Release mechanisms of PLGA-based drug delivery systems: A review

Poly(lactic-co-glycolic acid) (PLGA)-based microparticles and implants are of continuously increasing importance as parenteral controlled drug delivery systems. However, the underlying drug release mechanisms are often not understood, rendering product optimization difficult: The effects of formulation and processing parameters on drug release can be surprising. Also, upscaling and troubleshooting during production at industrial scale can be highly cumbersome. This can be attributed to the complexity of the physicochemical processes, which can be involved in the control of drug release. Generally, tri-phasic drug release patterns are observed: An initial burst release is followed by a zero order release phase and a final, again, rapid release phase. The relative importance of the different phases can strongly depend on the: (i) composition (e.g., type & amount of drug and polymer), geometry and dimensions of the system, (ii) manufacturing procedure, and (iii) conditions in the surrounding environment (e.g., bulk fluid versus human tissue). Water penetration into the system, drug dissolution, limited solubility effects, drug diffusion through an "intact polymeric matrix" (polymer phase) and/or through water filled pores, pore closure due to local PLGA swelling, osmotic effects, polymer degradation, local drops in micro-pH, autocatalytic effects, substantial swelling of the entire system as well as other phenomena can be of importance. This article aims at giving an overview on the current knowledge in this field. Please note that it is hypotheses-driven, thus, general conclusions should be seen with caution. Also, each drug delivery system should be considered on a case-by-case basis. This article also aims at raising awareness on two aspects, which are often neglected: (i) Substantial system swelling is likely the root cause for the onset of the third drug release phase in many systems. (ii) In the case of microparticles, only looking at drug release from ensembles (hundreds of thousands/millions) of particles can be misleading.