of HEMA and the carboxyl groups in FTS (Supplementary Figure S8)
Our results showed that addition of a hydrophilic diluent (HEMA) to hydrophobic resin formulation PCL700 -DMA lead to slower zero-order kinetics of FTS at 207 μg/day over 30 days compared to 282 μg/day obtained with FTS rings fabricated without HEMA (Figure 1)

Summary

Introduction

Eosinophilic esophagitis (EoE) is an emerging chronic allergic disease characterized by eosinophilic infiltration of the esophageal mucosa [1,2]. The European Medical Agency (EMA) has approved a dissolvable budesonide tablet (Jorveza) for both acute and a long-term treatment. While these treatment approaches can be effective [6,7,8], because the medication delivery does not target the esophagus, it leads to suboptimal outcomes and adherence [9]. Suggest that increased esophageal dwell time of pharmacologic agents is closely associated with subsequent treatment response [10]. To address these limitations, we aimed to produce strategies to more rationally provide drug exposure to the esophagus. We report the development of two esophageal-specific drug delivery platforms, a drug-eluting string and a 3D-printed ring for local rapid or sustained release of FTS in the esophagus

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