Anti-viral compounds

Abstract

To provide compositions and kits of antiviral agents having different mechanisms of action for treating or preventing viral infections such as COVID-19 (also known as SARS-CoV-2) and for reducing medical complications related to COVID-19 viral disease.SOLUTION: A pharmaceutical composition for treating COVID-19 is provided, comprising: a first antiviral agent consisting of a picornavirus 3C protease inhibitor or a pharmaceutically acceptable salt thereof in a therapeutically effective amount; a second antiviral agent consisting of ritonavir or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and having a different mechanism of action; and a third antiviral agent selected from a group consisting of dexamethasone and remdesivir.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] The anti-COVID-19 compounds of the present invention combine a core comprising compounds with specific antiviral mechanisms of action with other specific antiviral agents with different mechanisms of action. This core includes, but is not limited to, five major classes of antiviral agents: 1) phosphatidylserine (PS) modulators, which are cortisol and androgen receptor modulators (GCRM / ARMs); 2) attachment inhibitors (EIs), which are angiotensin-converting enzyme 2 (ACE-2) receptor blockers that act as ACE-2 attachment inhibitors (AEIs) and fusion inhibitors (FIs); 3) protease inhibitors (PIs); 4) RNA-dependent RNA polymerase inhibitors (RdRpIs), some of which act as endosomal acidifiers (EAs) to inhibit replicases and replicase complexes, such as NTPase / RNA helicase; and 5) microRNA inhibitors (MRIs). Background of the Invention

[0003] Rapid advances in all kinds of technology, travel, and globalization have had a profound impact on improving human life both in the United States and internationally. However, these advances have proven to be a double-edged sword, facilitating the spread, whether accidental or intentional, of invasive disease-causing pathogens. The U.S. government has been proactive in enacting and funding medical preparedness efforts to respond to potential public health emergencies caused by invading pathogens. Key among these are the Project Bioshield Act of 2004 and the Pandemic and All Disasters Preparedness Act of 2006, the latter supported by the Biomedical Advanced Research and Development Authority (BARDA).

[0004] The National Institute of Allergy and Infectious Diseases (NIAID), an agency of the National Institutes of Health (NIH), has prepared a list of emerging infectious diseases and pathogens for prioritization and research guidance. Pathogens are prioritized from A to C based on characteristics such as infectivity, morbidity, mortality, and diagnosability. The COVID-19 pandemic first emerged in Wuhan, Hubei Province, People's Republic of China, and subsequently spread to cities in China, South Korea, Taiwan, Japan, South Korea, and Taiwan. Because COVID-19 originated in Wuhan, Hubei Province, People's Republic of China and spread globally, medical countermeasures (MCMs) were listed as the highest priority. This prioritization of MCMs led to the identification of antiviral activity against COVID-19. Research was then conducted on a series of repurposed compounds with five mechanisms of action that could potentially serve as MCMs.

[0005] With the evolution of antiviral therapy for human immunodeficiency virus (HIV), current drug therapies consist almost entirely of drugs and regimens that target HIV viral replication and other processes. As a result, single approaches are often ineffective as monotherapy, and HIV viruses are known to rapidly develop resistance. Similarly, multi-mechanism treatments for the COVID-19 virus are expected to be more effective when drugs with different mechanisms of action are combined or combined into a single drug combination. The present invention describes these combination therapies, their use, and therapeutic methods, as well as novel dosing and delivery methods specifically tailored for the treatment of COVID-19. The present invention also includes novel pulmonary and oral delivery systems containing fixed-dose combinations of anti-COVID-19 drugs. These drugs dissociate into their original components as metabolites after administration, enabling more efficient administration and, in the case of pulmonary delivery, allowing for more direct delivery to the site of infection in the lungs.

[0006] Below, we discuss five major classes of compounds with antiviral mechanisms—steroid glucocorticoid receptor modulators, androgen receptor modulators, EIs, PIs, RdRpIs, and MRIs—using the example compounds dexamethasone, valsartan, rupintrivir, remdesivir, the ribose alcohol active metabolite GS-441524, and hydroxychloroquine, and explain why their levels of activity as antivirals against RNA viruses make them a priority for clinical trials to reduce the duration and severity of COVID-19 infection, reduce the incidence and mortality associated with COVID-19 infection, and reduce pneumonia caused by COVID-19 infection.

[0007] Dexamethasone is a drug being repurposed for COVID-19 and is a commercially available drug being utilized in human clinical trial populations. Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs, with pleiotropic effects on multiple signaling pathways. Its biological target is the glucocorticoid receptor. Dexamethasone's anti-inflammatory and immunosuppressive effects are approximately 30 times stronger than those of cortisol. Its anti-inflammatory effects are complex and primarily mediated by the suppression of inflammatory cells and the downregulation of inflammatory mediators. Steroid molecules exert their effects by diffusing across the cell membrane and binding to the glucocorticoid receptor, causing a conformational change in the receptor. The receptor-glucocorticoid complex then translocates to the cell nucleus, where it can dimerize and bind to the glucocorticoid response element.

[0008] The anti-inflammatory effects of dexamethasone are complex, but are primarily due to the suppression of inflammatory cells and the expression of inflammatory mediators. Dexamethasone is formulated for intravenous and oral administration and is used to treat inflammatory and immune-mediated diseases. In the present invention, dexamethasone formulations are delivered in free base gas form or ultrafine particles directly to the respiratory tract, including the nose, throat, and lung tissue, via inhalation from a portable medical vaporizer such as a vape pen or e-cigarette. During inhalation, dexamethasone is used in combination with antiviral agents such as remdesivir or its ribose alcohol active metabolite, GS-441524. Like other steroid compounds, dexamethasone is a cortisol, glucocorticoid, and androgen modulator (GCRM / ARM).

[0009] Second, these molecules bind to phosphatidylserine (PS), which is present in the envelopes of all enveloped viruses. Third, their signaling effects in the immune system regulate appropriate responses to viral pathogens, promoting immune responses without excessively damaging tissues.

[0010] The mechanism of action of GRE binding is as follows: Viruses that infect animals and humans infect cells by depositing their genetic material in the cytoplasm or nucleoplasm of the infected cell. "Response elements" within the genome, consisting of coding or non-coding regions, respond to molecular signaling in the host cell and to other elements in the virus's own molecular network. Viruses often possess GREs, or response elements, that are subject to glucocorticoid signaling mediated by the binding of cortisol (or other glucocorticoids) to the glucocorticoid receptor (GCR).

[0011] Viruses known to have GREs include COVID-19, MERS, SARS, herpesvirus-7 (HHV-7), Kaposi's sarcoma-associated herpesvirus (or HHV-8), smallpox virus, vaccinia virus, cowpox virus, and monkeypox.

[0012] Dexamethasone binds as a GCR and androgen receptor (AR) modulator, directly or indirectly inhibiting basic viral functions (gene replication, production of virus-associated proteins, assembly of genetic material and viral proteins into complete viruses, increasing genetic diversity, promoting active and passive viral release from cells, viral infectivity, etc.), while also appropriately treating viral GREs.

[0013] The mechanism of antiviral activity related to PS binding is as follows. PS is normally sequestered in the inner leaflet of the plasma membrane bilayer. However, during apoptosis, the mechanism that normally maintains PS in the inner leaflet is inhibited, causing PS to appear on the cell surface. Exposure of PS sends a recognition signal to phagocytes that remove dying cells. Various scavenger receptors, including CD36, CD14, and PS receptor (PSR), are known to be involved as macrophage receptors that recognize PS on apoptotic cells. This indicates that PS functions as a ligand for various PS-binding receptors through cell-cell interactions.

[0014] Enveloped viruses expose PS on the lipid bilayer membrane of host cells, which allows them to evade attack by the human immune system and penetrate phagocytes such as monocytes and macrophages. Therefore, the appearance of PS on the viral membrane is highly unlikely to be a factor in virus-target cell fusion.

[0015] Valsartan is an antiviral entry inhibitor (EI) and a commercially available drug that is readily available for human clinical trials for COVID-19. Valsartan is a compound approved as an antihypertensive agent and a type of angiotensin receptor blocker (ARB). ARBs block the angiotensin-2-converting enzyme (ACE-2) receptor, which plays a physiological role in regulating blood pressure. This ACE-2 receptor is also a ligand expressed on the surface of human lung cells and binds to the COVID-19 virus spike protein (SP), initiating the infection process, including cell attachment, membrane integration, and viral RNA insertion. By blocking access to the ACE-2 receptor expressed on human lung cells, valsartan and other ARBs act as attachment entry inhibitors (AEIs) and fusion inhibitors (FIs), inhibiting the binding of the COVID-19 spike protein to lung epithelial cells and causing a conformational change in the SP, enabling membrane fusion and viral RNA insertion.

[0016] Oral administration of valsartan, a representative ARB, is thought to be of limited utility when used as a treatment for COVID-19 because its systemic effects on blood pressure are dose-related.

[0017] Rupintrivir is an antiviral protease inhibitor (PI) that is readily available for human clinical trials for COVID-19. Rupintrivir was originally developed by Pfizer as an antiviral drug for the common cold caused by picornavirus infections. It belongs to a class of 3C protease drugs designed to inhibit proteases that cleave the polyproteins of RNA viruses. While the RNA gene sequence targeted by picornavirus proteases differs from the cleavage site of the COVID-19 coronavirus protease, the activity inhibited is "3C-like" (3CL). The proteases are sufficiently similar that they can be blocked or inhibited more efficiently in combination with other related protease inhibitors, such as HIV protease inhibitors such as ritonovir. This is likely due to enhanced stearic inhibition or the inhibitory effect of Hepatitis C proteinases on other proteinases involved in COVID-19 infection, including the cathepsin L-dependent viral glycoprotein involved in activation via SARS-CoV S-protein cleavage at the S1 / S2 boundary under low pH conditions, and the involvement of transmembrane proteinase serine 2 (TMPRSS2) active in inducing trimeric S-protein cleavage (Simmons et al., 2005; Millet and Whittaker, 2015).

[0018] Ritonovir is a commercially available anti-HIV drug that has been repurposed as an antiviral protease inhibitor (PI) and is readily available for human clinical trials for COVID-19. HIV PIs, such as ritonovir and atazanovir, were originally developed as HIV protease drugs and are designed to inhibit the proteases that cleave polyproteins. Because HIV and coronavirus proteases are functionally similar and the activity inhibited is "3C-like" (3CL), they can be blocked or inhibited in the same way. Furthermore, combining them with other related protease inhibitors, such as the picornavirus PI, lupintrivia, may enhance stearic inhibition and potentially lead to more efficient inhibition.

[0019] Myricetin is a commercially available supplement and is readily available for human clinical trials for COVID-19. Myricetin is an RNA-dependent RNA polymerase inhibitor (RdRpI) that inhibits the COVID-19 replicase / replicase complex. Specifically, it inhibits NTPase / RNA helicase, which unwinds highly base-paired regions of the RNA genome and provides energy for the polymerization process. Myricetin is a common plant-derived flavonoid well known for its value as a dietary supplement. It is also a key ingredient in various foods and beverages. Myricetin also affects the biochemical potency and binding capacity of large intracellular biomolecules. Furthermore, myricetin has been shown to inhibit intracellular RNA polymerase. Myricetin (CID 5281672) also inhibits the closely related SARS-CoV helicase with an IC50 value of 2.7 μM and an acceptable selectivity index.

[0020] Rifampin is a commercially available drug that is readily available for human clinical trials for COVID-19. Rifampin is an RNA-dependent RNA polymerase inhibitor (RdRpI) that interferes with COVID-19 replication enzymes and replication enzyme complexes. Like myricetin, it inhibits NTPase / RNA helicase, which unwinds highly base-paired regions of the RNA genome and provides energy for the polymerization process. Rifampin, also known as rifampicin, is used to treat several bacterial infections and is the prototype of this class of antibiotics. Crystal structure and biochemical data suggest that rifampicin binds to a pocket in the RNA polymerase β subunit. Rifampin acts as an inhibitor, physically blocking growth and inhibiting RNA synthesis, thereby preventing the synthesis of host bacterial proteins. This "steric blockade" prevents the synthesis of second or third phosphodiester bonds between nucleotides in the RNA backbone, preventing the 5' end of the RNA transcript from advancing more than two or three bases. Thus, rifampin binds to RNA polymerase at a site adjacent to the active center of the RNA polymerase, inhibiting RNA synthesis by physically blocking the formation of phosphodiester bonds in the RNA backbone, preventing the RNA product from exceeding a length of 2–3 nucleotides. Therefore, rifampin has been shown to inhibit intracellular RNA polymerase.

[0021] Remdesivir (GS-5734), a repurposed clinical-stage anti-Ebola RdRpI drug, may soon be available for human clinical trial populations as an inhaled delivery system and combination therapy with other antivirals for COVID-19. Remdesivir has been reported to inhibit SARS-CoV and MERS-CoV replication with submicromolar EC50 values ​​in multiple in vitro systems, including primary human airway epithelial cells (Sheahan et al., 2017). Experimental evaluation of GS-5734 in a mouse model of SARS-CoV infection demonstrated that its prophylactic and early therapeutic administration reduced lung viral load and improved respiratory function along with other clinical symptoms. Similarly, it has shown antiviral activity in in-vitro models of SARS-CoV-2 and has been evaluated in clinical trials for COVID-19 in the United States and elsewhere, where it has been approved first by Emergency Use Authorization (EUA) and then by New Drug Application (NDA) for intravenous administration in hospital settings for patients with moderate to severe COVID-19.

[0022] Hydroxychloroquine is a repurposed, over-the-counter drug that could soon be available for human clinical trial populations for COVID-19. Its respiratory delivery format, delivered via e-cigarette or vape pen, maximizes local concentrations in the nose, throat, and lung tissue while minimizing systemic concentrations that could accumulate in cardiac tissue and adversely affect heart rate. Hydroxychloroquine is an aminoquinoline antimalarial drug developed as a derivative of the pharmaceutical quinine, and is a microRNA inhibitor (MRI) and endosomal acidifier (EA). Hydroxychloroquine has demonstrated efficacy in inhibiting coronavirus replication in vitro and has anecdotal evidence of clinical utility in vivo in humans. MicroRNAs (miRNAs) are small, non-coding RNA molecules (containing approximately 22 bases) present in plants, animals, and some viruses, including SARS-CoV-2, that function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs function by base-pairing with complementary sequences within mRNA molecules. As a result, these mRNA molecules are silenced by one or more of the following processes: (1) cleavage of the mRNA strand in two, (2) destabilization due to shortening of the poly(A) tail, and (3) reduced efficiency of translation into protein by ribosomes. miRNAs are similar to small interfering RNAs (siRNAs) in the RNA interference pathway, but miRNAs are derived from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs are derived from long regions of double-stranded RNA. More than 1,900 miRNAs are estimated to be encoded in the human genome. Quinine and other miRNAs lack alkaloids like hydroxychloroquine and inhibit the formation and metabolic activity of miRNAs, which are essential for COVID-19 viral replication. Summary of the Invention [Means for solving the problem]

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

[0024] The present invention also relates to pulmonary administration of valsartan, including but not limited to, other drugs in the ARB class, administered by respiratory administration, including but not limited to, inhalers, nebulizers, and e-vapes.

[0025] The present invention also relates to the use of ARBs (e.g., valsartan) as EIs in combination with at least one other drug with a different COVID-19 antiviral mechanism for treating or preventing COVID-19 infectious disease and its complications. These ARBs can be delivered both orally and respiratoryly.

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

[0027] The present invention also relates to picornavirus 3C or 3C-like (3CL) PIs, such as rupintrivir, and the use of at least one other agent with a different COVID-19 antiviral mechanism, including PIs or drugs with activity against cathepsin L-dependent viral glycoproteins and / or transmembrane protease serine 2 (TMPRSS2), to treat or prevent COVID-19 infection and its complications. These PIs can be delivered in both oral and respiratory forms, optionally in combination with one or more complementary antivirals from the five classes listed above.

[0028] The present invention also relates to the use of flavonoids, exemplified by myricetin, as RdRpIs that interfere with the replicase complex to treat or prevent COVID-19 infection and its complications, optionally in combination with at least one other drug having a different COVID-19 antiviral mechanism than another RdRpI, such as rifampin, which can be delivered in both oral and respiratory forms.

[0029] The present invention also relates to antibiotics of the rifampicin class, exemplified by rifampin, for use as RdRpIs that interfere with the replicase complex to treat or prevent COVID-19 infection and its complications, optionally in combination with another RdRpI, such as myricetin, and at least one other agent with a different COVID-19 antiviral mechanism. These RdRpIs can be delivered either orally or through the respiratory system.

[0030] The present invention also relates to the use of remdesivir and its active ribose alcohol metabolite, optionally in combination with one or more RdRpIs, such as myricetin and / or rifampin, as RdRpIs that interfere with the replicase complex, and to the treatment or prevention of COVID-19 infection and its complications with at least one other drug having a different COVID-19 antiviral mechanism, such as dexamethasone or hydroxychloroquine (racemic mixture or purified enantiomers thereof). These RdRpIs can be administered either orally or via the respiratory route.

[0031] The present invention also relates to the use of hydroxychloroquine and related aminoquinolines and aryl-amino alcohols as MRIs and EAs that disrupt miRNA formation, which inhibit viral replication, to treat or prevent COVID-19 infection and its complications, and further relates to the use in combination with at least one other agent with a different COVID-19 antiviral mechanism. These MRIs can be delivered in both oral and respiratory forms.

[0032] In one embodiment, the present invention relates to a pulmonary delivery system that utilizes two, three, or more drugs joined via a chemical linkage or linker, one end of which is covalently attached to one drug compound on a suitable attachment chemical group and the other end of which is covalently attached to another drug compound, also on a suitable attachment group. These drugs form new chemical entity (NCE) bioconjugates that can be pyrolytically cleaved by heat in a medical vaporizer, including portable medical vaporizers such as e-cigarettes and vapes. Thus, new chemical entity (NCE) drug conjugates can be pyrolyzed in a medical vaporizer, including portable medical vaporizers such as e-cigarettes and vape pens, to present patients with an inhaled drug that is a combination of compounds characterized in gas or other settings that are introduced to the patient in ultrafine particle aerosol form. In one embodiment, an appropriate therapeutic dose level of the NCE is loaded into an e-cigarette with a replaceable cartridge or into the cartridge of a single-use e-cigarette. When a temperature-setting e-cigarette is activated, heat generated within the e-cigarette, between 380 and 480 degrees Fahrenheit, is sufficient to break the chemical linkage or bond on the linker to the attached therapeutic compound. This results in an inhaled drug vapor gas aerosol or ultrafine particle aerosol containing the therapeutic agent, which is released for inhalation into the human or animal patient. The chemical bond between the antiviral agent may consist of one or more carbonate or carbamate groups.

[0033] In one embodiment, the present invention involves pulmonary delivery of drugs comprising one or more entry inhibitors (EIs) paired with one or more RNA-dependent RNA polymerase inhibitors (RdRpIs), including, but not limited to, the combination of valsartan and rifampin, valsartan and myricetin, valsartan and remdesivir, or valsartan and remdesivir's ribose alcohol active metabolite GS-441524. The combination of valsartan and rifampin can be administered via vaporization via a nebulizer device containing a therapeutically appropriate dose in powder or paste form, or via an electronic cigarette in which the valsartan and rifampin compounds are covalently linked via a chemical linker to form the novel chemical entity, compound BB-700. Valsartan and rifampin form two major functional components that dissociate into metabolites consisting of valsartan and rifampin base compounds due to the heat of vaporization from the electronic cigarette, and the compound delivered in vapor form to lung cells is intended to be the valsartan and rifampin components. Valsartan and myricetin may be administered in a therapeutically appropriate dose in powder or paste form via a nebulizer device, or by vaporization via an electronic cigarette, in which the valsartan and myricetin compounds are covalently linked via a chemical linker to form the base compound and a novel chemical entity, BB-701. Valsartan and rifampin form two major functional components that dissociate into metabolites consisting of valsartan and rifampin base compounds due to the heat of vaporization from the electronic cigarette, and the compounds delivered to lung cells in vapor form are the valsartan and myricetin components. In another embodiment, valsartan and remdesivir can be administered in a therapeutically appropriate dose in powder or paste form via a nebulizer device or by vaporization via an electronic cigarette, in which the valsartan and remdesivir compounds are covalently linked via a chemical bond or linker to form the base compound and a novel chemical entity, BB-702 or BB-702B of valsartan and GS-441524, the ribose alcohol active metabolite of remdesivir.The heat that results in vaporization in an e-cigarette causes valsartan and remdesivir (or their ribose alcohol active metabolites) to dissociate into metabolites, including the base compounds of valsartan and remdesivir (or their ribose alcohol active metabolites), forming two major functional components, such that the compounds delivered in vapor form to lung cells are the components of valsartan and remdesivir (or their ribose alcohol active metabolites).

[0034] In one embodiment, the present invention involves pulmonary delivery of a drug having one or more entry inhibitors (EIs) paired with one or more protease inhibitors, including, but not limited to, the combination of valsartan and rupintrivir. The combination of valsartan and rupintrivir can be administered via a nebulizer device containing a therapeutically appropriate amount in powder or paste form, or via vaporization through an electronic cigarette. Here, the valsartan and rupintrivir compounds are covalently linked via a chemical linker to form the novel chemical entity BB-703, and the base compounds valsartan and rupintrivir dissociate into metabolites consisting of the valsartan and rupintrivir base compounds upon heat generation in an electronic cigarette, forming two major functional components that are delivered in vapor form to lung cells.

[0035] In one embodiment, the present invention involves pulmonary delivery of drugs with one or more entry inhibitors (EIs) paired with one or more MRIs, including, but not limited to, the combination of valsartan and hydroxychloroquine. The combination of valsartan and hydroxychloroquine can be administered via a nebulizer device loaded with a therapeutically appropriate amount in powder or paste form, or via vaporization through an electronic cigarette in which the valsartan and hydroxychloroquine compounds are covalently linked via a chemical linker to form a base compound and a new chemical entity, BB-704. The valsartan and hydroxychloroquine compounds form two major functional components that dissociate into metabolites consisting of the valsartan and hydroxychloroquine compounds due to the heat of vaporization from the electronic cigarette. The compounds delivered in vapor form to lung cells will be the valsartan and hydroxychloroquine components.

[0036] In one embodiment, the present invention involves pulmonary delivery of one or more RdRpIs, including, but not limited to, a combination of rifampin and myricetin. The combination of rifampin and myricetin can be administered via a nebulizer device loaded with a therapeutically appropriate amount in powder or paste form, or via vapor administration through an electronic cigarette in which the rifampin and myricetin compounds are covalently linked via a chemical linker to form the base compound and the novel chemical entity BB-705. The heat of vaporization from the electronic cigarette causes the rifampin and myricetin to form two primary functional components that dissociate into metabolites consisting of the base compounds of rifampin and myricetin, and the compound delivered in vapor form to lung cells is the original rifampin and myricetin components.

[0037] In certain embodiments, the present invention provides pulmonary administration of a combination of rifampin and hydroxychloroquine, a combination of myricetin and hydroxychloroquine, or a combination of remdesivir and hydroxychloroquine, a combination of GS-441524, the ribose alcohol active metabolite of remdesivir, and hydroxychloroquine, or one or more RNA-dependent RNA polymerase inhibitors (RdRpIs) and one or more MRI inhibitors. The rifampin and hydroxychloroquine combination can be administered via a nebulizer device containing a therapeutically appropriate powder or paste, or via vapor administration through an electronic cigarette in which the rifampin and hydroxychloroquine compounds are covalently linked via a chemical linker to form a new chemical entity, BB-706, with the base compound. The rifampin and hydroxychloroquine compounds form two major functional components that dissociate into metabolites, consisting of the rifampin and hydroxychloroquine compounds, due to the heat of vaporization from the electronic cigarette. The rifampin and hydroxychloroquine components are then delivered in vapor form to lung cells. Alternatively, myricetin and hydroxychloroquine can be administered in a therapeutically appropriate dose in powder or paste form via a nebulizer device, or via vaporization through an electronic cigarette, in which the myricetin and hydroxychloroquine compounds are covalently linked via a chemical linker to form the base compound and a new chemical entity, BB-707. Myricetin and hydroxychloroquine form two key functional components that dissociate into metabolites consisting of the base compound myricetin and hydroxychloroquine due to the heat of vaporization from the electronic cigarette, and the compound delivered to lung cells in vapor form is the myricetin and hydroxychloroquine components. In another embodiment, remdesivir, or its ribose alcohol active metabolite GS-441524, or hydroxychloroquine, can be administered in a therapeutically appropriate dose in powder or paste form via a nebulizer device, or via gas or ultrafine particle aerosol from an electronic cigarette (vape pen or medical vaporizer).Here, remdesivir (or its ribose alcohol active metabolite GS-441524) and hydroxychloroquine compounds are covalently linked via a chemical linkage or linker to form a novel chemical entity. Also, BB-708 (BB-708B when combined with remdesivir's ribose alcohol active metabolite GS-441524) forms a novel chemical entity, along with the base compound remdesivir (or its ribose alcohol active metabolite GS-441524) and hydroxychloroquine (either its racemic mixture or purified R- or S-enantiomers). The heat of vaporization from an e-cigarette dissociates the two main functional components into metabolites consisting of remdesivir (or its ribose alcohol active metabolite GS-441524) and hydroxychloroquine, resulting in a compound delivered in vapor form to lung cells.

[0038] In one embodiment, the present invention involves the pulmonary administration of one or more PIs, including, but not limited to, one or more RNA-dependent RNA polymerase inhibitors (RdRpIs) and the combination of rifampin and ritonavir. The rifampin and ritonavir combination can be administered in a therapeutically appropriate amount via a nebulizer device loaded with a powder or paste, or via vapor administration via an electronic cigarette in which the rifampin and ritonavir compounds are covalently linked via a chemical linker to form the base compound and the novel chemical entity BB-709. The rifampin and ritonavir form two major functional components that dissociate into metabolites consisting of the base compound rifampin and ritonavir due to the heat of vaporization from the electronic cigarette, and the compound delivered in vapor form to lung cells is the rifampin and ritonavir components.

[0039] In one embodiment, the present invention relates to pulmonary delivery of one or more RNA-dependent RNA polymerase inhibitors (RdRpIs) and one or more glucocorticoid steroids or glucocorticoid receptor or androgen receptor modulators, including but not limited to, combination therapy with remdesivir (or its ribose alcohol active metabolite GS-441524) plus dexamethasone. The combination of remdesivir (or remdesivir's ribose alcohol active metabolite GS-441524) and dexamethasone can be administered via a nebulizer device loaded with a therapeutically appropriate dose in powder or paste form, or via vapor administration via an e-cigarette in which the remdesivir (or remdesivir's ribose alcohol active metabolite GS-441524) and dexamethasone compounds are covalently linked via a chemical bond or linker to form new chemical entities, BB-710 (for remdesivir-containing compounds) and BB-710B (for remdesivir's ribose alcohol active metabolite GS-441524-containing compounds). The formulation is based on remdesivir (or its ribose alcohol active metabolite GS-441524) and dexamethasone, which comprise two key functional components that are broken down into metabolites consisting of remdesivir (or its ribose alcohol active metabolite GS-441524) and dexamethasone by the heat provided by vaporization in an e-cigarette or medical vaporizer. The compound, delivered in vapor form to lung cells as ultrafine particles in a gas or aerosol, becomes the remdesivir (or its ribose alcohol active metabolite GS-441524) and dexamethasone components.

[0040] In one embodiment, the present invention includes pulmonary delivery of one or more PIs and / or MRIs, including, but not limited to, the combination of rupintrivir and hydroxychloroquine. This combination can be administered via a nebulizer device containing a therapeutically appropriate dose in powder or paste form, or via e-cigarette vapor. In this e-cigarette, rupintrivir and hydroxychloroquine compounds are covalently linked via a linker to form the new chemical compound BB-711. This forms the two main functional components, rupintrivir and hydroxychloroquine base compounds, which dissociate into metabolites, and are vaporized via heat in the e-cigarette. This results in the compound being delivered to the lungs via vaporization: rupintrivir and hydroxychloroquine.

[0041] In some embodiments, the combination includes one or more glucocorticoid steroids or glucocorticoid receptor or androgen receptor modulators (GRSM / ARM) and one or more RNA-dependent RNA polymerase inhibitors (RdRpI). This includes, but is not limited to, the combination of mifepristone and rifampin. This combination can be administered as an oral solid or oral liquid suspension dosage form, or as a fixed-dose oral solid or oral liquid suspension dosage form in which the mifepristone and rifampin compounds are covalently linked via a chemical linker to form the base compound and the novel chemical entity BB-712. Mifepristone and rifampin form two major functional components that dissociate into metabolites consisting of the mifepristone and rifampin base compounds at gastric pH, which dissociate the base compound from the linker to form the mifepristone and rifampin components in the stomach when the stomach is acidic enough for absorption.

[0042] In one embodiment, the present invention involves oral delivery of one or more PSIs and at least two PIs, including, but not limited to, the combination of lilacorilant, rupintrivir, and ritonavir. This combination can be administered in an oral solid or oral liquid suspension dosage form. It can also be administered in a fixed-dose oral solid or oral liquid suspension dosage form, in which the lilacorilant, rupintrivir, and ritonavir compounds are covalently linked via a chemical linker to form a base compound and a new chemical entity, BB-713. Lilacorilant, rupintrivir, and ritonavir form three primary functional components that facilitate gastric absorption by dissociating the basic compounds from the linker at gastric pH and into metabolites with sufficient acidity to yield the lilacorilant, rupintrivir, and ritonavir components.

[0043] In one embodiment, the present invention includes oral delivery of one or more PSIs or MRIs, including, but not limited to, a combination of mylicholant and hydroxychloroquine. This combination can be administered in an oral solid or oral liquid suspension dosage form, or in a fixed-dose formulation in which the mylicholant and hydroxychloroquine compounds are covalently linked via a chemical linker to form a base compound and a new chemical entity, BB-714. Mylicholant and hydroxychloroquine form the two primary functional components, and gastric pH dissociates the base compound from the linker, resulting in metabolites consisting of mylicholant and hydroxychloroquine at gastric pHs acidic enough for absorption of the components.

[0044] In one embodiment, the present invention involves oral delivery of at least two PIs, including, but not limited to, rupintrivir + ritonavir and rupintrivir + ritonavir + lopinavir. These combinations can be administered in oral solid or oral liquid suspension or fixed-dose oral solid or liquid suspension formulations, in which the rupintrivir and ritonavir compounds are covalently linked via a chemical linker to form the new chemical compound BB-715. The base compounds, rupintrivir and ritonavir, form two major functional components that dissociate into metabolites consisting of the rupintrivir and ritonavir base compounds at gastric pH. The base compounds are acidic enough to separate from the linker and allow gastric absorption of the rupintrivir and ritonavir components. The addition of ritonavir to oral lopinavir for HIV treatment can block enzymes in the cytochrome P450 system, expanding the drug options available for human drug administration at effective antiviral levels against HIV. To achieve higher drug exposure in COVID-19 patients, the combination of rupintrivir, ritonavir, and lopinavir can be administered in oral solid or oral liquid suspension dosage forms, or in fixed-dose oral solid or oral liquid suspension dosage forms. Here, the fixed-dose rupintrivir, ritonavir, and lopinavir compounds are covalently linked via a chemical linker, forming the new chemical entity BB-716, which uses the base compounds rupintrivir, ritonavir, and lopinavir to form three main functional components that dissociate into metabolites: rupintrivir, ritonavir, and lopinavir. Furthermore, the compound has sufficient acidity to separate the base compounds from the linker, allowing the rupintrivir, ritonavir, and lopinavir components to be absorbed in the stomach.

[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), which also modulate phosphatidylserine (PS), such as, for example: Dexamethasone: [ka] or a pharmaceutically acceptable salt thereof, and Mifepristone: [ka] or a pharmaceutically acceptable salt thereof, and Relacorilant: [ka] or a pharmaceutically acceptable salt thereof, and Milicolant: [ka] or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0046] In one embodiment, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of at least one active agent selected from the group consisting of entry inhibitors (EIs), including angiotensin-converting enzyme-2 (ACE-2) receptor blockers that act as ACE-2 attachment entry inhibitors (AEIs) or fusion inhibitors (FIs), as exemplified below. Examples include angiotensin receptor blockers (ARBs), including, for example: Valsartan: [ka] 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, optionally selected from the group consisting of protease inhibitors (PIs), exemplified by: Rupintri Building: [ka] or a pharmaceutically acceptable salt thereof, and Ritonavir: [ka] 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, which may be selected from the group consisting of RNA-dependent RNA polymerase inhibitors (RdRpIs), which inhibit replicases and their complexes, including NTPase / RNA-helicase, such as: Myricetin: [ka] or a pharmaceutically acceptable salt thereof, and Rifampin: [ka] or a pharmaceutically acceptable salt thereof, and Remdesivir: [ka] or a pharmaceutically acceptable salt thereof, and Remdesivir's ribose alcohol active metabolite GS-441524: [ka] or pharmaceutically acceptable salts thereof, and combinations thereof

[0049] In certain embodiments, 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 a microRNA inhibitor (MRI) and an endosomal acidifying agent (EA), exemplified by: Hydroxychloroquine: [ka] or a pharmaceutically acceptable salt thereof

[0050] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of BB-708 (also known as plachemdesivir). [ka] or a pharmaceutically acceptable salt thereof

[0051] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of BB-708B (also known as riboplachemdesivir). [ka] or a pharmaceutically acceptable salt thereof

[0052] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of remdesivir and a drug conjugate of the free base of the ribose alcohol active metabolite of dexamethasone, which is coupled with a carbamate to form a new chemical entity, BB-710B, also known as dexadecivir. [ka] or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present invention provides a method for suspending hydroxychloroquine (100 mg, 1.0 equivalent, MW 335.88) in 2 mL of DCM and 2 mL of DMF, followed by the addition of BB-708, riboplachemdesivir, 1.2 equivalents of CDI (carbonyldiimidazole), and 5.0 equivalents of TEA. The reaction is then stirred at 45°C for 2.5 hours. The ribose alcohol active metabolite of remdesivir (GS-441524) is then added, and the reaction is heated to 55°C and stirred for 1 hour. The product from this reaction has a molecular weight of 964.45.

[0054] In one embodiment, the present invention provides a method for suspending hydroxychloroquine (100 mg, 1.0 equivalent, MW 335.88) in 2 mL of DCM and 2 mL of DMF, followed by the addition of BB-708B, riboplachemdesivir, 1.2 equivalents of CDI (carbonyldiimidazole), and 5.0 equivalents of TEA. The reaction is then stirred at 45°C for 2.5 hours. The ribose alcohol active metabolite of remdesivir (GS-441524) is then added, and the reaction is heated to 55°C and stirred for 1 hour. The molecular weight of the product from this reaction is 653.14.

[0055] In one embodiment, the present invention is a pharmaceutical composition selected from the group consisting of minicapsules, capsules, tablets, implants, troches, lozenges, minitablets, temporary or permanent suspensions, injectables, ovules, suppositories, wafers, chewable tablets, fast or rapid dissolving tablets, effervescent tablets, buccal or sublingual tablets, granules, films, sprinkles, pellets, topicals, patches, beads, pills, powders, triturates, smart pills, smart capsules, platelets, strips, sachets, and the like.

[0056] In some embodiments, the present invention provides a pharmaceutical composition in a respiratory dosage form, optionally including at least one pharmaceutically acceptable excipient, such as vegetable glycerin (VG) or propylene glycol (PG). In these embodiments, the dosage form is selected from the group consisting of sprays, inhalers, aerosols, vapors, electronic cigarettes (vaping cigarettes), electronic cigarettes with cartridges that store the drug to be vaporized, disposable electronic cigarettes, medical vaporizers, temperature-varying heating, paste or powder nebulizer preparations, etc. A delivery system may be any device capable of delivering a predetermined dose of a drug in a dosing regimen.

[0057] In another embodiment, the present invention provides a kit for use in treating or preventing a patient, comprising: (a) a therapeutically effective amount of a pharmaceutical composition; and (b) at least one blister package, blister with lid, blister card or packet, clamshell, intravenous (IV) package, IV packet, IV container, tray or shrink wrap containing instructions for use of the pharmaceutical composition.

[0058] In one embodiment, the present invention provides a method for treating or preventing COVID-19 infection in a patient, comprising: first selecting a patient in need of treatment or prevention; and then administering to the patient at least one active agent selected from the group consisting of dexamethasone, mifepristone, relacolinant, milicolinant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the active metabolite GS-441524 of remdesivir, hydroxychloroquine, and pharmaceutically acceptable salts thereof, with the goal of eliminating rapid spread of infection, reducing the severity of infection, shortening the duration of infection, preventing infection, and shortening the time to cure, while also reducing the infectivity of COVID-19 and increasing the likelihood of eradication.

[0059] In one embodiment, the present invention provides a method for treating or preventing COVID-19 infection in a patient, comprising: first selecting a patient in need of treatment or prevention; and then administering to the patient at least one active agent selected from the group consisting of dexamethasone, mifepristone, relacolinant, milicolinant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the active metabolite GS-441524 of remdesivir, hydroxychloroquine, and pharmaceutically acceptable salts thereof, with the goal of mitigating COVID-19 infection by reducing transmissibility and duration, eliminating rapid spread of infection, reducing the severity of infection, shortening the duration of infection, preventing infection, and shortening the time to cure, thereby reducing the infectiousness of COVID-19 and increasing the likelihood of eradication.

[0060] In one embodiment, the present invention provides a method for treating or preventing COVID-19 infection in a patient, comprising: first selecting a patient in need of treatment or prevention of a viral condition; and then administering to the patient at least one active agent selected from the group consisting of dexamethasone, mifepristone, relacolinant, milicolinant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the active metabolite of remdesivir GS-441524, hydroxychloroquine, and pharmaceutically acceptable salts thereof, with the goal of preventing an acute infection from becoming a chronic active or latent infection.

[0061] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the following: dexamethasone, mifepristone, relacolinant, milicolinant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the remdesivir ribose alcohol active metabolite GS-441524, hydroxychloroquine, viral PS, annexin-5, anti-PS monoclonal or polyclonal antibodies, bavituximab, and molecules having the potential to bind to viral glucocorticoid response elements (GREs), mifepristone derivatives, cell entry inhibitors, uncoating inhibitors, reverse transcriptase inhibitors, integrase inhibitors, transcription inhibitors, antisense translation inhibitors, ribozyme translation inhibitors, prion processing and targeting inhibitors, protease inhibitors, assembly inhibitors, release phase inhibitors, immune system modulators, vaccines, and pharmaceutically acceptable salts thereof, and combinations thereof.Suitable antiviral agents include abacavir, acyclovir, adefovir, Alferon LDO, amantadine, amdoxovir, Ampligen, amprenavir, aplaviroc, apricitabine, arbidol, atazanavir, ateviridin, atripla, baravir, bevirimat, BILN2061, brecanavir, brivudine, calanolide A, capravirine, cidofovir, combivir, condylox, cyanovirin-N, darunavir, delavirdine, deselvucitabine, diarylpyrimidines, didanosine, and docosanol. , dolutegravir, ecovir, 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, Quibexa / Epzicom, lamivudine, rhodenosine, lopinavir, loviride, MK-0518, maraviroc, miltefosine, moroxydine, methisazone, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, portmanteau inhibitors, PRO140, protease inhibitors, quinotarin, rasibir, raltegravir, reverse transcriptase inhibitors, ribavirin, rilpivirine, rimantadine These include, but are not limited to, ritonavir, R-roscovitine, pyramidine, saquinavir, SCH503034, sofosbuvir, stampidine, stavudine, synergistic enhancers, taribavirin, tea tree oil, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, vibecon, VX950 / telaprevir, zalcitabine, zanamivir, Ziagen, and zidovudine.

[0062] In some embodiments, compositions according to the present invention may be combined with one or more antiviral drugs and administered simultaneously to an individual in need thereof. Suitable antiviral drugs include abacavir, acyclovir, adefovir, Alferon LDO, amantadine, amdoxovir, Ampligen, amprenavir, aplaviroc, apricitabine, arbidol, atazanavir, ateviridin, atripla, Bevirimat, BILN2061, brecanavir, brivudine, calanolide A, capravirine, cidofovir, combivir, condylox, cyanovirin-N, darunavir, delavirdine, dexrubucitabine, diarylpivir, and thiazolinone. Rimidine, didanosine, docosanol, edoxudine, efavirenz, elvitegravir, elvucitabine, emivirine, emtricitabine, enfuvirtide, entecavir, epigallocatechin gallate, eclovrine, fialuridine, fomivirsen, fosamprenavir, foscamet, fosfonet, fusion inhibitors, ganciclovir, Gardasil, globoinan A, Griffithsin, GS-9137, ibacitabine, ibalizumab, Immunovir, idoxuridine, imiquimod, indi Nabil, inosine, interferon gamma, interferon type III, interferon type II, interferon type I, interferon, lamivudine, rhodenosine, lopinavir, loviride, MK-0518, maraviroc, miltefosine, moroxydine, nelfinavir, nevirapine, Nezavir, Oragen, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, portmanteau inhibitor, PRO140, quinotarin, rasibir, raltegravir, ribavirin, These include, but are not limited to, lupivirine, rimantadine, ritonavir, R-roscovitine, saquinavir, SCH503034, stampidine, stavudine, talibavirin, telbivudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, vibecon, VX950 / telaprevir, zalcitabine, zanamivir, and zidovudine (AZT).

[0063] In one embodiment, the present invention provides a composition for treating potential co-infections associated with COVID-19, comprising a therapeutically effective amount of one or a combination of dexamethasone, mifepristone, relacolinant, myricolinant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the active metabolite of remdesivir GS-441524, hydroxychloroquine, or a pharmaceutically acceptable salt thereof, and at least one antibacterial agent, including aztreonam, chlorhexidine gluconate, imidulea, lycetamine, nibroxan, pirazmonam sodium, propionic acid, pyrithione sodium, sanguinarium chloride, tigemonam dicholine, acedapsone, acetosulfonyl acetone, alamethicin, alexidine, amdinocillin, amdinocillin pivoxil, amicycline, amifloxacin, kasin mesilate, or amikacin sulfate. Aminosalicylic acid, Aminosalicylic acid sodium, Amoxicillin, Amphomycin, Ampicillin, Ampicillin sodium, Apalcillin sodium, Apramycin, Aspartocin, Astromycin sulfate, Avilamycin, Avoparcin, Azithromycin, Azlocillin, Azlocillin sodium, Bacampicillin hydrochloride, Bacitracin, Bacitracin methylenedisalicylate, Bacitracin zinc, Bambelmycin Benzoylpas calcium, verethromycin, betamycin sulfate, biapenem, vinilamycin, biphenamine hydrochloride, biphenamine hydrochloride buticacin, butirosin sulfate, capreomycin sulfate, carbadox, carbenicillin disodium, carbenicillin indanyl sodium, carbenicillin phenyl sodium, carbenicillin potassium, carumonam sodium, cefaclor, cefadroxil, cefamandole, cefamandole nafat, cefamandole sodium, cefaparol, cefatrizine, cefazaflur sodium, cefazolin, cefazolin sodium, cefbuperazone, cefdinir, cefepime, cefepime hydrochloride, cefetecol, cefixime, cefinenoxime hydrochloride, cefinetazole, cefinetazole sodium, cefonicid monosodium, cefonicid sodium, cefoperazone sodium,Ceforanide, cefotaxime sodium, cefotetan, cefotetan disodium, cefotiam hydrochloride, cefoxitin, cefoxitin sodium, cefpimizole, cefpimizole sodium, cefpiramide, cefpiramide sulfate, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin sodium, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime, cefuroxime sodium, cephacetrile sodium, cephalexin, cephalexin hydrochloride , cephaloglycin, cephaloridine, cephalosporin, cephalothin sodium, cephapirin sodium, cephradine, cetocycline hydrochloride, cetofenicol, chloramphenicol, chloramphenicol palmitate, chloramphenicol pantothenate complex, chloramphenicol sodium succinate, chlorhexidine phosphate nylate, chloroxylenol, chlortetracycline bisulfate, chlortetracycline hydrochloride, cinoxacin, ciprofloxacin, ciprofloxacin hydrochloride, ciloremycin, clarithromycin, Linafloxacin hydrochloride, clindamycin, clindamycin hydrochloride, clindamycin palmitate hydrochloride, clindamycin phosphate, clofazimine, cloxacillin benzathine, cloxacillin sodium, cloxiquin, colistimethate sodium, colistin sulfate, coumermycin, coumermycin sodium, cyclacillin, cycloserine, dalfopristin, dapsone, daptomycin, demeclocycline, denofungin, diaveridine, dicloxacillin, dicloxacillin sodium um, dihydrostreptomycin sulfate, dipyrithione, dirithromycin, doxycycline, doxycycline calcium, doxycycline phosphatex, doxycycline hydrate, droxacin sodium, enoxacin, epicillin, epitetracycline hydrochloride, erythromycin, erythromycin acetate, estromycin estolate, erythromycin erythromycin, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, ethambutol hydrochloride, ethionamide, fleroxacin,Floxacillin, fludalanine, flumequine, fosfomycin, fosfomycin tromethamine, fumoxicillin, furazolium chloride, furazolium tartrate, sodium fusidate, fusidic acid, gentamicin sulfate, gloximonam, gramicidin, haloprogin, hetacillin, hetacillin potassium, hexedine, ibafloxacin, imipenem, isoconazole, isepamicin, isoniazid, josamycin, kanamycin sulfate, kitasamycin, levofuraltadone, levopropylcillin potassium, lexithromycin, lincomycin hydrochloride Lincomycin, lomefloxacin, lomefloxacin hydrochloride, lomefloxacin mesylate, loracarbef, mafenide, meclocycline, meclocycline sulfosalicylate, megalomycin potassium phosphate, mequidox, meropenem, methacycline, methacycline hydrochloride, methenamine, methenamine hippurate, methenamine mandelate mandelate, methinicamine hydrochloride, methinicamine sodium, metronidazole phosphate, mezlocillin, mezlocillin sodium, minocycline, minocycline hydrochloride, mirincamycin hydrochloride, monensin, monen Nafcillin sodium, nalidixic acid sodium, nalidixic acid, natamycin, nebramycin, neomycin palmitate, neomycin sulfate, neomycin undecylenate, netilmicin sulfate, niflunemycin, nifuraldeson, nifuratel, nifuratron, nifurdazil, niflimide, nifurpirinol, nifurquinazole, nifurthiazole, nitrocycline, nitrofurantoin, nitromide, norfloxacin, novobiocin sodium, ofloxacin, ormetoprim, oxacillin sodium, oxytocin Monam, oximonam sodium, oxolinic acid, oxytetracycline, oxytetracycline calcium, oxytetracycline hydrochloride, paldimycin, parachlorophenol, paulomycin, pefloxacin, pefloxacin mesylate, penamecillin, penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penicillin V potassium, pentizidone sodium, phenylaminosalicylic acid, piperacillin sodium,Pirbenicillin sodium, pyridicillin sodium, pirimicin hydrochloride, pivampicillin hydrochloride, pivampicillin pamoate, pivampicillin probenoate, polymyxin B sulfate, porfiromycin, propicacin, pyrazinamide, pyrithione zinc, quindecamin acetate, quinupristin, racefenicin, racefenicol, repromycin, rifabutin, rifamethan, rifamexyl, rifamide, rifampin, rifapentine, rifaximin, rolitetracycline, rolitetracycline nitrate, rosaramycin, rosaramycin butyrate , Rosaramycin propionate, Rosaramycin sodium phosphate, Rosaramycin stearate, Rosoxacil, Roxarsone, Roxithromycin, Sancycline, Sanfetrin sodium, Salmoxicillin, Salpicillin, Sopimicin iso, Sulfate, Sparfloxacin, Spectinomycin hydrochloride, Spiramycin, Stalimycin hydrochloride, Stefimycin, Streptomycin sulfate, Streptonicozide, Sulfabenz, Sulfabenzamide, Sulfacetamide, Sulfacetamide sodium, Sulfacytine, Sulfadiazine, Sulfadiazine sodium, sulfadoxine, sulfalene, sulfamerazine, sulfamethoxazine, sulfamethoxazine, sulfamethoxazine, sulfamoxazole, zinc sulfanilate, sulfanitran, sulfasalazine, sulfasomizole, sulfathiazole, sulfazamet, sulfisoxazole, sulfisoxazole acetyl, sulfisoxazole diolamine, sulfomycin, sulopenem, sultamicillin, sultamicillin sodium, talampicillin hydrochloride, teicoplanin, temafloxacin hydrochloride , temocillin, tetracycline, tetracycline hydrochloride, tetracycline phosphate complex, tetroxoprim, thiamphenicol, tifencillin potassium, ticarcillin clesyl sodium, ticarcillin disodium, ticarcillin monosodium, ticlaton, thiodonium chloride, tobramycin, tobramycin sulfate, tosufloxacin, trimethoprim, trimethoprim sulfate, trisulfapyrimidine, troleandomycin, trospectomycin sulfate, tyrothricin, vancomycin, vancomycin hydrochloride, virginiamycin hydrochloride,These include, but are not limited to, dichlorvamycin, laurylisoquinolinium bromide, moxalactam disodium, ornidazole, pentisomycin, sarafloxacin hydrochloride, and the like.

[0064] In some embodiments, the compositions according to the present invention are combined with one or more antibiotics and administered simultaneously to an individual in need thereof. Suitable antibiotics include: Amikacin disulfate, amikacin hydrate, anisomycin from Streptomyces, apramycin sulfate, azithromycin, blasticidin S hydrochloride, brefeldin A, brefeldin A from Penicillium brefeldianum, butirosin sulfate, butirosin A from Bacillus vitellinus, chloramphenicol, chloramphenicol base, chloramphenicol sodium succinate, chlortetracycline hydrochloride, Streptomyces Chlortetracycline hydrochloride from Streptomycin aureofaciens, clindamycin 2-phosphate, clindamycin hydrochloride, clotrimazole, cycloheximide from microorganisms, demeclocycline hydrochloride, dibekacin sulfate, dihydrostreptomycin sesquisulfate, dihydrostreptomycin solution, doxycycline hydrate, duramycin erythromycin from streptovertin namicin hydrochloride, erythromycin USP, erythromycin powder, erythromycin, temephos, estromycin estolate, erythromycin ethyl succinate, erythromycin standard solution, erythromycin stearate, fusidic acid sodium salt, G418 disulfate, G418 disulfate powder, G418 disulfate solution, gentamicin solution, gentamicin solution, gentamicin sulfate from Micromonospora purpurea, gentamicin sulfate, gentamicin sulfate powder USP, Gentamicin Glutamine Solution, Helvolic Acid from Cephalosporium caerulescens, Hygromycin B Streptomyces hygroscopicus, Hygromycin B Streptomyces hygroscopicus powder, Hygromycin B Solution Streptomyces hygroscopicus, Josamycin, Josamycin Solution, Kanamycin B Sulfate, Kanamycin Disulfate Salt from Streptomyces kanamyceticus, Kanamycin Monosulfate from Streptomyces kanamyceticus, Kanamycin Monosulfate from Streptomyces kanamyceticus Powder USP, Kanamycin Solution from Streptomyces kanamyceticus, Kirromycin from Streptomyces corinus, Lincomycin Hydrochloride, Lincomycin Standard Solution, Meclocycline Sulfosalicylate, Mepartricin, Midecamycin from Streptomyces mycarofaciens,Minocycline hydrochloride crystals, neomycin solution, neomycin trisulfate hydrate, neomycin trisulfate hydrate powder, neomycin trisulfate hydrate USP powder, netilmicin sulfate, nitrofurantoin crystals, nourseothricin sulfate, oleandomycin phosphate, oleandomycin triacetate, oxytetracycline dihydrate, oxytetracycline hemi-calcium salt, oxytetracycline hydrochloride, paromomycin sulfate, puromycin dihydrochloride from Streptomyces alboniger, rapamycin from Streptomyces hygroscopicus, ribostamycin sulfate, rifampicin, rifamycin SV sodium salt, rosamicin from Micromonospora rosaria, sisomicin sulfate, spectinomycin disalt Acid Hydrate, Spectinomycin Dihydrochloride Hydrate Powder, Spectinomycin Dihydrochloride Pentahydrate, Spiramycin, Spiramycin from Streptomyces species, Spiramycin Solution, Streptomycin Solution, Streptomycin Sulfate, Streptomycin Sulfate Powder, Tetracycline, Tetracycline Hydrochloride, Tetracycline Hydrochloride USP, Tetracycline Hydrochloride Powder, Thiamphenicol, Thiostrepton from Streptomyces azureus, Tobramycin, Tobramycin Sulfate, Tunicamycin A1 Homologue, Tunicamycin C2 Homologue, Tunicamycin from Streptomyces species, Tylosin Solution, Tylosin Tartrate, Viomycin Sulfate, Virginiamycin M1, (S)-(+)-Camptothecin, Taxus 10-Deacetylbaccatin III from Streptomyces baccata, 5-azacytidine, 7-aminoactinomycin D, 8-quinolinol crystals, 8-quinolinol hemisulfate crystals, 13-acetyl-9-dihydrobaccatin III from Taxus spp., aclarubicin, aclarubicin hydrochloride, actinomycin D from Streptomyces spp., actinomycin I from Streptomyces spp., actinomycin V from Streptomyces spp., Aphidicolin nigrospora sphaerica, bafilomycin Al from Streptomyces griseus, bleomycin sulfate from Streptomyces verticillus, capreomycin sulfate from Streptomyces capreolus, chromomycin A3, streptomycin A3, cinoxacin, ciprofloxacin Biochemicacis-Diamineplatinum(II) dichloride, coumermycin Al, cytochalasin B Helminthosporium dematioideum, cytochalasin D Zygosporium mansonii, dacarbazine daunobicin hydrochloride, daunorubicin hydrochloride USP, distamycin A hydrochloride from Streptomyces distalicus, doxorubicin hydrochloride, echinomycin, echinomycin biochemica, enrofloxacin biochemica, etoposide, etoposide solid, Flumequine, Formycin, Fumagillin from Aspergillus fumigatus, Ganciclovir, Gliotoxin from Gliocladium fimbritum, Lomefloxacin hydrochloride, Lomefloxacin hydrochloride from Streptomyces plicatus, Mitomycin C from Streptomyces caespitosus, Nalidixic acid, Nalidixic acid sodium salt, Nalidixic acid sodium salt powder, Netropsin dihydrochloride hydrate, Nitrofurantoin, Streptomyces Nogalamycin from Streptomyces nogalater, Nonactin from Streptomyces tsushimaensis, Novobiocin sodium salt, Ofloxacin, Oxolinic acid, Paclitaxel from Taxus brevifolia, Paclitaxel from Taxus brevifolia, Phenazine methosulfate, Phleomycin from Streptomyces verticillus, Pipemidic acid, Rebeccamycin Sinefungin from Saccharothryx aerocolonigenes, Streptonigrin from Streptonyces phleomycin Loculus streptozocin, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidinepurum, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfaquinoxaline sodium salt, sulfasalazine, sulfathiazole sodium salt, trimethoprim, trimethoprim lactate, tubercidin from Streptomyces tubercicus, 5-azacytidine, cordycepin, formycin A, (+), -6-Aminopenicillanic acid, 7-aminodesacetoxycephalosporanic acid, amoxicillin, ampicillin, ampicillin sodium salt, ampicillin trihydrate, ampicillin trihydrate USP, azlocillin sodium salt, bacitracin bacillus licheniformis, bacitracin zinc salt, bacillus licheniformis, carbenicillin disodium salt, cefaclor, cefamandole lithium salt, cefamandole nafat, cefamandole sodium salt, cefazolin sodium salt, cefinetazole sodium salt, cefoperazone sodium salt, cefotaxime sodium salt, cefsulodin sodium salt, cefsulodin sodium salt hydrate, ceftriaxone sodium salt, cephalexin hydrate, cephalosporin C zinc salt, cephalothin sodium salt, cephapirin 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 salt, ethambutol dihydrochloride, lysostaphin from Staphylococcus aureus, moxalactam sodium salt, nafcillin sodium salt monohydrate, nikkomycin, nikkomycin Z actinomycete, 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, phenethicillin potassium salt, phenoxymethylpenicillin acid potassium salt, fosfomycin disodium salt, pipemidic acid, piperacillin sodium salt, ristomycin monosulfate, Streptomyces orientalis (Streptomycesorientalis), vancomycin hydrochloride, 2-mercaptopyridine N-oxide sodium salt, 4-bromocalcimycin A23187 Biochemica, alamethicin Trichoderma viride, amphotericin B Streptomyces, amphotericin B formulation, calcimycin A23187, calcimycin A23187 hemi(calcium-magnesium) salt, calcimycin A23187 hemicalcium salt, calcimycin A23187 hemimagnesium salt, chlorhexidine diacetate monohydrate, chlorhexidine diacetate hydrate, diglycerides Chlorhexidine leuconate, clotrimazole, colistin methanesulfonate sodium, colistin methanesulfonate sodium from Bacillus colistinus, colistin sulfate, econazole nitrate, hydrocortisone 21-acetate, Streptomyces philippinensis, gliotoxin from Gliocladium fimriatum, gramicidin A from Bacillus brevis, gramicidin A from Brevibacillus sp., gramicidin C from Brevibacillus sp., Bacillus annulinolyticus aneurinolyticus (Brevibacillus sp.), gramicidin from Streptomyces conglobatus, lonomycin calcium salt, lasalocid A sodium salt, lonomycin A sodium salt from Streptomyces ribosificus, monensin sodium salt, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride, narasin from Streptomyces aureofaciens, nigericin sodium salt from Streptomyces hygroscopicus, nisin from Lactococcus lactis, nonactin from spiramycin, nystatin, nystatin powder, phenazine methosulfate, pimaricin, Streptomyces chattanoogensis (Streptomyces chattanoogensis), pimaricin, polymyxin B solution, polymyxin B sulfate DL-penicillamine acetone hydrochloride monohydrate, polymyxin B sulfate powder USP, praziquantel, salinomycin from Streptomyces albus, surfactin from Bacillus subtilis, valinomycin, Usnea longissimus(+)-Usnic acid from Streptomyces dasypoga, (±)-Miconazole nitrate, (S)-(+)-camptothecin, 1-deoxymannojirimycin hydrochloride, 1-deoxynojirimycin hydrochloride, 2-heptyl-4-hydroxyquinoline N-oxide, cordycepin, 1,10-phenanthroline hydrochloride monohydrate puris, 6-diazo-5-oxo-L-norleucine, 8-quinolinol crystals, 8-quinolinol hemisulfate, antimycin A from Streptomyces dasypoga sp., antimycin A1, antimycin A2, antimycin A3, antipain, ascomycin, azaserine, bafilomycin Al from Streptomyces species, bafilomycin BL from Streptomyces species, cerulenin biochemica, chloroquine diphosphate, cinoxacin, ciprofloxacin, mevastatin biochemica, concanamycin A, concanamycin A from Streptomyces species, concanamycin C from Streptomyces species, coumermycin A1, cyclosporin A from Tolypocladium indilatum, cyclosporin A, econazole nitrate, enrofloxacin, etoposide, flumequine, formycin A, furazolidone, fusaric acid from Gibberella fujikuroi, geldanamycin from Streptomyces hygroscopicus, Gliocladium fimbriatum-derived gliotoxin, Bacillus brevis-derived gramicidin A, Bacillus brevis-derived gramicidin C, Bacillus subtilis (Bacillus brevis)-derived gramicidin, Gramicidin from Bacillus brevis, Herbimycin A from Streptomyces hygroscopicus, Indomethacin, Irgasan, Lomefloxacin Hydrochloride, Mycophenolic Acid Powder, Myxothiazol Biochemica, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide Hydrochloride, Nalidixic Acid, Netropsin Dihydrochloride Hydrate, Niclosamide, Nikkomycin Biochemica, Nikkomycin Z Methyl-1-deoxynojirimycin Nogalamycin from Streptomyces nogalate, Nonactin D80% from Streptomyces tsushimaensis, Nonactin from Streptomyces spp., Novobiocin sodium salt, Ofloxacin, Oleandomycin triacetate, Oligomycin from Streptomyces diastatochromogenes, Oligomycin A, Oligomycin B, Oligomycin C, Oligomycin from Streptomyces diastatochromogenes, Oxolin Acid, piericidin A from Streptomyces mobaraensis, pipemidic acid, radicicol from Diheterospora chlamydosporia solidus, rapamycin from Streptomyces hygroscopicus, rebeccamycin from Saccharothrix aerocolonigenes, sinefungin, staurosporin Streptomyces spp., stigmatellin, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine purum, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfaquinoxaline sodium salt, sulfasalazine, sulfathiazole sodium salt, triacsin C from Streptomyces spp., trimethoprim, trimethoprim lactate, vineomycin A1 from Streptomyces albogriseolus subsp., tectorigenin, and paracelsin Trichoderma reesei.

[0065] In one embodiment, the present invention provides a composition comprising dexamethasone, mifepristone, relacolinant, milicolinant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the active metabolite of remdesivir GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, or any combination thereof, for treating potential co-infections associated with COVID-19, in conjunction with at least one suitable antifungal agent. These include polyene antifungals such as natamycin, rimocidin, filipin, nystatin, amphotericin B, and candicin; imidazole and triazole antifungals such as miconazole (miconazole nitrate), ketoconazole, clotrimazole (miconazole nitrate) (Lotrimin, sold as Canesten in the UK); econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (sold as Eltaco), sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, and voriconazole. These include, but are not limited to, terbinafine (sold as Lamisil), amorolfine, naftifine (sold as Naftine), butenafine (sold as Lotrimin Ultra), echinocandins such as anidulafungin, caspofungin, and micafungin, benzoic acid in combination with a keratolytic agent (such as Whitfield's Ointment), ciclopirox olamine, flucytosine, or 5-fluorocytosine, griseofulvin, gentian violet, haloprogine, and tolnaftate (sold as Tinactin, Desenex, and Aftate).

[0066] In one embodiment, the present invention provides a composition comprising dexamethasone, mifepristone, lelacorilant, milicorilant, valsartan, rupintrivir, ritonavir, myricetin, rifampin, remdesivir, the active metabolite of remdesivir GS-441524, hydroxychloroquine, pharmaceutically acceptable salts thereof, or any combination thereof, for treating potential co-infections associated with COVID-19, in conjunction with at least one suitable antiparasitic agent. These include, but are not limited to, mebendazole (for most nematode infections), pyrantel pamoate (for most nematode infections), thiabendazole (for roundworm infections), and anti-trematodes such as diethylcarbazine (for the treatment of lymphatic filariasis), niclosamide (for tapeworm infections), praziquantel (for tapeworm infections), anti-trematodes such as praziquantel, anti-amebics such as rifampin, anti-protozoal agents such as amphotericin B, clioquinol, iodoquinol, metronidazole, tinidazole, ornidazole, secnidazole, atovaquone, emetine, fumagillin, trimetrexate, amphotericin, antimony, eflornithine, furazolidone, melarsoprol, metronidazole, miltefosine (Impavid), omidazole, paromomycin sulfate, pentamidine, pyrimethamine, tinidazole, and the like.

[0067] In another embodiment, the present invention 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 following: an antiretroviral reductase inhibitor (ARB) such as valsartan, a protease inhibitor (PI) such as rupintrivir or ritonavir, an antiretroviral reductase inhibitor (RdRpI) such as myricetin, rifampin, remdesivir or its ribose alcohol active metabolite GS-441524, an antiretroviral reductase inhibitor (MRI) such as hydroxychloroquine, and pharmaceutically acceptable salts thereof, and combinations thereof; ii) a second therapeutic agent, comprising a PSI, a GCR modulator / antagonist, selected from the group consisting of dexamethasone, mifepristone, lilacorilant, milicorilant, pharmaceutically acceptable salts thereof, and combinations thereof; and iii) at least one pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated as a liquid, elixir, aerosol, gas, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, sustained-release dosage form, or topical agent. wherein the antiviral agents, individually or in combination, are in therapeutically effective amounts to treat or prevent a viral infection in a patient. In some embodiments, the one or more antiviral agents in the pharmaceutical composition are effective against COVID-19.

[0068] In another embodiment, the present invention provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent, or a pharmaceutically acceptable salt thereof, selected from an antiretroviral reductase inhibitor (ARB) such as valsartan, a protease inhibitor (PI) such as rupintrivir or ritonavir, a remdesivir-like inhibitor (RdRpI) such as myricetin, rifampin, or remdesivir, or the ribose alcohol active metabolite GS-441524; ii) a second therapeutic agent comprising an MRI agent such as hydroxychloroquine or a pharmaceutically acceptable salt thereof; and iii) at least one pharmaceutically acceptable carrier. The pharmaceutical composition is then formulated or manufactured as a liquid, elixir, aerosol, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, sustained-release dosage, or topical application, wherein the antiviral agents are each present in a therapeutically effective amount in combination to treat or prevent infection in a patient. In one embodiment, the one or more antiviral agents in the pharmaceutical composition are effective against COVID-19.

[0069] In another embodiment, the present invention provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent selected from an antiretroviral reductase inhibitor (ARB) such as valsartan, a protease inhibitor (PI) such as rupintrivir or ritonavir, or a combination thereof, or a pharmaceutically acceptable salt thereof; ii) a second therapeutic agent comprising myricetin, rifampin, remdesivir, or its ribose alcohol active metabolite GS-441524, or a pharmaceutically acceptable salt thereof, and a RdRpI in combination; and iii) at least one pharmaceutically acceptable carrier. The pharmaceutical composition is then formulated or manufactured as a liquid, elixir, aerosol, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, sustained-release dosage, or topical application, wherein the antiviral agents are each present in a therapeutically effective amount in combination to treat or prevent infection in a patient. In one embodiment, the one or more antiviral agents in the pharmaceutical composition are effective against COVID-19.

[0070] In another embodiment, the present invention provides a pharmaceutical composition comprising: i) a first therapeutic agent comprising at least one antiviral agent selected from an ARB, such as valsartan, or a pharmaceutically acceptable salt thereof; ii) a second therapeutic agent comprising a PI, such as rupintrivir or ritonavir, and a pharmaceutically acceptable salt thereof, or a combination thereof; and iii) at least one pharmaceutically acceptable carrier. The pharmaceutical composition is then formulated or manufactured as a liquid, elixir, aerosol, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticles, sustained-release dosage, or topical application, wherein the antiviral agents are each present in a therapeutically effective amount in combination to treat or prevent infection in a patient. In one embodiment, the one or more antiviral agents in the pharmaceutical composition are effective against COVID-19. DETAILED DESCRIPTION OF THE INVENTION

[0071] As used herein, the term "effective amount" refers to an amount sufficient to prevent the onset, recurrence, or development of a disease or condition, such as a new formation or infection, and one or more symptoms thereof, enhance or improve the prophylactic efficacy of another therapy, reduce the severity or duration of treatment for a disease or condition, such as a viral infection, ameliorate one or more symptoms of a disease or condition, such as an infection, prevent the progression of an infection, ameliorate a disease or condition, such as an infection, cause regression of a disease or condition, such as an infection, or enhance or improve the therapeutic efficacy of another therapy. Thus, "effective" as used herein refers to an amount that provides an effect to a subject.

[0072] As used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopeia for use in animals, or more specifically, in humans.

[0073] As used herein, the terms "prevent," "preventing," and "prevention" refer to the prevention or inhibition of a disease or its recurrence, onset, or development in the context of administration of a therapy to a subject, e.g., a treatment (e.g., prescription of a prophylactic or therapeutic agent), or combination of therapies (e.g., prescription of a prophylactic or combination of therapeutic agents).

[0074] The terms "subject" and "patient" are used broadly herein. For example, the term "patient" refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.), a primate, or a human. In some embodiments, the subject is a non-human animal such as a farm animal (e.g., horses, pigs, cows) or a pet (e.g., dog or cat).

[0075] As used herein, the terms "therapy" and "regimen" refer to any method, composition, or agent that can be used to prevent, treat, or manage a viral infection, condition, or disease in any of its symptoms. In one embodiment, "therapy" or "regimen" refers to chemotherapy, small molecule therapy, radioimmunotherapy, toxin therapy, prodrug-activated enzyme therapy, biological therapy, antibody therapy, surgical therapy, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy, epigenetic therapy, demethylation therapy, histone deacetylase inhibitor therapy, differentiation therapy, radiation therapy, or a combination thereof that is useful in the prevention, management, or treatment of a viral infection.

[0076] As used herein, the terms "treatment," "treating," and "treating" in the context of administration to a subject refer to the reduction or inhibition of progression, duration, reduction or amelioration of the severity of a disease or condition, such as tumor formation or viral infection, or the amelioration of symptoms as a result of the administration of one or more therapies.

[0077] As used herein, the term "about" when referring to values, masses, weights, times, volumes, concentrations, and percentages is intended to cover variations from the specified amount of, in some embodiments, ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, as it is appropriate to allow for reasonable variations in the practice of the disclosed techniques.

[0078] As used herein, ranges are expressed as "approximately" from one particular value or from another particular value. Although many values ​​are disclosed herein, it is understood that each value is preceded by "approximately." For example, "10" means "approximately 10." The same applies to ranges between two numbers; for example, 10 and 15 also includes 11, 12, 13, and 14.

[0079] As used herein, the term "agent" refers to any molecule, compound, methodology, or substance for use in the prevention, treatment, management, or diagnosis of a viral disease.

[0080] As used herein, the term "therapeutic agent" refers to any molecule, compound, or substance used to treat or manage a disease or disorder, including, for example, proteins, immunoglobulins (e.g., multispecific Igs, single-chain Igs, Ig fragments, polyclonal antibodies and fragments thereof, monoclonal antibodies and fragments thereof), peptides (e.g., peptide receptors, selectins), binding proteins, biologics, chemospecific agents, chemotoxic agents (e.g., anti-cancer agents), proliferation-based therapies, chemotherapy, and small molecule drugs.

[0081] As used herein in the context of administering a drug to a subject, the terms "electronic cigarette" and "electronic cigarette" refer to a battery-operated drug delivery device used to administer one or more doses of a pharmaceutical 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 to a subject in the form of a mist. Nebulizers use oxygen, compressed air, or ultrasound to break solutions or suspensions into small aerosol droplets that can be inhaled directly through a mouthpiece. An aerosol is a suspension of solid or liquid particles in a gas. Nebulizers may be released into the atmosphere or may be a component of a closed system integrated into a patient's ventilation system.

[0083] As used herein, "ARB" or "angiotensin receptor blocker" refers to a group of drugs such as azilsartan (Edarbi), candesartan (Atacand), eprosartan (Tevene), irbesartan (Avapro), telmisartan (Micardis), valsartan (Diovan), losartan (Cozar), and olmesartan (Benicar).

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

[0085] Phosphatidylserine (PS) bonds represent an important membrane lipid in all human cells. PS is a type of phospholipid, along with phosphatidylcholine (lecithin) and phosphatidylethanolamine (cholamin-cephalin). PS is composed of 1,2-diacylglycerol-3-phospho-L-serine. 1,2-diacylglycerol-3-phosphate is also known as phosphatidic acid, hence the name "phosphatidyl." PS is typically exposed on human cells only during apoptosis (programmed cell death, or "spontaneous cell suicide"). Enveloped viruses consistently expose PS on the lipid bilayer membranes they capture in their host cells. Enveloped viruses utilize this PS exposure to evade attack by the human immune system and enter phagocytes, such as monocytes and macrophages.

[0086] 3-O-sn-Phosphatidyl-L-serine (PS): The typical PS structure is characterized by stearic acid at the 1-O position and docosa-4,7,10,13,16,19-hexaenoic acid at the 2-O position. This represents the major serine-cephalin from bovine brain. The fatty acid composition of the 1-O and 2-O positions varies depending on the cell type. The polar head group (phosphoserine) is negatively charged. The charge of the phosphate anion and the charge of the ammonium cation neutralize each other. Therefore, at physiological pH 7.4, PS has a net negative charge.

[0087] Sn-phosphatidylcholine (PC) This is a typical PC structure, with stearic acid at the 1-O position and linoleic acid at the 2-O position. This represents the major lecithin found in egg yolk and human cell membranes. The fatty acid composition at the 1-O and 2-O positions varies depending on the cell type. The polar head group (phosphocholine) is zwitterionic. The charge of the phosphate anion and the charge of the cation of the ammonium group neutralize each other. Therefore, PC is net neutral at physiological pH 7.4. Many PS-Interception-Susceptible enveloped viruses are RNA viruses, such as COVID-19.

[0088] Formulation and Administration The compounds and compositions of the present invention can be administered in a therapeutically effective dose. In some embodiments, the compounds and compositions of the present invention are administered in the following doses: 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 1 25 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, about 500 mg / day. In another embodiment, the compounds of the invention are administered at the following doses: 1mg / day or less, 2mg / day or less, 5mg / day or less, 10mg / day or less, 15mg / day or less, 20mg / day or less, 25mg / day or less, 30mg / day or less, 35mg / day or less, 40mg / day or less, 45mg / day or less, 50mg / day or less, 60mg / day or less, 70mg / day or less, 80mg / day or less, 90mg / day or less, 100mg / day or less, 120mg / day or less, 125mg / day or less, 140mg / day or less, 1 50 mg / day or less, 160 mg / day or less, 175 mg / day or less, 180 mg / day or less, 190 mg / day or less, 200 mg / day or less, 225 mg / day or less, 250 mg / day or less, 275 mg / day or less, 300 mg / day or less, 325 mg / day or less, 350 mg / day or less, 375 mg / day or less, 400 mg / day or less, 425 mg / day or less, 450 mg / day or less, 475 mg / day or less, 500 mg / day or less.1mg / day or more, 2mg / day or more, 5mg / day or more, 10mg / day or more, 15mg / day or more, 20mg / day or more, 25mg / day or more, 30mg / day or more, 35mg / day or more, 40mg / day or more, 45mg / day or more, 50mg / day or more, 60mg / day or more, 70mg / day or more, 80mg / day or more, 90mg / day or more, 100mg / day or more, 120mg / day or more, 125mg / day or more, 140mg / day or more, 15 ≥0 mg / day, ≥160 mg / day, ≥175 mg / day, ≥180 mg / day, ≥190 mg / day, ≥200 mg / day, ≥225 mg / day, ≥250 mg / day, ≥275 mg / day, ≥300 mg / day, ≥325 mg / day, ≥350 mg / day, ≥375 mg / day, ≥400 mg / day, ≥425 mg / day, ≥450 mg / day, ≥475 mg / day, or ≥500 mg / day.

[0089] The compounds and compositions of the present invention may be given one or more times daily, or may be given at 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, 12 weeks intervals.

[0090] The compounds and compositions of the present invention can be administered in an effective amount to an individual in need thereof. In a preferred embodiment, the amount of the composition of the present invention is about 0.01 to 1000 mg per kg of body weight per dose, e.g., about 0.01 to 0.025 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.025 to 0.5 mg per kg of body weight per dose, e.g., about 0.05 to 0.075 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.075 to 0.1 mg per kg of body weight per dose, e.g., about 0.1 to 0.25 mg per kg of body weight per dose, or about 0.25 to 0.5 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.5 to 0.75 mg per kg of body weight per dose, e.g., about 0.75 to 1.0 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 1.0 to 2.5 mg per kg of body weight per dose, for example, about 2.5 to 5 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 5 to 7.5 mg per kg of body weight per dose, for example, about 7.5 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 10 to 25 mg per kg of body weight per dose, for example, about 25 to 50 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 70 to 100 mg per kg of body weight per dose, for example, about 100 to 250 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 250 to 500 mg per kg of body weight per dose, for example, about 500 to 750 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 750 to 1000 mg per kg of body weight per dose.

[0091] The compounds and compositions of the present invention can be formulated in a range of about 0.02 mg to 20 mg / kg of body weight per dose. For example, the range is about 0.02 mg to 18 mg / kg of body weight per dose. For example, if the range is about 0.04 mg to 16 mg / kg of body weight per dose, the range is about 0.06 to 14 mg / kg of body weight per dose. For example, if the range is about 0.08 to 12 mg / kg of body weight per dose, the range is about 0.01 mg to 10 mg / kg of body weight per dose, or about 0.2 to 10 mg / kg of body weight per dose. For example, if the range is about 0.3 mg to 10 mg / kg of body weight per dose, the range is about 0.4 to 10 mg / kg of body weight per dose. For example, if the range is about 0.5 mg to 10 mg / kg of body weight per dose, the range is about 0.06 to 10 mg / kg of body weight per dose. For example, if the dosage is about 0.7 mg to 10 mg per kg of body weight, then the dosage is about 0.8 to 10 mg per kg of body weight. For example, if the dosage is about 0.9 mg to 10 mg per kg of body weight, then the dosage is about 1.0 to 10 mg per kg of body weight. For example, the amount of the composition of the present invention is about 1.2 to 10 mg per kg of body weight, for example, about 1.4 to 10 mg per kg of body weight. For example, the amount of the composition of the present invention is about 1.6 to 10 mg per kg of body weight, for example, about 1.8 to 10 mg per kg of body weight. For example, the amount of the composition of the present invention is about 2.0 to 10 mg per kg of body weight, for example, about 2.2 to 10 mg per kg of body weight. For example, the amount of the composition of the present invention is about 2.4 to 10 mg per kg of body weight per dose, e.g., about 2.6 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.8 to 10 mg per kg of body weight per dose, e.g., about 3.0 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 3.2 to 10 mg per kg of body weight per dose, e.g., about 3.4 to 10 mg per kg of body weight per dose.For example, the amount of the composition of the present invention is about 3.6 to 10 mg per kg of body weight per dose, for example, about 3.8 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.0 to 10 mg per kg of body weight per dose, for example, about 4.2 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.4 to 10 mg per kg of body weight per dose, for example, about 4.6 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.8 to 10 mg per kg of body weight per dose, for example, about 5.0 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 5.2 to 10 mg per kg of body weight per dose, for example, about 5.4 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 5.6 to 10 mg per kg of body weight per dose, for example, about 5.8 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 6.0 to 10 mg per kg of body weight per dose, for example, about 6.2 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 6.4 to 10 mg per kg of body weight per dose, for example, about 6.6 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 6.8 to 10 mg per kg of body weight per dose, for example, about 7.0 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 7.2 to 10 mg per kg of body weight per dose, for example, about 7.4 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 7.6 to 10 mg per kg of body weight per dose, e.g., about 7.8 to 10 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 8.0 to 10 mg per kg of body weight per dose, e.g., about 0.2 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.3 to 8 mg per kg of body weight per dose, e.g., about 0.4 to 8 mg per kg of body weight per dose.For example, the amount of the composition of the present invention is about 0.5 to 8 mg per kg of body weight per dose, for example, about 0.6 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.7 to 8 mg per kg of body weight per dose, for example, about 0.8 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.9 to 8 mg per kg of body weight per dose, for example, about 1.0 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 1.2 to 8 mg per kg of body weight per dose, for example, about 1.4 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 1.6 to 8 mg per kg of body weight per dose, for example, about 1.8 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.0 to 8 mg per kg of body weight per dose, for example, about 2.2 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.4 to 8 mg per kg of body weight per dose, for example, about 2.6 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.8 to 8 mg per kg of body weight per dose, for example, about 3.0 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 3.2 to 8 mg per kg of body weight per dose, for example, about 3.4 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 3.6 to 8 mg per kg of body weight per dose, for example, about 3.8 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.0 to 8 mg per kg of body weight per dose, for example, about 4.2 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.4 to 8 mg per kg of body weight per dose, for example, about 4.6 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.8 to 8 mg per kg of body weight per dose, for example, about 5.0 to 8 mg per kg of body weight per dose.For example, the amount of the composition of the present invention is about 5.2 to 8 mg per kg of body weight per dose, for example, about 5.4 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 5.6 to 8 mg per kg of body weight per dose, for example, about 5.8 to 8 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 6.0 to 8 mg per kg of body weight per dose, for example, about 0.2 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.3 to 6 mg per kg of body weight per dose, for example, about 0.4 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.5 to 6 mg per kg of body weight per dose, for example, about 0.6 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.7 to 6 mg per kg of body weight per dose, for example, about 0.8 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 0.9 to 6 mg per kg of body weight per dose, for example, about 1.0 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 1.2 to 6 mg per kg of body weight per dose, for example, about 1.4 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 1.6 to 6 mg per kg of body weight per dose, for example, about 1.8 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.0 to 6 mg per kg of body weight per dose, for example, about 2.2 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.4 to 6 mg per kg of body weight per dose, e.g., about 2.6 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 2.8 to 6 mg per kg of body weight per dose, e.g., about 3.0 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 3.2 to 6 mg per kg of body weight per dose, e.g., about 3.4 to 6 mg per kg of body weight per dose.For example, the amount of the composition of the present invention is about 3.6 to 6 mg per kg of body weight per dose, for example, about 3.8 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.0 to 6 mg per kg of body weight per dose, for example, about 4.2 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.4 to 6 mg per kg of body weight per dose, for example, about 4.6 to 6 mg per kg of body weight per dose. For example, the amount of the composition of the present invention is about 4.8 to 6 mg per kg of body weight per dose, for example, about 5.0 to 6 mg per kg of body weight per dose.

[0092] The compounds and compositions of the present invention can be administered enterally or by inhalation, such as with an electronic cigarette. The device contains a cartridge filled with a pharmaceutical agent (active pharmaceutical ingredient and excipients) and can be used for single or multiple doses. The compounds can also be compressed into solid dosage forms such as pills or tablets, or can be made into capsules or suppositories. Medically suitable liquids may be used and provided as solutions, suspensions, emulsions, injections or eye drops, or in the form of sprays, and may also be used in open and closed nebulizers, or carried in cartridges that are placed in e-cigarettes.

[0093] In some embodiments, the compositions of the present invention are administered via a portable medical vaporizer, including an electronic cigarette. These devices utilize a pharmaceutical product cartridge for single-use or multi-use electronic cigarettes, allowing for daily administration of approximately 60 milligrams to approximately 120 milligrams of BB-708 and plachemdesivir for 3 to 14 days. Each electronic cigarette cartridge or single-use electronic cigarette has a volume of approximately 0.75 milliliters (mL) to 2.0 mL, with a minimum weight per volume of BB-708 of 3% to 5%. An average patient will consume the entire drug after approximately 100 puffs from a 1 mL cartridge pod or electronic cigarette. Approximately 200 puffs can be achieved using a 2 mL cartridge pod or a larger-capacity electronic cigarette. The concentration of BB-708 can be increased to reduce the number of puffs required. For example, increasing the concentration of BB-708 in the pharmaceutical product can reduce the number of puffs to 10 or fewer. Thus, the dosing regimen can be tailored to achieve optimal results. The dosage can be reduced for children and can be increased or decreased depending on the patient's weight.

[0094] In some embodiments, the compositions of the present invention are administered via a portable medical vaporizer, including an electronic cigarette. This method uses a drug product cartridge for a single-use or multi-use electronic cigarette, allowing for daily administration of approximately 60 milligrams to approximately 120 milligrams of BB-708B and riboplachemdesvir for 3 to 14 days. Each e-cigarette cartridge or single-use electronic cigarette has a volume of approximately 0.75 milliliters (mL) to 2.0 mL, with a minimum weight of BB-708B per volume of 3% to 5%. An average patient will consume the entire drug after approximately 100 puffs from a 1 mL cartridge pod or electronic cigarette. A 2 mL cartridge pod or a larger-capacity electronic cigarette can provide approximately 200 puffs. Thus, the dosing regimen can be adjusted to achieve optimal results. The dosage can be reduced for pediatric patients and can be adjusted up or down depending on the patient's weight.

[0095] In some embodiments, the compositions of the present invention are administered via a portable medical vaporizer, including an electronic cigarette. This method uses a drug product cartridge for a single-use or multi-use electronic cigarette, allowing for daily administration of approximately 60 mg to approximately 120 mg of BB-710B and ribodexadecivir for 3 to 14 days. Each e-cigarette cartridge or single-use electronic cigarette has a volume of approximately 0.75 mL to 2.0 mL, with a minimum weight of BB-710B per volume of 3% to 5%. An average patient will consume the entire drug after approximately 100 puffs from a 1 mL cartridge pod or electronic cigarette. A 2 mL cartridge pod or a larger-capacity electronic cigarette can provide approximately 200 puffs. Thus, the dosing regimen can be adjusted to achieve optimal results. It can be reduced for pediatric patients and can be adjusted up or down depending on the patient's weight.

[0096] For example, to prepare dosage units such as tablets, additives such as fillers, coloring agents, polymer binders, etc. may be used. Generally, any pharmaceutically acceptable additives are allowed as long as they do not interfere with the function of the active compound. Suitable carriers include lactose, starch, cellulose derivatives, or mixtures thereof, used in appropriate amounts.

[0097] Special formulations to replace specific routes of administration The pharmaceutical composition of the present invention can also be optimized for the delivery of specific types of drugs.For example, pharmaceutical compositions for oral delivery can be formulated using pharmaceutically acceptable carriers well known in the art.The carrier can also make the drug in the composition into a tablet, pill, capsule, solution, suspension, sustained-release formulation, powder, liquid, or gel for oral ingestion.Also, the active agent can be formulated into a liquid containing vegetable glycerin or propylene glycol as a vape carrier.

[0098] The compounds of the present invention can also be delivered in aerosol spray formulations, including pressurized packs, nebulizers, dry powder inhalers, electronic cigarettes, etc. Suitable propellants that can be used in nebulizers include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. In the case of pressurized aerosols, the dosage can be determined by providing a valve to deliver a regulated amount of the compound.

[0099] Compositions for inhalation or pneumoperitoneum include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, or powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. The compositions may be administered orally, nasally, or via the respiratory route, depending on the desired effect, such as local or systemic. Ideally, the composition is sterile, and solutions may be nebulized using an inert gas. Nebulized solutions may be inhaled directly from the device, or the device may be attached to a mask, tent, or positive pressure breathing machine. Solution, suspension, and powder compositions may be administered orally or intranasally from a delivery device using an appropriate method. Compositions for use in e-cigarettes may be loaded into cartridges inserted into the device or into disposable devices.

[0100] The compositions of the present invention can be mixed with any medically suitable adjuvant and administered enterally, parenterally, or in the respiratory system, as described in the standard text, Gennaro et al., Remington's Pharmaceutical Sciences. The compounds can be compressed into solid dosage units such as pills or tablets, or processed into capsules or suppositories. They can also be administered in medically suitable liquids such as solutions, suspensions, and emulsions. For example, they can be used as injections or eye drops, or as aerosols such as nasal sprays.

[0101] Drug form The compositions of the present invention can be processed by agglomeration, air-suspension cooling, air-suspension drying, balling, coacervation, coating, milling, compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation, homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray cooling, spray congealing, spray drying, or other processes known in the art. The compositions can be used in the form of minicapsules, capsules, smart capsules, tablets, implants, troches, sachets, lozenges (minitablets), temporary or permanent suspensions, wafers, suppositories, wafers, chewable tablets, fast-dissolving tablets, effervescent tablets, buccal or sublingual solids, granules, films, dustings, pellets, beads, pills, powders, triturates, platelets, or strips. Additionally, the dosage form can be administered as a "dry syrup" that is placed directly on the tongue and swallowed or consumed with a beverage.

[0102] The pharmaceutical compositions can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compression coatings, fast-disintegrating coatings, and enzymatically degradable coatings. Multiple coatings can be applied to achieve desired performance. Furthermore, dosage forms can be adapted for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, and targeted delayed release. Solid carriers, with or without active ingredients, can be coated with various ingredients, levels, or thicknesses to control release and absorption. The solid carriers can be formulated to achieve desired performance. Furthermore, the release profile of the dosage form can be influenced by polymer matrix compositions, coated matrix compositions, multiparticulate compositions, coated multiparticulate compositions, ion-exchange resin-based compositions, osmotic-based compositions, and biodegradable polymer compositions.

[0103] When formulated as a capsule, hard or soft gelatin capsules, starch capsules, or cellulose-based capsules can be used. These dosage forms can also be further coated with, for example, seal coatings, enteric coatings, sustained-release coatings, or targeted delayed-release coatings, without limitation to capsules. While these coatings are already known in the art, a brief description is provided below. Seal coatings, or coatings with a separating layer, are thin layers up to 20 microns thick that can be used for a variety of purposes, including reducing particle porosity, reducing dust, chemical protection, taste masking, odor reduction, and minimizing gastrointestinal irritation. The effectiveness is proportional to the thickness of the coating. For this application, water-soluble cellulose ethers are preferred. A combination of HPMC and ethyl cellulose or Eudragit E100 appears particularly suitable for taste-masking applications. Other conventional enteric coating materials can also be applied to form the separating layer.

[0104] Extended-release coatings are designed to provide effective delivery over extended periods of time. These coatings are pH-independent and are made from, for example, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic acid esters, and sodium carboxymethyl cellulose. These various extended-release coatings, depending on the type and thickness of the coating, can be easily designed by those skilled in the art to deliver to both the small and large intestine, only the small intestine, or only the large intestine.

[0105] Enteric coatings involve adding, combining, mixing, or otherwise adding pharmaceutically acceptable excipients to the carrier or composition. Coatings can be applied to compressed, molded, or extruded tablets, gelatin capsules, pellets, beads, granules, or particles of the carrier or composition. Coatings can be applied via aqueous dispersion or after dissolution in a suitable solvent. The choice of additional additives and their amounts, as well as the primary coating material or materials, are determined by the following properties: resistance to dissolution in the stomach, impermeability to gastric juices and to the drug, carrier, and enzymes while in the stomach, rapid dissolution at the target intestinal site, physical and chemical stability during storage, non-toxicity, ease of application as a coating (substrate-friendly), and economic feasibility.

[0106] The compositions of the present invention are available as enterically coated delayed-release oral dosage forms. Oral dosage forms can also be formulated using the methods described above, such as using an enteric coating to affect release in the lower gastrointestinal tract. Enterically coated dosage forms can be granules, pellets, or beads of the active ingredient or other composition ingredients, as well as compressed, molded, or extruded tablets or molds (coated or uncoated). The enterically coated oral dosage forms can also be pellets, beads, or capsules (coated or uncoated) of the solid carrier or composition, which themselves can be coated or uncoated.

[0107] Delayed release is delivery used to roughly predict the location of the distal lower gastrointestinal tract that would otherwise be reached. The preferred method is coating. The coating should be thick enough to be insoluble in the stomach at pH values ​​below 5, but soluble at pH values ​​above 5. It is believed that the pH-dependent solubility properties of anionic polymers can be utilized to coat the entire composition and deliver the present invention to the lower gastrointestinal tract. The polymer for use in the present invention is an anionic carboxyl polymer.

[0108] Shellac, also known as purified lac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH of 7 or higher.

[0109] In addition to plasticizers, colorants, detackifiers, surfactants, defoamers, lubricants, stabilizers (e.g., hydroxypropyl cellulose), and acids / bases can be used to solubilize and disperse coating materials and improve coating performance and the coated product.

[0110] In practicing the methods of the present invention, the combinations of the present invention may be administered to mammalian species, such as dogs, cats, humans, etc., and for this purpose may be incorporated into conventional dosage forms for systemic administration, such as tablets, capsules, elixirs, or injectable solutions, which may include at least one carrier substance, excipient, lubricant, buffer, antimicrobial agent, bulking agent (such as mannitol), antioxidant (such as ascorbic acid or sodium bisulfite), etc.

[0111] Tablets containing the active ingredient can be prepared in various sizes, e.g., weighing approximately 1 to 2000 mg, and containing a pharmaceutically acceptable carrier. These tablets can be scored to provide divided doses. Gelatin capsules can also be formulated. Tablets can be formulated as crumbs, or gelatin capsules can be formulated.

[0112] Liquid formulations can be prepared by dissolving or suspending the compound of the present invention in a conventional liquid solvent, allowing a predetermined amount to be formulated.

[0113] To precisely control the time of administration, the active substances can be administered simultaneously or at carefully timed intervals in dosage units. The simultaneous presence of two substances can achieve similar results, as blood levels can be maintained by timed administration. Each substance can be formulated separately in separate dosage units in the same manner as described above.

[0114] In formulating the compositions, the active substance may be used in the amounts described above together with physiologically acceptable solvents, carriers, excipients, binders, preservatives, stabilizers, flavorings, etc., and compounded in accordance with pharmaceutical practice in specific types of units.

[0115] Examples of adjuvants that can be incorporated into tablets include: gum tragacanth, acacia, binders such as corn starch or gelatin; excipients such as dicalcium phosphate or cellulose; disintegrating agents such as corn starch, potato starch, or alginic acid; lubricants such as stearic acid or magnesium stearate; sweeteners such as sucrose, aspartame, lactose, or saccharin; and flavorings such as orange, peppermint, wintergreen oil, or cherry. When the dosage unit is a capsule, in addition to the above-mentioned materials, a liquid carrier such as a fatty oil can also be included. Various other materials can be used as coatings or to otherwise modify the dosage unit form. For example, tablets or capsules can be coated with shellac, sugar, or both. Elixir syrup can contain the active compound, water, alcohol, or the like as a carrier, glycerol as a solubilizer, sucrose as a sweetener, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange.

[0116] In some embodiments, the compositions are provided as methods for treating, preventing, or diagnosing certain COVID-19 diseases by administering them to a subject, either alone or within a pharmaceutical composition.

[0117] The compositions of the present invention include nanoparticles, composite nanoparticles, nanosuspensions, and nanocapsules. In some embodiments, the pharmaceutical compositions contain, for example, at least about 0.1% of an active ingredient or nanoparticles, composite nanoparticles, or nanocapsules. In other embodiments, the active ingredient or nanoparticles, composite nanoparticles, or nanocapsules may comprise from about 2% to about 75%, or from about 25% to about 60%, of the weight of the formulation, or any range derivable therein.

[0118] The compositions of the present invention may also include various antioxidants to retard oxidation of one or more active ingredients or nanoparticles, composite nanoparticles, nanosuspensions, or nanocapsules. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal preservatives, including, but not limited to, parabens (e.g., methylparaben, propylparaben), chlorobutanol, phenol, sorbic acid, thimerosal, or combinations thereof.

[0119] Packaging and treatment kit The present invention also relates to kits for conveniently and effectively practicing the methods described herein. The kits are suitable for delivering solid oral dosage forms, such as tablets or capsules, or inhalable dosage forms, such as e-cigarettes, that require a cartridge of pharmaceutical product for use in an appropriate device. Such kits can contain one or more dosage units. The kits also include a means for arranging the doses in the order of their intended use. One example of a method for arranging the doses in the order of their intended use is a card. Another example is a "blister pack." Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, the blister pack can be in the form of a childproof blister, i.e., a blister that is difficult for children to open but easily accessible by adults. Furthermore, the dosing schedule can be designated, for example, by numbers, letters, or other markings, or by a calendar feature. For example, a morning dose can be designated "daytime" and packaged with an afternoon dose. Alternatively, the morning and afternoon doses can be packaged together. The card with the blister can be attached to the e-cigarette cartridge.

[0120] In one embodiment, the package, kit, or container comprises a "blister package" (also called a blister pack or bubble pack). In another embodiment, the blister package comprises two or more separate compartments, such as a morning dose and an afternoon dose. The blister package comprises two separate material components: a clear plastic cavity shaped to fit the product, and a blister board backing. The two components are joined by a heat sealing process, allowing for hanging or in-store display. Examples of such blister packages include face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, and slide blister packages.

[0121] Blister packs, clamshells, and trays are packaging forms used for commercial products. The present invention also provides blister packs, clamshells, and trays for containing the compositions of the present invention. These blister packs, clamshells, and trays can be designed to be non-reclosable, allowing consumers to know if the package has been opened. In one embodiment, the blister pack of the present invention is comprised of a molded PVC base with raised areas ("blisters") for receiving tablets, pills, etc., comprising the combination of the present invention, and is covered with a foil laminate. The tablets, pills, etc. are removed from the pack by peeling back the foil or by pressing the blister, forcing the tablets to break the foil. In one embodiment, a special form of blister pack is a strip pack.

[0122] In some embodiments, a blister pack constitutes a packaging method in which a composition comprising the components of the present invention is contained between a card and a transparent PVC layer. The PVC is transparent, allowing for easy viewing and inspection of the contents (e.g., tablets, gel tabs, etc.). In some embodiments, the blister pack tightly encases the composition comprising the components of the present invention and includes a vacuum around the mold to provide space for opening after purchase. In other embodiments, the card is brightly colored and designed according to the contents (e.g., tablets, gel tabs, etc.), and the PVC is attached to the card using a tab along which adhesive is placed. This adhesive can be strong enough to hook onto a peg, or weak enough to allow for easy tearing of the bond and easy access to the contents. In some embodiments, for larger contents or multiple tablets, tablets, or gel tabs, the card may have a perforated window for access. In some embodiments, a more secure blister pack is employed, such as for the tablets, tablets, and gel tabs of the present invention. Here, the edges of the molded PVC sheet are interlocked, the interior is vacuum-filled, and an informational card may be included.

[0123] In some embodiments, the blister package may consist of at least two components: a "blister" containing the product (e.g., a pharmaceutical combination of the present invention) and a "blister card," which is a printed card with an adhesive coating on the front side. During the packaging process, the blister component, typically made of PVC, can be attached to the blister card using a blister machine. This machine applies heat to the flange of the blister, activating the adhesive on that portion of the card, ultimately securing the PVG blister to the printed blister card. The thermoformed PVG blister and printed blister card can be small or large. Conventional blister packs can also be sealed using standard heat-sealing tools (e.g., AERGO 8 DUO™, SCA Consumer Packaging, Inc., DeKalb, 111).

[0124] As described herein, the compositions of the present invention, alone or in combination, can be configured as multiple packets, including as "blister packages," blister packages with lids, blisters with lids, blister cards, packets, and shrink wrap.

[0125] In some embodiments, for example, laminated aluminum foil blister packs are used for medications designed to dissolve immediately in the patient's mouth. In this example, the drug combination of the present invention is prepared as an aqueous solution(s) that is dispensed (e.g., in measured doses) into the aluminum (e.g., Alfoil) laminate tray portion of the blister pack. This tray can be lyophilized to form tablets suitable for the blister pockets. Both the tray and lid are Alfoil laminated, providing high moisture absorption and complete protection for the dose. In some embodiments, a child-resistant peel-open security laminate is used. In some embodiments, the Alfoil pocket, which the tablet contacts as it transitions from an aqueous to a solid state, is designed and the tablet is marked with an identifying mark. In other embodiments, individual "push-through" blister packs or packets are used. For example, a hard-tempered aluminum (e.g., Alfoil) lid material is used. In some embodiments, a hermetically sealed high-barrier aluminum (e.g., Alfoil) laminate is used. In another embodiment, the articles of manufacture of the present invention, including kits or blister packs, use foil laminates, and some include strip packs, stick packs, sachets, pouches, peelable and non-peelable laminates that combine foil, paper, and film for high barrier packaging.

[0126] Other means for containing prescribed doses include bottles or vials, which may comprise a memory aid such as a printed label for administering the prescribed dose. The label may also include a reminder such as a calendar or tear-off sheet to ensure the patient keeps track of when the dose should be taken and when the dose has been taken.

[0127] dosage The pharmaceutical composition of the present invention may be optimized for a specific type of delivery.For example, pharmaceutical compositions for oral delivery are formulated using pharmaceutically acceptable carriers well known in the art.The carrier allows the drug in the composition to be formulated as, for example, vape solution, tablet, pill, capsule, solution, suspension, sustained release formulation, powder, liquid or gel for oral ingestion by the subject in respiratory and oral formats.

[0128] The pharmaceutical composition can also be delivered in an aerosol spray formulation from a pressurized pack, a nebulizer, or a dry powder inhaler. Suitable propellants for use in nebulizers include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. The dosage can be determined by providing a valve to deliver a regulated amount of the compound in the case of a pressurized aerosol. Compositions for inhalation or pneumoperitoneum include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Ideally, the compositions are administered orally, nasally, or via the respiratory route for local or systemic effect. Compositions in sterile, pharmaceutically acceptable solvents may also be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the device, or the device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Ideally, solution, suspension, or powder compositions can be administered orally or intranasally from a device that delivers the formulation in an appropriate manner. Electronic vaporizers, such as electronic cigarettes, may be disposable devices containing a pharmaceutical product or may be multi-use devices with pre-filled cartridges of pharmaceutical product containing a pharmaceutical active ingredient and excipients including a carrier.

[0129] In certain embodiments, the compositions of the invention can be administered repeatedly over a period of time, in such embodiments, the administration regimen generally allows for regular administration, such as daily, for a treatment period of at least 1 month, or at least 3 months, or at least 6 months.

[0130] Alternatively, the compositions of the present invention can be used intermittently or periodically, for example, the compositions can be used for two or more days, stopped, and then resumed after a period ranging from two weeks to three months, or even at longer intervals.

[0131] The route of administration of the compounds of the present invention varies depending on the site and nature of the condition to be treated. Examples include inhalation, intradermal, transdermal, parenteral, intravenous, intramuscular, nasal, subcutaneous, transdermal, intratracheal, intraperitoneal, perfusion, lavage, direct injection, and oral administration / formulation. As described in detail below, the compounds of the present invention can be administered by inhalation or intubation as medical gases, by intravascular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration as injections, as topical solutions or gels, or as oral solids (also referred to as solid oral dosage forms).

[0132] The length of administration time varies depending on the type of organism (e.g., cell type, tissue type, genus and species of organism) and its size (e.g., weight, surface area), as well as the dosage form and route of administration. In some embodiments, the compounds of the present invention are administered over a period of about 30 seconds, 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 24 hours, or even longer than 24 hours. The compounds of the present invention may be administered in a single dose or multiple doses, and may be administered at varying intervals.

[0133] Therapeutic agents include various "doses." A dosage unit contains a predetermined amount of a therapeutic composition. The amount to be administered, as well as the specific route and formulation, is within the skill of a clinical practitioner. The dose need not be administered as a single injection, but can be continuously infused over a period of time. The specified amount may be the amount administered as an average daily, weekly, or monthly dose.

[0134] In some embodiments, the present invention provides a topical pharmaceutical formulation for use in treatment, comprising a composition of the present invention and at least one pharmaceutically acceptable excipient. In such embodiments, the present invention may provide an external preparation 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 mucous membrane.

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

[0136] While the present invention has been described with reference to specific exemplary embodiments, it should be understood that these are merely illustrative of the invention and are not limiting. It should also be understood that modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited to the illustrated embodiments. It is not limited to the embodiments, but rather is limited only by the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising two chemically linked antiviral agents, wherein a first antiviral agent is an antiviral agent selected from the group consisting of entry inhibitors, RNA-dependent RNA polymerase inhibitors, protease inhibitors, glucocorticoid receptor modulators, androgen receptor modulators, and pharmaceutically acceptable salts thereof, and a second antiviral agent is selected from the group consisting of RNA-dependent RNA polymerase inhibitors, protease inhibitors, glucocorticoid receptor modulators, androgen receptor modulators, endosomal acidification microRNA inhibitors, and pharmaceutically acceptable salts thereof.

2. 10. The pharmaceutical composition of claim 1, wherein the entry inhibitor comprises valsartan, or a pharmaceutically acceptable salt thereof.

3. 2. The pharmaceutical composition of claim 1, wherein the RNA-dependent RNA polymerase activity inhibitor is selected from the group consisting of rifampin, myricetin, remdesivir, a ribose-active metabolite of remdesivir, and a pharmaceutically acceptable salt thereof.

4. 10. The pharmaceutical composition of claim 1, wherein the protease inhibitor is selected from the group consisting of rupintrivir, ritonavir, lopinavir, and pharmaceutically acceptable salts thereof.

5. 2. The pharmaceutical composition of claim 1, wherein the glucocorticoid receptor modulator and the androgen receptor modulator are selected from the group consisting of dexamethasone, mifepristone, lilacorilant, milicorilant, and pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition of claim 1, wherein the endosomal acidification microRNA inhibitor comprises hydroxychloroquine or a pharmaceutically acceptable salt thereof.

7. 10. The pharmaceutical composition of claim 1, comprising a chemically bonded third antiviral agent selected from the group consisting of a protease inhibitor and a pharmaceutically acceptable salt thereof.

8. 8. The pharmaceutical composition of claim 7, wherein the third antiviral agent is selected from the group consisting of rupintrivir, ritonavir, lopinavir, and pharmaceutically acceptable salts thereof.

9. 2. The pharmaceutical composition of claim 1, wherein the first antiviral agent comprises the group consisting of remdesivir, a ribose alcohol active metabolite of remdesivir, or a pharmaceutically acceptable salt thereof, and the second antiviral agent comprises the group consisting of hydroxychloroquine or a pharmaceutically acceptable salt thereof.

10. 2. The pharmaceutical composition of claim 1, wherein the first antiviral agent comprises the group consisting of remdesivir, a ribose alcohol active metabolite of remdesivir, or a pharmaceutically acceptable salt thereof, and the second antiviral agent comprises the group consisting of dexamethasone or a pharmaceutically acceptable salt thereof.

11. 10. The pharmaceutical composition of claim 1, wherein the two chemically bonded antiviral agents are vaporized in combination with a carrier suitable for respiratory administration to a patient, where the heat of vaporization can separate the two chemically bonded antiviral agents.

12. 8. The pharmaceutical composition of claim 7, wherein the three chemically bonded antiviral agents are vaporized in combination with a carrier suitable for respiratory administration to a patient, where the heat of vaporization also allows the three chemically bonded antiviral agents to separate.

13. 10. The pharmaceutical composition of claim 1, comprising an antibacterial agent, an antifungal agent, or an antiprotozoal agent.

14. 10. The pharmaceutical composition of claim 1, wherein the chemical bond between the antiviral agents comprises at least one carbamate or carbonate group.

15. A method of treating a viral disease, comprising administering to a patient by vaporization the pharmaceutical composition of claim 1 in combination with a carrier suitable for respiratory administration, including dissociating the chemically bound antiviral agent by the heat of vaporization.

16. 16. The method of claim 15, wherein the disease is selected from the group consisting of SARS, MERS, and SARS-CoV-2.

17. 16. The method of claim 15, wherein the first antiviral agent comprises the group consisting of remdesivir, a ribose active metabolite of remdesivir, or a pharmaceutically acceptable salt thereof, and the second antiviral agent comprises the group consisting of hydroxychloroquine or a pharmaceutically acceptable salt thereof.

18. 16. The method of claim 15, wherein the first antiviral agent comprises the group consisting of remdesivir, a ribose active metabolite of remdesivir, or a pharmaceutically acceptable salt thereof, and the second antiviral agent comprises the group consisting of dexamethasone or a pharmaceutically acceptable salt thereof.

19. 16. The method of claim 15, wherein the pharmaceutical composition comprises three chemically linked antiviral agents.

20. 16. The method of claim 15, wherein the pharmaceutical composition comprises an antibacterial agent, an antifungal agent, or an antiprotozoal agent.

Images