Long-acting injectable in situ forming implants: Impact of polymer attributes and API

Poly(DL-lactide-co-glycolide) (PLGA) and N-methyl-2-pyrrolidone (NMP)-based in situ forming implants are liquid formulations that solidify through phase separation following injection into the body. Drug is dissolved or suspended in the final formulation liquid prior to injection. Depending on the polymers used, the depots formed can deliver drug over different periods of time. Accordingly, it is important to understand the impact of PLGA properties on implant drug release. However, currently available publications only investigate such impacts based on a single drug, which is insufficient to determine the potential interplay between drug and PLGA properties affecting drug release, or to draw any solid conclusions concerning the general impact of PLGA on drug release. The current work explores in situ forming implants with different active pharmaceutical ingredients (APIs) to determine whether any interplay between the APIs and the polymer attributes might affect drug release. In particular, the drug state (solution or suspension form) may impact polymer interaction and drug release. Naproxen and meloxicam were chosen as model drugs and were loaded into in situ forming implants. The final implants of naproxen and meloxicam were solutions and suspensions, respectively. The impact of PLGA properties (slight changes in molecular weight (MW), slight/major changes in lactic/glycolic acid (L/G) ratio, as well as changes in polymer blockiness in end-cap (acid vs ester)) on drug release was investigated. The slight changes in PLGA MW (18-31 KDa), L/G ratio (75/15-85/15) and blockiness had similar impacts on the release of naproxen and meloxicam from the formulations. These impacts were consistent with a previous report on risperidone implants. However, the impact of end-cap and significant change in the L/G ratio (from 75/15-85/15 to 50/50) was determined to be drug dependent. For meloxicam and for risperidone (previous report), the ester end-cap (compared to the acid end-cap) and much higher L/G ratio (75/15-85/15 versus 50/50) resulted in significantly longer overall drug release durations. In contrast, the naproxen implants had shorter release durations when prepared with the ester end-caped polymer (compared to acid end-cap), and when prepared with significantly higher L/G ratio polymers (75/15-85/15 versus 50/50). In addition, using the same PLGA polymer, implants loading different APIs demonstrated different release durations. This work highlights the complexity of PLGA attributes in determining the performance of implant drug formulations and the critical role of the interplay with the API properties. This study provides valuable knowledge for the future development of in situ forming implant drug products.