Self-emulsifying Drug Delivery System for Improved Dissolution and Oral Absorption of Quetiapine Fumarate: Investigation of Drug Release Mechanism and In-vitro Intestinal Permeability

Abstract

In this study, we focused on quetiapine fumarate (QTF), a class II BCS drug. QTF is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders. Our objective was to develop a new QTF-loaded self-emulsifying drug delivery system (SEDDS) to improve the dissolution and absorption of the drug. An experimental design approach was used to develop and optimize QTF-loaded SEDDS. The optimized formulation was characterized for droplets size, zeta potential, PDI, and stability. It was then evaluated using an in-vitro combined test for dissolution and Everted gut sac technique. Mathematical modeling and Transmission electron microscopy (TEM) were used to elucidate the mechanism of release. The optimal formulation was type IIIB SEDDS, constituted of 9.1% of oleic acid, 51.6% of Tween^®20, and 39.3% of Transcutol^® P. It showed a droplets size of 144.8 ± 4.9nm with an acceptable PDI and zeta potential. For in-vitro evaluation tests, we noticed an enhancement of the dissolution rate of the optimal QTF-loaded SEDDS compared to the free drug (98.82 ± 1.24% for SEDDS after 30 min compared to 85.65 ± 2.5% for the pure drug). The release of QTF fitted with the Hopfenberg model indicating the drug was released by water diffusion and erosion mechanism. This result was confirmed by TEM images which showed a smaller droplet size after release. We also found an amelioration of the permeability of QTF of 1.69-fold from SEDDS compared to the free drug. Hence, the SEDDS formulation represented a new way to improve the dissolution and absorption of QTF.

Keywords: D-optimal mixture design; Everted Gut Sac; Quetiapine fumarate; release kinetics; self-emulsifying drug delivery system.

Figure 1

The system used for dissolution and permeation studies showing rat everted gut sac hanged into dissolution apparatus type II in vertical position containing Tyrode solution. The medium is constantly oxygenated through perfusion tubes

Figure 2

Ternary phase diagram composed of Oleic acid (oil), Tween 20 (surfactant), and Transcutol P (cosolvent). Both light grey (droplets size > 300 nm) and dark grey (droplets size between 100 and 300 nm) represent the self-emulsifying region

Figure 3

Contour plots (left) and 3D response surface plots (right) displaying the effect of independent factors on desirability, droplets size, and PDI

Figure 4

TEM images of the optimized formulation of QTF-Loaded SEDDS (a) after 15 min of reconstitution, magnification 100 000X; (b) after 60 minutes of the dissolution assay, magnification 100 000X

Figure 5

Dissolution and diffusion profiles of QTF free drug and optimal QTF loaded-SEDDS (a) Dissolution profile using type II dissolution apparatus in water (b) Diffusion profiles through rat everted gut sac membrane