CN117295494A - Methods of treating conjunctivitis and/or covd-19 using benzalkonium chloride - Google Patents

Abstract

Methods for treating coronavirus disease 2019 (COVID-19) including at least one ocular manifestation of COVID-19, methods for treating conjunctivitis, and methods for reducing the spread of COVID-19 are disclosed Including administering an effective amount of benzalkonium chloride. Pharmaceutical compositions containing benzalkonium chloride are also disclosed.

Description

Methods of using benzalkonium chloride to treat conjunctivitis and/or COVID-19

This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/092,399 filed on October 15, 2020, U.S. Provisional Patent Application No. 63/183,928 filed on May 4, 2021, and U.S. Provisional Patent Application No. 63/226,614 filed on July 28, 2021, the contents of each of which are incorporated herein by reference in their entirety.

Disclosed herein are methods of using benzalkonium chloride to treat conjunctivitis and/or coronavirus disease 2019 (COVID-19), including at least one ocular manifestation of COVID-19, and methods of using benzalkonium chloride to reduce the spread of COVID-19, including ocular spread of COVID-19. Also disclosed are pharmaceutical compositions comprising benzalkonium chloride.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 appears to be transmitted through direct or indirect contact with mucosal surfaces (e.g., nasal, oral, and/or ocular surfaces). Ocular surface cells (including corneal and conjunctival epithelial cells) express the receptors angiotensin I converting enzyme 2 (ACE2) and cluster of differentiation 147 (CD147), as well as transmembrane protease serine 2 (TMPRSS2), all of which have been implicated in SARS-CoV-2 host cell invasion.

Although symptomatic COVID-19 patients typically present with fever, respiratory symptoms (such as, for example, cough), and/or fatigue, extrapulmonary manifestations of the disease (such as, for example, ocular manifestations) have been reported. Exemplarily, SARS-CoV-2 has been identified in the tears and ocular secretions of some COVID-19 patients, and ocular infection by SARS-CoV-2 can lead to, for example, ocular disorders and disorders, such as, for example, redness of the eye, conjunctivitis, keratoconjunctivitis, dry eyes, blurred vision, conjunctival congestion, eye irritation, foreign body sensation, epiphora, eyelid swelling, and/or conjunctival edema. In addition, viruses on the surface of the eye can spread to the respiratory tract via the nasolacrimal duct, aggravating the pulmonary symptoms of COVID-19. Therefore, new prevention and treatment methods for COVID-19 are needed, including prevention and treatment methods for COVID-19-related ocular disorders and disorders.

Benzalkonium chloride (BAK) is a mixture of quaternary ammonium compounds of the following structure, where n is 8, 10, 12, 14, 16, or 18:

BAK is a cationic surfactant and antimicrobial agent, commonly used as a preservative in ophthalmic topical solutions. Typical BAK concentrations in ophthalmic topical solutions range from 0.001% (w/v) to 0.02% (w/v), such as, for example, 0.004% (w/v) to 0.02% (w/v).

Disclosed herein are methods for treating at least one ocular manifestation of coronavirus disease 2019 (COVID-19), the method comprising administering to a subject in need thereof an effective amount of benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference.

Additionally, liposomal aqueous suspensions containing benzalkonium chloride are described in US Pat. No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition described in US Pat. No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating at least one disease or condition selected from the group consisting of ocular redness, conjunctivitis, keratoconjunctivitis, dry eyes, blurred vision, conjunctival hyperemia, ocular irritation, foreign body sensation, epiphora, eyelid edema, and conjunctival edema. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating conjunctivitis. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises improving visual acuity. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises reducing ocular redness, ocular irritation, or foreign body sensation.

Also disclosed herein are methods for reducing the risk of ocular transmission of SARS-CoV-2, comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, at least some of the liposomes in the liposome composition are targeted liposomes. In some embodiments, the targeted liposomes are targeted to at least a portion of the eye. In some embodiments, the targeted liposomes include at least one ligand selected from an embedded ligand and a covalently coupled ligand (such as, for example, an antibody and a lectin). Targeted liposomes are known in the art and are described in, for example, Kelly et al., J. Drug Delivery, 2011: 727241 (2011); Wijetunge et al., ACS Appl. Bio Mater. 1 (5): 1487-1495 (2018); Mishra et al., J. Drug Delivery, DOI: 10.1155/2011/863734; and Agarwal et al., Drug Delivery, 23: 4, 1075-1091, DOI: 10.3109/10717544.2014.943336.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference. In addition, an aqueous liposome suspension comprising benzalkonium chloride is described in U.S. Patent No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposome composition described in U.S. Patent No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

Also disclosed herein is a method for preventing coronavirus disease 2019 (COVID-19), comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, at least some of the liposomes in the liposome composition are targeted liposomes. In some embodiments, the targeted liposomes are targeted to at least a portion of the eye. In some embodiments, the targeted liposomes include at least one ligand selected from an embedded ligand and a covalently coupled ligand (such as, for example, an antibody and a lectin). Targeted liposomes are known in the art and are described in, for example, Kelly et al., J. Drug Delivery, 2011: 727241 (2011); Wijetunge et al., ACS Appl. Bio Mater. 1 (5): 1487-1495 (2018); Mishra et al., J. Drug Delivery, DOI: 10.1155/2011/863734; and Agarwal et al., Drug Delivery, 23: 4, 1075-1091, DOI: 10.3109/10717544.2014.943336.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference. In addition, an aqueous liposome suspension comprising benzalkonium chloride is described in U.S. Patent No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposome composition described in U.S. Patent No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, preventing COVID-19 includes preventing at least one ocular manifestation of COVID-19.

Also disclosed herein is a method for reducing ocular SARS-CoV-2 viral load, comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a submicron dispersion of a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, at least some of the liposomes in the liposome composition are targeted liposomes. In some embodiments, the targeted liposomes are targeted to at least a portion of the eye. In some embodiments, the targeted liposomes include at least one ligand selected from an embedded ligand and a covalently coupled ligand (such as, for example, an antibody and a lectin). Targeted liposomes are known in the art and are described in, for example, Kelly et al., J. Drug Delivery, 2011: 727241 (2011); Wijetunge et al., ACS Appl. Bio Mater. 1 (5): 1487-1495 (2018); Mishra et al., J. Drug Delivery, DOI: 10.1155/2011/863734; and Agarwal et al., Drug Delivery, 23: 4, 1075-1091, DOI: 10.3109/10717544.2014.943336.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference. In addition, an aqueous liposome suspension comprising benzalkonium chloride is described in U.S. Patent No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposome composition described in U.S. Patent No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 25% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 50% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 75% compared to the ocular SARS-CoV-2 viral load before treatment.

Also disclosed herein are methods for treating conjunctivitis comprising administering to a subject in need thereof an effective amount of benzalkonium chloride.

In some embodiments, treating conjunctivitis comprises treating viral conjunctivitis. In some embodiments, treating conjunctivitis comprises treating conjunctivitis of unknown etiology.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, at least some of the liposomes in the liposome composition are targeted liposomes. In some embodiments, the targeted liposomes are targeted to at least a portion of the eye. In some embodiments, the targeted liposomes include at least one ligand selected from an embedded ligand and a covalently coupled ligand (such as, for example, an antibody and a lectin). Targeted liposomes are known in the art and are described in, for example, Kelly et al., J. Drug Delivery, 2011: 727241 (2011); Wijetunge et al., ACS Appl. Bio Mater. 1 (5): 1487-1495 (2018); Mishra et al., J. Drug Delivery, DOI: 10.1155/2011/863734; and Agarwal et al., Drug Delivery, 23: 4, 1075-1091, DOI: 10.3109/10717544.2014.943336.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference. In addition, an aqueous liposome suspension comprising benzalkonium chloride is described in U.S. Patent No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposome composition described in U.S. Patent No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

Also disclosed herein are methods for preventing conjunctivitis comprising administering to a subject in need thereof an effective amount of benzalkonium chloride.

In some embodiments, the subject exhibits at least one symptom of a viral infection. In some embodiments, the subject exhibits at least one symptom of a SARS CoV-2 infection.

In some embodiments, the subject is infected with a virus. In some embodiments, the subject is infected with SARS-CoV-2.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a submicron dispersion of a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, at least some of the liposomes in the liposome composition are targeted liposomes. In some embodiments, the targeted liposomes are targeted to at least a portion of the eye. In some embodiments, the targeted liposomes include at least one ligand selected from an embedded ligand and a covalently coupled ligand (such as, for example, an antibody and a lectin). Targeted liposomes are known in the art and are described in, for example, Kelly et al., J. Drug Delivery, 2011: 727241 (2011); Wijetunge et al., ACS Appl. Bio Mater. 1 (5): 1487-1495 (2018); Mishra et al., J. Drug Delivery, DOI: 10.1155/2011/863734; and Agarwal et al., Drug Delivery, 23: 4, 1075-1091, DOI: 10.3109/10717544.2014.943336.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference. In addition, an aqueous liposome suspension comprising benzalkonium chloride is described in U.S. Patent No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposome composition described in U.S. Patent No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition every 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate.

Also disclosed herein is a method for reducing intranasal SARS-CoV-2 viral load, comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.1% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics.

In some embodiments, the pharmaceutical composition is in the form of a spray.

In some embodiments, the pharmaceutical composition is administered intranasally.

In some embodiments, the method comprises administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent.

Also disclosed herein is a method for treating or preventing coronavirus disease 2019 (COVID-19), comprising administering an effective amount of benzalkonium chloride intranasally to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a drug delivery vehicle such as, for example, a dispersion system, a liposomal composition, or a micellar composition.

In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion selected from a submicron emulsion, an aqueous lecithin dispersion, an aqueous polysorbate 80 dispersion, and a submicron dispersion of a nanosphere suspension. In some embodiments, an effective amount of benzalkonium chloride is applied in the form of a submicron dispersion described in Watrobska-Swietlikowska, AAPS PharmSciTech, 21: 7 (2020), DOI: 10.1208/s12249-019-1540-7, which is incorporated herein by reference.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposomal composition, wherein at least some of the liposomes in the liposomal composition comprise benzalkonium chloride. In some embodiments, the benzalkonium chloride is sequestered within the aqueous compartment of the liposome. In some embodiments, the benzalkonium chloride is sequestered within the liposomal membrane.

In some embodiments, at least some of the liposomes in the liposome composition are targeted liposomes. In some embodiments, the targeted liposomes are targeted to at least a portion of the eye. In some embodiments, the targeted liposomes include at least one ligand selected from an embedded ligand and a covalently coupled ligand (such as, for example, an antibody and a lectin). Targeted liposomes are known in the art and are described in, for example, Kelly et al., J. Drug Delivery, 2011: 727241 (2011); Wijetunge et al., ACS Appl. Bio Mater. 1 (5): 1487-1495 (2018); Mishra et al., J. Drug Delivery, DOI: 10.1155/2011/863734; and Agarwal et al., Drug Delivery, 23: 4, 1075-1091, DOI: 10.3109/10717544.2014.943336.

In some embodiments, the liposome composition is an aqueous liposome suspension. In some embodiments, the liposome composition comprises neutral liposomes. In some embodiments, the liposome composition comprises positively charged liposomes. In some embodiments, the liposome composition comprises negatively charged liposomes. Liposome compositions that may also comprise at least one additional component (such as, for example, phosphatidylcholine (PC), cholesterol, and/or lipid-conjugated hydrophilic polymers) have been explored for ophthalmic drug delivery applications, as described in Mishra et al., J. Drug Delivery, 2011 volume, article ID 863734, DOI: 10.1155/2011/863734, which is incorporated herein by reference. In addition, an aqueous liposome suspension comprising benzalkonium chloride is described in U.S. Patent No. 5,565,213, which is incorporated herein by reference. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a liposome composition described in U.S. Patent No. 5,565,213.

In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a micellar composition, wherein at least some of the micelles in the micellar composition comprise benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.1% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics.

In some embodiments, the pharmaceutical composition is in the form of a spray.

In some embodiments, the method comprises administering intranasally an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent.

definition:

As used herein, unless otherwise indicated, "a" or "an" entity refers to one or more of that entity, e.g., "a compound" refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

As used herein, "administering" an API to a patient refers to any route of introducing or delivering the API to a subject. Administration includes self-administration as well as administration by another.

As used herein, "condition," "disorder," or "disease" refers to any unhealthy or abnormal state.

As used herein, "effective amount" or "effective dose" refers to the amount of a molecule that treats a patient suffering from a disorder, disease, or condition after single or multiple dose administration. The attending diagnostician can determine the effective amount by using known techniques and by observing the results obtained under similar circumstances. In determining the effective amount, the attending diagnostician considers a variety of factors, including, but not limited to: the species of the patient; his or her size, age, and general health; the specific condition, disorder, or disease involved; the extent or involvement or severity of the condition, disorder, or disease, the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the dosage regimen selected; the use of concomitant medications; and other relevant circumstances.

As used herein, when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, the term "in combination with" means that the two or more compounds, agents, or active pharmaceutical ingredients are administered to the patient before, at the same time, or after each other during the treatment period. Unless otherwise indicated, the two or more compounds, agents, or active pharmaceutical ingredients can be administered during the treatment period on different schedules, such as one or more compounds, agents, or active pharmaceutical ingredients are administered once a day, and one or more other compounds, agents, or active pharmaceutical ingredients are administered twice a day.

As used herein, the term "increase" refers to a positive change of at least 5%, including but not limited to a positive change of 5%, a positive change of 10%, a positive change of 25%, a positive change of 30%, a positive change of 50%, a positive change of 75%, or a positive change of 100%.

As used herein, "mammal" refers to domesticated animals (eg, dogs, cats, and horses) as well as humans. In some embodiments, the mammal is a human.

As used herein, a "manifestation" of a disorder, disease, or condition refers to a sign or symptom of the disorder, disease, or condition. For example, as used herein, a "manifestation of COVID-19" refers to a sign or symptom observed in a patient infected with SARS-CoV-2. Exemplarily, an ocular manifestation of COVID-19 refers to a sign or symptom observed in one or both eyes of a patient infected with SARS-CoV-2, such as, for example, redness of the eye, conjunctivitis, keratoconjunctivitis, dry eyes, blurred vision, conjunctival hyperemia, eye irritation, foreign body sensation, epiphora, eyelid swelling, and/or conjunctival edema.

As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammal, such as, for example, a human.

As used herein, "prevention" or "preventing" a disorder, disease, or condition refers to a decrease or reduction in the occurrence of the disorder, disease, or condition in a treated sample relative to an untreated control sample, and includes a delayed onset, delayed progression, or reduced severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition. For example, pharmaceutically acceptable excipients are generally safe and include carriers and excipients that are generally considered acceptable for mammalian pharmaceutical use. As a non-limiting example, a pharmaceutically acceptable excipient can be a solid, semisolid, or liquid material that can generally serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients, and include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavor enhancers, gel bases, sustained release bases, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, etc.

As used herein, the term "reduce" refers to a negative change of at least 5%, including but not limited to a negative change of 5%, a negative change of 10%, a negative change of 25%, a negative change of 30%, a negative change of 50%, a negative change of 75%, or a negative change of 100%.

As used herein, the terms "treat," "treating," or "treatment" when used in conjunction with a disorder or condition include any effect, such as alleviation, reduction, modulation, improvement, or elimination, which results in improvement of the disorder or condition. Improvement of any symptom of a disorder or condition or reduction in its severity can be readily assessed according to standard methods and techniques known in the art.

As will be understood by one of ordinary skill in the art, each range disclosed herein includes all possible subranges and individual numerical values within the range, including endpoints. As a non-limiting example, a range of "0.001% to 0.02%" includes and will be understood to specifically disclose subranges such as "0.004% to 0.01%", "0.005% to 0.02%", etc., as well as all individual numbers within the disclosed range, e.g., 0.001%, 0.004%, 0.005%, 0.01%, 0.02%, etc.

If one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process, a claim or description including "or" or "and/or" between at least one member of the group is considered satisfied unless otherwise indicated or otherwise obvious from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise relevant to a given product or process.

Some embodiments of the present disclosure relate to methods for treating at least one ocular manifestation of coronavirus disease 2019 (COVID-19), the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of suspensions. In some embodiments, the pharmaceutical composition is in the form of gels. In some embodiments, the pharmaceutical composition is in the form of ointments. In some embodiments, the pharmaceutical composition is in the form of injectable solutions. In some embodiments, the pharmaceutical composition is in the form of sprays.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents. In some embodiments, at least one additional therapeutic agent is selected from antibiotics.

In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones. In some embodiments, at least one additional therapeutic agent is selected from α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.02% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.002% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0025% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.003% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0035% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0045% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0055% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.006% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0065% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.007% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0075% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.008% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0085% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.009% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0095% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0125% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0175% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry EyeLubricant Eye Drops, Bepreve ^TM , Betoptic Children's Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), Pataday ^TM , Pred Soothe Long Lasting Hydration、 Xibrom ^TM , Zerviate ^TM , and

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry Eye Lubricant Eye Drops, Children's SootheLong Lasting Hydration, and

In some embodiments, the pharmaceutical composition is selected from Betoptic as well as

In some embodiments, the pharmaceutical composition is selected from Bepreve ^TM , Pataday ^TM , and Zerviate ^™ .

In some embodiments, the pharmaceutical composition is selected from Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), and Pred

In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition is selected from and Xibrom ^™ .

In some embodiments, the pharmaceutical composition is selected from as well as In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, at least one additional therapeutic agent is besifloxacin. In some embodiments, at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating at least one disease or condition selected from the group consisting of ocular redness, conjunctivitis, keratoconjunctivitis, dry eyes, blurred vision, conjunctival congestion, ocular irritation, foreign body sensation, epiphora, eyelid edema, and conjunctival edema.

In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating ocular redness. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating conjunctivitis. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating keratoconjunctivitis. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating dry eyes. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating blurred vision. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating conjunctival hyperemia. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating ocular irritation. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating foreign body sensation. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating epiphora. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating eyelid edema. In some embodiments, treating at least one ocular manifestation of COVID-19 comprises treating conjunctival edema.

In some embodiments, treating at least one ocular manifestation of COVID-19 comprises improving visual acuity.

In some embodiments, treating at least one ocular manifestation of COVID-19 includes reducing ocular redness, ocular irritation, or foreign body sensation. In some embodiments, treating at least one ocular manifestation of COVID-19 includes reducing ocular redness. In some embodiments, treating at least one ocular manifestation of COVID-19 includes reducing ocular irritation. In some embodiments, treating at least one ocular manifestation of COVID-19 includes reducing foreign body sensation.

Some embodiments of the present disclosure relate to methods for reducing the risk of ocular transmission of SARS-CoV-2, the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of suspensions. In some embodiments, the pharmaceutical composition is in the form of gels. In some embodiments, the pharmaceutical composition is in the form of ointments. In some embodiments, the pharmaceutical composition is in the form of injectable solutions. In some embodiments, the pharmaceutical composition is in the form of sprays.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents. In some embodiments, at least one additional therapeutic agent is selected from antibiotics.

In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones. In some embodiments, at least one additional therapeutic agent is selected from α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.02% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.002% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0025% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.003% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0035% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0045% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0055% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.006% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0065% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.007% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0075% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.008% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0085% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.009% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0095% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0125% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0175% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry EyeLubricant Eye Drops, Bepreve ^TM , Betoptic Children's Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), Pataday ^TM , Pred Soothe Long LastingHydration, Xibrom ^TM , Zerviate ^TM , and

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry Eye Lubricant Eye Drops, Children's SootheLong Lasting Hydration, and

In some embodiments, the pharmaceutical composition is selected from Betoptic as well as

In some embodiments, the pharmaceutical composition is selected from Bepreve ^TM , Pataday ^TM , and Zerviate ^™ .

In some embodiments, the pharmaceutical composition is selected from Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), and Pred

In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition is selected from and Xibrom ^™ .

In some embodiments, the pharmaceutical composition is selected from as well as In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

Some embodiments of the present disclosure relate to methods for preventing coronavirus disease 2019 (COVID-19), the methods comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of suspensions. In some embodiments, the pharmaceutical composition is in the form of gels. In some embodiments, the pharmaceutical composition is in the form of ointments. In some embodiments, the pharmaceutical composition is in the form of injectable solutions. In some embodiments, the pharmaceutical composition is in the form of sprays.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents. In some embodiments, at least one additional therapeutic agent is selected from antibiotics.

In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones. In some embodiments, at least one additional therapeutic agent is selected from α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.02% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.002% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0025% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.003% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0035% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0045% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0055% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.006% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0065% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.007% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0075% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.008% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0085% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.009% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0095% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0125% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0175% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry EyeLubricant Eye Drops, Bepreve ^TM , Betoptic Children's Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), Pataday ^TM , Pred Soothe Long LastingHydration, Xibrom ^TM , Zerviate ^TM , and

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry Eye Lubricant Eye Drops, Children's Naphcon- Soothe Long Lasting Hydration, and

In some embodiments, the pharmaceutical composition is selected from Betoptic as well as

In some embodiments, the pharmaceutical composition is selected from Bepreve ^TM , Pataday ^TM , and Zerviate ^™ .

In some embodiments, the pharmaceutical composition is selected from Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), and Pred

In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition is selected from and Xibrom ^™ .

In some embodiments, the pharmaceutical composition is selected from as well as In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, preventing COVID-19 includes preventing at least one ocular manifestation of COVID-19. In some embodiments, preventing COVID-19 includes preventing at least one ocular manifestation of COVID-19 selected from the group consisting of eye redness, conjunctivitis, keratoconjunctivitis, dry eyes, blurred vision, conjunctival hyperemia, eye irritation, foreign body sensation, epiphora, eyelid edema, and conjunctival edema.

Some embodiments of the present disclosure relate to methods for reducing ocular SARS-CoV-2 viral load, the method comprising administering to a subject in need thereof an effective amount of benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of suspensions. In some embodiments, the pharmaceutical composition is in the form of gels. In some embodiments, the pharmaceutical composition is in the form of ointments. In some embodiments, the pharmaceutical composition is in the form of injectable solutions. In some embodiments, the pharmaceutical composition is in the form of sprays.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents. In some embodiments, at least one additional therapeutic agent is selected from antibiotics.

In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones. In some embodiments, at least one additional therapeutic agent is selected from α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.02% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.002% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0025% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.003% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0035% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0045% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0055% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.006% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0065% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.007% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0075% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.008% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0085% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.009% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0095% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0125% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0175% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry EyeLubricant Eye Drops, Bepreve ^TM , Betoptic Children's Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), Pataday ^TM , Pred Soothe Long LastingHydration, Xibrom ^TM , Zerviate ^TM , and

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry Eye Lubricant Eye Drops, Children's Soothe Long Lasting Hydration, and

In some embodiments, the pharmaceutical composition is selected from Betoptic as well as

In some embodiments, the pharmaceutical composition is selected from Bepreve ^TM , Pataday ^TM , and Zerviate ^™ .

In some embodiments, the pharmaceutical composition is selected from Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), and Pred

In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition is selected from and Xibrom ^™ .

In some embodiments, the pharmaceutical composition is selected from as well as In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 25% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 50% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 75% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 80% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 90% compared to the ocular SARS-CoV-2 viral load before treatment. In some embodiments, reducing the ocular SARS-CoV-2 viral load comprises reducing the ocular SARS-CoV-2 viral load by 95% compared to the ocular SARS-CoV-2 viral load before treatment.

Some embodiments of the present disclosure are directed to methods for treating conjunctivitis, the method comprising administering to a subject in need thereof an effective amount of benzalkonium chloride.

In some embodiments, treating conjunctivitis comprises treating viral conjunctivitis. In some embodiments, treating conjunctivitis comprises treating conjunctivitis of unknown etiology.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of suspensions. In some embodiments, the pharmaceutical composition is in the form of gels. In some embodiments, the pharmaceutical composition is in the form of ointments. In some embodiments, the pharmaceutical composition is in the form of injectable solutions. In some embodiments, the pharmaceutical composition is in the form of sprays.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents. In some embodiments, at least one additional therapeutic agent is selected from antibiotics.

In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones. In some embodiments, at least one additional therapeutic agent is selected from α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.02% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.002% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0025% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.003% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0035% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0045% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0055% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.006% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0065% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.007% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0075% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.008% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0085% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.009% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0095% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0125% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0175% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry EyeLubricant Eye Drops, Bepreve ^TM , Betoptic Children's Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), Pataday ^TM , Pred Soothe Long Lasting Hydration、 Xibrom ^TM , Zerviate ^TM , and

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry Eye Lubricant Eye Drops, Children's Soothe Long Lasting Hydration, and

In some embodiments, the pharmaceutical composition is selected from Betoptic as well as

In some embodiments, the pharmaceutical composition is selected from Bepreve ^TM , Pataday ^TM , and Zerviate ^™ .

In some embodiments, the pharmaceutical composition is selected from Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), and Pred

In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition is selected from and Xibrom ^™ .

In some embodiments, the pharmaceutical composition is selected from as well as In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

Some embodiments of the present disclosure relate to methods for preventing conjunctivitis, the methods comprising administering to a subject in need thereof an effective amount of benzalkonium chloride.

In some embodiments, the subject exhibits at least one symptom of a viral infection. In some embodiments, the subject exhibits at least one symptom of a SARS CoV-2 infection.

In some embodiments, the subject is infected with a virus. In some embodiments, the subject is infected with SARS-CoV-2.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of suspensions. In some embodiments, the pharmaceutical composition is in the form of gels. In some embodiments, the pharmaceutical composition is in the form of ointments. In some embodiments, the pharmaceutical composition is in the form of injectable solutions. In some embodiments, the pharmaceutical composition is in the form of sprays.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotoxamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents. In some embodiments, at least one additional therapeutic agent is selected from antibiotics.

In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones. In some embodiments, at least one additional therapeutic agent is selected from α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.02% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.02% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) to 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.002% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0025% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.003% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0035% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.004% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0045% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0055% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.006% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0065% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.007% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0075% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.008% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0085% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.009% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0095% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0125% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.015% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.0175% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry EyeLubricant Eye Drops, Bepreve ^TM , Betoptic Children's Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), Pataday ^TM , Pred Soothe Long Lasting Hydration、 Xibrom ^TM , Zerviate ^TM , and

In some embodiments, the pharmaceutical composition is selected from Advanced Eye Relief Dry Eye Lubricant Eye Drops, Children's Soothe Long Lasting Hydration, and

In some embodiments, the pharmaceutical composition is selected from Betoptic as well as

In some embodiments, the pharmaceutical composition is selected from Bepreve ^TM , Pataday ^TM , and Zerviate ^™ .

In some embodiments, the pharmaceutical composition is selected from Gel (loteprednol 0.5%), SM gel (loteprednol 0.38%), Suspension (loteprednol 0.5%), and Pred

In some embodiments, the pharmaceutical composition is selected from as well as

In some embodiments, the pharmaceutical composition is selected from and Xibrom ^™ .

In some embodiments, the pharmaceutical composition is selected from as well as In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is In some embodiments, the pharmaceutical composition is

In some embodiments, an effective amount of benzalkonium chloride is topically administered. In some embodiments, an effective amount of benzalkonium chloride is administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to at least one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to one eye of a subject. In some embodiments, an effective amount of benzalkonium chloride is topically administered to both eyes of a subject.

In some embodiments, the method includes administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent. In some embodiments, at least one additional therapeutic agent is selected from antihistamines. In some embodiments, at least one additional therapeutic agent is selected from pheniramine maleate, rotosamine maleate, S-(+)-chlorpheniramine maleate, diphenhydramine, hydroxyzine, and azelastine. In some embodiments, at least one additional therapeutic agent is pheniramine maleate. In some embodiments, at least one additional therapeutic agent is selected from antihistamines, anti-inflammatory agents, and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from anti-inflammatory agents and antibiotics. In some embodiments, at least one additional therapeutic agent is selected from fluoroquinolones and α ₂ -adrenergic agonists.

In some embodiments, the at least one additional therapeutic agent is selected from besifloxacin and brimonidine tartrate. In some embodiments, the at least one additional therapeutic agent is besifloxacin. In some embodiments, the at least one additional therapeutic agent is brimonidine tartrate.

Some embodiments of the present disclosure relate to methods for reducing intranasal SARS-CoV-2 viral load, the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 6 to 8 hours. In some embodiments, an effective amount of benzalkonium chloride is administered as a pharmaceutical composition every 8 hours.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.1% (w/v) benzalkonium chloride.

In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, the pharmaceutical composition is in the form of a spray.

In some embodiments, the pharmaceutical composition is administered intranasally.

In some embodiments, the method comprises administering an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent.

Some embodiments of the present disclosure relate to methods for treating or preventing coronavirus disease 2019 (COVID-19), the methods comprising intranasally administering an effective amount of benzalkonium chloride to a subject in need thereof.

In some embodiments, an effective amount of benzalkonium chloride is administered intranasally as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered every 6 to 8 hours as a pharmaceutical composition. In some embodiments, an effective amount of benzalkonium chloride is administered every 8 hours as a pharmaceutical composition.

In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.2% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.1% (w/v) benzalkonium chloride.

In some embodiments, an effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. In some embodiments, an effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.02% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical composition further comprises an effective amount of at least one additional therapeutic agent.

In some embodiments, the pharmaceutical composition is in the form of a spray.

In some embodiments, the method comprises administering intranasally an effective amount of benzalkonium chloride in combination with an effective amount of at least one additional therapeutic agent.

Drug composition:

In some embodiments of the present disclosure, benzalkonium chloride is administered as part of a pharmaceutical composition comprising: an effective amount of benzalkonium chloride; and at least one pharmaceutically acceptable excipient.

Pharmaceutical compositions disclosed herein can be prepared according to any known method for making cosmetics and/or medical preparations or preparations. As understood by those of ordinary skill in the art, many methods are known. In some embodiments, pharmaceutical compositions disclosed herein can be prepared by any conventional technology, such as, for example, described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, D.B.Troy edited, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, J.Swarbrick and J.C.Boylan edited, 1988-1999, Marcel Dekker, New York.

The proportion and properties of any pharmaceutically acceptable excipient can be determined by the selected route of administration and standard pharmaceutical practice. One of ordinary skill in the art can easily select the appropriate form and route of administration depending on the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. In some embodiments, the pharmaceutical composition can be administered by any convenient route. In some embodiments, the pharmaceutical composition is topically administered. In some embodiments, the pharmaceutical composition is topically administered to the ocular surface. In some embodiments, the pharmaceutical composition is topically administered to the cornea. In some embodiments, the pharmaceutical composition is instilled into the conjunctival sac.

In some embodiments, the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays.

In some embodiments, the pharmaceutical composition is in any liquid form suitable for topical administration. In some embodiments, the pharmaceutical composition is in the form of eye drops. In some embodiments, the pharmaceutical composition is in the form of artificial tears. In some embodiments, the pharmaceutical composition is in the form of a contact lens adsorbent comprising a liquid carrier (such as, for example, a cellulose ether, such as, for example, methylcellulose).

In some embodiments, the pharmaceutical composition is in any liquid form suitable for intranasal administration. In some embodiments, the pharmaceutical composition is in the form of a nasal spray.

Unless any conventional pharmaceutically acceptable excipient is incompatible with benzalkonium chloride, for example by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is expected to be within the scope of the present disclosure. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York disclose non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for preparing and using the same.

In some embodiments, at least one pharmaceutical excipient is selected from humectants, tonicity agents, suspending agents, viscosity increasing agents, wetting agents, solubilizing agents, buffering agents, antioxidants, alkalizing agents, chelating agents, stabilizers, and pharmaceutical vehicles.

In some embodiments, the suspending agent and viscosity increasing agent are selected from povidone K90 (USP/EP), HPMC E15LV (USP), polycarbophil, and HPMC E4M USP.

In some embodiments, the wetting agent and solubilizing agent are selected from poloxamer 407 and PS80.

In some embodiments, the buffer is selected from boric acid NF and sodium borate decahydrate.

In some embodiments, the antioxidant is sodium thiosulfate pentahydrate.

In some embodiments, the alkalizing agent is sodium hydroxide NF (2N).

In some embodiments, the chelating agent is disodium EDTA dihydrate USP/EP.

In some embodiments, the stabilizer is selected from ascorbic acid, citric acid, sodium benzoate, calcium propionate, sodium erythorbate, sodium nitrite, calcium sorbate, potassium sorbate, BHA, BHT, EDTA, and tocopherol.

In some embodiments, the pharmaceutical vehicle is water USP/EP.

In some embodiments, the pharmaceutical composition is sterile. In some embodiments, sterility is imparted by any conventional method. In some embodiments, sterility is imparted by filtration. In some embodiments, sterility is imparted by irradiation. In some embodiments, sterility is imparted by heating. In some embodiments, sterility is imparted by conducting the manufacturing process under aseptic conditions.

Example

The following examples are intended to be illustrative and are not meant to limit the scope of the present disclosure in any way.

abbreviation

% Percent

ASTM American Society for Testing and Materials

BAK Benzalkonium Chloride

DMEM Dulbecco's Modified Eagle Medium

FBS Fetal Bovine Serum

h hour

ISO International Organization for Standardization

MEM Minimum Essential Medium

mL milliliters

NCS Newborn Calf Serum

TCID ₅₀ /mL 50% tissue culture infectious dose/mL

Embodiment 1: and In vitro antiviral activity of three benzalkonium chloride preservative eye drops against severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2)

Evaluation of three 0.01% benzalkonium chloride (BAK) preservative eye drops - 0.025% brimonidine tartrate eye drops using a Vero E6 host cell system 0.6% Besifloxacin ophthalmic suspension and an eye drop solution containing 0.02675% naphazoline hydrochloride and 0.315% pheniramine maleate - In vitro antiviral activity against SARS-CoV-2. Both BAK preservative eye drop formulations demonstrated in vitro antiviral activity against SARS-CoV-2.

SARS-CoV-2 (strain USA-WA1/2020) cultures were prepared by suspending the strain in minimal essential medium (MEM) with 5% heat-inactivated fetal bovine serum (FBS). The time-kill test of SARS-CoV-2 was performed by giving each test formulation multiple times at contact times representing those recommended in the instructions for use of each product. All tests were performed in triplicate and in accordance with the ASTM E1052-20 standard practice for suspension time-kill tests of viruses. In brief, the initial SARS-CoV-2 suspension was diluted 1:10 with the test formulation to a final concentration of 1×10 ^3.5 -1×10 ^4.5 infectious units/mL. After the desired contact time, the test solution was neutralized with 10mL MEM containing 10% newborn calf serum, serially diluted, and inoculated onto the VeroE6 host cell system. Appropriate controls and test samples were incubated with Vero cells at 36°C ± 2°C. After 4 to 9 days, the presence of residual live virus was scored. The Spearman-Karber calculation was used to calculate virus titers expressed as 50% tissue culture infectious dose/mL ( _TCID50 /mL) and the _log10 reduction was determined (Table 1).

The Log ₁₀ reduction of brimonidine tartrate 0.025% was ≥1.80, ≥2.14, and ≥2.02 at 8-hour, 24-hour, and 72-hour contact times, respectively. The Log _{10 reduction of besifloxacin was ≥1.95 at 24-hour contact time and ≥2.56 at 72-hour contact time. The Log 10 reduction} of naphazoline and pheniramine maleate was ≥2.14 at 24-hour contact time and ≥2.02 at 72-hour contact time. These results indicate that SARS-CoV-2 is completely inactivated at all contact times.

Table 1 : Log ₁₀ Reduction (SARS-CoV-2)

Example 2: SARS-CoV-2 Virucidal Efficacy Test of BAK Preservative Solution

The in vitro antiviral activity of five BAK preservative eye drops—Opcon-A (0.01% BAK), Advanced Eye Relief (0.01% BAK), Lumify (0.01% BAK), Soothe Maximum Hydration (0.005% BAK), and Advanced Eye Relief Eye Wash Eye Irrigating Solution (0.01% BAK)—against SARS-CoV-2 was evaluated using the Vero E6 host cell system. All five BAK preservative eye drop formulations exhibited in vitro antiviral activity against SARS-CoV-2 after a 7-day contact time.

Table 2 : Log ₁₀ reduction after 7 days of contact time (SARS-CoV-2)

SARS-CoV-2 (strain CDC 200300592) cultures were prepared by suspending the strain in minimal essential medium (MEM) with 2% newborn calf serum (NCS). The time-kill test of SARS-CoV-2 was performed by multiple administration of each test formulation at a specified contact time. All tests were performed in triplicate and in accordance with the ASTM E1052-20 standard practice for suspension time-kill tests of viruses. In short, the initial SARS-CoV-2 suspension was diluted 1:100 with the test formulation. After 7 days, the test solution was neutralized with MEM containing 10% NCS, serially diluted, and inoculated onto the Vero E6 host cell system. Appropriate controls and test samples were incubated with Vero cells, and the presence of residual live virus was scored.

Virus titers (expressed as 50% tissue culture infectious dose/mL ( _TCID50 /mL)) were determined using the Spearman-Karber calculation based on 0.05 mL of sample inoculum, and the _log10 reduction was determined (Table 2).

Example 3: Virucidal efficacy test of BAK preservative solution against adenovirus type 5 (ADV-5)

Adenoviral conjunctivitis is one of the most common eye infections worldwide. Five BAK preservative eye drops - Opcon-A (0.01% BAK), Advanced EyeRelief (0.01% BAK), Lumify (0.01% BAK), Soothe Maximum Hydration (0.005% BAK), and Advanced Eye Relief Eye Wash Eye Irrigating Solution (0.01% BAK) - were evaluated for in vitro antiviral activity against adenovirus ADV-5 using the A549 host cell system (ATCC CCL-185). All five BAK preservative eye drop formulations demonstrated in vitro antiviral activity against ADV-5 after a 7-day contact time.

ADV-5 (strain Adenoid 75, ATCC VR-5) cultures were prepared by suspending the strain in minimal essential medium (MEM) with 2% FBS. The time-kill test of ADV-5 was performed by multiple administration of each test formulation at a specified contact time. All tests were performed in triplicate and in accordance with ASTM E1052-20 Standard Practice for Suspension Time-Kill Tests of Viruses. In brief, the initial ADV-5 suspension was diluted 1:100 with the test formulation. After 7 days, the test solution was neutralized with Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS, serially diluted, and inoculated onto the A549 host cell system. Appropriate controls and test samples were incubated with A549 cells, and the presence of residual live virus was scored.

Virus titers (expressed as 50% tissue culture infectious dose/mL ( _TCID50 /mL)) were determined using the Spearman-Karber calculation based on 0.05 mL of sample inoculum, and the _log10 reduction was determined (Table 3).

Table 3 : Log ₁₀ reduction after 7 days contact time (ADV-5)

Example 4: Virucidal effectiveness of benzalkonium chloride (BAK) antiseptic eye drops under the conditions of the instructions for use

Three 0.01% benzalkonium chloride (BAK) preservative eye drops were measured following the principles outlined in ISO 14729:2001/Amd.1:2010 and ASTM Test Method E1052-20 - 0.025% brimonidine tartrate eye drops 0.6% Besifloxacin ophthalmic suspension and an eye drop solution containing 0.02675% naphazoline hydrochloride and 0.315% pheniramine maleate - Virucidal effectiveness against SARS-CoV-2. To simulate direct instillation into the eye and the maximum dose in vitro based on the instructions for use, one drop was administered every 8 hours Up to 24 hours (up to 3 drops); apply up to 1 drop every 6-8 hours Up to 24 hours (up to 4 drops); and one drop every 6-8 hours Up to 24 hours (max 4 drops).

A consistent test solution: virus inoculum ratio was used in the assay with approximately 1×10 ⁷ infectious units/mL of SARS-CoV-2 (strain USA-WA1/2020; source: BEI Resources, NR-52281) culture to ensure compliance with the ASTM method. Log ₁₀ reductions were measured after 2-minute, 5-minute, 10-minute, 15-minute, 30-minute, 8-hour, and 24-hour contact times (Tables 4-9). These results indicate that for After 1-hour, 8-hour, and 24-hour contact times, After 2-minute, 5-minute, 10-minute, 15-minute, 30-minute, 8-hour, and 24-hour contact times, and for In vitro virucidal inactivation of SARS-CoV-2 after 1-hour, 8-hour, and 24-hour contact times.

Table 4: Log ₁₀ reduction (up to 60 minutes contact time)

Table 5 : Log ₁₀ reduction (8-hour, 24-hour contact time)

*Average Viral Recovery Control (VRC) Initial Load

** indicates complete inactivation of the virus under these test conditions

Table 6 : Log ₁₀ reduction (up to 60 minutes contact time)

Table 7 : Log ₁₀ reduction (8-hour, 24-hour contact time)

*Average Viral Recovery Control (VRC) Initial Load

** indicates complete inactivation of the virus under these test conditions

Table 8 : Log ₁₀ reduction (up to 60 minutes contact time)

Table 9 : Log ₁₀ reduction (8-hour, 24-hour contact time)

*Average Viral Recovery Control (VRC) Initial Load

** indicates complete inactivation of the virus under these test conditions

For the purpose of clarity and understanding, the foregoing disclosure has been described in some detail by way of illustration and example. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive. Therefore, the scope of the present disclosure should not be determined with reference to the above description, but should be determined with reference to the following appended claims together with the full scope of equivalents to which these claims are authorized.

Claims (72)

1. A method for treating at least one ocular manifestation of coronavirus disease 2019 (COVID-19), the method comprising administering to a subject in need thereof an effective amount of benzalkonium chloride. 2. The method of claim 1, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 3. The method according to claim 1 or 2, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. 4. The method according to any one of claims 1 to 3, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 5. The method according to any one of claims 2 to 4, wherein the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. 6. The method according to any one of claims 2 to 4, wherein the pharmaceutical composition is selected from And Opcon- 7. The method of any one of claims 1 to 6, wherein the effective amount of benzalkonium chloride is administered topically. 8. The method of any one of claims 1 to 7, wherein the effective amount of benzalkonium chloride is administered to at least one eye of the subject. 9. The method of any one of claims 1 to 8, wherein treating at least one ocular manifestation of COVID-19 comprises treating at least one disease or condition selected from the group consisting of ocular redness, conjunctivitis, keratoconjunctivitis, dry eyes, blurred vision, conjunctival congestion, ocular irritation, foreign body sensation, epiphora, eyelid edema, and conjunctival edema. 10. The method of any one of claims 1 to 8, wherein treating at least one ocular manifestation of COVID-19 comprises treating conjunctivitis. 11. The method of any one of claims 1 to 8, wherein treating at least one ocular manifestation of COVID-19 comprises improving visual acuity. 12. The method of any one of claims 1 to 8, wherein treating at least one ocular manifestation of COVID-19 comprises reducing ocular redness, ocular irritation, or foreign body sensation. 13. A method for reducing the risk of ocular transmission of SARS-CoV-2, the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof. 14. The method of claim 13, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 15. The method of claim 13 or 14, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. 16. The method according to any one of claims 13 to 15, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 17. The method according to any one of claims 14 to 16, wherein the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. 18. The method according to any one of claims 14 to 16, wherein the pharmaceutical composition is selected from And Opcon- 19. The method of any one of claims 13 to 18, wherein the effective amount of benzalkonium chloride is administered topically. 20. The method of any one of claims 13 to 19, wherein the effective amount of benzalkonium chloride is administered to at least one eye of the subject. 21. A method for preventing Coronavirus Disease 2019 (COVID-19), the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof. 22. The method of claim 21, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 23. The method of claim 21 or 22, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. 24. The method according to any one of claims 21 to 23, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 25. The method according to any one of claims 22 to 24, wherein the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. 26. The method according to any one of claims 22 to 24, wherein the pharmaceutical composition is selected from And Opcon- 27. The method of any one of claims 21 to 26, wherein the effective amount of benzalkonium chloride is administered topically. 28. The method of any one of claims 21 to 27, wherein the effective amount of benzalkonium chloride is administered to at least one eye of the subject. 29. A method for reducing ocular SARS-CoV-2 viral load, the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof. 30. The method of claim 29, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 31. The method of claim 29 or 30, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. 32. The method of any one of claims 29 to 31, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 33. The method according to any one of claims 30 to 32, wherein the pharmaceutical composition is in the form of eye drops, suspensions, gels, ointments, injectable solutions, or sprays. 34. The method according to any one of claims 30 to 32, wherein the pharmaceutical composition is selected from And Opcon- 35. The method of any one of claims 29 to 34, wherein the effective amount of benzalkonium chloride is administered topically. 36. The method of any one of claims 29 to 35, wherein the effective amount of benzalkonium chloride is administered to at least one eye of the subject. 37. A method for treating conjunctivitis comprising administering to a subject in need thereof an effective amount of benzalkonium chloride. 38. The method of claim 37, wherein treating conjunctivitis comprises treating viral conjunctivitis. 39. The method of claim 37, wherein treating conjunctivitis comprises treating conjunctivitis of unknown etiology. 40. The method of any one of claims 37 to 39, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 41. The method of any one of claims 37 to 40, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. 42. The method of any one of claims 37 to 41, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 43. The method according to any one of claims 40 to 42, wherein the pharmaceutical composition is in the form of eye drops, a suspension, a gel, an ointment, an injectable solution, or a spray. 44. The method according to any one of claims 40 to 42, wherein the pharmaceutical composition is selected from And Opcon- 45. The method of any one of claims 37 to 44, wherein the effective amount of benzalkonium chloride is administered topically. 46. A method for preventing conjunctivitis, the method comprising administering to a subject in need thereof an effective amount of benzalkonium chloride. 47. The method of claim 46, wherein the subject exhibits at least one symptom of a viral infection. 48. The method of claim 46 or 47, wherein the subject exhibits at least one symptom of SARS-CoV-2 infection. 49. The method of claim 46, wherein the subject is infected with a virus. 50. The method of claim 46 or 49, wherein the subject is infected with SARS-CoV-2. 51. The method of any one of claims 46 to 50, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 52. The method of any one of claims 46 to 51, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.02% (w/v) benzalkonium chloride. 53. The method of any one of claims 46 to 52, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 54. The method of any one of claims 51 to 53, wherein the pharmaceutical composition is in the form of eye drops, a suspension, a gel, an ointment, an injectable solution, or a spray. 55. The method according to any one of claims 51 to 53, wherein the pharmaceutical composition is selected from And Opcon- 56. The method of any one of claims 46 to 55, wherein the effective amount of benzalkonium chloride is administered topically. 57. A method for reducing intranasal SARS-CoV-2 viral load, the method comprising administering an effective amount of benzalkonium chloride to a subject in need thereof. 58. The method of claim 57, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition. 59. The method of claim 57 or 58, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.2% (w/v) benzalkonium chloride. 60. The method of any one of claims 57 to 59, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.2% (w/v) benzalkonium chloride. 61. The method of any one of claims 57 to 60, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.1% (w/v) benzalkonium chloride. 62. The method of any one of claims 57 to 61, wherein the effective amount of benzalkonium chloride is administered in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 63. The method of any one of claims 58 to 62, wherein the pharmaceutical composition is in the form of a spray. 64. A method for treating or preventing Coronavirus Disease 2019 (COVID-19), the method comprising administering an effective amount of benzalkonium chloride intranasally to a subject in need thereof. 65. The method of claim 64, wherein the effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition. 66. The method of claim 64 or 65, wherein the effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.001% (w/v) to 0.2% (w/v) benzalkonium chloride. 67. The method of any one of claims 64 to 66, wherein the effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.2% (w/v) benzalkonium chloride. 68. The method of any one of claims 64 to 67, wherein the effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.005% (w/v) to 0.1% (w/v) benzalkonium chloride. 69. The method of any one of claims 64 to 68, wherein the effective amount of benzalkonium chloride is administered intranasally in the form of a pharmaceutical composition comprising 0.01% (w/v) benzalkonium chloride. 70. The method of any one of claims 65 to 69, wherein the pharmaceutical composition is in the form of a spray. 71. The method of any one of claims 64 to 70, wherein treating or preventing COVID-19 comprises treating COVID-19. 72. The method of any one of claims 64 to 70, wherein treating or preventing COVID-19 comprises preventing COVID-19.