PLGA microparticle drug delivery elucidated by in-depth mechanistic study

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polyesters including poly(lactide-co-glycolide) PLGA and related polymers. One of the common usages for this polymer is to use it for encapsulating a medicinal molecule inside and generating a micron sized spheres of PLGA (microspheres or microparticles) which can be directly injected into a patient via typical syringe and needle either intra-muscular or subcutaneous. Over time, the PLGA microparticles slowly releases the medicine into the patient’s blood-stream ideally maintaining the medicinal concentration within the therapeutic window (above the effective dose but below the toxic dose) over an extended course of time (weeks to months). Afterwards, the PLGA degrades into its nontoxic components lactic and glycolic acid and is naturally metabolized by the body. This delivery system is currently used for a variety of clinical formulations (Risperdal Consta®, Trelstar ®, and several others) so that there is no need for the patient to receive daily injections to maintain a therapeutic dose. The release mechanism is known to be a combination of diffusion of the drug through the PLGA matrix out into the blood-stream as well as the degradation of the polymer which contributes to drug release from PLGA microparticles. However, not all of these complex and overlapping processes are fully understood in a mechanistic sense. Without this understanding, development to drug delivery microparticles still require a great deal of trial-and-error. Recently, one of the most in-depth mechanistic studies to date regarding the PLGA controlled delivery of medicines has been reported by researchers at the University of Connecticut. Here they trapped the PLGA microspheres in a PVA hydrogel and imaged them in sequence during drug release and degradation. They correlated these results to polymer physicochemical properties to elucidate parameters which affect release in a micro-environment setting. They managed to track several complex and overlapping interactions including pore-formation and closure, microclimate acidification, water uptake, and microdialysis. You can learn more about these fascinating processes that affect PLGA microparticle performance here: Gu, Bing, Xuanhao Sun, Fotios Papadimitrakopoulos, and Diane J. Burgess. "Seeing is believing, PLGA microsphere degradation revealed in PLGA microsphere/PVA hydrogel composites." Journal of Controlled Release (2016). http://www.sciencedirect.com/science/article/pii/S0168365916301353

“Abstract: The aim of this study was to understand the polymer degradation and drug release mechanism from PLGA microspheres embedded in a PVA hydrogel. Two types of microspheres were prepared with different molecular weight PLGA polymers (approximately 25 and 7 kDa) to achieve different drug release profiles, with a 9-day lag phase and without a lag phase, respectively. The kinetics of water uptake into the microspheres coincided with the drug release profiles for both formulations. For the 25 kDa microspheres, minimal water uptake was observed in the early part of the lag phase followed by substantial water uptake at the later stages and in the drug release phase. For the 7 kDa microspheres, water uptake occurred simultaneously with drug release. Water uptake was approximately 2-3 times that of the initial microsphere weight for both formulations. The internal structure of the PLGA microspheres was evaluated using low temperature scanning electron microscopy (cryo-SEM). Burst drug release occurred followed by pore forming from the exterior to the core of both microspheres. A well-defined hydrogel/microsphere interface was observed. For the 25 kDa microspheres, internal pore formation and swelling occurred before the second drug release phase. The surface layer of the microspheres remained intact whereas swelling, and degradation of the core continued throughout the drug release period. In addition, microsphere swelling reduced glucose transport through the coatings in PBS media and this was considered to be a as a consequence of the increased thickness of the coatings. The combination of the swelling and microdialysis results provides a fresh understanding on the competing processes affecting molecular transport of bioanalytes (i.e. glucose) through these composite coatings during prolonged exposure in PBS. Keywords: swelling; release mechanism; heterogeneous degradation; outside-in pore formation; cryo-SEM; glucose diffusion”