Purpose: Self-assembled polymeric nanoparticles are finding a wide range of applications for delivery of hydrophobic drug substances. Their small size and unique in vivo targeting characteristics make them an ideal drug delivery system for therapeutic treatment involving anti-cancer and anti-inflammatory agents. However, ensuring manufacturing consistency could be challenging, in part attributed to the complex nature of the manufacturing processes and a lack of understanding of key properties such as drug-polymer interactions. To overcome potential batch-to-batch variation typically observed using traditional batch manufacturing processes, the current work focused on outlining key properties associated with the continuous processing of polymeric micelles. In this work, curcumin loaded polymeric micelles were prepared using an innovative co-axial turbulent jet in co-flow continuous technology to obtain a better understanding of the system and its potential application to manufacture complex drug products involving hydrophobic drugs.
Methods: Curcumin-loaded polymeric micelles were produced via a modified ethanol injection method using the co-axial turbulent jet in co-flow continuous technology. By changing parameters such as the dynamic fluid flow profile, polymer concentration,drug-polymer ratio, aqueous and organic phase temperature, the effects of these formulation parameters were studied on the critical quality attributes of the formed polymeric micelles. Based on a preliminary study, curcumin loaded polymeric micelles were prepared and further studied for quality attributes such as entrapment efficiency, zeta potential and the physical state of curcumin/polymer. The physical state was assessed using x-ray diffraction (PXRD), differential scanning calorimetry (DSC), polarized light microscopy (PLM).
Results: Curcumin-loaded polymeric micelles with precise particle size control (20-40 nm) were produced via co-axial jet in co-flow continuous technology. The fluid dynamics, as well as the drug-polymer ratio, were shown to influence the micellar quality attributes. By varying the flow conditions, uniformly sized polymeric micelles achieving a user-specified particle size could be obtained (Figure 1). Curcumin-loaded polymeric micelles at the specified particle size and PDI were further investigated for other quality attributes such as the encapsulation efficiency, polydispersity, z-average particle size, etc. (Table 1).
Conclusion: Depending on the formulation parameters such as flow velocity ratios, polymer concentration etc. polymeric micelles of varying particle size can be produced. The significance of this work is that the mean particle size was easily tunable for curcumin loaded polymeric micelles with a relatively narrow size distribution. The manufacturing process was flexible and easy to control and could ultimately lead to improved product quality. This processing method could be readily extended to the manufacturing of complex drug products with similarly desired physicochemical attributes.
Antonio Costa– Research Assistant Professor, University of Connecticut
Su-Lin Lee– Science Staff, USFDA
Xiaoming Xu– Senior Staff Fellow, U. S. Food and Drug Administration
Celia N. Cruz– Director, DPQR, FDA/CDER/OTR/DPQR, Silver Spring, Maryland
Diane Burgess– Distinguished Professor of Pharmaceutics, University of Connecticut, Storrs, Connecticut