Natural Penetration Enhancers and Nanocarriers for Advanced Transdermal Drug Delivery: From Mechanisms to Clinical Translation (Review Article)

Author(s): Samrat A. Khedkar, Onkar B. Doke*, Sejal A Inamke

Abstract: TDDS, which offer consistent drug release, good patient compliance, no first-pass effect, and few adverse reactions compared to oral and parenteral administrations, have attracted considerable interest as innovative TDDS. However, due to the densely organized arrangement of the SC, the most crucial barrier of effective transdermal transport is restricted delivery of drug through skin. NPEs including terpenes, essential oils, fatty acids and alkaloids are extensively studied owing to biocompatibility, low toxicity, and reversibly influencing the permeation of drug across skin lipids. Simultaneously, various nanotechnology-based DDS such as liposomes, transfersomes, ethosomes, niosomes, nanoemulsions, SLNs, NLCs were explored to overcome inherent problems in TDDS like poor drug solubility, stability, poor control of release, and improper targeting to the skin. Natural penetration enhancers along with the nanotechnology-based DDS offer a synergistic approach for significantly increasing drug flux, deposition, residence time, and bioavailability, as well as for decreasing skin irritation. This review summarizes structure and permeability of skin barrier; types and mechanisms of natural enhancers; main types of nanoscale carriers for TDDS; formulations and characterization techniques; safety evaluation methods; clinical considerations. The future breakthroughs for designing advanced formulation through AI assisted formulation design, artificial skin in 3D printed form, personalized medicine-based concept, and hybrid nanocarrier physical systems will greatly help the next-generation transdermal system. The combined application of natural enhancers and nanotechnology represents a promising avenue for the development of safe, effective, and patient-centric transdermal therapeutic systems.

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