Response Surface Optimization of Ultra-Elastic Nanovesicles Loaded with Deflazacort Tailored for Transdermal Delivery: Accentuated Bioavailability and Anti-Inflammatory Efficacy

Abstract

Purpose: The aim of the present study was to develop deflazacort (DFZ) ultra-elastic nanovesicles (UENVs) loaded gel for topical administration to evade gastrointestinal adverse impacts accompanying DFZ oral therapy.

Methods: UENVs were elaborated according to D-optimal mixture design employing different edge activators as Span-60, Tween-85 and sodium cholate which were incorporated into the nanovesicles to improve the deformability of vesicles bilayer. DFZ-UENVs were formulated by thin-film hydration technique followed by characterization for different parameters including entrapment efficiency (%EE), particle size, in vitro release and ex vivo permeation studies. The composition of the optimized DFZ-UENV formulation was found to be DFZ (10 mg), Span-60 (30 mg), Tween-85 (30 mg), sodium cholate (3.93 mg), L-α phosphatidylcholine (60 mg) and cholesterol (30 mg). The optimum formulation was incorporated into hydrogel base then characterized in terms of physical parameters, in vitro drug release, ex vivo permeation study and pharmacodynamics evaluation. Finally, pharmacokinetic study in rabbits was performed via transdermal application of UENVs gel in comparison to oral drug.

Results: The optimum UENVs formulation exhibited %EE of 74.77±1.33, vesicle diameter of 219.64±2.52 nm, 68.88±1.64% of DFZ released after 12 h and zeta potential of -55.57±1.04 mV. The current work divulged successful augmentation of the bioavailability of DFZ optimum formulation by about 1.37-fold and drug release retardation compared to oral drug tablets besides significant depression of edema, cellular inflammation and capillary congestion in carrageenan-induced rat paw edema model.

Conclusion: The transdermal DFZ-UENVs can achieve boosted bioavailability and may be suggested as an auspicious non-invasive alternative platform for oral route.

Keywords: D-optimal design; deflazacort; pharmacodynamics; pharmacokinetics; ultra-elastic nanovesicles.

Figure 1

Response surface plots for the effects of Span-60 (X₁) and Tween-85 (X₂) concentrations at lower and upper limits of Sodium Cholate (X₃) on: (A and B) particle size, (C and D) %EE and (E and F) Q_12h (%) of the prepared UENVs formulations, respectively.

Figure 2

Transmission electron photomicrograph of the optimized DFZ-UENVs formulation.

Figure 3

Ex vivo permeation profiles of DFZ from the optimized UENVs gel formulation compared to the free DFZ gel formulation (Data = Mean ± S.D, n =3).

Figure 4

% Swelling inhibition of the optimized DFZ-UENVs gel in comparison with the free DFZ gel using the carrageenan induced rat paw edema model. (Data = Mean ± S.D, n =6).

Figure 5

Light photomicrographs of morphology of rat’s skin after application of (A) control plain gel, (B) free DFZ gel and (C) optimized DFZ-UENVs gel.

Figure 6

Mean DFZ concentrations (ng/ml) in rabbit plasma following administration of oral tablet suspension, topical free DFZ gel and topical optimized DFZ-UENVs gel formulation. (Data = Mean ± S.D, n =3).