The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology Motivates Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Contagious Variants, and Other Respiratory Viral Infections

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<jats:title>Abstract</jats:title><jats:sec><jats:title>Motivation</jats:title><jats:p>With the coronavirus pandemic still raging, prophylactic nasal and early treatment throat sprays could help prevent infection and reduce viral load. Niclosamide has the potential to treat a broad range of viral infections if local bioavailability is optimized as mucin-penetrating solutions as opposed to more traditional microparticle-based sprays that cannot penetrate the mucin.</jats:p></jats:sec><jats:sec><jats:title>Experimental</jats:title><jats:p>pH-dependence of supernatant concentrations and dissolution rates of niclosamide were measured in buffered solutions by Nanodrop-UV/Vis-spectroscopy for niclosamide from different suppliers, as precipitated material, and as cosolvates. Data was compared to predictions from Henderson Hasselbalch and precipitation pH models. Optimal microscopy was used to observe the morphologies of precipitated and converted niclosamide.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Supernatant-concentrations of niclosamide increased with increasing pH, from 1.77uM at pH 3.66 to 30uM at pH 8, and more rapidly from 90uM at pH8.5 to 300uM at pH 9.1, reaching 641uM at pH 9.5. Logarithmic rates for dissolution increased by ∼3x for pHs 8.62 to 9.44. However, when precipitated from supersaturated solution, niclosamide equilibrated to much lower final supernatant concentrations, reflective of more stable polymorphs at each pH that were also apparent for niclosamide from other suppliers and cosolvates.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Given niclosamide’s activity against COVID19, its more contagious variants, and other respiratory viral infections, these niclosamide solutions, that <jats:italic>put the virus in lockdown,</jats:italic> could represent universal prophylactic nasal and early treatment throat sprays. As solutions they would be the simplest and potentially most effective formulations from both an efficacy standpoint as well as manufacturing and distribution, with no cold chain. They now just need testing.</jats:p></jats:sec>






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Needham, David (n.d.). The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology Motivates Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Contagious Variants, and Other Respiratory Viral Infections. 10.1101/2021.08.16.456531 Retrieved from

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David Needham

Professor Emeritus in the Thomas Lord Department of Mechanical Engineering and Materials Science

Professor Needham has been at Duke since 1987 and over the years has developed many collaborative and scholarly relationships across the campus and Medical School. He holds Faculty and membership appointments as: Associate Professor of Biomedical Engineering; Center for Bioinspired Materials and Material Systems; Center for Biomolecular and Tissue Engineering; Duke Comprehensive Cancer Center; and the Duke Cancer Institute.  Internationally, he holds a joint appointment as Professor of Translational Therapeutics in the School of Pharmacy, at the University of Nottingham, UK.  He also collaborates with preclinical researchers at the Erasmus University Medical Center, in Rotterdam, NL. 
For the past 35 years Needham's Lab has developed and used a platform technology of micropipette manipulation to manipulate single and pairs of micro bubbles, droplets and particles in order to assess their behavior in well-defined fluids and solution conditions.  Recently his research and development has focused on nucleation, growth and stability of nanoparticles.  Applications of these fundamental particle and interfacial studies have primarily focused on advanced drug delivery treatments for cancer and now COVID19 with a nasal and throat spray prophylactic and early treatment regimen.

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