Track: Formulation and Delivery - Chemical - Drug Delivery - Extended Release (Non-implant)
Category: Late Breaking Poster Abstract
Ultra-long-acting Oral Drug Delivery Using a Single-component Hydralese™ (PGSU) Gastroretentive Device
Purpose: Our team has developed Hydralese™ (PGSU) (poly(glycerol sebacate) urethane), a biodegradable, biocompatible elastomer for long-acting drug delivery. We have previously shown that Hydralese (PGSU) can achieve steady release of active pharmaceutical ingredients (APIs) for multiple weeks and potentially more than one year based on polymer crosslinking density and degradation rate. Because Hydralese (PGSU) degrades via hydrolytic surface erosion, it maintains its mechanical form longer without losing mechanical integrity. Hydralese (PGSU) also maintains excellent flexibility, as well as controlled release, at up to 80% w/w drug loading. This elastic resilience, surface erosion degradation, and high API loading capacity, combined with steady release over long durations, make Hydralese (PGSU) an attractive option for ultra-long-acting oral delivery via gastroretentive device. The confluence of these properties allows the entire gastroretentive device to be composed of a single component of drug-loaded Hydralese (PGSU), whereas alternative designs pursued for gastric retention necessitate a multi-component device consisting of an elastomeric hub, biodegradable linkers, and stiff drug-loaded thermoplastic arms. Drug-loaded Hydralese (PGSU) devices can be cast or reaction injection molded into complex geometries as a single part, reducing time and cost compared to multi-part manufacturing methods. Molded Hydralese (PGSU) devices, such as rings, can be folded or twisted into gelatin capsules for oral intake yet spring back with full elastic recovery upon capsule disintegration. Because Hydralese (PGSU) degrades via surface erosion, the device maintains a large hydrodynamic radius as it degrades in the stomach, preventing it from prematurely passing through the pyloric sphincter. Hydralese (PGSU) also presents a safer and more comfortable option for gastroretentive drug delivery. Due to its flexibility throughout degradation and because it degrades via surface erosion into micro-scale fragments, risk of blockage, puncture, and irritation within the stomach and bowel significantly decreases. Even in highly acidic and basic gastrointestinal conditions, Hydralese (PGSU) sustains multi-month API delivery and surface erosion degradation behavior, fulfilling an unmet need for ultra-long-acting oral delivery. Methods: Poly(glycerol sebacate) (PGS) pre-polymer resin was crosslinked using polyol-isocyanate chemistry into poly(glycerol sebacate) urethane (PGSU). The PGS:isocyanate mass ratio was varied at either 3.5:1 or 2:1 to create Hydralese (PGSU) of differing crosslinking density, and correspondingly differing elasticity and degradation rates. Model API caffeine was blended into PGS resin at 40% w/w loading during Hydralese (PGSU) thermoset device fabrication. Other APIs were also loaded into Hydralese (PGSU) at 40-80% w/w. Drug-loaded devices were exposed to simulated gastric fluid (SGF) of pH 1.22 at 37°C and evaluated for degradation by mass and dimensional loss, in addition to released drug concentration, over multiple weeks. Forced degradation of Hydralese (PGSU) in SGF of pH 1.22 and a basic solution of pH 11.4 was carried out at 70°C for multiple weeks in order to characterize polymer degradants, quantify mass and dimensional loss, and confirm surface erosion behavior. Hydralese (PGSU) devices, molded as a single component in rod, ring, and asterisk shapes with 2-3mm cross-sectional diameter, were folded or spiraled down into size 000 gelatin capsules. Capsules containing Hydralese (PGSU) devices were submerged in SGF of pH 1.22 at 37°C for 30 minutes until the capsules disintegrated. Video captured the springback behavior of Hydralese (PGSU) in this simulated gastroretention use case. Results: The manufacture of single-component drug-loaded Hydralese (PGSU) gastroretentive devices was demonstrated across a variety of complex geometries. Hydralese (PGSU) displayed striking flexibility even when loaded with APIs from 40-80% w/w. Hydralese (PGSU) devices loaded into capsules rapidly sprang back to their original shape upon capsule disintegration demonstrating full elastic recovery without plastic deformation. Hydralese (PGSU) devices exhibited surface erosion behavior in forced degradation studies using acidic or basic media at elevated temperatures, and at physiologically relevant temperatures using SGF. At 70°C, devices degraded 20% and 80% by mass at Weeks 3 and 5, respectively, and 25% diameter loss at Week 3 in both acidic and basic pH. At 37°C, devices degraded 3% by mass at Week 3 in acidic pH. Hydralese (PGSU) surface erosion allowed for controlled, linear release of 40% w/w loaded caffeine with 54% or 70% cumulative release of caffeine after 4 weeks, depending on polymer crosslinking. Hydralese (PGSU) sustained linear release of other hydrophilic APIs at 40-80% w/w loadings, such as 2’-deoxyadenosine which exhibited good dispersion within the polymer matrix, at two-fold slower rates than caffeine. Taken together, hydrophilic API-loaded Hydralese (PGSU) gastroretentive devices provide zero-order drug release lasting 1.5-4 months. Conclusion: Hydralese (PGSU) demonstrates advantages over common bulk-degrading polymers when used as a gastroretentive device for ultra-long-acting oral delivery. Hydralese (PGSU) not only survives acidic gastric conditions for multiple months, but it retains flexibility, maintains overall dimensions, and sustains drug release throughout surface erosion. As a unique polymer that is simultaneously flexible and biodegradable, Hydralese (PGSU) offers a single-component gastroretention solution that can be molded into complex geometries, folded into oral capsules, and rebounds to original shape upon gastric delivery, to slowly release its drug payload.