PLGA, PLA, and PCL from PolySciTech used in fundamental research on Penicillin depot delivery

There is great value in research for not only publishing results from successes but also from publishing results from lessons learned along the way (so-called ‘Negative results’). PLGA is a widely used polymer but its biodegradation naturally leads to formation of acidic products. These products (lactic/glycolic acid) are biocompatible, as they are common metabolic products already formed during normal cellular metabolism. However, they are still acidic in nature and can lead to a drop in pH within the PLGA carrier (For more on this, check out https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269251/). Penicillin is a widely used antibiotic that is also effective at treating rheumatic heart disease when applied as a series of injections. Recently, Researchers from Monash University, The University of Western Australia, and Princess Margaret Hospital for Children (Australia) used a variety of PLGA’s. PLA’s, and PCL polymers from PolySciTech (www.polyscitech.com) as part of a study on penicillin delivery. This included PolyVivo PLGA’s (AP021, AP043, and AP039) and PolyVivo PLA (AP071)  as well as other polymers from PolySciTech to develop an injectable depot formulation for penicillin based on biocompatible NMP solvent.  They discovered that the acid-sensitive nature of penicillin, however, prevented it from being used with PLGA as a carrier as the lactic/glycolic acid components degraded the penicillin. Use of PCL fixed this issue, however the total implant mass required an unwieldly 7 grams of material. This research provides critical understanding for others looking to develop long-acting injectable formulations. Read more: Montagnat, Oliver D., Graham R. Webster, Jurgen Bullita, Cornelia Landersdorfer, Rosemary Wyber, Meru Sheel, Jonathan R. Carapetis, and Ben J. Boyd. "Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD)." Drug Delivery and Translational Research (2018): 1-11. https://link.springer.com/article/10.1007/s13346-018-0482-z

“Abstract: The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development. Keywords Rheumatic fever Antibiotic Sustained release Drug delivery PLGA Therapeutic implant”