Elimination of "lag" and "burst" phases in drug release profiles of melt-extruded, PLGA-based intravitreal implants

Drug delivery products based on poly(lactic-co-glycolic acid) (PLGA) often have multiphasic drug release profiles with slow "lag phase(s)" and rapid "burst phase(s)," which can limit therapeutic efficacy. The purpose of this study was to develop voriconazole (VCZ)/PLGA intravitreal implants with steady drug release profiles, i.e., without lag and burst phases. This study was performed by manufacturing several implant formulations by melt extrusion and testing these formulations for in-vitro drug release. Prototype implants containing only VCZ and PLGA (Resomer® RG 502H) displayed triphasic release profiles with long lag phases and large burst phases, attributed to drug release occurring by autocatalytic PLGA erosion. Better drug release profiles were attained by incorporating water-soluble polymeric excipients into the VCZ/PLGA implants. Incorporation of poly(ethylene glycol) (PEG) resulted in extended first-order release via dissolution and diffusion of VCZ through an interconnected porous network within the implant's PLGA matrix. Incorporation of poly(vinyl pyrrolidone) (PVP) resulted in pseudo zeroth-order release by creating a viscous gel within an interconnected porous network, with the gel functioning as a barrier to diffusion of drug and PVP. Importantly, the formation of these interconnected porous networks depended on the implants being phase-separated suspensions of crystalline drug and soluble excipient in the implant's PLGA matrix. To ensure this phase state, the solubility/temperature phase diagram of VCZ/PLGA was determined using melting point depression measurements and Flory-Huggins modeling, and extrusion temperatures were selected at which VCZ is insoluble in PLGA and would not dissolve into the molten PLGA during extrusion. The miscibilities of PEG/PLGA and PVP/PLGA were also considered in the extrusion process design.