Abstract
Purpose :
A challenge in many treatments utilizing sustained drug-release formulations is an initial period of rapid drug release (or burst release) before achieving more stable drug-release kinetics. Methods to reduce this burst are important to improve predictability and avoid substantial fluctuations in the effective concentration of the released drug. The purpose of this study was to investigate the use of a low-affinity growth factor-binding molecule—heparin—as a method to modulate the early drug-release profile of a sustained-release hydrogel formulation.
Methods :
Hydrogels were prepared by solubilizing a lyophilized water-soluble polymer in an aqueous solution containing recombinant human nerve growth factor (rhNGF, 50 mg/mL) without (H-0) and with 0.25 or 0.5 mg/mL heparin sodium salt (H-0.25 or H-0.5), and then UV crosslinking. Drug-release testing was performed by placing 30 mL hydrogels in glass vials with 1 mL of phosphate buffered saline (PBS, drug-release media) at 100 rpm and 37 °C. The drug-release media was removed at various time points and replaced with fresh PBS. The rhNGF concentration in the drug-release media was quantified by enzyme-linked immunosorbent assay. Statistical analyses included student t-test and F-test for equality of variances. Statistical significance was set at P<0.05.
Results :
After 1, 3, and 8 hours of incubation, H-0 achieved 36.3±2.8, 73.2±4.6, and 92.2±14.5% rhNGF release, respectively. At the same time points, H-0.25 released 36.6±0.9, 24.2±1.1, and 4.2±7.5% less rhNGF, and H-0.5 released 32.3±1.9, 26.2±1.8, 13.1±2.4% less rhNGF. Both heparin concentrations significantly reduced burst release after 1 (P<0.01) and 3 (P<0.01) hours compared with H-0, with no significant reduction in overall drug release after 24 hours (P>0.05). No significant difference was observed between H-0.25 and H-0.5 formulations at all time points. After 3 hours, variance in cumulative rhNGF release was reduced by 76.4% in the H-0.25 formulation (P=0.042), thereby demonstrating that heparin incorporation provided more consistent early drug release rate.
Conclusions :
The incorporation of 0.25 mg/mL heparin reduced the burst release of rhNGF from an experimental hydrogel while also improving the consistency of the early drug release rate. Therefore, heparin is a useful adjunctive agent in the design of sustained growth factor-release formulations.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.