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Low-Frequency Sonophoresis as an Active Approach to Potentiate the Transdermal Delivery of Agomelatine-Loaded Novasomes: Design, Optimization, and Pharmacokinetic Profiling in Rabbits

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Abstract

The first melatonergic antidepressant drug, agomelatine (AGM), is commonly used for controlling major depressive disorders. AGM suffers low (< 5%) oral bioavailability owing to the hepatic metabolism. The current work investigated the potential of low-frequency sonophoresis on enhancing transdermal delivery of AGM-loaded novasomes and, hence, bioavailability of AGM. Drug-loaded novasomes were developed using free fatty acid (stearic acid or oleic acid), surfactant (span 60 or span 80), and cholesterol via thin-film hydration technique. The systems (N1-N16) were assessed for zeta potential (ZP), particle size (PS), encapsulation efficiency (EE%), and drug percent released after 0.5 h (Q0.5 h) and 8 h (Q8h), drug-crystallinity, morphology, and ex vivo drug permeation. Skin pre-treatment with low-frequency ultrasound (LFU) waves, via N13-novasomal gel systems, was optimized to enhance ex vivo drug permeation. Influences of LFU mode (continuous or pulsed), duty cycle (50% or 100%), and application period (10 or 15 min) were optimized. The pharmacokinetics of the optimized system (N13-LFU-C4) was assessed in rabbits. N13 was the best achieved novasomal system with respect to PS (471.6 nm), ZP (− 63.6 mv), EE% (60.5%), Q0.5 h (27.8%), Q8h (83.9%), flux (15.5 μg/cm2/h), and enhancement ratio (6.9). N13-LFU-C4 was the optimized novasomal gel system (desirability; 0.997) which involves skin pre-treatment with LFU in a continuous mode, at 100% duty cycle, for 15 min. Compared to AGM dispersion, the significantly (P < 0.05) higher flux (26.7 μg/cm2/h), enhancement ratio (11.9), Cmax (118.23 ng/mL), and relative bioavailability (≈ 8.6 folds) could elucidate the potential of N13-LFU-C4 system in improving transdermal drug permeability and bioavailability.

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Authors and Affiliations

  1. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Mai Ahmed Tawfik, Magdy Ibrahim Mohamed, Mina Ibrahim Tadros & Sara Nageeb El-Helaly

  2. Department of Pharmaceutics, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, Egypt

    Mina Ibrahim Tadros

  3. Department of Pharmaceutics and Industrial Pharmacy, School of Pharmacy, Newgiza University, Giza, Egypt

    Sara Nageeb El-Helaly

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  1. Mai Ahmed Tawfik
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Correspondence to Mina Ibrahim Tadros.

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Tawfik, M.A., Mohamed, M.I., Tadros, M.I. et al. Low-Frequency Sonophoresis as an Active Approach to Potentiate the Transdermal Delivery of Agomelatine-Loaded Novasomes: Design, Optimization, and Pharmacokinetic Profiling in Rabbits. AAPS PharmSciTech 22, 261 (2021). https://doi.org/10.1208/s12249-021-02147-y

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