Quality by design approach for development and characterization of gabapentin-loaded solid lipid nanoparticles for intranasal delivery: In vitro, ex vivo, and histopathological evaluation

Abstract

Objectives: "Quality by Design" (QbD) is a novel approach to product development that involves understanding the product and process, as well as the relationship between critical quality attributes (CQA) and critical process parameters (CPP). This study aimed to optimize the gabapentin-loaded solid lipid nanoparticle formulation (GP-SLN) using a QbD approach and evaluate in vitro and ex vivo performance.

Materials and methods: The GP-SLN formulation was created using the microemulsion method by combining Gelucire 48/16, Tween 80, and Plurol Oleique CC 497. The Box-Behnken experimental design was adopted to investigate the effects of independent factors on dependent factors. The GP-SLN formulation was assessed based on particle size and distribution, zeta potential, morphology, entrapment efficiency, release kinetics, permeation parameters, stability, and nasal toxicity.

Results: The nanoparticles had a cubical shape with a particle size of 185.3±45.6 nm, a zeta potential of -24±3.53 mV, and an entrapment efficiency of 82.57±4.02%. The particle size and zeta potential of the GP-SLNs remained consistent for 3 months and followed Weibull kinetics with a significantly higher ex vivo permeability (1.7 fold) than a gabapentin solution (GP-SOL). Histopathology studies showed that intranasal administration of the GP-SLN formulation had no harmful effects.

Conclusion: The current study reports the successful development of a GP-SLN formulation using QbD. A sustained release of GP was achieved and its nasal permeability was increased. Solid lipid nanoparticles with optimum particle size and high entrapment efficiency may offer a promising approach for the intranasal delivery of drugs.

Keywords: Box-Behnken design; Gabapentin; Histopathology; Nasal delivery; Permeation; Release kinetics; Solid lipid nanoparticle.

Figure 1

Box-Behnken design (BBD) 3D-graphs showing the effects of independent factor ratios on a) particle size, b) polydispersity index (PDI), and c) zeta potential

Figure 2

Particle size, polydispersity index (PDI), and zeta potential of the GP-SLN formulation (n=3±SD)

Figure 3

SEM images of the GP-SLN formulation showing cubical shaped nanoparticles

Figure 4

Differential scanning calorimetry (DSC) thermograms of gabapentin, Gelucire 48/16, and physical mixture (1:1)

Figure 5

Fourier transform infrared spectroscopy (FTIR) spectra of a) gabapentin, b) Gelucire 48/16, and c) physical mixture

Figure 6

Release profiles of the GP-SOL and GP-SLN formulation (n=3±SD)

Figure 7

Release kinetics curves obtained with the DDSolver software for the GP-SOL and GP-SLN formulation

Figure 8

Ex vivo permeation of GP from the GP-SOL and GP-SLN formulations (n=3±SD)

Figure 9

a) Degenerated bowman glands (arrowhead) and internal tissue damage (arrow); b) Degenerated respiratory epithelial cell (arrow), vascular wall (arrowhead), leukocyte infiltration (star); c) Regular glands and ducts (arrowhead); d) Regular lining epithelium of respiratory epithelial cell (arrow), normal vessels (arrowhead); e) Leukocyte infiltration (star); f) Bowman glands (arrowhead), connective tissue and lining epithelium (arrow)