QbD-guided development of a simvastatin-loaded transethosomal gel for enhanced transdermal delivery: optimization, characterization, and in vivo antihyperlipidemic evaluation.

BACKGROUND

Simvastatin, a lipid-lowering drug, has low oral bioavailability due to poor solubility and extensive first-pass metabolism. Transdermal delivery may overcome these limitations.

OBJECTIVES

The present study aimed to develop, optimize, and evaluate a simvastatin-loaded transethosomal gel for enhanced dermal permeation and improved antihyperlipidemic efficacy.

METHODS

Critical quality attributes, including particle size (PS), entrapment efficiency (%EE), and polydispersity index (PDI), were established through a Quality Target Product Profile. Transethosomes were optimized using a Face-Centered Central Composite Design (FCCCD) by varying Soya phosphatidylcholine and ethanol concentrations. The optimized formulation was characterized using dynamic light scattering, scanning electron microscope, and transmission electron microscope. It was incorporated into a 2% w/v carbopol gel and evaluated for pH, viscosity, and spreadability. In vitro diffusion, ex vivo skin permeation, and skin irritation studies were performed. Antihyperlipidemic efficacy was assessed in high-fat diet-induced hyperlipidemic rats, comparing oral simvastatin (10 mg/kg/day) and transethosomal gel (1 g containing 10 mg simvastatin).

RESULTS

Optimized vesicles showed nanoscale PS (104.9 ± 0.42 nm), high EE (79.92 ± 0.19%), low PDI (0.113 ± 0.45), and negative zeta potential (-32.1 ± 0.48 mV). Microscopy confirmed spherical morphology. The gel exhibited sustained release, good skin compatibility, and significantly improved lipid profile in high-fat diet-fed rats, reducing total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while elevating high-density lipoprotein cholesterol (HDL-C) compared to oral simvastatin (p < 0.05).

CONCLUSION

The simvastatin-loaded transethosomal gel demonstrated superior dermal delivery, efficacy, and safety, supporting its potential as a nanoenabled transdermal alternative for hyperlipidemia management.