(T1530-07-41) A Tunable, Biodegradable Drug Delivery Platform with Hydralese^TM for Long-Acting Implants

Purpose: The development of biodegradable polyurethanes for biomedical applications has garnered significant attention due to their potential benefits over non-degradable polyurethanes and conventional bioresorbable polyesters. Existing biodegradable polyesters such as poly(lactic-co-glycolic) acid (PLGA) and polylactic acid (PLA) lack the elastomeric properties needed to match the compliant viscoelastic behavior of native tissues, limiting their clinical applications and usability. A versatile biodegradable polyglycerol ester urethane (PGEU) platform (Hydralese^TM) demonstrates tunable biodegradation rates that can be used in applications such as drug delivery, tissue engineering, and implantable medical devices. Poly(glycerol sebacate) urethane (PGSU) is a surface-eroding, biodegradable polymeric delivery system that can provide release of zero-order release at high loading for at least six months. Our group developed a family of PGEUs to provide sustained delivery of small, hydrophilic drugs based on the polymer cross-linking density, monomer composition, molecular weights, and degradation rates.

Methods: 2-deoxyadenosine (2’-dA) was selected as a model Active Pharmaceutical Ingredient (API) based on its high solubility and high permeability in aqueous conditions. Four polyglycerol ester (PGE) resins were synthesized via a polycondensation reaction using a mixture of different diacids and triols. 2’-dA-loaded (40 to 50% w/w) PGEU cylindrical implants of 3 mm diameter and 40 mm length were manufactured from polyglycerol esters with varying hydrophilicities and molecular weights cross-linked using a diisocyanate in the presence of a tin catalyst using a reaction injection molding process. The microstructure of the implants was characterized by scanning electron microscopy (SEM), while the diameter was measured by optical microscope, and mass was recorded by a semi-ultramicrobalance. Total drug assay was performed by extraction in dimethyl sulfoxide (DMSO) and quantified by high- performance liquid chromatography (HPLC). The in vitro release and polymer degradation profiles of the drug-loaded rods were studied in 10 mM phosphate-buffered saline at 37°C and 50 RPM. Full media exchanges and media sampling occurred at timepoints of 1, 3, and 7 days, and then weekly. The concentration of the collected media was quantified using HPLC. Two rods from each formulation were removed at 90 days and lyophilized. The dry mass and diameter of each sample was measured, and SEM imaging was used to observe changes in surface and internal structure. The extraction of the remaining drug was performed in DMSO and quantified using HPLC.

Results: Nine rods from four 2’-dA-loaded PGEU formulations were selected and tested for the release of 2’-dA. A cumulative release of 89.23% at 180 days, 98.50% at 154 days, 92.80% at 119 days, and 98.71% at 63 days were observed for Original PGSU, Formulation 1, Formulation 2, and Formulation 3, respectively (Figure 1). SEM imaging was used to monitor surface and internal defects in each formulation, which can impact burst release (Figure 2). Air bubbles were observed along the surface of the rods for all four formulations and internally in Formulation 3. The in vitro polymer mass degradation at 90 days was 1.74%, 6.69%, 8.54%, and 6.12% for Original PGSU, Formulation 1, Formulation 2, and Formulation 3 respectively (data not shown).

Conclusion: The results highlight the flexibility of this platform to satisfy clinical needs requiring a range of drug release kinetics and degradation rates for a wide spectrum of therapeutic applications. PGEUs are unique in their ability to provide linear release kinetics and a surface-eroding degradation mechanism that minimizes burst release. Hydralese™ implants are an attractive carrier that provides efficient pharmacokinetics and long-lasting treatment at higher loadings for small, hydrophilic drugs, such as 2’-dA. Our group is expanding upon this technology for the delivery of poorly water-soluble APIs.

Figure 1: In vitro release kinetics over the course of 180 days of 40% w/w drug-loaded PGEU cylindrical rods. Drug release studies were carried out in 10 mM PBS pH 7.4 at 37°C and 50 RPM. All error bars are equivalent (positive and negative values) and represent a standard deviation with n=9.

Figure 2: Lateral and cross-sectional image of (a) 40% 2’-dA-loaded Original PGSU implant; (b) 40% 2’-dA-loaded Formulation 1 implant; (c) 40% 2’-dA-loaded Formulation 2 implant; and (d) 40% 2’-dA-loaded Formulation 3 implant.