EP4750460A2 - Solid dosage form of a small molecule antiviral and uses thereof - Google Patents

Abstract

The present disclosure is directed to oral dosage forms that comprise an antiviral nucleoside and one or more excipients, wherein the oral dosage form is a tablet. The antiviral nucleoside is selected from prodrugs of β-D-N(4)-hydroxycytidine (I) such as {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate): Compound (A), or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

Description

SOLID DOSAGE FORM OF A SMALL MOLECULE ANTIVIRAL AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/515,965 filed July 27, 2023, the entire contents of which are incorporated by reference herein.

FIELD

[0002] The present disclosure relates to solid dosage formulations of a small molecule antiviral. The solid dosage formulations of the invention are typically tablets, such as compressed tablets. The present disclosure also relates to uses and methods of using the solid dosage forms for the treatment or prevention of viral infection in a patient in need thereof.

BACKGROUND

[0003] Viral infections, such as infections caused by Eastern Equine Encephalitis Vims (EEEV), Western Equine Encephalitis Vims (WEEV), and Venezuelan Equine Encephalitis Vims (VEEV), Chikungunya fever virus (CHIK), Ebola virus, influenza virus, respiratory syncytial vims (RSV), Zika vims, and coronaviruses, such as Severe Acute Respiratory' Syndrome Coronavirus (SARS-CoV or SARS-CoV-1), Middle East Respiratory Syndrome Coronavims (MERS-CoV), and, most recently, SARS-CoV-2 (or 2019-nCoV), continue to cause illnesses, which can be mild to severe to life-threatening and fatal, across the globe.

[0004] EEEV, WEEV, VEEV, and CHIK virus are vector-bome viruses (family Togaviridae, genus Alphavirus') that can be transmitted to humans through mosquito bites. The equine encephalitis vimses are Centers for Disease Control (CDC) Category B pathogens, and the CHIK virus is Category C.

[0005] Coronaviruses cause a large percentage of respiratory illnesses in humans, which can be severe or life-threatening. SARS-CoV-1, which emerged in 2002, has caused at least 8439 human illnesses globally and at least 812 deaths WHO Cumulative Number of Reported Probable Cases ofSARS, From 1 Nov 2002 To 4 July 2003, downloaded from www.who.int/csr/sars/country/2003_07_04/en/. on August 12, 2020). Similarly, MERS-CoV emerged in 2012 and has caused at least 2519 human illnesses globally and at least 866 deaths WHO Middle East respiratory syndrome, MERS situation update, January 2020, downloaded from www.emro.who.int/health-topics/mers-cov/mers-outbreaks.html, on August 12, 2020).

More recently, SARS-CoV-2 emerged in 2019, and it has caused at least 629 million confirmed human illnesses globally and at least 6.5 million deaths {World Health Organization COVID-19 Weekly Epidemiological Update. Issue No. 117. published 9 November 2022, downloaded from www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19 — 9-november- 2022, on November 10, 2022). SARS-CoV-2 causes the disease referred to as COVID-19, which can include severe respiratory disease and systemic disease manifestations in humans. SARS- CoV-2 infection is also associated with mental and neurological symptoms that can include delirium or encephalopathy, agitation, stroke, meningo-encephalitis, impaired sense of smell or taste, anxiety, depression, and sleep problems, and these neurological symptoms can occur in the absence of respiratory symptoms (see Clinical management of COVID- 19 (Interim guidance, 27 May 2020), downloaded from www.who.int/publications/i/item/clinical-management-of-covid- 19, on September 15, 2020). Additional studies are needed to further characterize the SARS- CoV-2 virus and to identify ways to prevent and treat the COVID-19 disease, as well as diseases caused by other human coronaviruses.

[0006] Many patients with COVID-19 recover with no or minimal medical intervention.

However, clinical progression to severe disease severely impacts both patients and healthcare systems, increasing an individual’s risks of requiring mechanical ventilation and of death and potentially overburdening hospital capacity⁷ and available healthcare resources during COVID-19 surges. Reducing the number of patients requiring hospitalization for COVID- 19 is therefore critical. Vaccination remains by far the most important medical intervention available to reduce the risk of hospitalization or death from COVID-19. However, early treatment soon after symptom onset has also been shown as effective. Monoclonal antibodies bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab were originally the only treatments authorized for at-risk outpatients with COVID- 19. Because monoclonal antibodies require administration via infusion or injection in a medical setting, a direct-acting, oral agent that can be self-administered at home after diagnosis may be more practical for non-hospitalized patients and would be an important new tool in treating COVID-19 caused by SARS-CoV-2. [0007] Antiviral agents continue to be developed to treat viral infections. For example, the antiviral nucleoside fyD-M4)-hydroxy cytidine (NHC, l-((2 ,3 .4<S’,57?)-3.4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidin-2(777)-one), has antipestivirus and antihepacivirus activities. ANTIM1CROB AGENTS CHEMOTHER, 2003, 47(l):244-54. While NEIC has been shown to have limited oral bioavailability in nonhuman primates (see Toots et al., SCI. TRANSL. MED. 11, eaax5866 (2019)), prodrugs ofNHC, including {(2R, 3.S'.4/ .5/?)-3.4-dihy droxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin- 1 (277) -yl] oxolan-2-yl } methyl 2-methy Ipropanoate) : Compound A, which is also known as uridine 4-oxime 5'-(2-methylpropanoate) and molnupiravir, are orally bioavailable and are understood to be potentially useful for the treatment of viral infections caused by at least Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, and Venezuelan Equine Encephalitis Virus, Chikungunya fever virus, Ebola virus, influenza virus, respiratory syncytial virus, Zika virus, and coronaviruses, such as Severe Acute Respiratory⁷ Syndrome Coronavirus, Middle East Respiratory Syndrome Coronavirus, and, most recently, SARS-CoV-2.

[0008] P-D-JV(4)-hydroxycytidine, its prodrugs, its derivatives, and methods for making the same are illustrated in PCT International Patent Application No. PCT/US2015/066144, which published as PCT International Patent Application Publication No. W02016/106050, and United States Patent Application No. 15/537,087. which published as United States Patent Application Publication No. US2019/0022116, and United States Patent Application No. 16/921,359, which published as United States Patent Application No. US 2021/0060050 and issued as United States Patent No. 11, 628, 181, each of which are incorporated herein by reference in their entirety.

Compound A. and pharmaceutically acceptable salts, tautomers, and prodrugs thereof, as well as additional derivatives of P-D-/V(4)-hydroxy cytidine, and methods for making the same are illustrated in PCT International Patent Application No. PCT/US2018/064503, which published as PCT International Patent Application Publication No. WO2019/113462, and United States Patent Application No. 16/755,779. now United States Patent No. 11,331,331. and United States Patent Application No. 17/465,344. which published as US 2022/0016153 Al, and in United States Provisional Patent Application No. 63/127,484, and PCT International Patent Application No. PCT/US2021/064021, which published as PCT International Patent Application Publication No. WO2022/133205, each of which are incorporated herein by reference in their entirety⁷. [0009] Compound A is marketed for the treatment of viral infections caused by SARS-CoV-2 and other pathogens, as well as for the treatment of COVID-19 caused by SARS-CoV-2. However, the 800 mg dose, administered twice daily for five days, takes the form of four (4) capsules. Each of these capsules is a size 0 capsule that is 21.7 mm x 7.6 mm and has a 200 mg unit dosage strength, and each represents a unit dosage form. The size and number of unit dosage forms required at each dose administration creates a significant pill burden, both in terms of the size of each capsule and in terms of the number of capsules administered at each dosage interval. The pill burden can affect whether a patient takes the medication as prescribed (either by number of single dosage forms or by adherence to a schedule for dosing). With a high pill burden also come other risks, such as increased risks of medication errors and increased costs.

[0010] There is a need for oral dosage formulations of antiviral nucleosides, such as Compound A, that reduce pill burden by reducing the number of unit dosage forms required at each dose administration, by reducing the size of each unit dosage form, or both. Reducing the pill burden will ultimately improve compliance, and, therefore, efficacy, and will decrease risk of medication error and decrease costs. However, the design of such formulations remains largely unpredictable.

SUMMARY

[0011] The present disclosure relates to oral dosage forms of pharmaceutical formulations that comprise an antiviral nucleoside and one or more excipients, wherein the oral dosage form is a tablet. The antiviral nucleoside is selected from prodrugs of P-D-JV(4)-hydroxy cytidine, such as {(27?,3S,47?,57?)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2/Z)- yl]oxolan-2-yl} methyl 2-methylpropanoate): (Compound A) or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. Embodiments of such oral dosage forms may be prepared by wet granulation, direct compression, or by roller compaction. [0012] Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims. The summary of the technology described above is non-limiting, and other features and advantages of the technology will be apparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 shows the tablet-ability profile of the granules and powder blend of Compound A prepared using different techniques according to Example 2.

[0014] Figure 2 shows tablet friability for Formulation B of Compound A as compared to Formulation D of Compound A.

[0015] Figure 3 shows tablet-ability of the granules of the capsule formulation of Example 1 as compared to Formulation D of Compound A.

[0016] Figure 4 illustrates the effect of increasing amounts of sodium lauryl sulfate in high shear wet granulation formulations of Compound A.

[0017] Figure 5 compares the dissolution of high-shear, wet granulation formulations of Compound A having differing levels of extragranular excipients.

[0018] Figure 6 illustrates bioequivalence between the capsule formulation of Compound A and tablet Formulation D of Compound A.

DETAILED DESCRIPTION

DEFINITIONS

[0019] Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure relates. [0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry', and peptide chemistry are those well-known and commonly employed in the art.

[0021] As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise. [0022] The terms “administration of’ and or “administering” a compound should be understood to include providing a compound described herein, or a pharmaceutically acceptable salt thereof, and compositions of the foregoing to a subject.

[0023] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

[0024] The term “subject” (alternatively “patient” or “participant”, as in a clinical trial participant) as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g., pigs), ovine (e.g., sheep), capra (e.g., goats), equine (e.g., horses), canine (e.g., domestic dogs), feline (e.g., house cats), lagomorpha (e.g., rabbits), rodents (e.g., rats or mice), and procyon (e.g., raccoons). In particular embodiments, the subject is human. In some embodiments, the patient is an adult patient. In other embodiments, the patient is a pediatric patient. Those “in need of treatment” include those patients that may benefit from treatment with the formulations of the invention, e.g., a patient suffering from a viral infection, such as infection by SARS-CoV-2.

[0025] The term “viral infection” as used herein refers to infection by a virus. In embodiments, the virus is selected from the group consisting of Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV). Venezuelan equine encephalitis virus (VEEV), Chikungunya virus (CHIK), Ross River virus, orthomyxoviridae virus, paramyxoviridae virus, respiratory syncytial virus (RSV), influenza A virus, influenza B virus, filoviridae virus, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. Viral infection may be symptomatic or asymptomatic.

[0026] The term “subject in need thereof’ as used herein refers to a subject diagnosed with, or suspected of having, a viral infection, such as infection by SARS-CoV-2 (either symptomatic or asymptomatic), a subject at risk of being exposed to a viral infection, such as at risk of being exposed to a viral infection, such as infection by SARS-CoV-2 (such as, for example, health care workers who may be at risk of exposure to SARS-CoV-2), a subject exposed to a viral infection, such as infection by SARS-CoV-2 (such as household contacts of COVID-19 patients or asymptomatic patients infected with SARS-CoV-2), as defined herein.

[0027] As used herein, the term “COVID-19” refers to the disease caused by SARS-CoV-2 infection. Subjects infected with SARS-CoV-2 who have developed symptoms are considered to have COVID- 19.

[0028] Certain subjects may be considered to be at increased risk for severe illness from COVID-19. Such individuals may have one or more underlying medical conditions associated with being at increased risk for severe illness from COVID-19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding individuals on dialysis or who have reduced estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²), chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)Z(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus.

[0029] As used herein, the terms “treatment"’ and “treating’" refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.

[0030] As used herein, the terms “prophylaxis” and “antiviral prophylaxis” refer to all processes intended to prevent disease. Prophylaxis may occur prior to exposure to a viral infection, such as infection by SARS-CoV-2 (pre-exposure. for example, in health care workers who may be exposed to such infection) or after a potential exposure to a viral infection, such as infection by SARS-CoV-2 (post-exposure, for example, in household members or caregivers of symptomatic or asymptomatic patients infected with SARS-CoV-2).

[0031] The term “simultaneous administration” as used herein refers to the administration of medicaments such that the individual medicaments are present within a subject at the same time. In addition to the concomitant administration of medicaments (via the same or alternative routes), simultaneous administration may include the administration of the medicaments (via the same or an alternative route) at different times.

[0032] The term "tablet" or “compressed tablet” as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes. Typical tablets may be round, oval, shaped similarly to a capsule, or have other geometric shapes. Typical tablets may have a longest length or diameter (that is the length of the diameter, if the tablet is round, or the length of the longest dimension, if the tablet is oval, capsule-shaped, or having another shape) that is at least about 5.00 mm ± 0.15 mm, such as in a range from about 5.00 mm ± 0. 15 mm to about 22.00 mm ± 0.15 mm, from about 12.80 mm ± 0. 15 mm to about 19.00 mm ± 0. 15 mm, from about 13.00 mm ± 0. 15 mm to about 17.00 mm ± 0.15 mm, or about 13.36 mm ± 0.15 mm.

[0033] Unless expressly stated to the contrary, all ranges cited herein are inclusive, i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. All ranges also are intended to include all included sub-ranges, although not necessarily explicitly set forth. As an example, temperature ranges, percentages (%), ranges of equivalents, and the like descnbed herein include the upper and lower limits of the range and any value in the continuum there between. Numerical values provided herein, and the use of the term “about”, may include variations of ± 1%, ± 2%, ±3%, ± 4%, ± 5%, and ± 10% and their numerical equivalents.

[0034] “About” when used to modify a numerically defined parameter (e.g., the dose of an antiviral nucleoside, or the length of treatment time with a combination therapy described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter, where appropriate, the stated parameter may be rounded to the nearest whole number. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. In addition, the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined, that is, the term “or” includes each listed alternative separately as well as their combination. The term “about”, when modifying the quantify (e.g., mM, or M) of a substance or composition, the percentage (v/v or w/v) of a formulation component, the pH of a solution/formulation, or the value of a parameter characterizing a step in a method, or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and/or use of the substance or composition, through inadvertent error in these procedures, through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures, and the like. In certain embodiments, “about” can mean a variation of ± 0.100 %, 0.500 %, 1.00 %, 2.00 %, 3.00 %, 4.00 %, 5.00 %, or 10.0 %. [0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. In case of conflict, the present specification, including definitions, will control.

[0036] Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising” are used in an inclusive sense, i.e., to specify⁷ the presence of the stated features but not to preclude the presence or addition of further features that may materially enhance the operation or utility of any of the embodiments of the invention, unless the context requires otherwise due to express language or necessary implication. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

[0037] It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and/or “consisting essentially of’ are also provided. [0038] The phrase "consists essentially of.” or variations such as “consist essentially of’ or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion of other elements, of similar or different nature than the recited elements, that do not materially change the basic or novel properties of the specified dosage regimen, method, or composition.

[0039] The terms “pharmaceutically effective amount” and “effective amount” mean an amount whereby sufficient therapeutic composition or formulation is introduced to a patient to cause a therapeutic or prophylactic effect to treat a diseased or condition. One skilled in the art will recognize that this amount may vary according to a patient’s characteristics such as age, weight, etc.

[0040] “Pharmaceutically acceptable” refers to excipients (vehicles, additives) and compositions that can reasonably be administered to a subject to provide an effective dose of the active ingredient employed and that are “generally regarded as safe”, e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. In another embodiment, this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government or listed in the United States Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0041] The term “pharmaceutically acceptable carrier” refers to any inactive substance that is suitable for use in a formulation for the delivery⁷ of a therapeutic agent. A carrier may be an antiadherent, binder, coating, disintegrant. filler or diluent, lubricant, preservative (such as antioxidant, antibacterial, or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifying agent, buffer, and the like. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), dextrose, vegetable oils (such as olive oil), saline, buffer, buffered saline, and isotonic agents such as sugars, polyalcohols, sorbitol, and sodium chloride.

[0042] The term “pharmaceutical formulation” refers to preparations that are in such form as to permit the active ingredients to be effective. The term “formulation” and “pharmaceutical formulation” are used interchangeably throughout.

[0043] “Direct compression” is defined as a process involving pre-milling each ingredient of a formulation (e.g., the active drug substance and excipients) into a powder, mixing the powdered ingredients and any lubricants, and compressing the mixed powders into tablets. When the formulation is to be processed by direct compression, the active ingredient, herein an antiviral compound, may be provided for pre-milling either directly, “as is”. from synthesis or after purification by a suitable method, such as recrystallization.

[0044] “Wet granulation” is defined as a process involving granulating a powder with liquid (aqueous, non-aqueous, hot melt, etc.) to achieve the desired properties for subsequent downstream processes. The liquid (e.g., water, binder solution) is added to a powder blend while the powder blend is being continuously mixing, leading to granule nucleation and growth. When the formulation is to be processed by wet granulation, the antiviral compound may be provided directly, “as is”, from synthesis or after purification by a suitable method, such as recrystallization.

[0045] “Roller compaction” is defined as an agglomeration process where a powder is compressed into a dense compact (or ribbon) using two counter-rotating rollers. The pressing forces from the rollers cause the particles to deform plastically to achieve the dense compact. The dense compact is subsequently broken up and milled into granules. The advantages of roller compaction include improved flow, better content uniformity, and/or less sticking. Roller compaction is also preferred for moisture sensitive and/or heat sensitive formulations.

[0046] Excipients that are mixed with other ingredients (including the antiviral compound) prior to granulation, and are thus incorporated within the tablets, comprise the intragranular component of the formulation. Excipients that are mixed with the dry granules before the complete mixture is compacted comprise the extragranular component of the formulation. Excipients that may be suitable for inclusion in the oral dosage forms set forth herein include compression aids, diluents, disintegrants, lubricants, salts, glidants, surfactants, solubilizers, wetting agents, binders, and/or fillers.

[0047] The term “compression aid” refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that is a pharmacologically inactive substance that may be compacted easily even when mixed with an active drug substance, and that improves flowability and compressibility during manufacture of tablets. Examples of suitable pharmaceutically acceptable compression aids for use in the oral dosage forms described herein include directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, spray cry stallized maltose, cry stalline sorbitol, mannitol, microfine cellulose, and microcrystalline cellulose.

[0048] The term “diluent” refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that is a pharmacologically inactive substance that acts as fillers to increase weight and improve content uniformity. Diluents may also provide better tablet properties such as improved cohesion and flow. Diluents should be physically and chemically stable by themselves and in combination with the active ingredient. Examples of suitable pharmaceutically acceptable diluents for use in the oral dosage forms described herein include directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, spray crystallized maltose, crystalline sorbitol, mannitol, microfine cellulose, and microcrystalline cellulose.

[0049] Herein, a substance may be both a pharmaceutically acceptable compression aid and a pharmaceutically acceptable diluent and may be used for either purpose, or for both purposes, in a particular formulation.

[0050] The term “disintegrant” refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that causes them to disintegrate and release their medicinal substances on contact with moisture. In general, disintegrants absorb water and expand when wet, causing tablet formulations to break apart in the digestive tract, releasing the active ingredient(s) for absorption. Particular disintegrants, known as super-disintegrants. are disintegrants that have a greater effectiveness at low concentrations (when compared with other disintegrants) in tablet formulations. In some instances, the disintegrant can react with the active ingredient. Examples of suitable pharmaceutically acceptable disintegrants for use in the oral dosage forms described herein include calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, com starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium.

[0051] The term “lubricant” refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that decreases friction between the surfaces of the compression apparatus and the tablet itself. Examples of suitable pharmaceutically acceptable lubricants for use in the oral dosage forms described herein include magnesium silicate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, and magnesium stearate.

[0052] The term “glidant” refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that enhances the flow of a granular mixture by reducing friction between the particles. Examples of suitable pharmaceutically acceptable glidants for use in the oral dosage forms described herein include com starch, talc, colloidal silica, and tri-basic calcium phosphate (CasIPOrMOHj). [0053] The term "surfactant” and/or “wetting agent’; as used in the preparation of pharmaceutical dosage forms, such as tablets, refers to organic substances having amphipathic structures; namely, they are composed of groups of opposing solubility tendencies, typically an oil-soluble hydrocarbon chain and a water-soluble ionic group. Surfactants can be classified, depending on the charge of the surface-active moiety, into anionic, cationic, nonionic, and ampholytic or zwitterionic surfactants. Surfactants are often used as wetting, emulsifying, solubilizing, and dispersing agents for various pharmaceutical compositions and preparations of biological materials. Examples of pharmaceutically acceptable surfactants include polysorbates (e.g., polysorbates 20 or 80): polyoxamers (e.g.. POLOXAMER® 188. POLOXAMER® 407 copolymer; poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)); ethyl oxylate based surfactants (e.g., TRITON® surfactants, such as 2-[4-(2,4,4-trimethylpentan- 2-yl)phenoxy] ethanol); sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl- sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetylbetaine; lauroamidopropyl-, cocamidopropyl-. linoleamidopropyl-. myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium stearate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium dodecyl benzene sulfonate, sodium cholate, hexadecyltrimethylammonium bromide, dodecyl pyridinium chloride, heptaoxyethylene monodexadecyl ether, n-dodecyl alanine, lecithin; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUA® series (Mona Industries, Inc., Paterson, N.J.), polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68 etc.). Often surfactants are added to formulations to reduce aggregation.

[0054] The term “granulating liquid” or “granulating solvent” refers to a solvent used during a wet granulation process to form bonds between powder particles. The solvent must be volatile, so it can be removed by drying, and non-toxic. In some instances, the granulating liquid includes a binder such as starches, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose), polyvinyl pyrrolidone, and mixtures thereof. The granulating liquids may be prepared by dissolving or dispersing a binder in water or other solvents. Additionally, this granulation liquid may contain surfactants and drug substances. Examples of pharmaceutically acceptable granulating solvent for use in oral dosage forms and described herein include water, organic solvents, such as alcohols, and combinations thereof.

[0055] The terms “binder” and/or “filler” as used herein refer to excipients that are incorporated into the pharmaceutical formulation to ensure that the final form will have the required mechanical strength. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starches, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose (also known as hypromellose), hydroxypropyl cellulose), polyvinyl pyrrolidone, and mixtures thereof. Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof.

[0056] A “stable” formulation is one in which the antiviral compound therein essentially retains its physical stability and/or chemical stability upon storage. Stability can be measured at a selected temperature and relative humidity for a selected time period. For example, in one embodiment, a stable formulation is a formulation with no significant changes observed at ambient temperature (25.0°C to 30.0°C) and relative humidity below 75.0% for at least 12 months. In another embodiment, a stable formulation is a formulation with no significant changes observed at ambient temperature (25.0°C to 30.0°C) and relative humidity below 75.0% for at least 18 months.

[0057] Additional abbreviations may be defined throughout this disclosure.

Oral Dosage Forms

[0058] The present disclosure relates to oral dosage forms of pharmaceutical formulations that comprise an antiviral nucleoside and one or more excipients, wherein the oral dosage form is a tablet. The antiviral nucleoside is selected from prodrugs of P-D-A(4)-hydroxy cytidine, or pharmaceutically acceptable salts or tautomers thereof, such as {(27?,3S,47?,5.R)-3,4-dihydroxy-

5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(277)-yl]oxolan-2-yl} methyl 2- methy Ipropanoate) : Compound A or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. Embodiments of such oral dosage forms may be prepared by wet granulation, direct compression, or by roller compaction. [0059] In embodiments, the antiviral nucleoside is selected from prodrugs of (3-D-A(4)- hydroxy cytidine.

In specific embodiments, the antiviral nucleoside is {(2J?,3 ,4A,5A)-3,4-dihydroxy-5-[4-

(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(277)-yl]oxolan-2-yl}methyl 2-methylpropanoate): Compound A or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. In further embodiments, the antiviral nucleoside is {(27?,3S,4A.5J?)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4- dihydropyrimidin-l(277)-yl]oxolan-2-yl}methyl 2-methylpropanoate): (Compound A) or a tautomer thereof.

[0060] In specific embodiments, the antiviral nucleoside is selected from antiviral nucleosides as disclosed in PCT International Patent Application No. PCT/US2015/066144, which published as WO2016/106050; PCT International Application No. PCT/US2017/021759, which published as WO2017/156380; PCT International Patent Application No. PCT/US2018/064503, which published as PCT International Patent Application Publication No. WO2019/113462; PCT International Patent Application No. PCT/US2018/064503, which published as PCT International Patent Application Publication No. WO2019/113462; United States Patent Application No. 15/537,087, which published as United States Patent Application Publication No.

US2019/0022116; United States Patent Application No. 16/921,359, which published as United States Patent Application No. US 2021/0060050, now United States Patent No. 11.628,181; United States Patent Application No. 16/755,779, now United States Patent No. 11,331,331; United States Patent Application No. 17/465,344, which published as US 2022/0016153 Al; and in United States Provisional Patent Application No. 63/127.484, each of which are incorporated herein by reference in their entirety.

[0061] Methods of preparing NHC and prodrugs thereof are illustrated in PCT International Patent Application No. PCT/US2015/066144, which published as PCT International Patent Application Publication No. W02016/106050; United States Patent Application No. 15/537,087, which published as United States Patent Application Publication No. US2019/0022116; and United States Patent Application No. 16/921,359, which published as United States Patent Application No. US 2021/0060050, now United States Patent No. 11,628,181; each of which are incorporated herein by reference in their entirety. Methods of preparing additional prodrugs of NHC, including Compound A, and tautomers, prodrugs, and derivatives thereof, are disclosed in PCT International Patent Application No. PCT/US2018/064503, which published as PCT International Patent Application Publication No. WO2019/113462; PCT International Patent Application No. PCT/US2021/064021, which published as PCT International Patent Application Publication No. WO2022/ 133205; United States Patent Application No. 16/755,779, now United States Patent No. 11.331,331; United States Patent Application No. 17/465,344, which published as US 2022/0016153 Al, and in United States Provisional Patent Application No. 63/127,484, which are incorporated herein by reference in their entirety.

[0062] In aspects of embodiments, the antiviral nucleoside may be used either directly from synthesis or after purification and may be directly formulated as a solid dosage form by blending or granulating with excipients and compressed into tablets. The granulation process may be a wet granulation process, such as high-shear wet granulation or fluidized-bed granulation, or it may be a dry granulation process, such as roller-compaction.

[0063] The pharmaceutical formulations may be roller compacted or wet granulated to densify, improve flow attributes, and/or reduce the risk of segregation of components during subsequent handling (e.g., compression into tablets). Granulation steps can also be used to minimize the impact of raw material property variability (e.g., excipient particle size) on subsequent processing (e.g., tablet compression) and ultimate product performance. Lubrication is typically performed prior to roller compaction and tablet compression to reduce the tendency of material to adhere to compression surfaces (e.g., tablet tooling). In particular embodiments, the lubricant system is a combination of sodium stearyl fumarate and magnesium stearate. These methods can be carried out by those skilled in the art. See, e.g.. Ansel, INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS, Seventh Edition, 1999.

[0064] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. The tablets may be uncoated or they may be film coated to modify their appearance or may be coated so as to modulate the onset and/or rate of release in the gastrointestinal tract, so as to optimize or maximize the biological exposure of the patient to the antiviral compound. In embodiments, the tablets may be coated with a functional coat to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0065] To prepare the pharmaceutical compositions of the disclosure, the pharmaceutical formulation is compressed into an oral dosage form, such as tablets. Tablets can be prepared with a variety of possible shapes (ellipsoidal, capsule, biconvex round, etc.). Techniques suitable for preparing solid oral dosage forms of the present disclosure are described in REMINGTON’S PHARMACEUTICAL SCIENCES. 18th edition, edited by A. R. Gennaro. 1990, Chapter 89 and in REMINGTON - THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, Chapter 45.

[0066] In a first embodiment, the oral dosage form is a tablet having a longest length that is at least about 5.00 mm ± 0. 15 mm. In aspects of this embodiment, the oral dosage form is a tablet having a longest length in a range of from about 5.00 mm ± 0. 15 mm to about 22.00 mm ± 0. 15 mm, from about 12.80 mm ± 0. 15 mm to about 19.00 mm ± 0. 15 mm, from about 13.00 mm ± 0.15 mm to about 17.00 mm ± 0.15 mm, or about 13.36 mm ± 0.15 mm. Such tablets represent a reduction in size in at least one dimension when compared to size 0 capsules (21.7 mm x 7.6 mm).

[0067] In particular aspects of the first embodiment, the oral dosage form is a single tablet having a longest diameter or length of about 13.36 mm ± 0.15 mm. In further aspects of the first embodiment embodiments, the oral dosage form consists of two tablets, each having a longest diameter or length of about 13.36 mm ± 0. 15 mm. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0068] In a second embodiment, the oral dosage form is a tablet having a total weight when uncoated that is in a range of from about 30 mg to about 2000 mg, such as from about 30 mg to about 1600 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 800 mg, or about 600 mg. [0069] In a third embodiment, the oral dosage form is a tablet comprising an antiviral nucleoside in an amount of at least about 25 mg, such as from about 25 mg to about 800 mg, such as from about 100 mg to about 800 mg, from about 200 mg to about 800 mg, or about 400 mg. [0070] In a fourth embodiment, the oral dosage form is a tablet comprising an antiviral nucleoside in an amount relative to the total weight of the uncoated tablet of from about 6.250 wt% to about 80.00 wt%, such as from about 25.00 wt% to about 80.00 wt%, from about 50.00 wt% to about 75.00 wt%, or about 66.67 v %.

[0071] In a fifth embodiment, the one or more excipients is selected from the group consisting of compression aids, diluents, disintegrants, lubricants, glidants, surfactants or wetting agents, granulating liquids or granulating solvents, binders and/or fillers, and combinations thereof. [0072] In a first aspect of the fifth embodiment, the one or more excipients includes one or more compression aids selected from the group consisting of directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, spray crystallized maltose, spray crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microfine cellulose, and microcrystalline cellulose. In aspects of this embodiment, the one or more compression aid is selected from the group consisting of directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, mannitol, microfine cellulose, and microcrystalline cellulose, and combinations thereof. In instances of this aspect, the one or more compression aid is selected from spray dried lactose, microcrystalline cellulose, and combinations thereof. In specific instances of this aspect, the one or more compression aid is microcrystalline cellulose. In a first instance, the one or more compression aid is present in an amount of from about 6.000 mg to about 1440 mg, such as from about 12.00 mg to about 45. 10 mg. from about 76.65 mg to about 186.6 mg, or about 1 16.0 mg. In a second instance, the one or more compression aid is present in an amount relative to the total weight of the uncoated tablet of from about 1.500 wt% to about 90.00 wt%, such as from about 3.000 wt% to about 41.51 wt%, from about 15.33 wt% to about 23.33 wt%, or about 19.33 wt%.

[0073] In a second aspect of the fifth embodiment, the one or more excipients includes one or more diluents selected from the group consisting of directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, spray crystallized maltose, spray crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microfine cellulose, and microcry stalline cellulose. In aspects of this embodiment, the one or more diluent is selected from the group consisting of directly compressible starches, dibasic calcium phosphate, spray- dried lactose, anhydrous lactose, mannitol, microfine cellulose, and microcrystalline cellulose, and combinations thereof. In instances of this aspect, the one or more diluent is selected from spray dried lactose, microcrystalline cellulose, and combinations thereof. In specific instances of this aspect, the one or more diluent is microcrystalline cellulose. In a first instance, the one or more diluent is present in an amount of from about 6.000 mg to about 1440 mg, such as from about 12.00 mg to about 45. 10 mg, from about 76.65 mg to about 186.6 mg, or about 116.0 mg. In a second instance, the one or more diluent is present in an amount relative to the total weight of the uncoated tablet of from about 1 .500 wt% to about 90.00 wt%, such as from about 3.000 wt% to about 41.51 wt%, from about 15.33 wt% to about 23.33 wt%, or about 19.33 wt%.

[0074] In a third aspect of the fifth embodiment, the one or more excipients includes one or more disintegrants selected from the group consisting of calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium. In instances of this aspect, the one or more disintegrant is selected from the group consisting of calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium. In specific instances of this aspect, the one or more disintegrant is croscarmellose sodium. In a first instance, the one or more disintegrant is present in an amount of from about 0.000 mg to about 240.0 mg, such as from about 12.00 mg to about 120.0 mg, from about 45.00 mg to about 92.00 mg, or about 60.00 mg. In a second instance, the one or more disintegrant is present in an amount relative to the total weight of the tablet of from about 0.000 wt% to about 15.00 wt%, such as from about 3.000 wt% to about 12.00 wt%, from about 9.000 wt% to about 11.50 wt%, or about 10.00 wt%.

[0075] In a fourth aspect of the fifth embodiment, the one or more excipients includes one or more lubricants selected from the group consisting of magnesium silicate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, and magnesium stearate. In specific instances, the one or more lubricant is magnesium stearate. In more specific aspects, the one or more lubricant is extragranular magnesium stearate. In a first instance, the one or more lubricant is present in an amount of from about 0.080 mg to about 32.00 mg, such as from about 2.000 mg to about 20.00 mg, from about 2.500 mg to about 12.00 mg, or about 6.000 mg. In a second instance, the one or more lubricant is present in an amount relative to the total weight of the tablet of from about 0.250 wt% to about 2.000 wt%, such as from about 0.500 wt% to about 2.000 wt%, from about 0.500 wt% to about 1.500 wt%, or about 1.000 wt%.

[0076] In a fifth aspect of the fifth embodiment, the one or more excipients includes one or more glidants selected from the group consisting of com starch, talc, colloidal silica, and tri-basic calcium phosphate. In specific instances of this embodiment, the one or more glidant is tri-basic calcium phosphate. In a first instance, the one or more glidant is present in an amount of from about 0.000 mg to about 80.00 mg, such as from about 0.000 mg to about 25.00 mg, from about 0.000 mg to about 12.00 mg, or about 0.000 mg. In a second instance, the one or more glidant is present in an amount relative to the total weight of the tablet of from about 0.000 wt% to about 5.000 wt%, such as from about 0.000 wt% to about 2.500 wt%, from about 0.000 wt% to about 1.500 wt%, or about 0.000 wt%.

[0077] In a sixth aspect of the fifth embodiment, the one or more excipients includes one or more surfactants or wetting agents selected from the group consisting of polysorbates, poloxamers, TRITON® surfactants (such as 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol), sodium octyl glycoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl- sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine. linoleyl- betaine, myristyl-betaine, cetyl-betaine, lauroamidopropyl-betaine, cocamidopropyl-betaine. linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium stearate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium dodecyl benzene sulfonate, sodium cholate, hexadecyltrimethylammonium bromide, dodecyl pyridinium chloride, heptaoxy ethylene monodexadecyl ether, n-dodecyl alanine, lecithin, sodium methyl cocoyl-taurate, disodium methyl oleyl-taurate, polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol. In specific instances, the one or more surfactant is selected from the group consisting of poloxamers, sodium stearate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium dodecyl benzene sulfonate, and sodium cholate. In other specific instances, the one or more surfactant is selected from the group consisting of poloxamers. In more specific instances, the one or more surfactant is POLOXAMER® 407 copolymer, which is a poly(ethylene glycol)-block-poly(propylene glycol)- block-poly(ethylene glycol). In other specific instances, the one or more surfactant is selected from the group consisting of sodium stearate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium dodecyl benzene sulfonate, and sodium cholate. In more specific instances, the one or more surfactant is sodium laury l sulfate. In further instances, the one or more surfactant is present in an amount of from about 0.000 mg to about 80.00 mg, such as from about 0.000 mg to about 25.00 mg, from about 0.000 mg to about 12.00 mg, or about 0.000 mg. In a third instance, the one or more surfactant is present in an amount relative to the total weight of the tablet of from about 0.000 wt% to about 5.000 wt%, such as from about 0.000 wt% to about 2.500 wt%, from about 0.000 wt% to about 1.500 wt%, or about 0.000 wt%.

[0078] In a seventh aspect of the fifth embodiment, the one or more excipients includes one or more granulating liquids or granulating solvents selected from the group consisting of water, organic solvents, such as alcohols, and combinations thereof. In specific instances of this aspect, the one or more granulating liquids or granulating solvents is water. In a first instance, one or more granulating liquids or granulating solvents is present in an amount relative to the total weight of the tablet of from about 10 wt% to about 80 wt%, such as from about 30 wt% to about 70 wt%, from about 45 v % to about 60 wt%, or about 54 wt%.

[0079] In an eighth aspect of the fifth embodiment, the one or more excipients includes one or more binders and/or fillers selected from the group consisting of starches, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose), poly vinyl pyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof. In instances of this aspect, the one or more binders and/or fillers is selected from the group consisting of starches, cellulose, ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof. In specific instances of this aspect, the one or more binders and/or fillers is hydroxypropyl cellulose. In a first instance, the one or more binders and/or fillers is present in an amount of from about 0.000 mg to about 96.00 mg, such as from about 6.000 mg to about 45.00 mg, from about 7.500 mg to about 36.00 mg, or about 18.00 mg. In a second instance, the one or more binders and/or fillers is present in an amount relative to the total weight of the tablet of from about 0.000 wt% to about 6.000 wt%, such as from about 1.500 wt% to about 4.500 wt%, from about 1.500 wt% to about 4.500 wt%, or about 3.000 wt%.

[0080] In a sixth embodiment, the oral dosage form is a tablet optionally further comprising a coating. In a first aspect, the coating is a formulation that comprises one or more of polymers or film formers, opacifiers, adhesion modifiers, plasticizers, anti-tacking agents, colorants, and mixtures thereof. In specific instances, the coating is a formulation that comprises one or more of polymers opacifiers, adhesion modifiers, plasticizers, colorants, and mixtures thereof. In more specific instances, the coating is a formulation selected from those set forth in Table 1 below. In still more specific instances, the coating is Film Coating A (FC A), which consists of a polymer (hydroxypropyl methylcellulose), an adhesion modifier (lactose monohydrate), an opacifier (calcium carbonate), a placticizer (triacetin), and a colorant (iron oxide).

Table 1

[0081] In a second aspect of this sixth embodiment, the coating is present in an amount of from about 0.000 mg to about 128.0 mg, such as from about 0.000 mg to about 60.00 mg, from about 0.000 mg to about 45.00 mg. or about 24.00 mg. In a third instance, the one or more coating is present in an amount relative to the total weight of the tablet of from about 0.000 wt% to about 8.000 wt%, such as from about 0.000 wt% to about 6.000 wt%, from about 0.000 wt% to about 5.000 wt%, or about 4.000 wt%.

Treatment or Prevention of Viral Infection

[0082] Antiviral nucleosides, including NHC and prodrugs of NHC, such as Compound A, are known to be useful in treating viral infection and may be useful in preventing viral infection. [0083] The present disclosure relates to methods of treating a viral infection, wherein the method comprises administering to a subject in need thereof oral dosage forms as described herein, wherein the viral infection is an infection by a virus selected from the group consisting of EEEV, WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B virus, filoviridae. human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In a second aspect of these embodiments, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific aspects, the virus is selected from the group consisting of influenza A virus and influenza B virus. In further specific aspects, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0084] In embodiments of the treatment methods disclosed herein, the oral dosage forms are administered once daily, as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0085] In embodiments of the treatment methods disclosed herein, the oral dosage forms are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual dose may be provided as 800 mg tablets, 400 mg tablets. 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) to four (4) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength. [0086] In embodiments of the treatment methods disclosed herein, said method comprises administering to a subject in need thereof oral dosage forms as described herein, wherein the oral dosage forms are administered once daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 6 days, such as for 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage forms are administered once daily for 5 days.

[0087] In embodiments of the treatment methods disclosed herein, said method comprises administering to a subject in need thereof oral dosage forms as described herein, wherein the oral dosage forms are administered twice daily for 1 to 21 days, such as for 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. 15 days, 1 days, 17 days, 18 days, 19 days, 20 days or 21 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 6 days, such as for 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage forms are administered twice daily for 5 days.

[0088] The disclosure further relates to a method of treating a viral infection, said method comprising administering to a subject in need thereof oral dosage forms as described herein, wherein the therapy commences from 1 to 10 days after onset of symptoms of viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after the onset of symptoms of viral infection. In specific embodiments, the oral dosage forms are administered beginning less than 5 days after onset of symptoms, such as less than 1 day, 2 days, 3 days. 4 days, or 5 days after onset of symptoms of viral infection. Symptoms of viral infection may include one or more of cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue/tiredness, feeling hot/feverish, chills, headache, nausea, vomiting, and diarrhea, although symptoms may vary' by the ty pe and severity of the viral infection.

[0089] The disclosure further relates to the above described methods of treating a viral infection, wherein said subjects may⁷ be considered or is determined to be at increased risk for severe illness from C OVID- 19. Such individuals may have one or more underlying medical condition associated with being at increased risk for severe illness from C0V1D-19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding participants on dialysis or has reduced eGFR <30 mL/min/1.73 m²). chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)Z(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus. In one embodiment, the subject has not been vaccinated against COVID-19. In another embodiment, the subject has been vaccinated against COVID-19.

[0090] The disclosure further relates to methods of treating a viral infection, wherein said method reduces the risk of hospitalization or death for the subject. In embodiments, the method may result in a reduction in risk of hospitalization or death for the subject. In specific embodiments, the method may result in a reduction in risk of hospitalization or death for the subject of about 1% to about 10%. such as from about 5% to about 7.5%. or about 6.8%. In further embodiments, the method may result in a relative reduction in risk of hospitalization or death for the subject of up to about 50%.

[0091] The disclosure further relates to methods of providing antiviral prophylaxis, said method comprising administering the oral dosage form to a subject in need thereof, wherein the administering commences prior to exposure to a viral infection or after a potential exposure to a viral infection. In specific embodiments, the oral dosage form is administered beginning prior to potential exposure to viral infection. In other specific embodiments, the oral dosage form is administered from 1 to 10 days after potential exposure to a viral infection, such as 1 day, 2 days, 3 days. 4 days. 5 days. 6 days. 7 days. 8 days. 9 days, or 10 days after potential exposure. In specific embodiments, the oral dosage form is administered beginning less than 5 days after potential exposure, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after potential exposure.

[0092] The disclosure further relates to methods of providing antiviral prophylaxis, wherein said subjects may be considered to be at increased risk for severe illness from COVID-19. Such individuals may have one or more underlying medical condition associated with being at increased risk for severe illness from COVID-19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding participants on dialysis or has reduced eGFR <30 mL/min/1 .73 m²), chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)Z(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus. In one embodiment, the subject has not been vaccinated against COVID-19. In another embodiment, the subject has been vaccinated against COVID-19.

[0093] Additionally, the present disclosure relates to methods of providing antiviral prophylaxis, wherein the method comprises administering the oral dosage form to a subject in need thereof, wherein the virus is selected from the group consisting of EEEV, WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae virus, paramyxoviridae virus, RSV, influenza A virus, influenza B vims, filoviridae virus, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola vims, Marburg vims, and Zika vims. In specific embodiments, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae virus, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the vims is selected from the group consisting of influenza A virus and influenza B virus. In specific embodiments, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0094] In embodiments of the prophylaxis methods disclosed herein, the oral dosage forms are administered once daily, as a single dose. In aspects of these embodiments, the single dose maybe provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0095] In embodiments of the prophylaxis methods disclosed herein, the oral dosage forms are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual daily dose may be provided as 800 mg tablets, 400 mg tablets. 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) to four (4) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0096] The disclosure further relates to methods of providing antiviral prophylaxis, said method comprising administering to a subject in need thereof oral dosage forms as described herein, wherein the oral dosage forms are administered once daily for 1 to 42 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days. 40 days, 41 days, or 42 days. In specific embodiments, the oral dosage forms are administered once daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 14 days, such as for 3 days. 4 days. 5 days. 6 days. 7 days. 8 days. 9 days. 10 days, 11 days. 12 days, 13 days, or 14 days.

[0097] The disclosure further relates to methods of providing antiviral prophylaxis, said method comprising administering to a subject in need thereof oral dosage forms as described herein, wherein the oral dosage forms are administered twice daily for 1 to 42 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days. 40 days, 41 days, or 42 days. In specific embodiments, the oral dosage forms are administered twice daily for 1 to 21 days, such as for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 14 days, such as for 3 days. 4 days. 5 days. 6 days. 7 days. 8 days, 9 days, 10 days, 11 days. 12 days, 13 days, or 14 days.

[0098] The disclosure further relates to prophylaxis methods, wherein said method reduces the risk of hospitalization or death for the subj ect. In embodiments, the method may result in a reduction in risk of hospitalization or death for the subject. In specific embodiments, the method may result in a reduction in risk of hospitalization or death for the subject of about 1% to about 10%, such as from about 5% to about 7.5%, or about 6.8%. In further embodiments, the method may result in a relative reduction in risk of hospitalization or death for the subject of up to about 50%.

[0099] Embodiments provided by this disclosure also include oral dosage forms as described herein for use as a medicament for the treatment of viral infection. In specific embodiments, the viral infection is an infection by a virus selected from the group consisting of EEEV. WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B vims, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the vims is selected from the group consisting of influenza A virus and influenza B virus. In specific embodiments, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0100] The disclosure also provides oral dosage forms as described herein for use as a medicament for the treatment of viral infection, where the patient has previously (e.g., within 24 hours) been treated with another agent, which may be as described above.

[0101] In embodiments, the oral dosage forms as described herein for use as a medicament for the treatment of viral infection are administered once daily, as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength. [0102] In embodiments, the oral dosage forms as described herein for use as a medicament for the treatment of viral infection are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) to four (4) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0103] In embodiments of oral dosage forms for use as a medicament for the treatment of viral infection, the oral dosage forms are administered once daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 6 days, such as for 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage forms are administered once daily for 5 days.

[0104] In embodiments of oral dosage forms for use as a medicament for the treatment of viral infection, the oral dosage forms are administered twice daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 6 days, such as for 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage forms are administered twice daily for 5 days.

[0105] The disclosure further relates to oral dosage forms for use as a medicament for the treatment of viral infection, wherein administration of the oral dosage forms are commenced 1 to 10 days after onset of symptoms of viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after the onset of symptoms of viral infection. In specific embodiments, the oral dosage forms are administered beginning less than 5 days after onset of symptoms, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after onset of symptoms of viral infection. Symptoms of viral infection may be as described above.

[0106] The disclosure further relates to oral dosage forms for use as a medicament for the treatment of viral infection, wherein the tablets are administered to a subject who may be considered to be at increased risk for severe illness from COVID-19. Such individuals may have one or more underlying medical condition(s) associated with being at increased risk for severe illness from COVID-19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding participants on dialysis or has reduced eGFR <30 mL/min/1.73 tn²), chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)Z(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus. In one embodiment, the subject has not been vaccinated against COVID-19. In another embodiment, the subject has been vaccinated against COVID-19.

[0107] The disclosure further relates to oral dosage forms for use as a medicament for the treatment of viral infection, wherein administration of oral dosage forms reduces the risk of hospitalization or death for the subject. In embodiments, administration of oral dosage forms may result in a reduction in risk of hospitalization or death for the subject. In specific embodiments, administration of oral dosage forms may result in a reduction in risk of hospitalization or death for the subject of about 1% to about 10%, such as from about 5% to about 7.5%, or about 6.8%. In further embodiments, administration of oral dosage forms may result in a relative reduction in risk of hospitalization or death for the subject of up to about 50%.

[0108] The present disclosure also relates to oral dosage forms for use as a medicament for prevention of viral infection or for providing antiviral prophylaxis, wherein the viral infection to be prevented is caused by a vims selected from the group consisting of EEEV, WEEV. VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika vims. In specific embodiments, the virus is selected from the group consisting of RSV. influenza A virus, influenza B vims, filoviridae, human coronavirus, SARS- CoV-1. MERS-CoV. SARS-CoV-2. and Ebola vims. In specific embodiments, the virus is selected from the group consisting of influenza A virus and influenza B virus. In specific embodiments, the vims is selected from the group consisting of human coronavirus, SARS-CoV- 1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0109] The disclosure also provides oral dosage forms as described herein for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, where the patient has previously (e.g., within 24 hours) been treated with another agent, which may be as described herein.

[0110] In embodiments of the oral dosage forms as described herein for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, the oral dosage forms are administered once daily, as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets. 400 mg tablets. 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[OHl] In embodiments of the oral dosage forms as described herein for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, the oral dosage forms are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) to four (4) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0112] The disclosure further relates to oral dosage forms for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, wherein the oral dosage forms are administered once daily for 1 to 42 days, such as for 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. 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific embodiments, the oral dosage forms are administered once daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days. 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0113] The disclosure further relates to oral dosage forms for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, wherein the oral dosage forms are administered twice daily for 1 to 42 days, such as for 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. 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific embodiments, the oral dosage forms are administered twice daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0114] The disclosure further relates to oral dosage forms for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, wherein the therapy commences prior to exposure to a viral infection or after a potential exposure to a viral infection. In specific embodiments, the oral dosage forms are administered beginning prior to potential exposure to viral infection. In other specific embodiments, the oral dosage forms are administered from 1 to 10 days after potential exposure to a viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after potential exposure. In specific embodiments, the oral dosage forms are administered beginning less than 5 days after potential exposure, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after potential exposure.

[0115] The disclosure further relates to oral dosage forms for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, wherein the oral dosage forms are administered to a subject who may be considered to be at increased risk for severe illness from COVID-19. Such individuals may have one or more underlying medical condition(s) associated with being at increased risk for severe illness from COVID-19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding participants on dialysis or has reduced eGFR <30 mL/min/1.73 m²), chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)Z(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus. In one embodiment, the subject has not been vaccinated against COVID-19. In another embodiment, the subject has been vaccinated against COVID-19.

[0116] Additionally, present disclosure relates to oral dosage forms for use as a medicament for the prevention of viral infection or for providing antiviral prophylaxis, wherein the oral dosage forms are administered to a subject who may have been exposed to a virus selected from the group consisting of EEEV. WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the virus is selected from the group consisting of influenza A virus and influenza B virus. In specific embodiments, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0117] In embodiments of oral dosage forms as described herein for use as a medicament for the treatment of viral infection, where the patient has previously (e.g., within 24 hours) been treated with another agent, the oral dosage forms are administered once daily, as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0118] In embodiments of tablets for use as a medicament for the treatment of viral infection, where the patient has previously (e g., within 24 hours) been treated with another agent, the tablets are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength. Combination Therapy

[0119] In another embodiment, the at least one tablet as described herein can be combined with one or more additional therapeutic agents present methods useful for treating or preventing viral infection.

[0120] In one embodiment, the additional therapeutic agent is an antiviral agent.

[0121] In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.

[0122] Accordingly, in one embodiment, the present disclosure provides methods for treating a viral infection in a subject, the method comprising administering to the subject: (i) the oral dosage forms as described herein, and (ii) at least one additional therapeutic agent, wherein the amounts administered are together effective to treat or prevent a viral infection.

[0123] When administering a combination therapy as described herein to a subject, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as. for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, at least one tablet as described herein and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit.

[0124] In one embodiment, at least one tablet as described herein is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

[0125] In another embodiment, at least one tablet as described herein is administered in doses commonly employed when such agents are used as monotherapy for treating a viral infection. [0126] In another embodiment, at least one tablet as described herein and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.

[0127] In still another embodiment, at least one tablet as described herein and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection. [0128] Viral infections and virus-related disorders that may be treated or prevented using the combination therapy methods as described therein include, but are not limited to, those listed above. [0129] The oral dosage forms as described herein and additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.

[0130] In one embodiment, the administration of oral dosage forms as described herein and the additional therapeutic agent(s) may inhibit the resistance of a viral infection to these agents. [0131] The therapies disclosed herein may be used in combination with one or more other active agents, including but not limited to. antiviral agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., viral infection). In one embodiment, a compound disclosed herein is combined with one or more other antiviral agents for use in the prevention, treatment, control amelioration, or reduction of risk of a particular disease or condition for which the compounds disclosed herein are useful. Such other active agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure.

[0132] When the therapies disclosed herein are used contemporaneously with one or more other active agents, oral dosage forms as described herein may be administered either simultaneously with, or before or after, one or more other active agent(s). Oral dosage forms as described herein may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).

[0133] The dosage amount of the oral dosage forms as described herein and of the one or more other active agent(s) may be varied and will depend upon the therapeutically effective dose. Generally, a therapeutically effective dose of each will be used. Combinations including oral dosage forms as described herein, and other active agents will generally include a therapeutically effective dose of each active agent. In such combinations, oral dosage forms as described herein and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agent(s).

[0134] In one embodiment, this disclosure provides oral dosage forms as described herein, and at least one other active agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is the treatment of a viral infection, such as infection by a virus selected from the group consisting of EEEV, WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In aspects of this embodiment, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS- CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In more specific aspects, the virus is selected from the group consisting of influenza A virus and influenza B virus. In other specific aspects, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In even more specific aspects, the virus is SARS-CoV-2.

[0135] In another embodiment, this disclosure provides oral dosage forms as described herein, and at least one other active agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is antiviral prophylaxis, such as for potential infection, either pre-exposure or post-exposure, by a virus selected from the group consisting of EEEV, WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In aspects of this embodiment, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS- CoV-2, and Ebola virus. In more specific aspects, the virus is selected from the group consisting of influenza A virus and influenza B virus. In other specific aspects, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In even more specific aspects, the virus is SARS-CoV-2.

[0136] The disclosure also provides the use of oral dosage forms as described herein for treating a viral infection, where the patient has previously (e.g., within 24 hours) been treated with another agent.

[0137] The additional active agent(s) may be one or more agents selected from the group consisting of antiviral compounds, antigens, adjuvants, anti-cancer agents, CTLA-4 agonists, LAG-3 agonists, PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, antibiotics, anti-metabolites, retinoids, steroids, and immunomodulatory agents, including but not limited to antiviral vaccines. It will be understood the descriptions of the above additional active agents, and of those listed below, may be overlapping. It will also be understood that the treatment combinations are subject to optimization, and it is understood that the best combination to use of the antiviral nucleoside, and one or more additional active agents will be determined based on the individual patient needs. [0138] Antiviral compounds that may be used in combination with the therapies disclosed herein include direct acting antivirals and antiviral compounds that target intracellular environments. In particular, antiviral compounds that may be used in combination with the therapies disclosed herein include antivirals that target SARS-CoV-2 virus (and COVID-19 caused by SARS-CoV-2 infection), influenza, hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors. Such antiviral compounds include but are not limited to 2-DG, 2x-121, AB001, avifavir, AVM-0703, C21, CAL-02, CYTO-201 (naltrexone hydrochloride), conronavir (TL-FVP-t). DW-2008S, DWJ-1248, elsufavinne, emtncitabine, eFT226, HP-163, IML-206, IMU-838, LAU-7b, MAN- 19, MMS-019, OBP-2001, omega 3 viruxide, OPN-019, OYA-1, PP-001, PRTX-007, RBI-5000, RBT-9, RECCE529, RS-5614, SK11, SLV-213, T-COVID, TL-895, TYME-19, UCI-1, XC-221, fenretinide, nafamostat, nafamostat mesylate, nanomedivir (atazanavir/dexamethasone), nanofenretinide (ST-001), necuparanib (M-402), nelfinavir. nitazoxanide, piclidenoson, pixatimod, polyinosinic-plycytidylic acid, proxalutamide, hydrochloroquine, hydroxychloroquine, chloroquine, oseltamivir, oseltamivir phosphate, zanamivir, peramivir, baloxavir marboxil, remdesivir, favilavir, avifavir, favilavir/avifavir, vaniprevir, grazoprevir, elbasvir, narlaprevir. nitazoxanide, atazanavir, ritonavir, daclatasvir, farunavir, darunavir/cobicistat, saquinavir, indinavir, carfilzomib, ivaltinostat (CG200745), isotretinoin/tamoxifen, isotretinoin, tamoxifen, levamisole, prexasertib, ebselen, merimepodib, 1- deoxy -D-glucose prodrugs, formoterol, budesonide, rigosertib, erlotinib, silmitasertib, favipiravir. galidesivir. ledipasvir, lopinavir, lopinavir/ritonavir, levovir, tenofovir, and sofosbuvir. and combinations thereof.

[0139] Additional therapies that may be used in combination with the therapies disclosed herein include but are not limited to immunomodulators, such as interleukin 6 (IL-6) inhibitors, corticosteroids, TNF-inhibitors, and other immune-dependent therapies, antibody therapies, such as convalescent plasma therapies, hyperimmune globulin therapies, monoclonal antibodies, polyclonal antibodies, and neutralizing antibodies, soluble guanylate cyclase stimulator, such as riociguat, cannibidiols, and vaccines. The additional therapies contemplated include biological products that are biosimilar to any biological product or therapy expressly listed herein.

[0140] In particular, the additional therapies that may be used in combination with the therapies disclosed herein include but are not limited to 2,3,4,5,6-pentafluoro-N-(3-fluoro-4- methoxyphenyl) benzene sulfonamide, 3',4'-didehydro-4'deoxy-8'-norvin-caleukoblastine,

47D11, 5 -fluorouracil, abatacept, abiraterone acetate, ABX464, abibertinib, acalabrutinib, ACE2- Fc. ACE-MAB (STI-4920, CMAB020). acetylsalicylic acid, acetaminophen. ACT-20. Actemra. Actemra/RoActemra, adalimumab, adipose mesenchymal cells, AdMSCs (autologous adipose- derived stem cells), ADR-001, adrecizumab (HAM8101), ADX-629/reproxalap, AK-119, Alferon N, Allocetra (leukocyte cell based therapy), AlloStim, Allorx stem cells, ALT- 100 (enamptcumab), ALT-803, Amnioboost, Ampion. altretamine, amiodarone, Anaferon, Anakinra, AMG-3777, anhydrovinblastine, anti-nCoV nanoviricides, aprepitant, AP-003 (AntiCovir), APL- 9 (pegylated synthetic cyclic peptide), APX-115, AQCH, AR-701, ARO-COV, AS-1411, ascorbic acid, asunercept, atovaquone/azithromycin, AT-100 (rhSP-D), AT-301, AT-H201, ATI- 450, ATR-002. auristatin, avdoralimab (IPH5401), axatilimab, AZD-1061, AZD-7442, alvelestat (AZD-9668), AZD-8895, azvudine, azvudine/tetrandrine, azithromycin, bardoxolone, bardoxolone methyl, baricitinib, BBT-032, bemcentinib, BGE-175, BIO-300, BIOMEDIVR, bevacizumab, bexarotene, bicalutamide, BIO-1106, BLD-2660, BLD-2736, BOLD-100, bomedemstat, brequinar sodium, brilacidin, bromhexine hydrochloride. BTL-TML001, bleomycin. BMS-986253, BMS 184476, BT-086. BT-588, BXCL501, BXT-25, bucillamine, budesonide, cachectin, acalabrutinib, camrelizumab, camrelizumab/thymosin, captopril, CardioIRx, carrimycin, cavaltinib, comostat, camostat mesylate, canakinumab, CAP- 1002, carboplatin, carmustine, CB5064 analogs, CD24Fc (recombinant fusion protein), cepharanthine, cemadotin. cenicriviroc, canthaquine, CERC-002. chlorambucil, chloropromazine, cholecalciferoL ciclesonide, cisplatin, ci-trimoxazole, CK-0802, clazakizumab, clarithromycin, CLBS-119, CM4620-IE, colchicine, CorLiCyte (umbilical cord lining stem cells), COVID-19 aptamer therapy, COVID-19 human mAb, COVID-19 neutralizing antibodies, COVID-19 siRNA therapy, COVID-HIG, COVID-EIG, spike glycoproteins, CoviGlobulin, COVI-GUARD (STI- 1499), CPI-006, crizanlizumab, cryptophycin. CSL-324, CT-P59. CTAP-101, CV-15, CVL-218, cyclosporine, cell replacement therapies, cyclophosphamide, CYNK-001, cytarabine, dacarbazine, dactolisib, dactinomycin, dalargin, DAS-181, dapagliflozin, dapansurtrile, daunorubicin, decitabine, dexamethasone, DNL758 (SAR443122, RIPK1 inhibitor), dipyridamole, DMX-200, DS-2319, deupirfenidone, duvelisib, DV-890, DWRX-2003. docetaxol, dolastatin, doxetaxel, doxorubicin (adriamycin), DP-710, EB-05, EB-201, ebastine, eculizumab, EDP-1815, efineptakin alfa, emapalumab, emtricitabine, ensifentrine, ENU-200, enoxaparin, enzalutamide, epaspire, etanercept, etoposide, eravacycline, famotidine, finasteride, fingolimod, flebogamma (IGIV31), fluvoxamine, foalumab (NI-0401, TZLS-401), fostamatinib. flutamide, FSD-201, FW1022, FT516, Gamunex (IGIV-C), ganetespib, GC-376, Giapreza, GLS- 1200, garadacimab, GC-5131A (hyperimmune globulin), GIGA-2050 rCIG), gimsilumab,

GNS561, GP1681, GSK-2586881/APN-1, GSK-4182136, GTB-3550 (Trike 161533), haNK:CD- 16. HB-adMSCs, HFB30132A, HLCM-051, heparin, hydrocortisone, hydroxyurea, ibuprofen, ibudilast (MN-166), icosapent ethyl, IC14, IDB-003, IFX-l/BDB-1, IgY-110, IMM101 IMS001, IMS002, ifosfamide, imatinib, infliximab, INM-005, interferon alfa, interferon alfa IB, interferon alfa 2B, interferon beta 1A, interferon beta IB, interleukin-6, interleukin-7, isoquercetin, itanapraced (CHF-5074), itolizumab, ivermectin, IVIG. JS012 (monoclonal antibody, LY- C0VOI6), jaktmib, kagocel, KB109, sanlumab, K-NK-ID101, KTH-222, lactoferrin, LAM-002A (apilimod dimesylate), lanadelumab, lamellasome, LB-1148, larazotide, leflunomide, lenzilumab, leronlimab (monoclonal antibody), levilimab (BCD-089), levamisole, liarozole, linagliptin, lipocurc, losartan, livilimab, lomustine (CCNU), lonidamine, losmapimod, lostartan, LY- CoV555 (LY-3819253), LY-3127804, mannitol, maraviroc, mastinib, mavrilimumab, MDV3100, mechlorethamine, MEDI-3506, melatonin, melphalan, meplazumab, merimepodib, Mesenchymal stem cells (MSCs), mesencure (cell replacement), metablok (anti-inflammatory), metformin, methotrexate, methylprednisolone, mitomycin, mivobulin isethionate, mosedipimod (EC-18). MP-0420, MP-0423. MRx4DP0004. N-acetylcysteine, N.N-dimethyl-L-valyl-L-valyl- N-methyl-L-valyl-L-prolyl- 1 -Lproline-t-butylamide, namilumab (IZN-101), nangibotide, narsoplimab, nebulized domase alfa, NED-260, Niagen (nicotinamide riboside, Vitamin B3), NK cell therapy, niclosamide, nilutamide, nintedanib, nitric oxide, nivolumab, NL-CVX1, NLP-21, NP-02. N-120 (ifenprodil), novaferon. NT-17 (efmeptakin alfa), NTR-441. octagam. olokizumab, omeprazole, onapristone, opaganib, OP-101, OT-101 (trabedersen), otilimab, ozanimod, paclitaxel, pacritinib, panaphix, pamrevlumab, paracetamol, PB1046, PTC299, pegylated interferon alpha, pegy lated interferon alpha 2b, pegylated interferon lambda, pembrolizumab, PL-8177, pirfenidone, plitidepsin (aplidin), PneumoBlast, polyoxidonium, prazosin, prednimustine. prednisolone, prednisone, pritumumab, procarbazine, prolastin. PTC-299, pyronaridine/artesunate, radotinib, RAPA-501, ravulizumab, razuprotafib, interferon beta 1 agonists, RECC327, REGN-COV2 (antibody cocktail), reparixin, rintatolimod (ampligen), RLF- 100 (aviptadil), RLS-0071, STI-5656 (abivertinib), Rhu-pGSN (gelsolin), rhizoxin, RPR109881, RoActemra, RUCONEST (conestat alfa), ruxolitinib, SAB- 185, SAR443122, SARS-CoV-2 antibodies, SARS-CoV-2 monoclonal antibodies, SARS-CoV-2 polyclonal antibodies, SARS- CoV-2 neutralizing antibodies, SCTA01, Leukine (sargramostim), selenexor, sevoflurane, sertenef, siltuximab, sildenafil citate, silymarin, simvastatin, sirolimus, sirukumab, SIWA-318, solnatide, SNG-001, ST-266, stem cell educator therapy, STI-1499, STI-2020dna (COVI-MAB), STI-4398 (Covidtrap), stramustine phosphate, streptozocin, T cell therapies (TargNaturTa), TAK-671, TAK-888, TATX-36, TATX-99, TCB-007, TJ003234/TJM-2, TP508, TRV027, TD- 0903, TLC19, tekruma, tafenoquine, tamoxifen, tasonermin, taxanes, taxol, tetradrine, thalidomide, thimerosal. thymalfasin, tinzaparin, tocilizumab. tofacitinib. toremifene, tradipitant, tranexamic acid, trans sodium crocetinate (TSC), tramadol, tretinoin, TXA127 (antiotensin-(l-7) peptide), TY027, TZLS-501, UNI-911, ulinastatin, upamostat, vafidemstat, valsartan, icosapent ethyl, vazegepant, VBI-S, VERU-111, VHH72-Fc, vinblastine, vincristine, vindesine sulfate, vinflunine. VIR-2703 ALN-COV), VIR-7831, VIR-7832. Vitamin C. Vitamin D, XAV-19, Xpro-1595, XRx-101, zanubrutinib, zilucoplan, and zinc, and combinations thereof.

[0141] The vaccine therapies that may be used in combination with the therapies disclosed herein include but are not limited to inactivated vaccines, live-attenuated vaccines, recombinant vaccines, replication-deficient viral vector vaccines. mRNA-based vaccines, DNA vaccines, nanoparticle vaccines, non-replicating viral vectors, self-replicating RNA vaccines, selfamplifying RNA vaccines, protein subunit vaccines, li-Key peptide COVID- 19 vaccines, gp96- based vaccines, intranasal vaccines, and mRNA lipid nanoparticle (mRNA-LNP) vaccine. In particular, the vaccine therapies that may be used in combination with the therapies disclosed herein include but are not limited to 7HP-349. AAVCOVID (gene-based vaccine). Ad26.COV2- S (non-replicating viral vector), Ad5-nCoV (recombinant vaccine, adenovirus type 5 vector), Ad5-S-nb2, AdCOVID (intranasal vaccine), AdimrSC-2F (protein subunit vaccine), AG0301- COVID19 (DNA vaccine), AKS-446, ARCoV, AV-COVID-19, AVI-205, AZD1222 (replication-deficient viral vector vaccine (adenovirus from chimpanzees)). Bacillus Calmette- Guerin (BCG) vaccine (live attenuated vaccines), bacTRL-Spike (monovalent oral vaccine (bifidobacterial)), BBIBP-CorV (inactivated vaccine), BC-PIC COVID-19 vaccine, BNT-162 (mRNA-based vaccine), BVX-0320, CDX-005, ChAd-SARS-CoV-2-S (adenovirus-based vaccine, Chimigen vaccine, CIGB-2020, CiVax, Coravax, CoroFlu, COVOOl/AZD-1222), CoronaVac (inactivated vaccine (formalin with alum adjuvant)), Corvax. CORV ax-12. COVAX- 19 (monovalent recombinant protein vaccine), Covaxin (BBV-152, inactivated vaccine), CoVepiT, CVnCoV (mRNA-based vaccine), DPX-COVID-19, DS-5670, E-6020, ELI-005, EpiVacCorona, EPV-CoV19, Flowvax. GC-004/Covax-19, GRAd-COV2 (adenovirus-based vaccine). GX-19 (DNA vaccine), HaloVax (self-assembling vaccine), HDT-301 (RNA vaccine). iBIO-201, IK-15800, INO-4700, INO-4800 (DNA vaccine (plasmid)), IPT-001, ISR-50, KBP- COVID-19, LEAPS COVID- 19 vaccine, LineaDNA (DNA vaccine), LNP-mRNA, LNP- nCoVsaRNA, LUNAR-COW 19 (ARCT-021, self-replicating RNA vaccine), mRNA- 1273 (mRNA-based vaccine), MAPS vaccine, MT-2766, MV-014-210, MVA-S. MVC-COV-1901, NVX-CoV233 (nanoparticle vaccine), NVX-CoV2373, Oncoquest, OraCOV, PDS-0203, PDS- 0204, PiCoVacc, PittCoVacc (Recombinant protein subunit vaccine (delivered through microneedle array)), PolyPEPI-SCoV-2, QAZCOVID-IN, repRNA-CoV2S (LION/repRNA- CoV2S). RNAi vaccine. RV-1730m, rVSV COVID-19 vaccine, S-268019. Saponin vaccine adjuvant, SCB-2019 (protein subunit vaccine), Shingrix vaccine (GSK-1437173A), Sputnik-V (Gam-COVID-Vac), STI-6991, T-COVIDTM (intranasal vaccine), TaliCoVax-19, TerraCoV2, Tertomotide (GV-1001), Tiba-pitt RNA vaccine, TNX-1800, TNX-1810. TNX- 1820, TNX- 2300, T-VIVA-19. V-590 (recombinant vaccine (vesicular stomatitis virus)). V-591 (measles vector vaccine), VBI-2900, VBI-2901, VBI-2902, VLA2001, Vivagel (SPL-7013), YF17D vector, ZIP- 1642, and ZyCoV-D (DNA vaccine (plasmid)), and combinations thereof.

Uses

[0142] The present disclosure also relates to uses of the oral dosage forms described herein to treat a viral infection in a subject in need thereof, wherein the viral infection is an infection by a virus selected from the group consisting of EEEV, WEEV, VEEV, CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In a second aspect of these embodiments, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific aspects, the virus is selected from the group consisting of influenza A virus and influenza B virus. In further specific aspects, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1. MERS-CoV. and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0143] In embodiments of the uses disclosed herein, the oral dosage forms are administered once daily, as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets. 400 mg tablets. 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0144] In embodiments of the uses disclosed herein, the oral dosage forms are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength. [0145] In embodiments of the uses disclosed herein, the oral dosage forms are administered once daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 6 days, such as for 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage forms are administered once daily for 5 days.

[0146] In embodiments of the uses disclosed herein, the oral dosage forms are administered twice daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days. 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 6 days, such as for 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage forms are administered twice daily for 5 days.

[0147] The disclosure further relates to uses of the oral dosage forms described herein to treat a viral infection in a subject in need thereof, wherein the use commences from 1 to 10 days after onset of symptoms of viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after the onset of symptoms of viral infection. In specific embodiments, the oral dosage forms are administered beginning less than 5 days after onset of symptoms, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after onset of symptoms of viral infection. Symptoms of viral infection may include one or more of cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue/tiredness. feeling hot/feverish, chills, headache, nausea, vomiting, and diarrhea, although symptoms may vary by the type and severity of the viral infection. For example, symptoms of COVID- 19 caused by SARS-CoV-2 viral infection may include one or more of cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue/tiredness, feeling hot/feverish, chills, headache, nausea, vomiting, diarrhea, loss of taste, and loss of smell.

[0148] The disclosure further relates to the above described uses, wherein said subjects may be considered or is determined to be at increased risk for severe illness from COVID-19. Such individuals may have one or more underlying medical condition associated with being at increased risk for severe illness from COVID- 19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding participants on dialysis or has reduced eGFR <30 mL/min/1.73 m²). chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)/(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus. In one embodiment, the subject has not been vaccinated against COVID-19. In another embodiment, the subject has been vaccinated against COVID-19.

[0149] The disclosure further relates to the above described uses, wherein said use reduces the risk of hospitalization or death for the subject. In embodiments, the use may result in a reduction in risk of hospitalization or death for the subject. In specific embodiments, the use may result in a reduction in risk of hospitalization or death for the subject of about 1% to about 10%, such as from about 5% to about 7.5%, or about 6.8%. In further embodiments, the use may result in a relative reduction in risk of hospitalization or death for the subject of up to about 50%.

[0150] Additionally, present disclosure relates to uses of the oral dosage forms described herein to prevent a viral infection in a subject in need thereof or to provide antiviral prophylaxis to a subject in need thereof (hereinafter “prophylactic use(s)”, wherein the viral infection is caused by virus is selected from the group consisting of EEEV, WEEV. VEEV. CHIK, Ross River virus, orthomyxoviridae, paramyxoviridae, RSV, influenza A virus, influenza B virus, filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from the group consisting of RSV, influenza A virus, influenza B virus, filoviridae. human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the virus is selected from the group consisting of influenza A virus and influenza B virus. In specific embodiments, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0151] In embodiments of the prophylactic uses disclosed herein, the oral dosage forms are administered once daily, as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, the single dose may be provided as 800 mg tablets. 400 mg tablets. 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In additional particular aspects of these embodiments, the single daily may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0152] In embodiments of the prophylactic uses disclosed herein, the oral dosage forms are administered twice daily, as two individual doses. In aspects of these embodiments, each individual dose may be provided as a single tablet or as two or more tablets, such as from two to four tablets. In further aspects, each individual daily dose may be provided as 800 mg tablets, 400 mg tablets, 200 mg tablets, 100 mg tablets, or 50 mg tablets. In particular aspects of these embodiments, each individual dose may be provided as two (2) 800 mg tablets. In additional particular aspects of these embodiments, each individual dose may be provided as two (2) 400 mg tablets. Such aspects represent a reduction in pill burden both in size and in number when compared to administration of an 800 mg dose of Compound A, twice daily for five days, in the form of four (4) size 0 capsules that are each 21.7 mm x 7.6 mm and have a 200 mg unit dosage strength.

[0153] The disclosure further relates to prophylactic uses, wherein the oral dosage forms are administered once daily for 1 to 42 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days. 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days. 32 days, 33 days. 34 days, 35 days, 36 days. 37 days, 38 days. 39 days, 40 days, 41 days, or 42 days. In specific embodiments, the oral dosage forms are administered once daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days. 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage forms are administered once daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0154] The disclosure further relates to prophylactic uses, wherein the oral dosage forms are administered twice daily for 1 to 42 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days. 39 days, 40 days, 41 days, or 42 days. In specific embodiments, the oral dosage forms are administered twice daily for 1 to 21 days, such as for 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, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage forms are administered twice daily for 3 to 14 days, such as for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0155] The disclosure further relates to prophylactic uses, wherein the use commences prior to exposure to a viral infection or after a potential exposure to a viral infection. In specific embodiments, the oral dosage forms are administered beginning prior to potential exposure to viral infection. In other specific embodiments, the oral dosage forms are administered from 1 to 10 days after potential exposure to a viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after potential exposure. In specific embodiments, the oral dosage forms are administered beginning less than 5 days after potential exposure, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after potential exposure.

[0156] The disclosure further relates to the above described prophylactic uses, wherein said subjects may be considered to be at increased risk for severe illness from COVID-19. Such individuals may have one or more underlying medical condition associated with being at increased risk for severe illness from COVID-19, such as age greater than 60 years, active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity/mortality (e.g., basal cell carcinomas)), chronic kidney disease (excluding participants on dialysis or has reduced eGFR <30 mL/min/1.73 m²), chronic obstructive pulmonary disease, obesity (body mass index of 30 or higher, where body mass index = weight (kg)/(height (m))²), serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), and/or diabetes mellitus. In one embodiment, the subject has not been vaccinated against COVID-19. In another embodiment, the subject has been vaccinated against COVID-19.

[0157] The disclosure relates to prophylactic uses as described above, wherein said method reduces the risk of hospitalization or death for the subject. In embodiments, the method may result in a reduction in risk of hospitalization or death for the subject. In specific embodiments, the method may result in a reduction in risk of hospitalization or death for the subject of about 1 to about 10 percent, such as from about 5 to about 7.5 percent, or about 6.8 percent. In further embodiments, the method may result in a relative reduction in risk of hospitalization or death for the subject of up to about 50 percent.

[0158] Many patients with COVID-19 recover with no or minimal medical intervention.

However, clinical progression to severe disease severely impacts both patients and healthcare systems, increasing an individual’s risks of requiring mechanical ventilation and of death and potentially overburdening hospital capacity and available healthcare resources during COVID- 19 surges. Reducing the number of patients requiring hospitalization for COVID-19 is therefore critical. Vaccination remains by far the most important medical intervention available to reduce the risk of hospitalization or death from COVID-19. However, early treatment soon after symptom onset has also been shown as effective. A direct-acting, oral agent such as the herein described oral dosage forms that can be administered at home after diagnosis may be more practical for non-hospitalized patients and would be an important new tool in treating viral infection and viral diseases, including COVID- 19 caused by SARS-CoV-2.

[0159] Additional embodiments of the disclosure include the pharmaceutical compositions, combinations, uses, and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.

EXAMPLES

[0160] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.

Comparative Example: Compound A Capsule Formulation

[0161] The capsule formulation for Compound A uses a wet granulated mixture filled into size 0 hypromellose capsules at a unit dose strength of 200mg (fill weight of 285.7mg). The composition of the capsule formulation is shown in Table 2.

Table 2

Example 1: Compound A Tablet Formulation: High-Shear Wet Granulation, Roller Compaction, and Direct Compaction Methods [0162] Tablets were prepared using different tableting methods, to determine whether the tableting process used would affect the size and drug load achievable as well as to assess different formulations for processability. The unit dose strength for each tablet was 400. Omg. [0163] A high-shear wet-granulation (HSWG) process was used to prepare tablets of Formulation A, by dispensing Compound A, hydroxypropyl cellulose, and sodium lauryl sulfate into a high shear wet granulator bowl. The ingredients were granulated with water. The wet granules were de-agglomerated, fluid-bed dried and milled. The granules were blended with extragranular ingredients and lubricated with magnesium stearate.

[0164] A high-shear wet-granulation (HSWG) process was used to prepare tablets of Formulation D, by dispensing Compound A, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium into a high shear wet granulator bowl. The ingredients were granulated with water. The wet granules were de-agglomerated, fluid-bed dried and milled. The granules were blended with extragranular ingredients and lubricated with magnesium stearate.

[0165] A roller compaction (RC) process was used to prepare tablets by dispensing Compound A, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, tri-basic calcium phosphate and sodium lauryl sulfate into a blender vessel preserving the following proportion. The ingredients were blended. The blend was granulated by roller compaction. The granules were added to a blender vessel with magnesium stearate added, and the ingredients were blended. Subsequently, the blend was compressed into tablets. This process was used to prepare Formulation B.

[0166] A direct compression (DC) process was used to prepare tablets by dispensing Compound A and tri-basic calcium phosphate into a blender vessel preserving the following proportion. The ingredients were pre-blended to improve flow. Then, the Compound A and tri- basic calcium phosphate blend, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate were dispensed into a blender, and the ingredients were blended. Subsequently, the blend was compressed into tablets. This process was used to prepare Formulation C.

Example 2: Comparison of Tablet Formulations Having Similar Drug Load

[0167] Tablet formulations A, B, C, and D were prepared according to the process and proportions indicated in Table 3. Table 3

[0168] To reduce pill burden and to achieve the requisite tablet mechanical strength for push through blisters and film coating, multiple formulations and processes were developed across roller compaction, direct compression, and high shear wet granulation (HSWG) platforms. Figure 1 shows the tablet-ability profile of the granules and powder blend of Compound A prepared using different techniques, specifically Formulation A, Formulation B, and Formulation C. A common formulation was chosen to be processed by RC and DC, while a different formulation composition was selected for HSWG (Table 3). Granules (HSWG and RC) and DC blend were compressed at different stresses and the tensile strength of each tablet was determined. The tablet strength was impacted by the manufacturing process. At a similar drug load of 50% (400.0 mg) and tablet core weight of 800.0 mg, the HSWG formulation (Formulation A) yielded tablets the best mechanical strength, while the tablets prepared by RC (Formulation B) were the weakest. The granules manufactured by roller compaction showed loss in tablet-ability, while the DC tablets (Formulation C) had improved tablet-ability since the formulation was not granulated. Tablets produced by HSWG (Formulation A) had the best tensile strength (Figure 1).

[0169] The HSWG tablets of Formulation D demonstrated improved strength relative to the RC tablets of Formulation B as indicated by better friability (Figure 2), which increases robustness for downstream operations such as film coating and packaging. The superior strength of the HSWG tablets of Formulation D relative to the RC tablets of Formulation B may be attributed to the flexibility of the HSWG process, which allows the use of significant levels of extragranular compression aid/filler (see Formulation A and Formulation D in Table 3) to boost tablet-ability while maintaining superior processability (Figure 3).

[0170] Significantly, each of the tablet formulations contained 400mg of Compound A in a single tablet, which is equivalent amount of Compound A in two capsules of the approved and marketed formulation, as shown in the Compartative Example.

Example 3: Impact of Sodium Lauryl Sulfate on In-Vitro Tablet Dissolution for HSWG Formulations of Compound A

[0171] Tablet formulations E, F, G, and H were prepared using a HSWG process by dispensing the following ingredients into a high shear wet granulator bowl preserving the following proportions as indicated in Table 4. The ingredients were granulated with water. The wet granules were de-agglomerated, fluid bed dried and milled. The granules were blended with extragranular ingredients as indicated in Table 4 and lubricated with magnesium stearate. Sodium lauryl sulfate (SLS) was added intragranularly to Formulations E, F, and G at 1.00% (6.000mg), 0.75% (4.500mg) and 0.25% (1.500mg) levels, respectively, while SLS was added extragranularly to Formulation H at a 0.50% (3.000 mg) level.

Table 4

*removed during drying

[0172] A 100 RPM USP I (20 mesh) dissolution method was used to evaluate these samples. The dissolution media consisted of 500mL of 0.1N HC1. Following dissolution, samples were analyzed using a gradient reversed phase HPLC method. When SLS was added intragranularly (Formulations E. F, and G), the dissolution rate of tablets increased with increasing levels of SLS. Figure 4 shows the dissolution of these formulations. Although Compound A (>10 mg/mL in water) has good aqueous solubility at 37°C, it exhibits poor wettability' in aqueous media. Intragranular addition of SLS improves wettability and enhanced the contact between tablet surface and dissolution media, which in turn resulted in rapid tablet disintegration and dissolution. In contrast, dissolution rate was slowest with extragranular addition of SLS (Formulation H indicative that SLS needs to be in close proximity (intimately mixed) with Compound A to have a notable impact on dissolution rate. Example 4: Impact of Extragranular Components on In-Vitro Tablet Dissolution for HSWG Formulations of Compound A

[0173] For HSWG formulations of Compound A, and in the absence of a surfactant, excipients may be used to modulate the release of Compound A from a formulation. The type of excipient used, quantitative levels of excipient, and placement of excipients - either intragranular or extragranular - all can affect the release of Compound A. The effects of excipients on Compound A release were evaluated using a 50 RPM USP II dissolution method using 0. IN HC1 as the dissolution media with a 500 mL vessel fill. Following dissolution, samples were analyzed using a gradient reversed phase HPLC method. An increase in the extragranular levels of a water soluble compression aid and disintegrant, lactose monohydrate and croscarmellose sodium, respectively, results in increase in dissolution rate of HSWG tablets. Formulation D releases Compound A faster compared to Formulation I, the slow variant (Table 5 and Figure 5). Croscarmellose sodium facilitates the rapid release of Compound A from the tablet, due to the inherent wicking and swelling ability when exposed to water. Because it is water soluble and hydrophilic, lactose monohydrate facilitates gel formation and shortens the penetration time of the dissolution media into the tablet matrix.

Table 5

*removed during drying

Example 5: Absorption of Compound A, Systemic Pharmacokinetics, and Bioequivalence [0174] To characterize the human absorption of Compound A and systemic pharmacokinetics (PK) of NHC and to assess the bioequivalence of the capsule formulation (Comparative Example) and the tablet formulation (Formulation D). a physiologically based biopharmaceutics model (PBBM) was developed using a dissolution method as per FDA guidance document. The model was qualified with multiple clinically observed PK results (See Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR, Human safety/, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2, 65(5) ANTIMICROB. AGENTS CHEMOTHER. 1-14 (May 2021); available as 65:e02428-20 from doi.org/10.1128/AAC.02428-20). Briefly, physiologically based biopharmaceutics models are newer tools that can be used throughout drug product development and post approval and have found broader use in the FDA with a draft guidance (See U.S. FOOD AND DRUG ADMINISTRATION. DRAFT GUIDANCE FOR INDUSTRY: THE USE OF PHYSIOLOGICALLY BASED PHARMACOKINETIC ANALYSES— BIOPHARMACEUTICS APPLICATIONS FOR ORAL DRUG PRODUCT DEVELOPMENT. MANUFACTURING CHANGES, AND CONTROLS 2020; Available from: www.fda.gov/regulatory-information/searchfda-guidance-documents/use-physiologically-based- pharmacokinetic-analyses-biopharmaceutics-applications-oral-drug-product). PBBM focuses on the generation of mechanistic understanding of how⁷ drug product quality attributes interact with physiology to influence the in vivo drug performance and pharmacokinetics. PBBM allows establishing a dissolution bioequivalence safe space; dissolution profiles that are within the safe space lead to bioequivalent pharmacokinetics in Cmax and AUC. (See Wu F, Shah H, Li M, Duan P, Zhao P, Suarez S, Raines K, Zhao Y, Wang M, Lin HP, Duan J, Yu L, Seo P, Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs. 23(31) The AAPS J. (Feb. 2021); available as doi: 10.1208/sl2248-021-00564-2. PMID: 33619657).

[0175] The Compound A dissolution curves w ere obtained for the capsule formulation and tablet Formulation D using a USP 2 method. The dissolution profiles are a key input data to the PBBM and are used together with the in vitro dissolution conditions (volume, solubility in the dissolution medium, and dose). The Compound A dissolution data w ere then modeled to calculate z-factors on the basis of Takano et al. (Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, Yamashita S, Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from, a miniscale dissolution test, 23(6) PHARM RES. 1144-1 156 (June 2006); available as doi: 10. 1007/s 11095-006-0162-4. Epub 2006 May 25.

PMID: 16715363.). The z-factor calculation tool in GastroPlus was used, and the results of the z- factors from in vitro data were used for the simulation by setting the dissolution model as z-factor model in GastroPlus (See Wu D. Li M, Current State and Challenges of Physiologically Based Biopharmaceutics Modeling (PBBM) in Oral Drug Product Development, 40(2) PHARM RES. 321-336 (Feb. 2023, published online 8 Sep. 2022); available as doi: 10. 1007/sl 1095-022-03373- 0; see also Kollipara, S., Bhatiprolu, A.K , Boddu, R., Ahmed T., Chachad S., Best Practices for Integration of Dissolution Data into Physiologically Based Biopharmaceutics Models (PBBM): A Biopharmaceutics Modeling Scientist Perspective, 24(59) AAPS PHARMSCITECH (Feb. 2023); available as doi.org/10.1208/sl2249-023-02521-y.).

[0176] Overall, the bioequivalence safe space lower bound is Q = 80% dissolved in 37 min in 0. IN HC1 dissolution media in Figure 6. Based on the dissolution safe space (shaded area), the dissolution capsule formulation of Compound A is bioequivalent to the Formulation D tablet. The dissolution profile for Formulation I, the slow variant, is shown for illustration purposes to be outside of the bioequivalence safe space. Formulation I is expected to be bioequivalent to, or nearly bioequivalent to, Formulation D and the capsule formulation of the Comparative Example. [0177] It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. It will also be appreciated that various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.

Claims

WHAT IS CLAIMED IS:

1. An oral dosage form comprising an antiviral nucleoside and one or more excipients, wherein

(a) the antiviral nucleoside is selected from prodrugs of P-D-7V(4)-hydroxy cytidine, or a pharmaceutically acceptable salt or tautomer thereof, in an amount of from about 25 mg to about 800 mg, and

(b) the oral dosage form is a tablet having a longest length that is equal or greater than about 5.00 mm ± 0.15 mm.

2. The oral dosage form according to claim 1, wherein the antiviral nucleoside is {(27?,3A,47?,57?)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(277)- y 1] oxol an-2-y 1 } methyl 2-methy Ipropanoate) : Compound A or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

3. The oral dosage form according to claim 2, wherein the antiviral nucleoside is {(27?.3<S’,47?,57?)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3.4-dihydropyrimidin-l(277)- yl] oxolan-2-yl } methyl 2-methylpropanoate): Compound A or a tautomer thereof.

4. The oral dosage form according to claim 2, wherein the antiviral nucleoside is a prodrug of {(2J?,3S,47?,5J?)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin- 1 (2H) -y 1] oxolan-2-y 1 } methyl 2-methy Ipropanoate) : Compound A or a pharmaceutically acceptable salt or tautomer thereof.

5. The oral dosage form according to any one of claims 1 to 4, wherein the oral dosage form is a tablet having a longest length in a range of from about 5.00 mm ± 0.15 mm to about 22.00 mm ± 0.15 mm.

6. The oral dosage form according to any one of claims 1 to 5, wherein the oral dosage form is a tablet having a total weight when uncoated that is in a range of from about 30 mg to about 2000 mg.

7. The oral dosage form according to any one of claims 1 to 6, wherein the one or more excipients is selected from the group consisting of compression aids, diluents, disintegrants, lubricants, glidants, surfactants or wetting agents, granulating liquids or granulating solvents, binders and fillers, and combinations thereof.

8. The oral dosage form according to claim 7, wherein the one or more excipients includes one or more compression aids selected from the group consisting of directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, spray crystallized maltose, spray crystallized dextrose, cry stalline sorbitol, mannitol, sucrose, microfine cellulose, and microcrystalline cellulose.

9. The oral dosage form according to claim 8, wherein the one or more compression aid is present in an amount of from about 6.000 mg to about 1440 mg.

10. The oral dosage form according to claim 8, wherein the one or more excipients includes one or more diluents selected from the group consisting of directly compressible starches, dibasic calcium phosphate, spray-dried lactose, anhydrous lactose, spray crystallized maltose, spray crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microfine cellulose, and microcrystalline cellulose.

11. The oral dosage form according to claim 10, wherein the one or more diluents is present in an amount of from about 6.000 mg to about 1440 mg.

12. The oral dosage form according to claim 8, wherein the one or more excipients includes one or more disintegrants selected from the group consisting of calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium.

13. The oral dosage form according to claim 12. wherein the one or more disintegrant is present in an amount of from about 0.000 mg to about 240.0 mg.

14. The oral dosage form according to claim 8, wherein the one or more excipients includes one or more lubricants selected from the group consisting of magnesium silicate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, and magnesium stearate.

15. The oral dosage form according to claim 14, wherein the one or more lubricant is present in an amount of from about 0.080 mg to about 32.00 mg.

1 . The oral dosage form according to claim 8, wherein the one or more excipients includes one or more glidants selected from the group consisting of com starch, talc, colloidal silica, and tri-basic calcium phosphate.

17. The oral dosage form according to claim 16, wherein the one or more glidant is present in an amount of from about 0.000 mg to about 80.00 mg.

18. The oral dosage form according to claim 8, wherein the one or more excipients includes one or more surfactants or wetting agents selected from the group consisting of polysorbates, poloxamers, 2-[4-(2.4,4-trimethylpentan-2-yl)phenoxy]ethanol, sodium octyl glycoside, lauryl-sulfobetaine. myristyl-sulfobetaine, linoleyl-sulfobetaine. stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauroamidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine. palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium stearate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium dodecyl benzene sulfonate, sodium cholate, hexadecyltrimethylammonium bromide, dodecyl pyridinium chloride, heptaoxy ethylene monodexadecyl ether, n-dodecyl alanine, lecithin, sodium methyl cocoyl-taurate, disodium methyl oleyl-taurate. polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol.

19. The oral dosage form according to claim 18, wherein the one or more one or more surfactants or wetting agents is present in an amount of from about 0.000 mg to about 80.00 mg.

20. The oral dosage form according to claim 8, wherein the one or more excipients includes one or more granulating liquids or granulating solvents selected from the group consisting of water, organic solventshols, and combinations thereof.

21. The oral dosage form according to claim 20. wherein the one or more granulating agents is present in an amount relative to the total weight of the tablet of from about 10 wt% to about 80 wt%.

22. The oral dosage form according to claim 8, wherein the one or more excipients includes one or more binders and/or fillers selected from the group consisting of starches, cellulose and its derivatives, polyvinyl pyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof.

23. The oral dosage form according to claim 22, wherein the one or more binders and/or fillers is present in an amount of from about 0.000 mg to about 96.00 mg.

24. The oral dosage form according to any one of claims 1 to 23, wherein the oral dosage form is a tablet comprising a coating.

25. The oral dosage form according to claim 24. wherein the coating comprises one or more of one or more of polymers or film formers, opacifiers, adhesion modifiers, plasticizers, anti-tacking agents, colorants, and mixtures thereof.

26. The oral dosage form according to claim 24, wherein the coating is present in an amount of from about 0.000 mg to about 60.0 mg.

27. The oral dosage form according to any one of claim 1 to claim 26, wherein the oral dosage form has a dissolution rate in 0. IN HC1 dissolution media sufficient to dissolve about 80% of the oral dosage form in about 37 minutes.