Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability

Abstract

Context: The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development.

Objective: Optimization of the FD to improve long-term stability of ocular administration’s FB-PɛCL-NPs.

Methods: FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components.

Results: Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at −50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, −16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD.

Conclusions: An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.

Keywords:

• Flurbiprofen
• poly-ɛ-caprolactone
• nanoparticles
• freeze-drying optimization
• design of experiments
• poly(ethylene glycol)
• d-(+)-trehalose

Acknowledgements

Ramos Y. Gladys would like to thank Center of Excellence in Lyophilization (CoEL), part of REIG JOFRE Group, for their support in FD process. Special thanks to PhD. J. Barange and PhD. S. Nikolic for their training and helpful suggestions in the freeze drying field.

Disclosure statement

The authors report no conflicts of interest whatsoever to declare, and report no declarations of interest.

Additional information

Funding

This work was supported by Ministerio de economía y competitividad from Spain from Spain (MCYT), project MAT2014-59134R, for financial support.