Antiviral compounds and methods of administration thereof

Abstract

The present invention relates to the use of antiviral drugs having different mechanisms of action for the treatment or prophylaxis of COVID-19 (also known as SARS-CoV-2) viral infections and for the reduction of medical complications associated with COVID-19 viral diseases. The invention also relates to compositions and combinations of novel antiviral drugs formed from existing drugs having antiviral activity, as well as the administration of these compounds for use in these various novel combinations, which are incorporated into the pulmonary and oral delivery systems.

Description

TECHNICAL FIELD

[0001] The present invention relates to the use of antiviral drugs with different mechanisms of action for the treatment or prevention of COVID-19 (also known as SARS-CoV-2) viral infection and reduction of medical complications associated with COVID-19 viral disease. The present invention also relates to new compositions of chemical entities antiviral drugs and the repurposing of existing drugs with antiviral activity for new compositions and combinations, including the introduction of these compounds in these various new combinations for incorporation into new pulmonary and new oral delivery systems.

[0002] The anti-COVID-19 compounds of the present invention comprise a backbone that includes drug compounds with specific antiviral mechanisms of action, and other specific antiviral drugs with different mechanisms of action. The mechanisms included in the backbone include, but are not limited to, five major antiviral drugs: 1) phosphatidylserine (PS) modulators, which are glucocorticoid and androgen receptor modulators (GCRM / ARM); 2) entry inhibitors (EI), which are angiotensin-converting enzyme 2 (ACE-2) receptor blockers, used as ACE-2 attachment entry inhibitors (AEI) and / or fusion inhibitors (FI); 3) protease inhibitors (PI); 4) RNA-dependent RNA polymerase inhibitors (RdRpI), some of which are endosomal acidifiers (EA), which interfere with the replicase and replicase complex, including NTPase / RNA-helicase; 5) MicroRNA inhibitors (MRI). BACKGROUND

[0003] The rapid progress of various technologies, as well as the progress of travel and globalization, have had a major impact on improving the human condition in the United States and internationally. However, these advances have proven to be a double-edged sword, whether accidental or intentional, that can easily spread invasive pathogens that cause disease. The U.S. government has been active in enacting legislation and funding medical countermeasures to address the possibility of public health emergencies triggered by the introduction of pathogens. Key to these countermeasures are the 2004 Project BioShield Act and the 2006 Pandemic and All-Hazards Preparedness Act, which provided opportunities through the Biomedical Advanced Research and Development Authority (BARDA).

[0004] The National Institute of Allergy and Infectious Diseases (NIAID) is a component of the National Institutes of Health (NIH) that maintains a list of emerging infectious diseases and pathogens for prioritization and research guidance. Pathogens are prioritized from A-C based on infectivity, morbidity, mortality, and diagnostic characteristics. With the global pandemic of COVID-19, COVID-19 was added to this list and Medical Countermeasures (MCMs) were given the highest priority. The priority of MCMs was used as a springboard to research a series of repurposed compounds with five different mechanisms of action that have been shown to have COVID-19 antiviral activity and therefore have potential as MCMs.

[0005] In the development of antiviral therapy for the human immunodeficiency virus (HIV), drug therapy now consists almost entirely of drugs and drug regimens that contain multiple mechanisms of action to control the initiation and process of HIV viral replication. Through empirical discovery, single mechanisms are generally not effective as monotherapies and HIV viruses rapidly develop resistance. Likewise, for the COVID-19 virus, multi-mechanism therapy, co-administration of drugs with different mechanisms as a cocktail or fixed-dose combination, will be more effective. The present invention identifies these combination therapies, their use and methods of treatment, and a new mode of administration and delivery specifically tailored for the treatment of COVID-19. The present invention also includes a new pulmonary and oral delivery system for a new chemical entity combination of fixed-dose combinations of anti-COVID-19 drugs that dissociate into their original components as metabolites after administration, which makes the administration more effective and, in this case, pulmonary delivery, more directly to the site of infection in the lungs.

[0006] The following sections will provide detailed information on the five main antiviral drug mechanisms of compounds with steroid glucocorticoid receptor and androgen receptor modulators, EIs, PIs, RdRpIs, and MRIs, such as the compounds Dexamethasone, Valsartan, Rupintrivir, Remdesivir and its ribitol active metabolite GS-441524, and Hydroxychloroquine, and explain why their levels of activity as antiviral drugs against RNA viruses are prioritized for use in alleviating the duration of COVID-19 infection, the severity of COVID-19 infection, and reducing mortality associated with COVID-19 infection and reducing the incidence of pneumonia caused by COVID-19 infection.

[0007] Dexamethasone is a repurposed marketed drug that has entered the human clinical trial population for COVID-19 as a single agent. Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs that has pleiotropic effects on multiple signaling pathways. The biological target is the glucocorticoid receptor. The anti-inflammatory and immunosuppressive effects of dexamethasone are about 30 times stronger than those of Cortisol. The anti-inflammatory effects are complex but primarily through the suppression of inflammatory cells and suppression of inflammatory mediator expression. To exert its effects, the steroid molecule diffuses across the cell membrane and binds to the glucocorticoid receptor, causing a conformational change in the receptor. The receptor-glucocorticoid complex is able to enter the nucleus, where it dimerizes and binds to glucocorticoid response elements.

[0008] The anti-inflammatory effects of dexamethasone are complex but primarily through the suppression of inflammatory cells and suppression of inflammatory mediator expression. Uses are for the treatment of inflammation and immune-mediated diseases, for intravenous and oral administration. In the present invention, the dexamethasone drug product will be inhaled via an e-vape pen / portable medical vaporizer in free base gas form or ultrafine particle form and used in conjunction with the inhalation of an antiviral drug such as Remdesivir or the ribosyl alcohol active metabolite of Remdesivir, GS-441524, directly delivered to the respiratory tract, including the nasal, throat, and lung tissues. Like most steroid compounds, dexamethasone is a Cortisol / glucocorticoid and androgen regulator (GCRM / ARM).

[0009] Dexamethasone has at least three general antiviral mechanisms of action against COVID-19. The first antiviral effect is mediated through its molecules binding to glucocorticoid response elements (GREs) present in some viral genomes. The second is through these molecules binding to phosphatidylserine (PS) present in the envelope of all enveloped viruses, and the third is through signaling effects in the immune system that modulate the appropriate response to viral pathogens, promoting an immune response without producing an amplification effect that damages tissues.

[0010] The mechanism of action through binding to GREs is as follows: viruses that infect animals and humans infect cells by placing their genetic material within the cytoplasm and / or nucleoplasm of the infected cell. The “response elements” within the genome can include coding or non-coding regions that respond to host cell molecular signals and / or other elements of the virus’s own molecular network. Viruses often have GREs, i.e., response elements that are affected by glucocorticoid signaling mediated through the binding of Cortisol (or other glucocorticoids) to the glucocorticoid receptor (GCR).

[0011] Viruses that have been identified as having GREs include: COVID-19, MERS, SARS, herpesvirus 7 (HHV-7), Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8 [HHV-8], variola (smallpox) virus, vaccinia virus, cowpox virus, and monkeypox virus.

[0012] The binding of dexamethasone, as a GCR and androgen receptor (AR) modulator, also modulates viral GREs to directly or indirectly inhibit essential viral functions including, but not limited to, gene replication, production of viral-associated proteins, assembly of genetic material and viral proteins into a complete virus, increase genetic diversity, promote active or passive viral release from the cell, and viral transmission.

[0013] The antiviral mechanism associated with PS binding is as follows: PS is normally sequestered to the inner leaflet of the plasma membrane bilayer, but during apoptosis, the mechanisms that normally maintain PS in the inner leaflet are downregulated, allowing PS to appear on the cell surface. PS exposure is a recognition signal for phagocytic cells that clear dying cells. Several macrophage receptors are involved in recognizing PS on apoptotic cells, including various scavenger receptors, CD36, CD14, and PS receptor (PSR). Thus, PS has the ability to mediate intercellular interactions and serve as a ligand for multiple PS-binding receptors.

[0014] Enveloped viruses continuously expose PS on the lipid bilayer membrane of their host capture. Enveloped viruses exploit this PS exposure to evade the human immune system’s attack and enter phagocytic cells such as monocytes / macrophages, making its appearance in the viral membrane highly suspect as a factor in virus-target cell fusion.

[0015] Valsartan, as an antiviral entry inhibitor (EI), is a repurposed drug that can be used in COVID-19 human clinical trials populations. Valsartan is a compound that has been approved as an antihypertensive drug, belonging to the angiotensin receptor blocker (ARB) drug class. ARBs block the angiotensin 2 converting enzyme (ACE-2) receptor, which is involved in physiological functions such as blood pressure regulation. This ACE-2 receptor is also a ligand expressed on the surface of human lung cells to which the COVID-19 virus spike protein (SP) binds to initiate the cell infection process, including attachment, membrane fusion, and viral RNA insertion. By blocking access to the ACE-2 receptor expressed on human lung cells, valsartan or other ARBs can act as an attachment entry inhibitor (AEI) and / or fusion inhibitor (FI) that inhibits the binding of the COVID-19 spike protein to lung epithelial cells (which causes a conformational change in the SP to allow membrane fusion and viral RNA insertion).

[0016] As an example of ARB, oral administration of valsartan will be limited in its utility in the case of COVID-19 due to its systemic effects on blood pressure, which are dose dependent.

[0017] Rupintrivir, as an antiviral protease inhibitor (PI), is a repurposed clinical stage drug that can be rapidly used in human clinical trials in COVID-19 patients. Rupintrivir is a compound originally developed by Pfizer as an antiviral drug for the treatment of the common cold caused by picornavirus infection, belonging to the 3C protease drug class, designed to block the protease that cleaves the polyprotein of RNA viruses. Although the RNA gene sequence of the cleavage site targeted by the picornavirus protease differs from that of the COVID-19 coronavirus protease, these proteases are very similar: the activity inhibited is “3C-like” (3CL) and can be blocked or inhibited in the same way, even more effectively in combination with other related protease inhibitors, such as HIV protease inhibitors (such as ritonavir), possibly due to enhanced stearic hindrance or inhibition of other proteases associated with COVID-19 infection, including cathepsin L-dependent viral glycoproteins activated by cleavage of the SARS-CoV S protein at the S1 / S2 boundary under low pH conditions, and the involvement of transmembrane protease serine 2 (TMPRSS2) active in triggering cleavage of the trimeric S protein (Simmons et al., 2005; Millet and Whittaker, 2015).

[0018] Ritonavir, as an antiviral protease inhibitor (PI), is a repurposed marketed anti-HIV drug that can be rapidly used in human clinical trials in COVID-19 patients. Ritonavir and other HIV PIs (such as atazanavir) are compounds originally developed as antiviral drugs in the class of HIV protease drugs, designed to block proteases that cleave polyproteins. HIV and coronavirus proteases are very similar in function, the activity inhibited is “3C-like” (3CL) and can be blocked or inhibited in the same way, even more effectively in combination with other related protease inhibitors (such as picornavirus PI, rupintrivir), possibly due to enhanced stearic hindrance.

[0019] Myricetin is a repurposed, already-marketed supplement that can be rapidly used in COVID-19 human clinical trials populations. Myricetin is an RNA-dependent RNA polymerase inhibitor (RdRpI) that interferes with the COVID-19 replicase / replisome complex. Specifically, it inhibits the NTPase / RNA helicase (unwinds the highly base-paired regions of the RNA genome and provides energy for the polymerization process). Myricetin is a common plant flavonoid that is well known for its nutritional value. It is one of the key ingredients in a variety of foods and beverages. Myricetin also affects the biochemical efficacy and binding capacity of biological molecules within large cells. Myricetin has been shown to inhibit cellular RNA polymerase. Myricetin (CID 5281672) also inhibits the closely related SARS-CoV helicase with an IC50 value of 2.7 μΜ and an acceptable selectivity index.

[0020] Rifampin is a repurposed, already-marketed drug that can be rapidly used in COVID-19 human clinical trials populations. Rifampin is an RNA-dependent RNA polymerase inhibitor (RdRpI) that interferes with the COVID-19 replicase / replisome complex. Like myricetin, it inhibits the NTPase / RNA helicase (unwinds the highly base-paired regions of the RNA genome and provides energy for the polymerization process). Rifampin, also known as rifampycin, is a typical antibiotic of its class used to treat a variety of bacterial infections. Crystal structure data and biochemical data indicate that rifampin binds to a pocket of the beta subunit of the RNA polymerase. As an inhibitor, the rifampin drug prevents RNA synthesis by physically blocking elongation, thereby preventing the synthesis of host bacterial proteins. Through this “steric closure” mechanism, rifampin blocks the synthesis of the second or third phosphodiester bond between nucleotides in the RNA backbone, preventing the 5’ end of the RNA transcript from extending beyond 2 or 3 nucleotides. Thus, rifampin binds to the RNA polymerase at a site adjacent to the active center of the RNA polymerase and blocks RNA synthesis by physically blocking the formation of phosphodiester bonds in the RNA backbone, thereby preventing the length of the RNA product from exceeding 2-3 nucleotides. Thus, rifampin has been shown to inhibit cellular RNA polymerase.

[0021] Remdesivir (GS-5734) is a repurposed clinical-stage anti-Ebola RdRpI drug that can be rapidly deployed in human clinical trials for COVID-19 in inhaled delivery systems as well as in combination therapy with other antiviral drugs. Remdesivir has been reported to inhibit replication of SARS-CoV and MERS-CoV in multiple in vitro systems, including primary human airway epithelial cell cultures with sub-micromolar EC50values (Sheahan et al., 2017). Experimental evaluation of GS-5734 in a SARS-CoV infected mouse model indicated that prophylactic and early therapeutic administration reduced lung viral load and improved respiratory function as well as other clinical symptoms. Likewise, it has shown antiviral activity in in vitro models of SARS-CoV-2 and is being evaluated in COVID-19 clinical trials in the United States and other countries and has been approved by the FDA for use in the United States, first as an Emergency Use Authorization (EUA) and then through a New Drug Application (NDA) for intravenous injection formulations in hospital settings for patients with moderate to severe COVID-19.

[0022] Hydroxychloroquine is a repurposed, already-marketed drug that can be rapidly inhaled into the respiratory tract of human subjects in clinical trials for COVID-19 by e-cigarette or e-cig pen to maximize local concentrations in nasal, throat, and lung tissues while minimizing systemic concentrations that can accumulate in cardiac tissues at concentrations that can adversely affect heart rhythm. Hydroxychloroquine is a microRNA inhibitor (MRI) and endosome acidifier (EA), an aminoquinoline antimalarial drug that was developed as a derivative of the drug quinine. Hydroxychloroquine has shown in vitro systems to have inhibitory effects on coronavirus replication and has anecdotal evidence of clinical benefit in human use in vivo. MicroRNAs (miRNAs) are small non-coding RNA molecules (comprising about 22 nucleotides) found in plants, animals, and some viruses that play a role in post-transcriptional regulation of gene expression and RNA silencing of SARS-CoV-2. miRNAs have been found to act by base pairing with complementary sequences within the mRNA molecule. As a result, these mRNA molecules are silenced by one or more of the following processes: (1) cleaving the mRNA strand into two pieces, (2) destabilizing the mRNA by shortening its poly(A) tail, and (3) inefficiently translating the mRNA into protein by the ribosome. miRNAs are similar to small interfering RNAs (siRNAs) of the RNA interference (RNAi) pathway, except that miRNAs are derived from regions of RNA transcripts that fold into short hairpins (short hairpin) themselves, whereas siRNAs are derived from longer regions of double-stranded RNA. The human genome can encode more than 1900 miRNAs. MRIs (such as quinine) lack alkaloids (such as hydroxychloroquine) and interfere with the formation and metabolic activity of miRNAs that are integral to the replication process of COVID-19 virus. SUMMARY

[0023] The present invention relates to the use of PS GR / AR modulators or active agents (e.g., dexamethasone), optionally in combination with at least one other agent, for the treatment or prevention of COVID-19 infection disease and its complications.

[0024] The present invention also relates to the pulmonary administration of valsartan, including but not limited to other drugs in the ARB class, in this respiratory mode of administration, including but not limited to inhalers, nebulizers, and e-cigarettes / e-cigs.

[0025] The present invention also relates to the use of ARBs as EIs (e.g., valsartan), optionally in combination with at least one other agent with a different COVID-19 antiviral mechanism, for the treatment or prevention of COVID-19 infection disease and its complications. These ARBs can be provided in both oral and respiratory forms.

[0026] The present invention also relates to the use of lupintravir as a PI, optionally in combination with a complimentary PI (including an HIV PI such as ritonavir) and at least one other agent with a different antiviral mechanism against COVID-19, for the treatment or prevention of COVID-19 and its complications. These PIs can be provided in both oral and respiratory forms.

[0027] The present invention also relates to the use of picornavirus 3C or 3C-like (3CL) PIs (e.g., lupinquvir) and at least one other agent with a different COVID-19 antiviral mechanism for the treatment or prevention of COVID-19 infectious diseases and its complications, including PIs and drugs active against cathepsin L-dependent viral glycoprotein and / or transmembrane protease serine 2 (TMPRSS2). These PIs can be provided in both oral and respiratory forms, optionally in combination with one or more complimentary antiviral drugs from the five categories mentioned above.

[0028] The present invention also relates to the use of flavonoids (such as myricetin) as RdRpIs that interfere with the replicase complex, optionally in combination with another RdRpI (such as rifampicin) and at least one other agent with a different antiviral mechanism against COVID-19, for the treatment or prevention of COVID-19 infectious diseases and their complications. These RdRpIs can be provided in both oral and respiratory forms.

[0029] The present invention also relates to the use of a rifampicin antibiotic (such as rifampicin) as an RdRpI that interferes with the replicase complex, optionally in combination with another RdRpI (such as myricetin) and at least one other agent with a different antiviral mechanism against COVID-19, for the treatment or prevention of COVID-19 infectious diseases and their complications. These RdRpIs can be provided in both oral and respiratory forms.

[0030] The present invention also relates to the use of remdesivir and its active ribitol metabolite as RdRpIs that interfere with the replicase complex, optionally in combination with one or more RdRpIs (such as myricetin and or rifampicin) and at least one other agent with a different COVID-19 antiviral mechanism (such as dexamethasone or hydroxychloroquine (in their racemic mixtures or purified enantiomers) for the treatment or prevention of COVID-19 infectious diseases and their complications. These RdRpIs can be provided in both oral and respiratory forms.

[0031] The present invention also relates to the use of hydroxychloroquine and related aminoquinolines and arylamino alcohols as MRIs and EAs that interfere with the formation of miRNAs that inhibit viral replication, optionally with at least one other agent with a different COVID-19 antiviral mechanism, for the treatment or prevention of COVID-19 infectious diseases and their complications. These MRIs can be provided in both oral and respiratory forms.

[0032] In one embodiment, the present invention includes a pulmonary delivery system containing two, three or more drugs connected by a chemical bond or linker that is covalently attached at one end to one drug compound on a suitable linking chemical group and at the other end to another drug compound (also on a suitable linking group) to form a new chemical entity (NCE) drug conjugate that can then be uncoupled by pyrolysis in a medical vaporizer including portable medical vaporizers such as electronic cigarettes and electronic cigarette pens to present inhaled drugs to a patient that are combinations of compounds that are introduced to a patient in other settings in a gas or ultrafine particle aerosol form. In one embodiment, the NCE is loaded into the cartridge of an electronic cigarette with replaceable cartridges or the cartridge of a disposable electronic cigarette at the appropriate therapeutic dosage level. When the electronic cigarette with temperature setting function is activated, the heat generated in the electronic cigarette, 380-480 degrees Fahrenheit, is sufficient to break the bond on the chemical bond or linker to the attached therapeutic compound, resulting in an inhaled drug vapor or ultrafine particle aerosol containing the therapeutic drug released for inhalation by a human or animal patient. The chemical bond between the antiviral agents can include one or more carbonate or carbamate groups.

[0033] In one embodiment, the present invention includes pulmonary delivery of one or more entry inhibitors (EI) paired with one or more RNA-dependent RNA polymerase inhibitors (RdRpI), including but not limited to the combination of valsartan + rifampicin, the combination of valsartan + myricetin, and the combination of valsartan + remdesivir or the combination of valsartan + the ribosyl active metabolite of remdesivir, GS-441524. The valsartan / rifampicin combination can be administered via a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or via the vapor of an e-cigarette, where the valsartan and rifampicin compounds are covalently linked via a chemical bond to form a new chemical entity compound, BB-700, where the base compounds, valsartan and rifampicin, form the two primary functional components that are broken down into metabolites by the heat provided in the e-cigarette to produce vapor, including the base compounds of valsartan and rifampicin, so that the compound delivered to the pulmonary cells in vapor form will be the valsartan and rifampicin components. Alternatively, the valsartan + myricetin can be administered via a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or via the vapor of an e-cigarette, where the valsartan and myricetin compounds are covalently linked via a chemical bond to form a new chemical entity compound, BB-701, where the base compounds, valsartan and rifampicin, form the two primary functional components that are broken down into metabolites by the heat provided in the e-cigarette to produce vapor, including the base compounds of valsartan and rifampicin, so that the compound delivered to the pulmonary cells in vapor form will be the valsartan and myricetin components. In another embodiment, the valsartan and remdesivir can be administered via a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or via the vapor of an e-cigarette, where the valsartan and remdesivir compounds are covalently linked via a chemical bond or linker to form a new chemical entity compound, BB-702 or BB-702B for the ribosyl active metabolite of valsartan and remdesivir, GS-441524, where the base compounds, valsartan and remdesivir (or its ribosyl active metabolite), form the two primary functional components that are broken down into metabolites by the heat provided in the e-cigarette to produce vapor, including the base compounds of valsartan and remdesivir (or its ribosyl active metabolite), so that the compound delivered to the pulmonary cells in vapor form will be the valsartan and remdesivir (or its ribosyl active metabolite) components.

[0034] In one embodiment, the present application includes pulmonary delivery of one or more entry inhibitors (EI) paired with one or more protease inhibitors, including but not limited to the combination of valsartan + umifenovir. The valsartan and umifenovir combination can be administered by a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or by vapor administered through an electronic cigarette, where the valsartan and umifenovir compounds are covalently linked by a chemical bond to form a new chemical entity compound BB-703, where the base compounds - valsartan and umifenovir - form the two main functional components that are broken down into metabolites, including the valsartan and umifenovir base compounds, by the heat provided in the electronic cigarette to produce vapor, so the compound delivered to the lung cells in vapor form will be the valsartan and umifenovir components.

[0035] In one embodiment, the present application includes pulmonary delivery of one or more entry inhibitors (EI) paired with one or more MRI, including but not limited to the combination of valsartan + hydroxychloroquine. The valsartan and hydroxychloroquine combination can be administered by a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or by vapor administered through an electronic cigarette, where the valsartan and hydroxychloroquine compounds are covalently linked by a chemical bond to form a new chemical entity compound BB-704, where the base compounds - valsartan and hydroxychloroquine - form the two main functional components that are broken down into metabolites, including the valsartan and hydroxychloroquine base compounds, by the heat provided in the electronic cigarette to produce vapor, so the compound delivered to the lung cells in vapor form will be the valsartan and hydroxychloroquine components.

[0036] In one embodiment, the present application includes pulmonary delivery of one or more RdRpI, including but not limited to the combination of rifampicin and myricetin. The rifampicin and myricetin combination can be administered by a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or by vapor administered through an electronic cigarette, where the rifampicin and myricetin compounds are covalently linked by a chemical bond to form a new chemical entity compound BB-705, where the base compounds - rifampicin and myricetin - form the two main functional components that are broken down into metabolites, including the rifampicin and myricetin, by the heat provided in the electronic cigarette to produce vapor, so the compound delivered to the lung cells in vapor form will be the original rifampicin and myricetin components.

[0037] In one embodiment, the present application comprises one or more RNA-dependent RNA polymerase inhibitors (RdRpI) and one or more MRI pulmonary delivery, including but not limited to the combination of rifampicin + hydroxychloroquine, the combination of myricetin + hydroxychloroquine, or the combination of remdesivir + hydroxychloroquine or the combination of the ribitol-active metabolite of remdesivir, GS-441524 + hydroxychloroquine. The combination of rifampicin and hydroxychloroquine can be administered by a nebulizer device loaded with a therapeutically appropriate dose in the form of a powder or paste, or by the vapor of an electronic cigarette, where the rifampicin and hydroxychloroquine compounds are covalently linked by a chemical bond to form a new chemical entity compound BB-706, where the base compounds, rifampicin and hydroxychloroquine, form the two main functional components that are broken down into metabolites by the heat provided in the electronic cigarette to vaporize, including the rifampicin and hydroxychloroquine base compounds, so that the compounds delivered to the pulmonary cells in the form of vapor will be the rifampicin and hydroxychloroquine components. Alternatively, myricetin + hydroxychloroquine can be administered by a nebulizer device loaded with a therapeutically appropriate dose in the form of a powder or paste, or by the vapor of an electronic cigarette, where the myricetin and hydroxychloroquine compounds are covalently linked by a chemical bond to form a new chemical entity compound BB-707, where the base compounds, myricetin and hydroxychloroquine, form the two main functional components that are broken down into metabolites by the heat provided in the electronic cigarette to vaporize, including the myricetin and hydroxychloroquine base compounds, so that the compounds delivered to the pulmonary cells in the form of vapor will be the myricetin and hydroxychloroquine components. In another embodiment, remdesivir or the ribitol-active metabolite of remdesivir, GS-441524, and hydroxychloroquine can be administered by a nebulizer device loaded with a therapeutically appropriate dose in the form of a powder or paste, or by the vapor of an electronic cigarette (e-cig pen or medical vaporizer) in the form of gas or ultrafine particle aerosol, where the remdesivir (or its ribitol-active metabolite GS-441524) and hydroxychloroquine compounds are covalently linked by a chemical bond or linker to form a new chemical entity compound BB-708 (or BB-708B in the case of the combination with the ribitol-active metabolite of remdesivir, GS-441524), where the base compounds, remdesivir (or its ribitol-active metabolite GS-441524) and hydroxychloroquine (in its racemic mixture or purified R or S enantiomer), form the two main functional components that are broken down into metabolites by the heat provided in the electronic cigarette to vaporize, including the remdesivir (or its ribitol-active metabolite GS-441524) and hydroxychloroquine base compounds, so that the compounds delivered to the pulmonary cells in the form of vapor will be the remdesivir (or its ribitol-active metabolite GS-441524) and hydroxychloroquine components.

[0038] In one embodiment, the present application includes pulmonary delivery of one or more RNA-dependent RNA polymerase inhibitors (RdRpI) and one or more PI, including but not limited to the combination of Rifampicin + Ritonavir. The Rifampicin and Ritonavir combination can be administered through a nebulizer device loaded with therapeutically appropriate doses in the form of a powder or paste, or through the vapor of an electronic cigarette, where the Rifampicin and Ritonavir compounds are covalently linked through a chemical bond to form a new chemical entity compound BB-709, where the base compounds - Rifampicin and Ritonavir - form two major functional components that are broken down into metabolites, including the Rifampicin and Ritonavir base compounds, through the heat provided in an electronic cigarette to provide a vapor, so the compound delivered to the pulmonary cells in the form of a vapor will be the Rifampicin and Ritonavir components.

[0039] In one embodiment, the present application includes pulmonary delivery of one or more RNA-dependent RNA polymerase inhibitors (RdRpI) and one or more glucocorticoid steroids or glucocorticoid receptor or androgen receptor modulators, including but not limited to the combination of Remdesivir (or the ribosyl active metabolite of Remdesivir, GS-441524) + Dexamethasone. The Remdesivir (or the ribosyl active metabolite of Remdesivir, GS-441524) and Dexamethasone combination can be administered through a nebulizer device loaded with therapeutically appropriate doses in the form of a powder or paste, or through the vapor of an electronic cigarette, where the Remdesivir (or the ribosyl active metabolite of Remdesivir, GS-441524) and Dexamethasone compounds are covalently linked through a chemical bond or linker to form a new chemical entity compound BB-710 (for compounds containing Remdesivir) and BB-710B (for compounds containing the ribosyl active metabolite of Remdesivir, GS-441524), where the base compounds - Remdesivir (or the ribosyl active metabolite of Remdesivir, GS-441524) and Dexamethasone - form two major functional components that are broken down into metabolites, including the Remdesivir (or the ribosyl active metabolite of Remdesivir, GS-441524) and Dexamethasone base compounds, through the heat provided in an electronic cigarette or medical vaporizer to provide a vapor, so the compound delivered to the pulmonary cells in the form of a vapor as a gas or ultrafine particles in an aerosol will be the Remdesivir (or the ribosyl active metabolite of Remdesivir, GS-441524) and Dexamethasone components.

[0040] In one embodiment, the present invention includes oral delivery of one or more PSI and one or more PI, including but not limited to a combination of Relacorilant + Ledipasvir + Ritonavir. This combination can be administered in oral solid or oral liquid suspension dosage forms or through fixed dose oral solid or oral liquid suspension dosage forms, where the Relacorilant and Ledipasvir and Ritonavir compounds in the fixed dose formulation are covalently linked through a chemical bond to form a new chemical entity compound BB-713, where the base compounds - Relacorilant and Ledipasvir and Ritonavir - form three major functional components that are broken down into metabolites including the base compounds of Relacorilant and Ledipasvir and Ritonavir by the pH of the stomach, which is acidic enough to break the base compounds from the bond, resulting in the Relacorilant and Ledipasvir and Ritonavir components in the stomach for gastric absorption.

[0041] In one embodiment, the present invention includes oral delivery of one or more glucocorticoid steroid or glucocorticoid receptor or androgen receptor modulator (GRSM / ARM) and one or more RNA dependent RNA polymerase inhibitor (RdRpI), including but not limited to a combination of Mifepristone + Rifampicin. This combination can be administered in oral solid or oral liquid suspension dosage forms or through fixed dose oral solid or oral liquid suspension dosage forms, where the Mifepristone and Rifampicin compounds in the fixed dose formulation are covalently linked through a chemical bond to form a new chemical entity compound BB-712, where the base compounds - Mifepristone and Rifampicin - form two major functional components that are broken down into metabolites including the base compounds of Mifepristone and Rifampicin by the pH of the stomach, which is acidic enough to break the base compounds from the bond, resulting in the Mifepristone and Rifampicin components in the stomach for gastric absorption.

[0042] In one embodiment, the present invention includes oral delivery of one or more PSI and one or more PI, including but not limited to a combination of Relacorilant + Ledipasvir + Ritonavir. This combination can be administered in oral solid or oral liquid suspension dosage forms or through fixed dose oral solid or oral liquid suspension dosage forms, where the Relacorilant and Ledipasvir and Ritonavir compounds in the fixed dose formulation are covalently linked through a chemical bond to form a new chemical entity compound BB-713, where the base compounds - Relacorilant and Ledipasvir and Ritonavir - form three major functional components that are broken down into metabolites including the base compounds of Relacorilant and Ledipasvir and Ritonavir by the pH of the stomach, which is acidic enough to break the base compounds from the bond, resulting in the Relacorilant and Ledipasvir and Ritonavir components in the stomach for gastric absorption.

[0043] In one embodiment, the present application includes oral delivery of one or more PSI and one or more MRI, including but not limited to the combination of Miricorilant + hydroxychloroquine. This combination can be administered in oral solid or oral liquid suspension dosage forms or through fixed dose oral solid or oral liquid suspension dosage forms, where the Miricorilant and hydroxychloroquine compounds in the fixed dose form are covalently linked through a chemical bond to form a new chemical entity compound BB-714, where the base compounds - Miricorilant and hydroxychloroquine - form two major functional components that are broken down into metabolites, including the Miricorilant and hydroxychloroquine base compounds, by the pH of the stomach, which is acidic enough to cause the base compounds to separate from the bond, resulting in the Miricorilant and hydroxychloroquine components in the stomach for gastric absorption.

[0044] In one embodiment, the present application includes oral delivery of at least two PI, including but not limited to the combination of Omipalisib + ritonavir and the combination of Omipalisib + ritonavir + lopinavir. These combinations can be administered in oral solid or oral liquid suspension dosage forms or through fixed dose oral solid or oral liquid suspension dosage forms, where the Omipalisib and ritonavir compounds in the fixed dose form are covalently linked through a chemical bond to form a new chemical entity compound BB-715, where the base compounds - Omipalisib and ritonavir - form two major functional components that are broken down into metabolites, including the Omipalisib and ritonavir base compounds, by the pH of the stomach, which is acidic enough to cause the base compounds to separate from the bond, resulting in the Omipalisib and ritonavir components in the stomach for gastric absorption. In the oral lopinavir treatment of HIV, the available drug, which can block enzymes in the cytochrome P450 system, can be potentiated by the addition of ritonavir, making it possible for human drug dosages to reach effective HIV antiviral drug levels. Thus, to potentially gain a higher COVID-19 drug exposure benefit, an alternative combination of Omipalisib + ritonavir + lopinavir can be administered in oral solid or oral liquid suspension dosage forms or through fixed dose oral solid or oral liquid suspension dosage forms, where the Omipalisib and ritonavir and lopinavir compounds in the fixed dose form are covalently linked through a chemical bond to form a new chemical entity compound BB-716, where the base compounds - Omipalisib and ritonavir and lopinavir - form three major functional components that are broken down into metabolites, including the Omipalisib and ritonavir and lopinavir base compounds, by the pH of the stomach, which is acidic enough to cause the base compounds to separate from the bond, resulting in the Omipalisib and ritonavir and lopinavir components in the stomach for gastric absorption.

[0045] In one embodiment, the present invention provides a compound selected from the group consisting of glucocorticoids and glucocorticoid receptor modulators and androgen receptor modulators (GCRM / ARM) that also modulate phosphatidylserine (PS), such as: Dexamethasone: or a pharmaceutically acceptable salt thereof; Mifepristone: or a pharmaceutically acceptable salt thereof; Rila Coran: or a pharmaceutically acceptable salt thereof; and Miliclan: or a pharmaceutically acceptable salt thereof, and combinations thereof.

[0046] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one active agent, wherein the active agent is selected from entry inhibitors (EIs) that are angiotensin converting enzyme-2 (ACE-2) receptor blockers that act as ACE-2 attachment entry inhibitors (AEIs) or fusion inhibitors (FIs), such as angiotensin receptor blockers (ARBs), for example: Valsartan: or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one active agent, wherein the active agent is selected from the group consisting of protease inhibitors (PIs), such as: Lupingquwei: or a pharmaceutically acceptable salt thereof, and Ritonavir: or a pharmaceutically acceptable salt thereof, and combinations thereof.

[0048] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one active agent, wherein the active agent is selected from the group consisting of RNA-dependent RNA polymerase inhibitors (RdRpI) that interfere with replicase and replicase complexes (including NTPase / RNA helicase), such as: myricetin: or a pharmaceutically acceptable salt thereof, Rifampicin: or a pharmaceutically acceptable salt thereof, Remdesivir: or a pharmaceutically acceptable salt thereof, Riboside active metabolite of Remdesivir, GS-441524: or a pharmaceutically acceptable salt thereof, and combinations thereof.

[0049] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least one active agent, wherein the active agent is selected from the group consisting of a MicroRNA Inhibitor (MRI) and an Endosome Acidifying Agent (EA), for example: Hydroxychloroquine: or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of BB-708, also labeled as Plaquemdesivir: or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of BB-708B, also labeled as Riboplaquemdesivir: or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a drug conjugate of the riboside active metabolite of Remdesivir and the free base of Dexamethasone, linked with a carbamate to form a new chemical entity, BB-710B, also labeled as Dexadesivir: or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present application includes the synthesis of BB-708, Plaquemdesivir, in one embodiment, the chemical method used includes suspending hydroxychloroquine (100 mg, 1.0 equiv, MW 335.88) in 2 mL DCM and 2 ML DMF and 1.2 equiv CDI (carbonyldiimidazole) and TEA 5.0 equiv is added. The reaction will be stirred at 45 °C for 2.5 hours. Then add Remdesivir and heat the reaction to 55 °C and stir for 1 hour. The molecular weight of the product of the reaction is 964.45.

[0054] In one embodiment, the present application includes the synthesis of BB-708B, Riboplaquemdesivir, in one embodiment, the chemical method used includes suspending hydroxychloroquine (100 mg, 1.0 equiv, MW 335.88) in 2 mL DCM and 2 ML DMF and 1.2 equiv CDI (carbonyldiimidazole) and TEA 5.0 equiv is added. The reaction will be stirred at 45 °C for 2.5 hours. Then add the ribitol active metabolite of Remdesivir (GS-441524) and heat the reaction to 55 °C and stir for 1 hour. The molecular weight of the product of the reaction is 653.14.

[0055] In one embodiment, the present application includes a pharmaceutical composition in a dosage form selected from the group consisting of microcapsules, capsules, tablets, implants, troches, lozenges, minitablets, extemporaneous or permanent suspensions, injections, ovules, suppositories, wafers, chewable tablets, rapidly or fast dissolving tablets, effervescent tablets, oral or sublingual solids, granules, films, sprinkles, pellets, topical formulations, patches, beads, pills, powders, triturates, smart pills, smart capsules, wafers, strips, and sachets.

[0056] In one embodiment, the present application includes a pharmaceutical composition in a dosage form for respiratory applications, and optionally at least one pharmaceutically acceptable excipient, such as vegetable glycerin (VG) and / or propylene glycol (PG). In such embodiments, the dosage form can be selected from the group consisting of a nebulizer, an inhaler, an aerosol, a vapor, an electronic cigarette, an electronic cigarette with a cartridge for storing a vaporized medicament, a disposable electronic cigarette, a medical vaporizer, a portable medical vaporizer with a heating temperature regulation, and a preparation in a paste or powder form with an atomizer. The delivery system can be a device and a drug system capable of delivering a fixed dose of a pharmaceutical composition in a regimen.

[0057] In one embodiment, the present application provides a kit for treating or preventing a condition in a patient, the kit comprising: (a) a therapeutically effective amount of a pharmaceutical composition; (b) at least one blister pack, lidded blister, blister card or packet, a vial, an intravenous (IV) pack, IV pouch or IV container, a tray or shrink wrap containing the pharmaceutical composition and instructions for using the pharmaceutical composition.

[0058] In one embodiment, the present application provides a method of treating and / or preventing a viral condition caused by COVID-19 in a patient, comprising: selecting a patient in need of treatment and / or prevention of the viral condition; and administering to the patient at least one active agent selected from the group consisting of: dexamethasone, mifepristone, rilapenavir, milicoranib, valsartan, umifenovir, ritonavir, myricetin, rifampin, remdesivir, remdesivir active metabolite GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, wherein the viral condition is preventing or eliminating acute viral infection, reducing the intensity of viral infection, reducing the length of viral infection, expediting the time to resolution and healing of viral infection, expediting the time to suppression of viral infection, increasing the likelihood of viral eradication, and / or reducing the transmissibility of viral infection COVID-19.

[0059] In one embodiment, the present application provides a method of treating and / or preventing a viral condition caused by COVID-19 in a patient, comprising: selecting a patient in need of treatment and / or prevention of the viral condition; and administering to the patient at least one active agent selected from the group consisting of: dexamethasone, mifepristone, rilapenavir, milicoranib, valsartan, umifenovir, ritonavir, myricetin, rifampin, remdesivir, remdesivir active metabolite GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, wherein the viral condition is preventing or eliminating acute viral infection, reducing the intensity of viral infection, reducing the length of viral infection, expediting the time to resolution and healing of viral infection, expediting the time to suppression of viral infection, increasing the likelihood of viral eradication, and / or reducing the transmissibility of viral infection COVID-19.

[0060] In one embodiment, the present application provides a method of treating and / or preventing a viral condition caused by COVID-19 in a patient, comprising: selecting a patient in need of treatment and / or prevention of the viral condition; and administering to the patient at least one active agent selected from the group consisting of: dexamethasone, mifepristone, rilapenavir, milicoranib, valsartan, umifenovir, ritonavir, myricetin, rifampin, remdesivir, remdesivir active metabolite GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, wherein the viral condition is preventing or eliminating acute viral infection, reducing the intensity of viral infection, reducing the length of viral infection, expediting the time to resolution and healing of viral infection, expediting the time to suppression of viral infection, increasing the likelihood of viral eradication, and / or reducing the transmissibility of viral infection COVID-19.

[0061] In one embodiment, the present application provides a pharmaceutical composition comprising: a therapeutically effective amount of one or more of dexamethasone, mifepristone, rilapenavir, milatuzumab, valsartan, ravidasuvir, luteolin, rifampicin, remdesivir, remdesivir ribosyl alcohol active metabolite GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, and at least one additional active antiviral agent selected from the group consisting of molecules with binding viral PS, Annexin-5, anti-PS monoclonal or polyclonal antibodies, bavituximab, and viral glucocorticoid response element (GRE), mifepristone derivatives, cell entry inhibitors, uncoating inhibitors, reverse transcriptase inhibitors, integrase inhibitors, transcription inhibitors, anti-sense translation inhibitors, ribozyme translation inhibitors, prion processing and targeting inhibitors, protease inhibitors, assembly inhibitors, release phase inhibitors immune system modulators, and vaccines. Suitable antiviral agents include, but are not limited to, Abacavir, Aciclovir, Acyclovir, Adefovir, Alferon LDO, Amantadine, Amdoxovir, Ampligen, Amprenavir, Aplaviroc, Apricitabin, Arbidol, Atazanavir, Ateviridine, Atripla, Balavir, Bevirimat, BILN 2061, Brecanavir, Brivudine, Calanolide A, Capravirine, Cidofovir, Combivir, Condylox, Cyanovirin-N, Darunavir, Delavirdine, Dexelvucitabine, Diarylpyrimidine, Didanosine, Docosanol, Dolutegravir, Ecoliever, Edoxudine, Efavirenz, Elvitegravir,Elvucitabine, Emivirine, Emtricitabine, Enfuvirtide, Entecavir, Epigallocatechin gallate, Etravirine, Famciclovir, Fialuridine, Fomivirsen, Fosamprenavir, Foscamet, Fosfonet, Fusion inhibitors, Ganciclovir, Gardasil, Globoidnan A, Griffithsin, GS-9137, Ibacitabine, Ibalizumab, Immunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Interferon gamma, Interferon type III, Interferon type II, Interferon type I, Interferon, Integrase inhibitors, Kivexa / Epzicom, Lamivudine, Lodenosine, Lopinavir, Loviride, MK-0518, Maraviroc, Miltefosine, Moroxydine, Methisazone, Peginterferon Alfa-2a alfa-2a), Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Portmanteau inhibitor, PRO140, Protease inhibitors, Quinotaline, Racivir, Raltegravir, Reverse transcriptase inhibitors, Ribavirin, Rilpivirine, Rimantadine, Ritonavir, R-roscovitine, Pyramidine, Saquinavir, SCH503034, Sofosbuvir, Stampidine, Stavudine, Synergistic enhancer, Taribavirin, Tea tree oil, Telaprevir, Telbivudine, Tenofovir, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Vivecon, VX 950 / Telaprevir, Zalcitabine, Zanamivir, Ziagen, and Zidovudine.

[0062] In one embodiment, the composition according to the present invention can be administered to an individual in need thereof in combination with one or more antiviral drugs. Suitable antiviral drugs include, but are not limited to, Abacavir, Acyclovir, Acyclovir, Adefovir, Alferon LDO, Amantadine, Amdoxovir, Ampligen, Amprenavir, Aplaviroc, Apricitabin, Arbidol, Atazanavir, Ateviridine, Atripla, Balavir, BILN 2061, Brecanavir, Brivudine, Calanolide A, and more. A), Capravirine, Cidofovir, Combivir, Condylox, Cyanovirin-N, Darunavir, Delavirdine, Dexelvicitabine, Diarylpyrimidine, Didanosine, Docosanol, Edoxudine, Efavirenz, Elvitegravir, Elvucitabine, Emivirine, Emtricitabine, Enfuvirtide, Entecavir, Epigallocatechin gallate, Etravirine, Famciclovir, Fialuridine, Fomivirsen, Fosamprenavir, Foscamet, Fosfonet, Fusion inhibitors, Ganciclovir, Gardasil, GloboidnanA, Griffithsin, GS-9137, Ibacitabine, Ibalizumab, Immunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Interferon gamma, Interferon type III, Interferon type II, Interferon type I, Interferon, Lamivudine, Lodenosine, Lopinavir, Lovi ride), MK-0518, Maraviroc, Miltefosine, Moroxydine, Nelfinavir, Nevirapine, Nexavir, Oragen, Oseltamivir, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Portmanteau inhibitor, PRO140, Quinotaline, Racivir, Raltegravir, Ribavirin, Rilpivirine, Rimantadine, Ritonavir, R-roscovitine, Saquinavir, SCH 503034, Stampidine, Stavudine, Taribavirin, Telbivudine, Tenofovir, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Vivecon, VX950 / Telaprevir, Zalcitabine, Zanamivir, and Zidovudine (AZT).

[0063] In one embodiment, the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of one or more of dexamethasone, mifepristone, relaquintin, milicorin, valsartan, lupinquvir, ritonavir, myricetin, rifampicin, remdesivir, remdesivir active metabolite GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, and at least one antibacterial agent (to address potential comorbid superinfections associated with COVID-19). Suitable antibacterial agents include, but are not limited to, aztreonam, chlorhexidine gluconate, imidurea, lesidamide, nitrobenzene, piramonam sodium, propionic acid, sodium pyrithione, hemin chloride, teigmonam dicholine, acetanilide, sodium acetylsulfone, aletomycin, alexidin, amdenocillin amdenocillin diester, amicycline, amifloxacin, amifloxacin mesylate, amikacin, amikacin sulfate, aminosalicylic acid, sodium aminosalicylate, amoxicillin, ampicillin, ampicillin sodium, apamycin, aspartame, tegramycin sulfate, avilamycin, avoparcin, azithromycin, azlocillin, Azlocillin sodium, bacamycin hydrochloride, bacitracin, bacitracin methylene disalicylate, bacitracin zinc, bammycin, benzoylpazol calcium, erythromycin, betamycin sulfate, biapenem, biniramycin, bipheniramine hydrochloride, disopyridinethione, butikacin, butirosin sulfate, capreomycin sulfate, carbadox, carbenicillin disodium, carbenicillin indanyl sodium, carbenicillin phenyl sodium, carbenicillin potassium, coumarin sodium, cefaclor, cefadroxil, cefamandole, cefamandole emulsifiable concentrate sodium, cefamandole sodium, cefparoyl, ceftriaxone, cefazolin sodium, cefoperazone, cefdinir , Cefepime, Cefepime Hydrochloride, Cefotecol, Cefixime Cefuroxime Hydrochloride, Cefmetazole, Cefmetazole Sodium, Cefonicid Sodium, Cefoperazone Sodium, Cefoperazone Sodium, Cefuroxime Sodium, Cefotetan, Cefotetan Disodium, Ceftioxime Hydrochloride, Cefoxitin, Cefoxitin Sodium, Cefpirazol, Cefpirazol Sodium, Cefpiramide, Cefpiramide Sodium, Cefpiramide Sulfate, Cefpodoxime, Cefprozil, Cefoxadiazine, Cefsulodin Sodium, Ceftazidime, Ceftibutin, Ceftriaxone Sodium, Cefuroxime, Cefuroxime Axetil, Cefuroxime Piperazine Axetil, Cefuroxime Sodium, Ceftaxime Sodium, Cephalexin, Cephalexin hydrochloride, Cephalexin, Cefalotin, Cephalosporin, Ceftriaxone sodium, Cefpirin sodium hydrochloride, Cephradine, Cetuximab hydrochloride, Chloramphenicol, Chloramphenicol palmitate, Chloramphenicol pantothenate complex, Chloramphenicol sodium succinate, Chlorhexidine phosphate, Chloroxylenol, Chlortetracycline hydrogen sulfate, Chlortetracycline hydrochloride, Cinofloxacin, Ciprofloxacin, Ciprofloxacin hydrochloride, Cyclomycin, Clarithromycin, Clinfloxacin hydrochloride, Clindamycin, Clindamycin hydrochloride, Clindamycin palmitate, Clindamycin phosphate, Clofazimine, Cloxacillin benzylcin, Cloxacillin sodium, Chloroxyquin, Collistat sodium, Colistin sulfate, Coumarin,Coumamycin sodium, cyclocillin, cycloserine, dalfopristin, dapsone, daptomycin, demeclocycline, demeclocycline hydrochloride, demeclocycline, dinofungin, trimethoprim, dicloxacillin, dicloxacillin sodium, dihydrotoxin, dithiothreitol, dirithromycin, doxycycline, doxycycline calcium, doxycycline ester, doxycycline hydrochloride, drofloxacin sodium, enoxacin, epicillin, epitetracycline hydrochloride, erythromycin, erythromycin acetate , erythromycin estolate, erythromycin ethylsuccinate, erythromycin gluconate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, ethambutol hydrochloride, ethionamide, fleroxacin, flucillin, fludalanine, flumequine, fosfomycin, fosfomycin tromethamine, flumoxicillin, furazolidone sodium chloride, furazolidone tartrate, gentamicin sulfate, gloximab, gramicidin, halopropylamine, hertacillin, hertacillin potassium, hexidine, ibacillin floxacin, imipenem, isoconazole, isoprenaline, isoniazid, josamycin, kanamycin sulfate, benzathine, levofloxacin, levopropylthiazolin potassium, erythromycin, lincomycin, lincomycin hydrochloride, lomefloxacin, lomefloxacin hydrochloride, lomefloxacin mesylate, lolacarb, mafenidone, meclocycline, meclocycline sulfosalicylate, meclocycline potassium phosphate, methoxyquin, meropenem, meclocycline, meclocycline hydrochloride, methoxyamine, horse urine Methoxyamine acid, trimethoprim, methicillin sodium, trimethoprim, methicillin sodium, metronidazole phosphate, mezlocillin, mezlocillin sodium, minocycline, minocycline hydrochloride, milinomycin hydrochloride, monensin, monensin sodium, nafcillin sodium, nalidixic acid sodium, nalidixic acid, natamycin, nabumycin, neomycin palmitate, neomycin sulfate, neomycin undecylenate, netilmicin sulfate, neutrophil, nifuradine, nifuratel, nifuratel, Nitrofuranone, nifurdazil, nitrofuranamide, nitrofuran, nitroquinazole, nitrofurthiazole, nitrocycline, nitrofurantoin, nitramine, norfloxacin, neomycin sodium, ofloxacin, trimethoprim, oxacillin sodium, oxytetracycline, oxytetracycline sodium, oxolinic acid, oxytetracycline calcium, oxytetracycline hydrochloride, padrimycin, parachlorophenol, paclobutrazol, pefloxacin, pefloxacin mesylate, penicillin, penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V, penicillin V benzathine, penicillin V helapamine, penicillin V potassium, pentaxylone sodium, aminosalicylate phenyl ester, piperacillin sodium, Pibenicillin sodium, Piperidin sodium, Piperidin hydrochloride, Pibenicillin hydrochloride, Pibenicillin pamoate, Pibenicillin benzoate, Polymyxin B sulfate, Propiramycin, Propikacin, Pyrazinamide, Pyrithione zinc, Quinamide acetate, Quinupristin, Racemol, Ramoplanin, Ralomycin, Repromicin, Rifabutin, Riformestane, Riformidine, Rifampicin, Rifampin, Rifapentine, Rifaximin, Rolitracycline, Rolitracycline nitrate, Rosamycin, Rosalicylic acid butyrate, Rosalicylic acid propionate, Rosalicylic acid sodium phosphate, Rosalicylic acid stearate, Rosalicylic acid, Roxacin, Roxithromycin,Sancycline, cyclosanitizer sodium, samoxicillin, sabicillin, scopafungin, sisomicin, sisomicin sulfate, sparfloxacin, spectinomycin hydrochloride, spiramycin, slithromycin hydrochloride, streptomycin, streptomycin sulfate, streptonizide, sulfabenzoic acid, sulfabenzamide, sulfadiazine, sulfadiazine sodium, sulfadiazine, sulfadiazine, sulfadiazine sodium, sulfadoxine, sulfamethazine, sulfamethazine, sulfadimethoxine, sulfamethoxazole, sulfamethoxazole, sulfamethoxazole, zinc sulfa, sulfanilbetazoline, sulfasalazine, sulfisothiazole, sulfathiazole, sulfamethazine, sulfisoxazole, acetylsulfisoxazole, sulfisoxazole diamine, sulfocin, sulfa Trimethoprim, sultamicillin, ampicillin sodium sulfonate, ampicillin phthalate hydrochloride, teicoplanin, temafloxacin hydrochloride, temocillin, tetracycline, tetracycline hydrochloride, tetracycline phosphate complex, tetracycline, trimethoprim, thifencillin potassium, ticarcillin cresol sodium, ticarcillin disodium, ticarcillin monosodium, ticarcillinone, ammonium iodide, tobramycin, tobramycin sulfate, tofloxacin, trimethoprim, trimethoprim sulfate, trisulfadiazine, tolandomycin, pyrimidine sulfate, tyrosinase, vancomycin, vancomycin hydrochloride, virginiamycin, zobamycin, difloxacin hydrochloride, laurylisoquinoline bromide, moxanetan disodium, ornidazole, pentomycin and sarafloxacin hydrochloride.

[0064] In one embodiment, the composition according to the present invention may be administered to a subject in need thereof in combination with one or more antibiotics. Suitable antibiotics include, but are not limited to, amikacin disulfate, amikacin hydrate, anisomycin from Streptomyces griseus, apramycin sulfate salt, azithromycin, blasticidin S hydrochloride, brefeldin A, brefeldin A from Penicillium brefeldinii, tyrosine sulfate, tyrosine A from Bacillus yolk, chloramphenicol, chloramphenicol base, chloramphenicol succinate sodium salt, chlortetracycline hydrochloride, chlortetracycline hydrochloride from Streptomyces aureus, clindamycin 2-phosphate, clindamycin hydrochloride, clotrimazole, cycloheximide from microorganisms, demeclocycline hydrochloride, dibekacin sulfate, dihydrostreptomycin sesquisulfate, dihydrostreptomycin solution, doxycycline hydrochloride, duramycin from Streptomyces cinnamomi, emetine dihydrochloride hydrate, erythromycin, erythromycin USP, erythromycin powder, erythromycin, temetin, erythromycin ester, erythromycin ethylsuccinate, erythromycin standard solution, erythromycin stearate, fusidic acid sodium salt, G 418 disulfate, G 418 disulfate powder, G418 disulfate solution, Gentamycin solution, Gentamycin solution, Gentamycin sulfate Micromonospora purpurea, Gentamycin sulfate salt, Gentamycin sulfate salt powder USP, Gentamycin-glutamine solution, Conic acid from Cephalosporium cyanobacteria, Hygromycin B hygroscopic Streptomyces, Hygromycin B hygroscopic Streptomyces powder, Hygromycin B solution hygroscopic Streptomyces, Josamycin, Josamycin solution, Kanamycin B sulfate, Kanamycin disulfate from Streptomyces kanamycinii, Kanamycin monosulfate from Streptomyces kanamycinii, Kanamycin powder from Streptomyces kanamycinii USPCefonicid, Cefonicid Monosodium, Kanamycin Monosulfate, Kanamycin Solution from Streptomyces kanamyceticus, Clindamycin from Streptomyces clavuligerus, Lincomycin Hydrochloride, Lincomycin Standard Solution, Methacycline Sulfosalicylate, Mepartricin, Midecamycin from Streptomyces mitbratus, Minocycline Hydrochloride Crystalline, Neomycin Solution, Neomycin Trisulfate Hydrate, Neomycin Trisulfate Hydrate Powder, Neomycin Trisulfate Hydrate USP Powder, Netilmicin Sulfate, Nitrofurantoin Crystalline, Nourseothricin Sulfate, Oleandomycin Phosphate, Oleandomycin Triacetate, Oxytetracycline Dihydrate, Oxytetracycline Hemicalcium Salt, Oxytetracycline Hydrochloride, Paromomycin Sulfate, Puromycin Dihydrochloride from Streptomyces fungjungensis, Rapamycin from Streptomyces hygroscopicus, Ribostamycin Sulfate Salt, Rifampin, Rifampin SV Sodium Salt, Roxithromycin Micromonospora, Sisomicin Sulfate, Spectinomycin Dihydrochloride Hydrate, Spectinomycin Dihydrochloride Hydrate Powder, Spectinomycin Dihydrochloride Pentahydrate, Spiramycin, Spiramycin from Streptomyces, Spiramycin Solution, Streptomycin Sulfate Salt, Streptomycin Sulfate Salt Powder, Tetracycline, Tetracycline Hydrochloride, Tetracycline Hydrochloride USP, Tetracycline Hydrochloride Powder, Methanethiol, Sulfotetracycline from Streptomyces coelicolor, Tobramycin, Tobramycin Sulfate, Tylosin Solution, Tylosin Tartrate, Virginiamycin M1, (S)-(+)-Camptothecin, 10-Deacetylbaccatin III from Taxus brevifolia, 5-Azacytidine, 7-Aminocapronomycin D, 8-Quinolone Crystalline, 8-Quinolone Hemisulfate Crystalline, 9-Dihydro-13-acetylbaccatin III from Taxus canadensis, Aclarubicin, Aclarubicin Hydrochloride, Actinomycin D from Streptomyces, Actinomycin I from Streptomyces antibioticus, Actinomycin V from Streptomyces antibioticus, Afegimycin, Bafilomycin A1 from Streptomyces griseus, Bleomycin Sulfate from Streptomyces verticillus, Capreomycin Sulfate from Streptomyces, Chromomycin A3 from Streptomyces griseus, Cinoxacin, Cosmocin A, Cytochalasin B from Myceliopthora, Cytochalasin D from Emmonsia paronikiana, Dacarbazine, Daunorubicin Hydrochloride,USP, from Streptomyces distallicus, Hydrochloric Acid Isoformin A, Hydrochloric Acid Doxorubicin, Echinomycin, Echinomycin BioChemika, Enrofloxacin BioChemika, Etoposide, Etoposide Solid, Flumequine, Foymycin, from Aspergillus fumigatus, Fumigillin, Ganciclovir, from Glibberella fimbriata, Glibertoxin, Hydrochloric Acid Lomefloxacin, Pure Metronidazole, from Streptomyces, Mitomycin A, Mitomycin C Streptonic Acid, Nalidixic Acid Sodium Salt, Nalidixic Acid Sodium Salt Powder, Spindle Mycin Di-Hydrochloride Hydrate, Nitrofurantoin, from Streptomyces nigriviridis, Nonviablein, Neomycin Sodium Salt, Ofloxacin, Oxolinic Acid, from Taxus yannanensis, Paclitaxel, from Taxus brevifolia, Phenazine Methosulfate, Plicamycin Streptomyces, Piperinic Acid, from Saccharothrix aerocolonigene, Rebescamycin, Sinefungin, from Streptoniyces flocculus Streptozocin, Streptonigrin, Sulfasalazine, Sodium Salt of Sulfathiazole, Trimethoprim, Trimethoprim Lactate, Tuberculin, 5-Azacytidine, Cordycepin, Foymycin A, (+)-6-Aminopenicillanic Acid, 7-Amino Desacetoxy Cephalosporanic Acid, Amoxicillin, Ampicillin, Ampicillin Sodium Salt, Ampicillin Trihydrate, Ampicillin Trihydrate USP, Sodium Salt of Alloxicillin, Bacillus Licheniformis, Bacitracin Zinc Salt, Bacillus Licheniformis, Carbenicillin Disodium Salt, Cefaclor, Cefamandole Lithium Salt, Cefamandole Nafate, Cefamandole Sodium Salt, Cefazolin Sodium Salt, Cefoperazone Sodium Salt, Cefoperazone Sodium Salt, Cefotaxime Sodium Salt, Cefsulodin Sodium Salt, Cefsulodin Sodium Salt Hydrate, Ceftriaxone Sodium Salt, Cephalexin Hydrate, Cephalothin Zinc Salt, Cephalothin Sodium Salt, Cephalosporin Sodium Salt, Cephradine, Cloxacillin Sodium Salt, Cloxacillin Sodium Salt Monohydrate, D-Penicillamine Hydrochloride, D-Cycloserine Microorganism, D-Cycloserine Powder, Dicloxacillin Sodium Salt Monohydrate, D-Penicillamine, Econazole Nitrate, Ethambutol Di-Hydrochloride, Lysostaphin, Moxalactam Sodium Salt, Nafcillin Sodium Salt Monohydrate, Sun Mycin, Sun Mycin Z Streptomyces, Nitrofurantoin Crystals, Oxacillin Sodium Salt, Penicillin Acid Powder, Penicillin G Potassium Salt, Penicillin G Potassium Salt Powder, Penicillin G Potassium Salt, Penicillin G Sodium Salt Hydrate Powder, Penicillin G Sodium Salt Powder, Penicillin G Sodium Salt, Phenoxymethylpenicillin Potassium Salt, Phenoxymethylpenicillin Acid Potassium Salt, Phosphomycin Disodium Salt, Piperinic Acid, Piperacillin Sodium Salt, Rustocicin Sulfate, Vancomycin Hydrochloride from Streptomyces orientalis, 2-Mercapto Pyridine N-Oxide Sodium Salt, 4-Bromo Calicheamicin A23187 BioChemika, AlamethicinTrichodermaviride), amphotericin B streptomyces, amphotericin B preparation, calcimycin A23187, calcimycin A23187 hemi (calcium magnesium) salt, calcimycin A23187 hemicalcium salt, calcimycin A23187 hemimagnesium salt, chlorhexidine diacetate monohydrate, chlorhexidine diacetate hydrate, chlorhexidine digluconate, clotrimazole, colistimethate sodium, colistimethate sodium from colistin, colistin sulfate, econazole nitrate, hydrocortisone 21-acetate, filipin complex streptomyces filipin, gellumacydin from gellumacydin, gramicidin A from bacillus brevis, gramicidin C from bacillus brevis, gramicidin from bacillus mycoides (b. brevis), lonomycin calcium streptomyces, lasalocid A sodium salt, lasalocid A sodium salt from streptomyces lactclis, monensin sodium salt, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride, narasin from streptomyces aureofaciens, nigericin sodium salt from streptomyces hygroscopicus, streptococcus lactis from streptococcus lactis, nonactin from streptomyces, nystatin, nystatin powder, phenazine methosulfate, pimaricin, pimaricin from streptomyces, polymyxin B solution, polymyxin B sulfate DL-penicillinamine acetone adduct hydrochloride monohydrate, polymyxin B sulfate powder USP, pteridin, salinomycin from streptomyces albus, salinomycin from streptomyces albus, surfactin from bacillus subtilis, valinomycin, (+)-usaramic acid from usnea, (±)-miconazole nitrate, (S)-(+)-camptothecin, 1-deoxymannojirimycin hydrochloride, 1-deoxynojirimycin hydrochloride, 2-heptyl-4-hydroxyquinoline N-oxide, cordycepin, 1,10-phenanthroline hydrochloride monohydrate (pure), 6-diazo-5-oxo-L-norleucine, 8-quinolinol crystalline, 8-quinolinol hemisulfate, antifungin A from streptomyces, antifungin A1, antifungin A2, antifungin A3, antalgic, ascomycin, azaserine, bafilomycin A1 from streptomyces griseus, bafilomycin B1 from streptomyces, blue-green BioChemika, chloroquine diphosphate, cinoxacin, ciprofloxacin, mifamurt BioChemika, kanamycin A, kanamycin AStreptomyces, kanamycin C from Streptomyces, coumermycin Al, cyclosporin A from Polyangium fungus, cyclosporin A, econazole nitrate, enrofloxacin, etoposide, fluoro-methoxin, foimycin A, furazolium, fusaric acid from Fusarium japonicum, geldanamycin from Streptomyces hygroscopicus, gummtoxin from Gummiglobus sylvestris, gramicidin A from Bacillus brevis, gramicidin C from Bacillus brevis, gramicidin from Bacillus mycoides (Bacillus brevis), gramicidin from Bacillus brevis, herbicide A from Streptomyces hygroscopicus, indomethacin, triclosan, lomefloxacin hydrochloride, mycophenolic acid powder, mucidin BioChemika, N-(6-aminohexyl)-5-chloro-l-naphthalenesulfonamide hydrochloride, nafuramide, netropsin dihydrochloride hydrate, niclosamide, solimycin BioChemika, solimycin Z Streptomyces, N-methyl-1-deoxynojirimycin, nogalamycin from Streptomyces nigrescens, paracins D 80% from Streptomyces, paromomycin sodium salt, ofloxacin, zioomycin, oligomycin Streptomyces, oligomycin A, oligomycin B, oligomycin C, oligomycin Chromosporium, oxolinic acid, piperidic acid A from Streptomyces mobaraensis, piperidic acid, radicicol from Myxococcus variabilis, rapamycin from Streptomyces, rebeccamycin from Saccharomonilicola aerogenes, sinapultim, staurosporin Streptomyces, thymol, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfonamides, salicylazosulfapyridine, sulfathiazole, trinitrophenylsulfonamide from Streptomyces, trimethoprim, trimethoprim lactate, vitriyomycin Al from Streptomyces albus subsp., irisone and paracine Trichoderma reesei.

[0065] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of dexamethasone, mifepristone, relacorilane, milicorilane, valsartan, ravidasuvir, ritonavir, myricetin, rifampicin, remdesivir, remdesivir active metabolite GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, and at least one antifungal agent (to address potential co-morbid superinfection with COVID-19). Suitable antifungal agents include, but are not limited to, polyene antifungals such as nystatin, amphotericin B, and candicidin; imidazole and triazole antifungals such as imidazoles like miconazole nitrate, ketoconazole, clotrimazole (sold in the UK as Lotrimin, Canesten), econazole, bifonazole, butoconazole, fenticonazole, isoconazole, omoconazole, sertaconazole (sold as Ertaczo), sulconazole, terconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, and terconazole; allylamines such as terbinafine (sold as Lamisil), amorolfine, naftifine (sold as Naftin), and butenafine (sold as Lotrimin Ultra); echinocandins such as anidulafungin, caspofungin, and micafungin, benzocaine with keratolytic agents (such as Whitfield's ointment), ciclopirox olamine, flucytosine or 5-flucytosine, griseofulvin, and halogenated gestrinone (sold as Tinactin, Desenex, Aftate).

[0066] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of dexamethasone, mifepristone, relacorilant, miricorilant, valsartan, ravidasvir, ritonavir, myricetin, rifampicin, remdesivir, a metabolically active metabolite of remdesivir, GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, and combinations thereof, and at least one antiparasitic agent (to address potential co-morbid super-infection with COVID-19). Suitable antiparasitic agents include, but are not limited to, anti-nematodes such as mebendazole (for most nematode infections), pyrimethamine (for most nematode infections), thiabendazole (for roundworm infections), and diethylcarbamazine (for treatment of lymphatic filariasis); one or more antiparasitic agents comprising anti-tapeworm agents (such as niclosamide (for tapeworm infections) and praziquantel (for tapeworm infections)), anti- trematode agents (such as praziquantel), anti-amoebic agents (such as rifampicin, amphotericin B, chloroquine, iodoquinol metronidazole, tinidazole, omidazole, secnidazole atovaquone, eflornithine, fumidil B and suramin); anti-protozoal agents such as amphotericin, antimony, eflornithine, furazolium, melarsoprol, metronidazole, impavido, omidazole, paromomycin sulfate, pentamidine, allopurinol, and tinidazole.

[0067] In one embodiment, the present application provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent or a pharmaceutically acceptable salt thereof selected from the group consisting of ARBs (e.g., valsartan), PIs (e.g., ravidasvir or ritonavir), RdRpIs (e.g., myricetin, rifampicin, remdesivir, or its ribosidic active metabolite, GS-441524), MRIs (e.g., hydroxychloroquine, pharmaceutically acceptable salts thereof), and combinations thereof; ii) a second therapeutic agent comprising a PSI that is a GCR modulator / antagonist selected from the group consisting of dexamethasone, mifepristone, relacorilant, miricorilant, pharmaceutically acceptable salts thereof, and combinations thereof; and iii) at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated as a liquid, an elixir, an aerosol, a gas, a spray, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, an extended release dosage form, or a topical formulation, wherein the antiviral agents are each present in an amount that, in combination, is therapeutically effective for treating or preventing a viral infection in a patient. In certain embodiments, one or more of the antiviral agents in the pharmaceutical composition is active against COVID-19.

[0068] In one embodiment, the present application provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent or a pharmaceutically acceptable salt thereof selected from the group consisting of ARBs (e.g., valsartan), PIs (e.g., umifenovir or ritonavir), RdRpIs (e.g., myricetin, rifampicin, remdesivir or its ribosyl active metabolite GS-441524), and combinations thereof; ii) a second therapeutic agent comprising an MRI (e.g., hydroxychloroquine or a pharmaceutically acceptable salt thereof); and iii) at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated or manufactured as a liquid, an elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, a gel, a gel tablet, a nanosuspension, a nanoparticle, an extended release dosage form, or a topical formulation, wherein the antiviral agents are each present in an amount that is therapeutically effective when combined to treat or prevent a viral infection in a patient. In certain embodiments, one or more of the antiviral agents in the pharmaceutical composition is active against COVID-19.

[0069] In one embodiment, the present application provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent or a pharmaceutically acceptable salt thereof selected from the group consisting of ARBs (e.g., valsartan), PIs (e.g., umifenovir or ritonavir), RdRpIs (e.g., myricetin, rifampicin, remdesivir or its ribosyl active metabolite GS-441524), and combinations thereof; ii) a second therapeutic agent comprising an MRI (e.g., hydroxychloroquine or a pharmaceutically acceptable salt thereof); and iii) at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated or manufactured as a liquid, an elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, a gel, a gel tablet, a nanosuspension, a nanoparticle, an extended release dosage form, or a topical formulation, wherein the antiviral agents are each present in an amount that is therapeutically effective when combined to treat or prevent a viral infection in a patient. In certain embodiments, one or more of the antiviral agents in the pharmaceutical composition is active against COVID-19.

[0070] In one embodiment, the present application provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent or a pharmaceutically acceptable salt thereof selected from the group consisting of ARBs (e.g., valsartan), PIs (e.g., umifenovir or ritonavir), RdRpIs (e.g., myricetin, rifampicin, remdesivir or its ribosyl active metabolite GS-441524), and combinations thereof; ii) a second therapeutic agent comprising an MRI (e.g., hydroxychloroquine or a pharmaceutically acceptable salt thereof); and iii) at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated or manufactured as a liquid, an elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, a gel, a gel tablet, a nanosuspension, a nanoparticle, an extended release dosage form, or a topical formulation, wherein the antiviral agents are each present in an amount that is therapeutically effective when combined to treat or prevent a viral infection in a patient. In certain embodiments, one or more of the antiviral agents in the pharmaceutical composition is active against COVID-19. DETAILED DESCRIPTION

[0071] As used herein, the term "effective amount" refers to an amount that is sufficient to prevent the development, recurrence, or onset of a disease or disorder (e.g., a neoplasia or an infection) and one or more symptoms thereof, to enhance or improve the prophylactic effect of another therapy, to reduce the severity and / or duration of a disease or disorder (e.g., a viral infection), to alleviate one or more symptoms of a disease or disorder (e.g., an infection), to prevent the progression of a disease or disorder (e.g., an infection), to cause regression of a disease or disorder (e.g., a viral infection), and / or to enhance or improve the therapeutic effect of another therapy. As used herein, an amount is "effective" when it provides an effect in a subject.

[0072] As used herein, the phrase "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0073] As used herein, the terms "prevent," "preventing," and "prevention" in the context of administering a therapy to a subject refer to preventing or inhibiting the recurrence, onset, and / or development of a disease or disorder, such as a neoplasia, a viral infection, a latent viral infection, or a symptom thereof in a subject resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent) or combination of therapies (e.g., a combination of prophylactic or therapeutic agents).

[0074] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to an animal, preferably a mammal, such as a non-primate (e.g., a cow, pig, horse, cat, dog, rat, etc.), a primate, or a human. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, pig, or cow) or a pet (e.g., a dog or cat).

[0075] As used herein, the terms "therapy" and "therapeutic method" can refer to any method, composition, and / or agent that can be used to prevent, treat, and / or manage a disease or disorder (e.g., a neoplasia or a viral infection) or one or more symptoms thereof. In certain embodiments, the terms "therapy" and "therapeutic method" refer to chemotherapy, small molecule therapy, radioimmunotherapy, toxin therapy, prodrug-activating enzyme therapy, biologic therapy, antibody therapy, surgical therapy, hormonal therapy, immunotherapy, anti-angiogenic therapy, targeted therapy, epigenetic therapy, demethylation therapy, histone deacetylase inhibitor therapy, differentiation therapy, radiation therapy, or a combination of the foregoing and / or other therapies that can be used to prevent, manage, and / or treat a viral infection or one or more symptoms thereof.

[0076] As used herein, the terms "treat," "treatment," and "treating" in the context of administering a therapy to a subject refer to a reduction or inhibition of the progression and / or duration of a disease or condition, e.g., a neoplasia or viral infection, a reduction or alleviation of the severity of a disease or condition, e.g., a neoplasia or infection, and / or an amelioration of one or more symptoms resulting from the administration of one or more therapies.

[0077] As used herein, the term "about" when used in the context of a value or amount of a mass, weight, time, volume, concentration, or percentage is meant to encompass variations of ±20% in some embodiments, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% of the specified amount in some embodiments, as such variations are suitable to perform the disclosed methods.

[0078] As used herein, ranges can be expressed as from "about" one particular value and / or "about" another particular value. It is also understood that throughout the application, where ranges are disclosed, each intervening value, to the extent that it does not expressly exclude the intervening value, is encompassed. The terms "about" and "approximately" can be used interchangeably herein. For example, if the disclosure discloses a value of "10," then "about 10" is also disclosed. It is also understood that each

[0079] As used herein, the term "medicament" refers to any molecule, compound, method, and / or substance used to prevent, treat, manage, and / or diagnose a viral disease.

[0080] As used herein, the term "therapeutic agent" refers to any molecule, compound, and / or substance used to treat and / or control a disease or disorder. Examples of therapeutic agents include, but are not limited to, proteins, immunoglobulins (e.g., multispecific Ig, single chain Ig, Ig fragments, polyclonal antibodies and fragments thereof, monoclonal antibodies and fragments thereof), peptides (e.g., peptide receptors, selectins), binding proteins, biologies, chemospecific agents, chemotoxic agents (e.g., anticancer agents), proliferation-based therapies, chemotherapies, and small molecule drugs.

[0081] As used herein, the terms "e-vaping device," "e-cigarette," and "e-cig" in the context of administering a medicament to a subject refer to a battery-operated medicament delivery device for administering one or more doses of a medicament composition in the form of a vapor for inhalation by a subject.

[0082] As used herein, the term "nebulizer" refers to a drug delivery device used to administer one or more doses of a pharmaceutical composition in the form of a mist for inhalation by a subject. Nebulizers can use oxygen, compressed air, or ultrasonic power to break down solutions and suspensions into small aerosol droplets that can be inhaled directly from the mouthpiece of the device. Aerosols are suspensions of solid or liquid particles in a gas. Nebulizers can be open to air or a component of a closed system incorporated into a patient's breathing machine.

[0083] As used herein, the term "ARB" or "angiotensin receptor blocker" refers to a class of drugs including Azilsartan (Edarbi); Candesartan (Atacand); Eprosartan (Teveten); Irbesartan (Avapro); Telmisartan (Micardis), valsartan (Diovan); Losartan (Cozaar) and Olmesartan (Benicar).

[0084] As used herein, the terms "glucocorticoid" and "glucocorticoid receptor modulator" refer to a group of drugs including, but not limited to, beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

[0085] Phosphatidylserine (PS) binding represents an important inner membrane lipid in all human cells. PS represents a phospholipid, along with phosphatidylcholine (lecithin) and phosphatidylethanolamine (cephalin). PS is composed of 1,2-diacylglycero-3-phospho-L-serine. The 1,2-diacylglycero-3-phosphate is also known as phosphatidic acid, hence the term "phosphatidyl". PS is normally only exposed on human cells in the case of apoptosis (programmed cell death, "voluntary cell suicide"). Enveloped viruses constantly expose PS on the lipid bilayer membrane they capture in their host. Enveloped viruses exploit this PS exposure to evade the human immune system and enter phagocytic cells, such as monocytes / macrophages.

[0086] 3-O-sn-phosphatidyl-L-serine (PS): Structure of a typical PS, as shown by stearic acid at the 1 -O position and docosahexaenoic acid at the 2-O position. This represents the major serine- brain phospholipid from bovine brain. The fatty acid composition at positions 1 -O and 2-O varies, for example depending on the cell type. The polar head group (phospho serine) is negatively charged. The phosphate anion charge and the cationic charge of the ammonium group neutralize each other. Thus, PS is net negatively charged at physiological pH 7.4.

[0087] Sn-Phosphatidylcholine (PC): Structure of a typical PC, as shown by stearic acid at the 1 -O position and linoleic acid at the 2-O position. This represents the major lecithin from egg yolk and human cell membranes. The fatty acid composition at positions 1 -O and 2-O varies, for example depending on the cell type. The polar head group (phosphocholine) is zwitterionic. The phosphate anion charge and the cationic charge of the ammonium group neutralize each other. Thus, PC is net neutral at physiological pH 7.4. Most of the identified PS-intercept susceptible enveloped viruses are RNA viruses, such as COVID-19.

[0088] Formulations and administration The compounds and compositions of the present application can be administered in a therapeutically effective dose. In some embodiments, the compounds and compositions of the present application are administered in a dose of about 1 mg / day, about 2 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 120 mg / day, about 125 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 175 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, or about 500 mg / day. In certain embodiments, the compounds of the present application are administered in a dose of less than 1 mg / day, less than 2 mg / day, less than 5 mg / day, less than 10 mg / day, less than 15 mg / day, less than 20 mg / day, less than 25 mg / day, less than 30 mg / day, less than 35 mg / day, less than 40 mg / day, less than 45 mg / day, less than 50 mg / day, less than 60 mg / day, less than 70 mg / day, less than 80 mg / day, less than 90 mg / day, less than 100 mg / day, less than 120 mg / day, less than 125 mg / day, less than 140 mg / day, less than 150 mg / day, less than 160 mg / day, less than 175 mg / day, less than 180 mg / day, less than 190 mg / day, less than 200 mg / day, less than 225 mg / day, less than 250 mg / day, less than 275 mg / day, less than 300 mg / day, less than 325 mg / day, less than 350 mg / day, less than 375 mg / day, less than 400 mg / day, less than 425 mg / day, less than 450 mg / day, less than 475 mg / day, or less than 500 mg / day.In some embodiments, the compounds of the application are administered at a dose of more than 1 mg / day, more than 2 mg / day, more than 5 mg / day, more than 10 mg / day, more than 15 mg / day, more than 20 mg / day, more than 25 mg / day, more than 30 mg / day, more than 35 mg / day, more than 40 mg / day, more than 45 mg / day, more than 50 mg / day, more than 60 mg / day, more than 70 mg / day, more than 80 mg / day, more than 90 mg / day, more than 100 mg / day, more than 120 mg / day, more than 125 mg / day, more than 140 mg / day, more than 150 mg / day, more than 160 mg / day, more than 175 mg / day, more than 180 mg / day, more than 190 mg / day, more than 200 mg / day, more than 225 mg / day, more than 250 mg / day, more than 275 mg / day, more than 300 mg / day, more than 325 mg / day, more than 350 mg / day, more than 375 mg / day, more than 400 mg / day, more than 425 mg / day, more than 450 mg / day, more than 475 mg / day, or more than 500 mg / day.

[0089] The compounds and compositions of the application can be administered once daily or more, or can be administered at intervals of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 12 weeks.

[0090] The compounds and compositions of the present application can be administered in an effective amount to an individual in need thereof. In a preferred embodiment, the amount of the composition according to the present application is in the range of about 0.01 mg per kilogram of body weight per dose to about 1000 mg per kilogram of body weight per dose, such as about 0.01 mg per kilogram of body weight per dose to about 0.025 mg per kilogram of body weight per dose, such as about 0.025 mg per kilogram of body weight per dose to about 0.05 mg per kilogram of body weight per dose, such as about 0.05 mg per kilogram of body weight per dose to about 0.075 mg per kilogram of body weight per dose, such as about 0.075 mg per kilogram of body weight per dose to about 0.1 mg per kilogram of body weight per dose, such as about 0.1 mg per kilogram of body weight per dose to about 0.25 mg per kilogram of body weight per dose, such as about 0.25 mg per kilogram of body weight per dose to about 0.5 mg per kilogram of body weight per dose, such as about 0.5 mg per kilogram of body weight per dose to about 0.75 mg per kilogram of body weight per dose, such as about 0.75 mg per kilogram of body weight per dose to about 1.0 mg per kilogram of body weight per dose, such as about 1.0 mg per kilogram of body weight per dose to about 2.5 mg per kilogram of body weight per dose, such as about 2.5 mg per kilogram of body weight per dose to about 5 mg per kilogram of body weight per dose, such as about 5 mg per kilogram of body weight per dose to about 7.5 mg per kilogram of body weight per dose, such as about 7.5 mg per kilogram of body weight per dose to about 10 mg per kilogram of body weight per dose, such as about 10 mg per kilogram of body weight per dose to about 25 mg per kilogram of body weight per dose, such as about 25 mg per kilogram of body weight per dose to about 50 mg per kilogram of body weight per dose, such as about 50 mg per kilogram of body weight per dose to about 75 mg per kilogram of body weight per dose, such as about 75 mg per kilogram of body weight per dose to about 100 mg per kilogram of body weight per dose, such as about 100 mg per kilogram of body weight per dose to about 250 mg per kilogram of body weight per dose, such as about 250 mg per kilogram of body weight per dose to about 500 mg per kilogram of body weight per dose, such as about 500 mg per kilogram of body weight per dose to about 750 mg per kilogram of body weight per dose, such as about 750 mg per kilogram of body weight per dose to about 1000 mg per kilogram of body weight per dose.

[0091] The compounds and compositions of the present invention can be administered in the range of about 0.01 mg per kg body weight per dose to about 20 mg per kg body weight per dose, for example, about 0.02 mg per kg body weight per dose to about 18 mg per kg body weight per dose, for example, about 0.04 mg per kg body weight per dose to about 16 mg per kg body weight per dose, for example, about 0.06 mg per kg body weight per dose to about 14 mg per kg body weight per dose, for example, about 0.08 mg per kg body weight per dose to about 12 mg per kg body weight per dose, for example, about 0.1 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 0.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 0.3 mg per kg body weight per dose to about 1 0 mg per kg body weight per dose, for example about 0.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 0.5 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 0.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 0.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 0.7 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 0.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 0.9 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 1.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 1 .2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 1.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 1.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 1.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 2.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 2.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 2.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 2.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example about 2.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 3.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 3.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 3.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 3.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 3.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 4.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 4.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 4.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, for example, about 4.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 4.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 5.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 5.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 5.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 5.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 5.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 6.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 6.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 6.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 6.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 6.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 7 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 7.2 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 7.4 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 7.6 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 7.8 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 8.0 mg per kg body weight per dose to about 10 mg per kg body weight per dose, such as about 0.2 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.3 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.4 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.5 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.7 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.8 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 0.9 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 1.0 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 1.2 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 1.4 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 1.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 1.8 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 2.0 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 2.2 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 2.4 mg per kg body weight per dose to about 8 mg per kg body weight per dose, such as about 2.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 2.8 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 3.0 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 3.2 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 3.4 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 3.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 3.8 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 4.0 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 4.2 mg per kg body weight per dose to about 8 mg per kg body weight per dose The dosage of the drug is preferably about 4.4 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 4.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 4.8 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 5.0 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 5.2 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 5.4 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 5.6 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 5.8 mg per kg body weight per dose to about 8 mg per kg body weight per dose, for example about 6.0 mg per kg body weight per dose to about 8 mg Grams per kilogram of body weight per dose, for example, about 0.2 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.3 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.4 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.5 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.6 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.7 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.8 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 0.9 mg per kilogram of body weight per dose to about 6 mg per kilogram of body weight per dose, for example, about 1.0 mg per kilogram of body weight The dosage range of the drug is from about 1.2 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 1.4 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 1.6 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 1.8 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 2.0 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 2.2 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 2.4 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 2.6 mg / kg body weight to about 6 mg / kg body weight per dose, for example, from about 2.8 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 3.0 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 3.2 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 3.4 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 3.6 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 3.8 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example About 4.0 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 4.2 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 4.4 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 4.6 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 4.8 mg per kg body weight per dose to about 6 mg per kg body weight per dose, for example about 5.0 mg per kg body weight per dose to about 6 mg per kg body weight per dose.

[0092] The compounds and compositions of the present invention can be administered enterally or by inhalation using a device including an electronic cigarette, which can be single-use or provided with a cartridge containing a drug (active pharmaceutical ingredient plus excipient). The compound can be pressed into a solid dosage unit, such as a pill or tablet, or processed into a capsule or suppository. By using a pharmaceutically suitable liquid, the compound can also be provided in the form of a solution, suspension, emulsion, for example, for use as an injection or eye drop, or as a spray, for example, as a nasal spray. These compounds can also be prepared for use in open and closed system atomizers and delivered in a cartridge placed in an electronic cigarette.

[0093] In one embodiment, a composition according to the present invention is administered to an individual in need thereof via a portable medical vaporizer including an electronic cigarette, whereby the patient will receive a total daily dose of BB-708 Plaquemdesivir of about 60 mg to about 120 mg per day for 3 to 14 days in a disposable electronic cigarette or multi-use electronic cigarette drug cartridge. Each electronic cigarette cartridge or disposable electronic cigarette may contain 0.75 milliliters (mL) to 2.0 (mL), with a minimum weight of BB-708 of 3% to 5% per volume, such that an average patient will consume all of the drug in about 100 inhalations per (1 mL) cartridge capsule or disposable electronic cigarette, or in about 20,000 inhalations per 2 (mL) cartridge capsule or higher capacity disposable electronic cigarette. The concentration of BB-708 can be adjusted upward to reduce the number of inhalations required to consume a prescribed dose, for example, a higher concentration of BB-708 in the drug product may require 10 or fewer inhalations. The dosage regimen may be adjusted within or outside this range to provide the optimal therapeutic response and may be adjusted downward for pediatric use and may be adjusted upward or downward based on the patient's weight.

[0094] In one embodiment, the composition according to the present application is administered to an individual in need thereof by a portable medical vaporizer comprising an electronic cigarette, whereby the patient will receive the total daily dose of BB-708B, Riboplaquemdesivir, in a drug cartridge of a disposable or multi-use electronic cigarette, from about 60 mg to about 120 mg per day, for 3 to 14 days. Each electronic cigarette cartridge or disposable electronic cigarette can contain from 0.75 milliliter (mL) to 2.0 (mL), with a minimum weight of BB-708B per volume of 3% to 5%, so that an average patient will consume all of the drug in about 100 puffs per (1 mL) cartridge pod or disposable electronic cigarette, or in about 20000 puffs per 2 (mL) cartridge pod or higher capacity disposable electronic cigarette. The concentration of BB-708B can be adjusted upward to reduce the number of puffs required to consume the prescribed dose, for example, 10 or fewer puffs can be required when using a higher concentration of BB-708B in the drug. The dosage regimen can be adjusted within this range or outside of it to provide the optimal therapeutic response, and downward for pediatric use, and upward or downward according to the patient’s weight.

[0095] In one embodiment, the composition according to the present application is administered to an individual in need thereof by a portable medical vaporizer comprising an electronic cigarette, whereby the patient will receive the total daily dose of BB-710B, Ribodexadesivir, in a drug cartridge of a disposable or multi-use electronic cigarette, from about 60 mg to about 120 mg per day, for 3 to 14 days. Each electronic cigarette cartridge or disposable electronic cigarette can contain from 0.75 milliliter (mL) to 2.0 (mL), with a minimum weight of BB-710B per volume of 3% to 5%, so that an average patient will consume all of the drug in about 100 puffs per (1 mL) cartridge pod or disposable electronic cigarette, or in about 20000 puffs per 2 (mL) cartridge pod or higher capacity disposable electronic cigarette. The concentration of BB-710B can be adjusted upward to reduce the number of puffs required to consume the prescribed dose, for example, 10 or fewer puffs can be required when using a higher concentration of BB-710B in the drug. The dosage regimen can be adjusted within this range or outside of it to provide the optimal therapeutic response, and downward for pediatric use, and upward or downward according to the patient’s weight.

[0096] For the preparation of dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additives which do not interfere with the function of the active compound can be used. Suitable carriers include lactose, starch, cellulose derivatives, and the like, or mixtures thereof, used in suitable amounts.

[0097] Special formulations for alternative routes of administration The pharmaceutical compositions of the present application can be optimized for a particular type of delivery. For example, pharmaceutical compositions for oral delivery can be formulated using pharmaceutically acceptable carriers well known in the art. The carriers enable the agents in the composition to be formulated, for example, into tablets, pills, capsules, solutions, suspensions, sustained release formulations, powders, liquids, or gels for oral ingestion by a subject, as well as liquids containing vegetable glycerin or propylene glycol as active substances for vape carriers.

[0098] The compounds of the present application can also be delivered in an aerosol spray formulation from pressurized packs, a nebulizer, a dry powder inhaler or an electronic cigarette. Suitable propellants include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide. In the case of a pressurized aerosol, the amount of compound delivered can be regulated by a valve to deliver a metered amount.

[0099] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can include suitable pharmaceutically-acceptable excipients as described supra. Compositions can be administered by oral, intranasal or respiratory routes for local or systemic effect. Compositions in preferably sterile pharmaceutically-acceptable solvents can be nebulized by use of inert gases or aerosols. Nebulized solutions can be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or tracheal tube. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0100] The compounds of the present application can be administered enterally, parenterally, or in a respiratory form, optionally mixed with a pharmaceutically suitable auxiliary, for example, as described in standard reference texts (Gennaro et al., Remington's Pharmaceutical Sciences). The compounds can be compressed into solid dosage units, for example, pills or tablets, or processed into capsules or suppositories. In the form of a solution, suspension, emulsion, the compounds can also be provided by a pharmaceutically suitable liquid, for example, for use as an injection or eye drop, or as a spray, for example, as a nasal spray.

[0101] Dosage forms The compositions of the present application can be processed by agglomeration, air suspension cooling, air suspension drying, spheronization, coacervation, coating, comminution, compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation, homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other methods known in the art. The compositions can be provided in the form of microcapsules, capsules, smart capsules, tablets, implants, lozenges, sachets, troches (small tablets), extemporaneous or permanent suspensions, ovules, suppositories, wafers, chewable tablets, fast melt or fast melt tablets, effervescent tablets, oral or sublingual solids, granules, films, sprinkles, pellets, beads, pellets, powders, triturations, wafers, or strips. The compositions can also be administered as "dry syrup," where the finished dosage form is placed directly on the tongue and swallowed or subsequently sipped.

[0102] The pharmaceutical compositions can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compression coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings can be applied to achieve desired properties. In addition, the dosage forms can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release. For release / absorption control, the solid carriers can be made from various ingredient types and coating levels or thicknesses, with or without active ingredients. Such solid carriers can be mixed in the dosage form to achieve desired properties. In addition, the dosage form release pattern can be affected by polymer matrix compositions, coating matrix compositions, multiparticulate compositions, coated multiparticulate compositions, ion exchange resin-based compositions, osmotic-based compositions, or biodegradable polymers.

[0103] When formulated into capsules, the capsules can be hard or soft gelatin capsules, starch capsules, or cellulose capsules. While not limited to capsules, such dosage forms can be further coated with, for example, seal coatings, enteric coatings, sustained release coatings, or targeted delayed release coatings. These different coatings are known in the art, but for the sake of clarity, the following brief explanation of seal coatings or coatings with a barrier layer is provided: A thin layer up to 20 microns thick can be applied for various reasons, including reducing particle porosity, reducing dust, chemical protection, masking taste, reducing odor, reducing gastrointestinal irritation, etc. The barrier effect is directly proportional to the thickness of the coating. This application preferably uses water-soluble cellulose ethers. A combination of HPMC and ethyl cellulose, or Eudragit E100, can be particularly suitable for taste-masking applications. Traditional enteric coating materials listed elsewhere can also be used to form a barrier layer.

[0104] Sustained release coatings are designed to effectuate delivery over an extended period of time. Sustained release coatings are pH independent coatings formed from, for example, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic acid esters, or sodium carboxymethyl cellulose. Depending on the choice of coating material and / or coating thickness, one skilled in the art can readily design various sustained release dosage forms to effectuate delivery to the small and large intestine, to the small intestine only, or to the large intestine only.

[0105] An enteric coating is a mixture of pharmaceutically acceptable excipients that is applied to, combined with, mixed with, or otherwise added to a carrier or composition. The coating can be applied to tablets, gelatin capsules and / or pellets, beads, granules or particles of compressed or molded or extruded carriers or compositions. The coating can be applied through an aqueous dispersion or after dissolution in a suitable solvent. The additional additives and their amounts, as well as the choice of one or more primary coating materials will depend on the following properties: resistance to dissolution and disintegration in the stomach; impermeability to gastric fluids and drugs / carriers / enzymes while in the stomach; ability to dissolve or disintegrate rapidly at the target site in the intestine; physical and chemical stability during storage; non-toxicity; ease of use as a coating (friendly to the substrate); and economic practicality.

[0106] Dosage forms of the compositions of the present application can also be formulated as enteric coated delayed release oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions as described herein that utilize an enteric coating to effect release in the lower digestive tract. The enteric coated dosage forms can be compressed or molded or extruded tablets / molds (coated or uncoated) that contain particles, pellets, beads or granules of the active ingredient and / or other composition components that are themselves coated or uncoated. The enteric coated oral dosage forms can also be capsules (coated or uncoated) that contain pellets, beads or granules of the solid carrier or composition that are themselves coated or uncoated.

[0107] Delayed release generally refers to delivery such that release can be accomplished in some generally predictable location in the lower intestine, which is further along than would be reached if there were no delayed release modification. The preferred method of delayed release is coating. Any coating should be applied to a sufficient thickness that the entire coating does not dissolve in the gastrointestinal fluids at a pH less than about 5, but does dissolve at a pH of about 5 or greater. It is contemplated that any anionic polymer that exhibits a pH dependent solubility profile can be used as an enteric coating to effect delivery to the lower digestive tract in the practice of the present application. The polymer used in the present application is an anionic carboxylic acid polymer.

[0108] Shellac, also known as purified shellac, is a refined product obtained from the resinous secretions of an insect. This coating dissolves in media with a pH > 7.

[0109] In addition to plasticizers, colorants, anti-sticking agents, surfactants, antifoaming agents, lubricants, stabilizers (e.g., hydroxypropyl cellulose), acids / bases can also be added to the coating to dissolve or disperse the coating material and improve the coating performance and the coated product.

[0110] In practicing the methods of the present application, the combinations of the present application can be administered to mammalian species, such as dogs, cats, humans, and the like, and thus can be incorporated into conventional systemic dosage forms, such as tablets, capsules, elixirs or injectables. The above-mentioned dosage forms can also include at least one carrier material, excipient, lubricant, buffer, antimicrobial agent, filler (e.g., mannitol), antioxidant (ascorbic acid sodium bisulfite), and the like.

[0111] Tablets containing various amounts of the active pharmaceutical ingredient can be prepared in various sizes, e.g., from about 1 to 2000 mg total weight, the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can be scored to provide for division into smaller doses. Gelatin capsules can be similarly formulated.

[0112] Liquid formulations can also be prepared by dissolving or suspending the compounds of the present application in a conventional liquid vehicle for pharmaceutical administration in the required dosage.

[0113] For more precise dosing regimens, the active substances can be administered separately in separate dosage units at the same time or in close succession. The simultaneous presence of both substances in the bloodstream can achieve the same result, since the blood levels are established and maintained by the prescribed dosage schedule. The individual substances can be formulated separately in separate unit dosage forms in a manner similar to that described above.

[0114] In formulating the compositions, the above-mentioned amounts of the active substances can be combined with physiologically acceptable excipients, carriers, adjuvants, binders, preservatives, stabilizers, flavoring agents, and the like, in accordance with accepted pharmaceutical practice, in the particular type of unit dosage form.

[0115] Examples of excipients that can be incorporated into tablets are binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate or cellulose; disintegrating agents such as corn starch, potato starch, alginic acid and the like; lubricants such as stearic acid or magnesium stearate; sweetening agents such as sucrose, aspartame, lactose or saccharin; flavoring agents such as orange flavoring, peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules can be coated with shellac, sugar or both. A syrup of elixir can contain the active compound, water, alcohol, etc. as carriers, glycerol as a solubilizing agent, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

[0116] In one embodiment, a method of treating, preventing, or diagnosing a particular COVID-19 disease or condition by administering the disclosed compositions to a subject is provided. In certain embodiments, the disclosed compositions are administered alone or can be included in a pharmaceutical composition.

[0117] The compositions of the present application can include nanoparticles, composite nanoparticles, nanosuspensions, or nanocapsules. In certain embodiments, a pharmaceutical composition can include, for example, at least about 0.1% of the active ingredient or nanoparticles, composite nanoparticles, or nanocapsules. In other embodiments, the active ingredient or nanoparticles, composite nanoparticles, or nanocapsules can comprise from about 2% to about 75%, or from about 25% to about 60%, of the weight of the unit, as well as any range derivable therein.

[0118] The compositions of the present application can also include various antioxidants to retard oxidation of one or more active ingredients or nanoparticles, composite nanoparticles, nanosuspensions, or nanocapsules. Prevention can be ensured by the use of a preservative agent such as various antibacterial and antifungal agents, including, but not limited to, parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.

[0119] Packaging / Therapeutic Kits The present invention relates to kits for facilitating and efficiently implementing the methods according to the present invention. Such kits can be suitable for delivery of solid oral dosage forms (e.g. tablets or capsules) as well as inhalation dosage forms (e.g. e-cigarettes) which can require a cartridge for a medicament which can be used in a suitable device. Such kits can comprise one or more dosage units. Such kits can comprise a device for holding the dosage units in an order which is directed to their intended use. One example of a method for holding the dosage units in an order which is directed to their intended use is a card. Another example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, the blisters can be in the form of child-resistant blisters, i.e. blisters which are difficult for children to open but which can be easily opened by adults. If desired, a memory aid can be provided, e.g. in the form of numbers, letters or other indicia or with a calendar feature and / or calendar insert, specifying the day and part of the day in a treatment schedule in which a dosage can be administered, e.g. a morning dosage packed together with a "midday" and afternoon dosage; or a morning dosage packed together with an afternoon dosage. The card with blisters can contain cartridges for e-cigarettes.

[0120] In one aspect, the package, kit or container comprises a "blister pack" (also known as a blister pack or bubble pack). In one aspect, the blister pack is comprised of two or more separate compartments: a morning dosage of the present invention, and an afternoon dosage of the present invention, or a midday dosage of the present invention. Such a blister pack is comprised of two independent elements of material: a transparent plastic cavity which adapts to the shape of the product and its blister board backing. These two elements are then joined together by a heat sealing process, allowing the product to be hung or displayed. Exemplary types of "blister packs" include: face-seal blister packs, combination blister packs, simulated blister packs, interactive blister packs, slide blister packs.

[0121] Blister packs, clamshells or trays are a form of packaging for goods; thus, the present invention provides a blister pack, clamshell or tray containing a composition of the present invention. The blister pack, clamshell or tray can be designed to be non-reclosable, thus allowing the consumer to determine if the package has been opened. In one embodiment, the blister pack of the present invention comprises a molded PVC base with raised areas ("blister") to hold tablets, pills, etc. containing a composition of the present invention, and is covered by a foil laminate. The tablet, pill, etc. is removed from the package by peeling the foil back or pushing the blister to force the tablet to break the foil. In one embodiment, a special form of the blister pack is a strip pack.

[0122] In one embodiment, the blister pack can also include a packaging method in which the composition containing the combination of ingredients of the present invention is housed between a card and a clear PVC layer. The PVC can be clear so that the contents (pills, tablets, geltabs, etc.) can be easily viewed and inspected. In one embodiment, the blister pack can be vacuum formed around a mold so that it can tightly house the composition containing the combination of ingredients of the present invention and have an opening space at the time of purchase. In one embodiment, the card is brightly colored and designed according to the contents (pills, tablets, geltabs, etc.) inside and is secured to the PVC using pre-formed joints that place adhesive. The adhesive can be strong enough so that the package can be hung on a nail, but weak enough so that a person can tear the joint apart and access the contents. In embodiments with large contents or multiple enclosed pills, tablets, geltabs, etc., the card can have perforated windows for access. In one embodiment, a more secure blister pack can be used, such as for the pills, tablets, geltabs, etc. of the present invention, and can include two vacuum formed PVC sheets that are mated together at the edges and have an information card inside.

[0123] In one embodiment, the blister pack can contain at least two components (e.g., is a multi-component combination of the drug of the present invention): a thermoformed "blister" that houses the product (e.g., the drug combination of the present invention), followed by a "blister card," which is a printed card with an adhesive coating on the front. During assembly, the blister assembly, most commonly made of PVC, can be attached to the blister card using a blister machine. The machine introduces heat to the edge area of the blister, which activates the glue in a specific area on the card and ultimately secures the PVC blister to the printed blister card. The thermoformed PVC blister and printed blister card can be small or large. The conventional blister pack can also be sealed using conventional heat sealing tools (e.g., using AERGO 8 DUO®, SCA Consumer Packaging, Inc., DeKalb, 111.).

[0124] As discussed herein, the manufactured products of the present invention can include packaging of the therapeutic drug combination of the present invention, alone or in combination, as "blister packs" or multiple packets, including blister packs with lids, blister packs with lids or blister cards or pouches, or shrink packs.

[0125] In one embodiment, a laminated aluminum foil blister pack is used, for example, for the preparation of a medicament designed to dissolve immediately in the mouth of a patient. This exemplary method includes preparing the pharmaceutical combination of the present application as an aqueous solution, which is dispensed (e.g., by measured doses) into the aluminum (e.g., aluminum foil) laminated tray portion of a blister pack. The tray is then freeze-dried to form tablets having a blister shape. The aluminum foil lamination of the tray and lid completely protects any highly hygroscopic and / or sensitive individual doses. In one aspect, the packaging contains a child-resistant peel-open safety laminate. In one embodiment, the system provides an identification mark for the tablet by imprinting a design into the aluminum foil pouch that it occupies when the tablet changes from a water state to a solid state. In one aspect, a separate "push-in" blister pack / pouch is used, for example, using a hard temper aluminum (e.g., aluminum foil) lidding material. In one embodiment, a sealed high barrier aluminum (e.g., aluminum foil) lamination is used. In one embodiment, any manufactured product of the present application (including a kit or blister pack) uses foil layers and strip, stick, pouch, and packet packaging, peelable and non-peelable layers for high barrier packaging in combination with foil, paper, and film.

[0126] Other devices for containing the unit dose can include bottles and vials, where the bottle or vial contains a memory aid, such as a printed label for administering the unit dose or multiple doses. The label can also contain a removable reminder sticker for placement on a calendar or daily reminder to further assist the patient in remembering when to take a dose or that a dose has been taken.

[0127] Dosing The pharmaceutical compositions of the present application can be optimized for a particular type of delivery. For example, pharmaceutical compositions for oral delivery are formulated using pharmaceutically acceptable carriers well known in the art. The carriers enable the agents in the composition to be formulated, for example, in inhaled and oral forms, as nebulized liquids, tablets, pills, capsules, solutions, suspensions, sustained release formulations; powders, liquids, or gels for oral ingestion by a subject.

[0128] Pharmaceutical compositions can also be delivered in the form of aerosol spray formulations from pressurized packaging, nebulizers, or dry powder inhalers. Suitable propellants that can be used in nebulizers include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. In the case of pressurized aerosols, a valve can be provided to deliver an adjustable amount of compound to determine the dosage. Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered orally, intranasally, or by the respiratory route to achieve a local or systemic effect. Compositions in preferably sterile, pharmaceutically acceptable solvents can be atomized using an inert gas. The atomized solution can be breathed directly from the atomizing device, or the atomizing device can be connected to a mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally. Electronic vaporizers like e-cigarettes can be single-use devices containing a drug product or multiple-use devices containing pre-filled cartridges containing a drug product containing an active pharmaceutical ingredient and excipients (including carriers).

[0129] In one embodiment, the compositions of the present invention can be administered repeatedly over a period of time. In such embodiments, the administration regimen typically includes regular administration, such as daily administration, over a treatment period of at least 1 month, or at least 3 months, or at least 6 months.

[0130] Alternatively, the compositions of the invention may be administered intermittently or in a pulsed manner. For example, the compositions of the invention may be used for two days or longer, stopped, and then restarted again after a period of 2 weeks to 3 months (or at even longer intervals).

[0131] The route of administration of the compounds of the present invention will vary with the site and nature of the condition to be treated and includes, for example, inhalation, intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, transdermal, intratracheal, intraperitoneal, infusion, lavage, direct injection and oral administration and formulations. As described in detail below, the compounds of the present invention can be administered as a medicinal gas by inhalation or intubation, as an injectable liquid by intravascular, intravenous, intraarterial, intracerebroventricular, intraperitoneal, subcutaneous administration, as a topical liquid or gel, or in a solid oral dosage form.

[0132] The length of time of administration can vary depending on the type of biological material (cell type, tissue type, biological genus and species, etc.) and / or its size (weight, surface area, etc.) and will depend in part on the dosage form and route of administration. In particular embodiments, the compounds of the present application can be provided for about or at least 30 seconds, 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, four hours, five hours, six hours, eight hours, twelve hours, twenty-four hours, or greater than twenty-four hours. The compounds of the present application can be administered in a single dose or multiple doses with varying amounts of time between doses.

[0133] Treatment can include various "unit doses." Unit dose is defined as containing a predetermined quantity of the therapeutic composition. The amount to be administered, and in particular the route and formulation, are within the skill of those in the clinical arts. The unit dose need not be administered as a single injection, but can include continuous infusion over a set period of time. Alternatively, the specified amount can be administered as an average daily, weekly, or monthly dose.

[0134] In one embodiment, the present application provides a topical pharmaceutical formulation for treating a subject comprising a composition of the present application and at least one pharmaceutically acceptable excipient. In such embodiments, the present application can provide a topical formulation, wherein the form of the formulation is selected from the group consisting of a cream, lotion, gel, oil, ointment, suppository, spray, foam, liniment, aerosol, buccal and sublingual tablet, or transdermal device or patch for absorption through the skin or mucosa.

[0135] All references cited herein are incorporated by reference in their entirety.

[0136] While the application has been shown and described with reference to certain exemplary embodiments thereof, it is to be understood that the application is not to be limited to the specific embodiments shown and described, and that modifications and changes can be made by those skilled in the art without departing from the spirit and scope of the application. Therefore, the application is not limited to the specific embodiments shown and described, but only by the scope of the appended claims.

Claims

1. A pharmaceutical composition for treating COVID-19, comprising: a therapeutically effective amount of a first antiviral agent, wherein the first antiviral agent consists of a picornavirus 3C protease inhibitor or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a second antiviral agent having a different mechanism of action consisting of ritonavir or a pharmaceutically acceptable salt thereof, and A third antiviral agent is selected from dexamethasone and remdesivir.

2. The pharmaceutical composition according to claim 1, wherein The picornavirus 3C protease inhibitor is lupinquvir or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein The first antiviral agent and the second antiviral agent are provided in separate fixed solid oral dosage forms.

4. The pharmaceutical composition according to claim 3, wherein The solid oral dosage form is a tablet.

5. The pharmaceutical composition according to claim 3, wherein The first antiviral agent is present in the first solid oral dosage form in an amount of about 100 mg to about 1500 mg, and the second antiviral agent is present in the second solid oral dosage form in an amount of about 100 mg to about 1000 mg.

6. The pharmaceutical composition according to claim 3, wherein The first antiviral agent is present in the first solid oral dosage form in an amount of about 150 mg to about 300 mg, and the second antiviral agent is present in the second solid oral dosage form in an amount of about 100 mg.

7. A kit for treating COVID-19, comprising: Multiple solid oral dosage forms of a first antiviral agent, wherein the first antiviral agent consists of a picornavirus 3C protease inhibitor; multiple solid oral dosage forms of a second antiviral agent, wherein the second antiviral agent has a different mechanism of action and consists of ritonavir or a pharmaceutically acceptable salt thereof; and at least one additional antiviral agent selected from dexamethasone and remdesivir.

8. The kit according to claim 7, wherein The picornavirus 3C protease inhibitor is lupinquvir or a pharmaceutically acceptable salt thereof.

9. The kit according to claim 7, wherein The solid oral dosage form is administered twice every 24 hours.

10. The kit according to claim 7, wherein The solid oral dosage form is administered at intervals of 5 to 10 days.

11. The kit according to claim 7, wherein The solid oral dosage form is provided in the form of a blister pack.

12. A method for treating COVID-19, comprising administering to a patient: a therapeutically effective amount of a first antiviral agent, wherein the first antiviral agent consists of a picornavirus 3C protease inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second antiviral agent, wherein the second antiviral agent has a different mechanism of action and consists of ritonavir or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12, wherein: The picornavirus 3C protease inhibitor is lupinquvir or a pharmaceutically acceptable salt thereof.

14. The method of claim 12, further comprising the administration of one or more additional antiviral drugs selected from the group consisting of phosphatidylserine modulators, entry inhibitors, protease inhibitors, RNA-dependent RNA polymerase inhibitors, and endosomal acidification agents.

15. The method according to claim 14, wherein The one or more additional antiviral agents include dexamethasone.

16. The method according to claim 14, wherein The one or more additional antiviral agents include remdesivir.

17. The method according to claim 12, wherein: The first and second antiviral agents are administered orally in combination to the patient.

18. The method according to claim 17, wherein About 100 mg to about 1500 mg of the first antiviral agent and about 100 mg to about 1000 mg of the second antiviral agent are administered orally to the patient in combination.

19. The method according to claim 17, wherein About 150 mg to about 300 mg of the first antiviral agent and about 100 mg of the second antiviral agent are co-administered orally to the patient twice daily.

20. The method according to claim 19, wherein The first antiviral agent and the second antiviral agent are orally administered to the patient in combination at intervals of 5 to 10 days.

Images