(T1130-01-04) Expandable Single-Component Gastroretention Devices: Shape Optimization and Proof of Concept for Extended Gastric Residency and Drug Release In Vivo

Purpose: Gastroretentive drug administration strategies prolong the release of an orally dosed active pharmaceutical ingredient (API) within the stomach, leading to greater patient convenience and compliance through the reduced need for redosing. Our group has developed an expandable gastroretentive platform based on the flexible, biocompatible, and biodegradable polymer, Hydralese^TM (poly(glycerol sebacate) urethane; PGSU). Even at high levels of API encapsulation (API content up to 60% of overall device mass), Hydralese (PGSU)-based constructs are highly elastic – they can fold up to fit inside oral delivery capsules and spring back to their expanded form upon reaching the stomach. Once expanded, the device remains in the stomach and releases the API payload until eventual degradation and loss of mechanical integrity leads to device elimination. In this study, our three main aims were (1) to demonstrate that a single-component Hydralese (PGSU)-based device can remain in the stomach for as long as one month, (2) to quantify the release kinetics of a model API-loaded gastroretentive device in vivo, and (3) to optimize device shape for effective long-term residency in the stomach.

Methods: Hydralese (PGSU) is synthesized from Regenerez^TM (PGS) using hexamethylene diisocyanate as a crosslinking agent. Use of a tin catalyst enables rapid curing under ambient conditions. Various API-loaded device geometries were produced by reaction injection molding, including a 35 mm diameter ring used for in vivo studies. A domestic swine porcine model was used to confirm that Hydralese (PGSU)-based constructs without API payloads can survive in the stomach environment for one month without causing harm to the host animal. BaSO₄ (5% w/w) was included in these devices to impart radiopacity, allowing visualization of the devices in the porcine gastrointestinal (GI) tract by radiography. A beagle dog canine model was used to measure the in vivo release profile of the model drug dexamethasone from API-loaded Hydralese (PGSU) constructs. High-pressure liquid chromatography (HPLC) was used to quantify the level of dexamethasone in canine plasma as well as the total dexamethasone released from explanted rings at various time points. A concurrent in vitro release profile was obtained using the UPS dissolution Apparatus II. Finally, optimal device shapes were investigated by finite element analysis (FEA) to maximize payload size and improve device mechanical performance in terms of packing the construct into oral delivery capsules and resisting the expulsive forces of the stomach.

Results: In a porcine model, two out of the three Hydralese (PGSU) rings with BaSO₄ (5% w/w) and without API remained in the stomach until the study ended at Day 28. One ring passed early and was eliminated intact at Day 19. Gross pathology and animal behavior surveillance revealed no major findings related to safety and tolerability of the rings. In the canine model, dexamethasone-loaded Hydralese (PGSU) rings were retained in the dog GI tract between six and 24 days. Bioanalysis of blood draws demonstrated sustained dexamethasone levels in the dog plasma, with rapid drug clearance following device elimination. Extraction of remaining dexamethasone from the eliminated constructs revealed similar release profiles in vivo to the in vitro release collected in the Apparatus II. In silico FEA modeling revealed that shape plays an important role in the Hydralese (PGSU) device’s capacity to fold up and spring open as well as its resistance to being pushed through the pyloric sphincter prematurely. Geometric features were optimized to reduce regions of high-stress concentration and high-strain deformation when folded. They were also optimized to improve overall resistance to compression and early passage.

Conclusion: Hydralese (PGSU)-based gastroretentive devices have demonstrated the potential to be administered in domestic swine and canine models. The single-component constructs remained within the stomach up to one month without health or safety concerns. Devices containing an API payload sustained drug delivery for the duration of their residency in the GI tract, with rapid API clearance following elimination. Based on these exciting findings and FEA modeling, gastroretentive device shapes can be developed with optimized performance for future drug delivery applications.

Figure 1. Schematic of unfolding expandable gastroretentive device.



Figure 2. Comparison of dexamethasone release from Hydralese (PGSU) devices in vitro and in vivo.



Figure 3. FEA model showing stress concentrations at different locations in a folded ring packed into a 000 oral delivery capsule, as was administered in the swine and canine models.