Autophagy-Inducing Inhalable Co-crystal Formulation of Niclosamide-Nicotinamide for Lung Cancer Therapy

• Published in: AAPS PharmSciTech Vol. 21; no. 7; p. 260
• Main Authors: Ray, Eupa, Vaghasiya, Kalpesh, Sharma, Ankur, Shukla, Rahul, Khan, Rehan, Kumar, Anil, Verma, Rahul Kumar
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 17.09.2020
• Subjects: Administration, Inhalation; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Calorimetry, Differential Scanning; Crystallization; Desiccation; Drug Compounding; Lung Neoplasms - drug therapy; Niacinamide - administration & dosage; Niacinamide - pharmacology; Niclosamide - administration & dosage; Niclosamide - pharmacology; Particle Size; Pharmacology/Toxicology; Pharmacy; Research Article; Solubility; Spectrum Analysis, Raman; lung cancer; niclosamide; improved solubility; spray drying; co-crystals; nicotinamide
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-020-01803-z

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 anti-proliferative 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 niclosamide-nicotinamide (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.