Formulation development and upscaling of lipid nanocapsules as a drug delivery system for a novel cyclic GMP analogue intended for retinal drug delivery

Dileep Urimi,Ronja Widenbring,Raúl Oswaldo Pérez García,Lars Gedda,Katarina Edwards,Thorsteinn Loftsson,Nicolaas Schipper

doi:10.1016/j.ijpharm.2021.120640

Abstract

Lipid nanocapsules (LNCs) were prepared with a novel cyclic GMP analogue, DF003, intended for the treatment of neurodegenerative retinal degenerations. LNCs loaded with DF003 were prepared by a phase inversion method and characterized for particle size, polydispersity index, drug loading, entrapment efficiency, stability, and in vitro drug release. Particle size, PdI and zeta potential of selected optimized formulation were 76 ± 1.2 nm, 0.16 ± 0.02, and −11.6 ± 0.4 mV, respectively, with an entrapment efficiency of 69 ± 0.5%. The selected formulation showed a sustained drug release for up to 6 days in phosphate buffer as well as in vitreous components. Stability evaluation of LNCs in presence of vitreous components demonstrated structural stability and compatibility. Further, the nanoparticle preparation process was upscaled to 1000 times (10 L) of the typical lab scale (0.01 L). Product parameters were observed to be unaffected by the upscaling, demonstrating that the LNCs were of the same quality as those prepared at lab scale. Additionally, the manufacturing process was adapted and assessed for a continuous production of LNCs to leverage it for industrial viability. Overall, these findings reveal the remarkable potential of LNCs as drug delivery vehicles and their possibility for clinical translation.

Highlights

Lipid nanocapsules (LNCs) are nanoparticles prepared by a solventfree, low-energy phase inversion method (Hirsjarvi et al, 2013; Huynh et al, 2009; Thomas and Lagarce, 2013; Valcourt et al, 2016), and consist of an oily core composed of medium chain triglycerides which is enveloped by a layer of hydrophilic and hydrophobic surfac tants (Heurtault et al, 2002; Mouzouvi et al, 2017; Valcourt et al, 2016)
The present study mainly focused on lab scale development of LNCs loaded with a novel cyclic guanosine- 3′,5′-monophosphate analogue (DF003), their characterization, and scale-up studies of the manufacturing process
Lipid nanocapsules were developed as a lipid nano delivery system for the novel drug molecule, DF003 that has showed neuroprotective properties in previous studies

Summary

Introduction

Lipid nanocapsules (LNCs) are nanoparticles prepared by a solventfree, low-energy phase inversion method (Hirsjarvi et al, 2013; Huynh et al, 2009; Thomas and Lagarce, 2013; Valcourt et al, 2016), and consist of an oily core composed of medium chain triglycerides which is enveloped by a layer of hydrophilic and hydrophobic surfac tants (Heurtault et al, 2002; Mouzouvi et al, 2017; Valcourt et al, 2016). The components of LNCs are pharmaceutically acceptable and are regarded as generally recognized as safe (i.e. are included in FDA’s GRAS list), and pharmacopoeial grades are commercially available. The characteristics of these nanoparticles can be adjusted to suit various applications with a possibility of loading both hydrophobic and hydro philic drugs (Thomas and Lagarce, 2013). No strong toxicological adversities were noted when administrating DF003 to mice and rats According to these studies, DF003 (Fig. 1) could become a potential molecule for the treatment of inherited retinal degeneration

Methods

Results

Conclusion