Fabrication and Evaluation of Quercetin Nanoemulsion: A Delivery System with Improved Bioavailability and Therapeutic Efficacy in Diabetes Mellitus

Abstract

The current study was intended to fabricate and evaluate ultrasonically assisted quercetin nanoemulsion (Que-NE) for improved bioavailability and therapeutic effectiveness against diabetes mellitus in rats. Ethyl oleate, Tween 20, and Labrasol were chosen as oil, surfactant, and cosurfactant, respectively. Box-Behnken design (BBD) was employed to study the influence of process variables such as % surfactant and cosurfactant mixture (Smix) (5 to 7%), % amplitude (20-30%) and sonication time (2.5-7.5 min) on droplet size, polydispersibility index (PDI), and % entrapment efficiency (%EE) were studied. The optimization predicted that 9% Smix at 25% amplitude for 2.5 min would produce Que-NE with a droplet size of 125.51 nm, 0.215 PDI, and 87.04% EE. Moreover, the optimized Que-NE exhibited appreciable droplet size and PDI when stored at 5, 30, and 40 °C for 45 days. Also, the morphological characterization by transmission electron microscope (TEM) indicated the spherical shape of the optimized nanoemulsion. Furthermore, the Que-NE compared to pure quercetin exhibited superior release and enhanced oral bioavailability. The streptozocin-induced antidiabetic study in rats revealed that the Que-NE had remarkable protective and therapeutic properties in managing body weight, blood glucose level, lipid profile, and tissue injury markers, alongside the structure of pancreatic β-cells and hepatocytes being protected. Thus, the developed Que-NE could be of potential use as a substitute strategy for diabetes.

Keywords: Box–Behnken design; diabetes mellitus; nanoemulsion; optimization; quercetin; ultrasonication.

Figure 1

(A) Quercetin solubility in various nanoemulsion components; (B) ethyl oleate emulsification by selected surfactants.

Figure 2

Ternary phase diagrams of nanoemulsions consisting of ethyl oleate and Tween 20 with different cosurfactants: (A) isopropyl alcohol; (B) propylene glycol; (C) Transcutol P; (D) Labrasol at a 1:1 ratio.

Figure 3

TPDs of nanoemulsions consisting of ethyl oleate and Smix (Tween 20:Labrasol) at Smix ratios of: (A) 1:0; (B) 1:1; (C) 2:1; (D) 3:1; (E) 4:1; (F) 5:1; (G) 1:2; (H) 1:3; (I) 1:4; (J) 1:5.

Figure 4

3D Response surface plots representing the interaction effect for the droplet size of Que-NE (A) Smix and % amplitude, (B) Smix and sonication time, and (C) % amplitude and sonication time; the interaction effect for PDI of Que-NE (D) Smix and % amplitude, (E) Smix and sonication time, and (F) % amplitude and sonication time; and the interaction effect for %EE of Que-NE (G) Smix and % amplitude.

Figure 5

(A) Effect of storage temperature on droplet size (Z-average (nm)) and PDI of Que-NE at 5, 30, and 40 °C for 45 days; (B) TEM image of optimized Que-NE.

Figure 6

Plasma concentration–time profile of optimized Que-NE and Que-PD.

Figure 7

Effect of Que-NE and Que-NE (P) on body weight (BW) measured on days 1, 7, 14, and 21 of treatment. Data presented are the mean ± standard deviation. Significance was measured using one-way ANOVA. *** p < 0.001 vs. Normal group. # p < 0.05 and ## p < 0.01 vs. Control group (n = 6).

Figure 8

Effects of Que-NE and Que-NE (P) on: (A) oral glucose tolerance test on the 10th day; (B) oral glucose tolerance test on the 20th day; (C) blood glucose level (BGL); (D) food intake; (E) water intake. Data presented are the mean ± standard deviation. Significance was measured using one-way ANOVA: *** p < 0.001 vs. Normal group. # p < 0.05, ## p < 0.01, and ### p < 0.001 vs. Control group. ¥ p < 0.05 vs. Standard group, and ^φ p < 0.05 vs. Que-NE treatment (n = 6).

Figure 9

Effect of Que-NE and Que-NE (P) on various lipid profiles: (A) total cholesterol—TC; (B) total glycerides—TG; (C) high-density lipoproteins—HDL; (D) low-density lipoproteins—LDL; (E) cholesterol-to-HDL ratio—CHOL/HDL ratio; (F) HDL/LDL ratio; (G) very-low-density lipoproteins—VLDL. Data presented are the mean ± standard deviation (n = 6). Significance was measured using one-way ANOVA. *** p < 0.001 vs. Normal group. ### p < 0.001 vs. Control group. ¥ p < 0.05, ¥¥ p < 0.01, and ¥¥¥ p < 0.001 vs. Standard group (n = 6).

Figure 10

Effect of Que-NE and Que-NE (P) on: (A) alanine aminotransferase—ALT; (B) aspartate aminotransferase—AST; (C) creatinine; (D) blood–urea–nitrogen—BUN; (E) lipid peroxidation; (F) superoxide dismutase—SOD. Data presented are the mean ± standard deviation. Significance was measured using one-way ANOVA. *** p < 0.001 vs. Normal group. # p < 0.05, and ### p < 0.001 vs. Control group. ¥¥ p < 0.01, and ¥¥¥ p < 0.001 vs. Standard group (n = 6).

Figure 11

Histopathological observation of the effect of Que-NE and Que-NE (P) treatment on pancreatic and liver tissue after 21-day treatment (scale bar = 50 µm).