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WO2021168173A1 - Méthodes et compositions pour le traitement d'infections respiratoires virales - Google Patents

Méthodes et compositions pour le traitement d'infections respiratoires virales Download PDF

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Publication number
WO2021168173A1
WO2021168173A1 PCT/US2021/018663 US2021018663W WO2021168173A1 WO 2021168173 A1 WO2021168173 A1 WO 2021168173A1 US 2021018663 W US2021018663 W US 2021018663W WO 2021168173 A1 WO2021168173 A1 WO 2021168173A1
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WIPO (PCT)
Prior art keywords
quercetin
composition
carrageenan
subject
iota
Prior art date
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PCT/US2021/018663
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English (en)
Inventor
Peter SUZMAN
Jason FISHERMAN
Walter Lunsmann
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Synkine Therapeutics Inc
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Synkine Therapeutics Inc
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Publication of WO2021168173A1 publication Critical patent/WO2021168173A1/fr
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/731—Carrageenans
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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

  • viruses are known to cause respiratory infections in humans, resulting in illnesses that are typically classified according to their clinical presentation, such as the common cold, influenza, bronchiolitis, croup or pneumonia.
  • infections are generally self-limiting, but in certain patients, notably the elderly, infants, and those with compromised immune systems, can lead to more severe disease, including pneumonia, which can be life threatening.
  • Most medications prescribed for these diseases provide only relief of symptoms, and there are few available drugs which modify the course of any of these diseases.
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • MERS-CoV Middle East Respiratory Syndrome coronavirus
  • SARS-CoV -2 Severe Acute Respiratory Syndrome coronavirus-2
  • the present invention provides compositions and methods of use thereof for treating or preventing a viral respiratory infection.
  • the invention provides a composition comprising quercetin or a pharmaceutically acceptable ester thereof or other derivative which is suitable for nasal or pulmonary administration.
  • the quercetin or ester thereof is dissolved or suspended in a liquid or gel vehicle.
  • the vehicle preferably has a viscosity sufficiently high to maintain contact of quercetin with the nasal membrane following nasal administration.
  • the invention includes compositions for the pulmonary delivery of quercetin.
  • the composition further comprises iota- carrageenan.
  • the composition comprises quercetin and ethyl lactate and optionally further comprises glycerin or glycerol.
  • the composition comprises quercetin, ethyl lactate, and iota-carrageenan, and optionally further comprises glycerin or glycerol.
  • the invention provides a method of treating or preventing a viral respiratory infection, including for example a SARS-CoV-2 (COVID-19) infection, in a subject in need thereof comprising administering an effective amount of quercetin or a pharmaceutically acceptable ester or derivative thereof as described herein.
  • the method comprises the step of nasally administering to the subject or administering by inhalation an effective amount of a composition described herein.
  • the method further comprises administration of iota-carrageenan, including, for example, administration of a pharmaceutical composition comprising quercetin or pharmaceutically acceptable ester or derivative thereof and iota-carrageenan.
  • the invention is directed to a composition comprising quercetin or a pharmaceutically acceptable ester or derivative thereof, wherein the composition further comprises a carrageenan.
  • the invention is directed to a composition comprising quercetin or a pharmaceutically acceptable ester or derivative thereof, wherein the composition further comprises iota-carrageenan.
  • the composition can further comprise a solubilizing agent, a polysaccharide gum, or a water-soluble solvent, or a combination of any of thereof.
  • the composition further comprises one or more of ethyl lactate, sclerotium gum, and glycerin or glycerol.
  • the composition further comprises ethyl lactate, sclerotium gum, and glycerin or glycerol.
  • the invention additionally includes a method for the treatment or prevention of a viral respiratory infection, e.g., SARS-CoV-2 (COVID-19) respiratory infection, in a subject in need thereof comprising administering to the subject an effective amount of quercetin or a pharmaceutically acceptable ester or derivative thereof by nasal administration, wherein the method further comprises nasally co-administering to the subject an effective amount of iota-carrageenan.
  • the quercetin or the ester or derivative thereof, and the iota-carrageenan are administered as part of the same pharmaceutical composition as described herein, wherein the pharmaceutical composition is suitable for nasal administration.
  • the invention is directed to a composition comprising quercetin or a pharmaceutically acceptable ester or derivate thereof, wherein the composition further comprises a solubilizing agent, a polysaccharide gum, or a water-soluble solvent, or a combination of any of thereof.
  • the composition further comprises one or more of ethyl lactate, sclerotium gum, and glycerol or glycerin.
  • the composition further comprises ethyl lactate, sclerotium gum, and glycerin or glycerol.
  • the invention additionally includes a method for the treatment or prevention of a viral respiratory infection, e.g., a SARS-CoV-2 (COVID-19) respiratory infection, in a subject in need thereof comprising administering to the subject the pharmaceutical composition as described herein.
  • a viral respiratory infection e.g., a SARS-CoV-2 (COVID-19) respiratory infection
  • the invention also includes a composition comprising an effective amount of iota- carrageenan suitable for nasal administration, wherein the composition does not comprise benzalkonium chloride. Also included is a method of treating or preventing a viral respiratory infection, including for example a SARS-CoV-2 (COVID-19) infection, in a subject in need thereof comprising administering an effective amount of iota-carrageenan by nasal or pulmonary administration in the absence of benzalkonium chloride.
  • the composition further comprises a solubilizing agent, a polysaccharide gum, or a water-soluble solvent, or a combination of any of thereof.
  • the composition further comprises one or more of ethyl lactate, sclerotium gum, and glycerin or glycerol. In certain aspects, the composition further comprises ethyl lactate, sclerotium gum, and glycerin or glycerol.
  • the invention further provides methods of preparing the compositions of the invention.
  • FIG. 1 is a graph showing the ratio of infected cells to total cells over concentration for vehicle, iota-carrageenan, and iota-carrageenan and benzalkonium chloride.
  • FIG. 2 is a table summarizing iota-carrageenan activity against SARS-CoV-2. Specifically shown are the fraction of infected cells per total cells for Vehicle (control), Vehicle with iota-carrageenan, and Vehicle with iota-carrageenan and benzalkonium chloride.
  • the Vehicle with iota-carrageenan (alone) showed a greater effect on the fraction of infected cells than iota-carrageenan in the presence of benzalkonium chloride.
  • FIG. 3A is graph showing the normalized ratio of infection over the concentration of VIG (vehicle and iota-carrageenan) and l.VIG (VIG and quercetin).
  • FIG. 3B is a graph showing the normalized ratio of infected cells to total cells over the concentration of VIP (vehicle, iota-carrageenan, and benzalkonium chloride) and l.VIP (VIP and quercetin).
  • VIP vehicle, iota-carrageenan, and benzalkonium chloride
  • l.VIP VIP and quercetin
  • the flavonoid quercetin is known to have antiviral properties and has been shown to block entry of SARS-CoV into host cells (Yi et ak, J. Virol. 2004, 78(20)) and in vitro and in vivo replication of rhinovirus (Ganesan et ak, Antiviral Res. 2012, 94(3): 258-271).
  • the development of quercetin as an antiviral agent has been hampered by the compound’s poor absorption and short half-life following oral administration.
  • the present invention provides compositions comprising quercetin, or a pharmaceutically acceptable ester or derivative thereof, which are suitable for intranasal or pulmonary administration.
  • the invention additionally includes compositions comprising quercetin or an ester or derivative thereof and iota-carrageenan wherein the compound is suitable for nasal administration.
  • the present invention also includes methods for the treatment or prevention of a SARS-CoV-2 (COVID19) respiratory infection in a subject in need thereof comprising administering to the subject an effective amount of quercetin or a pharmaceutically acceptable ester thereof by nasal or pulmonary administration; for example, using the compositions as described herein.
  • the invention further includes compositions comprising quercetin or ester or derivative thereof and iota-carrageenan as well as methods for the treatment or prevention of a respiratory infection, such as a SARS-CoV-2 infection, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of quercetin or ester or derivative thereof and a therapeutically effective amount of iota-carrageenan, wherein the quercetin and the iota-carrageenan are administered nasally.
  • a respiratory infection such as a SARS-CoV-2 infection
  • quercetin would have activity in inhibiting SARS-CoV-2 infected cells at a concentration of at least about 10 uM. It was discovered that quercetin, when used in combination with iota-carrageenan, was effective in the nanomolar range. This change in potency was surprising and indicates that the combination of quercetin and iota-carrageenan have a more than additive on decreasing the ratio of infected cells.
  • compositions described herein provide effective amounts of quercetin and/or carrageenan to the nasal mucosa and therefore are useful for treating or preventing a viral respiratory infection.
  • quercetin encompasses quercetin dihydrate as well as anhydrous quercetin.
  • quercetin glycosides can include rutin, (for example, rutoside, sophorin, and quercetin-3 -O-rutinoside), quercetin-7-O-glucoside and quercetin-3-O- rhamnoside-7-O-glucoside.
  • Quercetin glycoside can also include quercitrin, which is a 3-0- a-L-rhamnoside.
  • Quercetin glycoside can also include guaijaverin, which is a 3-0- arabinoside.
  • Quercetin glycoside can also include hyperoside, which is a 3-O-galactoside. Quercetin glycoside can also include isoquercetin, which is a 3-O-glucoside. Quercetin glycoside can also include spiraeoside, which is a 4'-0-glucoside. Quercetin glycoside can also include miquelianin, which is a quercetin 3-O-B-d-glucuronopyranoside.
  • compositions comprising iota- carrageenan which are suitable for intranasal administration, wherein the composition does not comprise benzalkonium chloride.
  • the invention further includes methods of treating or preventing a SARS-CoV-2 (COVID-19) respiratory infection in a subject in need thereof comprising administering to the subject an effective amount of iota-carrageenan by nasal administration in the absence of benzalkonium chloride.
  • compositions of the invention comprise an active agent selected from the group consisting of quercetin or a pharmaceutically acceptable ester or derivative thereof and iota- carrageenan, and combinations thereof, and wherein the composition further comprises a liquid vehicle which is suitable nasal administration.
  • the vehicle is preferably an aqueous solution. More preferably, the vehicle is an aqueous solution which includes a viscosity enhancing agent and, optionally one or more additional excipients which, for example, improve formulation stability and/or comfort upon administration.
  • Viscosity enhancing agents include hydrophilic polymers, such as polysaccharides, polysaccharide derivatives, proteins and synthetic polymers. Examples include, but are not limited to, acacia, tragacanth, alginic acid, carrageenan, locust bean gum, guar gum, gelatin, hyaluronic acid, polyacrylate, poly acrylate/alkylacry late copolymers, polyvinyl alcohol, polyvinylpyrrolidone, starch, propylene glycol alginate, maltodextrin, and cellulose ether derivatives, such as methylcellulose, hydroxy ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose.
  • hydrophilic polymers such as polysaccharides, polysaccharide derivatives, proteins and synthetic polymers. Examples include, but are not limited to, acacia, tragacanth, alginic acid, carrageenan, locust bean gum,
  • Preferred viscosity enhancing agents include hyaluronic acid, including sodium hyaluronate; carboxymethylcellulose, including sodium carboxymethylcellulose and calcium carboxymethylcellulose; methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and hydroxypropylcellulose.
  • hyaluronic acid including sodium hyaluronate
  • carboxymethylcellulose including sodium carboxymethylcellulose and calcium carboxymethylcellulose
  • methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and hydroxypropylcellulose are examples of xylitol and grapefruit seed extract.
  • the viscosity of the composition is preferably high enough to maintain contact of quercetin with the mucous membrane of the nose and/or sinus following administration to facilitate uptake of an effective amount of quercetin into these tissues.
  • the composition preferably has a viscosity in the range of about 500 to about 40,000 centipoise, about 1,000 to about 30,000 centipoise, about 2,500 to about 25,000 centipoise, or about 5,000 to about 20,000 centipoise when determined as set forth in ASTM D18242016 Edition, incorporated herein by reference in its entirety.
  • the viscosity enhancing agent is dissolved in water, preferably purified water, such as USP grade purified water, at a concentration which provides a solution having the desired viscosity.
  • Thermosetting gels can also be used in the compositions of the invention. Without being bound by theory, it may be beneficial to formulate the composition with a viscosity approaching normal saline at room temperature to facilitate the formation of a spray with low energy.
  • a thermosetting gel such as Poloxamer 407, can increase viscosity upon contact with the nasal mucosa and improve adhesion.
  • the composition optionally includes one or more additional excipients which, for example, increase the ease of administration, the comfort of the subject, or the stability of the composition.
  • additional excipients include, but are not limited to, tonicity modifiers, such as sodium chloride and dextrose; antioxidants, such as butylated hydroxyanisole; buffers, such as sodium bicarbonate, sodium citrate and sodium phosphate; preservatives, such as benzalkonium chloride, ethanol, propylene glycol, benzoyl alcohol, phenethyl alcohol, chlorobutanol or methylparaben; pH adjusters, such as hydrochloric acid, sulfuric acid and sodium hydroxide; surfactants, such as Polysorbate 80, Polysorbate 20, and polyoxyl 400 stearate; chelating agents, such as disodium EDTA; antioxidants; co-solvents, such as ethanol, PEG 400, and propylene glycol; penetration enhancers, such as oleic acid; and hum
  • the vehicle consists of sodium hyaluronate, aloe vera, allantoin, sodium chloride, sodium bicarbonate, glycerin, propylene glycol, propylene glycol, benzalkonium chloride and USP grade purified water.
  • a suitable vehicle is sold by NeilMedTM under the tradename NasoGELTM.
  • the amount of quercetin or pharmaceutically acceptable ester or derivative thereof in the composition can vary, for example, from about 0.5% by weight to about 25% by weight, about 0.1 to about 5% w/w, or about 0.1 to about 1.0% w/w.
  • the amount of iota-carrageenan in the composition can vary, for example, from about 0.1 to about 2% by weight or about 0.1 to about 1% by weight.
  • the pH of the formulation is tolerable in the nasal cavity, and can be in the range of pH about 2.5 to about 8.5. In certain aspects, the pH at least about 8.0. In yet additional aspects, the pH is between about 6.8 to about 8.4. In certain aspects, the pH is between about 6.0 and 7.0, for example, about 6.5 or about 6.4. In yet further aspects, the pH is about 7. In additional aspects, the pH is between about 2.5 and about 5.5.
  • Buffers that can be used in the formulation include, but are not limited to citrate and citric acid, phosphate, TRIS, tris(hydroxymethyl)methylamino]propanesulfonic acid, 2-(bis(2-hydroxyethyl)amino)acetic acid, and N-[tris(hydroxymethyl)methyl]glycine, and Alkaline Buffer (Seachem).
  • citrate and citric acid phosphate
  • TRIS tris(hydroxymethyl)methylamino]propanesulfonic acid
  • 2-(bis(2-hydroxyethyl)amino)acetic acid 2-(bis(2-hydroxyethyl)amino)acetic acid
  • N-[tris(hydroxymethyl)methyl]glycine and Alkaline Buffer (Seachem).
  • Alkaline Buffer Alkaline Buffer
  • Quercetin or the pharmaceutically acceptable ester or derivative thereof can be dissolved or suspended in the vehicle.
  • the vehicle can be an aqueous solution.
  • Quercetin is soluble in polar aprotic organic solvents but poorly soluble in water.
  • formation of a quercetin solution will typically require the presence of a solubilizing agent or cosolvent in the vehicle.
  • An exemplary solubilizing agent is ethyl lactate. As described in the examples below, ethyl lactate significantly increased the solubility of quercetin (for example, by greater than ten-fold).
  • quercetin is suspended in the vehicle.
  • quercetin can be mixed with the vehicle as a fine powder to form a substantially homogeneous suspension.
  • the quercetin or ester or derivative thereof, and/or the iota- carrageenan can be administered as part of a pharmaceutical composition suitable for nasal administration comprising a water-soluble solvent selected from the group consisting of propylene glycol, glycerin or glycerol, polyethylene glycol, and combinations thereof.
  • the water-soluble solvent is glycerin or glycerol.
  • the composition can comprise a solubilizing agent, such as ethyl lactate, and glycerin or glycerol.
  • the glycerin or glycerol can act as a humectant and/or a solvent.
  • composition can further comprise one or more of a polysaccharide gum.
  • Exemplary polysaccharide gums are xanthan gum, hydroxypropyl xanthan gum, undecylenoyl xanthan gum, dehydro xanthan gum, xanthan gum crosspolymer, xanthan hydroxypropyltrimonium chloride, gellan gum, wellan gum, biosaccharide gum-1, biosaccharide gum-2, biosaccharide gum-3, biosaccharide gum-4, biosaccharide gum-5, pseudoalteromonas exopolysaccharides, dextran, carboxymethyl dextran, dextran hydroxypropyltrimonium chloride, sodium carboxymethyl dextran, dextran sulfate, sclerotium gum, hydrolyzed sclerotium gum, beta-glucan, beta-glucan hydroxypropyltrimonium chloride, beta-glucan palmitate, hydrolyzed beta-glucan, oxidized beta-glucan, sodium carboxymethyl beta-glucan, pullulan
  • An exemplary polysaccharide gum is sclerotium gum.
  • Another example of a polysaccharide gum is xanthan gum.
  • the composition comprises sclerotium gum.
  • the composition comprises sclerotium gum and xanthan gum.
  • the composition comprises a solubilizing agent, such as ethyl lactate, and sclerotium gum.
  • the composition comprises ethyl lactate, sclerotium gum, and glycerin or glycerol.
  • the sclerotium gum can be present in the composition in an amount from about 0.05 to about 1.0% w/w; or about 0.05 to about 0.5% w/w.
  • the amount of sclerotium gum is about 0.25% to about 0.5% w/w. In certain additional aspects, the composition comprises about 0.05 to about 0.5% w/w sclerotium gum and about 0.05 to about 0.5% w/w xanthan gum.
  • Additional excipients that can be included in the composition include a non-ionic surfactant, and a preservative.
  • exemplary surfactants are poloxamers, including, but not limited, to poloxamer 188.
  • the preservative can, for example, be benzalkonium chloride.
  • a preservative other than benzalkonium chloride is used.
  • aloe vera e.g., aloe vera powder
  • aloe vera powder can be included in an amount from about 0.05 to about 2% w/w; for example about 1% w/w aloe vera.
  • the quercetin or ester thereof, and/or the iota- carrageenan can be administered as part of a pharmaceutical composition suitable for nasal administration comprising an aqueous vehicle and further comprising a solubilizer.
  • the solubilizer can be ethyl lactate.
  • the formulation comprises quercetin or an ester thereof, and/or the iota-carrageenan, and the formulation further comprises ethyl lactate, and glycerin or glycerol.
  • the formulation comprises quercetin, ethyl lactate, and glycerin or glycerol.
  • the formulation comprises quercetin, iota carrageenan, ethyl lactate and glycerin or glycerol.
  • the formulation suitable for nasal administration comprises iota- carrageenan and further comprises ethyl lactate, wherein the formulation does not comprise benzalkonium chloride.
  • the formulation comprising iota-carrageenan and ethyl lactate can further comprise glycerin or glycerol.
  • the compositions comprising the active agent and ethyl lactate can further comprise one or more of a polysaccharide gum, a non-ionic surfactant, and a preservative.
  • An exemplary polysaccharide gum is sclerotium gum.
  • Exemplary surfactants are poloxamers, including, but not limited, to poloxamer 188.
  • the ethyl lactate can be present in the composition in an amount from about 0.5 to about 15% w/w, or about 5 to about 15% w/w.
  • the amount of ethyl lactate is about 8% to about 12% w/w, for example about 10% w/w.
  • the glycerin or glycerol is present in an amount from about 2 to about 10% w/w.
  • the sclerotium gum is present in the composition in an amount from about 0.05 to about 1.0% w/w; about 0.05 to about 0.5% w/w, or about 1 to about 5% w/w.
  • the iota- carrageenan can be present in the composition in an amount from about 0.05 to about 5.0% w/w.
  • the quercetin or pharmaceutically acceptable ester or derivative thereof can be present in the composition in an amount from about 0.5% by weight to about 25% by weight, 0.1 to about 5% w/w, or about 0.1 to about 1.0% w/w.
  • the poloxamer 188 can be present in the composition in an amount from about 0.1 to about 1% w/w.
  • the amount of water in the composition can be about 80% to about 90% by weight or about 80% to about 85% by weight.
  • compositions of the invention comprise an active agent selected from the group consisting of quercetin or a pharmaceutically acceptable ester thereof, and iota-carrageenan, and combinations thereof, suitable for pulmonary administration.
  • the composition can be a dry powder and delivered by a dry powder inhaler, suspended in a propellant or in an aqueous suspension or solution and delivered via a nebulizer.
  • a solution or suspension of quercetin and a pulmonary excipient such as lactose, can be spray dried to form particles having a fine particle fraction sufficient to deliver to the lungs or upper respiratory system.
  • an aqueous solution or suspension of quercetin can be sonicated, thereby aerosolizing the solution/suspension to a droplet size that can be inhaled, e.g., via a nebulizer.
  • Pulmonary excipients include carbohydrates including monosaccharides, disaccharides and polysaccharides.
  • monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffmose and the like; and other carbohydrates such as starches (hydroxy ethylstarch), cyclodextrins and maltodextrins.
  • excipients suitable for use with the present invention including amino acids, are known in the art such as those disclosed in WO 95/31479, WO 96/32096, and WO 96/32149. Mixtures of carbohydrates and amino acids are further held to be within the scope of the present invention.
  • inorganic e.g., sodium chloride, etc.
  • organic acids and their salts e.g., carboxylic acids and their salts such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.
  • buffers is also contemplated.
  • the inclusion of salts and organic solids such as ammonium carbonate, ammonium acetate, ammonium chloride or camphor are also contemplated.
  • the composition can also be a lipid-based composition, such as coated lipid particles, liposomes, emulsions, micelles, and the like.
  • the lipids used in the pharmaceutical formulations of the present invention can be synthetic, semi-synthetic or naturally-occurring lipids, including phospholipids, tocopherols, sterols, fatty acids, glycoproteins such as albumin, negatively-charged lipids and cationic lipids.
  • phospholipids could include such lipids as egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE), and phosphatidic acid (EPA); the soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), other phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the I position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids.
  • EPC egg phosphatidylcholine
  • the chains on these fatty acids can be saturated or unsaturated, and the phospholipid may be made up of fatty acids of different chain lengths and different degrees of unsaturation.
  • the compositions of the formulations can include dipalmitoylphosphatidylcholine (DPPC), a major constituent of naturally-occurring lung surfactant.
  • DPPC dipalmitoylphosphatidylcholine
  • DMPC dimyristoylphosphatidy choline
  • DMPG dimyristoylphosphatidylglycerol
  • DPPQ dipalmitoylphosphatideholine
  • DPPG dipalmitoylphosphatidylglycerol
  • DSPQ dipalmitoylphosphatidylglycerol
  • DSPQ distearoylphosphatidylcholine
  • DSPG distearoylphosphatidylglycerol
  • DOPE dioleylphosphatidyl-ethanolamine
  • PSPC palmitoylstearoylphosphatidyl-choline
  • PSPG palmitoylstearolphosphatidylglycerol
  • MOPE mono- oleoyl-phosphatidylethanolamine
  • the sterols can include, cholesterol, esters of cholesterol including cholesterol hemi- succinate, salts of cholesterol including cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, esters of ergosterol including ergosterol hemi-succinate, salts of ergosterol including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, esters of lanosterol including lanosterol hemi-succinate, salts of lanosterol including lanosterol hydrogen sulfate and lanosterol sulfate.
  • the tocopherols can include tocopherols, esters of tocopherols including tocopherol hemi-succinates, salts of tocopherols including tocopherol hydrogen sulfates and tocopherol sulfates.
  • the term "sterol compound” includes sterols, tocopherols and the like.
  • the cationic lipids used can include ammonium salts of fatty acids, phospholids and glycerides.
  • the fatty acids include fatty acids of carbon chain lengths of 12 to 26 carbon atoms that are either saturated or unsaturated. Some specific examples include: myristylamine, palmitylamine, laurylamine and stearylamine, dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP) and distearoyl ethylphosphocholine (DSEP), N-(2,3-di-(9-(Z)-octadecenyloxy)-prop-l-yl- N,N,N-trimethylammoniu- m chloride (DOTMA) and l,2-bis(oleoyloxy)-3- (trimethylammonio)propane (DOTAP).
  • DLEP d
  • Negatively-charged lipids which can be used include phosphatidyl-glycerols (PGs), phosphatidic acids (PAs), phosphatidylinositols (Pis) and the phosphatidyl serines (PSs).
  • PGs phosphatidyl-glycerols
  • PAs phosphatidic acids
  • PSs phosphatidyl serines
  • Examples include DMPG, DPPG, DSPG, DMPA, DPP A, DSPA, DMPI, DPPI, DSPI,
  • Phosphatidylcholines such as DPPC aid in the uptake by the cells in the lung (e.g., the alveolar macrophages) and helps to sustain release of the bioactive agent in the lung.
  • the negatively charged lipids such as the PGs, PAs, PSs and Pis, in addition to reducing particle aggregation, are believed to play a role in the sustained release characteristics of the inhalation formulation as well as in the transport of the formulation across the lung (transcytosis) for systemic uptake.
  • the sterol compounds are believed to affect the release characteristics of the formulation.
  • compositions may be used in the form of dry powders or in the form of stabilized dispersions comprising a non-aqueous phase. Accordingly, the dispersions or powders of the present invention may be used in conjunction with metered dose inhalers (MDIs), dry powder inhalers (DPIs), atomizers, nebulizers or liquid dose instillation (LDI) techniques to provide for effective drug delivery.
  • MDIs metered dose inhalers
  • DPIs dry powder inhalers
  • atomizers atomizers
  • nebulizers nebulizers
  • LLI liquid dose instillation
  • the hollow and porous microparticles of the present invention are particularly useful in DPIs.
  • Conventional DPIs comprise powdered formulations and devices where a predetermined dose of medicament, either alone or in a blend with lactose carrier particles, is delivered as an aerosol of dry powder for inhalation.
  • the medicament is formulated in a way such that it readily disperses into discrete particles with a mass median aerodynamic diameters of the powders will characteristically range from about 0.5-10, preferably from about 0.5-5.0 microns MMAD.
  • the stabilized dispersions disclosed herein may also be administered to the nasal or pulmonary air passages of a patient via aerosolization, such as with a metered dose inhaler.
  • MDIs are well known in the art and could easily be employed for administration of the claimed dispersions without undue experimentation. Breath activated MDIs, as well as those comprising other types of improvements which have been, or will be, developed are also compatible with the stabilized dispersions and present invention and, as such, are contemplated as being within the scope thereof.
  • the stabilized dispersions may be administered with an MDI using a number of different routes including, but not limited to, topical, nasal, pulmonary or oral. Those skilled in the art will appreciate that, such routes are well known and that the dosing and administration procedures may be easily derived for the stabilized dispersions of the present invention.
  • the stabilized dispersions of the present invention may also be used in conjunction with nebulizers as disclosed in PCT Publication WO 99/16420, the disclosure of which is hereby incorporated in its entirety by reference, in order to provide an aerosolized medicament that may be administered to the pulmonary air passages of a patient in need thereof.
  • Nebulizers are well known in the art and could easily be employed for administration of the claimed dispersions without undue experimentation. Breath activated nebulizers, as well as those comprising other types of improvements which have been, or will be, developed are also compatible with the stabilized dispersions and present invention and are contemplated as being within the scope thereof.
  • the stabilized dispersions of the present invention may be used in conjunction with liquid dose instillation or LDI techniques as disclosed in, for example, WO 99/16421 hereby incorporated in its entirety by reference.
  • Liquid dose instillation involves the direct administration of a stabilized dispersion to the lung.
  • direct pulmonary administration of bioactive compounds is particularly effective in the treatment of disorders especially where poor vascular circulation of diseased portions of a lung reduces the effectiveness of intravenous drug delivery.
  • the stabilized dispersions are preferably used in conjunction with partial liquid ventilation or total liquid ventilation.
  • the present invention may further comprise introducing a therapeutically beneficial amount of a physiologically acceptable gas (such as nitric oxide or oxygen) into the pharmaceutical microdispersion prior to, during or following administration.
  • a physiologically acceptable gas such as nitric oxide or oxygen
  • a solution or suspension of quercetin or an ester or derivative thereof and a pulmonary excipient, such as lactose can be spray dried to form particles having a fine particle fraction sufficient to deliver to the lungs or upper respiratory system.
  • the quercetin or ester thereof, and/or the iota-carrageenan can be administered as part of a pharmaceutical composition suitable for pulmonary administration (e.g., capable of aerosolization) comprising lactose as a carrier agent and further comprising an aqueous vehicle, the composition further comprising a solubilizer; for example, the solubilizer can be ethyl lactate.
  • the formulation comprises quercetin or an ester thereof, and/or the iota-carrageenan, and the formulation further comprises ethyl lactate and glycerin or glycerol.
  • the formulation comprises quercetin, ethyl lactate and glycerin or glycerol. In further aspects, the formulation comprises quercetin, iota carrageenan, ethyl lactate and glycerin or glycerol. In yet further embodiments, the formulation suitable for nasal administration comprises iota-carrageenan and further comprises ethyl lactate, wherein the formulation does not comprise benzalkonium chloride. The formulation comprising iota-carrageenan and ethyl lactate can further comprise glycerin or glycerol. The compositions comprising the active agent and ethyl lactate can further comprise one or more of a polysaccharide gum, a non-ionic surfactant, and a preservative.
  • An exemplary polysaccharide gum is sclerotium gum.
  • Exemplary surfactants are poloxamers, including, but not limited, to poloxamer 188.
  • the ethyl lactate can be present in the composition in an amount from about 5 to about 15% w/w.
  • the glycerin or glycerol is present in an amount from about 2 to about 10% w/w.
  • the sclerotium gum is present in the composition in an amount from about 0.05 to about 1.0% w/w; or about 0.05 to about 0.5% w/w.
  • the iota-carrageenan can be present in the composition in an amount from about 0.05 to about 5.0% w/w.
  • the quercetin or pharmaceutically acceptable ester or derivative thereof can be present in the composition in an amount from about 0.1 to about 1.0% w/w.
  • the invention also includes methods of using the composition of the invention for treating or preventing a viral respiratory infection in a subject in need thereof.
  • the method comprises the step of nasally administering an effective amount of the composition to the subject.
  • the composition comprises an active agent selected from the group consisting of quercetin or a pharmaceutically acceptable ester thereof, and iota- carrageenan, as well as combinations thereof.
  • the iota-carrageenan can be administered in the absence of benzalkonium chloride.
  • “In the absence of benzalkonium chloride” encompasses nasal administration of iota-carrageenan in a composition that does not comprise benzalkonium chloride.
  • the methods also encompass pulmonary administration of an effective amount of the composition to a subject.
  • the viral respiratory infection can be any infection of the upper or lower respiratory tract, including the common cold, influenza, rhinovirus, respiratory syncytial virus infection, Severe Acute Respiratory Syndrome, Middle East Respiratory Syndrome, COVID-19, or a respiratory disease caused by another emerging zoonotic virus, such as a zoonotic coronavirus.
  • respiratory viruses are Influenza virus type A, Influenza A H3N2; Influenza A H5N1 (low path); Influenza B (Victoria); Influenza B (Yamagata); Parainfluenza virus-3; Rhinovirus- 14; Influenza A H7N9 virus; Influenza A H5N1 (high path), Adenoviruses, Avian influenza, Measles, Parainfluenza virus, Respiratory syncytial virus (RSV), Rhinoviruses, and coronavirus.
  • the viral respiratory infection is a SARS-CoV-2 (COVID-19) respiratory infection.
  • a “subject” includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
  • the animal is a mammal such as a non-primate and a primate (e.g., monkey and human).
  • the subject is a human subject.
  • a human subject can also be referred to as a “patient.”
  • a patient is a human, such as a human infant, child, adolescent or adult.
  • the terms “patient” and “subject” are used interchangeably.
  • the subject preferably a human, can be an individual diagnosed with the viral respiratory infection and is either symptomatic, pre-symptomatic, or asymptomatic, or at risk for developing the viral respiratory infection.
  • the subject can be at risk for developing the viral respiratory infection due to direct or indirect exposure or possible exposure to the virus, such as via exposure to an infected individual or a virus-contaminated fomite.
  • the subject can be a resident of, or a visitor to, a community (e.g., a residential care, nursing home, or long-term care facility) in which the viral respiratory infection has been identified.
  • the subject can also be a family member of an infected individual or the subject can work in a health care setting caring for infected individuals.
  • the subject at risk for infection is asymptomatic and/or has tested negative for presence of the virus prior to the commencement of therapy.
  • the subject can be at risk for developing COVID-19 due to exposure to the SARS-CoV-2 virus, for example, contact with an individual that has been diagnosed positive or other contact or possible exposure to the respiratory droplets or aerosols of an infected individual and/or contact with a contaminated fomite/surface.
  • the subject is suffering from COVID-19 including subjects suffering from mild, moderate, or severe COVID-19.
  • the subject suffers from another disease or condition, such as asthma and/or chronic obstructive pulmonary disease (COPD), which can be exacerbated by a viral respiratory infection.
  • COPD chronic obstructive pulmonary disease
  • the composition is preferably administered to the subject before the subject is symptomatic (e.g., pre-symptomatic), or at the onset of symptoms.
  • the composition can be administered at a variety of dosing schedules. For example, the composition can be administered one or more times and over a course of one or more days. In certain embodiments, the composition is administered one or more times per day for one or more days, one or more weeks, one or months, one or more years, or on as needed basis.
  • the composition is administered from 1 to 30 days, from 1 to 20 days, from 1 to 15 days, or from 1 to 10 days. In certain embodiments, the composition is administered one or more times per day until the subject is asymptomatic and/or testing for the virus is negative.
  • the composition can be administered to the nasal passages using routine methods and devices (see D. Marx et al., IntechOpen, DOI: 10.5772/59468. Available from: https://www.intechopen.com/books/drug-discovery-and-development-from-molecules-to- medicine/intranasal-drug-administration-an-attractive-delivery-route-for-some-drugs).
  • the composition can be administered to the nasal passages as drops or as an aerosol spray, for example, using an aerosol bottle or a multi-dose spray pump, which can provide a uniform metered dose.
  • the volume per dose will depend on the delivery device and thus can vary; in specific examples the dose is from about 50 to about 150 pi.
  • the desired volume will depend on the desired dose of the active agent and the concentration of the active agent in the composition, among other factors.
  • the product or composition described herein can be co-administered with other active agents and therapies.
  • the active agents and compositions of the present invention are also intended for use with general care provided patients with viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antiviral prophylaxis, fever (e.g., acetaminophen) and pain medication, anti emetic (such as metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common diseases in the patient population, such as artemether, artesunate-lumefantrine combination therapy), quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, or aminopen
  • the active agent or composition described herein is co administered with an additional anti-viral agent.
  • the active agent or composition can be co-administered with remdesivir, a corticosteroid, or a combination thereof.
  • exemplary corticosteroids include dexamethasone, prednisone, methylprednisolone, and hydrocortisone.
  • the active agent or composition is co-administered with the standard of care.
  • the subject is suffering from COVID-19 and the composition is co-administered with chloroquine, hydroxychloroquine, and azithromycin, or a combination thereof.
  • the active agent or composition described herein is co-administered with one or more antibodies that bind the SARS-CoV-2 S-protein and/or its receptor-binding domain (RBD), including, for example, Regeneron Pharmaceuticals’ experimental monoclonal antibody (mAb) cocktail REGN- COV2, and Lilly’s LY-CoV555, which is a cocktail of two human IgGl mAbs targeting different spike (S) glycoprotein epitopes.
  • mAb monoclonal antibody
  • REGN- COV2 receptor-binding domain
  • LY-CoV555 which is a cocktail of two human IgGl mAbs targeting different spike (S) glycoprotein epitopes.
  • the composition comprising quercetin, or a pharmaceutically acceptable ester or derivative of any of thereof is co-administered with a carrageenan.
  • the composition comprises quercetin and a carrageenan.
  • the invention also encompasses methods comprising co-administration of quercetin, or a pharmaceutically ester of any thereof, with a carrageenan.
  • Administration of carrageenan as an anti-viral agent, including nasal administration, has been described, for example, in U.S. Pat. No. 10,342,820, U.S. Pat. No. 8,282,969, U.S. Pat. No. 10,376,537, U.S. Pat. No. 10,022,449, and U.S. Pat.
  • carrageenan encompasses iota- and kappa-carrageenan or a mixture of both.
  • a “carrageenan” can be a homopolymer or a heteropolymer.
  • a carrageenan homopolymer is built of subunits of only one kind of either iota-, or kappa-carrageenan, whereas a carrageenan heteropolymer comprises subunits of both said carrageenans.
  • a “mixture” of carrageenans can thus refer to a composition of matter comprising a mixture of different carrageenan subunits as part of at least one heteropolymeric carrageenan present in said composition.
  • the carrageenan composition is substantially free of carrageenans other than iota- and kappa-carrageenan, for example, comprises either iota- or kappa-carrageenan, or a mixture of both, in an amount of 80% or more, 90% or more, and or up to 99% (w/w) or more, relative to the dry weight of all carrageenans present in the composition.
  • the composition comprises iota- carrageenan and is substantially free (e.g., less that about 10%, less than about 5%, or less than about 1%) of other carrageenans, including kappa-carrageenan.
  • the composition comprises more than 50%, more than 70%, more than 90%, or more than 95% (w/w) by dry weight of iota-carrageenan, relative to the total dry weight of all carrageenans present in the composition.
  • the composition comprises kappa-carrageenan and is substantially free (e.g., less that about 10%, less than about 5%, or less than about 1%) of other carrageenans, including iota-carrageenan.
  • the composition comprises more than 50%, more than 70%, more than 90%, or more than 95% (w/w) by dry weight of kappa-carrageenan, relative to the total dry weight of all carrageenans present in the composition.
  • the carrageenan can have molecular weight ranging from about 15,000 to 5,000,000 Da, fractions having average molecular weights of more than 50,000 Da, or fractions having average molecular weights in the range of from 50,000 to 3,000,000 Da.
  • the carrageenan is in an amount of between 0.01 and 10%, relative to the total volume of the composition.
  • a preferred formulation is an oral or buccal formulation for the controlled release of zinc and quercetin.
  • a lozenge comprising zinc and quercetin can release the compounds over a few minutes to allow buccal absorption.
  • a buccal spray comprising zinc and quercetin can be used.
  • Another buccal delivery form can be a dissolvable film or paper comprising zinc and quercetin to be placed under the tongue.
  • Buccal delivery can also be achieved by a mucosal film comprising zinc and quercetin that can be adhered to the gums.
  • Buccal delivery can also be achieved by a chewing gum comprising zinc and quercetin.
  • the quercetin and zinc deposit on the buccal mucosa (including the nasal passages, mouth and pharynx) and prevent viral uptake.
  • the method comprises co-administration of zinc and an active agent selected from an active agent selected from the group consisting of quercetin or a pharmaceutically acceptable ester thereof, and iota-carrageenan, as well as combinations thereof.
  • an active agent selected from an active agent selected from the group consisting of quercetin or a pharmaceutically acceptable ester thereof, and iota-carrageenan as well as combinations thereof.
  • a lozenge comprising zinc, quercetin and iota-carrageenan can release the compounds over a few minutes to allow buccal absorption.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • Simultaneous administration can include administration of the active therapeutic agents as part of the same composition.
  • Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents and/or as part of the same treatment regimen.
  • a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
  • a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.
  • the combination therapy may provide "synergy” and “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • an agent encompasses both a single agent and a combination of two or more agents.
  • treating covers the treatment of the disease or condition of interest (e.g., a respiratory infection) in a mammal, preferably a human, having the disease or condition of interest, and includes, for example: preventing or delaying the onset of the disease or condition from occurring in a mammal, in particular, when such mammal is at risk of developing the disease but has not yet become symptomatic and/or been diagnosed as having it; inhibiting the disease or condition, i.e., arresting its development; relieving the disease or condition, i.e., causing regression of the disease or condition; and/ or stabilizing the disease or condition.
  • the disease or condition of interest e.g., a respiratory infection
  • Treatment includes ameliorating or lessening the severity of symptoms of the disease or condition, and/or inhibition of further progression or worsening of those symptoms. Treatment also includes shortening the time course and/or severity of a disease or condition compared to the expected or historical time course and/or severity of the disease.
  • preventing means causing the clinical symptoms of a disease or condition not to develop and includes inhibiting the onset of a viral infection in a subject that may be exposed to or predisposed to the viral infection but does not yet experience or display symptoms of the infection.
  • an “effective amount” or a “therapeutically effective amount” of a compound or composition described herein refers to an amount of the compound that is sufficient to achieve a specific effect or result, and/or prevents or treats the disease or condition and/or the symptoms therefore, for example, alleviating, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • the “effective amount” and “therapeutically effective amount” includes specifically an anti-viral amount of quercetin (alone or in combination with another active agent) or the composition described herein.
  • a “pharmaceutically acceptable ester” as used herein, is an ester of a parent hydroxyl- containing compound with a pharmaceutically acceptable carboxylic acid, such as acetic acid, propionic acid, butyric acid, benzoic acid or an amino acid.
  • Disulfuram (a known protease inhibitor), quercetin at 140 uM, were tested in the MPro inhibition assay as described in Jin et al. (2020), Structure of Mpro from SARS-CoV2 and discovery of its inhibitors, Nature 582: 289- 293; the contents of which are expressly incorporated by reference herein.
  • quercetin in DMSO vehicle provided about 95% MPro inhibition.
  • Vero cells were infected with SARS-CoV-2 according to the method described in Hoffman et al. (2020), SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181(2): 271-280.e8 and Ou et al. (2020), Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 11, 1-12; the contents of each of which are expressly incorporated by reference herein.
  • iota-carrageenan treatment reduced the proportion of infected cells in a dose-dependent manner and the presence of benzalkonium chloride reduced that inhibitory effect.
  • Example 3 Quercetin and iota-carrageenan, alone and in combination, reduced the ratio of infected cells
  • A549 cells were infected with SARS-CoV-2 according to methods described in Hoffman et al. (2020), SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181(2): 271-280.e8 and Ou et al. (2020), Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 11, 1-12; the contents of each of which are expressly incorporated by reference herein.
  • VIG included 0.25% w/w/ iota-carrageenan, 10% w/w ethyl lactate, and 6% w/w glycerin.
  • l.VIG quercetin in VIG
  • VIG itself vehicle in the absence of the quercetin; but including iota-carrageenan
  • concentrations of 1 uM or more reduced the normalized ratio of infection to 0.
  • Example 4 Formulations comprising quercetin and iota-carrageenan
  • the preferred preparation procedure separately makes an iota-Carrageenan solution, an aqueous sub-mix and a Quercetin sub-mix.
  • the sub-mixes are combined to complete the final product formulation.

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Abstract

La présente invention concerne des compositions et des méthodes pour le traitement ou la prévention d'une infection respiratoire virale. Les compositions et les méthodes comprennent l'utilisation de la quercétine ou d'un ester ou d'un dérivé pharmaceutiquement acceptable de celle-ci pour une administration nasale.
PCT/US2021/018663 2020-02-20 2021-02-19 Méthodes et compositions pour le traitement d'infections respiratoires virales Ceased WO2021168173A1 (fr)

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WO2022084931A1 (fr) * 2020-10-23 2022-04-28 Antonio Bianchi Formulation de pulvérisation à usage nasal/oral ayant une activité contre les coronavirus respiratoires et en particulier contre le virus sars-cov-2
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EP4387734A4 (fr) * 2021-08-22 2025-08-20 Viron Inc Procédé destiné à empêcher l'entrée et la réplication de virus enveloppés
WO2023031929A1 (fr) * 2021-08-31 2023-03-09 Polyrizon Ltd. Polymères mucoadhésifs pour administration nasale de médicament
US12226431B2 (en) 2021-09-11 2025-02-18 Porosome Therapeutics, Inc. Aerosol and topical administration of a formulation containing cyclodextrin, quercetin and zinc, in combination or separately, to mitigate infection by enveloped viruses
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