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

Abstract

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.

Highlights

Drug release from VCZ/PLGA/PEG or VCZ/PLGA/PVP implants was relatively continuous without lag or burst phases.

Drug release from VCZ/PLGA/PEG or VCZ/PLGA/PVP implants occurred primarily by porous diffusion rather than PLGA erosion.

Porous network formation required that VCZ, PEG and PVP were suspended, not dissolved, in the PLGA matrix.

A Flory-Huggins drug/polymer solubility model was used to ensure that VCZ did not dissolve in PLGA during extrusion.

PEG/PLGA and PVP/PLGA miscibility were also considered in the extrusion process design.

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.

Materials

Voriconazole (VCZ, aqueous solubility 0.5 mg/mL, basic pKa 1.8, LogP 1.8) was acquired from Shenzhen Nexconn Pharmatechs Ltd. (Shenzhen, China) (Theurillat et al., 2010). Other physical/chemical properties are shown in Table 2; the glass transition temperature (Tg), melting point, and particle size were measured in our previous study (Johnson and Zhang, 2025).

Four PLGA grades were acquired from Evonik Corporation (Darmstadt, Germany); their properties are shown in Table 2.

Coleman Johnson, Beibei Chen, Aanya Bhalla, Eric Crowell, Feng Zhang, Elimination of “lag” and “burst” phases in drug release profiles of melt-extruded, PLGA-based intravitreal implants, International Journal of Pharmaceutics, Volume 681, 2025, 125822, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125822.