Abstract
Purpose :
Sustained drug delivery system (DDS) for anti-vascular endothelial growth factors such as aflibercept is in great demand for better management of chronic neovascular eye diseases. However, maintaining drug stability and bioactivity during DDS fabrication and long-term release remains a big challenge. The purpose of this study was to investigate the effects of varying microsphere formulation on the aflibercept stability during fabrication and release from our recently developed microsphere-hydrogel DDS.
Methods :
The aflibercept was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres using double emulsion technique. Effects of organic solvents (dichloromethane (DCM), triacetin, or ethyl acetate) and bovine serum albumin (BSA) contents (w/v%) (0%, 4%, 8%, 12%, 16%, or 20%) on aflibercept stability during primary emulsification was investigated using a simulated microencapsulation test. Stability of aflibercept after simulated emulsification was measured using enzyme-linked immunosorbent assays (ELISA) to determine optimal combination of organic solvent and BSA. Effects of various Mg(OH)2 loadings relative to PLGA (w/w%) (0%, 3%, 6%, or 9%) on aflibercept stability during release from DDS were also investigated using ELISA.
Results :
In each organic solvent group with different BSA contents, 8% BSA contents generated the highest bioactive aflibercept recovery rate: 92.16±6.35% (n=3) in triacetin; 91.46±3.90% (n=3) in ethyl acetate; and 97.26±5.38% in DCM (n=3). Based on the results, 8% BSA with DCM combination provided an optimal recovery rate. Addition of Mg(OH)2 to organic phase improve aflibercept stability during release timeframe from DDS. The stability of aflibercept after one-month release from DDS with various Mg(OH)2 loadings was determined as follows: 4.66±2.56% for 0% Mg(OH)2; 19.64±4.35% for 3% Mg(OH)2; 1.95±1.24% for 6% Mg(OH)2; and 1.97±1.45% for 9% Mg(OH)2. It was found that 3% Mg(OH)2 produced highest aflibercept stability after one-month release from PLGA microsphere-based DDS.
Conclusions :
The current data suggest that a combination of BSA and DCM protects aflibercept from interfacial stress during primary emulsification. Addition of Mg(OH)2 in organic phase can help improve aflibercept stability during release timeframe. Incorporating optimal ratio of BSA and Mg(OH)2 may improve the long-term release of aflibercept from our DDS.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.