Design And Evaluation Of A Self-Nanoemulsifying Drug Delivery System For Improved Topical Delivery Of 5-Fluorouracil In Actinic Keratosis

Abstract

Background: Topical 5-Fluorouracil (5-FU) is a standard therapy for actinic keratosis (AK), yet its clinical use is often restricted by inadequate skin penetration and dose-related irritation from conventional formulations. Formulating 5-FU as a Self-Nanoemulsifying Drug Delivery System (SNEDDS) may improve drug delivery efficiency and minimize adverse reactions.

Methods: Preformulation compatibility between 5-FU and excipients was investigated through Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and X-ray Diffraction (XRD) analysis. Using a Central Composite Design (CCD), a SNEDDS containing isopropyl myristate, Tween 80, and Transcutol P was optimized. The selected formulation (F2) underwent characterization for particle size, zeta potential, polydispersity index (PDI), drug content, and entrapment efficiency. This optimized SNEDDS was incorporated into a cream (CF2) and assessed for spreadability, drug release, and in vitro cytotoxicity against A549 skin carcinoma cells via the MTT assay.

Results: Analytical studies confirmed the absence of drug–excipient incompatibility. The optimized SNEDDS (F2) exhibited a particle size of 178.8 nm, zeta potential of −20 mV, PDI of 0.828, drug content of 88.19 %, and entrapment efficiency of 87.13 %. The SNEDDS-loaded cream (CF2) demonstrated excellent spreadability, drug release (88.67 %), and entrapment efficiency (90.13 %). Cytotoxic evaluation revealed an IC₅₀ value of 39.53 µg/mL, indicating comparable efficacy to pure 5-FU.

Conclusion: Incorporating 5-FU into a SNEDDS-based cream improved its topical delivery and anticancer activity, suggesting its potential as an effective and patient-compliant therapy for precancerous skin conditions.