Autophagy-Inducing Inhalable Co-crystal Formulation of Niclosamide-Nicotinamide for Lung Cancer Therapy
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Research Article Autophagy-Inducing Inhalable Co-crystal Formulation of Niclosamide-Nicotinamide for Lung Cancer Therapy Eupa Ray,1 Kalpesh Vaghasiya,1 Ankur Sharma,1 Rahul Shukla,2 Rehan Khan,1 Anil Kumar,3 and Rahul Kumar Verma1,4
Received 7 March 2020; accepted 25 August 2020 Abstract. Niclosamide (NIC), an anthelminthic drug, is found to be promising in overcoming the problem of various types of drug-resistant cancer. In spite of strong antiproliferative effect, NIC shows low aqueous solubility, leading to poor bioavailability. To overcome this limitation, and enhance its physicochemical properties and pharmacokinetic profile, we used co-crystallization technique as a promising strategy. In this work, we brought together the crystal and particle engineering at a time using spray drying to enhance physicochemical and aerodynamic properties of co-crystal particle for inhalation purpose. We investigated the formation and evaluation of pharmaceutical co-crystals of niclosamidenicotinamide (NIC-NCT) prepared by rapid, continuous and scalable spray drying method and compared with conventional solvent evaporation technique. The newly formed co-crystal was evaluated by XRPD, FTIR, Raman spectroscopy and DSC, which showed an indication of formation of H bonds between drug (NIC) and co-former (NCT) as a major binding force in co-crystal development. The particle geometry of co-crystals including spherical shape, size 1–5 μm and aerodynamic properties (ED, 97.1 ± 8.9%; MMAD, 3.61 ± 0.87 μm; FPF, 71.74 ± 6.9% and GSD 1.46) attributes suitable for inhalation. For spray-dried co-crystal systems, an improvement in solubility characteristics (≥ 14.8-fold) was observed, relative to pure drug. To investigate the anti-proliferative activity, NIC-NCT co-crystals were investigated on A549 human lung adenomas cells, which showed a superior cytotoxic activity compared with pure drug. Mechanistically, NIC-NCT co-crystals enhanced autophagic flux in cancer cell which demonstrates autophagy-mediated cell death as shown by confocal microscopy. This technique could help in improving bioavailability of drug, hence reducing the need for high dosages and signifying a novel paradigm for future clinical applications. KEY WORDS: niclosamide; nicotinamide; co-crystals; lung cancer; spray drying; improved solubility.
INTRODUCTION Co-crystal engineering exemplifies an emerging strategy to solve the issues related to pharmaceutical formulations, by altering its physicochemical properties and hence improving drug delivery (1,2). Co-crystals includes two components with fixed stoichiometric ratio, connected by non-covalent bonds including π–π stacking, electrostatic interactions, van der Anil Kumar and Rahul Kumar Verma share equal corresponding authorship. 1
Institute of Nano Science and Technology (INST), Habitat Centre, Phase- 10, Sector- 64, Mohali, Punjab 160062, India. 2 National Institute of Pharmaceutical Education and Research (Rae Bareli), Lucknow, India. 3 University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
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