HK40084501A - Sialic acid compositions for use in inhibiting and treating coronavirus infection - Google Patents

Description

Sialic acid compositions for inhibiting and treating coronavirus infection

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application 63/003,477, filed on 1/4/2020, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to the use of compositions comprising sialic acid to inhibit or treat coronavirus infections and in particular those infections caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

Background

Coronaviruses are a family of viruses that can cause diseases such as the common cold, severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS). In 2019, a new coronavirus outbreak. This virus is now known as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease it causes is called 2019 coronavirus disease (COVID-19). Cases of COVID-19 have been reported around the world, and the WHO announced a global pandemic in 3 months of 2020.

Signs and symptoms of COVID-19 may appear two to 14 days after exposure and may include: fever is caused; cough; and shortness of breath or dyspnea. Other symptoms may include: tiredness; pain; runny nose; and sore throat. The severity of the COVID-19 symptoms can range from very mild to severe. Some people are asymptomatic. Persons older in age or suffering from an existing chronic medical condition (such as heart or lung disease or diabetes) may be at higher risk of a serious condition.

There is a need in the art for safe compositions for inhibiting or treating SARS-CoV-2 infection.

Disclosure of Invention

The present invention relates to the use of compositions comprising sialic acid to inhibit or treat coronavirus infections, and in particular those infections caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

Thus, in some preferred embodiments, the present invention provides a method for treating or inhibiting a SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject, the method comprising: administering to the subject a composition comprising an effective concentration of sialic acid under conditions such that SARS-CoV-2 infection is inhibited or treated.

In some preferred embodiments, the present invention provides a method for preventing SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject, the method comprising: administering to the subject a composition comprising an effective concentration of sialic acid under conditions such that SARS-CoV-2 infection is inhibited.

In some preferred embodiments, the invention provides sialic acid for use in treating or inhibiting SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject.

In some preferred embodiments, the invention provides sialic acid for use in preventing SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject.

In some preferred embodiments, the sialic acid is selected from the group consisting of n-acetylneuraminic acid (NANA) and n-glycolylneuraminic acid (NGNA). In some preferred embodiments, the sialic acid is NANA.

In some preferred embodiments, the sialic acid is administered intranasally. In some preferred embodiments, the effective concentration of sialic acid is from about 0.1 to about 100mg/ml in aqueous solution. In some preferred embodiments, the effective concentration of sialic acid is from about 0.5 to about 50mg/ml in the aqueous solution. In some preferred embodiments, the daily dose of sialic acid is about 0.1 to 100mg sialic acid per nostril per day. In some preferred embodiments, the daily dose of sialic acid is about 0.1 to 10mg sialic acid per nostril per day. In some preferred embodiments, the pH of the composition comprising sialic acid is preferably in the range of 2.0 to 4.0 in aqueous solution. In some preferred embodiments, the pH of the composition comprising sialic acid is preferably in the range of 2.5 to 3.7 in aqueous solution. In some preferred embodiments, the pH of the composition comprising sialic acid is preferably in the range of 2.8 to 3.2 in aqueous solution. In some preferred embodiments, the daily dose of sialic acid is delivered in 2 to 8 administrations per day. In some preferred embodiments, the composition further comprises a thixotropic agent.

In some preferred embodiments, the sialic acid is administered orally. In some preferred embodiments, the daily dose of sialic acid is from 20 to 200 grams. In some preferred embodiments, the daily dose of sialic acid is 50 to 150 grams. In some preferred embodiments, the daily dose is administered in 1 to 20 doses. In some preferred embodiments, the sialic acid is administered as an aqueous solution. In some preferred embodiments, the aqueous solution includes an additive selected from the group consisting of a fragrance, a stabilizer, and a preservative, wherein the additive does not naturally occur with sialic acid.

In some preferred embodiments, the subject is at risk of being infected with SARS-CoV-2.

In some preferred embodiments, the subject has COVID-19.

Additional embodiments are described herein.

Definition of

As used herein, the term "SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2)" includes any strain of coronavirus identified as SARS-CoV-2, including mutants of the SARS-CoV-2 reference genomic sequence.

As used herein, the term "inhibit" when used in reference to SARS-CoV-2 infection refers to a reduction in infection in a subject exposed to SARS-CoV-2.

"patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cattle, swine, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

"administering" or "administering" a substance, compound, or agent to a subject can be performed using one of a variety of methods known to those of skill in the art. For example, sialic acid can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a dermal catheter). The compound or agent may also be suitably introduced by a rechargeable or biodegradable polymeric device or other device (e.g., patch and pump) or formulation that provides for extended, slow or controlled release of the compound or agent. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time. In some aspects, administration includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a physician who instructs a patient to self-administer a drug or has a drug administered by another person and/or provides a prescription for a drug to a patient is to administer a drug to a patient.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent (such as sialic acid) is the amount of the drug or agent that will have the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur by administration of one dose, and may only occur after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The exact effective amount required by a subject will depend, for example, on the size, health and age of the subject, the nature and extent of the symptoms of the condition being treated (such as COVID-19). The skilled person can readily determine the effective amount for a given situation by routine experimentation.

A "prophylactically effective amount" or "prophylactically effective dose" of a drug or agent (such as sialic acid) is an amount of the drug or agent that will have the intended prophylactic effect when administered to a subject. A complete prophylactic effect does not necessarily occur by administration of one dose, and may only occur after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact effective amount required by a subject will depend upon, for example, the size, health and age of the subject, the nature and extent of the symptoms of the condition being treated (such as SARS-CoV-2 infection). The skilled person can readily determine the effective amount for a given situation by routine experimentation.

"treating" a condition or patient refers to taking measures to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation, amelioration, or slowing of the progression of one or more symptoms associated with COVID-19. In certain embodiments, the treatment may be prophylactic, such as for preventing SARS-CoV-2 infection.

As used herein, the term "dietary supplement" refers to a small amount of a compound packaged in single or multiple dose units for supplementing the diet of a human or animal. Dietary supplements do not typically provide substantial calories, but may include other micronutrients (e.g., vitamins or minerals).

As used herein, the term "nutritional supplement" refers to a composition that includes a "dietary supplement" in combination with a source of calories. In some embodiments, the nutritional supplement is a meal replacement or supplement (e.g., a nutritional or energy bar or a nutritional beverage or concentrate).

Drawings

FIG. 1 provides data from one replicate showing infection of cells with CoV-OC43 at different concentrations of Neu5Ac or Neu5Gc.

FIG. 2 provides data from another replicate showing infection of cells by CoV-OC43 at different concentrations of Neu5Ac or Neu5Gc.

Figure 3 provides data from experiments in which Neu5Ac inhibition of infection was compared to the control sugar galactose.

Detailed Description

The present invention relates to the use of compositions comprising sialic acid to inhibit or treat coronavirus infections, and in particular those infections caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

Sialic acid is the generic name for N-or O-substituted derivatives of the monosaccharide neuraminic acid having nine carbon atoms. These substances are originally described in saliva, and therefore their name is derived from Greek saliva (sialon). Sialic acids are naturally present on the cell surface and at the ends of dense and complex braids of sugar molecules, proteins and lipids on many soluble proteins. Molecular, cellular and genetic studies have shown that sialic acid is involved in the control of cell and cell matrix interactions, intermolecular interactions on the cell surface and interactions with other molecules in the direct extracellular environment of cells 1.

Sialic acids are a family of nine-carbon keto-aldehyde nonanoic acids (keto-aldonolonic acids) present at the glycan end on the cell membrane. They are shown in large numbers on the surface of vertebrate cells, and in particular on all mucosal surfaces. N-acetyl neuraminic acid (Neu 5 Ac) is the most common form in mammalian cells.

Neu5Ac can be converted to Neu5Gc by the enzyme CMAH (cytidine monophosphate-N-acetylneuraminic acid hydroxylase). This enzyme is not found in humans because of a deletion in the gene encoding it. Therefore, it is assumed that humans lost the function of this gene in prehistoric times and, therefore, lost the ability to convert NeuAc to Neu5Gc. Unlike animals and some other organisms, humans can only synthesize Neu5Ac.

The two most common sialic acids are N-acetylneuraminic acid (Neu 5 Ac) and N-glycolylneuraminic acid (Neu 5 Gc). Carbon atom number 5 in Neu5AC (square) can be enzymatically modified to an N-acetyl group and further hydroxylated to form Neu5Gc (circle). The hydroxyl groups on a plurality of carbon atoms (C4, C7; C8 and C9) may further be modified, for example with O-acetyl, O-sulfate, O-lactyl, O-methyl and O-phosphate groups. Sialic acids are linked to carbohydrate chains on glycoproteins and glycolipids by different glycosidic linkages. The most common linkages are α 2,3 linkages to galactose moieties, α 2,6 linkages to galactose or N-acetylgalactosamine moieties, and α 2.8 linkages to another sialic acid moiety on the glycan. Sialic acid cleaves airway epithelium-and can act as a receptor for viruses. Recent studies using glycan microarrays and other complex methods have shown the complexity of interactions between sialic acid-containing receptors on cell surfaces and viral proteins. This provides an opportunity to study how the virus adheres to the cell surface in the airway epithelium (4).

According to Schalcter (2017) (5), neu5Ac is rapidly absorbed after ingestion. It is also rapidly excreted by urine. The highest concentrations of sialic acid are found in saliva, urine and in human brain.

The structure of Neu5Ac is characterized by four prominent functional groups (carboxylate, hydroxyl, N-acetyl, and glycerol functional groups). This large number of functional groups enables sialic acids to participate simultaneously in many hydrogen bonds, salt bridges and non-polar interactions. Since sialic acid is usually located at the ends of glycans, its binding site is readily accessible for interactions. A large number of viruses, including many serious human pathogens (e.g. human influenza a, b and c, coxsackie a24 variants and enterovirus 70, human JC and BK polyomaviruses, rotaviruses) use sialic acid in sialylated oligosaccharides for cell attachment. Neu et al, viral and clinical Acids, rules of engage, current Optin Structure biol. (2011) 21 (5), 610-618).

In most cases, the interaction between viral adsorption proteins and their glycan receptors is primarily related to sialic acid itself, which binds to a relatively small contact area in solvent exposed regions of the viral protein. In line with this, the affinity of such interactions is very low. Many viruses achieve significant specificity for sialylated oligosaccharides by establishing a minor auxiliary interaction with functional groups located outside sialic acid. After binding, they enter the cell using different mechanisms (endocytosis, pinocytosis, fusion) in order to take over the system for virus replication. A recent publication (Totororii et al, structural basis for human coronavirus attachment to a systemic acid receiver. Nat Structural Mol biol.2019Jun;26 (6): 481-489) proposes the structure of a human coronavirus site that binds to 9-0-acetylated sialic acid at the mucosa.

For viruses to be able to propagate and produce infection, the virus should not only adhere to epithelial surfaces, but should also enzymatically penetrate cells to take advantage of the cell's own replication machinery. In addition, new viral particles can emerge from the cell. The "opening" of the cell membrane may occur by neuraminidase, an enzyme that cleaves sialic acid from glycoconjugates. Thus, viral enzymes provide additional transmission of new viral particles. Studies have shown that they will also be able to neutralize silicic acid-containing soluble proteins that would otherwise interfere with surface-bound viruses (6,7).

Despite decades of research, effective antiviral compounds remain relatively rare compared to the burden of human disease caused by viruses. Coupled with the high mutation rate of certain viruses, which enables the emergence of antiviral resistant mutants at a surprising rate and frequency, the need for universal antiviral agents is now as important as before.

Accordingly, provided herein are compositions comprising sialic acid for use in treating or inhibiting SARS-CoV-2 infection. Administration of sialic acid is expected to increase the natural content of sialic acid in the nasal mucosa. In some preferred embodiments, sialic acid is delivered directly to the nasal mucosa via a spray, gel or other solution comprising an effective amount of sialic acid. In some preferred embodiments, the sialic acid is NANA. The present invention is not limited to any particular mechanism of action. However, it is expected that the administered sialic acid molecule covers the epithelium of the respiratory tract and may act as a receptor to "hook" the virus. In other words, free sialic acid molecules (which do not adhere to the nasal mucosa) competitively bind to soluble virus particles, thereby inhibiting viral attachment to the nasal epithelium. Since free sialic acid is in excess, binding to cell-bound receptors and transport into cells is reduced, thus reducing the risk of viral infection and inhibiting infection.

The use of various sialic acids is contemplated. In some embodiments, the sialic acid or sialic acid precursor has a purity selected from the group consisting of greater than 90%, 95%, 99%, and 99.5% purity. In some preferred embodiments, the sialic acid or sialic acid precursor is selected from the group consisting of N-acetylneuraminic acid (NANA), N-glycoloylneuraminic acid (NGNA), N-acetyl-D-mannosamine, and combinations thereof. In other preferred embodiments, the composition may include one or more of the following sialic acids: neuraminic acid, 5-N-acetyl-4-O-acetyl-neuraminic acid, 5-N-acetyl-7-O-acetyl-neuraminic acid, 5-N-acetyl-8-O-acetyl-neuraminic acid, 5-N-acetyl-9-O-acetyl-neuraminic acid, 5-N-acetyl-4, 9-di-O-acetyl-neuraminic acid, 5-N-acetyl-7, 9-di-O-acetyl-neuraminic acid, 5-N-acetyl-8, 9-di-O-acetyl-neuraminic acid, 5-N-acetyl-7,8,9-tri-O-acetyl-neuraminic acid, 5-N-acetyl-9-O-L-lactoyl-acetyl-neuraminic acid, 5-N-acetyl-4-O-acetyl-9-O-lactoyl-acetyl-neuraminic acid, 5-N-acetyl-8-O-methyl-neuraminic acid, 5-N-acetyl-9-O-acetyl-8-O-methyl-neuraminic acid, 5-N-acetyl-8-O-sulfo-neuraminic acid, 5-N-acetyl-9-O-phosphono-neuraminic acid, L-acetyl-4-O-lactyl-neuraminic acid, L-acetyl-4-O-L-neuraminic acid, L-acetyl-4-O-acetyl-8-O-L-neuraminic acid, L-acetyl-neuraminic acid, L-N-acetyl-9-L-neuraminic acid, 5-N-acetyl-2-deoxy-2, 3-didehydro-neuraminic acid, 5-N-acetyl-9-O-acetyl-2-deoxy-2, 3-didehydro-neuraminic acid, 5-N-acetyl-2-deoxy-2, 3-didehydro-9-O-lactyl-neuraminic acid, 5-N-acetyl-2, 7-anhydro-neuraminic acid, 4-O-acetyl-5-N-glycolyl-neuraminic acid, 7-O-acetyl-5-N-glycolyl-neuraminic acid, 8-O-acetyl-5-N-glycolyl-neuraminic acid, 9-O-acetyl-5-N-glycolyl-neuraminic acid, 7, 9-di-O-acetyl-5-N-glycolyl-neuraminic acid, 8, 9-di-O-acetyl-5-N-glycolyl-neuraminic acid, 7,8, 9-tri-O-acetyl-5-N-glycolyl-neuraminic acid, 5-N-acetyl-9-glycolyl-neuraminic acid, 8, 9-tri-O-acetyl-5-glycolyl-N-glycolyl-neuraminic acid, 8, 9-O-acetyl-5-hydroxymethyl-glycolyl-neuraminic acid, 7,9-di-O-acetyl-5-N-glycolyl-8-O-methyl-neuraminic acid, 5-N-glycolyl-8-O-sulfo-neuraminic acid, N- (O-acetyl) glycolylneuraminic acid, N- (O-methyl) glycolylneuraminic acid, 2-deoxy-2, 3-didehydro-5-N-glycolyl-neuraminic acid, 9-O-acetyl-2-deoxy-2, 3-didehydro-5-N-glycolyl-neuraminic acid, 2-deoxy-2, 3-didehydro-5-N-glycolyl-9-O-lactyl-neuraminic acid, 2-deoxy-2, 3-didehydro-5-N-glycolyl-8-O-methyl-neuraminic acid, 2, 7-anhydro-5-N-glycolyl-8-O-methyl-neuraminic acid, 2-3-keto-nonanoic acid and 9-O-acetyl-2-nonanoic acid.

In some particularly preferred embodiments, the sialic acid is NANA.

Exemplary formulations are described in detail below. However, in some embodiments, the sialic acid is formulated as a lotion, spray, gel, ointment, powder, aqueous or non-aqueous solution for topical, intranasal, intravaginal, intraanal or sublingual administration; capsules, powders or tablets for enteral administration; or solutions for parenteral administration.

The saliva compositions of the invention may be delivered in any suitable form. In some embodiments, the sialic acid is preferably about greater than 90%, 95%, 99%, or 99.9% pure. In some embodiments, the sialic acid is purified by HPLC. For example, NANA is commercially available from, for example, sigma Chemical Company, st.

In some embodiments, the invention provides methods of treating, ameliorating, or inhibiting a SARS-CoV-2 infection, or alleviating a symptom or outbreak associated with a SARS-CoV-2 infection, comprising administering an effective concentration of sialic acid (e.g., NANA). In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is from about 0.1 to about 10mg/ml in an aqueous solution, e.g., for treating, ameliorating, reducing or inhibiting SARS-CoV-2 infection or a symptom associated with SARS-CoV-2. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.5 to about 100mg/ml in an aqueous solution. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.5 to about 50mg/ml in an aqueous solution. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.5 to about 5mg/ml in an aqueous solution. In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.1 to 5.0mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.1 to 1.0mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.5 to about 100mg/ml in an aqueous solution. In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.1 to 100mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.1 to 50mg sialic acid (e.g., NANA) per nostril/day.

In some preferred embodiments, the pH of the composition comprising sialic acid (e.g., NANA) is preferably from 2.0 to 4.0 in aqueous solution. In some preferred embodiments, the pH of the composition comprising sialic acid (e.g., NANA) is preferably 2.5 to 3.7 in aqueous solution. In some preferred embodiments, the pH of the composition comprising sialic acid (e.g., NANA) is preferably from 2.8 to 3.2 in aqueous solution.

In some embodiments, the sialic acid (e.g., NANA) composition is provided in an aqueous solution (including a gel) suitable for use as a spray or mist (mist). In some embodiments, the aqueous sialic acid (e.g., NANA) solution is incorporated into a pump spray container, such as a pre-compression pump, or a device such as a nebulizer or cold mist system, for delivery to the nose, mouth, or lungs as a fine mist or spray. In some preferred embodiments, the present invention provides a spray bottle configured for applying a nasal spray to the nose of an animal or human, comprising any of the above compositions.

In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.1 to 5.0mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the daily dose of NANA is about 0.1 to 1.0mg sialic acid (e.g., NANA)/nostril/day. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 0.03 to 1.0mg sialic acid (e.g., NANA)/spray. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 0.05 to 0.3mg sialic acid (e.g., NANA)/spray. In some preferred embodiments, a daily dose of sialic acid (e.g., NANA) is delivered to each nostril from a spray bottle (i.e., from 2 to 8 pumps of the spray) at 2 to 8 administrations per day.

In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.1 to 100mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the daily dose of NANA is about 1.0 to 100mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 1.0 to 100mg sialic acid (e.g., NANA)/spray. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 1.0 to 50mg sialic acid (e.g., NANA)/spray. In some preferred embodiments, a daily dose of sialic acid (e.g., NANA) is delivered to each nostril from a spray bottle (i.e., pumped from 2 to 8 times of the spray) at 2 to 8 administrations per day.

In some embodiments, the composition further comprises a thixotropic agent (e.g., including, but not limited to, fucoidan, alginate, or chitosan). In some embodiments, the thixotropic agent is mannuronic acid. In some embodiments, mannuronic acid is present in the composition in a w/w percentage range of 0.01 to 2.0% (e.g., 0.01 to 1.0% or 0.1% to 0.5%).

In some embodiments, the sialic acid (e.g., NANA) compositions of the present invention comprise pharmaceutically acceptable excipients that are effective to form thixotropic suspensions of solid particles of the drug comprising the composition, such as those described in U.S. patent No. 7,122,206. The excipients are preferably present in amounts of: the drug particles suspended in the composition are maintained during periods of non-use and during spraying of the composition into the nasal cavity, and also when the composition is deposited on mucosal surfaces of the nasal cavity or endothelial surfaces of the nasal cavity or other parts of the body. In some embodiments, the viscosity of the composition at rest is relatively high, for example from about 400 to about 1000cp. As the composition is subjected to shear forces, for example, the forces involved in stirring it prior to spraying, the viscosity of the composition decreases (e.g., to about 50 to about 200 cp) and it readily flows through the spray device and exits therefrom in the form of a fine plume which infiltrates and deposits on mucosal surfaces of the nose at least in the following locations: the anterior region of the nose (frontal nasal cavity); the frontal sinus; the maxillary sinus; and a turbinate covering the nasal cavity lining (conchas). Therefore, NANA compositions include free flowing liquids, as well as fine mist in the form of a spray, which finds its way and deposits on the desired mucosa. In a sedimentary and relatively unstressed form, the composition increases in viscosity and assumes its gelatinous form, which includes drug particles suspended therein and resists clearance from the nasal passages by the inherent mucociliary force (mucociliary force) present in the nasal cavity.

Any pharmaceutically acceptable material that is capable of maintaining the solid particles of the drug substantially uniformly dispersed in the composition and imparting the desired thixotropic properties to the composition may be used. Such materials are known as "suspending agents". Examples of suspending agents include carboxymethylcellulose, magnesium aluminium silicate (veegum), tragacanth, bentonite, methylcellulose and polyethylene glycols. The preferred suspending agent is a mixture of microcrystalline cellulose and carboxymethylcellulose, the former preferably being present in a major amount, most preferably in an amount of from about 85 to about 95wt.%, the latter component constituting from about 5 to about 15wt.% of the mixture.

The amount of suspending agent comprising the composition will vary depending on the particular drug and amount used, the particular suspending agent used, the nature and amount of the other ingredients comprising the composition, and the particular viscosity value desired. Generally, it is believed that the most widely used compositions will include from about 1 to about 5wt.% of a suspending agent.

The sialic acid (e.g., NANA) compositions of the present invention preferably comprise other ingredients that impart desirable properties to the composition. In some embodiments, a dispersant or wetting agent is utilized. Any pharmaceutically acceptable dispersing agent that effectively wets the particles may be used. Examples of dispersants that may be used are fatty alcohols, esters and ethers, including for example those sold under the trademarks Pluronic, tergitol, span and Tween. Hydrophilic, nonionic surfactants are preferably used. Excellent results have been obtained with the sorbitan monooleate polyoxyethylene available under the trademark Polysorbate 80.

In some embodiments, the composition comprises an antioxidant. Examples of pharmaceutically acceptable antioxidants that can be used in the composition include ascorbic acid, sodium ascorbate, sodium bisulfite, sodium thiosulfate, 8-hydroxyquinoline, and N-acetylcysteine. It is recommended that the composition include from about 0.001 to about 0.01 wt.% antioxidant.

Furthermore, sialic acid (e.g., NANA) compositions should be protected from microbial contamination and growth for stability purposes. Examples of pharmaceutically acceptable antimicrobial agents that may be used in the compositions include quaternary ammonium compounds, for example, benzalkonium chloride, benzethonium chloride, cetrimide (cetrimide) and cetylpyridinium chloride (cetylpyridinium chloride); mercurials, for example, phenylmercuric nitrate, phenylmercuric acetate, and thimerosal (thimerosal); alcohol agents, for example, chlorobutanol, phenethyl alcohol and benzyl alcohol; antibacterial esters, for example, esters of p-hydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chlorocresol, and polymyxin. It is recommended that the composition include about 0.001 to about 1wt.% antimicrobial agent.

As noted above, aspects of the invention include a composition that is odorless and contains a mixture of stabilizers that act as antioxidants and antimicrobials. The mixture includes a quaternary ammonium compound having antimicrobial properties and a material commonly referred to as a chelating agent. The use of such a combination of material and drug (e.g. triamcinolone acetonide) in the composition results in a highly stable composition which is resistant to oxidative degradation and bacterial growth, etc. In a preferred form, the mixture comprises benzalkonium chloride and disodium edetate.

The non-odorous composition will typically comprise from about 0.004 to about 0.02wt.% of the quaternary ammonium compound and from about 0.01 to about 0.5wt.% of the chelating agent. Due to the use of mixtures of the above compounds, it is not necessary to include materials in the composition that are considered antioxidants.

The composition of the invention preferably comprises an isotonic agent, the function of which is to prevent irritation of the nasal mucosa by the composition. Dextrose in anhydrous form is a preferred isotonic agent. Examples of other pharmaceutically acceptable isotonic agents that may be used include sodium chloride, dextrose and calcium chloride. It is recommended that the composition include up to about 5wt.% isotonic agent.

Sialic acid (e.g., NANA) compositions of the invention can be prepared in any suitable manner. In a preferred form, an aqueous suspension of solid particles of the drug and the dispersing agent is formed and combined with an aqueous suspension containing the suspending agent. The former is preferably prepared by adding the drug to an aqueous solution of the dispersant and mixing thoroughly. The latter is prepared by acidifying (pH about 4.7 to about 5.3) the water before adding the suspending agent. In a particularly preferred form, an aqueous solution of a quaternary compound (antimicrobial agent) is added to an aqueous suspension of the drug, and other ingredients (e.g., isotonic agents, antioxidants, or chelating agents) are added to the thixotropic suspension. Each of the above batches of the composition was mixed thoroughly prior to combination. A preferred method of combining batches of the composition is to introduce one batch (preferably a "drug" batch) into the bottom of another batch, for example, by pumping the batch up through the other batch. The compositions comprising the combined batches were mixed thoroughly. The use of the preferred manufacturing process provides an efficient and effective method for formulating compositions having solid particles of a drug substantially uniformly dispersed therein, while avoiding the problems typically associated with the preparation of water-based pharmaceutical compositions, such as excessive foaming and non-uniform particle dispersion.

The amount of sialic acid (e.g., NANA) applied to each nasal channel will vary depending on the nature of the condition being treated and the nature of the individual being treated. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.1 to about 100mg/ml in an aqueous solution. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 1.0 to about 100mg/ml in an aqueous solution. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 1.0 to about 50mg/ml in an aqueous solution. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.1 to about 10mg/ml in an aqueous solution. In some preferred embodiments, the effective concentration of sialic acid (e.g., NANA) is about 0.5 to about 5mg/ml in an aqueous solution. In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.001 to 0.1 mg sialic acid (e.g., NANA) per nostril/day. In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is about 0.01 to 0.05mg sialic acid (e.g., NANA) per nostril/day.

In some preferred embodiments, the daily dose of sialic acid (e.g., NANA) is delivered in 2 to 8 administrations per day.

Accordingly, the present invention provides an article of manufacture comprising a spray bottle having therein a sialic acid (e.g., NANA) solution or powder for delivery into a body cavity, such as the nose. The spray bottle may preferably comprise a pump system, such as a compression pump, spray pump, or pre-compression pump, for discharging the NANA composition from the bottle. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 0.1 to 10mg sialic acid (e.g., NANA)/spray. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 0.001 to 0.02mg sialic acid (e.g., NANA)/spray. In some preferred embodiments, the spray bottle is calibrated to deliver a spray dose comprising 0.004 to 0.01 mg sialic acid (e.g., NANA)/spray.

In some embodiments, the invention provides an article that is a device that can be worn on a body cavity, such as the mouth or nose, of an individual. In some embodiments, the device is a mask, such as a medical surgical mask. In a preferred embodiment, the mask includes a combination into which sialic acid (e.g., NANA) is incorporatedA solid support or matrix of matter, such as a polymer matrix or a woven fabric matrix. In some embodiments, the sialic acid (e.g., NANA) composition is sprayed onto the substrate as an aqueous solution, gel, or powder. In some embodiments, when breathing through the mask, the virus is inactivated when the virus contacts the mask. In some embodiments, the substrate is coated with a sialic acid (e.g., NANA) composition to provide per cm ² About 0.01 microgram to about 100 milligrams of sialic acid per cm of matrix, preferably ² About 1 microgram to about 1 milligram of sialic acid (e.g., NANA).

In some embodiments, sialic acid (e.g., NANA) is formulated for oral delivery. The ingredients of the supplement of the present invention are preferably contained in acceptable excipients and/or carriers for oral consumption. The actual form of the carrier and hence the supplement itself is not critical. The carrier may be a liquid, gel, caplet (gelcap), capsule, powder, solid tablet (coated or uncoated), tea, or the like. The supplement is preferably in the form of a tablet or capsule, and most preferably in the form of a hard gelatin capsule. Suitable excipients and/or carriers include maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums, lactose, methylcellulose, povidone, carboxymethylcellulose, corn starch, and the like (including mixtures thereof). Preferred carriers include calcium carbonate, magnesium stearate, maltodextrin, and mixtures thereof. The various ingredients and excipients and/or carriers are mixed and formed into the desired form using conventional techniques. The tablets or capsules of the invention may be coated with an enteric coating that dissolves at a pH of about 6.0 to 7.0. A suitable enteric coating that dissolves in the small intestine but not in the stomach is cellulose acetate phthalate. Additional details regarding formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., easton, pa.).

In some embodiments, the oral delivery vehicle described above is formulated to provide a daily dose of 0.1g to 10.0g sialic acid (e.g., NANA), preferably 0.5 to 2.0g NANA, and even more preferably about 1.0g sialic acid (e.g., NANA). In some embodiments, the effective amount of NANA is the amount required to inhibit growth and proliferation of or inactivate a target virus. In some embodiments, an effective amount is an amount of sialic acid (e.g., NANA) sufficient to provide a NANA concentration of about 1 nanomolar to 10 micromolar in a target site, such as the circulating blood stream or a body cavity, such as a nasal passage or sinus.

In some preferred embodiments, the sialic acid is administered orally. In some preferred embodiments, the daily dose of sialic acid is from 20 to 200 grams. In some preferred embodiments, the daily dose of sialic acid is 50 to 150 grams. In some preferred embodiments, the daily dose is administered in 1 to 20 doses. In some preferred embodiments, the sialic acid is administered as an aqueous solution. In some preferred embodiments, the aqueous solution includes an additive selected from the group consisting of a fragrance, a stabilizer, and a preservative, wherein the additive does not naturally occur with sialic acid.

In some embodiments, sialic acid (e.g., NANA) is provided in a fluid that is useful for atmospheric treatment, such as by fog. In some embodiments, the present invention provides an apparatus comprising a reservoir, a pump, and a nozzle, wherein the reservoir comprises a fluid comprising sialic acid (e.g., NANA) that can be expelled through the nozzle by the pump to provide a mist comprising sialic acid (e.g., NANA). In some embodiments, the device is a humidifier, while in other embodiments, the device is an automatic mist dispenser. In some embodiments, sialic acid (e.g., NANA) is provided as an aerosol spray in a suitable aerosol spray dispensing device. Accordingly, in some embodiments, the present invention provides a device or composition comprising sialic acid (e.g., NANA) and an aerosol propellant. Propellants include, but are not limited to, mixtures of volatile hydrocarbons, typically propane, n-butane and isobutylene, dimethyl ether (DME), methylethyl ether, nitrous oxide, carbon dioxide and Hydrofluoroalkanes (HFA): HFA 134a (1, 2, tetrafluoroethane) or HFA 227 (1, 2, 3-heptafluoropropane) or a combination of the two. Typically, the sialic acid (e.g., NANA) fluid will be miscible with the propellant. Sialic acid (e.g., NANA) fluids may preferably be formulated as aerosol, foaming gel, cream or lotion.

Modern aerosol spray products have three main components; a canister, a valve, and an actuator or button. Cans are most commonly painted tinplate (steel with a tin coating) and can be made of 2 or 3 pieces of metal that are crimped together. Aluminum cans are also common and are typically used for more expensive products. The valve is crimped to the can's equipment (rig) and the design of this part is important in determining the spray rate. The actuator is depressed by a user to open the valve; the shape and size of the nozzle in the actuator controls the dispersion of the aerosol spray.

In some embodiments, the devices of the present invention comprise a piston barrier system. Packaging using a piston barrier system is commonly used for high viscosity products such as post foaming gels, thick creams and lotions. The primary benefit of the piston barrier system is to ensure that the product is separated from the propellant, maintaining the purity and integrity of the formulation throughout its consumer lifetime. The piston barrier system also provides a controlled and uniform product discharge rate with minimal product retention and is economical.

In some embodiments, the devices of the present invention comprise a bag-in-can (bag-in-can) system (or BOV "bag-on-valve"). The system uses a hermetically sealed multilayer laminated pouch to separate the product from the pressurizing agent, which maintains complete formulation integrity, thus dispensing only pure product. In this embodiment, the NANA fluid is provided in a bag. Among its many benefits, the bag-in-can system extends the shelf life of the product. Other advantages include full attitude (360 degree) distribution, quiet and non-cooling emissions.

These devices are used in environments requiring an anti-viral spray, foam, gel or other fluid. For example, the apparatus is used to dispense an anti-viral mist to treat a desired environment or space, such as a room in a building, such as an office, kitchen, compartment or toilet, or a vehicle, such as a rail car, airplane, bus or taxi, van or car, or an animal confinement facility, such as a barn, slaughterhouse, poultry house, or the like. The device may also be used to dispense fluids containing sialic acid (e.g., NANA) on surfaces such as countertops, floors, showers, and the like. In some embodiments, the apparatus is used to inject a mist containing sialic acid (e.g., NANA) into the ventilation system of a building, barn, or vehicle.

In still further embodiments, the present invention provides a sialic acid (e.g., NANA) composition comprising a solution of sialic acid (e.g., NANA), such as a physiological saline solution, which can be applied to the eye. Accordingly, in some embodiments, the present invention provides an article comprising a container equipped with a nozzle to provide a drop of a sialic acid (e.g., NANA) solution to an eye. It is expected that in addition to the effects on the eye and surrounding tissues, administration of sialic acid (e.g., NANA) through the eye and tear channel will directly access the sinuses and associated cavities. Thus, administration of sialic acid (e.g., NANA) and/or additional antimicrobial or antiviral agents in eye drops is an effective method of administration of sialic acid (e.g., NANA) or other compounds for treating ocular infections, sinus infections, and systemic treatment through the eye and tear channels and sinuses, effective adsorption of the inner mucus surface to provide local and systemic treatment.

In other embodiments, the sialic acid (e.g., NANA) is provided as a powder or liquid suitable for addition by a consumer to a food or beverage. For example, in some embodiments, the dietary supplement may be administered to an individual in the form of a powder, for example, by mixing into a beverage, or by stirring into a semi-solid food such as pudding, topping, sauce, puree, cooked cereal, or salad dressing, for example, or by otherwise adding to the food.

In some embodiments, sialic acid (e.g., NANA) is provided in water supplied to farm animals such as poultry, cattle, pigs, sheep, etc., or used in fishery water. In other embodiments, the sialic acid (e.g., NANA) is provided in tap water or water bottle water for human use.

The sialic acid (e.g., NANA) composition may include one or more inert ingredients, particularly if it is desired to limit the amount of calories added to the diet by dietary supplements. For example, the dietary supplement of the present invention may also contain optional ingredients including, for example, herbs, vitamins, minerals, enhancers, colorants, sweeteners, flavorings, inert ingredients, and the like. For example, the compositions of the present invention may comprise one or more of the following: ascorbate (ascorbic acid, mineral salts of ascorbic acid, rosehips, acerola, etc.), dehydroepiandrosterone (DHEA), polygonum multiflorum (Fo-Ti) or Ho Shu Wu (herbs common in traditional asia treatments), catclaw buttercup (Cat's paw) (ancient herbal components), green tea (polyphenols), inositol, kelp, red algae (dulse), bioflavonoids (biflavonoids), maltodextrin, nettle, niacin, niacinamide, rosemary, selenium, silica (silica) (silica dioxide), silica gel, horsetail (horetail), horsetail (shavograms), etc.), spirulina (spirulina), zinc, etc. Such optional ingredients may be in naturally occurring or concentrated form.

In some embodiments, the composition further comprises vitamins and minerals, including but not limited to: tricalcium phosphate or tricalcium acetate; dipotassium hydrogen phosphate; magnesium sulfate or magnesium oxide; salt (sodium chloride); potassium chloride or potassium acetate; ascorbic acid; ferric orthophosphate; nicotinamide; zinc sulfate or zinc oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamine mononitrate; folic acid; biotin; chromium chloride or chromium picolinate; potassium iodide; sodium selenate; sodium molybdate; phylloquinone; vitamin D ₃ (ii) a Cyanocobalamin; sodium selenite; copper sulfate; a vitamin A; vitamin C; inositol; and (3) potassium iodide. Suitable dosages of vitamins and minerals may be obtained, for example, by consulting the U.S. RDA guidelines.

The present invention provides dietary supplements comprising a nutraceutical, preferably sialic acid (e.g., NANA), alone or in combination with one or more additional nutraceuticals. Nutraceuticals are natural bioactive compounds with health promoting, disease preventing, or pharmaceutical properties. Examples of nutrients include, but are not limited to: onion (Allium Cepa), garlic (Allium Sativum), aloe Vera (Aloe Vera), angelica (Angelica) species, naturally occurring antioxidants, aspergillus Oryzae (Aspergillus Oryzae) enzyme therapy, barley grass (barley grass), bromelain (brooelain), carnitine, carotenoids and flavonoids, catechins, and mixtures thereof Centella Asiatica (Centella Asiatica) (Centella Asiatica (Gotu kola)), coenzyme Q10, chinese patent medicine, coleus Forskohlii (Coleus Forskohlii), commiphora Mukul (Commiphora Mukul), conjugated Linoleic Acid (CLA), crataegus Oxyacantha (Crataegus Oxyacantha) (Hawthorne), curcuma Longa (Curcuma Longa) (Curcuma genus), echinacea species (echinacea), and combinations thereof Acanthopanax Senticosus (Eleutherococcus Senticosus) (Siberian Ginseng), ephedra species, dietary fish oil consumption and fish oil supplements, genistein (Genistein), ginkgo Biloba (Ginko Biloba), glycyrrhiza (Glycyrrhiza) (Licorice), hypericum Perforatum (Hypericum Perforatum) (St. John's Wort)), ranunculaceae (Hydrastis) (Goldenseal), and other berberine containing plants, lactobacillus, lobelia (Lobelia) (Indian grass (Indian Tobacco)), melaleruca (Melaleica), menaquinone (Melinoquinone), mentha Piperita (Meltha), ginseng (Panax, gienna), and Ginseng (Sing), pancreatin, piper methysticum (pepper), oligomeric proanthocyanidins (Procyanidolic Oligomers), prunus africana fruit tree (Pygeum Africanum), quercetin (Quercetin), saxago sp (sarcasarilla) species, serenoa Repens (Serenoa Repens) (Saw palms (Saw palmetto), hippophae rhamnoides (sea buckthorn)), silybum Marianum (Milk Thistle), rosemary/lemongrass (Lemon palm), selenite, tabebuia avens (Tabebuia Avellanedae) (LaPacho), taraxacum Officinalis (Taraxacum Officinalis), feverfew (chrysanthemum), bearberry (Uva), valerian (honey chrysanthemum) (honey apple), and other vitamins (ginkgo biloba)), paclitaxel (Uva Officinalis) (honey apple), valerian (honey apple), blueberry (honey apple white chrysanthemum) (honey apple), and Blueberry (ginkgo biloba)), and other vitamins (ginkgo biloba), ginkgo biloba (ginkgo biloba), and ginkgo biloba (ginkgo biloba).

A variety of nutrients are used to treat viral disorders (e.g., genistein (in soybean/red clover), rosemary/lemongrass, selenite, barley grass, lauric acid, phyllanthus/niruri (Phyllanthus amarus/niruri) (see, e.g., nicolson, g. (1998) j. Medicine 1 123-128; incorporated herein by reference in its entirety).

Examples

Example 1

A nasal spray was formulated comprising 1mg/ml of n-acetylneuraminic acid (NANA) in a sterile 0.9% saline solution at pH 3.0. The formulation may be provided in a 20ml pump spray bottle calibrated to deliver an average of 140 sprays, with each pump of the bottle delivering 1 spray.

Example 2

A nasal spray was formulated to include 1mg/ml n-glycolyl neuraminic acid (NGNA) in a sterile 0.9% saline solution at pH 3.0. The formulation may be provided in a 20ml pump spray bottle calibrated to deliver an average of 140 sprays, with each pump of the bottle delivering 1 spray.

Example 3

Sialic acid (Neu 5Ac or Neu5 Gc) was evaluated in vitro in model systems for effectiveness in preventing coronavirus infection. Different dilutions of sialic acid were tested for their ability to inhibit the test virus CoV-OC43 from infecting cells. The results are presented in fig. 1 to 3. Figures 1 and 2 provide data from two replicates showing infection of cells with CoV-OC43 at different concentrations of Neu5Ac or Neu5Gc (Neu 5Ac left hand bar, neu5Gc right hand bar). It can be seen that the infection is inhibited in a dose-dependent manner. Figure 3 provides data from experiments in which Neu5Ac (left hand bar) inhibition of infection was compared to the control sugar galactose (right hand bar). As can be seen, neu5Ac prevents infection compared to controls.

Reference documents

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7 Thilo Stehle,Zaigham M.Khan:Rules and Exceptions:sialic Acid Variants and Their Role in Determining Viral Tropism.Journal of Virology p.7696-7699 July 2014 Volume 88 Number 14

8 Muriel Bardor,Dzung H.Nguyen,Sandra Diaz,and Ajit Varki:Mechanism of Uptake and Incorporation of the Non-human sialic acid N- Glycolylneuraminic Acid into Human Cells.J Biol Chem Vol.280,No.6,Issue of February 11,pp.4228-4237,2005

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12 Martín-Sosa,S,Martín,M-J and Hueso,P:The Sialylated Fraction of Milk oligosaccharides Ice Partially Responsible for Binding two enterotoxigenic and Uropathogenic Escherichia coli Human Strains.J.Nutr.132:3067-3072,2002

13 Samraj AN,Pearce OM,H,Crittenden AN,Bergfeld AK,Banda K,Gregg CJ,Bingman AE,Secrest P,Diaz SL,Varki NM,Varki A.:A red meat-derived glycan promoter inflammation and cancer progression.Proc Natl Acad Sci US A.2015Jan.13；112(2):542to-7.doi:10.1073/pnas.1417508112. Epub 2014December 29.

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All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and systems of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been described in connection with certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

Claims (24)

1. A method for treating or inhibiting a SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject, the method comprising:

administering to the subject a composition comprising an effective concentration of sialic acid under conditions such that SARS-CoV-2 infection is inhibited or treated.

2. A method for preventing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject, the method comprising:

administering to the subject a composition comprising an effective concentration of sialic acid under conditions such that SARS-CoV-2 infection is inhibited.

3. Sialic acid for use in the treatment or inhibition of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject.

4. Sialic acid for use in the prevention of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection in a human or animal subject.

5. The method or use according to any one of claims 1 to 4, wherein the sialic acid is selected from the group consisting of n-acetylneuraminic acid (NANA) and n-glycolylneuraminic acid (NGNA).

6. The method or use of any one of claims 5, wherein the sialic acid is NANA.

7. The method or use of any one of claims 1 to 6, wherein the sialic acid is administered intranasally.

8. The method or use of claim 7, wherein the effective concentration of sialic acid is from about 0.1 to about 100mg/ml in the aqueous solution.

9. The method or use of claim 7, wherein the effective concentration of sialic acid is from about 0.5 to about 50mg/ml in the aqueous solution.

10. The method or use of any one of claims 8 to 9, wherein the daily dose of sialic acid is about 0.1 to 100mg sialic acid per nostril/day.

11. The method or use of any one of claims 8 to 9, wherein the daily dose of sialic acid is about 0.1 to 10mg sialic acid per nostril/day.

12. Method or use according to any one of claims 8 to 11, wherein the pH of the composition comprising sialic acid is preferably in aqueous solution from 2.0 to 4.0.

13. Method or use according to any one of claims 8 to 11, wherein the pH of the composition comprising sialic acid is preferably in aqueous solution from 2.5 to 3.7.

14. The method or use according to any one of claims 8 to 11, wherein the pH of the composition comprising sialic acid is preferably in the range of 2.8 to 3.2 in aqueous solution.

15. The method or use of any one of claims 8 to 14, wherein the daily dose of sialic acid is delivered in 2 to 8 administrations per day.

16. The method or use of any one of claims 8 to 15, wherein the composition further comprises a thixotropic agent.

17. The method or use of any one of claims 1-7, wherein the sialic acid is administered orally.

18. The method or use according to claim 17, wherein the daily dose of sialic acid is from 20 to 200 g.

19. The method or use according to claim 17, wherein the daily dose of sialic acid is from 50 to 150 grams.

20. The method or use according to any one of claims 17 to 19, wherein the daily dose is administered in 1 to 20 doses.

21. The method or use of any one of claims 17 to 20, wherein the sialic acid is administered as an aqueous solution.

22. The method or use of claim 21, wherein the aqueous solution comprises an additive selected from the group consisting of a fragrance, a stabilizer, and a preservative, wherein the additive does not naturally occur with sialic acid.

23. The method or use of any one of claims 1 to 22, wherein the subject is at risk of being infected with SARS-CoV-2.

24. The method or use of any one of claims 1-22, wherein the subject has COVID-19.