Purdue University, Departments of Biomedical Engineering and Pharmaceutics, West Lafayette, IN 47907, USA.
Purdue University, Departments of Biomedical Engineering and Pharmaceutics, West Lafayette, IN 47907, USA.
J Control Release. 2022 Aug;348:841-848. doi: 10.1016/j.jconrel.2022.06.036. Epub 2022 Jun 28.
The complexity of scale-up manufacturing of PLGA microparticles creates a significant challenge when transitioning from benchtop-scale formulation development into larger clinical scale batches. Minor changes in the initial formulation composition (e.g., PLGA molecular weight, solvent type, and drug concentration) and processing parameters (e.g., extraction kinetics and drying condition) during scale-up production can result in significantly different performance of the prepared microparticles. The objectives of the present study were to highlight the in vitro and in vivo performance of a candidate benchtop-scale batch created with a rotor-stator mixer, transitioned into an in-line manufacturing process at ~15× scale of a long-acting naltrexone formulation. Physicochemical properties (such as drug loading, residual benzyl alcohol content, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microparticles between the benchtop-scale and in-line process pilot-scale were determined. The pharmacokinetics of the naltrexone microspheres were investigated using the rat model. The results demonstrate that while the morphologies of the particles were different from a visual assessment and slight differences were observed in the in vitro release profiles, the in vivo pharmacokinetics illustrate similar kinetics. Our study shows that scale-up production having the same drug release kinetics can be made by controlling the formulation and processing parameters.
PLGA 微球放大制造的复杂性在从台式配方开发过渡到更大的临床规模批次时带来了重大挑战。在放大生产过程中，初始配方组成（如 PLGA 分子量、溶剂类型和药物浓度）和加工参数（如萃取动力学和干燥条件）的微小变化可能导致制备的微球性能显著不同。本研究的目的是强调候选台式批次的体外和体内性能，该批次是使用转子-定子混合器制备的，并过渡到长效纳曲酮制剂的在线制造工艺中，放大约 15 倍。对制备的纳曲酮微球的物理化学性质（如载药量、残留苯甲醇含量和形态）以及在台式和在线工艺中进行了评估。通过大鼠模型研究了纳曲酮微球的药代动力学。结果表明，尽管从视觉评估来看颗粒的形态不同，并且体外释放曲线略有差异，但体内药代动力学表明相似的动力学。我们的研究表明，可以通过控制配方和加工参数来生产具有相同药物释放动力学的放大生产。
