(M1030-11-75) The Impacts of PLGA’s Material Characteristics on the Performance of PLGA-Based Implant Prepared by Hot Melt Extrusion

Purpose: The objective of this study is to investigate the impacts of polymer material characteristics on PLGA-based implants degradation and subsequent drug release behavior from the implants.

Methods: Three grades of viatel™ PLGA, with different co-polymer ratios, molecular weights, end groups, and levels of residual monomer, were formulated with three model drugs with different chemistries. A Three-Tec ZE 9 mm extruder (Three-Tec GmbH, Switzerland) equipped with a volumetric feeder was utilized to prepare PLGA/drug implants. Freshly manufactured extrudates were cut into implants with defined lengths containing a specified amount of drug. To assess the implant’s erosion and degradation behavior and to evaluate their impact on the subsequent drug release performance, the pre-cut implants were kept in a 50ml centrifuge tube fulfilled with 40 mL of dissolution media. The centrifuge tubes were incubated in a water shaker bath at 37 °C for an extended time with multiple pre-defined sampling time intervals. The drug release profile was quantified by employing a high-performance liquid chromatography (HPLC) system coupled with a photodiode array detector. In conjunction with the existing dissolution profile, the changes in the physiochemical characteristics of the implants through the dissolution period were monitored by light and scanning electron microscopes (SEM), size-exclusion chromatography (SEC) and intrinsic viscosity measurement. Moreover, numerical evaluation and fitting were conducted to depict the PLGA degradation and subsequent drug release kinetics. Analytical quantification results were summarized and correlated with the experimental observations.

Results: In the first case study, carbamazepine (CBZ), a poorly water-soluble drug, was formulated with viatel™ DLG 5003 A (acid end-caped PLGA with a molar ratio of D,L-lactide:glycolide of 50:50 and an inherent viscosity of 0.2-0.4 dl g⁻¹) containing different residual monomer contents (low: 0.01wt%; high: 1.24wt%) were used and the weight ratio of PLGA:CBZ was 40:60. All implants exhibited a triphasic in vitro release profile, comprising a burst release (10%) within 24h, a limited and slow release ( < 20%) up to 12 days and a substantial drug release to completion on the 33^rd day. Although the implant made by PLGA with high monomer content displayed a similar release profile within the first two phases as the implant made by PLGA with less monomer, the onset and progress of its third phase was shorter and faster than the implant with less monomer, owing to the monomer catalyzed PLGA hydrolysis. Additionally, morphological observations of the implant’s external and internal structures throughout the dissolution process confirmed that the implant with higher monomer content degraded faster via a bulk erosion mechanism, conversely, implant with less monomer was surface erosion dominated (Figure. 1). In the second case study, metformin hydrochloride (MF.HCl), a highly water-soluble drug, was formulated with viatel™ DLG 7509 E (an ester end-caped PLGA with molar ratios of D,L-lactide:glycolide of 75:25 and an inherent viscosity of 0.8-1.0 dl g⁻¹) containing different residual monomer contents (low: 0.08wt%; high: 1.79wt%) were used and the weight ratio of PLGA:MF.HCl was 85:15. Implants of both grades displayed a zero-order metformin release profile, manifested by a nearly linear release up to completion on the 34^th day. Neglectable differences were observed between the two grades, indicating that the release of the metformin was independent of the structure of the implant due to the high solubility of metformin. However, implants with higher monomer content degraded faster, evidenced by a faster decrease in both molecular weight and intrinsic viscosity than the implants with less monomer (Figure. 2). In the third case study, dexamethasone (DEX), a poorly water-soluble drug, was formulated with viatel™ DLG 5002 A (an acid end-caped PLGA with molar ratios of D, L-lactide:glycolide of 50:50 and an inherent viscosity of 0.1-0.3 dl g⁻¹) containing different residual monomer contents (low: 0.02wt%; high: 1.06wt%) were used and the weight ratio of PLGA:DEX was 40:60. In both 37 ^oC normal saline and PBS buffered saline (pH 7.2), the release profiles were triphasic in nature despite distinct release durations. A small burst release was observed in the first 24 h, followed by a lag phase where limited drug release occurred, and a final release phase where most of the drug was liberated. Starting from the lag phase, implants with higher monomer content released DEX faster than the implants with less monomer (Figure. 3). Residual monomers accelerated the autocatalytic hydrolysis of the PLGA dominantly near the core of the implant, accompanied with both microstructure and physical changes of the implants. All case studies revealed that the residual monomer accelerated the degradation of the implant and more rapidly impaired the implant’s integrity, which impacts the subsequent drug release behavior and performance of the implant. These results provided insights to formulators on rational implant design and polymer selection.

Conclusion: Polymer characteristics and quality are critical to the stability and performance of PLGA-based drug-loaded implants. New Viatel™ bioresorbable polymers with supreme quality and purity open the door for optimal and innovative implant-based drug delivery systems.

Figure. 1 Morphological SEM images of the implant’s cross-sections throughout the dissolution process.

Figure 2. Molecular weight (left) and intrinsic viscosity (right) changes throughout the dissolution process.

Figure 3. Dexamethasone released profiles in normal saline (left) and PBS buffered saline (right).