The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections

Needham, David

doi:10.1007/s11095-021-03112-x

Cited by 14 publications

(25 citation statements)

References 55 publications

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“…It can be present in one of several anhydrous and hydrated polymorphs, each having different water solubilities, thereby affecting formulation and clinical utility (de Villiers et al 2004). Pure niclosamide has an intrinsic solubility of ~ 1-2 µM for its most stable monohydrate H B polymorph (Needham 2022;van Tonder et al 2004). Other intranasal formulations under current clinical testing (Backer et al 2021;Sommer et al 2021;Weiss et al 2021) have sought to increase the amount of niclosamide in solution by resorting to niclosamide ethanolamine (NE) that is slightly more soluble, but is generally more toxic, as a skin, eye, and respiratory irritant (AKSci 2022;Cayman-Chemicals 2019;DHSS 2002).…”

Section: Scientific Motivation Preformulation Drug Characterizationmentioning

confidence: 99%

“…Recognizing that niclosamide is a weak acid with a pKa ~ 7.12, the data in the earlier paper (Needham 2022) showed that excess pure, probably anhydrous (AK Sci), niclosamide could readily dissolve and equilibrate in aqueous buffered solution. Solubilities ranged from an intrinsic solubility of 2.53 µM at pH 3.66 to 30 µM a nasally safe pH 8.3, just by slightly increasing the alkalinity.…”

Section: Scientific Motivation Preformulation Drug Characterizationmentioning

confidence: 99%

“…Interestingly, there was some dependence of solubility on the polymorphic nature of the niclosamide obtained from certain suppliers (AK Sci and Sigma), and a pH dependence of the solubility of all polymorphs and solvates was shown (for the first time) to exist across the whole pH range (Needham 2022).…”

Section: Scientific Motivation Preformulation Drug Characterizationmentioning

confidence: 99%

“…This is the second paper in a series of studies starting in 2021-2022 (Needham 2021(Needham , 2022) that report on the potential application of a simple aqueous buffered solution of niclosamide as a potential preventative nasal spray and early treatment throat spray for COVID-19 and other respiratory virus infections. While ostensibly simple in concept, a considerable amount of data is required to comprehensively characterize the solubility, dissolution, morphology, polymorphic states, precipitation, and interactions with common mucin-binding cellulosic polymers that would go into an effective formulation.…”

Section: Introductionmentioning

confidence: 99%

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Extraction of niclosamide from commercial approved tablets into aqueous buffered solution creates potentially approvable oral and nasal sprays against COVID-19 and other respiratory infections

Needham

2023

AAPS Open

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Motivation The low solubility, weak acid drug, niclosamide is a host cell modulator with broad-spectrum anti-viral cell-activity against many viruses, including stopping the SARS-CoV-2 virus from infecting cells in cell culture. As a result, a simple universal nasal spray preventative was proposed and investigated in earlier work regarding the dissolution of niclosamide into simple buffers. However, starting with pharmaceutical grade, niclosamide represents a new 505(b)(2) application. The motivation for this second paper in the series was therefore to explore if and to what extent niclosamide could be extracted from commercially available and regulatory-approved niclosamide oral tablets that could serve as a preventative nasal spray and an early treatment oral/throat spray, with possibly more expeditious testing and regulatory approval. Experimental Measurements of supernatant niclosamide concentrations were made by calibrated UV-Vis for the dissolution of niclosamide from commercially available Yomesan crushed into a powder for dissolution into Tris Buffer (TB) solutions. Parameters tested were as follows: time (0–2 days), concentration (300 µM to -1 mM), pH (7.41 to 9.35), and anhydrous/hydrated state. Optical microscopy was used to view the morphologies of the initial crushed powder, and the dissolving and equilibrating undissolved excess particles to detect morphologic changes that might occur. Results Concentration dependence: Niclosamide was readily extracted from powdered Yomesan at pH 9.34 TB at starting Yomesan niclosamide equivalents concentrations of 300 µM, 600 µM, and 1 mM. Peak dissolved niclosamide supernatant concentrations of 264 µM, 216 µM, and 172 µM were achieved in 1 h, 1 h, and 3 h respectively. These peaks though were followed by a reduction in supernatant concentration to an average of 112.3 µM ± 28.4 µM after overnight stir on day 2. pH dependence: For nominal pHs of 7.41, 8.35, 8.85, and 9.35, peak niclosamide concentrations were 4 µM, 22.4 µM, 96.2 µM, and 215.8 µM, respectively. Similarly, the day 2 values all reduced to 3 µM, 12.9 µM, 35.1 µM, and 112.3 µM. A heat-treatment to 200 °C dehydrated the niclosamide and showed a high 3 h concentration (262 µM) and the least day-2 reduction (to 229 µM). This indicated that the presence, or formation during exposure to buffer, of lower solubility polymorphs was responsible for the reductions in total solubilities. These morphologic changes were confirmed by optical microscopy that showed initially featureless particulate-aggregates of niclosamide could grow multiple needle-shaped crystals and form needle masses, especially in the presence of Tris-buffered sodium chloride, where new red needles were rapidly made. Scale up: A scaled-up 1 L solution of niclosamide was made achieving 165 µM supernatant niclosamide in 3 h by dissolution of just one fifth (100 mg niclosamide) of a Yomesan tablet. Conclusion These comprehensive results provide a guide as to how to utilize commercially available and approved tablets of niclosamide to generate aqueous niclosamide solutions from a simple dissolution protocol. As shown here, just one 4-tablet pack of Yomesan could readily make 165 L of a 20 µM niclosamide solution giving 16,500 10 mL bottles. One million bottles, from just 60 packs of Yomesan, would provide 100 million single spray doses for distribution to mitigate a host of respiratory infections as a universal preventative-nasal and early treatment oral/throat sprays throughout the world. Graphical Abstract pH dependence of niclosamide extraction from crushed Yomesan tablet material into Tris buffer (yellow-green in vial) and Tris-buffered saline solution (orange-red in vial). Initial anhydrous dissolution concentration is reduced by overnight stirring to likely monohydrate niclosamide; and is even lower if in TBSS forming new niclosamide sodium needle crystals grown from the original particles.

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Section: Scientific Motivation Preformulation Drug Characterizationmentioning

confidence: 99%

Section: Scientific Motivation Preformulation Drug Characterizationmentioning

confidence: 99%

Section: Scientific Motivation Preformulation Drug Characterizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extraction of niclosamide from commercial approved tablets into aqueous buffered solution creates potentially approvable oral and nasal sprays against COVID-19 and other respiratory infections

Needham

2023

AAPS Open

Self Cite

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“…Later in 2021, universal prophylactic nasal throat sprays as early treatments against SARS-CoV-2 and its more contagious variants were investigated. In particular, a low dose, prophylactic solution of niclosamide (20 μM) at a nasally safe and acceptable pH of 7.96, and a throat spray of up to 300 μM at pH 9.19 were proposed as the simplest and potentially the most effective formulations from both an efficacy as well as manufacturing and distribution standpoints, since no cold chain would be then required [ 168 ].…”

Section: Anthelmintic Drugs Against Sars-cov-2mentioning

confidence: 99%

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey

et al. 2022

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More than two years have passed since the viral outbreak that led to the novel infectious respiratory disease COVID-19, caused by the SARS-CoV-2 coronavirus. Since then, the urgency for effective treatments resulted in unprecedented efforts to develop new vaccines and to accelerate the drug discovery pipeline, mainly through the repurposing of well-known compounds with broad antiviral effects. In particular, antiparasitic drugs historically used against human infections due to protozoa or helminth parasites have entered the main stage as a miracle cure in the fight against SARS-CoV-2. Despite having demonstrated promising anti-SARS-CoV-2 activities in vitro, conflicting results have made their translation into clinical practice more difficult than expected. Since many studies involving antiparasitic drugs are currently under investigation, the window of opportunity might be not closed yet. Here, we will review the (controversial) journey of these old antiparasitic drugs to combat the human infection caused by the novel coronavirus SARS-CoV-2.

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Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep

Weiss¹,

Bischof²,

Landersdorfer³

et al. 2023

Pharm Res

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Purpose Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization. Methods We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups. Results Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide. Conclusions Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose.

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The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections

Cited by 14 publications

References 55 publications

Extraction of niclosamide from commercial approved tablets into aqueous buffered solution creates potentially approvable oral and nasal sprays against COVID-19 and other respiratory infections

Extraction of niclosamide from commercial approved tablets into aqueous buffered solution creates potentially approvable oral and nasal sprays against COVID-19 and other respiratory infections

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey

Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep

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