Journal
AAPS PHARMSCITECH
Volume 21, Issue 7, Pages -Publisher
SPRINGER
DOI: 10.1208/s12249-020-01803-z
Keywords
niclosamide; nicotinamide; co-crystals; lung cancer; spray drying; improved solubility
Categories
Funding
- Science and Engineering Research Board, Government of India [CRG/2019/001483]
- Nanomission, India, Government of India [SR/NM/NS-1123/2016]
- ICMR, India
- Council of Scientific and Industrial Research (CSIR), India
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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 mu m and aerodynamic properties (ED, 97.1 +/- 8.9%; MMAD, 3.61 +/- 0.87 mu m; 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.
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