Continuous preparation of long-acting hydromorphone PLGA microspheres using an automatic and scalable microfluidic process system.

Abstract

The long-acting hydromorphone loaded poly-lactic-co-glycolic acid (HM-PLGA) microspheres for chronic pain management were developed and prepared using an automatic and scalable microfluidic process system in this study. The system consists of a novel designed micro-mixer for particle generation, syringe and HPLC pumps for continuous dosing, a process Raman spectrometer as process analytical technology (PAT) tool and an automation system for programmable automatic control. With the benefits of the automation and digitalization of the system, a wide range of formulation parameters was investigated for its impact on the properties of the microspheres. The particle size of the HM-PLGA microspheres was tunable with the automatic microfluidic process system. The long-acting injectable homogeneous HM-PLGA microspheres were successfully prepared with maximum drug-loading capacity of 7.71 % and drug encapsulation efficiency of 69.40 %. The physical and chemical properties were characterized using various analytical technologies. Pharmacokinetic experiments in female ICR mice confirmed prolonged exposure in plasma compared to the HM hydrochloride injection. In vivo studies in beagle dogs showed that the HM-PLGA microspheres provided sustained drug release for over 11 days. The results demonstrated the potential of the novel automatic microfluidic process system in the development and continuous manufacturing of the particle size-controllable drug loaded microspheres.