Rebamipide Loaded Ethosomes as a Potential Trans-Eyelid Delivery

Dry Eye Disease (DED) is a multifactorial condition characterized by tear film instability, leading to discomfort, visual disturbances, and potential ocular damage. Conventional treatments, such as topical eye drops, suffer from poor bioavailability due to rapid clearance, low drug penetration, and frequent dosing requirements, which negatively impact patient compliance. This study aimed to develop and evaluate a novel ethosome-based formulation for the trans-eyelid delivery of rebamipide, a mucoprotective and anti-inflammatory drug, to enhance its solubility, stability, therapeutic efficacy, and patient adherence.

The optimized ethosomal formulation (E6) exhibited a particle size of 242 ±11.8 nm polydispersity index (PDI) of 0.221 ± 0.003, and an entrapment efficiency (EE%) of 94.5 ± 0.6%, confirming its suitability for drug delivery. Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC) confirmed the stability of rebamipide within the ethosomal system, while X-ray Diffraction (XRD) revealed a transition to an amorphous state, enhancing drug solubility. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) demonstrated a smooth, spherical morphology with uniform particle distribution. Stability studies showed that E6 maintained its physicochemical properties over 180 days at both 4°C and ambient temperature.

In vitro drug release studies indicated a sustained release profile over 12 hours, with a controlled release pattern fitting the zero-order kinetic model. Ex vivo permeation studies revealed that E6 significantly enhanced drug penetration through the eyelid skin, achieving a flux of 0.4285 mg·cm⁻¹·h⁻¹ and a permeability coefficient of 0.1071 cm·h⁻¹, approximately three times higher than the control formulation. These findings highlight the potential of ethosome-based trans-eyelid delivery as an effective alternative to conventional ocular drug delivery, providing prolonged drug retention, reduced dosing frequency, and improved patient compliance.

Overall, this study supports the development of rebamipide-loaded ethosomes as a promising strategy for DED management. Further in vivo evaluations and clinical trials are recommended to establish their therapeutic efficacy, safety, and long-term adherence benefits.