WO2023114971A1 - Nitric oxide-releasing nasal compositions and methods of use thereof - Google Patents

Nitric oxide-releasing nasal compositions and methods of use thereof Download PDF

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Publication number
WO2023114971A1
WO2023114971A1 PCT/US2022/081754 US2022081754W WO2023114971A1 WO 2023114971 A1 WO2023114971 A1 WO 2023114971A1 US 2022081754 W US2022081754 W US 2022081754W WO 2023114971 A1 WO2023114971 A1 WO 2023114971A1
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WIPO (PCT)
Prior art keywords
composition
buffer
nitric oxide
optionally
sodium
Prior art date
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PCT/US2022/081754
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English (en)
French (fr)
Inventor
Daniel Albert RICCIO
Carri Brodnax GEER
Benjamin Joseph Monroe PRIVETT
Shaylyn Elizabeth WALTER
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NVN Liquidation Inc
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Novan Inc
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Priority to KR1020247024094A priority Critical patent/KR20240125633A/ko
Priority to CA3240044A priority patent/CA3240044A1/en
Priority to JP2024536373A priority patent/JP2024547022A/ja
Priority to IL313526A priority patent/IL313526A/en
Priority to AU2022409833A priority patent/AU2022409833A1/en
Priority to CN202280092092.3A priority patent/CN118742298A/zh
Priority to EP22908737.4A priority patent/EP4447946A4/en
Priority to US18/719,012 priority patent/US20250049841A1/en
Publication of WO2023114971A1 publication Critical patent/WO2023114971A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention relates generally to nitric oxide (NO)-releasing nasal compositions and to methods of using the same.
  • SARS- CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • SARS-CoV-2 is an enveloped, single, positive- stranded RNA virus within the Coronaviridae family.
  • Coronaviruses commonly encode 4 structural proteins, including envelope (E) protein, membrane (M) protein, nucleocapsid (N) protein, and spike (S) protein. While the E and M proteins participate in viral assembly and the N protein encapsulates viral RNA within the virion particle, the S protein is critical in receptorbinding and allows the virion particle to gain entry into host cells and propagate infection.
  • the human angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the predominant host cell access point for both SARS-CoV and SARS-CoV-2.
  • the nasal epithelium is postulated as the major target for viral entry for SARS-CoV-2.
  • expression of ACE2 throughout the respiratory tract has been shown to follow a gradient that is greatest in nasal tissue and decreases down the respiratory tract. Due to the high expression of ACE2, the nasal cavity is hypothesized to serve as an initial site for SARS-CoV-2 infection. Indeed, in vitro infection with SARS-CoV-2 is rampant in nasal epithelial cells.
  • viral load is highest in nasal and oropharyngeal samples from the upper respiratory tract for those infected with SARS-CoV-2, both asymptomatic and symptomatic.
  • ACE2 expression in numerous tissues reflects the wide array of reported symptoms (e.g., gastrointestinal, vascular) associated with COVID-19.
  • the upper respiratory tract being a large reservoir of viral burden creates a high potential for transmission between individuals and for aspiration of virus-containing droplets to the lower respiratory tract within an individual, which can lead to damage in the lungs (e.g., acute respiratory distress syndrome (ARDS)).
  • ARDS acute respiratory distress syndrome
  • One aspect of the present invention is directed to a composition
  • a composition comprising: a nitric oxide-releasing active pharmaceutical ingredient; and a buffer configured to maintain the pH of the composition in a range of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, or 8.5.
  • Another aspect of the present invention is directed to a composition
  • a composition comprising: a nitric oxide-releasing active pharmaceutical ingredient; and a buffer, the buffer comprising a citrate (e.g., a citrate salt) and/or citric acid in an amount of at least 100 mM.
  • a citrate e.g., a citrate salt
  • An additional aspect of the present invention is directed to a kit comprising: a first composition comprising a nitric oxide-releasing active pharmaceutical ingredient; and a second composition comprising a buffer configured to maintain the pH of a composition comprising the first and second compositions in a range of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, wherein the first composition and second composition are separately stored in the kit.
  • a further aspect of the present invention is directed to a kit comprising: a first composition comprising a nitric oxide-releasing active pharmaceutical ingredient; and a second composition comprising a buffer comprising a citrate (e.g., a citrate salt) and/or citric acid in an amount of at least 100 mM, wherein the first composition and second composition are separately stored in the kit.
  • a first composition comprising a nitric oxide-releasing active pharmaceutical ingredient
  • a second composition comprising a buffer comprising a citrate (e.g., a citrate salt) and/or citric acid in an amount of at least 100 mM
  • Another aspect of the present invention is directed to a method of treating and/or preventing an infection in a subject, the method comprising administering a composition of the present invention to the subject.
  • the infection is a viral infection and/or an infection caused by SARS-CoV-2.
  • FIG. 2 is a graph showing lung virus titers of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. Treatment with berdazimer sodium did not significantly reduce lung virus titers in animals infected with SARS- CoV-2. Treatment with EIDD-2801 reduced lung virus titers on day 6 post-infection (**** ⁇ 0.0001 compared to placebo-treated hamsters).
  • FIG. 3 is a graph showing nasal tissue virus titers of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. Treatment with berdazimer sodium did not significantly reduce nasal tissue virus titers in animals infected with SARS-CoV-2. Treatment with EIDD-2801 did not significantly reduce nasal virus titers after infection.
  • FIG. 4 is a graph showing oropharyngeal swab virus titers of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. No significant differences in oropharyngeal swab virus titers were determined by one-way ANOVA.
  • Fig. 5 is a graph showing lung weights of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. Lung weights were not statistically different between treatment groups when compared by one-way ANOVA.
  • FIG. 7 is a graph showing day 4 lung virus titers of hamsters treated with berdazimer sodium and exposed to SARS-CoV-2-infected hamsters. Cohabitation of animals occurred on study days 1-3. Treatment with berdazimer sodium significantly reduced lung virus titers naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium (**** ⁇ 0.0001 compared to placebo-treated naive animals).
  • FIG. 8 is a graph showing day 4 nasal tissue virus titers of hamsters treated with berdazimer sodium and exposed to SARS-CoV-2-infected hamsters. Cohabitation of animals occurred on study days 1-3. Treatment with berdazimer sodium did not significantly reduce nasal tissue virus titers in animals cohabitated with SARS-CoV-2-infected hamsters.
  • FIG. 9 is a graph showing oropharyngeal swab virus titers of 5-week-old golden Syrian hamsters after treatment with berdazimer sodium and cohabitation with SARS-CoV-2-infected hamsters. Treatment with berdazimer sodium at a dose of 2 mg/mL did not significantly reduce oropharyngeal swab titers in hamsters cohabitated with SARS-CoV-2-infected hamsters.
  • Fig. 10 is a graph showing lung weights of 5-week-old golden Syrian hamsters after treatment with berdazimer sodium and cohabitation with SARS-CoV-2-infected animals. Lung weights were not statistically different between groups when compared by one-way ANOVA.
  • Fig. 13 is a graph showing day 4 lung virus titers of hamsters treated with berdazimer sodium (8 mg/ml) and exposed to SARS-CoV-2-infected hamsters. Cohabitation of animals occurred on study days 1-3. Treatment with berdazimer sodium (8 mg/ml) significantly reduced lung virus titers in naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium (8 mg/ml) (****P ⁇ 0.0001 compared to placebo-treated naive animals).
  • FIG. 14 is a graph showing day 4 lung virus titers of hamsters treated with berdazimer sodium (2 or 1 mg/ml) and exposed to SARS-CoV-2-infected hamsters. Cohabitation of animals occurred on study days 1-3. Treatment with berdazimer sodium (2 mg/ml) significantly reduced lung virus titers of naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium (2 mg/ml).
  • Fig. 15 is a graph showing day 4 nasal tissue virus titers of hamsters treated with berdazimer sodium (8 mg/ml) and exposed to SARS-CoV-2-infected hamsters. Cohabitation of animals occurred on study days 1-3. Treatment with berdazimer sodium (8 mg/ml) did not significantly reduce nasal tissue virus titers in animals cohabitated with SARS-CoV-2-infected hamsters.
  • Fig. 16 is a graph showing day 4 nasal tissue virus titers of hamsters treated with berdazimer sodium (2 or 1 mg/ml) and exposed to SARS-CoV-2-infected hamsters. Cohabitation of animals occurred on study days 1-3. Treatment with berdazimer sodium (2 or 1 mg/ml) did not significantly reduce nasal tissue virus titers in animals cohabitated with SARS-CoV-2-infected hamsters.
  • Fig. 17 is a graph showing lung weights of 16-week-old golden Syrian hamsters after treatment with berdazimer sodium (8 mg/ml) and cohabitation with SARS-CoV-2-infected animals. Lung weights were not statistically different between groups when compared by oneway ANOVA.
  • Fig. 18 is a graph showing lung weights of 16-week-old golden Syrian hamsters after treatment with berdazimer sodium (2 or 1 mg/ml) and cohabitation with SARS-CoV-2-infected animals. Lung weights were not statistically different between groups when compared by oneway ANOVA.
  • Fig. 19 is a graph showing percent initial body weight of hamsters treated once daily with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2. Treatment with berdazimer sodium began 24 hours prior to infection. No statistically significant protection from weight loss was observed in hamsters treated with 2, 4, or 8 mg/mL of berdazimer sodium once daily. Although not statistically significant, hamsters treated with 8 mg/mL of berdazimer sodium lost less body weight compared to placebo-treated animals. A similar trend was observed in the hamsters treated with EIDD-2801 at a dose of 500 mg/kg/d.
  • Fig. 20 is a graph showing lung virus titers at days 3 and 6 post-infection from hamsters treated once daily with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2.
  • Treatment with berdazimer sodium began 24 hours prior to infection.
  • Treatment with berdazimer sodium at a dose of 4 mg/mL significantly reduced lung virus titers on day 3 postinfection.
  • Treatment with EIDD-2801 at a dose of 500 mg/kg/d significantly reduced lung virus titers on day 3 post-infection (* ⁇ 0.05, ** ⁇ 0.01 compared to placebo-treated animals).
  • Fig. 21 is a graph showing nasal tissue virus titers at days 3 and 6 post-infection from hamsters treated with once daily berdazimer sodium (2, 4, or 8 mg/ml) and infected with S ARS- CoV-2. Treatment with berdazimer sodium began 24 hours prior to infection. Once daily treatment with berdazimer sodium at doses of 2, 4, or 8 mg/mL did not significantly reduce nasal tissue virus titers. Treatment with EIDD-2801 at a dose of 500 mg/kg/d did not significantly reduce nasal tissue virus titers.
  • Fig. 22 is a graph showing lung weights at days 3 and 6 post-infection from hamsters treated once daily with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2. Treatment with berdazimer sodium began 24 hours prior to infection. Once daily treatment with berdazimer sodium at doses of 2, 4, or 8 mg/mL did not significantly reduce lung weights. Treatment with EIDD-2801 at a dose of 500 mg/kg/d did not significantly reduce lung weights.
  • Fig. 23 is a graph showing percent initial body weight of hamsters treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2.
  • berdazimer sodium Treatment with berdazimer sodium began 24 hours prior to infection. Twice daily treatment with berdazimer sodium at a dose of 2 mg/mL did not prevent weight loss in hamsters infected with SARS- CoV-2. Although not statistically significant, hamsters treated with EIDD-2801 at a dose of 500 mg/kg/d lost less body weight than placebo-treated hamsters.
  • Fig. 24 is a graph showing lung virus titers at days 3 and 6 post-infection from hamsters treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2.
  • Treatment with berdazimer sodium began 24 hours prior to infection. Twice daily treatment with berdazimer sodium at a dose of 2 mg/mL did not significantly reduce lung virus titers on day 3 or 6 post-infection.
  • Fig. 25 is a graph showing nasal tissue virus titers at days 3 and 6 post-infection from hamsters treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV- 2. Treatment with berdazimer sodium began 24 hours prior to infection. Twice daily treatment with berdazimer sodium at a dose of 2 mg/mL significantly reduce lung virus titers on day 3 post-infection. Treatment with EIDD-2801 at a dose of 500 mg/kg/d significantly reduced nasal tissue virus titers on day 3 post-infection (** ⁇ 0.01 compared to placebo-treated animals). [0037] Fig.
  • 26 is a graph showing lung weights at days 3 and 6 post-infection from hamsters treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2. Treatment with berdazimer sodium began 24 hours prior to infection. Lung weights were significantly affected by twice daily treatment with berdazimer sodium and EIDD-2801 at Day 6 (**P ⁇ 0.01, *** ⁇ 0.0001 compared to placebo-treated animals).
  • a measurable value such as an amount or concentration and the like, is meant to encompass variations of ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of the specified value as well as the specified value.
  • “about X” where X is the measurable value is meant to include X as well as variations of ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of X.
  • a range provided herein for a measurable value may include any other range and/or individual value therein.
  • phrases such as “between X and Y” and “between about X and Y” should be interpreted to include X and Y.
  • phrases such as “between about X and Y” mean “between about X and about Y” and phrases such as “from about X to Y” mean “from about X to about Y.”
  • the term “consisting essentially of’ when used in a claim of this invention is not intended to be interpreted to be equivalent to “comprising.”
  • the terms “increase,” “increasing,” “enhance,” “enhancing,” “improve” and “improving” describe an elevation of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500% or more such as compared to another measurable property or quantity (e.g., a control value).
  • the terms “reduce,” “reduced,” “reducing,” “reduction,” “diminish,” and “decrease” describe, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% such as compared to another measurable property or quantity (e.g., a control value).
  • the reduction can result in no or essentially no (i.e., an insignificant amount, e.g., less than about 10% or even 5%) detectable activity or amount.
  • nitric oxide (NO)-releasing compositions may be a nasal composition and/or may be configured for intranasal delivery.
  • a composition of the present invention comprises a nitric oxi de-releasing active pharmaceutical ingredient; and a buffer configured to maintain the pH of the composition in a range of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5.
  • a buffer can include a weak acid and a salt of the weak acid or a weak base and a salt of the weak base.
  • a buffer of the present invention comprises a weak acid that has at least two pKa values in a range of about 2.5 to about 6.5. In some embodiments, the weak acid has a pKa value of about
  • the buffer may have a pH of about 3, 3.5, or 4 to about
  • Exemplary buffers include, but are not limited to, citrate, acetate, phosphate, and/or maleate buffers.
  • An acetate buffer may comprise acetic acid and/or an acetate (e.g., sodium acetate).
  • a phosphate buffer may comprise phosphoric acid and/or a phosphate (e.g., monobasic dihydrogen phosphate and dibasic monohydrogen phosphate).
  • a maleate buffer may comprise maleic acid and/or a maleate (e.g., tromethamine maleate salt).
  • a citrate buffer may comprise citric acid and/or a citrate (e.g., a citrate salt such as sodium citrate tribasic and/or tri sodium citrate dihydrate).
  • a composition of the present invention comprises a citrate buffer.
  • a citrate buffer may comprise a citrate ion (e.g., tricarboxylic acid trianion) and/or mono-hydrogen citrate ion.
  • a buffer of the present invention may have a concentration of an acid and/or a corresponding salt of the acid in an amount that is at least 50 mM or at least 100 mM or more.
  • a buffer has a concentration of an acid and/or a corresponding salt of the acid in an amount of about 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mM or more.
  • a buffer has a concentration of an acid and/or a corresponding salt of the acid in an amount of about 50 mM to about 150 mM, about 100 mM to about 300 mM, about 150 mM to about 300 mM, about 200 mM to about 1000 mM, about 200 mM to about 500 mM, about 250 mM to about 600 mM, or about 500 mM to about 1000 mM.
  • the buffer comprises a citrate (e.g., a citrate salt) and/or citric acid in an amount of about 200 mM or more.
  • the buffer has a concentration of an acid and/or a corresponding salt of the acid in an amount that would not be expected to be tolerated by a subject and/or suitable for intranasal administration. In some embodiments, the buffer has a concentration of an acid and/or a corresponding salt of the acid in an amount that exceeds what is typically established as tolerable by a subject and/or suitable for intranasal administration.
  • a buffer of the present invention may comprise at least one additional acid (e.g., HC1) and/or base (e.g., NaOH) in an amount sufficient to adjust the pH of the buffer such as to a pH of about 3, 3.5, or 4 to about 4.5, 5, 5.5, or 6.
  • the buffer has a pH of about 3, 3.5, 4, 4.5, 5, 5.5, or 6.
  • the buffer is a citrate buffer.
  • the citrate buffer may comprise a citrate (e.g., a citrate salt) and/or citric acid.
  • Exemplary citrates include, but are not limited to, trisodium citrate, potassium citrate, calcium citrate, and/or a hydrate thereof and/or anhydrous form thereof.
  • a citrate buffer comprises a citrate and citric acid.
  • the citrate is sodium citrate tribasic.
  • the citrate is tri sodium citrate dihydrate.
  • a citrate buffer of the present invention comprises citric acid in an amount of about 1%, 1.25%, 1.5%, or 1.75% to about 2%, 2.25%, or 2.5% w/w; sodium citrate tribasic, tri sodium citrate dihydrate, and/or anhydrous sodium citrate in an amount of about 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, or 3% to about 3.25%, 3.5%, 3.75%, or 4% w/w; optionally an additional acid (e.g., HC1) and/or base (e.g., NaOH) in an amount sufficient to adjust the pH of the buffer to about 3, 3.5, or 4 to about 4.5, 5, 5.5, or 6 (e.g., about 4.5); and a remainder of water.
  • additional acid e.g., HC1
  • base e.g., NaOH
  • a citrate buffer of the present invention comprises citric acid in an amount of about 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, or 2.5% w/w and sodium citrate tribasic, tri sodium citrate dihydrate, and/or anhydrous sodium citrate in an amount of about 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, or 4% w/w, and has a pH of about 4.5.
  • the nitric oxide-releasing active pharmaceutical ingredient (API) may be suspended in the buffer and/or composition of the present invention.
  • the NO-releasing API may be an insoluble, particulate such as an insoluble, nonbiodegradable particulate.
  • the NO-releasing API does not comprise a biopolymer and/or is not prepared from a biopolymer.
  • the pH of a composition in which the NO-releasing API is present may increase.
  • a composition of the present invention comprises a nitric oxidereleasing active pharmaceutical ingredient in an amount of about 0.1 mg/mL to about 30 mg/mL and a buffer configured to maintain the pH of the composition in a range of about 3,
  • the buffer is configured to maintain the pH of the composition including the NO-releasing API at about 8.5 or less such as a pH of about 8, 7.5, 7, 6.5, 6, 5.5, 5 or less. In some embodiments, the buffer is configured to maintain the pH of the composition including the NO-releasing API at a pH in a range of about 4.5 to about 5.5 or about 4.5 to about 7.
  • the NO-releasing API is present in the composition in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg/mL. In some embodiments, the NO-releasing API is present in the composition in an amount of about 1 mg/mL to about 20 mg/mL. In some embodiments, the NO-releasing API is present in the composition in an amount of about 2, 4, 6, 8, 10, 12, or 14 mg/mL.
  • a composition of the present invention may have a pH that varies over time, optionally due to the presence of the NO-releasing API in the composition and/or release of nitric oxide from the NO-releasing API.
  • the pH of the composition upon initial formation of the composition (e.g., combining the NO-releasing API and the buffer), is about 4.5 to about 6.
  • the buffer may be configured to maintain the pH of the composition including the NO-releasing API and the buffer in a range of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, or 8.5; in this manner, the composition may have a pH of about 3, 3.5, 4, or 4.5 to about 8.5.
  • the composition has a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6,
  • the composition has a pH of about 7 or less. In some embodiments, the composition has a pH of about 5.5.
  • Nitric oxide-releasing active pharmaceutical ingredient refers to a compound or other composition that provides nitric oxide to the skin (e.g., mucosa) and/or tissue of a subject, but is not gaseous nitric oxide.
  • the NO-releasing API is also not acidified nitrite.
  • the NO-releasing API includes a nitric oxide-releasing compound, hereinafter referred to as a "NO-releasing compound.”
  • a NO-releasing compound includes at least one NO donor, which is a functional group that may release nitric oxide under certain conditions.
  • the NO-releasing compound includes a small molecule compound that includes an NO donor group.
  • "Small molecule compound” as used herein is defined as a compound having a molecular weight of less than 500 Daltons, and includes organic and/or inorganic small molecule compounds.
  • the NO-releasing compound includes a macromolecule that includes an NO donor group.
  • a "macromolecule” is defined herein as any compound that has a molecular weight of 500 Daltons or greater.
  • a NO-releasing macromolecule comprises a crosslinked or noncrosslinked polymer, dendrimer, metallic compound, organometallic compound, inorganicbased compound, and/or other macromolecular scaffold.
  • the macromolecule has a nominal diameter ranging from about 0.1 nm to about 100 pm and may comprise the aggregation of two or more macromolecules, whereby the macromolecular structure is further modified with an NO donor group.
  • the NO-releasing compound includes a diazeniumdiolate functional group as an NO donor.
  • the diazeniumdiolate functional group may produce nitric oxide under certain conditions, such as upon exposure to water or a proton.
  • the NO-releasing compound includes a nitrosothiol functional group as the NO donor.
  • the NO donor may produce nitric oxide under certain conditions, such as upon exposure to light. Examples of other NO donor groups include nitrosamine, hydroxyl nitrosamine, hydroxyl amine and hydroxyurea.
  • a combination of NO donors and/or NO-releasing compounds may be present in a composition of the present invention. Additionally, the NO donor may be incorporated into and/or onto the small molecule or macromolecule through covalent and/or non-covalent interactions.
  • An NO-releasing macromolecule may be in the form of an NO-releasing particle, such as those described in U.S. Patent No. 8,282,967, U.S. Patent No. 8,962,029 or U.S. Patent No. 8,956,658, the disclosures of which are incorporated by reference herein in their entirety.
  • NO-releasing compounds include NO-releasing zeolites as described in United States Patent Publication Nos. 2006/0269620 or 2010/0331968; NO-releasing metal organic frameworks (MOFs) as described in United States Patent Application Publication Nos. 2010/0239512 or 2011/0052650; NO-releasing multi-donor compounds as described in International Application No.
  • PCT/US2012/052350 entitled "Tunable Nitric Oxide-Releasing Macromolecules Having Multiple Nitric Oxide Donor Structures”; NO-releasing dendrimers or metal structures as described in U.S. Publication No. 2009/0214618; nitric oxide releasing coatings as described in U.S. Publication No. 2011/0086234; and compounds as described in U.S. Publication No. 2010/0098733.
  • NO-releasing macromolecules may be fabricated as described in International Application No. PCT/US2012/022048 entitled “Temperature Controlled Sol-Gel Co-Condensation" filed January 20, 2012, the disclosure of which is incorporated herein by reference in its entirety.
  • a nitric oxide-releasing active pharmaceutical ingredient may include NO-loaded precipitated silica.
  • the NO-loaded precipitated silica may be formed from nitric oxide donor modified silane monomers into a cocondensed siloxane network.
  • the nitric oxide donor may be an N-diazeniumdiolate.
  • the nitric oxide-releasing active pharmaceutical ingredient may comprise, consist essentially of, or consist of a co-condensed siloxane network comprising a diazeniumdiolate (e.g., a N- di azeniumdi ol ate) .
  • the nitric oxide donor may be formed from an aminoalkoxysilane by a pre-charging method
  • the co-condensed siloxane network may be synthesized from the condensation of a silane mixture that includes an alkoxysilane and the aminoalkoxysilane to form a nitric oxide donor modified co-condensed siloxane network.
  • the "pre-charging method” means that aminoalkoxysilane is “pretreated” or “precharged” with nitric oxide prior to the co-condensation with alkoxysilane.
  • precharging with nitric oxide may be accomplished by chemical methods.
  • the “pre-charging” method may be used to create co-condensed siloxane networks and materials more densely functionalized with NO-donors.
  • the nitric oxide-releasing active pharmaceutical ingredient may comprise, consist essentially of, or consist of a co-condensed silica network synthesized from the condensation of a silane mixture comprising an alkoxysilane and at least one aminoalkoxysilane having an amine substituted by a diazeniumdiolate (e.g., a N- di azeniumdi ol ate) .
  • the co-condensed siloxane network may be silica particles with a uniform size, a collection of silica particles with a variety of size, amorphous silica, a fumed silica, a nanocrystalline silica, ceramic silica, colloidal silica, a silica coating, a silica film, organically modified silica, mesoporous silica, silica gel, bioactive glass, and/or any suitable form or state of silica.
  • the alkoxysilane is a tetraalkoxysilane having the formula Si(OR)4, wherein R is an alkyl group.
  • the R groups may be the same or different.
  • the tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS) or tetraethyl orthosilicate (TEOS).
  • the aminoalkoxysilane has the formula: R"-(NH- R')n-Si(OR)3, wherein R is alkyl, R' is alkylene, branched alkylene, or aralkylene, n is 1 or 2, and R" is selected from the group consisting of alkyl, cycloalkyl, aryl, and alkylamine.
  • the aminoalkoxysilane may be selected from N-(6- aminohexyl)aminopropyltrimethoxysilane (AHAP3); N-(2-aminoethyl)-3- aminopropyltrimethoxysilane (AEAP3); (3 -trimethoxy silylpropyl)di- ethylenetriamine (DET3); (aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3); [3- (methylamino)propyl]trimethoxysilane (MAP3); N-butylamino-propyltrimethoxysilane(n- BAP3); t-butylamino-propyltrimethoxysilane(t-BAP3);N- ethylaminoisobutyltrimethoxysilane(EAiB3); N-phenylamino-propyltrimethoxysilane(EAiB3);
  • the aminoalkoxy silane has the formula: NH [R'-Si(OR)3]2, wherein R is alkyl and R' is alkylene.
  • the aminoalkoxysilane may be selected from bis(3-triethoxysilylpropyl)amine, bis-[3-(trimethoxysilyl)propyl]amine and bis- [(3-trimethoxysilyl)propyl]ethylenediamine.
  • the aminoalkoxysilane is precharged for NO-release and the amino group is substituted by a diazeniumdiolate. Therefore, in some embodiments, the aminoalkoxysilane has the formula: R"-N(NONO-X+)-R'-Si(OR)3, wherein R is alkyl, R' is alkylene or aralkylene, R" is alkyl or alkylamine, and X+ is a cation selected from the group consisting of Na+, K+ and Li+.
  • composition of the siloxane network (e.g., amount or the chemical composition of the aminoalkoxysilane) and the nitric oxide charging conditions (e.g., the solvent and base) may be varied to optimize the amount and duration of nitric oxide release.
  • the composition of the silica particles may be modified to regulate the half-life of NO release from silica particles.
  • the amino group of aminoalkoxysilane is substituted with a diazeniumdiolate, and the aminoalkoxysilane having a formula of R"-N(NONO-X+)-R'- Si(OR)3, wherein: R is alkyl, R' is alkylene or aralkylene, R" is alkyl or alkylamine, and X+ is a cation selected from the group consisting of Na+ and K+.
  • the NO-releasing API may comprise a co-condensed silica network comprising and/or formed from diazeniumdiolated aminoethylaminopropyl trimethoxy silane (AEAP3-NONOate) and tetra methyl orthosilicate (TMOS) and/or a cocondensed silica network comprising and/or formed from diazeniumdiolated aminoethylaminopropyl trimethoxy silane (AEAP3-NONOate) and tetraethyl orthosilicate (TEOS).
  • AEAP3-NONOate diazeniumdiolated aminoethylaminopropyl trimethoxy silane
  • TMOS tetra methyl orthosilicate
  • TEOS tetraethyl orthosilicate
  • the NO-releasing API may comprise a co-condensed silica network comprising and/or formed from diazeniumdiolated methylaminopropyl trimethoxysilane (MAP3-NONOate) and tetra methyl orthosilicate (TMOS) and/or a cocondensed silica network comprising and/or formed from diazeniumdiolated methylaminopropyl trimethoxysilane (MAP3-NONOate) and tetraethyl orthosilicate (TEOS).
  • MAP3-NONOate diazeniumdiolated methylaminopropyl trimethoxysilane
  • TMOS tetra methyl orthosilicate
  • the NO-releasing API may comprise a co-condensed silica network comprising and/or formed from diazeniumdiolated methyl aminopropyl trimethoxysilane (MAP3-NONOate), ethylaminoisobutylsiloxane (EAIB3), and tetraethyl orthosilicate (TEOS).
  • MAP3-NONOate diazeniumdiolated methyl aminopropyl trimethoxysilane
  • EAIB3 ethylaminoisobutylsiloxane
  • TEOS tetraethyl orthosilicate
  • the NO-releasing API may comprise a co-condensed silica network comprising and/or formed from diazeniumdiolated ethylaminoisobutylsiloxane (EAIB3- NONOate) and tetraethyl orthosilicate (TEOS) and/or tetra methyl orthosilicate (TMOS).
  • the NO-releasing API may be ethylaminoisobutylsiloxane/methylaminopropylsiloxane-co-polysiloxane (EAIB3 AP3- NONOate/TEOS).
  • the NO-releasing API may comprise an amorphous polymer.
  • the particle size (e.g., diameter) of a NO-releasing API may be in a range of about 20 nm to about 20 pm or any range therein, such as, but not limited to, about 100 nm to about 20 pm or about 1 pm to about 20 or 30 pm.
  • the particle size may be tailored to minimize or prevent toxicity and/or penetration through the epidermis (or compromised dermis) and into the blood vessels.
  • the particle size is distributed around a mean particle size (e.g., mean diameter) of less than 20 pm, or any range therein, and the size may allow the particle to enter a follicle.
  • a NO-releasing API may have a particle size that is distributed around a mean particle size of about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 pm. In some embodiments, a NO-releasing API may have a particle size that is distributed around a mean particle size of less than 10 pm, or any range therein, such as, but not limited to about 2 pm to about 10 pm or about 4 pm to about 8 pm. In some embodiments, the particle size may be distributed around a mean particle size of greater than 20 pm, or any range therein, and the size may prevent the particle from entering a follicle. In some embodiments, a mixture of particles with mean particle sizes distributed around two or more mean particle sizes may be provided.
  • a NO-releasing API may be micronized e.g., ball and/or jet milled). Methods for providing a desired particle size and/or micronization include, but are not limited to, those described in U.S. Patent Application Publication No. 2013/0310533, which is incorporated herein by reference in its entirety.
  • the nitric oxide-releasing active pharmaceutical ingredient has a mean particle size of about 20 nm to about 30 pm. In some embodiments, the nitric oxide-releasing active pharmaceutical ingredient has a mean particle size of about 2 pm to about 20 pm.
  • a NO-releasing API may have a low charge. In some embodiments, charge on a NO-releasing API may be controlled and/or modulated.
  • a composition of the present invention may comprise a NO-releasing API and may store and/or release nitric oxide in an amount of about 0.001% to about 10% by weight of the composition, such as, but not limited to, about 0.001% to about 0.05%, about 0.01% to about 0.1%, about 0.15% to about 2%, about 0.15% to about 1%, about 0.3% to about 1.2%, about 0.15% to about 6%, about 1% to about 10%, about 3% to about 6%, or about 1% to about 5% by weight of the composition.
  • a composition of the present invention may comprise a nitric oxide-releasing active pharmaceutical and may store and/or release nitric oxide in an amount of about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.15%, 0.3%, 0.6%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, or 10% by weight of the composition.
  • the amount of nitric oxide released may be determined using real time in vitro release testing. In some embodiments, nitric oxide release may be determined using a chemiluminescent ni
  • a composition of the present invention may include one or more excipient(s).
  • the composition comprises a flavoring agent.
  • the buffer and/or composition is/are devoid of a diluent (e.g., an additional diluent), a co-solvent, a preservative, an antioxidant, a suspending agent, a penetration enhancer, a surfactant, a viscosity-increasing agent, a humectant, a stabilizer, and/or a wetting agent.
  • kits may include a first composition comprising a nitric oxide-releasing active pharmaceutical ingredient; and a second composition comprising a buffer of the present invention, wherein the first composition and second composition are separately stored in the kit.
  • the buffer is configured to maintain the pH of a composition comprising the first composition and second composition (e.g., a combined combination) in a range of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, or 8.5.
  • the buffer is a citrate buffer such as a citrate buffer comprising a citrate and/or citric acid in an amount of at least 100 mM.
  • the first composition comprising the nitric oxide-releasing active pharmaceutical ingredient may be a solid and/or the nitric oxide-releasing active pharmaceutical ingredient may be in a particulate form.
  • the second composition may be a solution.
  • the kit is configured to combine the first composition and the second composition to provide a combined composition.
  • the combined composition can be a composition as described herein.
  • the kit is configured to provide a combined composition that comprises the nitric oxide-releasing active pharmaceutical ingredient in an amount of about 0.1 mg/mL to about 30 mg/mL and the buffer (e.g., a citrate buffer) is configured to maintain the pH of the combined composition in a range of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, or 8.5.
  • the buffer e.g., a citrate buffer
  • kits are configured to administer and/or release the composition.
  • a kit of the present invention comprises a device configured for administering the composition.
  • a kit and/or device may administer and/or release a volume of about 15, 25, 50, 75, or 100 pL to about 150, 200, 300, 400, or 500 pL.
  • the kit and/or device is configured to administer and/or release a volume of about 15, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500 pL.
  • the kit and/or device is configured to aerosolize and/or atomize a composition of the present invention (e.g., a composition comprising the first and second compositions).
  • an aerosolized and/or atomized composition of the present invention has a mean droplet size (e.g., droplet diameter) of about 10, 20, 30, or 40 pm to about 50, 60, 70, 80, 90, or 100 pm. In some embodiments, an aerosolized and/or atomized composition of the present invention has a mean droplet size (e.g., droplet diameter) of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 pm. In some embodiments, an aerosolized and/or atomized composition of the present invention has a mean droplet size that limits or avoids inhalation of the droplets/aerosol into the lungs.
  • a composition of the present invention may be configured for intranasal administration.
  • a composition of the present invention is configured to be sprayed and/or is a sprayable composition.
  • the composition may be sprayed onto nasal mucosa and/or oral mucosa.
  • the composition may contact oropharyngeal tissue.
  • a composition of the present invention may be configured to be aerosolized and/or atomized and/or may be in the form of an aerosol and/or in the form of small droplets in a gas phase.
  • a composition of the present invention is configured to be administered to the nasal cavity of a subject and/or to oral mucosa of a subject.
  • the NO- releasing API may be locally delivered to the subject (e.g., to the nasal cavity and/or oral mucosa of the subject).
  • the local delivery of the NO-releasing API has a local effect and/or a systemic effect.
  • a composition of the present invention may be antiviral, antimicrobial, and/or antibacterial.
  • a buffer of the present invention may not be antiviral and/or is not viricidal.
  • a composition of the present invention administers and/or delivers nitric oxide in an amount sufficient to induce apoptosis in cells infected with a pathogen (e.g., a virus and/or bacteria).
  • a composition of the present invention administers and/or delivers nitric oxide in an amount sufficient to induce apoptosis in virally infected cells.
  • a composition of the present invention administers and/or delivers nitric oxide in an amount sufficient to reduce or eliminate viral replication, optionally with less than about 50% host cell cytotoxicity.
  • a method of treating and/or preventing an infection comprising administering a composition of the present invention to the subject.
  • the composition is administered to the subject by applying and/or spraying the composition onto nasal mucosa and/or oral mucosa of a subject.
  • the administering comprises intranasally administering the composition to the subject.
  • the method comprises, prior to administering the composition to the subject, combining a nitric oxide-releasing active pharmaceutical ingredient and a buffer of the present invention to provide the composition.
  • Combining the nitric oxide-releasing active pharmaceutical ingredient and the buffer may comprise adding the NO-releasing API to the buffer or adding the buffer to the NO-releasing API.
  • the nitric oxide-releasing active pharmaceutical ingredient and buffer are present in a device (e.g., a kit) that is configured to combine the nitric oxide-releasing active pharmaceutical ingredient and the buffer.
  • the NO-releasing API and buffer are combined and then provided in a device for administration.
  • a kit of the present invention may be a device configured for administration of the composition.
  • a device of the present invention may be for single use or multiple use.
  • the device is refillable.
  • the device is a nasal spray device and/or an atomization device.
  • the device comprises a syringe and a plug at the tip of the syringe that is configured to atomize the composition as it moves from the syringe and through the plug.
  • administering the composition comprises administering a volume of about 15, 25, 50, 75, or 100 pL to about 150, 200, 300, 400, or 500 pL of the composition to the subject.
  • a volume of about 15, 25, 50, 75, or 100 pL to about 150, 200, 300, 400, or 500 pL of the composition may be administered to each nostril of a subject per dose.
  • the method comprises administering a volume of about 15, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 pL of the composition/dose.
  • a method of the present invention may comprise administering a composition of the present invention to a subject at a time in which the composition has a pH of about 3, 3.5, 4, or 4.5 to about 5, 5.5, 6, 6.5, 7, 7.5, 8, or 8.5.
  • the composition is administered to the subject at a time in which the composition has a pH of about 5.5.
  • a method of the present invention may comprise administering and/or delivering exogenous, gaseous nitric oxide to the upper respiratory tract, lower respiratory tract, and/or lungs of a subject.
  • the exogenous, gaseous NO may be delivered to the upper respiratory tract, lower respiratory tract, and/or lungs upon administering a composition of the present invention to the nasal mucosa and/or oral mucosa of the subject.
  • the NO-releasing API and/or composition e.g., aerosolized composition
  • the NO-releasing API and/or composition are locally delivered to the subject.
  • a method of the present invention may reduce or prevent transmission of a pathogen to an uninfected subject, optionally compared to the amount of transmission in the absence of a method of the present invention.
  • the method reduces or prevents transmission of a virus (i.e., viral transmission) to an uninfected subject, optionally compared to the amount of viral transmission in the absence of a method of the present invention.
  • a virus i.e., viral transmission
  • a method of the present invention reduces the amount of a pathogen (e.g., a virus, bacteria, etc.) present in a subject (e.g., in a nasal cavity and/or lung of the subject) by at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the initial amount of the virus present in the subject.
  • a method of the present invention reduces the amount of a pathogen (e.g., a virus, bacteria, etc.) present in the lung(s) of the subject, optionally compared to the amount of the pathogen present in the lung(s) of the subject in the absence of a method of the present invention.
  • a method of the present invention reduces or prevents progression of pathogen and/or infection (e.g., a viral infection) into the lung(s) of the subject, optionally compared to the progression of the pathogen and/or infection into the lung(s) of the subject in the absence of a method of the present invention.
  • a method of the present invention may reduce the severity of an infection (e.g., a viral infection), optionally compared to the severity in the absence of a method of the present invention.
  • a composition and/or method of the present invention may reduce or prevent growth and/or replication of a pathogen (e.g., a virus).
  • the composition and/or method reduces or prevents viral replication.
  • the composition and/or method reduces or prevents bacterial growth.
  • the method may reduce or inhibit replication of the pathogen (e.g., virus) by disrupting a protein function.
  • a composition and/or method of the present invention may reduce or prevent shedding of a virus, optionally compared to a method in the absence of the present invention.
  • a method of the present invention increases oxygenation in the blood of a subject, optionally compared to the oxygen level in the blood prior to administration.
  • the method may provide a local and/or transient increase in oxygen in the blood of the subject.
  • the pathogen is a virus or bacteria.
  • a method of the present invention may treat and/or prevent an infection caused by the pathogen.
  • the infection may be a nosocomial infection.
  • a method of the present invention may treat and/or prevent an infection that is caused by a pathogen selected from a Coronaviridae virus, Staphylococcus aureus, influenza, and/or respiratory syncytial virus (RSV).
  • a pathogen selected from a Coronaviridae virus, Staphylococcus aureus, influenza, and/or respiratory syncytial virus (RSV).
  • RSV respiratory syncytial virus
  • the pathogen is a Coronaviridae virus such as, but not limited to, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory coronavirus 2 (SARS-CoV-2), a common cold virus (e.g., hCoV-229E and/or hCoV-OC43) and/or a variant thereof.
  • SARS-CoV-2 include, but not limited to, SARS-CoV-2 Alpha variant, SARS-CoV-2 Beta variant, SARS-CoV-2 Gamma variant, SARS-CoV-2 Delta variant, SARS-CoV-2 Omicron variant, and/or a variant thereof (e.g., an emerging variant).
  • a method of the present invention treats and/or prevents infection by a Coronaviridae virus such as SARS-CoV-2 and/or treats and/or prevents a coronavirus disease (e.g., COVID-19).
  • the pathogen is an influenza virus, such as Influenza A/California/7/2009 (H1N1) and/or a variant thereof.
  • a method of the present invention treats and/or prevents infection by an influenza virus, such as H1N1, and/or treats and/or prevents an influenza disease.
  • the pathogen is a respiratory syncytial virus, such as Respiratory syncytial virus strain A2 (RSV-A2) and/or a variant thereof.
  • a method of the present invention treats and/or prevents infection by a respiratory syncytial virus, such as RSV-A2), and/or treats and/or presents a respiratory syncytial viral disease.
  • a method of the present invention may comprise administering a composition of the present invention one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) times a day, optionally for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more days.
  • the composition is administered one, two, or three times a day for about 7 to about 14 days.
  • the method may comprise administering the composition to one or both nostrils of a subject optionally one, two, or three times a day for a period of time (e.g., 1 to 14 or more days).
  • a composition and/or method of the present invention provides a localized, topical treatment that can reduce pathogen burden (e.g., viral burden) in the nasal and/or oral epithelium and/or lung(s) of an infected subject and/or may reduce shedding (e.g., viral shedding) and/or transmission of the pathogen to another subject (e.g., an uninfected subject).
  • pathogen burden e.g., viral burden
  • a composition and/or method of the present invention may treat and/or reduce one or more symptom(s) of an infection and/or may disrupt progression of a disease (e.g., infection) before the disease spreads to the lower respiratory tract of a subject.
  • a composition and/or method of the present invention may treat and/or prevent an infection (e.g., a SARS-CoV-2 infection) in a subject by disrupting an ACE2 and/or S protein interaction and/or activity.
  • a composition and/or method of the present invention may inhibit bruton tyrosine kinase (BTK) and/or NF-KB and/or inhibit formation of the NLRP3 inflammasome.
  • a composition and/or method of the present invention may disrupt a protease function (e.g., a viral protease function) necessary for pathogen replication (e.g., viral replication).
  • Treat refers to any type of treatment that imparts a benefit to a subject and may mean that the severity of the subject’s condition is reduced, at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom associated with the condition (e.g., a viral infection) is achieved and/or there is a delay in the progression of the condition.
  • the severity of a condition such as, e.g., a viral infection (e.g., a viral infection caused by SARS-CoV-2), may be reduced in a subject compared to the severity of the condition in the absence of a method of the present invention.
  • a method of the present invention may treat a viral infection by eliminating at least one clinical symptom associated with the viral infection for a given period of time (e.g., 1, 2, 3, 4, 5, or 6 day(s), or 1, 2, 3, 4, or more weeks, etc.).
  • a composition of the present invention is administered in a treatment effective amount.
  • a “treatment effective amount” and “therapeutically effective amount” are used interchangeably herein and refer to an amount that is sufficient to treat (as defined herein) a subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
  • a treatment effective amount of a composition of the present invention may be administered and may include administering a treatment effective amount of a nitric oxidereleasing active pharmaceutical ingredient.
  • a treatment effective amount of nitric oxide may be administered and/or applied in a method of the present invention.
  • a method of the present invention is carried out in a manner such that the administration of a composition comprising a nitric oxide (NO)-releasing active pharmaceutical ingredient (API) does not produce systemic effects (e.g., adverse systemic effects) from the administration of nitric oxide, such as, for example, when the composition, NO-releasing API, and/or NO is administered in a treatment effective amount.
  • NO nitric oxide
  • API active pharmaceutical ingredient
  • a condition e.g., a viral infection
  • a clinical symptom associated therewith e.g., a viral infection
  • the prevention can be complete, e.g., the total absence of the condition and/or clinical symptom.
  • the prevention can also be partial, such that the occurrence of the condition and/or clinical symptom in the subject and/or the severity of onset is less than what would occur in the absence of a method of the present invention.
  • a method of the present invention prevents a viral infection in a subject, such as a viral infection that is caused by SARS-CoV-2.
  • a composition of the present invention is administered in a prevention effective amount.
  • a "prevention effective" amount as used herein is an amount that is sufficient to prevent (as defined herein) the condition (e.g., viral infection) and/or clinical symptom in the subject. Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.
  • a prevention effective amount of a composition of the present invention may be administered and may include administering a prevention effective amount of a nitric oxide-releasing active pharmaceutical ingredient.
  • a prevention effective amount of nitric oxide may be administered and/or applied in a method of the present invention.
  • a method of the present invention is carried out in a manner such that the administration of a composition comprising a NO-releasing API does not produce systemic effects (e.g., adverse systemic effects) from the administration of nitric oxide, such as, for example, when the composition, NO-releasing API, and/or NO is administered in a prevention effective amount.
  • systemic effects e.g., adverse systemic effects
  • the present invention finds use in both veterinary and medical applications. Suitable subjects of the present invention include, but are not limited to, avians and mammals.
  • avian as used herein includes, but is not limited to, chickens, ducks, geese, quail, turkeys, pheasants, parrots, parakeets, macaws, cockatiels, canaries, and finches.
  • mammal includes, but is not limited to, primates (e.g., simians and humans), non-human primates (e.g., monkeys, baboons, chimpanzees, gorillas), bovines, ovines, caprines, ungulates, porcines, equines, felines, canines, lagomorphs, pinnipeds, rodents (e.g., rats, hamsters, and mice), etc.
  • the subject is a mammal and in certain embodiments the subject is a human.
  • Human subjects include both males and females and subjects of all ages including fetal, neonatal, infantjuvenile, adolescent, adult, and geriatric subjects.
  • the methods of the present invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and/or for drug screening and drug development purposes.
  • the subject is "in need of' or "in need thereof a method of the present invention, for example, the subject is in an at-risk population (e.g., the subject may be at-risk for or more susceptible to a viral infection), the subject has findings typically associated with a viral infection, and/or the subject is suspected to be or to have been exposed to a virus.
  • a subject in need thereof has a viral infection and/or a clinical sign or symptom associated therewith that may be treated with a method of the present invention.
  • the present invention may be particularly suitable for children, adolescents, adults, and/or geriatric subjects.
  • a method of the present invention may administer nitric oxide to the basal layer of a subject's epithelium.
  • a method of the present invention may administer a treatment effective and/or a prevention effective amount of nitric oxide to the basal layer of a subject's epithelium.
  • nitric oxide may be administered to the basement membrane of a subject's epithelium.
  • a method of the present invention may administer nitric oxide in an amount sufficient to induce apoptosis or other cellular damage in virally infected cells. In some embodiments, a method of the present invention may administer nitric oxide in an amount sufficient to inhibit and/or prevent viral replication in virally infected cells. A method of the present invention may reduce viral replication by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% compared to the rate of replication prior to the method of the present invention.
  • a method of the present invention may treat and/or prevent a viral infection in a subject without cytotoxicity to host cells or with reduced cytotoxicity to host cells.
  • the method may treat and/or prevent the viral infection in the subject with reduced host cell cytotoxicity compared to a different method for treating the viral infection, such as, for example, one that does not administer nitric oxide to the skin and/or tissue of a subject or one that uses acidified nitrite.
  • a method of the present invention may reduce host cell cytotoxicity by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% compared to a different method for treating the viral infection.
  • a method of the present invention may reduce and/or eliminate viral replication with no or minimal host cell cytotoxicity.
  • the method may provide a host cell cytotoxicity of about 50% or less (e.g., about 40%, 30%, 20%, 10%, 5%, or less).
  • Cytotoxicity may be determined using methods known to those of skill in the art, such as, for example, a qualitative reading of hematoxylin & eosin (H&E) slides, a lactate dehydrogenase (LDH) assay and/or a 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H- tetrazolium bromide (MTT) assay.
  • a method of the present invention may not cause apoptosis.
  • the method may not cause apoptosis in keratinocyte layers of the skin and/or tissue.
  • a method of the present invention may reduce the amount of viral DNA in virally infected cells of a subject and/or in the nasal cavity of a subject.
  • a method of the present invention may reduce the amount of viral DNA (e.g., in virally infected cells) by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% compared to the amount of viral DNA present prior to the method of the present invention.
  • berdazimer sodium a polysiloxane, polymeric scaffold including tetraethoxysilane (TEOS), /'/-methylaminopropyl trimethoxysilane (MAP3), and N, A-methyl ami nopropyl diazenium diolate trimethoxy silane (MAP3-NONOate)) and MAP3- NONOate were evaluated against SARS-CoV-2 (strain USA-WA1/2020) in a highly differentiated, three-dimensional (3-D), in vitro model of normal, human-derived tracheal/bronchial epithelial (TBE) cells.
  • the compounds were tested at 4 concentrations in singlet or duplicate inserts of the 3D tissue models of the human airway (MatTek Life Sciences) as indicated in Table 1. Antiviral activity was measured by virus yield reduction assays 5 days after infection.
  • test compounds were provided as solids and stored at -20 °C upon arrival.
  • a single aliquot of the compound Berdazimer Sodium was dissolved in 100% DMSO at concentrations of 200, 160, 80, and 20 mg/mL just prior to the start of the experiment then further diluted to the test dilutions in the MatTek culture medium (AIR-100-MM).
  • a single aliquot of the compound MAP3-NONOate was dissolved in 100% methanol at concentrations of 200, 160, 80, and 20 mg/mL the morning of the experiment then further diluted to the test dilutions in the MatTek culture medium.
  • Remdesivir (MedChemExpress, cat# HY-104077) was tested in singlet wells at 1, 0.1, 0.01, and 0.001 pg/mL as the positive control.
  • the EpiAirwayTM Model consists of normal, human-derived tracheal/bronchial epithelial (TBE) cells which have been cultured to form a multi layered, highly differentiated model which closely resembles the epithelial tissue of the respiratory tract.
  • TBE tracheal/bronchial epithelial
  • the cell cultures were made to order by MatTek Life Sciences (https://www.mattek.com) (Ashland, MA) and arrived in kits with either 12- or 24-well inserts each.
  • the TBE cells were grown on 6mm mesh disks in transwell inserts. During transportation the tissues were stabilized on a sheet of agarose, which was removed upon receipt.
  • One insert was estimated to consist of approximately 1.2 x 106 cells.
  • Kits of cell inserts originated from a single donor, # 9831, a 23-year old, healthy, non-smoking, Caucasian male.
  • the cells have unique properties in forming layers, the apical side of which is exposed only to air and that creates a mucin layer.
  • the cell transwell inserts were immediately transferred to individual wells of a 6-well plate according to manufacturer’s instructions, and 1 mL of MatTek’ s proprietary culture medium (AIR-100-MM) was added to the basolateral side, whereas the apical side was exposed to a humidified 5% CO2 environment.
  • the TBE cells were cultured at 37°C for one day before the start of the experiment.
  • Viruses SARS-CoV-2 strain USA-WA1/2020 was passaged three times in Vero 76 cells to create the virus stock. Virus was diluted in AIR-100-MM medium before infection, yielding a multiplicity of infection (MOI) of approximately 0.01 CCID50 per cell.
  • test compounds were prepared fresh, drug was removed from the duplicate wells and treated with fresh drug.
  • the basal side of the singlet wells were replaced with fresh growth medium containing the DMSO or methanol only, no test compound.
  • the medium was removed and discarded from the basal side.
  • Virus released into the apical compartment of the tissues was harvested by the addition of 400 pL of culture medium that was pre-warmed at 37°C. The contents were incubated for 30 min, mixed well, collected, thoroughly vortexed and plated on Vero 76 cells for VYR titration. Triplicate and singlet wells were used for virus control and cell controls, respectively.
  • Vero 76 cells were seeded in 96-well plates and grown overnight (37°C) to 90% confluence. Samples containing virus were diluted in 10-fold increments in infection medium and 200 pL of each dilution transferred into respective wells of a 96-well microtiter plate. Four microwells were used for each dilution to determine 50% viral endpoints. After 7 days of incubation, each well was scored positive for virus if any cytopathic effect (CPE) was observed as compared with the uninfected control, and counts were confirmed for endpoint on day 10.
  • CPE cytopathic effect
  • the virus dose that was able to infect 50% of the cell cultures was calculated by the Reed-Muench method (Reed, L.J., Muench, H., 1938. A simple method of estimating fifty percent endpoints. The American Journal of Hygiene 27, 493-497). The day 7 values are reported. Untreated, uninfected cells were used as the cell controls.
  • Virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) USA_WAl/2020 strain was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). The virus was passaged two times in Vero 76 cells to generate a working stock for infection of hamsters.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) USA_WAl/2020 strain was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). The virus was passaged two times in Vero 76 cells to generate a working stock for infection of hamsters.
  • EIDD-2801 was purchased from MedChem Express by USU.
  • EIDD- 2801 (Molnupravir) is a ribonucleoside analog that has demonstrated activity across a wide range of RNA viruses including coronaviruses (2).
  • Berdazimer sodium was prepared for dosing by preparing a stock in 100% dimethyl sulfoxide (DMSO) at 400, 200, and 100 mg/mL which was then diluted 200-fold into a buffer made up of a 1 : 1 ratio of Hy clone MEM from USU and 50 mM and pH 4.5 citrate.
  • DMSO stocks of berdazimer sodium prepared 20-30 minutes prior to dosing were added to the MEM/citrate buffer within 5 minutes prior to dosing of animals.
  • EIDD-2801 was administered per os (PO) twice daily beginning 4 hours post-infection.
  • EIDD-2801 was solubilized in 10% DMSO and 90% com oil. Five animals per group were euthanized on study days 3 and 6 to evaluate lung virus titers, nasal virus titers, and lung weights. Oropharyngeal swabs were collected from 5 animals per group on study days 1- 6.
  • Experiment Design Transmission Study (PHA-254B): A total of 20 5-week-old female golden Syrian hamsters were randomized into 2 groups of 2 animals and 4 groups of 4 animals (Table 3). Animals in groups 1 and 4 served as infected donor animals. Animals in group 2, 3, 5, and 6 were uninfected (naive) animals and were cohabitated with animals from groups 1 or 4 for 4 hours each day on study days 1, 2, and 3. Animals in groups 1, 2, and 5 were treated with DMSO in MEM/citrate buffer as a placebo. Animals in groups 3, 4, and 6 were treated once daily with 2 mg/mL (2 mg/kg/d) berdazimer sodium 2 hours prior to cohabitation with infected animals.
  • Treatment with berdazimer sodium began on the day of infection which was 24 hours prior to the first cohabitation session. Hamsters were weighed prior to infection and then everyday thereafter to evaluate infection-associated weight loss. All animals were euthanized on study day 4 to evaluate lung vims titers, nasal tissue vims titers, lung weights, and the transmission of vims from infected animals to naive animals. Daily oropharyngeal swabs were collected on all animals.
  • Tissues homogenates and oropharyngeal swab samples were titrated by endpoint dilution.
  • Serial logio dilutions of tissue homogenate or oropharyngeal swab samples were plated in quadruplicate wells of 96-well microplates containing confluent monolayers of Vero 76 cells. The plates were incubated in a 37°C incubator with 5% CO2 for 6 days. The plates were then scored by visual observation under a light microscope for the presence of cytopathic effect (CPE). Vims titer for each sample was calculated by linear regression using the Reed-Muench method.
  • CPE cytopathic effect
  • Fig. 1 Percent initial body weight of 5-week-old golden Syrian hamsters following challenge with SARS-CoV-2 and treatment with berdazimer sodium is shown in Fig. 1.
  • Treatment with berdazimer sodium did not prevent weight loss following infection.
  • Treatment with EIDD- 2801 at a dose of 200 mg/kg/d prevented weight loss in hamsters infected with SARS-CoV-2.
  • Percent weight loss was evaluated using a one-way ANOVA comparing the average weight loss over the entire experiment for each treatment group.
  • Fig. 2 shows lung virus titers of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. Treatment with berdazimer sodium did not significantly reduce lung virus titers in animals infected with SARS-CoV-2. Treatment with EIDD-2801 reduced lung virus titers of SARS-CoV-2-infected animals on day 6 postinfection. One animal in the group treated with 2 mg/kg/d of berdazimer sodium did not recover from the anesthesia following infection and was not included in the data set.
  • Table 4 shows the lung and nasal virus titers on study days 3 and 6. [00133] Table 4: Lung and nasal tissue virus titers on study days 3 and 6 of golden Syrian hamsters after treatment with berdazimer sodium and infection with SARS-CoV-2.
  • FIG. 3 shows nasal tissue virus titers of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. Treatment with berdazimer sodium did not significantly reduce nasal tissue virus titers in animals infected with SARS-CoV-2. Treatment with EIDD-2801 did not significantly reduce nasal virus titers after infection.
  • Table 5 Oropharyngeal swab virus titers on study days 1 through 6 of golden Syrian hamsters after treatment with berdazimer sodium and infection with SARS-CoV- 2-infected animals.
  • Fig. 5 shows lung weights of 5-week-old golden Syrian hamsters after challenge with SARS-CoV-2 and treatment with berdazimer sodium. Lung weights were not significantly affected by treatment with berdazimer sodium or EIDD-2801.
  • Fig. 6 shows percent initial body weight of 5-week-old golden Syrian hamsters treatment with berdazimer sodium and cohabitation with SARS-CoV-2-infected hamsters. Animals with the same color symbols were cohabitated on study days 1-3. Placebo-treated animals were protected from weight loss when the donor animals were treated with berdazimer sodium. Treatment with berdazimer sodium prevented weight loss following exposure to SARS-CoV-2-infected hamsters when the donor animals were also treated with berdazimer sodium. Percent weight loss was evaluated with a one-way ANOVA so weight loss for each treatment group was compared over the entire study.
  • Lung virus titers of hamsters on day 4 treated with berdazimer sodium and exposed to SARS-CoV-2-infected hamsters are shown in Fig. 7. Animals that were cohabitated on study days 1-3 are denoted with brackets. Treatment with berdazimer sodium significantly reduced lung virus titers in treated naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium. Virus was only detected in one of four animals that were treated with berdazimer sodium and cohabitated with donor animals that were also treated with berdazimer sodium. The virus titer detected in the one animal was reduced by over two logs compared to naive placebo-treated animals.
  • FIG. 8 shows nasal tissue virus titers of hamsters on day 4 treated with berdazimer sodium and exposed to SARS-CoV-2-infected hamsters. Animals that were cohabitated on study days 1-3 are denoted with brackets. Treatment with berdazimer sodium did not significantly reduce nasal tissue virus titers in animals cohabitated with SARS-CoV-2-infected hamsters.
  • Table 6 shows lung and nasal tissue virus titers of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2-infected animals.
  • Table 6 Lung and nasal tissue virus titers of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2-infected animals.
  • FIG. 9 shows oropharyngeal swab virus titers of 5-week-old golden Syrian hamsters after treatment with berdazimer sodium and cohabitation with SARS-CoV-2-infected hamsters. Treatment with berdazimer sodium at a dose of 2 mg/kg/d did not significantly reduce oropharyngeal swab titers.
  • Table 7 shows oropharyngeal swab virus titers on study days 1 through 4 of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2-infected animals.
  • Table 7 Oropharyngeal swab virus titers on study days 1 through 4 of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2-infected animals.
  • Lung weights of 5-week-old golden Syrian hamsters after treatment with berdazimer sodium and cohabitation with SARS-CoV-2-infected animals are shown in Fig. 10. Lung weights were not statistically different between groups when compared by one-way ANOVA.
  • berdazimer sodium treatment was able to decrease transmission of SARS-CoV-2 from infected animals even though no effect was observed in the efficacy study. No adverse events were observed in the hamsters treated with 2 mg/kg/d of berdazimer sodium.
  • Virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) USA_WAl/2020 strain was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). The virus was passaged two times in Vero 76 cells to generate a working stock for infection of hamsters.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) USA_WAl/2020 strain was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). The virus was passaged two times in Vero 76 cells to generate a working stock for infection of hamsters.
  • Animals in groups 3, 4, 6, 7, 9, 10, and 12 were treated once daily with either, 1, 2, or 8 mg/mL (1,2, or 8 mg/kg/d) berdazimer sodium 2 hours prior to cohabitation with infected animals.
  • treatment with berdazimer sodium began on the day of infection which was 24 hours prior to the first cohabitation session.
  • Hamsters were weighed prior to infection and then everyday thereafter to evaluate infection- associated weight loss. All animals were euthanized on study day 4 to evaluate lung virus titers, nasal tissue virus titers, lung weights, and the transmission of virus from infected animals to naive animals.
  • Tissues homogenates were titrated by endpoint dilution. Serial logio dilutions of tissue homogenates were plated in quadruplicate wells of 96-well microplates containing confluent monolayers of Vero 76 cells. The plates were incubated in a 37°C incubator with 5% CO2 for 6 days. The plates were then scored by visual observation under a light microscope for the presence of cytopathic effect (CPE). Virus titer for each sample was calculated by linear regression using the Reed-Muench method.
  • CPE cytopathic effect
  • Fig. 11 shows percent initial body weight of 16-week-old golden Syrian hamsters treatment with berdazimer sodium (8 mg/ml) and cohabitation with SARS-CoV-2-infected hamsters. Animals with the same color symbols were cohabitated on study days 1-3. No significant differences in body weight were observed in hamsters treated with berdazimer sodium (8 mg/ml) and cohabitated with SARS-CoV-2-infected hamsters.
  • Fig. 12 shows percent initial body weight of 16-week-old golden Syrian hamsters after treatment with berdazimer sodium (2 or 1 mg/ml) and cohabitation with SARS-CoV-2-infected hamsters. Animals with the same color symbols were cohabitated on study days 1-3. No significant differences in body weight were observed in hamsters treated with berdazimer sodium (2 or 1 mg/ml) and cohabitated with SARS-CoV-2-infected hamsters.
  • Lung virus titers of hamsters on day 4 treated with berdazimer sodium (8 mg/ml) and exposed to SARS-CoV-2-infected hamsters are shown in Fig. 13. Animals that were cohabitated on study days 1-3 are denoted with brackets. Treatment with berdazimer sodium (8 mg/ml) significantly reduced lung virus titers in treated naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium (8 mg/ml). Virus was only detected in two of four animals that were treated with berdazimer sodium (8 mg/ml) and cohabitated with donor animals that were also treated with berdazimer sodium (8 mg/ml). The virus titers detected in the two animals were reduced by over five logs compared to naive placebo-treated animals.
  • Lung virus titers of hamsters on day 4 treated with berdazimer sodium (2 or 1 mg/ml) and exposed to SARS-CoV-2-infected hamsters are shown in Fig. 14. Animals that were cohabitated on study days 1-3 are denoted with brackets. Treatment with berdazimer sodium (2 mg/ml) significantly reduced lung virus titers in treated naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium (2 mg/ml).
  • Virus was only detected in two of four animals that were treated with berdazimer sodium (2 mg/ml) and cohabitated with donor animals that were also treated with berdazimer sodium (2 mg/ml). The virus titers detected in the two animals were reduced by over five logs compared to naive placebo-treated animals. Treatment with berdazimer sodium (1 mg/ml) did not significantly reduce lung virus titers in treated naive animals that were cohabitated with infected animals that were also treated with berdazimer sodium (1 mg/ml).
  • Table 9 shows Lung virus titers of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2-infected animals. [00169] Table 9: Lung virus titers of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-
  • FIG. 15 shows nasal tissue virus titers of hamsters on day 4 treated with berdazimer sodium (8 mg/ml) and exposed to SARS-CoV-2-infected hamsters. Animals that were cohabitated on study days 1-3 are denoted with brackets. Treatment with berdazimer sodium (8 mg/ml) did not significantly reduce nasal tissue virus titers in animals cohabitated with SARS-CoV-2-infected hamsters.
  • FIG. 16 shows nasal tissue virus titers of hamsters on day 4 treated with berdazimer sodium (2 or 1 mg/ml) and exposed to SARS-CoV-2-infected hamsters. Animals that were cohabitated on study days 1-3 are denoted with brackets. Treatment with berdazimer sodium (2 or 1 mg/ml) did not significantly reduce nasal tissue virus titers in animals cohabitated with SARS-CoV-2-infected hamsters.
  • Table 10 shows the nasal tissue virus titers of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2- infected animals.
  • Table 10 Nasal tissue virus titers of golden Syrian hamsters after treatment with berdazimer sodium prior to cohabitation with SARS-CoV-2-infected animals.
  • Lung weights of 16-week-old golden Syrian hamsters after treatment with berdazimer sodium (2 or 1 mg/ml) and cohabitation with SARS-CoV-2-infected animals are shown in Fig. 18. Lung weights were not statistically different between groups when compared by one-way ANOVA.
  • the virus was not detected in the lungs of two of the four naive animals that were exposed to infected animals and was reduced by five logs in the remaining animals.
  • Virus was detected in the nasal tissue samples of all four animals per dose group indicating that the animals were infected but that treatment with berdazimer sodium prevented the virus from infecting the lungs.
  • the objective of this study was to assess the efficacy of berdazimer sodium for treatment of a SARS-CoV-2 infection in wild-type golden Syrian hamsters.
  • Administration of berdazimer sodium in either daily or twice daily treatment regimens at a 2 mg/mL treatment dose and in daily treatment regimens at 4 and 8 mg/mL treatment doses were evaluated.
  • Virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) USA_WAl/2020 strain was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). The virus was passaged two times in Vero 76 cells to generate a working stock for infection of hamsters.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) USA_WAl/2020 strain was obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). The virus was passaged two times in Vero 76 cells to generate a working stock for infection of hamsters.
  • EIDD-2801 was purchased from MedChem Express by USU.
  • EIDD- 2801 (Molnupravir) is a ribonucleoside analog that has demonstrated activity across a wide range of RNA viruses including coronaviruses.
  • Berdazimer sodium was prepared for dosing by first preparing a stock. Briefly, stock was prepared in 100% dimethylsful oxide (DMSO) at 1600, 800, and 400 mg/mL which was then diluted 200-fold into a buffer made up of a 1 : 1 ratio of Hyclone MEM from USU and 50 mM and pH 4.5 citrate.
  • DMSO dimethylsful oxide
  • DMSO stocks of berdazimer sodium were prepared 20-30 minutes prior to dosing and were added to the MEM/citrate buffer within 5 minutes prior to dosing of animals.
  • EIDD-2801 was administered per os (PO) twice daily beginning 4 hours post-infection.
  • EIDD-2801 was solubilized in 10% DMSO and 90% corn oil.
  • Five animals per group were euthanized on study days 3 and 6 to evaluate lung virus titers, nasal virus titers, and lung weights. In groups 1 and 2, 10 animals from each group were euthanized on day 6 since 5 extra animals were included in these groups in the event that they did not recover from anesthesia.
  • Table 11 Experimental Design - Efficacy Study
  • Fig. 19 shows percent initial body weight of hamsters treated once daily with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2. Treatment with berdazimer sodium began 24 hours prior to infection.
  • Fig. 20 shows lung virus titers of hamsters on day 3 and 6 treated once daily with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2.
  • Treatment with berdazimer sodium began 24 hours prior to infection.
  • Treatment with berdazimer sodium at a dose of 4 mg/mL significantly reduced lung virus titers on day 3 post-infection.
  • Treatment with EIDD-2801 at a dose of 500 mg/kg/d significantly reduced lung virus titers on day 3 postinfection. This one logio reduction in virus titers is comparable to other studies completed using EIDD-2801.
  • FIG. 21 shows nasal tissue virus titers of hamsters on day 3 and 6 treated with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2. Treatment with berdazimer sodium began 24 hours prior to infection. Once daily treatment with berdazimer sodium at doses of 2, 4, or 8 mg/mL did not significantly reduce nasal tissue virus titers. Treatment with EIDD-2801 at a dose of 500 mg/kg/d did not significantly reduce nasal tissue virus titers.
  • Fig. 22 shows lung weights of hamsters on day 3 and 6 treated with berdazimer sodium (2, 4, or 8 mg/ml) and infected with SARS-CoV-2.
  • Treatment with berdazimer sodium began 24 hours prior to infection. Once daily treatment with berdazimer sodium at doses of 2, 4, or 8 mg/mL did not significantly reduce lung weights.
  • Treatment with EIDD-2801 at a dose of 500 mg/kg/d did not significantly reduce lung weights.
  • hamsters treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2 are shown in Fig. 23.
  • Treatment with berdazimer sodium began 24 hours prior to infection. Twice daily treatment with berdazimer sodium at a dose of 2 mg/mL did not prevent weight loss in hamsters infected with SARS-CoV-2.
  • hamsters treated with EIDD-2801 at a dose of 500 mg/kg/d lost less body weight than placebo-treated hamsters.
  • Lung virus titers of hamsters on day 3 and 6 treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2 are shown in Fig. 24.
  • Treatment with berdazimer sodium began 24 hours prior to infection. Twice daily treatment with berdazimer sodium at a dose of 2 mg/mL did reduce lung virus titers on day 3 post-infection by approximately /i log, however, the difference was not statistically significant.
  • FIG. 25 Nasal tissue virus titers of hamsters on day 3 and 6 treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2 are shown in Fig. 25.
  • Treatment with berdazimer sodium began 24 hours prior to infection. Twice daily treatment with berdazimer sodium at a dose of 2 mg/mL significantly reduced nasal tissue virus titers on day 3 postinfection.
  • Treatment with EIDD-2801 at a dose of 500 mg/kg/d significantly reduced nasal tissue virus titers on day 3 post-infection.
  • Table 12 shows the lung and nasal tissue virus titers on study days 3 and 6 of golden Syrian hamsters after treatment with berdazimer sodium and infection with SARS-CoV-2.
  • Table 12 Lung and nasal tissue virus titers on study days 3 and 6 of golden Syrian hamsters after treatment with berdazimer sodium and infection with SARS-CoV-2.
  • Lung weights of hamsters on day 3 and 6 treated twice daily with berdazimer sodium (2 mg/ml) and infected with SARS-CoV-2 are shown in Fig. 26.
  • Treatment with berdazimer sodium began 24 hours prior to infection.
  • Lung weights were significantly increased on day 6 post-infection by twice daily treatment with berdazimer sodium. This is not likely due to the intranasal treatments since a similar increase in lung weights was observed in hamsters treated with EIDD-2801.
  • hamsters treated with 8 mg/mL of berdazimer sodium lost less weight than placebo-treated hamsters.
  • two of the ten animals treated with 8 mg/mL of berdazimer sodium died on day 3 post-infection.
  • Wild-type hamsters infected with SARS-CoV-2 do not normally succumb to infection but intranasal treatment may have exacerbated the infection.
  • a prior study was conducted at the same regimen and dose level (8 mg/mL) and no premature deaths were observed.
  • the objectives of this study were to determine the potential toxicity of a composition (also referred to as test article) comprising berdazimer sodium (API) and a buffer, when the composition is administered intranasally 5 times a day for 14 days to dogs and to evaluate the potential reversibility of any findings.
  • the buffer in the composition was a 200 mM citrate buffer having a pH of 4.5.
  • the experimental design is provided in Table 13.
  • the approximate daily dose levels were based on mean bodyweights of 8.5 kg for males and 6.5 kg for females, so the Daily Dose Level (mg/kg/day) was, for males, 0 mg/kg/day for Group 1, 0.47 mg/kg/day for Group 2, 0.94 mg/kg/day for Group 3, and 1.65 mg/kg/day for Group 4, and, for females, 0 mg/kg/day for Group 1, 0.61 mg/kg/day for Group 2, 1.23 mg/kg/day for Group 3, and 2.15 mg/kg/day for Group 4.
  • Table 13 Experimental Design. a Dosed intranasally 5 times a day (2 hours ⁇ 30 minutes apart) for 14 days. b Dose volume was equally split between both nostrils. c 200 mM Citrate Buffer, pH 4.5.
  • the no-observed-adverse-effect level was considered to be 14 mg/day (i.e., 1.65 mg/kg/day in males and 2.15 mg/kg/day in females).
  • NOAEL no-observed-adverse-effect level
  • the mean Cmax and AUC(o-24h) values for males were 11,800 pg/mL and 179,000 h»pg/mL, and for females 10,700 pg/mL and 173,000 h»pg/mL, respectively, after 14 days of treatment.
  • Buffer concentration, pH, and osmolality were evaluated in view of the alkaline API (berdazimer sodium).
  • test formulations 11b - 17b were prepared at multiple berdazimer sodium concentrations between 2 mg/mL and 18 mg/mL, using only buffer as the test formulation vehicle. All samples were prepared w/v by weighing API into glass vials and diluting with 10 mL of the respective buffer to target the necessary berdazimer sodium concentration. The samples were then assessed for test formulation pH and osmolality. The vehicle samples were also assessed for pH and osmolality. For test formulations 6b and 7b, the samples were prepared at a 2 mg/mL and 24 mg/mL concentration.
  • test formulations 15b and 16b Upon compounding, a large amount of thick foam was produced in test formulations 15b and 16b, while a small amount of foam was produced in test formulations 17b and 1 lb.
  • API wetting and dispersibility the API readily wetted, creating a finely dispersed suspension.
  • all test formulations expect 15b returned near the target pH of pH 5.50.
  • the pH value of test formulation 15b returned at pH 7.07, suggesting that a 100 mM buffer concentration is not strong enough to buffer against a 12 mg/mL API concentration.
  • osmolality similar trends were observed, and all values returned within the tolerable range for intranasal dosing.
  • test formulations 15b- 17b Upon compounding, a large amount of thick foam was produced in test formulations 15b- 17b, while a small amount of foam being produced in test formulation 1 lb.
  • API wetting and dispersibility the API readily wetted, creating a finely dispersed suspension.
  • pH all test formulations expect 15b returned near the target pH of pH 5.50.
  • osmolality similar trends were observed, and all values returned within the tolerable range for intranasal dosing.
  • 16 mg/mL Samples Upon compounding, a large amount of thick foam was produced in test formulations 15b and 1 lb, while a small amount of foam was produced in test formulations 16b and 17b.
  • the antiviral activity of berdazimer sodium was evaluated against Respiratory syncytial virus (RSV-A2) and Influenza A/California/7/2009 (H1N1) in a highly differentiated, three-dimensional (3-D), in vitro model of normal, human-derived tracheal/bronchial epithelial (TBE) cells.
  • the compound was tested at various concentrations in triplicate inserts of the 3D tissue models of human Epi Airway (MatTek Life Sciences).
  • Antiviral activity was measured by virus yield reduction assays 3 (H1N1) and 6 (RSV-A2) days after infection.
  • the Epi AirwayTM Model consists of normal, human-derived tracheal/bronchial epithelial (TBE) cells which have been cultured to form a multi layered, highly differentiated model which closely resembles the epithelial tissue of the respiratory tract.
  • TBE tracheal/bronchial epithelial
  • the cell cultures were made to order by MatTek Life Sciences (https://www.mattek.com) (Ashland, MA) and arrived in kits with either 12- or 24-well inserts each.
  • the TBE cells were grown on 6mm mesh disks in transwell inserts. During transportation, the tissues were stabilized on a sheet of agarose, which was removed upon receipt, 24 hours after being shipped.
  • One insert was estimated to consist of approximately 1.2 x 10 6 cells.
  • Kits of cell inserts originated from a single, healthy, non-smoker donor #9831.
  • the cell transwell inserts were immediately transferred to individual wells of a 6-well plate according to manufacturer’s instructions. 1 mL of MatTek’s proprietary culture medium (AIR-100-MM) was then added to the basolateral side, whereas the apical side was exposed to a humidified 5% CO2 environment.
  • the TBE cells were cultured at 37°C for two days before the start of the experiment.
  • the mucin layer secreted from the apical side of the cells, was removed by washing three times with 400 pL pre-warmed 30 mM HEPES buffered saline solution. Culture medium was replenished to the basal side following the wash steps. The tissues were then allowed to rest in a 37°C and 5% CO2 environment for a minimum of 1 hour prior to the assay.
  • Viruses RSV-A2 (ATCC VR-1540) was passaged twice in MA-105 cells to create the virus stock. The virus dose that was able to infect 50% of the cell cultures (CCID50 per 0.2 mL) was calculated by the Reed-Muench method (1938). The virus stock was then diluted in AIR-100-MM and infected at MOI 0.1 CCID50 per cell. Influenza A (H1N1) was passaged twice in MDCK cells to create the virus stock. The virus dose that was able to infect 50% of the cell cultures (CCID50 per 0.2 mL) was calculated by the Reed-Muench method (1938). The virus stock was then diluted in AIR-100-MM and infected at MOI 0.001 CCID50 per cell.
  • Cytotoxicity assay The CCK-8 colorimetric assay is based on the reduction of highly water-soluble tetrazolium salt, WST-8, which produces orange water-soluble formazan dye in the presence of an electron mediator. The amount of formazan is directly proportional to the number of living cells and the resulting colored solution is quantified by measuring absorbance at 450 nanometers using a multi-well spectrophotometer. Drug concentrations of 2 mg/ml and 1 mg/ml were tested in duplicate wells, and a drug concentration of 0.5 mg/ml was tested in singlet wells. On day 3 (H1N1) or day 6 (RSV), the apical side was washed one time with 400 pL pre-warmed PBS.
  • the CCK-8 solution was added (200 pL) to the apical side and incubated at 37°C for 2 hours.
  • the formazan (100 pl) was placed into a 96-well plate and the 450 nm absorbance was recorded.
  • Percent toxicity values were calculated as a percentage of the cell control test wells (no drug treatment) and reported as the 50% cell cytotoxic concentration (CC50) of compound (no virus). Tissues were also observed via microscopy to assess cytotoxicity.
  • VYR titer data, EC90 and CC50 values are summarized in Tables 23-25.
  • Table 23 Antiviral efficacy against Respiratory syncytial virus strain A2 (RSV- A2) when fresh drug was prepared on days 1, 2, and 5 of the infection.
  • VYR virus yield reduction
  • b EC9o VYR 90% effective concentration (reduce virus yield by 1 logio) as determined by regression analysis.
  • c CCso 50% cell cytotoxic concentration of compound (no virus)
  • d SI CC50/ EC90; Selectivity Index is a measure of the window between cytotoxicity and antiviral activity. The higher the SI ratio, the more effective and safe a drug would be during in vivo treatment for a given viral infection.
  • Table 24 Antiviral efficacy against Respiratory syncytial virus strain A2 (RSV- A2) when fresh drug was prepared on days 1-5 of the infection.
  • VYR virus yield reduction
  • b EC9o VYR 90% effective concentration (reduce virus yield by 1 logio) as determined by regression analysis.
  • c CCso 50% cell cytotoxic concentration of compound (no virus)
  • d SI CCso/ EC90; Selectivity Index is a measure of the window between cytotoxicity and antiviral activity. The higher the SI ratio, the more effective and safe a drug would be during in vivo treatment for a given viral infection.
  • Table 25 Antiviral efficacy against Influenza A/California/7/2009 (H1N1) when fresh drug was prepared on days 1 and 2 of the infection.
  • VYR virus yield reduction
  • b EC9o VYR 90% effective concentration (reduce virus yield by 1 logio) as determined by regression analysis.
  • c CCso 50% cell cytotoxic concentration of compound (no virus)
  • d SI CCso/ EC90; Selectivity Index is a measure of the window between cytotoxicity and antiviral activity. The higher the SI ratio, the more effective and safe a drug would be during in vivo treatment for a given viral infection.

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US20100098733A1 (en) * 2008-10-16 2010-04-22 Novan, Inc. Nitric oxide releasing particles for oral care applications
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