Highly Biocompatible Lamellar Liquid Crystals Based on Hempseed or Flaxseed Oil with Incorporated Betamethasone Dipropionate: A Bioinspired Multi-Target Dermal Drug Delivery System for Atopic Dermatitis Treatment

Mercedes Vitek,1 Žiga Medoš,2 Zoran Lavrič,1 Matjaž Jeras,3 Odon Planinšek,1 Alenka Zvonar Pobirk,1 Mirjam Gosenca Matjaž1 1Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia; 2Chair of Physical Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia; 3Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, SloveniaCorrespondence: Alenka Zvonar Pobirk; Mirjam Gosenca Matjaž, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia, Tel +386 147 69 652; +386 147 69 616, Email [email protected]; [email protected]: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease that severely impairs patient’s life quality and represents significant therapeutic challenge due to its pathophysiology arising from skin barrier dysfunction. Topical corticosteroids, the mainstay treatment for mild to moderate AD, are usually formulated into conventional dosage forms that are impeded by low drug permeation, resulting in high doses with consequent adverse effects, and also lack properties that would strengthen the skin barrier. Herein, we aimed to develop biomimetic lamellar lyotropic liquid crystals (LLCs), offering a novel alternative to conventional AD treatment.Methods: In screening studies, pseudoternary phase diagrams alongside polarized light microscopy (PLM) and viscosity measurements were utilized. Next, the selected LCCs underwent comprehensive characterization via PLM, small-angle X-ray scattering, differential scanning calorimetry, and rheological analysis. Lastly, their performance was evaluated and compared with the commercially available reference medicine in chemical stability study, in vitro permeation testing, in vitro safety assessment using cell proliferation assay, inverted light microscopy, and Raman mapping of keratinocytes, besides gap closure assay performed by live-cell imaging.Results: Formulation (L/T)Ho30, containing the highest amount of lecithin/Tween 80 mixture (21%) and hempseed oil (28%), demonstrated lamellar microstructure with high skin hydration potential and favourable rheological features for skin administration. Moreover, in comparison with the reference medicine, it stood out by providing suitable chemical BD (betamethasone dipropionate) stability, improved 3-fold BD permeation, and excellent biocompatibility with over 85% cell proliferation at all tested concentrations, ensuring keratinocytes’ integrity, as well as promoting skin healing with gap closure observed after 36 hours.Conclusion: Unique multi-target drug delivery strategy depicted in newly developed bioinspired lamellar LCCs structurally resembling stratum corneum intercellular lipids, with incorporated BD drug, and composed of multifunctional components that synergistically strengthen skin barrier, was presented here and shows a promising approach for improved AD treatment. Keywords: skin barrier, biomimetic, microstructure, keratinocytes, Raman microspectroscopy, gap closure assay