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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

Needham, D., Pharmaceutical Research, doi:10.1007/s11095-021-03112-x
Dec 2021  
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In Vitro study showing that niclosamide has potential as a prophylactic nasal spray and early treatment throat spray for COVID-19 and other respiratory viral infections. Authors find that niclosamide's solubility and dissolution rate are pH-dependent, with concentrations increasing from 2.53μM at pH 3.66 to 704μM at pH 9.63. A 20μM prophylactic nasal spray can be formulated at pH 7.96, while a 300μM early treatment throat spray can be formulated at pH 9.19. These concentrations are 10-150 times higher than the 100% inhibitory concentration of 1-3μM reported for SARS-CoV-2 infected Vero 6 and Calu-3 cells. Niclosamide's broad antiviral activity is attributed to its ability to disrupt pH gradients and reduce ATP production in host cells, inhibiting viral uncoating, replication, and assembly. Niclosamide inhibits the following stages of viral infection: uncoating - preventing viral RNA release from the endosome; replication - reducing ATP available for viral transcription and translation; and assembly - interfering with capsid assembly in the Golgi, promoting secretion of non-competent virions.
8 preclinical studies support the efficacy of niclosamide for COVID-19:
Needham et al., 28 Dec 2021, peer-reviewed, 1 author. Contact: d.needham@duke.edu.
This PaperNiclosamideAll
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
David Needham
Pharmaceutical Research, doi:10.1007/s11095-021-03112-x
63. However, the "Sigma-polymorph" equilibrated to much lower final supernatant concentrations, reflective of more stable polymorphs at each pH. Similarly, when precipitated from supersaturated solution, or as cosolvates, niclosamide also equilibrated to lower final supernatant concentrations. Polymorph equilibration though was avoided by using a solvent-exchange technique to make the solutions. Conclusions Given niclosamide's activity as a host cell modulator, optimized niclosamide solutions could represent universal prophylactic nasal and early treatment throat sprays against COVID19, its more contagious variants, and other respiratory viral infections. They are the simplest and potentially most effective formulations from both an efficacy standpoint as well as manufacturing and distribution, (no cold chain). They now just need testing.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s11095-021-03112-x. Declarations Conflict of Interest Statement Duke University has assigned the rights for the provisional patent applications to David Needham and his entity, Needham Material Science LLC. Author contributions for all authors David Needham was the sole contributor and sole author. Data Availability Statement The datasets generated during and/ or analyzed during the current study are available from the corresponding author on reasonable request. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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' 'https://www.promega.com/products/cell-health-assays/cell-viability-and-cytotoxicity-assays/celltiter_glo-2_0-assay. ' '2021 (Accessd on 2021–11–21).'}, { 'issue': '1', 'key': '3112_CR32', 'doi-asserted-by': 'publisher', 'first-page': '80-', 'DOI': '10.1186/1423-0127-16-80', 'volume': '16', 'author': 'C-W Chang', 'year': '2009', 'unstructured': 'Chang C-W, Li H-C, Hsu C-F, Chang C-Y, Lo S-Y. Increased ATP generation ' 'in the host cell is required for efficient vaccinia virus production. J ' 'Biomed Sci. 2009;16(1):80-.', 'journal-title': 'J Biomed Sci.'}, { 'key': '3112_CR33', 'doi-asserted-by': 'publisher', 'first-page': '56', 'DOI': '10.3390/v12010056', 'volume': '12', 'author': 'PD Nagy', 'year': '2020', 'unstructured': 'Nagy PD, Lin W. Taking over Cellular Energy-Metabolism for TBSV ' 'Replication: The High ATP Requirement of an RNA Virus within the Viral ' 'Replication Organelle. Viruses. 2020;12:56.', 'journal-title': 'Viruses'}, { 'key': '3112_CR34', 'unstructured': 'Kim S, Bear S, Needham D, Lee P. Effect of Niclosamide on cytotoxicity ' 'and cell viability in small airway epithelial cells in preparation. ' '2021.'}, { 'key': '3112_CR35', 'doi-asserted-by': 'crossref', 'unstructured': 'Ko M, Jeon S, Ryu W-S, Kim S. Comparative analysis of antiviral efficacy ' 'of FDA-approved drugs against SARS-CoV-2 in human lung cells: Nafamostat ' 'is the most potent antiviral drug candidate. bioRxiv. ' '2020:2020.05.12.090035.', 'DOI': '10.1101/2020.05.12.090035'}, { 'key': '3112_CR36', 'unstructured': 'clinicaltrials.gov. COVID19 Niclosamide ' 'https://clinicaltrials.gov/ct2/results?term=Niclosamide&cond=Covid19. ' '2021 Accessd on 2021-11-21.'}, { 'key': '3112_CR37', 'unstructured': 'Daewoong-Pharmaceutical. Daewoong Pharmaceutical Partners with Tufts ' 'Medical Center for Phase 2 Clinical Trial with Niclosamide. 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Physicochemical properties of mucus and ' 'their impact on transmucosal drug delivery. Int J Pharm. ' '2017;532(1):555–72.', 'journal-title': 'Int J Pharm'}, { 'key': '3112_CR41', 'doi-asserted-by': 'publisher', 'first-page': '299', 'DOI': '10.25004/IJPSDR.2017.090603', 'volume': '9', 'author': 'AD Paul', 'year': '2017', 'unstructured': 'Paul AD, Samatha P, Manasa SL, Munemma R, Supriya D. Modeling the oral ' 'cavity with mucoadhesive drug delivery systems - a potential alternative ' 'to conventional therapy. Int J Pharm Sci Drug Res. 2017;9:299–307.', 'journal-title': 'Int J Pharm Sci Drug Res'}, { 'issue': '2', 'key': '3112_CR42', 'doi-asserted-by': 'publisher', 'first-page': '429', 'DOI': '10.1016/j.cell.2020.05.042', 'volume': '182', 'author': 'YJ Hou', 'year': '2020', 'unstructured': 'Hou YJ, Okuda K, Edwards CE, Martinez DR, Asakura T, Dinnon KH 3rd, et ' 'al. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in ' 'the Respiratory Tract. 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Current Provisional ' 'Patent Portfolio USPO: a) DU7305PROV, US 63/111,184 “ANTI-VIRAL ' 'NICLOSAMIDE COMPOSITIONS AS VIROSTATIC THERAPEUTICS AND METHODS OF ' 'MAKING AND USING SAME” (filed 11/9/2020). b) DU7185PROV, US 63/049,160, ' '“NICLOSASPRAY” AND “NICLOSADROPS” FOR BUCCAL/THROAT, NASAL, AND EYE ' 'DROPS AND METHODS OF USING SAME” (filed 7/8/2020). c) DU7175PROV, US ' '63/049,153, “ANTIVIRAL NICLOSAMIDE COMPOSITIONS AS VIROSTATIC ' 'THERAPEUTICS AND METHODS OF MAKING AND USING SAME” (filed 7/8/2020). d) ' 'DU7109PROV, US 63/021,250, “COMPOSITIONS COMPRISING NICLOSAMIDE AND ' 'METHODS OF USING SAME AS PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS” ' '(filed 5/7/2020). e) DU6187PROV, US 63/021,241, PRECIPITATION OF ' 'HYDROPHOBIC DRUGS AS NANOCRYSTALS FOR INJECTION TO A SUBJECT AND METHODS ' 'OF USING SAME (filed 5/72020). f) DU7099PROV, US 63/014,748, ' '“COMPOSITIONS COMPRISING NICLOSAMIDE AND METHODS OF MAKING AND USING ' 'SAME FOR THE PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS” (filed ' '4/24/2020). g) DU7065PROV2, US 63/111,785, “COMPOSITIONS AND ' 'FORMULATIONS COMPRISING NICLOSAMIDE AND METHODS OF MAKING AND USING SAME ' 'FOR THE TREATMENT OF VIRAL INFECTIONS” (filed 4/17/2020). h) DU7065PROV, ' 'US 63/006,527, “NICLOSAMIDE COMPOSITIONS AND METHODS OF USING SAME FOR ' 'THE TREATMENT OF VIRAL INFECTIONS” (filed 4/7/2020). i) DU7308PROV, US ' '63/007,007, “ANTI-VIRAL NICLOSAMIDE COMPOSITIONS AS VIROSTATIC ' 'THERAPEUTICS AND METHODS OF MAKING AND USING SAME” (filed 3/26/2020). ' 'USA2020.'}, { 'issue': '7', 'key': '3112_CR49', 'doi-asserted-by': 'publisher', 'first-page': 'e00819', 'DOI': '10.1128/AAC.00819-20', 'volume': '64', 'author': 'S Jeon', 'year': '2020', 'unstructured': 'Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, et al. Identification of ' 'Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs. ' 'Antimicrob Agents Chemother. 2020;64(7):e00819-e820.', 'journal-title': 'Antimicrob Agents Chemother'}, { 'key': '3112_CR50', 'doi-asserted-by': 'crossref', 'unstructured': 'CDC. COVID-19 Vaccine Breakthrough Infections Reported to CDC — United ' 'States, January 1–April 30, 2021, ' 'https://www.cdc.gov/mmwr/volumes/70/wr/mm7021e3.htm. 2021 Accessed on ' '2021–11–21.', 'DOI': '10.15585/mmwr.mm7021e3'}, { 'key': '3112_CR51', 'unstructured': 'Delta Variant Key to Breakthrough Infections in Vaccinated Israelis ' '[press release]. Medscape2021.'}, { 'key': '3112_CR52', 'unstructured': 'Ourworldindata. 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' 'Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic ' '(NSPT) shows efficacy against Osteosarcoma. Mol Cancer Ther. ' '2020;19(7):1448.', 'journal-title': 'Mol Cancer Ther.'}, { 'key': '3112_CR56', 'unstructured': 'FAO. Food and Agriculture Organization of the United Nations (FAO) ' 'SPECIFICATIONS AND EVALUATIONS FOR AGRICULTURAL PESTICIDES NICLOSAMIDE ' '2’,5-dichloro-4’-nitrosalicylanilide 2004.'}, { 'issue': '18', 'key': '3112_CR57', 'doi-asserted-by': 'publisher', 'first-page': '9998', 'DOI': '10.1021/acs.est.6b02607', 'volume': '50', 'author': 'MB McConville', 'year': '2016', 'unstructured': 'McConville MB, Hubert TD, Remucal CK. Direct Photolysis Rates and ' 'Transformation Pathways of the Lampricides TFM and Niclosamide in ' 'Simulated Sunlight. 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J Inclusion Phenom Mol Recognit Chem. 1998;31(1):1–16.', 'journal-title': 'J Inclusion Phenom Mol Recognit Chem'}, { 'issue': '6', 'key': '3112_CR60', 'doi-asserted-by': 'publisher', 'first-page': '581', 'DOI': '10.1081/DDC-120037489', 'volume': '30', 'author': 'MM de Villiers', 'year': '2004', 'unstructured': 'de Villiers MM, Mahlatji MD, van Tonder EC, Malan SF, Lötter AP, ' 'Liebenberg W. Comparison of the physical and chemical stability of ' 'niclosamide crystal forms in aqueous versus nonaqueous suspensions. Drug ' 'Dev Ind Pharm. 2004;30(6):581–92.', 'journal-title': 'Drug Dev Ind Pharm'}, { 'issue': '1', 'key': '3112_CR61', 'doi-asserted-by': 'publisher', 'first-page': 'E12-E', 'DOI': '10.1007/BF02830580', 'volume': '5', 'author': 'EC van Tonder', 'year': '2004', 'unstructured': 'van Tonder EC, Mahlatji MD, Malan SF, Liebenberg W, Caira MR, Song M, et ' 'al. Preparation and physicochemical characterization of 5 niclosamide ' 'solvates and 1 hemisolvate. 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Test of the Epstein-Plesset model for gas ' 'microparticle dissolution in aqueous media: Effect of surface tension ' 'and gas undersaturation in solution. Langmuir. 2004;20(7):2567–78.', 'journal-title': 'Langmuir'}, { 'issue': '9', 'key': '3112_CR65', 'doi-asserted-by': 'publisher', 'first-page': '4190', 'DOI': '10.1021/la053314e', 'volume': '22', 'author': 'PB Duncan', 'year': '2006', 'unstructured': 'Duncan PB, Needham D. Microdroplet dissolution into a second-phase ' 'solvent using a micropipet technique: Test of the Epstein-Plesset model ' 'for an aniline-water system. Langmuir. 2006;22(9):4190–7.', 'journal-title': 'Langmuir'}, { 'issue': '11', 'key': '3112_CR66', 'doi-asserted-by': 'publisher', 'first-page': '1505', 'DOI': '10.1063/1.1747520', 'volume': '18', 'author': 'PS Epstein', 'year': '1950', 'unstructured': 'Epstein PS, Plesset MS. On the Stability of Gas Bubbles in Liquid-Gas ' 'Solutions. J Chem Phys. 1950;18(11):1505–2409.', 'journal-title': 'J Chem Phys'}, { 'issue': '44', 'key': '3112_CR67', 'doi-asserted-by': 'publisher', 'first-page': '13339', 'DOI': '10.1021/la402533j', 'volume': '29', 'author': 'JT Su', 'year': '2013', 'unstructured': 'Su JT, Needham D. Mass transfer in the dissolution of a multicomponent ' 'liquid droplet in an immiscible liquid environment. Langmuir. ' '2013;29(44):13339–45.', 'journal-title': 'Langmuir'}, { 'issue': '20', 'key': '3112_CR68', 'doi-asserted-by': 'publisher', 'first-page': '8455', 'DOI': '10.1021/la034779c', 'volume': '19', 'author': 'DH Kim', 'year': '2003', 'unstructured': 'Kim DH, Costello MJ, Duncan PB, Needham D. Mechanical properties and ' 'microstructure of polycrystalline phospholipid monolayer shells: Novel ' 'solid microparticles. Langmuir. 2003;19(20):8455–66.', 'journal-title': 'Langmuir'}, { 'issue': '2', 'key': '3112_CR69', 'first-page': 'A313-A', 'volume': '74', 'author': 'DH Kim', 'year': '1998', 'unstructured': 'Kim DH, Klibanov AL, Evans EA, Needham D. Viscoelastic properties of ' 'phospholipid monolayer shells on air microbubbles. Biophys J. ' '1998;74(2):A313-A.', 'journal-title': 'Biophys J.'}, { 'issue': '2', 'key': '3112_CR70', 'doi-asserted-by': 'publisher', 'first-page': '379', 'DOI': '10.1107/S0021889807007832', 'volume': '40', 'author': 'A Llinàs', 'year': '2007', 'unstructured': 'Llinàs A, Box KJ, Burley JC, Glen RC, Goodman JM. A new method for the ' 'reproducible generation of polymorphs: two forms of sulindac with very ' 'different solubilities. J Appl Crystallogr. 2007;40(2):379–81.', 'journal-title': 'J Appl Crystallogr'}, { 'key': '3112_CR71', 'doi-asserted-by': 'crossref', 'unstructured': 'Jara MO, Warnken ZN, Sahakijpijarn S, Moon C, Maier EY, Christensen DJ, ' 'et al. Niclosamide Inhalation Powder Made by Thin-Film Freezing: ' 'Pharmacokinetic and Toxicology Studies in Rats and Hamsters. bioRxiv. ' '2021:2021.01.26.428293.', 'DOI': '10.1101/2021.01.26.428293'}, { 'key': '3112_CR72', 'unstructured': 'Union-Therapeutics. UNION therapeutics A/S completes dosing of healthy ' 'volunteers with UNI911 (inhaled niclosamide) for COVID-19 ' 'https://www.uniontherapeutics.com/news-events/news/union-therapeutics-a-s-completes-dosing-of-healthy-volunteers-with-uni911-inhaled-niclosamide-for-covid-19. ' '2020 Accessed on 2021–11–21.'}, { 'key': '3112_CR73', 'unstructured': 'CDC. Global COVID-19 Vaccinations ' 'https://covid.cdc.gov/covid-data-tracker/#global-vaccinations. 2021 ' 'Accessed on 2021–11–21.'}], 'container-title': 'Pharmaceutical Research', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1007/s11095-021-03112-x.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1007/s11095-021-03112-x/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1007/s11095-021-03112-x.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 10, 28]], 'date-time': '2022-10-28T02:14:32Z', 'timestamp': 1666923272000}, 'score': 1, 'resource': {'primary': {'URL': 'https://link.springer.com/10.1007/s11095-021-03112-x'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 12, 28]]}, 'references-count': 73, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 1]]}}, 'alternative-id': ['3112'], 'URL': 'http://dx.doi.org/10.1007/s11095-021-03112-x', 'relation': { 'has-preprint': [ { 'id-type': 'doi', 'id': '10.1101/2021.08.16.456531', 'asserted-by': 'object'}]}, 'ISSN': ['0724-8741', '1573-904X'], 'subject': [ 'Pharmacology (medical)', 'Organic Chemistry', 'Pharmaceutical Science', 'Pharmacology', 'Molecular Medicine', 'Biotechnology'], 'container-title-short': 'Pharm Res', 'published': {'date-parts': [[2021, 12, 28]]}, 'assertion': [ { 'value': '13 August 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '14 September 2021', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '28 December 2021', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'Duke University has assigned the rights for the provisional patent applications ' 'to David Needham and his entity, Needham Material Science LLC.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Conflict of Interest Statement'}}, { 'value': 'David Needham was the sole contributor and sole author.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Author contributions for all authors'}}, { 'value': 'The datasets generated during and/or analyzed during the current study are ' 'available from the corresponding author on reasonable request.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Data Availability Statement'}}, { 'value': 'This content has been made available to all.', 'name': 'free', 'label': 'Free to read'}]}
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