Efficient Delivery of Hydrophilic Small Molecules to Retinal Cell Lines Using Gel Core-Containing Solid Lipid Nanoparticles.

In this study, we developed a novel solid lipid nanoparticle (SLN) formulation for drug delivery of small hydrophilic cargos to the retina. The new formulation, based on a gel core and composite shell, allowed up to two-fold increase in the encapsulation efficiency. The type of hydrophobic polyester used in the composite shell mixture affected the particle surface charge, colloidal stability, and cell internalization profile. We validated SLNs as a drug delivery system by performing the encapsulation of a hydrophilic neuroprotective cyclic guanosine monophosphate analog, previously demonstrated to hold retinoprotective properties, and the best formulation resulted in particles with a size of ±250 nm, anionic charge > -20 mV, and an encapsulation efficiency of ±60%, criteria that are suitable for retinal delivery. In vitro studies using the ARPE-19 and 661W retinal cell lines revealed the relatively low toxicity of SLNs, even when a high particle concentration was used. More importantly, SLN could be taken up by the cells and the release of the hydrophilic cargo in the cytoplasm was visually demonstrated. These findings suggest that the newly developed SLN with a gel core and composite polymer/lipid shell holds all the characteristics suitable for the drug delivery of small hydrophilic active molecules into retinal cells.

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

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.