Solid dosage forms of small molecule antiviral drugs and uses thereof

Abstract

The present disclosure relates to an oral dosage form of a pharmaceutical formulation comprising an antiviral nucleoside, one or more compression aids, one or more glidants, one or more lubricants, and one or more disintegrants, wherein the oral dosage form is a pellet having a diameter of 4.0 mm or less.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This international application claims the benefit of priority to U.S. Provisional Application No. 63 / 433,155, filed December 16, 2022, which is incorporated herein by reference in its entirety. [Technical Field]

[0002] The present disclosure relates to a solid dosage formulation of a small molecule antiviral drug.The solid dosage formulation of the present disclosure is typically a tablet, such as a pellet, a mini-tablet, or a granule.The present disclosure also relates to the use and method of using the solid dosage form for the treatment or prevention of viral infection in patients in need thereof. [Background technology]

[0003] Viral infections, such as those caused by Eastern Equine Encephalitis Virus (EEEV), Western Equine Encephalitis Virus (WEEV), and Venezuelan Equine Encephalitis Virus (VEEV), Chikungunya Virus (CHIK), Ebola Virus, Influenza Virus, Respiratory Syncytial Virus (RSV), Zika Virus, and coronaviruses, such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and more recently SARS-CoV-2 (also known as 2019-nCoV), continue to cause mild to severe, life-threatening, and potentially fatal illnesses worldwide.

[0004] EEEV, WEEV, VEEV, and CHIK viruses are vector-borne viruses (family Togaviridae, genus Alphavirus) that can be transmitted to humans via mosquito bites. Equine encephalitis virus is a CDC category B pathogen, and CHIK virus is a category C.

[0005] Coronaviruses cause the majority of severe or potentially life-threatening respiratory illnesses in humans. SARS-CoV-1, which emerged in 2002, has caused at least 8,439 cases of human illness and at least 812 deaths worldwide (WHO Cumulative Number of Reported Probable Cases of SARS, November 1, 2002–July 4, 2003. Downloaded from www.who.int / csr / sars / country / 2003_07_04 / en / on August 12, 2020). Similarly, MERS-CoV, which emerged in 2012, has caused at least 2,519 cases of human illness and at least 866 deaths worldwide (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 has caused at least 629 million confirmed cases of human illness and at least 6.5 million deaths worldwide (World Health Organization COVID-19 Weekly Epidemiological Update, Issue No. 117, published November 9, 2022. Downloaded November 10, 2022 from www.who.int / publications / m / item / weekly-epidemiological-update-on-covid-19---9-november-2022). SARS-CoV-2 causes the disease called COVID-19, which can include the emergence of severe respiratory and systemic illness in humans.SARS-CoV-2 infection is also associated with psychiatric and neurological symptoms, which can include confusion, encephalopathy, agitation, seizures, meningoencephalitis, olfactory or gustatory disorders, anxiety, depression, and sleep disorders; these neurological symptoms can occur without 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). Further research is needed to further characterize the SARS-CoV-2 virus and to identify ways to prevent and treat COVID-19 disease and diseases caused by other human coronaviruses.

[0006] Many patients with COVID-19 recover without or with minimal medical intervention. However, clinical progression to severe disease can have serious consequences for both patients and healthcare systems, increasing individuals' risk of requiring mechanical ventilation and death and potentially placing an undue strain on hospital capacity and available healthcare resources during COVID-19 surges. Therefore, it is important to reduce the number of patients requiring hospitalization for COVID-19. Vaccination is by far the most important medical intervention available to reduce the risk of hospitalization or death from COVID-19. However, early treatment immediately after onset of symptoms has also been shown to be effective. Currently, the only approved treatments for outpatients at risk for COVID-19 are the monoclonal antibodies bamlanivimab / etesevimab, casirivimab / imdevimab, and sotrovimab. Because monoclonal antibodies require administration by infusion or injection in a healthcare setting, direct-acting oral agents that can be administered at home after diagnosis may be more practical for non-hospitalized patients and could represent an important new tool in the treatment of COVID-19 caused by SARS-CoV-2.

[0007] Antiviral agents have been developed to treat viral infections, such as β-DN(4)-hydroxycytidine (NHC, 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidin-2(1H)-one), [ka] has antipestivirus and antihepacivirus activity. ANTIMICROB AGENTS CHEMOTHER, 2003, 47(1):244-54. NHCs have been shown to have limited oral bioavailability in non-human primates (see Toots et al., SCI. TRANSL. MED. 11, eaax5866 (2019)). However, prodrugs of NHCs, including {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate: [ka] Also known as uridine 4-oxime 5'-(2-methylpropanoate) and molnupiravir, it is orally bioavailable and is understood to be potentially useful in the treatment of viral infections caused by at least Eastern Equine Encephalitis Virus (EEEV), Western Equine Encephalitis Virus (WEEV), and Venezuelan Equine Encephalitis Virus (VEEV), Chikungunya Virus (CHIK), Ebola Virus, Influenza Virus, Respiratory Syncytial Virus (RSV), Zika Virus, and coronaviruses such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and more recently SARS-CoV-2 (also known as 2019-nCoV).

[0008] β-DN(4)-hydroxycytidine, its prodrugs, its derivatives, and methods for making them are set forth in U.S. Patent Application Publication No. 2015 / 066144, published as WO 2016 / 106050, U.S. Patent Application Publication No. 15 / 537,087, published as U.S. Patent Application Publication No. 2019 / 0022116, and U.S. Patent Application Publication No. 16 / 921,359, each of which is incorporated herein by reference in its entirety. Compound A, as well as pharmaceutically acceptable salts, tautomers, and prodrugs thereof, and additional derivatives of β-DN(4)-hydroxycytidine, and methods for making the same, are set forth in U.S. Patent Application Publication No. 2018 / 064503, published as WO 2019 / 113462, U.S. Patent Application No. 16 / 755,779, now U.S. Patent No. 11,331,331, U.S. Patent Application No. 17 / 465,344, published as U.S. Patent Application Publication No. 2022 / 0016153, and U.S. Provisional Patent Application No. 63 / 127,484, each of which is incorporated herein by reference in its entirety.

[0009] Compound A is being developed for the treatment of viral infections caused by SARS-CoV-2 and other pathogens, as well as for the treatment of COVID-19, also caused by SARS-CoV-2. However, the 800 mg dose, administered twice daily for 5 days, takes the form of four size 0 capsules measuring 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg, which results in a significant pill burden, both in terms of the size of each capsule and the number of capsules administered at each dosing interval. Some patient populations, such as pediatric patients, elderly patients, and other patient populations with specific medical limitations, may have difficulty swallowing these capsules. Furthermore, the 800 mg dose cannot be adjusted for pediatric patients or other medical reasons other than adjusting the number of size 0 capsules having a unit dose strength of 200 mg.

[0010] The goal of any drug delivery system is to deliver and achieve a therapeutic amount of drug to the appropriate site in the body, and then maintain the desired drug concentration.The most convenient and commonly used route of drug delivery has historically been through solid oral dosage forms, especially tablets and capsules.However, the difficulty of swallowing tablets and capsules is a problem for many patients, including pediatric and elderly patients, and can lead to various adverse events and patient non-compliance with treatment regimens.In addition, traditional tablets and capsules are limited by their strict dosage content.

[0011] There remains a need for novel antiviral oral dosage forms that are more suitable for patient populations that avoid standard oral dosage forms and that offer the ability to administer to patient populations that are unable to swallow traditional tablet or capsule formulations intact. There is also a need for antiviral oral dosage forms that allow for dose adjustment for specific patient populations. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2016 / 106050 (U.S. Patent Application Publication No. 2015 / 066144) [Patent Document 2] U.S. Patent No. 2019 / 0022116 (U.S. Patent Application Publication No. 15 / 537,087) [Patent Document 3] U.S. Patent Application Publication No. 16 / 921,359 [Patent Document 4] International Publication No. 2019 / 113462 (U.S. Patent Application Publication No. 2018 / 064503) [Patent Document 5] U.S. Patent No. 11,331,331 (U.S. Patent Application No. 16 / 755,779) [Patent Document 6] U.S. Patent Application Publication No. 2022 / 0016153 (U.S. Patent Application No. 17 / 465,344) [Patent Document 7] U.S. Provisional Patent Application No. 63 / 127,484 [Non-patent literature]

[0013] [Non-Patent Document 1] WHO Cumulative Number of Reported Probable Cases of SARS, 1 November 2002–4 July 2003. Downloaded on 12 August 2020 from www.who.int / csr / sars / country / 2003_07_04 / en / [Non-patent document 2] 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. [Non-patent document 3] World Health Organization COVID-19 Weekly Epidemiological Update, Issue No. 117, published November 9, 2022. Downloaded from www.who.int / publications / m / item / weekly-epidemiological-update-on-covid-19---9-november-2022 on November 10, 2022 [Non-patent document 4] 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. [Non-Patent Document 5] ANTIMICROB AGENTS CHEMOTHER,2003,47(1):244-54 Summary of the Invention

[0014] The present disclosure relates to an oral dosage form of a pharmaceutical formulation comprising an antiviral nucleoside, one or more compression aids, one or more glidants, one or more lubricants, and one or more disintegrants, wherein the oral dosage form is a pellet having a diameter of 4.0 mm or less. The antiviral nucleoside is β-DN(4)-hydroxycytidine. [ka] Prodrugs of, for example, {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate: [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof.

[0015] Other embodiments, aspects, and features of the present invention will be further described in or will be apparent from the following description, examples, and appended claims. The above summary of the technology is non-limiting, and other features and advantages of the technology will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere herein, 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 pertains.

[0017] 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. 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 used in the art.

[0018] As used in this specification, 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.

[0019] The terms "administration" and / or "administering" a compound should be understood to include providing a compound described herein, or a pharmaceutically acceptable salt thereof, and the aforementioned compositions to a subject.

[0020] As used herein, the terms "at least one" item or "one or more" items include, respectively, a single item selected from a list, as well as a mixture of two or more items selected from a list.

[0021] As used herein, the term "subject" (or "patient," or, as in the case of a clinical trial participant, "participant") refers to a mammal that is the object of treatment, observation, or experimentation. The mammal can be male or female. The mammal can be one or more selected from the group consisting of humans, bovines (e.g., cows), porcines (e.g., pigs), ovines (e.g., sheep), caprines (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., house cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), and procyonrotae (e.g., raccoons). In certain embodiments, the subject is a human. In some embodiments, the subject is an adult patient. In other embodiments, the subject is a pediatric patient. Those "in need of treatment" include subjects who may benefit from treatment with the formulations of the invention, for example, patients suffering from a viral infection, such as an infection with SARS-CoV-2.

[0022] The term "subject in need thereof," as used herein, refers to a subject (whether symptomatic or asymptomatic) who has been diagnosed with or is suspected of having a viral infection, such as an infection by SARS-CoV-2; a subject who is at risk of being exposed to a viral infection, such as an infection by SARS-CoV-2 (such as, for example, a healthcare worker who may be at risk of exposure to SARS-CoV-2); or a subject who has been exposed to a viral infection, such as an infection by SARS-CoV-2 (such as a household contact of a COVID-19 patient or an asymptomatic patient infected with SARS-CoV-2), as defined herein.

[0023] As used herein, the term "COVID-19" refers to the disease caused by SARS-CoV-2 infection. A SARS-CoV-2 infected subject who develops symptoms is considered to have COVID-19.

[0024] Certain subjects may be considered at high risk for severe illness from COVID-19. Such individuals include, for example, those over 60 years of age; active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (individuals on dialysis or individuals with an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m); 2 excluding individuals with a blood cholesterol level below 50; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 may have one or more underlying conditions associated with a higher risk of severe illness from COVID-19, such as: a body mass index of 30 or greater; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes mellitus.

[0025] As used herein, the terms "treatment" and "treating" refer to any process that may slow, interrupt, prevent, control, or stop the progression of a disease or disorder described herein. These terms do not necessarily indicate the complete elimination of all disease or disorder symptoms.

[0026] As used herein, the terms "prophylaxis" and "antiviral prophylaxis" refer to any process intended to prevent disease. Prophylaxis can occur before exposure to a viral infection, such as infection with SARS-CoV-2 (e.g., before exposure in healthcare workers who may be exposed to such an infection), or after potential exposure to a viral infection, such as infection with SARS-CoV-2 (e.g., after exposure in family members or caregivers of symptomatic or asymptomatic patients infected with SARS-CoV-2).

[0027] As used herein, the term "co-administration" refers to administration of pharmaceutical agents such that the individual pharmaceutical agents are present in a subject at the same time. In addition to simultaneous administration of pharmaceutical agents (via the same or alternative routes), co-administration can include administration of pharmaceutical agents (via the same or alternative routes) at different times.

[0028] As used herein, the term "tablet" is intended to encompass compressed pharmaceutical dosage forms of all shapes and sizes. Tablets that are smaller in size compared to traditional tablet and capsule formulations may alternatively be referred to herein as "pellet(s)," "granule(s)," or "minitablet(s)." Pellets may have a diameter range of about 1.00 mm to about 4.00 mm.

[0029] Unless expressly stated otherwise, all ranges cited herein are inclusive. Ranges include the upper and lower limits of the range, as well as all values ​​therebetween. All ranges are also intended to include all subranges included, although not necessarily explicitly stated. As an example, temperature ranges, percentages, equivalent ranges, and the like described herein include the upper and lower limits of the range, as well as any value in the continuum therebetween. Numerical values ​​provided herein, and the use of the term "about" may include variations of ±1.00%, ±2.00%, ±3.00%, ±4.00%, ±5.00%, and ±10.0% and their numerical equivalents. When used to modify a numerically defined parameter (e.g., the dose of an antiviral nucleoside or the length of treatment with a combination therapy described herein), "about" means that the parameter may vary by as much as 10.0% below or above the numerical value stated for that parameter. Where appropriate, the stated parameter may be rounded to the nearest integer. For example, a dose of about 5.00 mg / kg can vary between 4.50 mg / kg and 5.50 mg / kg. Furthermore, as used herein, the term "or" indicates alternatives that can be combined where appropriate. That is, the term "or" includes each of the options listed separately and combinations thereof.

[0030] 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 pertains. In case of conflict, the present specification, including definitions, will control.

[0031] Throughout this specification and claims, the word "comprise" or variations such as "comprises" or "comprising" are used in an inclusive sense, i.e., to identify the presence of stated features, but do not exclude the presence or addition of further features that could materially enhance the operation or utility of any of the embodiments of the invention, unless the context requires otherwise by express language or necessary implication. Unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. Any example(s) following the term "eg" or "for example" are not meant to be exhaustive or limiting.

[0032] Whenever an embodiment is described herein with the term "comprising," it is understood that other similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0033] As used throughout the specification and claims, the phrase "consists essentially of" or variations such as "consist essentially of" or "consisting essentially of" indicates the inclusion of the recited element or group of elements, and the optional inclusion of other elements of similar or different nature to the recited elements that do not materially alter the basic or novel characteristics of the specified dosage regimen, method, or composition.

[0034] The term "pharmaceutically effective amount" or "effective amount" refers to the amount of a therapeutic composition or formulation introduced into a patient that is sufficient to treat a disease or condition. Those skilled in the art will recognize that this level may vary depending on patient characteristics such as age, weight, etc.

[0035] The term "about" refers to variations in a numerical quantity that may occur when modifying the amount of a substance or composition (e.g., mM or M), the proportions of formulation components (v / v or w / v), the pH of a solution / formulation, or the value of a parameter characterizing a method step, etc., for example, through typical measuring, handling, and sampling procedures involved in preparing, characterizing, and / or using a substance or composition; through inadvertent errors in these procedures; or due to differences in the manufacture, source, or purity of components used to make or use a composition or perform a procedure. 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%.

[0036] "Pharmaceutically acceptable" refers to excipients (vehicles, additives) and compositions that can be reasonably administered to a subject to provide an effective amount of the active ingredient being used, and that are "generally regarded as safe," e.g., physiologically tolerated, and do not typically cause allergic or similar adverse reactions, such as stomach upset, when administered to humans. In another embodiment, the term refers to molecular entities and compositions approved by a federal or state government regulatory agency, or listed in the United States Pharmacopoeia or another generally recognized pharmacopoeia, for use in animals, more specifically humans.

[0037] The term "pharmaceutically acceptable carrier" refers to any inert substance suitable for use in a formulation for delivering a therapeutic agent. Carriers can be antiadherents, binders, coatings, disintegrants, fillers or diluents, lubricants, preservatives (antioxidants, antibacterial agents, antifungal agents, etc.), sweeteners, absorption delaying agents, wetting agents, emulsifiers, buffers, etc. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), dextrose, vegetable oils (e.g., olive oil), saline, buffer solutions, buffered saline solutions, and isotonic agents, such as sugars, polyalcohols, sorbitol, and sodium chloride.

[0038] The term "pharmaceutical formulation" refers to a preparation in a form that allows the active ingredient to be effective. The terms "formulation" and "pharmaceutical formulation" are used interchangeably throughout.

[0039] Direct compression is defined as a process that involves pre-milling each component of the formulation (e.g., active drug substance and excipients) into a powder, mixing the powdered components and any lubricants, and compressing the mixed powder into a tablet. When a formulation is processed by direct compression, the active ingredient, herein the antiviral compound, can be provided for pre-milling "as is" directly from synthesis or after purification by an appropriate method, such as recrystallization.

[0040] Wet granulation is defined as a process that involves granulating powders with a liquid (aqueous, non-aqueous, hot melt, etc.) to achieve desired properties for subsequent downstream processing. A liquid (e.g., water, binder solution) is added to the powder blend while the powder blend is continuously mixed, resulting in granule nucleation and growth. When a formulation is processed by wet granulation, the active ingredient, herein the antiviral compound, can be provided "as is" directly from synthesis or after purification by an appropriate method, such as recrystallization.

[0041] Roller compaction is defined as an agglomeration process that uses two counter-rotating rollers to compress powder into a dense compact (or ribbon). The compressive force from the rollers plastically deforms the particles to achieve a dense compact. The dense compact is then broken down and ground into granules. Advantages of roller compaction include improved flow, better content uniformity, and / or less stickiness. Roller compaction is also preferred for moisture- and / or heat-sensitive formulations.

[0042] Excipients that are mixed with other ingredients (including active ingredients) prior to granulation and are therefore incorporated within the granules 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. In certain embodiments, an individual excipient may be incorporated as an intragranular component, an extragranular component, or both an intragranular and an extragranular component.

[0043] The term "compression aid" refers to any substance used in the preparation of pharmaceutical dosage forms, such as pellets, that is a pharmacologically inactive substance that can be easily compacted when mixed with an active drug substance, improving flow and compressibility during the manufacture of pellets by direct compression. Examples of suitable pharmaceutically acceptable compression aids for use in the oral dosage forms described herein include directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, crystalline sorbitol, mannitol, microfine cellulose, and microcrystalline cellulose.

[0044] The term "glidant" refers to any substance used in the preparation of pharmaceutical dosage forms, such as pellets, that promotes the flow of a granular mixture by reducing friction between particles. Examples of suitable pharmaceutically acceptable glidants for use in the oral dosage forms described herein include cornstarch, talc, colloidal silica, and tribasic calcium phosphate (Ca5(PO4)3(OH)).

[0045] The term "disintegrant" refers to any substance used in the preparation of pharmaceutical dosage forms, such as pellets, that disintegrates and releases the pharmaceutical substance upon contact with moisture. Generally, disintegrants and superdisintegrants absorb water, swell when wet, and disintegrate the tablet formulation in the gastrointestinal tract, releasing the active ingredient(s) for absorption. Superdisintegrants have higher effectiveness at lower concentrations (compared to disintegrants) in tablet or pellet formulations. In some cases, the disintegrant or superdisintegrant 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, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium.

[0046] The term "lubricant" refers to any substance used in preparing pharmaceutical dosage forms, such as pellets, that reduces friction between the surfaces of the compression equipment and the pellets themselves. 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, and magnesium stearate.

[0047] As used herein, the terms "binder" and / or "filler" refer to excipients incorporated into pharmaceutical formulations to ensure the final formulation has the required mechanical strength. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starch, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose), polyvinylpyrrolidone, 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, pregelatinized starch, and mixtures thereof.

[0048] A "stable" formulation is one in which the antiviral compound therein essentially retains its physical and / or chemical stability upon storage. Stability can be measured over a selected period of time at a selected temperature and relative humidity. For example, in one embodiment, a stable formulation is one in which no significant change is observed for at least 12 months at ambient temperature (25.0°C-30.0°C) and a relative humidity of less than 75.0%. In another embodiment, a stable formulation is one in which no significant change is observed for at least 18 months at ambient temperature (25.0°C-30.0°C) and a relative humidity of less than 75.0%. Potency is typically within 90.0-110% of the target potency value.

[0049] Throughout this disclosure, additional abbreviations may be defined.

[0050] Oral dosage form The present disclosure relates to an oral dosage form of a pharmaceutical formulation comprising an antiviral nucleoside, one or more compression aids, one or more glidants, one or more lubricants, and one or more disintegrants, wherein the oral dosage form is a pellet having a diameter of 4.0 mm or less.

[0051] In embodiments, the antiviral nucleoside is β-DN(4)-hydroxycytidine [ka] is selected from the prodrugs of

[0052] In certain embodiments, the antiviral nucleoside is selected from antiviral nucleosides as disclosed in International Patent Application No. PCT / US2015 / 066144, published as WO 2016 / 106050, International Patent Application No. PCT / US2017 / 021759, published as WO 2017 / 156380, and International Patent Application No. PCT / US2018 / 064503, published as WO 2019 / 113462, which are incorporated herein by reference in their entireties. In more specific embodiments, the antiviral nucleoside is {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate: [ka] or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. In more specific embodiments, the antiviral nucleoside is Compound A. In other specific embodiments, the antiviral nucleoside is a prodrug of Compound A.

[0053] Methods for preparing NHCs and prodrugs thereof are set forth in PCT International Patent Application No. PCT / US2015 / 066144, published as PCT International Patent Application Publication No. WO2016 / 106050, U.S. Patent Application No. 15 / 537,087, published as U.S. Patent Application Publication No. 2019 / 0022116, and U.S. Patent Application No. 16 / 921,359, each of which is incorporated herein by reference in its entirety. Methods for preparing additional prodrugs of NHCs, including Compound A, as well as tautomers, prodrugs, and derivatives thereof, are set forth in PCT International Patent Application No. PCT / US2018 / 064503, published as PCT International Patent Application Publication No. WO2019 / 113462, U.S. Patent Application No. 16 / 755,779, now U.S. Patent No. 11,331,331, U.S. Patent Application No. 17 / 465,344, published as U.S. Patent Application Publication No. 2022 / 0016153, and U.S. Provisional Patent Application No. 63 / 127,484, which are incorporated herein by reference in their entireties.

[0054] In a first embodiment, the oral dosage form is a pellet having a diameter ranging from about 1.00 mm to about 4.00 mm, for example, from about 1.00 mm to about 2.80 mm, from about 1.80 mm to about 2.20 mm, or about 2.00 mm.

[0055] Conventional oral dosage forms may not be suitable for use in the treatment or prevention of viral infections in all subjects. Oral dosage forms with smaller sizes compared to conventional tablet and capsule formulations are desirable for many applications, including pediatric dosages, for patients with dysphagia (difficulty swallowing), and for applications requiring rapid and / or flexible dose adjustment. Pellets with a diameter of 4 mm or less may be desirable in such applications. For example, the oral dosage forms described herein may be used to provide incremental changes in pediatric dosage by varying the number of pellets administered, or the desired dose may be provided as pellets rather than as traditional capsules or tablets to facilitate swallowing. Such pellets can be relatively easily manufactured with uniform size and consistent active substance content. Highly accurate individual division of doses can be achieved by counting the pellets.

[0056] Because the oral dosage forms described herein have the dimensions of the first embodiment, the pellet size allows them to be more easily swallowed by young children and geriatric patients who may have difficulty swallowing. For pediatric patients, the oral dosage forms described herein allow for the use of weight-based dosing for children as young as 6 months to 2 years of age. Furthermore, the oral dosage forms described herein can be easily mixed with liquids and soft foods to aid administration to young pediatric patients, and the oral dosage forms described herein can be dissolved in water (or other suitable liquids) and administered to infants, including newborns and premature newborns.

[0057] The oral dosage forms described herein can be administered as multiple unit dosage forms, can be dosed in adjustable doses, and are often easy for patients to swallow due to their small size. The oral dosage forms, such as the pellet formulations described herein, provide better swallowing properties and dosage flexibility, making them more suitable for pediatric and geriatric patients than traditional capsules or tablets.

[0058] Additionally, the small size of the pellets in these formulations facilitates rapid disintegration times, allowing for dispersion in liquid prior to administration, which may be necessary or desirable for young pediatric patients and patients unable to swallow traditional tablet or capsule dosage forms. Once the pellets are dispersed in liquid, the liquid can be administered by swallowing or via nasogastric tube as needed.

[0059] For at least these reasons, the oral dosage forms, pellet formulations described herein, are particularly useful for administration to pediatric and elderly patients because they can be easily swallowed and can be readily dissolved and dispersed in liquids. Thus, such formulations offer several additional advantages over standard tablets and capsules.

[0060] In embodiments, the present disclosure provides an oral dose comprising about 1 to about 400 pellets provided herein. In a further aspect of this embodiment, the oral dose comprises about 1 to about 400 pellets packaged in a pouch. In yet a further aspect of this embodiment, the oral dosage form is provided as about 1 to about 400 pellets in a capsule.

[0061] In a second embodiment, the oral dosage form is an uncoated pellet having a weight ranging from about 1.00 mg to about 10.0 mg, for example, from about 6.00 mg to about 7.00 mg, from about 6.25 mg to about 6.75 mg, or about 6.50 mg.

[0062] In a third embodiment, the oral dosage form is a pellet comprising the antiviral nucleoside in an amount of about 0.0650 mg to about 5.20 mg, for example, about 1.30 mg to about 4.60 mg, about 1.80 mg to about 2.20 mg, or about 2.00 mg.

[0063] In a fourth embodiment, the oral dosage form is a pellet comprising the antiviral nucleoside in an amount of about 10.0% to about 80.0% by weight, e.g., about 20.0% to about 40.0% by weight, about 20.8% to about 40.8% by weight, or about 30.8% by weight, based on the total weight of the tablet.

[0064] In a fifth embodiment, the one or more compression aids are selected from the group consisting of directly compressible starch, dicalcium 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 aids are selected from the group consisting of directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, mannitol, microfine cellulose, and microcrystalline cellulose. In a particular aspect of this embodiment, the one or more compression aids are microcrystalline cellulose. In a first example, the one or more compression aids are present in an amount of about 0.195 mg to about 6.00 mg, e.g., about 0.90 mg to about 5.12 mg, about 2.71 mg to about 4.52 mg, or about 3.92 mg. In a second example, the one or more compression aids are present in an amount of about 3.00% to about 92.3% by weight, e.g., about 13.9% to about 78.8% by weight, about 41.7% to about 69.5% by weight, or about 60.2% by weight, based on the total weight of the pellet.

[0065] In a sixth embodiment, the one or more glidants are selected from the group consisting of starch, cornstarch, talc, silica, colloidal silica, and tribasic calcium phosphate. In aspects of this embodiment, the one or more glidants are selected from the group consisting of starch, talc, and tribasic calcium phosphate. In particular aspects of this embodiment, the one or more glidants are tribasic calcium phosphate. In a first example, the one or more glidants are present in an amount of about 0.016 mg to about 0.195 mg, e.g., about 0.0325 mg to about 0.130 mg, about 0.0488 mg to about 0.975 mg, or about 0.0650 mg. In a second example, the one or more glidants are present in an amount of about 0.250 wt% to about 3.00 wt%, e.g., about 0.500 wt% to about 2.00 wt%, about 0.750 wt% to about 1.50 wt%, or about 1.00 wt%, based on the total weight of the pellet.

[0066] In a seventh embodiment, the one or more lubricants are 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 an aspect of this embodiment, the one or more lubricants are magnesium stearate. In a particular aspect of this embodiment, the one or more lubricants are extragranular magnesium stearate. In a first example, the one or more lubricants are present in an amount of about 0.0325 mg to about 0.3250 mg, e.g., about 0.0650 mg to about 0.260 mg, about 0.114 mg to about 0.146 mg, or about 0.130 mg. In a second example, the one or more lubricants are present in an amount of about 0.500% to about 5.00% by weight, for example, about 1.00% to about 4.00% by weight, about 1.75% to about 2.25% by weight, or about 2.00% by weight, based on the total weight of the pellet.

[0067] In an eighth embodiment, the one or more disintegrants are selected from the group consisting of calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium. In an aspect of this embodiment, the one or more disintegrants are selected from the group consisting of calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium. In certain aspects of this embodiment, the one or more disintegrants are croscarmellose sodium. In a first example, the one or more disintegrants are present in an amount of about 0.0163 mg to about 0.585 mg, e.g., about 0.065 mg to about 0.488 mg, about 0.195 mg to about 0.423 mg, or about 0.390 mg. In a second example, the one or more glidants are present in an amount of about 0.250 wt% to about 9.00 wt%, e.g., about 1.00 wt% to about 7.50 wt%, about 3.00 wt% to about 6.50 wt%, or about 6.00 wt%, based on the total weight of the pellet.

[0068] In a ninth embodiment, the oral dosage form further comprises one or more binders. In aspects of this embodiment, the one or more binders are selected from the group consisting of starch, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose), polyvinylpyrrolidone, and mixtures thereof, and fillers such as microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof. In aspects of this embodiment, the one or more binders are selected from the group consisting of starch, cellulose, ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof. In a specific aspect of this embodiment, the one or more binders are hydroxypropylcellulose. In a first example, the one or more binders are present in an amount of about 0.000 mg to about 0.3900 mg, e.g., about 0.0975 mg to about 0.2925 mg, about 0.1625 mg to about 0.2275 mg, or about 0.1950 mg. In a second example, the one or more binders are present in an amount of about 0.000 wt.% to about 6.000 wt.%, e.g., about 1.500 wt.% to about 4.500 wt.%, about 2.500 wt.% to about 3.500 wt.%, or about 3.000 wt.%, based on the total weight of the pellet.

[0069] In a tenth embodiment, the oral dosage form is a pellet and may further comprise a coating. In an aspect, the coating may comprise hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, calcium carbonate, polyvinyl acetate, talc, a sweetener, and a colorant.

[0070] An embodiment of the present disclosure comprises: β-DN(4)-hydroxycytidine [ka] an antiviral nucleoside selected from the group consisting of: one or more compression aids selected from the group consisting of directly compressible starch, dicalcium phosphate, spray dried lactose, anhydrous lactose, spray crystallized maltose, spray crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microfine cellulose, and microcrystalline cellulose; one or more glidants selected from the group consisting of starch, corn starch, talc, silica, colloidal silica, and tribasic calcium phosphate; 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; one or more disintegrants selected from the group consisting of calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium; The present invention relates to an oral dosage form of a pharmaceutical preparation comprising Here, the oral dosage form is a pellet having a diameter of 4.0 mm or less.

[0071] Certain embodiments of the present disclosure include: An antiviral nucleoside, {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate: [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof; one or more compression aids selected from the group consisting of directly compressible starch, dicalcium phosphate, spray dried lactose, anhydrous lactose, mannitol, microfine cellulose, and microcrystalline cellulose; one or more glidants selected from the group consisting of starch, talc, silica, and tribasic calcium phosphate; one or more lubricants being magnesium stearate; one or more disintegrants selected from the group consisting of calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium; The present invention relates to an oral dosage form of a pharmaceutical preparation comprising Here, the oral dosage form is a pellet having a diameter of 4.0 mm or less.

[0072] Certain specific embodiments of the present disclosure include: {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate: [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof; Microcrystalline cellulose, tribasic calcium phosphate; Magnesium stearate, Croscarmellose sodium and The present invention relates to an oral dosage form of a pharmaceutical preparation comprising Here, the oral dosage form is a pellet having a diameter of 4.0 mm or less.

[0073] In terms of manufacturing, the oral dosage forms described herein have robust mechanical properties due to the combination of Compound A and excipients as described in the above embodiments and combinations of these embodiments. Due to their consistent specific surface area, smooth outer surface, and robust mechanical properties, the oral dosage forms can be reproducibly coated and require less coating material. See Munday, DL, 1994. Drug Dev. Ind. Pharm. 20, 2369-2379. Therefore, such formulations offer several additional advantages over standard tablets and capsules.

[0074] Treating or preventing viral infections Antiviral agents, including NHCs and prodrugs of NHCs, such as Compound A, are known to be useful in the treatment of viral infections and may be useful in the prevention of viral infections. Oral dosage forms, such as pellets, described herein may be useful in the treatment and prevention of viral infections in applications such as dosing pediatric patients, dosing patients with swallowing disorders, and when rapid and / or flexible dose adjustments are needed to appropriately treat the patient.

[0075] The present disclosure relates to a method of treating a viral infection, the method comprising administering an oral dosage form described herein to a subject in need thereof, wherein the viral infection is an infection by a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, 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 a particular aspect, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In further particular aspects, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV and SARS-CoV-2. In particular embodiments, the virus is SARS-CoV-2.

[0076] In embodiments of the methods of treatment disclosed herein, the oral dosage form is administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 individual 2 mg pellets.

[0077] In embodiments of the methods of treatment disclosed herein, the oral dosage form is administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0078] In embodiments of the methods of treatment disclosed herein, the method comprises administering an oral dosage form described herein to a subject in need thereof, wherein the oral dosage form is administered once daily for 1 to 20 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 14 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 6 days, e.g., 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered once daily for 5 days.

[0079] In embodiments of the methods of treatment disclosed herein, the method comprises administering an oral dosage form described herein to a subject in need thereof, wherein the oral dosage form is administered twice daily for 1 to 20 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 14 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 6 days, e.g., 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered twice daily for 5 days.

[0080] The present disclosure further relates to a method of treating a viral infection, the method comprising administering an oral dosage form described herein to a subject in need thereof, wherein therapy is initiated 1 to 10 days after the onset of symptoms of the viral infection, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after the onset of symptoms of the viral infection. In certain embodiments, the oral dosage form is administered less than 5 days after the onset of symptoms, e.g., less than 1, 2, 3, 4, or 5 days after the onset of symptoms of the viral infection. Symptoms of a viral infection may include one or more of cough, sore throat, stuffy nose, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue / fatigue, fever / feverishness, chills, headache, nausea, vomiting, and diarrhea, although symptoms may vary depending on the type and severity of the viral infection. For example, symptoms of COVID-19 caused by SARS-CoV-2 virus infection may include one or more of the following: cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue / tiredness, feeling hot or feverish, chills, headache, nausea, vomiting, diarrhea, loss of taste, and loss of smell.

[0081] The present disclosure further relates to the above-described methods of treating a viral infection, wherein the subject may be considered or determined to be at high risk for severe illness from COVID-19. Such individuals include, for example, those over 60 years of age; those with active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); those with chronic kidney disease (participants on dialysis or with an eGFR of 30 mL / min / 1.73 m); 2 Except for participants who fell below 50%; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 The subject may have one or more underlying conditions associated with a high risk of severe illness from COVID-19, such as: a body mass index of 30 or greater when calculated based on a mean age of 18 years; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); 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.

[0082] The present disclosure further relates to the above-described methods of treating a viral infection, wherein the method reduces the subject's risk of hospitalization or death. In embodiments, the method may result in a reduction in the subject's risk of hospitalization or death. In certain embodiments, the method may result in a reduction in the subject's risk of hospitalization or death of about 1 to about 10%, e.g., about 5 to about 7.5%, or about 6.8%. In further embodiments, the method may result in a relative reduction in the subject's risk of hospitalization or death of up to about 50%.

[0083] The present disclosure further relates to the above-described methods of providing antiviral prophylaxis, wherein the viral infection is caused by a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, and Zika Virus. In certain 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 certain embodiments, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In certain embodiments, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In certain embodiments, the virus is SARS-CoV-2.

[0084] In embodiments of the prophylaxis methods disclosed herein, the oral dosage form is administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 individual 2 mg pellets.

[0085] In embodiments of the prophylaxis methods disclosed herein, the oral dosage form is administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0086] The present disclosure further relates to a method of providing antiviral prophylaxis, the method comprising administering an oral dosage form described herein to a subject in need thereof, wherein the oral dosage form is administered once daily for 1 to 42 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 1 to 21 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 14 days, e.g., 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.

[0087] The present disclosure further relates to a method of providing antiviral prophylaxis, the method comprising administering an oral dosage form described herein to a subject in need thereof, wherein the oral dosage form is administered twice daily for 1 to 42 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 1 to 21 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 14 days, e.g., 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.

[0088] The present disclosure further relates to a method of providing antiviral prophylaxis, the method comprising administering an oral dosage form described herein to a subject in need thereof, wherein administration is initiated prior to exposure to a viral infection or after potential exposure to a viral infection. In certain embodiments, the oral dosage form is administered prior to potential exposure to a viral infection. In other specific embodiments, the oral dosage form is administered 1-10 days after potential exposure to a viral infection, e.g., 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 certain embodiments, the oral dosage form is administered less than 5 days after potential exposure, e.g., less than 1 day, less than 2 days, less than 3 days, less than 4 days, or less than 5 days after potential exposure.

[0089] The present disclosure further relates to the above-described methods of providing antiviral prophylaxis, wherein the subject may be considered at high risk for severe disease from COVID-19. Such individuals may include, for example, those over 60 years of age; those with active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); those with chronic kidney disease (participants on dialysis or with an eGFR of 30 mL / min / 1.73 m); 2 Except for participants who fell below 50%; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 The subject may have one or more underlying conditions associated with a high risk of severe illness from COVID-19, such as: a body mass index of 30 or greater when calculated based on a mean age of 18 years; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); 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 present disclosure relates to the above-described prevention methods, wherein the method reduces a subject's risk of hospitalization or death. In embodiments, the method may result in a reduction in the subject's risk of hospitalization or death. In certain embodiments, the method may result in a reduction in the subject's risk of hospitalization or death of about 1 to about 10%, e.g., about 5 to about 7.5%, or about 6.8%. In further embodiments, the method may result in a relative reduction in the subject's risk of hospitalization or death of up to about 50%.

[0091]

[0013] Embodiments provided by the present disclosure also include the oral dosage form described herein for use as a medicament for treating a viral infection. In certain embodiments, the viral infection is an infection by a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, and Zika virus. In certain 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 certain embodiments, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In certain embodiments, the virus is selected from the group consisting of a human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In certain embodiments, the virus is SARS-CoV-2.

[0092] The present disclosure also provides an oral dosage form as described herein for use as a medicament for treating a viral infection, wherein the patient has previously (e.g., within 24 hours) been treated with another agent, which may be as described above.

[0093] In embodiments, the oral dosage forms described herein for use as pharmaceuticals for treating viral infections are administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 individual 2 mg pellets.

[0094] In embodiments, the oral dosage forms described herein for use as pharmaceuticals for treating viral infections are administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0095] In an embodiment of the oral dosage form for use as a pharmaceutical for treating a viral infection, the oral dosage form is administered once daily for 1 to 20 days, e.g., 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 a specific embodiment, the oral dosage form is administered once daily for 3 to 14 days, e.g., 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 a specific embodiment, the oral dosage form is administered once daily for 3 to 6 days, e.g., 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered once daily for 5 days.

[0096] In an embodiment of the oral dosage form for use as a pharmaceutical for treating a viral infection, the oral dosage form is administered twice daily for 1 to 20 days, e.g., 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 a specific embodiment, the oral dosage form is administered twice daily for 3 to 14 days, e.g., 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 a specific embodiment, the oral dosage form is administered twice daily for 3 to 6 days, e.g., 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered twice daily for 5 days.

[0097] The present disclosure further relates to an oral dosage form for use as a pharmaceutical for treating a viral infection, wherein administration of the oral dosage form is initiated 1 to 10 days after the onset of symptoms of the viral infection, e.g., 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 the viral infection. In certain embodiments, administration of the oral dosage form is initiated less than 5 days after the onset of symptoms, e.g., less than 1 day, less than 2 days, less than 3 days, less than 4 days, or less than 5 days after the onset of symptoms of the viral infection. The symptoms of the viral infection may be as described above.

[0098] The present disclosure further relates to an oral dosage form for use as a pharmaceutical for treating a viral infection, wherein the pellets are administered to subjects who may be considered at high risk for severe illness from COVID-19. Such individuals may include, for example, individuals over 60 years of age; individuals with active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); individuals with chronic kidney disease (participants on dialysis or with an eGFR of 30 mL / min / 1.73 m); 2 Except for participants who fell below 50%; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 The subject may have one or more underlying conditions associated with a high risk of severe illness from COVID-19, such as: a body mass index of 30 or greater when calculated based on a mean age of 18 years; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); 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.

[0099] The present disclosure further relates to an oral dosage form for use as a pharmaceutical for treating a viral infection, wherein administration of the oral dosage form reduces a subject's risk of hospitalization or death. In embodiments, administration of the oral dosage form may result in a reduction in the subject's risk of hospitalization or death. In certain embodiments, administration of the oral dosage form may result in a reduction in the subject's risk of hospitalization or death of about 1 to about 10%, e.g., about 5 to about 7.5%, or about 6.8%. In further embodiments, administration of the oral dosage form may result in a relative reduction in the subject's risk of hospitalization or death of up to about 50%.

[0100] The present disclosure also relates to an oral dosage form for use as a pharmaceutical for preventing or providing antiviral prophylaxis against a viral infection, wherein the viral infection to be prevented is caused by a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, and Zika Virus. In certain 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 certain embodiments, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In certain embodiments, the virus is selected from the group consisting of a human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In certain embodiments, the virus is SARS-CoV-2.

[0101] The present disclosure also provides the oral dosage forms described herein for use as a pharmaceutical for preventing viral infection or providing antiviral prophylaxis, wherein the patient has previously (e.g., within 24 hours) been treated with another agent, which may be as described above.

[0102] In embodiments of the oral dosage forms described herein for use as pharmaceuticals for preventing viral infections or providing antiviral prophylaxis, the oral dosage forms are administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 individual 2 mg pellets.

[0103] In embodiments of the oral dosage forms described herein for use as pharmaceuticals for preventing viral infections or providing antiviral prophylaxis, the oral dosage forms are administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0104] The present disclosure further relates to an oral dosage form for use as a pharmaceutical for preventing viral infection or providing antiviral prophylaxis, wherein the oral dosage form is administered once daily for 1 to 42 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 1 to 21 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 14 days, e.g., 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.

[0105] The present disclosure further relates to an oral dosage form for use as a pharmaceutical for preventing viral infection or providing antiviral prophylaxis, wherein the oral dosage form is administered twice daily for 1 to 42 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 1 to 21 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 14 days, e.g., 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.

[0106] The present disclosure further relates to oral dosage forms for use as pharmaceuticals for preventing viral infection or providing antiviral prophylaxis, wherein therapy is initiated prior to exposure to a viral infection or after potential exposure to a viral infection. In certain embodiments, the oral dosage form is administered prior to potential exposure to a viral infection. In other specific embodiments, the oral dosage form is administered 1-10 days after potential exposure to a viral infection, e.g., 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 certain embodiments, the oral dosage form is administered less than 5 days after potential exposure, e.g., less than 1 day, less than 2 days, less than 3 days, less than 4 days, or less than 5 days after potential exposure.

[0107] The present disclosure further relates to an oral dosage form for use as a pharmaceutical for preventing viral infection or providing antiviral prophylaxis, wherein the oral dosage form is administered to subjects who may be considered at high risk for severe disease from COVID-19. Such individuals include, for example, those over 60 years of age; those with active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); those with chronic kidney disease (participants on dialysis or with an eGFR of 30 mL / min / 1.73 m); 2 Except for participants who fell below 50%; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 The subject may have one or more underlying conditions associated with a high risk of severe illness from COVID-19, such as: a body mass index of 30 or greater when calculated based on a mean age of 18 years; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); 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.

[0108] Additionally, the present disclosure relates to an oral dosage form for use as a pharmaceutical for preventing viral infection or providing antiviral prophylaxis, wherein the oral dosage form is administered to a subject who may have been exposed to a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, and Zika virus. In certain 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 certain embodiments, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In certain embodiments, the virus is selected from the group consisting of a human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In certain embodiments, the virus is SARS-CoV-2.

[0109] In embodiments of the oral dosage forms described herein for use as pharmaceuticals for treating viral infections in which the patient has previously (e.g., within 24 hours) been treated with another agent, the oral dosage form is administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 2 mg pellets.

[0110] In embodiments of pellets for use as a pharmaceutical for treating viral infections in which the patient has previously been treated with another agent (e.g., within 24 hours), the pellets are administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0111] Combination therapy In another embodiment, the oral dosage forms described herein can be combined with the present methods with one or more additional therapeutic agents useful for treating or preventing viral infections.

[0112] In one embodiment, the additional therapeutic agent is an antiviral agent.

[0113] In another embodiment, the additional therapeutic agent is an immunomodulatory agent, eg, an immunosuppressant.

[0114] Accordingly, in one embodiment, the present disclosure provides a method for treating a viral infection in a subject, the method comprising administering to the subject (i) an oral dosage form described herein and (ii) at least one additional therapeutic agent, wherein the administered amounts together are effective to treat or prevent the viral infection.

[0115] When administering the combination therapies described herein to a subject, the therapeutic agents of the combination, or pharmaceutical compositions or compositions comprising the therapeutic agents, can be administered in any order (e.g., sequentially, together, concurrently, simultaneously, etc.). The amounts of the various active agents in such combination therapy can be different amounts (different dosage amounts) or same amounts (same dosage amounts).

[0116] In one embodiment, the oral dosage forms described herein are administered during the period during which the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

[0117] In another embodiment, the oral dosage forms described herein are administered in doses typically used when such agents are used as monotherapy to treat viral infections.

[0118] In another embodiment, the oral dosage forms described herein and the additional therapeutic agent(s) are administered at doses lower than those typically used when such agents are used as monotherapy to treat a viral infection.

[0119] In yet another embodiment, the oral dosage forms described herein and the additional therapeutic agent(s) act synergistically and are administered at doses lower than those typically used when such agents are used as monotherapy to treat viral infections.

[0120] Viral infections and virus-related disorders that can be treated or prevented using the combination therapies described herein include, but are not limited to, those listed above.

[0121] The oral dosage forms described herein and the (one or more) additional therapeutic agents can act additively or synergistically. A synergistic combination can allow for the use of a lower dosage of one or more agents and / or a less frequent administration of one or more agents in the combination therapy. A lower dosage or less frequent administration of one or more agents can reduce the toxicity of the treatment without reducing the effectiveness of the treatment.

[0122] In one embodiment, administration of an oral dosage form described herein and an additional therapeutic agent(s) may inhibit the resistance of a viral infection to these agents.

[0123] The therapies disclosed herein may be used in combination with one or more other active agents, including, but not limited to, antiviral agents used in the prevention, treatment, control, amelioration, or risk reduction of a particular disease or condition (e.g., viral infection). In one embodiment, the compounds disclosed herein are combined with one or more other antiviral agents for use in the prevention, treatment, improved control, or risk reduction of a particular disease or condition for which the compounds disclosed herein are useful. Such other active agents may be administered contemporaneously or sequentially with the compounds of the present disclosure, by a route and in an amount commonly used therefor.

[0124] When the therapies disclosed herein are used contemporaneously with one or more other active agents, the oral dosage forms described herein can be administered simultaneously with, before, or after the one or more other active agents. The oral dosage forms described herein can be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).

[0125] The dosage of the oral dosage form described herein and one or more other active agents may vary and will depend on the therapeutically effective dose. Generally, a therapeutically effective dose of each is used. A combination comprising the oral dosage form described herein and other active agents generally comprises a therapeutically effective dose of each active agent. In such a combination, the oral dosage form described herein and other active agents can be administered separately or together. Furthermore, the administration of one element can be before, simultaneously with, or after the administration of (one or more) other agents.

[0126] In one embodiment, the present disclosure provides an oral dosage form 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 treatment of a viral infection, such as an infection with a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, and Zika virus. In an aspect 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 a more particular aspect, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In another specific embodiment, the virus is selected from the group consisting of a human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In an even more specific embodiment, the virus is SARS-CoV-2.

[0127] In another embodiment, the present disclosure provides an oral dosage form 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- or post-exposure, with a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, 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 a more particular aspect, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In another specific embodiment, the virus is selected from the group consisting of a human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In an even more specific embodiment, the virus is SARS-CoV-2.

[0128] The present disclosure also provides for the use of the oral dosage forms described herein to treat a viral infection, where the patient has previously (eg, within 24 hours) been treated with another agent.

[0129] The additional active agent(s) may be one or more agents selected from the group consisting of antiviral compounds, including, but not limited to, antiviral vaccines, antigens, adjuvants, anticancer drugs, 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, smoothening inhibitors, alkylating agents, antibiotics, antimetabolites, retinoids, steroids, and immunomodulators. It is understood that the descriptions of the additional active agents listed above and below may overlap. It is also understood that therapeutic combinations are subject to optimization, and that the best combination for use of the antiviral nucleoside and one or more additional active agents will be determined based on the needs of the individual patient.

[0130] Antiviral compounds that may be used in combination with the therapies disclosed herein include direct-acting antivirals and antiviral compounds that target the intracellular environment. In particular, antiviral compounds that may be used in combination with the therapies disclosed herein include antivirals that target the 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), conlonavir (TL-FVP-t), DW-2008S, DWJ-1248, ersufavirine, emtricitabine, eFT226, HP-163, IML-206, IMU-838, LAU-7b, MAN-19, MMS-019, OBP-2001, omega-3 viroxide, OPN-019, O YA-1, PP-001, PRTX-007, RBI-5000, RBT-9, RECCE529, RS-5614, SK1l, SLV-213, T-COVID, TL-895, TYME-19, UCI-1, XC-221, fenretinide, nafamostat, nafamostat mesylate, nanomedivir (atazanavir / dexamethasone), nanofenretinide (ST-001), necpranib (M-402), nelfinavir, nitazoxanide, piclidenoson, pixatimod, polyinosine Acid-precipitidylic acid, proxalutamide, hydrochloroquine, hydroxychloroquine, chloroquine, oseltamivir, oseltamivir phosphate, zanamivir, peramivir, baloxavir marboxil, remdesivir, favilavir, avifavir, favilavir / avifavir, vaniprevir, grazoprevir, elbasvir, narulaprevir, nitazoxanide, atazanavir, ritonavir, daclatasvir, farnavir, darunavir / cobicistat, saquinavir, indinavir, carfil These include zomib, ivartinostat (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.

[0131] Additional therapies that can 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 therapy, immunoglobulin excess therapy, monoclonal antibodies, polyclonal antibodies, and neutralizing antibodies; soluble guanylate cyclase stimulators, such as riociguat; cannibidiol; and vaccines. Additional therapies contemplated include any biological product or biological product that is biosimilar to any of the therapies explicitly listed herein.

[0132] In particular, 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)benzenesulfonamide, 3',4'-didehy-4'deoxy-8'-norvin-caleucoblastine, 47D11, 5-fluorouracil, abatacept, abiraterone acetate, ABX464, abivertinib, acalabrutinib, ACE2-Fc, ACE-MAB (STI-4920, CMAB020), acetylsalicylic acid, acetonitrile ... Toxaminophen, 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, Alosetra (white blood cell-based therapy), Allostim, Allorx stem cells, ALT-100 (enamptocumab), ALT-803, Amniobost, Ampion, altretamine, amiodarone, Anaferon, anakinra, AMG-3777, and Hydrovinblastine, anti-nCoV nanoviral agent, aprepitant, AP-003 (Anticovir), APL-9 (pegylated synthetic cyclic peptide), APX-115, AQCH, AR-701, ARO-COV, AS-1411, ascorbic acid, asnercept, atovaquone / azithromycin, AT-100 (rhSP-D), AT-301, AT-H201, ATI-450, ATR-002, auristatin, abdullimab (IPH5401), axatilimab, AZD-1061, AZD-7442, alberestat (AZD-9668), AZD-8895, azuvudine, azuvudine / 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, 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, cabaltinib, comostat, camostat mesylate, canakinumab, CAP-1002, carboplatin, carmustine, CB5064 analog, CD24Fc (recombinant fusion protein), cepharanthine, cemadotin, cenicriviroc, cantaquin, CERC-002, chlorambucil, chlorpromazine, cholecalciferol, ciclesonide, cisplatin, citrimoxazole, CK-0802, clazakizumab, clarithromycin, CLBS-119, CM4620-IE, colchicine, corlicytes (umbilical cord lining stem cells), COVID-19 aptamer therapy, COVID-19 human mAb, COVID-19 neutralizing antibody, COVID-19 siRNA therapy, COVID-HIG, COVID-EIG, spike glycoprotein, coviglobulin, COVI-GUARD (STI-1499), CPI-006, crizanlizumab, cryptophycin, CSL-324, CT-P59, CTAP-101, CV-15, CVL-218, cyclosporine, cell replacement therapy, cyclophosphamide, CYNK-001, cytarabine, dacarbazine, dactolisib, dactinomycin, dalargin, DAS-181, dapagliflozin, dapansultril, daunorubicin, decitabine, dexamethasone, DNL758 (SAR443122, RIPK1 inhibitor), dipyridamole, DMX-200, DS-2319, deupirfenidone, duvelisib, DV-890 , DWRX-2003, docetaxel, dolastatin, doxetaxel, doxorubicin (adriamycin), DP-710, EB-05, EB-201, ebastine, eculizumab, EDP-1815, efineptaquine alfa, emapalumab, emtricitabine, ensifentrine, ENU-200, enoxaparin, enzalutamide, epaspamine IA, etanercept, etoposide, eravacycline, famotidine, finasteride, fingolimod, flebogamma (IGIV31), fluvoxamine, foalumab (NI-0401, TZLS-401), fostamatinib, flutamide, FSD-201, FW1022, FT516, Gamnex (IGIV-C), ganetespib, GC-376,Ziapreza, GLS-1200, Galadacimab, GC-5131A (hyperimmune globulin), GIGA-2050 (rCIG), Gimsilumab, GNS561, GP1681, GSK-2586881 / APN-1, GSK-4182136, GTB-3550 (Trike 161533), haNK:CD-16, HB-adMSC, HFB30132A, HLCM-051, heparin, hydrocortisone, hydroxyurea, ibuprofen, ibudilast (MN-166), icosapent ethyl, IC14, IDB-003, IFX-1 / BDB-1, IgY-110, IMM101 IMS001, IMS002, ifosfamide, imatinib, infliximab, INM-005, interferon alpha, interferon alpha 1B, interferon alpha 2B, interferon beta 1A, interferon beta 1B, interleukin-6, interleukin-7, isoquercetin, itanapresed (CHF-5074), itolizumab, ivermectin, IVIG, JS012 (monoclonal antibody, LY-CoV016), jactinib, kagocel, KB109, sarilumab, K-NK-ID101, KTH-222, lactoferrin, LAM-002A (apilimod dimesylate), lanadelumab, lamellasome, LB-1148, larazotide, leflunomide, lenzilumab, leronlimab (monoclonal antibody) body), revilimab (BCD-089), levamisole, liarozole, linagliptin, lipocurc, losartan, rivilimab, lomustine (CCNU), lonidamine, rosmapimod, rosartan, LY-CoV555 (LY-3819253), LY-3127804, mannitol, maraviroc, mastinib, mavrilimumab, MDV3100, mechlorethamine, MEDI -3506, melatonin, melphalan, meplasmab, merimepodib, mesenchymal stem cells (MSC), Mesencure (cell replacement), Metabloc (anti-inflammatory), metformin, methotrexate, methylprednisolone, mitomycin, mibobulin isethionate, mocedipimod (EC-18), MP-0420, MP-0423, MRx4DP0004, N-acetylcysteine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-l-proline-t-butylamide, namilumab (IZN-101), nangibotide, narsoplimab, nebulized dornase 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 (efineptakine alfa), NTR-441, Octagam, olokizumab, omeprazole, onapristone, opaganib, OP-101, OT-101 (travedersen), otilimab, ozanimod, paclitaxel, pacritinib, panafix, pamrevlumab, paracetamol, PB1046, PTC299, pegylated interferon alpha, pegylated 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 agonist, RECC327, REGN-COV2 (antibody cocktail), reparixin, lintatolimod (Ampligen), RLF-100 (aviptadil), RLS-0071, STI-5656 (abivertinib), Rhu-pGSN (gelsolin), rhizoxin, RPR109881, RoActemra, RUCO NEST (Conestat alfa), ruxolitinib, SAB-185, SAR443122, SARS-CoV-2 antibody, SARS-CoV-2 monoclonal antibody, SARS-CoV-2 polyclonal antibody, SARS-CoV-2 neutralizing antibody, SCTA01, Leukin (sargramostim), selenexor, sevoflurane, sertenef, siltuximab, sildenafil citrate, silymarin, simvastatin, sirolimus, sirukumab, SIWA-318, solunatide, SNG-001, ST-266, stem cell education therapy, STI-1499,STI-2020dna (COVI-MAB), STI-4398 (Covidtrap), stramstine phosphate, streptozocin, T-cell therapy (TargNaturTa), TAK-671, TAK-888, TATX-36, TATX-99, TCB-007, TJ003234 / TJM-2, TP508, TRV027, TD-0903, TLC19, Tekluna, tafenoquine, tamoxifen, tasonermin, taxane, taxol, tetradrine, thalidomide, thimerosal, thymalfasin, tinzaparin , tocilizumab, tofacitinib, toremifene, tradipitant, tranexamic acid, trans sodium crocetinate (TSC), tramadol, tretinoin, TXA127 (antitensin-(1-7) peptide), TY027, TZLS-501, UNI-911, urinastatin, upamostat, bafidemstat, valsartan, icosapent ethyl, bazegepant, 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.

[0133] Additional 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, self-amplifying RNA vaccines, protein subunit vaccines, Ii-Key peptide COVID-19 vaccines, gp96-based vaccines, intranasal vaccines, and mRNA-lipid nanoparticle (mRNA-LNP) vaccines. In particular, additional 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 (chimpanzee-derived adenovirus)), Bacillus Calmette-Guerin (BCG) vaccine (live attenuated vaccine), bacTRL-spike (monovalent oral vaccine (bifidobacterium)), 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, COV001 / AZD-1222), CoronaVac (inactivated vaccine (formalin with alum adjuvant)), Corvax, CORVax-12, COVAX-19 (monovalent recombinant protein vaccine), Covaxin (BBV-152, inactivated vaccine), CoVepiT, CV nCoV (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-COV19 (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 via 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-COVID™ (intranasal vaccine), TaliCoVax-19, TerraCoV2, Tertomotide (GV-1001), Tiba-pitt These include RNA vaccines, 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;

[0134] use The present disclosure also relates to the use of an oral dosage form described herein for treating a viral infection in a subject in need thereof, wherein the viral infection is an infection with a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, Ross River Virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A Virus, Influenza B, Filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola 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 a particular aspect, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In further particular aspects, the virus is selected from the group consisting of human coronavirus, SARS-CoV-1, MERS-CoV and SARS-CoV-2. In particular embodiments, the virus is SARS-CoV-2.

[0135] In embodiments of the uses disclosed herein, the oral dosage form is administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 individual 2 mg pellets.

[0136] In embodiments of the uses disclosed herein, the oral dosage form is administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0137] In embodiments of the uses disclosed herein, the oral dosage form is administered once daily for 1 to 20 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 14 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 6 days, e.g., 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered once daily for 5 days.

[0138] In embodiments of the uses disclosed herein, the oral dosage form is administered twice daily for 1 to 20 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 14 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 6 days, e.g., 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered twice daily for 5 days.

[0139] The present disclosure further relates to the use of the oral dosage forms described herein to treat a viral infection in a subject in need thereof, wherein use is initiated 1 to 10 days after the onset of symptoms of the viral infection, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after the onset of symptoms of the viral infection. In certain embodiments, the oral dosage form is administered less than 5 days after the onset of symptoms, e.g., less than 1, 2, 3, 4, or 5 days after the onset of symptoms of the viral infection. Symptoms of a viral infection may include one or more of cough, sore throat, stuffy nose, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue / fatigue, fever / feverishness, chills, headache, nausea, vomiting, and diarrhea, although symptoms may vary depending on the type and severity of the viral infection. For example, symptoms of COVID-19 caused by SARS-CoV-2 virus infection may include one or more of the following: cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue / tiredness, fever / feverishness, chills, headache, nausea, vomiting, diarrhea, loss of taste, and loss of smell.

[0140] The present disclosure further relates to the above uses, wherein the subject may be considered or determined to be at high risk for severe illness from COVID-19. Such individuals include, for example, those over 60 years of age; those with active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); those with chronic kidney disease (participants on dialysis or with an eGFR of 30 mL / min / 1.73 m); 2 Except for participants who fell below 50%; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 The subject may have one or more underlying conditions associated with a high risk of severe illness from COVID-19, such as: a body mass index of 30 or greater when calculated based on a mean age of 18 years; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); 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.

[0141] The present disclosure further relates to the above uses, wherein the use reduces the subject's risk of hospitalization or death. In embodiments, the use may result in a reduction in the subject's risk of hospitalization or death. In certain embodiments, the use may result in a reduction in the subject's risk of hospitalization or death of about 1 to about 10%, e.g., about 5 to about 7.5%, or about 6.8%. In further embodiments, the use may result in a relative reduction in the subject's risk of hospitalization or death of up to about 50%.

[0142] Additionally, the present disclosure relates to uses of the oral dosage forms described herein for preventing a viral infection in a subject in need thereof or for providing antiviral prophylaxis to a subject in need thereof (hereinafter "prophylactic use(s)"), wherein the viral infection is caused by a virus selected from the group consisting of Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, 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, and Zika Virus. In certain 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 certain embodiments, the virus is selected from the group consisting of Influenza A Virus and Influenza B Virus. In certain embodiments, the virus is selected from the group consisting of a human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In certain embodiments, the virus is SARS-CoV-2.

[0143] In the prophylactic use embodiments disclosed herein, the oral dosage form is administered once daily as a single dose. In certain aspects of these embodiments, the once daily dose may be provided as 1 to 400 individual 2 mg pellets.

[0144] In embodiments of the prophylactic uses disclosed herein, the oral dosage form is administered twice daily as two individual doses. In certain aspects of these embodiments, each individual dose may be provided as 1 to 400 individual 2 mg pellets.

[0145] The present disclosure further relates to prophylactic uses, wherein the oral dosage form is administered once daily for 1 to 42 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 1 to 21 days, e.g., 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 certain embodiments, the oral dosage form is administered once daily for 3 to 14 days, e.g., 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.

[0146] The present disclosure further relates to prophylactic uses, wherein the oral dosage form is administered twice daily for 1 to 42 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 1 to 21 days, e.g., 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 certain embodiments, the oral dosage form is administered twice daily for 3 to 14 days, e.g., 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.

[0147] The present disclosure further relates to prophylactic uses, wherein use is initiated prior to exposure to a viral infection or after potential exposure to a viral infection. In certain embodiments, the oral dosage form is administered prior to potential exposure to a viral infection. In other specific embodiments, the oral dosage form is administered 1-10 days after potential exposure to a viral infection, e.g., 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 certain embodiments, the oral dosage form is administered less than 5 days after potential exposure, e.g., less than 1 day, less than 2 days, less than 3 days, less than 4 days, or less than 5 days after potential exposure.

[0148] The present disclosure further relates to the above-mentioned prophylactic uses, wherein the subject may be considered at high risk for severe illness from COVID-19. Such individuals include, for example, those over 60 years of age; those with active cancer (excluding mild cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); those with chronic kidney disease (participants on dialysis or with an eGFR of 30 mL / min / 1.73 m); 2Except for participants who fell below 50%; chronic obstructive pulmonary disease; obesity (body mass index = weight (kg) / (height (m)) 2 The subject may have one or more underlying conditions associated with a high risk of severe illness from COVID-19, such as: a body mass index of 30 or greater when calculated based on a mean age of 18 years; a serious cardiac condition (heart failure, coronary artery disease, or cardiomyopathy); 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 present disclosure relates to the above prophylactic uses, wherein the method reduces the subject's risk of hospitalization or death. In embodiments, the method may result in a reduction in the subject's risk of hospitalization or death. In certain embodiments, the method may result in a reduction in the subject's risk of hospitalization or death of about 1 to about 10%, e.g., about 5 to about 7.5%, or about 6.8%. In further embodiments, the method may result in a relative reduction in the subject's risk of hospitalization or death of up to about 50%.

[0150] Many patients with COVID-19 recover without or with minimal medical intervention. However, clinical progression to severe disease can have serious consequences for both patients and healthcare systems, increasing individuals' risk of requiring mechanical ventilation and death and potentially placing an undue strain on hospital capacity and available healthcare resources during COVID-19 surges. Therefore, it is important to reduce the number of patients requiring hospitalization for COVID-19. Vaccination is by far the most important medical intervention available to reduce the risk of hospitalization or death from COVID-19. However, early treatment immediately after onset of symptoms has also been shown to be effective. Currently, the only approved treatments for at-risk outpatients with COVID-19 are the monoclonal antibodies bamlanivimab / etesevimab, casirivimab / imdevimab, and sotrovimab. Because monoclonal antibodies require administration by infusion or injection at a healthcare setting, direct-acting oral agents, such as the oral dosage form described herein, which can be administered at home after diagnosis for pediatric patients or patients requiring flexible dosing or who have difficulty swallowing traditional forms, may be more practical for non-hospitalized patients and could be an important new tool in the treatment of COVID-19 caused by SARS-CoV-2.

[0151] Further embodiments of the present disclosure include the pharmaceutical compositions, combinations, uses, and methods described above, and it is understood that each embodiment may be combined with one or more other embodiments, so long as such combinations are consistent with the description of the embodiment. It is further understood that the embodiments provided above are understood to include all embodiments, including those resulting from combinations of embodiments.

[0152] [Example] The following examples are intended to be illustrative and should not be construed as further limiting. The contents of all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0153] [Reference Example 1] Compound A capsule formulation The capsule formulation for Compound A uses a wet granulation mixture filled into size 0 hypromellose capsules at a dosage strength of 200 mg (285.7 mg fill weight). The composition of the adult capsule formulation is shown in Table 1. The excipients used in the drug product are commonly used in pharmaceutical manufacturing.

[0154] [Table 1]

[0155] [Example 1] Compound A pellets Pellets were prepared by dispensing the following ingredients into a blender container, maintaining the proportions shown in Table 2. The ingredients were blended. The blend was then granulated by roller compaction. The granules were added to the blender container with magnesium stearate, and the ingredients were blended. The blend was then compressed into pellets.

[0156] [Table 2]

[0157] As shown in Table 3, the inclusion of a glidant improved the flow characteristics of the blend. Table 3 presents the results of a quantitative evaluation of flow data ("flodex") evaluating a wide range of SiO2 (0.00% to 2.00%) and tribasic calcium phosphate (0.00% to 2.00%). In general, materials with flodex values ​​greater than 28 mm are considered to have poor flowability, materials with flodex values ​​between 16 mm and 28 mm are considered to be moderately cohesive, and materials with flodex values ​​less than 16 mm are considered to have good flowability. For roller compaction, a flodex value of less than 30 is recommended. As can be seen from Table 3, the inclusion of a glidant improved the flow of the blend, making it suitable for roller compaction to form pellets. The use of tribasic calcium phosphate as a glidant improved the flow and process robustness of the blend, ultimately affecting important quality attributes of the granules.

[0158] [Table 3]

[0159] [Example 2] Compound A pellets with various image sizes Pellets were prepared by dispensing the following ingredients into a blender container, maintaining the following proportions as shown in Table 4. The ingredients were blended. The blend was then granulated by roller compaction. The granules were added to the blender container with magnesium stearate, and the ingredients were blended. The blend was then compressed into pellets in a tablet press.

[0160] [Table 4]

[0161] As the level of compound A in the formulation increases, the flow properties of the pre-roller compacted powder blend deteriorate due to the cohesive nature of the material. Compound A also has good water solubility but poor wettability in aqueous media. As the level of compound A in the formulation increases, the powder blend's properties are dominated by the properties of compound A, resulting in poor water wettability, dispersibility, and uniformity. Therefore, the proportion of compound A in the formulation with desirable properties is limited.

[0162] Example 3: Compound A pellets containing varying amounts of croscarmellose sodium and magnesium stearate Pellets were prepared by dispensing the following ingredients into a blender container, maintaining the following proportions as shown in Table 5. The ingredients were blended. The blend was then granulated by roller compaction. The granules were added to the blender container with magnesium stearate, and the ingredients were blended. The blend was then compressed into pellets in a tablet press.

[0163] [Table 5]

[0164] The hydrophilic agent croscarmellose sodium is added to the formulation. The level of croscarmellose sodium does not significantly affect the physical attributes of the powder blend. At various amounts of croscarmellose sodium, the dissolution behavior of the pellets is not significantly affected due to the high surface area, which promotes rapid disintegration. For young pediatric patients, such as infants, the pellets can be dissolved in water (or other suitable liquid) and administered. The level of disintegrant affects the size and uniformity of the dispersed particles in the aqueous medium. This allows for improved performance and ease of administration by having the patient swallow the aqueous dispersion or by administering the aqueous dispersion via a nasogastric tube.

[0165] Magnesium stearate is used as a lubricant both intragranularly (after blending the pre-granulated blend) and extragranularly (after roller compaction). Intragranular lubrication is performed to minimize adhesion of the powder mixture to the roller surfaces during roller compaction. The resulting pellets are lubricated to prevent pellet adhesion during the compression process. Various levels of magnesium stearate did not significantly affect in vitro dissolution performance. However, pellet hardness decreased with increasing magnesium stearate levels, resulting in a decrease in formulation robustness.

[0166] Example 4: Compound A pellets containing hydroxypropyl cellulose and various amounts of Compound A Pellets were prepared by dispensing the following ingredients (except magnesium stearate) into a wet granulation bowl maintaining the following proportions as shown in Table 6. Microcrystalline cellulose may be added intragranularly, extragranularly, or both intragranularly and extragranularly. The ingredients were mixed and then granulated with water. The resulting wet granules were deagglomerated, dried, and milled to obtain the appropriate particle size. The granules were added to the blender container with the magnesium stearate and blended. The blend was then compressed into pellets in a tablet press.

[0167] [Table 6]

[0168] Hydroxypropyl cellulose is commonly used as a binder to facilitate granule blending during wet granulation. It effectively promotes controlled granule growth while also allowing for rapid dissolution of the drug product. The binder level can affect the particle size distribution of the resulting granulation and the dissolution rate of compressed minitablets. Granule particle size increases with increasing levels of hydroxypropyl cellulose. The dissolution behavior of pellets was not significantly affected by varying levels of binder due to the pellets' high surface area. However, increasing the binder level reduces the rate at which disintegrated particles disperse to form a uniform suspension.

[0169] As the level of Compound A in a formulation increases, the properties of the powder blend become dominated by the properties of Compound A, resulting in decreased water wettability, dispersibility, and uniformity, thus limiting the proportion of Compound A in the formulation that has the desired properties.

[0170] It will be appreciated that various of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications, and that various presently unforeseen or unanticipated substitutions, 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

1. 1. An oral dosage form comprising an antiviral nucleoside, one or more compression aids, one or more glidants, one or more lubricants, and one or more disintegrants, wherein: (a) the oral dosage form is a pellet having a diameter of 4.0 mm or less; (b) the antiviral nucleoside is β-DN(4)-hydroxycytidine 【Chemistry 1】 selected from the prodrugs of Oral dosage form.

2. The antiviral nucleoside is {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate: 【Chemistry 2】 10. The oral dosage form of claim 1, wherein the oral dosage form is:

3. 3. The oral dosage form of claim 2, wherein the antiviral nucleoside is Compound A.

4. 3. The oral dosage form of claim 2, wherein the antiviral nucleoside is a prodrug of Compound A.

5. 10. The oral dosage form of claim 1, wherein the pellets have a diameter ranging from about 1.00 mm to about 4.00 mm.

6. 6. The oral dosage form of claim 5, wherein the pellets have a diameter of about 2.00 mm.

7. 7. The oral dosage form of claim 1, wherein the pellets have a weight in the range of about 1.00 mg to about 10.0 mg.

8. 8. The oral dosage form of claim 7, wherein the pellet has a weight of about 6.50 mg.

9. 9. The oral dosage form of claim 1, wherein the pellet comprises the antiviral nucleoside in an amount of from about 0.0650 mg to about 5.20 mg.

10. 10. The oral dosage form of claim 9, wherein the pellet comprises the antiviral nucleoside in an amount of about 2.00 mg.

11. 11. The oral dosage form of claim 1, wherein the pellets comprise Compound A in an amount of about 10.0% to about 80.0% by weight, based on the total weight of the tablet.

12. 12. The oral dosage form of claim 11, wherein the pellets contain the antiviral nucleoside in an amount of about 30.8% by weight based on the total weight of the tablet.

13. 2. The oral dosage form of claim 1, wherein the one or more compression aids are selected from the group consisting of directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, spray-crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microfine cellulose, and microcrystalline cellulose.

14. 14. The oral dosage form of claim 13, wherein the one or more compression aids are selected from the group consisting of directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, mannitol, microfine cellulose, and microcrystalline cellulose.

15. 15. The oral dosage form of any one of claims 13 to 14, wherein the one or more compression aids is microcrystalline cellulose.

16. 16. The oral dosage form of any one of claims 13 to 15, wherein the one or more compression aids are present in an amount of from about 0.195 mg to about 6.00 mg.

17. 17. The oral dosage form of claim 16, wherein the one or more compression aids are present in an amount of about 3.92 mg.

18. 16. The oral dosage form of any one of claims 13 to 15, wherein the one or more compression aids are present in an amount of about 3.00% to about 92.3% by weight, based on the total weight of the tablet.

19. 20. The oral dosage form of claim 18, wherein the one or more compression aids are present in an amount of about 60.2% by weight, based on the total weight of the pellet.

20. 10. The oral dosage form of claim 1, wherein the one or more glidants are selected from the group consisting of starch, corn starch, talc, silica, colloidal silica, and tribasic calcium phosphate.

21. 21. The oral dosage form of claim 20, wherein the one or more glidants is tribasic calcium phosphate.

22. 22. The oral dosage form of any one of claims 20-21, wherein the one or more glidants are present in an amount of from about 0.016 mg to about 0.195 mg.

23. 23. The oral dosage form of claim 22, wherein the one or more glidants are present in an amount of about 0.0650 mg.

24. 22. The oral dosage form of any one of claims 20-21, wherein the one or more glidants are present in an amount of about 0.250% to about 3.00% by weight, based on the total weight of the pellet.

25. 25. The oral dosage form of claim 24, wherein the one or more glidants are present in an amount of about 1.00% by weight, based on the total weight of the pellet.

26. 10. The oral dosage form of claim 1, wherein the one or more lubricants are selected from the group consisting of magnesium silicate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, magnesium lauryl sulfate, and magnesium stearate.

27. 27. The oral dosage form of claim 26, wherein the one or more lubricants is magnesium stearate.

28. 28. The oral dosage form of claim 27, wherein the one or more lubricants is extragranular magnesium stearate.

29. 29. The oral dosage form of any one of claims 26 to 28, wherein the one or more lubricants are present in an amount from about 0.0325 mg to about 0.3250 mg.

30. 30. The oral dosage form of claim 29, wherein the one or more lubricants are present in an amount of about 0.130 mg.

31. 29. The oral dosage form of any one of claims 26 to 28, wherein the one or more lubricants are present in an amount of about 0.500% to about 5.00% by weight, based on the total weight of the pellet.

32. 32. The oral dosage form of claim 31, wherein the one or more lubricants are present in an amount of about 2.00% by weight, based on the total weight of the pellet.

33. 2. The oral dosage form of claim 1, wherein the one or more disintegrants are selected from the group consisting of calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium.

34. 34. The oral dosage form of claim 33, wherein the one or more disintegrants are selected from the group consisting of calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, carmellose calcium, crospovidone, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, sodium alginate, starch, sodium starch glycolate, and croscarmellose sodium.

35. 35. The oral dosage form of any one of claims 33 to 34, wherein the one or more disintegrants is croscarmellose sodium.

36. 36. The oral dosage form of any one of claims 33 to 35, wherein the one or more disintegrants are present in an amount from about 0.0163 mg to about 0.585 mg.

37. 37. The oral dosage form of claim 36, wherein the one or more disintegrants are present in an amount of about 0.390 mg.

38. 36. The oral dosage form of any one of claims 33 to 35, wherein the one or more disintegrants are present in an amount of about 0.250% to about 9.00% by weight, based on the total weight of the pellet.

39. 39. The oral dosage form of claim 38, wherein the one or more disintegrants are present in an amount of about 6.00% by weight, based on the total weight of the pellet.

40. 40. The oral dosage form of any one of claims 1 to 39, further comprising one or more binders.

41. 41. The oral dosage form of claim 40, wherein the one or more binders are selected from the group consisting of starch, cellulose, ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and mixtures thereof, and a filler, wherein the filler is selected from the group consisting of microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof.

42. 42. The oral dosage form of any one of claims 40 to 41, wherein the one or more binders are selected from the group consisting of starch, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof.

43. 43. The oral dosage form of any one of claims 40 to 42, wherein the one or more binders is hydroxypropyl cellulose.

44. 44. The oral dosage form of any one of claims 40 to 43, wherein the one or more binders are present in an amount from about 0.000 mg to about 0.3900 mg.

45. 45. The oral dosage form of claim 44, wherein the one or more binders are present in an amount of about 0.1950 mg.

46. 44. The oral dosage form of any one of claims 40 to 43, wherein the one or more binders are present in an amount of about 0.000% to about 6.000% by weight, based on the total weight of the pellet.

47. 47. The oral dosage form of claim 46, wherein the one or more binders are present in an amount of about 3.000% by weight, based on the total weight of the pellet.

48. 10. An oral dose comprising from about 1 to about 400 pellets of the oral dosage form of claim 1.

49. 49. The oral dose of claim 48, wherein the pellets are packaged in a pouch.

50. 49. The oral dose of claim 48, wherein the oral dosage form is provided as pellets in a capsule.

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