Solid dosage forms of small molecule antiviral agents and uses thereof

Abstract

The present disclosure relates to oral dosage forms comprising an antiviral nucleoside and one or more excipients, wherein the oral dosage form is a tablet. The antiviral nucleoside is selected from a prodrug of beta-D-N (4)-hydroxycytidine (I), such as 2-methylpropionic acid {(2R, 3S, 4R, 5R)-3, 4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3, 4-dihydropyrimidin-1 (2H)-yl] oxacyclopentane-2-yl} methyl ester)-compound (A), or a pharmaceutically acceptable salt, tautomer or prodrug thereof. (I) (A)

Description

Cross-references to related applications

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

[0002] This disclosure relates to solid dosage forms of small molecule antiviral agents. The solid dosage forms of the present invention are typically tablets, such as compressed tablets. This disclosure also relates to the use of this solid dosage form for treating or preventing viral infections in patients in need, and to methods of using this solid dosage form for treating or preventing viral infections in patients in need. Background Technology

[0003] Viral infections, such as those caused by Eastern Equine Encephalitis Virus (EEEV), Western Equine Encephalitis Virus (WEEV), 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 or SARS-CoV-1), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and more recently SARS-CoV-2 (or 2019-nCoV)), continue to cause illness worldwide that can range from mild to severe and even life-threatening and fatal.

[0004] EEEV, WEEV, VEEV, and CHIK viruses are all vector-borne viruses (Viraviridae family). Togctvihdae ) Avira ( Alphavirus It can be transmitted to humans through mosquito bites. Equine encephalitis virus is a CDC Category B pathogen, while CHIK virus is a Category C pathogen.

[0005] Coronaviruses account for a large proportion of human respiratory diseases, which can be severe or life-threatening. SARS-CoV-1, which emerged in 2002, has caused at least 8,439 human cases and at least 812 deaths worldwide. WHO Cumulative number of suspected SARS cases reported from November 1, 2002 to July 4, 2003 Downloaded on August 12, 2020 from www.who.int / csr / sars / country / 2003_07_04 / en / . Similarly, MERS-CoV, which emerged in 2012, has caused at least 2,519 human cases and at least 866 deaths globally. WHO Middle East Respiratory Syndrome (MERS) Situation UpdateJanuary 2020; August 12, 2020 (downloaded from www.emro.who.int / health-topics / mers-cov / mers-outbreaks.html). Recently, SARS-CoV-2, which emerged in 2019, has caused at least 629 million confirmed human cases and at least 6.5 million deaths globally. World Health Organization COVID-19 Weekly Epidemiological Update, Issue 117 Published on November 9, 2022, and available for download on November 10, 2022 from www.who.int / publications / m / item / weekly-epidemiological-update-on-covid-19---9-november-2022. SARS-CoV-2 causes a disease known as COVID-19, which can cause severe respiratory and systemic symptoms in humans. SARS-CoV-2 infection is also accompanied by psychiatric and neurological symptoms, which may include delirium or encephalopathy, agitation, stroke, meningoencephalitis, loss of smell or taste, anxiety, depression, and sleep problems, and these neurological symptoms may occur without respiratory symptoms (see [link to relevant documentation]). Clinical Management of COVID-19 (Interim Guidance, May 27, 2020) (Downloaded from www.who.int / publications / i / item / clinical-management-of-covid-19 on September 15, 2020). Further research is needed to characterize the SARS-CoV-2 virus and identify methods for preventing and treating COVID-19 disease, as well as diseases caused by other human coronaviruses.

[0006] Many COVID-19 patients recover with little or no medical intervention. However, clinical progression to severe illness severely impacts patients and the healthcare system, increasing not only the risk of mechanical ventilation and death but also potentially overwhelming hospital capacity and existing medical resources during COVID-19 surges. Therefore, reducing the number of COVID-19 patients requiring hospitalization is crucial. Vaccination remains the most important medical intervention currently available to reduce the risk of hospitalization or death due to COVID-19. However, early treatment after symptom onset has also proven effective. Monoclonal antibodies bamlanivimab / etesevimab, casirivimab / imdevimab, and sotrovidumab were initially the only approved treatment options for high-risk outpatients with COVID-19. Because monoclonal antibodies need to be administered via infusion or injection in a medical setting, direct-acting oral formulations that can be taken at home after diagnosis may be more practical for non-hospitalized patients and will become an important new tool for treating COVID-19 caused by SARS-CoV-2.

[0007] Antiviral agents are still under development to treat viral infections. For example, antiviral nucleoside β-D- N (4)-Hydroxycytidine (NHC, 1-((2) R ,3 R 4 S 5 R )-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidine-2-yl 1H )-ketone), , It possesses anti-antipestivirus and anti-hepatitis virus activity. ANTIMICROB AGENTSCHEMOTHER, 2003, 47(1):244-54. Although NHC has been shown to have limited oral bioavailability in non-human primates ( See Toots et al. , SCI. TRANSL. MED 11, eaax5866 (2019)), but NHC prodrugs, including 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H[2-yl]oxacyclopentane-2-yl methyl ester: Compound A, It is also known as uridine 4-oxime 5'-(2-methylpropionate) and monoravir, has oral bioavailability, and is considered at least promising for the treatment of viral infections caused by Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus and Venezuelan Equine Encephalitis Virus, Chikungunya Virus, Ebola Virus, Influenza Virus, Respiratory Syncytial Virus, Zika Virus, and coronaviruses such as Severe Acute Respiratory Syndrome Coronavirus, Middle East Respiratory Syndrome Coronavirus and the more recent SARS-CoV-2.

[0008] β-D- N (4)-Hydroxycytidine, its prodrug, its derivatives, and methods of preparation thereof are set forth in PCT International Patent Application No. PCT / US2015 / 066144 (published under PCT International Patent Application Publication No. WO2016 / 106050), U.S. Patent Application No. 15 / 537,087 (published under U.S. Patent Application Publication No. US2019 / 0022116), and U.S. Patent Application No. 16 / 921,359 (published under U.S. Patent Application No. US2021 / 0060050 and granted under U.S. Patent No. 11,628,181), all of which are incorporated herein by reference in their entirety. Compound A, its pharmaceutically acceptable salts, tautomers, and prodrugs, as well as other β-D- N (4) Hydroxycytidine derivatives and their preparation methods are set forth in PCT International Patent Application No. PCT / US2018 / 064503 (published under 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 under US2022 / 0016153 A1), U.S. Provisional Patent Application No. 63 / 127,484, and PCT International Patent Application No. PCT / US2021 / 064021 (published under PCT International Patent Application Publication No. WO2022 / 133205), all of which are incorporated herein by reference in their entirety.

[0009] Compound A is marketed for the treatment of viral infections caused by SARS-CoV-2 and other pathogens, as well as for the treatment of COVID-19 caused by SARS-CoV-2. However, the 800 mg dose, administered twice daily for five days, is in the form of four (4) capsules. Each of these capsules is a size 0 capsule, measuring 21.7 mm x 7.6 mm, with a unit dose strength of 200 mg, and each capsule represents a unit dose form. The size and number of unit dose forms required for each administration, both in terms of the size of each capsule and the number of capsules administered at each dosing interval, create a significant medication burden. This medication burden can affect patient adherence to medication orders (both in terms of the number of doses administered at a time and adherence to the dosing schedule). A high medication burden also carries other risks, such as an increased risk of medication errors, and increased costs.

[0010] Oral formulations of antiviral nucleosides (such as compound A) are needed to reduce the burden of medication administration by decreasing the number of unit doses required per administration, by reducing the size of the unit dose, or both. Reducing the burden of medication administration will ultimately improve adherence and thus improve efficacy, and will also reduce the risk of medication errors and lower costs. However, the design of such formulations remains largely unpredictable. Summary of the Invention

[0011] This disclosure relates to an oral dosage form of a pharmaceutical preparation comprising an antiviral nucleoside and one or more excipients, wherein the oral dosage form is a tablet. The antiviral nucleoside is selected from β-D- N (4)-Hydroxycytidine Prodrugs, such as 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: (Compound A) Or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. Implementation methods for such oral dosage forms may include wet granulation, direct tableting, or roll forming.

[0012] Other embodiments, aspects, and features of the invention will be further described in the following description, examples, and appended claims, or will become apparent from the following description, examples, and appended claims. The foregoing technical overview is not restrictive, and other features and advantages of the technology will become apparent from the following detailed description and from the claims. Attached Figure Description

[0013] Figure 1 The tablet-ability curves of the particle and powder blends of compound A prepared using different techniques according to Example 2 are shown.

[0014] Figure 2 The comparison of tablet friability between formulation B of compound A and formulation D of compound A is shown.

[0015] Figure 3 The comparison of the granulation properties of the capsule formulation of Example 1 with that of formulation D of compound A is shown.

[0016] Figure 4 The effect of increasing the amount of sodium lauryl sulfate in the high-shear wet granulation formulation of compound A is illustrated.

[0017] Figure 5 The dissolution rates of high-shear wet granulation formulations of compound A with different contents of excipients were compared.

[0018] Figure 6 This illustrates the bioequivalence between the capsule formulation of compound A and the tablet formulation D of compound A. Detailed Implementation

[0019] definition The following provides specific definitions for certain technical and scientific terms. Unless otherwise specified herein, all other technical and scientific terms used herein will have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0020] 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 terms used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well-known and commonly used in the art.

[0021] As used herein (including the appended claims), singular terms such as “a” and “the” include their corresponding plural references, unless the context clearly specifies otherwise.

[0022] The terms “administration” and / or “application” of a compound should be understood to include providing a subject with the compound described herein or a pharmaceutically acceptable salt thereof, as well as the aforementioned combinations.

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

[0024] As used herein, the term "subject" (or "patient" or "participant," as in a clinical trial) refers to a mammal as the subject of treatment, observation, or experimentation. The mammal can be male or female. The mammal can be one or more selected from: humans, bovids (e.g., cattle), suidae (e.g., pigs), ovids (e.g., sheep), caprides (e.g., goats), equines (e.g., horses), canids (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), and raccoons (e.g., raccoons). In certain embodiments, the subject is a human. In some embodiments, the patient is an adult patient. In other embodiments, the patient is a pediatric patient. Those "in need of treatment" include patients who can benefit from treatment using the formulations of the present invention, for example, patients suffering from a viral infection (such as SARS-CoV-2 infection).

[0025] As used herein, the term "viral infection" refers to an infection caused by a virus. In the implementation plan, the viruses selected are Eastern Equine Encephalitis Virus (EEEV), Western Equine Encephalitis Virus (WEEV), Venezuelan Equine Encephalitis Virus (VEEV), Chikungunya Virus (CHIK), Ross River Virus, Orthomyxoviridae Viruses, Paramyxoviridae Viruses, Respiratory Syncytial Virus (RSV), Influenza A Virus, Influenza B Virus, Filoviridae Viruses, Human Coronaviruses, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola Virus, Marburg Virus, and Zika Virus. Viral infections may be symptomatic or asymptomatic.

[0026] As used herein, the term “subject in need” means a subject who has been diagnosed with or is suspected of having a viral infection (such as SARS-CoV-2 infection, whether symptomatic or asymptomatic); a subject at risk of exposure to a viral infection, such as a healthcare worker who may be at risk of exposure to a viral infection such as SARS-CoV-2 (e.g., healthcare workers who may be at risk of exposure to SARS-CoV-2); or a subject who has been exposed to a viral infection (such as SARS-CoV-2 infection) (e.g., a COVID-19 patient or a household contact of an asymptomatic patient infected with SARS-CoV-2), as defined herein.

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

[0028] Some participants may be considered to have a higher risk of developing severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of developing severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with an estimated glomerular filtration rate (eGFR) reduced to <30 mL / min / 1.73 m). 2 Individuals with chronic obstructive pulmonary disease (COPD); obesity (BMI of 30 or higher, where BMI = weight (kg) / (height (m)) 2 ); serious heart disease (heart failure, coronary artery disease or cardiomyopathy); and / or diabetes.

[0029] As used herein, the terms “treatment” and “to perform treatment” refer to any process that may slow, interrupt, stop, control, or halt the progression of the disease or condition described herein. These terms do not necessarily imply the complete elimination of all symptoms of the disease or condition.

[0030] As used herein, the terms “prevention” and “antiviral prophylaxis” refer to processes designed to prevent all diseases. Prophylaxis can be performed before exposure to a viral infection (such as SARS-CoV-2 infection) (pre-exposure, e.g., among healthcare workers who may be exposed to such an infection) or after potential exposure to a viral infection (such as SARS-CoV-2 infection) (post-exposure, e.g., among cohabitants or caregivers of symptomatic or asymptomatic patients infected with SARS-CoV-2).

[0031] As used herein, the term "simultaneous administration" refers to the administration of drugs in such a manner that each individual drug is present in the subject's body simultaneously. In addition to concurrent administration of drugs (via the same or different routes), simultaneous administration may also include administration of drugs at different times (via the same or different routes).

[0032] As used herein, the terms “tablet” or “compressed tablet” are intended to encompass all compressed pharmaceutical dosage forms of all shapes and sizes. Typical tablets may be round, oval, capsule-like, or have other geometric shapes. Typical tablets may have a maximum length or diameter of at least about 5.00 mm ± 0.15 mm (the length of the diameter if the tablet is round, or the length of the longest dimension if the tablet is oval, capsule-shaped, or has other shapes), such as in the range of about 5.00 mm ± 0.15 mm to about 22.00 mm ± 0.15 mm, about 12.80 mm ± 0.15 mm to about 19.00 mm ± 0.15 mm, about 13.00 mm ± 0.15 mm to about 17.00 mm ± 0.15 mm, or about 13.36 mm ± 0.15 mm.

[0033] Unless explicitly stated otherwise, all ranges referenced herein include endpoints; that is, a range includes its upper and lower limits, and all values ​​in between. All ranges are also intended to include all subranges included therein, although not necessarily explicitly stated. As an example, temperature ranges, percentage (%), equivalent ranges, etc., described herein include their upper and lower limits, and any consecutive values ​​in between. Numerical values ​​provided herein and the use of the term "about" may include deviations from ±1%, ±2%, ±3%, ±4%, ±5%, and ±10% and their equivalents.

[0034] When used to modify parameters defining numerical values ​​(e.g., the dose of an antiviral nucleoside or the duration of treatment with a combination therapy described herein), "about" means that the parameter may be up to 10% lower or higher than the value stated for that parameter, and where appropriate, the stated parameter may be rounded to the nearest integer. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. Additionally, as used herein, the term "or" indicates alternatives that can be combined where appropriate; that is, the term "or" includes both each listed alternative individually and combinations thereof. When referring to the amount of a modifying substance or composition (e.g., mM or M), the percentage of a formulation component (v / v or w / v), the pH of the solution / formulation, or parameter values ​​of steps in a characterization method, the term "about" refers to a possible deviation in numerical quantity, such as: attributable to typical measurement, handling, and sampling procedures involved in the preparation, characterization, and / or use of the substance or composition; attributable to unintentional errors in these procedures; attributable to differences in the manufacture, origin, or purity of the ingredients used to prepare or use the composition or perform the procedure; and so on. In some embodiments, "about" may refer to a variation of ± 0.100%, 0.500%, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, or 10.0%.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the event of any conflict, this specification (including the definitions) shall prevail.

[0036] Throughout this specification and claims, the word “comprising” or variations thereof (such as “containing” or “including”) is used in an inclusive sense, that is, unless the context requires otherwise by express expression or necessary implication, it is intended to indicate the presence of the stated feature, but does not exclude the presence or addition of other features that may substantially enhance the operation or utility of any embodiment of the invention. Unless the context requires otherwise, singular terms shall include plural references and plural terms shall include singular references. Any instances following the terms “for example” or “for instance” are not intended to be exhaustive or limiting.

[0037] It should be understood that any implementation scheme described in this document using the word "comprising" is also accompanied by similar implementation schemes described as "consisting of" and / or "substantially consisting of".

[0038] As used throughout the specification and claims, the phrase “consistent essentially of” means to include any of the described elements or groups of elements, and optionally to include other elements that are similar or different in nature from the described elements, such other elements not materially altering the fundamental or novel characteristics of the specified dosing regimen, method, or composition.

[0039] The terms "pharmaceutical effective amount" and "effective amount" refer to a therapeutic composition or preparation provided to a patient in an amount sufficient to cause a therapeutic or preventive effect in treating a disease or condition. Those skilled in the art will recognize that this amount can vary depending on patient characteristics such as age and weight.

[0040] "Pharmaceutical acceptable" means excipients (mediators, additives) and compositions that can be reasonably administered to a subject to provide an effective dose of the active ingredient and are "generally considered safe," for example, that are physiologically tolerable and do not typically cause allergic reactions or similar undesirable reactions, such as gastrointestinal upset, when administered to humans. In another embodiment, the term refers to molecular entities and compositions approved by a U.S. federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0041] The term "pharmaceutically acceptable carrier" refers to any inactive substance suitable for use in a formulation to deliver a therapeutic agent. Carriers can be anti-adhesion agents, binders, coating agents, disintegrants, fillers or diluents, lubricants, preservatives (such as antioxidants, antibacterial agents, or antifungal agents), sweeteners, absorption delay agents, wetting agents, emulsifiers, buffers, etc. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), dextrose, vegetable oils (such as olive oil), saline, buffers, buffered saline, and isotonic agents such as sugars, polyols, sorbitol, and sodium chloride.

[0042] The term "pharmaceutical preparation" refers to a preparation in a form that enables the active ingredient to be effective. The terms "preparation" and "pharmaceutical preparation" are used interchangeably throughout this text.

[0043] "Direct compression" is defined as a process involving pre-grinding each component of a formulation (e.g., the active pharmaceutical ingredient and excipients) into a powder, mixing the powdered components with any lubricant, and compressing the mixture into tablets. When a formulation is processed by direct compression, the active ingredient (in this context, the antiviral compound) can be pre-grinded directly from its synthetic state "as is," or it can be pre-grinded after purification by a suitable method, such as recrystallization.

[0044] "Wet granulation" is defined as a process involving the granulation of powders with a liquid (aqueous, non-aqueous, hot melt, etc.) to obtain the properties required for subsequent downstream processes. A liquid (e.g., water, binder solution) is added to the powder blend while it is being continuously mixed, resulting in particle nucleation and growth. When formulations are processed via wet granulation, antiviral compounds can be provided directly from their synthetic state "as is," or after purification by a suitable method (such as recrystallization).

[0045] "Roll pressing" is defined as an agglomeration process in which powder is pressed into a dense compact (or strip) using two counter-rotating rollers. The pressing force from the rollers causes the particles to plastically deform to form a dense compact. This dense compact is then broken up and ground into particles. The advantages of roll pressing include improved flow, better content uniformity, and / or less agglomeration. Roll pressing is also preferred for formulations that are sensitive to moisture and / or heat.

[0046] Excipients that are mixed with other ingredients (including antiviral compounds) and thus incorporated into the tablet before granulation constitute the in-granule component of the formulation. Excipients that are mixed with the dry granules before the complete mixture is compacted constitute the out-of-granule component of the formulation. Excipients suitable for inclusion in the oral dosage forms described herein include tableting aids, diluents, disintegrants, lubricants, salts, glidants, surfactants, solubilizers, wetting agents, binders, and / or fillers.

[0047] The term "compression adjuvant" refers to any substance used in the preparation of pharmaceutical dosage forms (such as tablets) that is pharmacologically inactive, even when mixed with an active pharmaceutical ingredient, and that will improve flowability and compressibility during tablet manufacturing. Examples of pharmaceutically acceptable compression adjuvants suitable for use in the oral dosage forms described herein include starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, crystalline sorbitol, mannitol, microcellulose, and microcrystalline cellulose that can be directly compressed into tablets.

[0048] The term "diluent" refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that is a pharmacologically inactive substance that acts as a filler to increase weight and improve the homogeneity of contents. Diluents may also provide better tablet properties, such as improved cohesion and flowability. Diluents should be physically and chemically stable, both on their own and in combination with the active ingredient. Examples of pharmaceutically acceptable diluents suitable 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, microcellulose, and microcrystalline cellulose.

[0049] In this document, a substance may be either a pharmaceutically acceptable tableting adjuvant or a pharmaceutically acceptable diluent, and may be used for either or both purposes in a particular formulation.

[0050] The term "disintegrant" refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that causes them to disintegrate and release their pharmaceutical substances upon contact with water. Typically, disintegrants absorb water and swell upon contact with water, causing the tablet formulation to break down in the digestive tract, thereby releasing the active ingredient for absorption. A specific disintegrant, referred to as a superdisintegrant, is one that exhibits greater efficacy at low concentrations in the tablet formulation compared to other disintegrants. In some cases, disintegrants may react with the active ingredient. Examples of pharmaceutically acceptable disintegrants suitable for use in the oral dosage forms described herein include calcium alginate, sodium calcium alginate, calcium carboxymethyl cellulose, calcium cellulose glycolate, calcium carboxymethyl cellulose, 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 glycolate starch, and crospovidone carboxymethyl cellulose.

[0051] The term "lubricant" refers to any substance used in the preparation of pharmaceutical dosage forms (such as tablets) that reduces friction between the surface of the tableting device and the tablet itself. Examples of pharmaceutically acceptable lubricants suitable for use in the oral dosage forms described herein include magnesium silicate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearate fumarate, and magnesium stearate.

[0052] The term "flow aid" refers to any substance used in the preparation of pharmaceutical dosage forms, such as tablets, that enhances the flow of a mixture of particles by reducing friction between the particles. Examples of pharmaceutically acceptable flow aids suitable for use in the oral dosage forms described herein include corn starch, talc, colloidal silica, and tricalcium phosphate (Ca5(PO4)3(OH)).

[0053] When used in the preparation of pharmaceutical dosage forms (such as tablets), the terms "surfactant" and / or "wetting agent" refer to organic substances with an amphiphilic structure; that is, they consist of groups with opposite solubility tendencies, typically consisting of oil-soluble hydrocarbon chains and water-soluble ionic groups. Depending on the charge of the surface-active moiety, surfactants can be classified as anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric or zwitterionic surfactants. Surfactants are commonly used as wetting agents, emulsifiers, solubilizers, and dispersants in various pharmaceutical compositions and biomaterial preparations. Examples of pharmaceutically acceptable surfactants include polysorbates (e.g., polysorbate 20 or 80); poloxamers (e.g., POLOXAMER® 188, POLOXAMER® 407 copolymers; poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)); and ethoxylated surfactants (e.g., TRITON). Surfactants, such as 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol; sodium octyl glycoside; lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, or stearyl-sulfobetaine; lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, or stearyl-sarcosine; linoleyl-betaine, myristyl-betaine, or cetyl-betaine; lauramidopropyl-betaine, cocamidopropyl-betaine, linolemidopropyl-betaine Betaine, myristamidopropyl betaine, palmitopropyl betaine, or isostearamidopropyl betaine (e.g., lauramidopropyl betaine); myristamidopropyl dimethylamine, palmitopropyl dimethylamine, or isostearamidopropyl dimethylamine; sodium stearate, sodium lauryl sulfate, sodium laurylbenzene sulfonate, sodium cholate, hexadecyltrimethylammonium bromide, pyridine dodecyl chloride, heptaoxyethylene monodexadecyl ether, n-dodecyl alanine, lecithin; sodium methylcocoyl taurate or disodium methyloleoyl taurate; and the MONAQUA® series (Mona Industries, Inc., Paterson, NJ), polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., Pluronics, PF68, etc.). Surfactants are typically added to formulations to reduce aggregation.

[0054] The term "granulating liquid" or "granulating solvent" refers to a solvent used during a wet granulation process to form bonds between powder particles. This solvent must be volatile so that it can be removed by drying and must be non-toxic. In some cases, the granulating liquid contains binders such as starch, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose), polyvinylpyrrolidone, and mixtures thereof. The granulating liquid can be prepared by dissolving or dispersing the binder in water or other solvents. Additionally, the granulating liquid may contain surfactants and pharmaceutical substances. Examples of pharmaceutically acceptable formulation solvents used in the oral dosage forms described herein include water, organic solvents (such as alcohols), and combinations thereof.

[0055] As used herein, the terms "binder" and / or "filler" refer to excipients incorporated into pharmaceutical formulations to ensure the final form has the desired mechanical strength. Suitable binders 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, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose (also known as hydroxypropyl methyl cellulose), hydroxypropyl cellulose), polyvinylpyrrolidone, and mixtures thereof. Examples of suitable fillers 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.

[0056] A "stable" formulation is one in which the antiviral compound substantially maintains its physical and / or chemical stability during storage. Stability can be measured at selected temperatures and relative humidity over selected time periods. For example, in one embodiment, a stable formulation is one in which no significant changes are observed for at least 12 months at ambient temperature (25.0°C to 30.0°C) and relative humidity below 75.0%. In another embodiment, a stable formulation is one in which no significant changes are observed for at least 18 months at ambient temperature (25.0°C to 30.0°C) and relative humidity below 75%.

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

[0058] oral dosage form This disclosure relates to an oral dosage form of a pharmaceutical preparation comprising an antiviral nucleoside and one or more excipients, wherein the oral dosage form is a tablet. The antiviral nucleoside is selected from β-D- N (4)-Hydroxycytidine The prodrug, or a pharmaceutically acceptable salt or tautomer thereof, such as 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: Compound A Or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. Implementation methods for such oral dosage forms may include wet granulation, direct tableting, or roll forming.

[0059] In the implementation plan, the antiviral nucleoside is selected from β-D- N (4)-Hydroxycytidine The prodrug. In a specific embodiment, the antiviral nucleoside is 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: Compound A Or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. In a further embodiment, the antiviral nucleoside is 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: (Compound A) Or its tautomers.

[0060] In certain embodiments, the antiviral nucleoside is selected from the antiviral nucleosides disclosed as follows: PCT International Patent Application No. PCT / US2015 / 066144 (published under WO2016 / 106050); PCT International Application No. PCT / US2017 / 021759 (published under WO2017 / 156380); PCT International Patent Application No. PCT / US2018 / 064503 (published under PCT International Patent Application Publication No. WO2019 / 113462); PCT International Patent Application No. PCT / US2018 / 064503 (published under PCT International Patent Application Publication No. WO2019 / 113462); U.S. Patent Application No. 15 / 537,087 (published under U.S. Patent Application Publication No. US2019 / 0022116); U.S. Patent Application No. 16 / 921,359 (published under U.S. Patent Application No. US2019 / 0022116); 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 No. 17 / 465,344); and U.S. Provisional Patent Application No. 63 / 127,484 are all incorporated herein by reference in their entirety.

[0061] Methods for preparing NHC and its prodrugs are set forth in PCT International Patent Application No. PCT / US2015 / 066144 (published under PCT International Patent Application Publication No. WO2016 / 106050); U.S. Patent Application No. 15 / 537,087 (published under U.S. Patent Application Publication No. US2019 / 0022116); and U.S. Patent Application No. 16 / 921,359 (published under U.S. Patent Application No. US2021 / 0060050, now U.S. Patent No. 11,628,181), all of which are incorporated herein by reference in their entirety. Methods for preparing additional NHC prodrugs (including compound A) and their tautomers, prodrugs, and derivatives are set forth in PCT International Patent Application No. PCT / US2018 / 064503 (published under PCT International Patent Application Publication No. WO2019 / 113462); PCT International Patent Application No. PCT / US2021 / 064021 (published under PCT International Patent Application Publication No. WO2022 / 133205); 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 under US 2022 / 0016153 A1); and U.S. Provisional Patent Application No. 63 / 127,484, all of which are incorporated herein by reference in their entirety.

[0062] In terms of implementation, the antiviral nucleoside can be used directly from its synthetic state or after purification, and can be directly formulated into a solid dosage form by blending with excipients or by granulating with excipients and compressing into tablets. The granulation process can be a wet granulation process, such as high-shear wet granulation or fluidized bed granulation, or a dry granulation process, such as roller pressing.

[0063] Pharmaceutical formulations can be granulated by rolling or wet granulation to densify them, improve flow properties, and / or reduce the risk of component segregation during subsequent processing (e.g., tableting). The granulation step can also be used to minimize the impact of raw material property variability (e.g., excipient particle size) on subsequent processing (e.g., tablet compression) and final product performance. Lubrication is typically performed before rolling and tablet compression to reduce the tendency of material to adhere to the tableting surface (e.g., tablet die). In certain embodiments, the lubricant system is a combination of sodium stearate fumarate and magnesium stearate. These methods can be performed by those skilled in the art. See, for example, Ansel, INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS, 7th Edition, 1999.

[0064] The tablets may contain an active ingredient and pharmaceutically acceptable, non-toxic excipients suitable for tablet manufacturing, mixed with the active ingredient. The tablets may be uncoated, film-coated to modify their appearance, or coated to modulate the release onset time and / or release rate in the gastrointestinal tract, thereby optimizing or maximizing the patient's biological exposure to the antiviral compound. In some embodiments, the tablets may be coated with a functional coating to delay disintegration and absorption in the gastrointestinal tract and thus provide a longer duration of action.

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

[0066] In a first embodiment, the oral dosage form is a tablet having a maximum length of at least about 5.00 mm ± 0.15 mm. In an aspect of this embodiment, the oral dosage form is a tablet having a maximum length ranging from about 5.00 mm ± 0.15 mm to about 22.00 mm ± 0.15 mm, about 12.80 mm ± 0.15 mm to about 19.00 mm ± 0.15 mm, about 13.00 mm ± 0.15 mm to about 17.00 mm ± 0.15 mm, or about 13.36 mm ± 0.15 mm. Compared to a size 0 capsule (21.7 mm x 7.6 mm), such tablets are smaller in at least one dimension.

[0067] In a particular aspect of the first embodiment, the oral dosage form is a single tablet having a longest diameter or length of approximately 13.36 mm ± 0.15 mm. In a further aspect of the first embodiment, the oral dosage form consists of two tablets, each having a longest diameter or length of approximately 13.36 mm ± 0.15 mm. Compared to the administration of Compound A at a dose of 800 mg twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg), this aspect reduces the burden of medication administration, both in terms of size and quantity.

[0068] In the second embodiment, the oral dosage form is a tablet, the total weight of which, when uncoated, is in the range of about 30 mg to about 2000 mg, such as about 30 mg to about 1600 mg, about 400 mg to about 1000 mg, about 500 mg to about 800 mg, or about 600 mg.

[0069] In the third embodiment, the oral dosage form is a tablet containing at least about 25 mg of antiviral nucleoside, such as about 25 mg to about 800 mg, such as about 100 mg to about 800 mg, about 200 mg to about 800 mg, or about 400 mg.

[0070] In the fourth embodiment, the oral dosage form is a tablet containing an amount of antiviral nucleoside in a quantity of about 6.250% to about 80.00% by weight relative to the total weight of the uncoated tablet, such as about 25.00% to about 80.00% by weight, about 50.00% to about 75.00% by weight, or about 66.67% by weight.

[0071] In the fifth embodiment, the one or more excipients are selected from tableting aids, diluents, disintegrants, lubricants, flow aids, surfactants or wetting agents, granulation solutions or granulation solvents, binders and / or fillers, and combinations thereof.

[0072] In a first aspect of the fifth embodiment, the one or more excipients include one or more tableting aids selected from directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, spray-crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microcellulose, and microcrystalline cellulose. In an aspect of this embodiment, the one or more tableting aids are selected from directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, mannitol, microcellulose, and microcrystalline cellulose, and combinations thereof. In an example of this aspect, the one or more tableting aids are selected from spray-dried lactose, microcrystalline cellulose, and combinations thereof. In a specific example of this aspect, the one or more tableting aids are microcrystalline cellulose. In a first example, the one or more tableting aids are present in an amount from about 6,000 mg to about 1440 mg, such as about 12.00 mg to about 45.10 mg, about 76.65 mg to about 186.6 mg, or about 116.0 mg. In the second example, the one or more tableting adjuvants are present in an amount of about 1,500% by weight to about 90.00% by weight relative to the total weight of the uncoated tablets, such as about 3,000% by weight to about 41.51% by weight, about 15.33% by weight to about 23.33% by weight, or about 19.33% by weight.

[0073] In a second aspect of the fifth embodiment, the one or more excipients include one or more diluents selected from directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, spray-crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microcellulose, and microcrystalline cellulose. In this aspect of the embodiment, the one or more diluents are selected from directly compressible starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, mannitol, microcellulose, and microcrystalline cellulose, and combinations thereof. In an example of this aspect, the one or more diluents are selected from spray-dried lactose, microcrystalline cellulose, and combinations thereof. In a specific example of this aspect, the one or more diluents are microcrystalline cellulose. In a first example, the one or more diluents are present in an amount from about 6,000 mg to about 1440 mg, such as about 12.00 mg to about 45.10 mg, about 76.65 mg to about 186.6 mg, or about 116.0 mg. In the second example, the one or more diluents are present in an amount of about 1,500% by weight to about 90.00% by weight relative to the total weight of the uncoated tablets, such as about 3,000% by weight to about 41.51% by weight, about 15.33% by weight to about 23.33% by weight, or about 19.33% by weight.

[0074] In a third aspect of the fifth embodiment, the one or more excipients include one or more disintegrants selected from calcium alginate, sodium calcium alginate, calcium carboxymethyl cellulose, calcium cellulose glycolate, calcium carboxymethyl cellulose, 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 glycolate starch, and crospovidone carboxymethyl cellulose. In an example of this aspect, the one or more disintegrants are selected from calcium alginate, sodium calcium alginate, calcium carboxymethyl cellulose, calcium cellulose glycolate, calcium carboxymethyl cellulose, 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 glycolate starch, and crospovidone carboxymethyl cellulose. In a specific example of this aspect, the one or more disintegrants are crospovidone carboxymethyl cellulose. In a first example, the one or more disintegrants are present in an amount from about 0.000 mg to about 240.0 mg, such as about 12.00 mg to about 120.0 mg, about 45.00 mg to about 92.00 mg, or about 60.00 mg. In a second example, the one or more disintegrants are present in an amount from about 0.000% by weight to about 15.00% by weight relative to the total weight of the tablet, such as about 3.000% by weight to about 12.00% by weight, about 9.000% by weight to about 11.50% by weight, or about 10.00% by weight.

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

[0076] In a fifth aspect of the fifth embodiment, the one or more excipients include one or more flow aids selected from corn starch, talc, colloidal silica, and tricalcium phosphate. In a specific example of this embodiment, the one or more flow aids are tricalcium phosphate. In a first example, the one or more flow aids are present in an amount from about 0.000 mg to about 80.00 mg, such as from about 0.000 mg to about 25.00 mg, from about 0.000 mg to about 12.00 mg, or about 0.000 mg. In a second example, the one or more flow aids are present in an amount from about 0.000% by weight to about 5.000% by weight relative to the total weight of the tablet, such as from about 0.000% by weight to about 2.500% by weight, from about 0.000% by weight to about 1.500% by weight, or about 0.000% by weight.

[0077] In a sixth aspect of the fifth embodiment, the one or more excipients comprise one or more surfactants or wetting agents selected from polysorbates, poloxamer, Triton® surfactants (such as 2-[4-(2,4,4-trimethylpentyl-2-yl)phenoxy]ethanol), sodium octyl glycoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, Cocamidopropyl betaine, linoleamidopropyl betaine, myristamidopropyl betaine, palmitoamide propyl betaine, isostearamidopropyl betaine, myristamidopropyl dimethylamine, palmitoamide propyl dimethylamine, isostearamidopropyl dimethylamine, sodium stearate, sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium cholate, hexadecyltrimethylammonium bromide, dodecylpyridine chloride, heptapolyoxyethylene glycol monohexadecyl ether, n-dodecyl alanine, lecithin, sodium methylcocoyl taurate, disodium methyloleoyl taurate, polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol. In specific examples, one or more surfactants are selected from poloxamer, sodium stearate, sodium lauryl sulfate, sodium dodecylbenzenesulfonate, and sodium cholate. In other specific examples, the one or more surfactants are selected from poloxamer. In a more specific example, the one or more surfactants are POLOXAMER® 407 copolymers, which are poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol). In other specific examples, the one or more surfactants are selected from sodium stearate, sodium lauryl sulfate, sodium lauryl sulfate, sodium dodecylbenzenesulfonate, and sodium cholate. In a more specific example, the one or more surfactants are sodium lauryl sulfate. In further examples, the one or more surfactants are present in amounts from about 0.000 mg to about 80.00 mg, such as from about 0.000 mg to about 25.00 mg, from about 0.000 mg to about 12.00 mg, or about 0.000 mg. In the third example, the one or more surfactants are present in an amount of about 0.000% by weight to about 5.000% by weight relative to the total weight of the tablet, such as about 0.000% by weight to about 2.500% by weight, about 0.000% by weight to about 1.500% by weight, or about 0.000% by weight.

[0078] In a seventh aspect of the fifth embodiment, the one or more excipients comprise one or more granulation solutions or granulation solvents selected from water, organic solvents (such as alcohols), and combinations thereof. In a specific example of this aspect, the one or more granulation solutions or granulation solvents are water. In a first example, the one or more granulation solutions or granulation solvents are present in an amount of about 10% to about 80% by weight relative to the total weight of the tablets, such as about 30% to about 70% by weight, about 45% to about 60% by weight, or about 54% by weight.

[0079] In an eighth aspect of the fifth embodiment, the one or more excipients include one or more binders and / or fillers selected from starch, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose), polyvinylpyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof. In an example of this aspect, the one or more binders and / or fillers are selected from starch, cellulose, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof. In a specific example of this aspect, the one or more binders and / or fillers are hydroxypropyl cellulose. In a first example, the one or more binders and / or fillers are present in amounts from about 0.000 mg to about 96.00 mg, such as about 6.000 mg to about 45.00 mg, about 7.500 mg to about 36.00 mg, or about 18.00 mg. In a second example, the one or more binders and / or fillers are present in amounts from about 0.000% by weight to about 6.000% by weight relative to the total weight of the tablets, such as about 1.500% by weight to about 4.500% by weight, about 1.500% by weight to about 4.500% by weight, or about 3.000% by weight.

[0080] In a sixth embodiment, the oral dosage form is a tablet, which optionally further comprises a coating. In a first aspect, the coating is a formulation comprising one or more of the following: a polymer or film-forming agent, a light-blocking agent, an adhesion modifier, a plasticizer, an anti-adhesive agent, a colorant, and mixtures thereof. In a specific example, the coating is a formulation comprising one or more of the following: a polymeric light-blocking agent, an adhesion modifier, a plasticizer, a colorant, and mixtures thereof. In a more specific example, the coating is a formulation selected from those listed in Table 1 below. In still a more specific example, the coating is film coating A (FC A), which consists of a polymer (hydroxypropyl methylcellulose), an adhesion modifier (lactose monohydrate), a light-blocking agent (calcium carbonate), a plasticizer (triacetin), and a colorant (iron oxide).

[0081] Table 1

[0082] In a second aspect of this sixth embodiment, the coating is present in an amount from about 0.000 mg to about 128.0 mg, such as from about 0.000 mg to about 60.00 mg, from about 0.000 mg to about 45.00 mg, or about 24.00 mg. In a third example, the one or more coatings are present in an amount from about 0.000% by weight to about 8.000% by weight relative to the total weight of the tablet, such as from about 0.000% by weight to about 6.000% by weight, from about 0.000% by weight to about 5.000% by weight, or about 4.000% by weight.

[0083] Treatment or prevention of viral infections Antiviral nucleosides, including NHC and NHC prodrugs (such as compound A), are known to be used to treat viral infections and to prevent viral infections.

[0084] This disclosure relates to a method for treating a viral infection, wherein the method comprises administering to a subject in need an oral dosage form as described herein, wherein the viral infection is an infection caused by a virus selected from the group consisting of: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In a second aspect of these embodiments, the virus is selected from RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In a specific aspect, the virus is selected from Influenza A virus and Influenza B virus. In a further specific aspect, the virus is selected from Human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In a specific embodiment, the virus is SARS-CoV-2.

[0085] In embodiments of the treatment methods disclosed herein, the oral dosage form is administered once daily as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In further aspects, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects reduce the burden of medication administration, both in size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0086] In embodiments of the treatment methods disclosed herein, the oral dosage form is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, each separate dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) to four (4) 400 mg tablets. Such aspects reduce the burden of administration, both in size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0087] In an embodiment of the treatment method disclosed herein, the method includes administering an oral dosage form as described herein to a subject in need, wherein the oral dosage form is administered once daily for 1 to 21 days, such as 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, such as 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, such as 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered once daily for 5 days.

[0088] In an embodiment of the treatment method disclosed herein, the method includes administering to a subject in need an oral dosage form as described herein, wherein the oral dosage form is administered twice daily for 1 to 21 days, such as 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, such as 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, such as 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered twice daily for 5 days.

[0089] This disclosure also relates to a method of treating a viral infection, the method comprising administering an oral dosage form as described herein to a subject in need, wherein treatment begins 1 to 10 days after the onset of symptoms of the viral infection, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after the onset of symptoms. In a specific embodiment, the oral dosage form is administered less than 5 days after the onset of symptoms, such as less than 1, 2, 3, 4, or 5 days after the onset of symptoms. Symptoms of a viral infection may include one or more of cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue / weakness, fever / feeling of heat, chills, headache, nausea, vomiting, and diarrhea, but symptoms may vary depending on the type and severity of the viral infection.

[0090] This disclosure also relates to the aforementioned methods for treating viral infections, wherein the subjects may be considered or have been identified as having a higher risk of developing severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of developing severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with eGFR reduced to <30 mL / min / 1.73 m). 2 (Participants); chronic obstructive pulmonary disease; obesity (body mass index of 30 or higher, where body mass index = weight (kg) / (height (m)) 2 Subjects with: serious heart disease (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes. In one implementation, the subject had not been vaccinated against COVID-19. In another implementation, the subject had been vaccinated against COVID-19.

[0091] This disclosure also relates to methods for treating viral infections, wherein the methods reduce the risk of hospitalization or death in subjects. In embodiments, the methods can result in a reduction in the risk of hospitalization or death in subjects. In specific embodiments, the methods can result in a reduction in the risk of hospitalization or death in subjects of about 1% to about 10%, such as about 5% to about 7.5%, or about 6.8%. In further embodiments, the methods can result in a relative reduction in the risk of hospitalization or death in subjects of up to about 50%.

[0092] This disclosure also relates to a method of providing antiviral prophylaxis, the method comprising administering an oral dosage form to a subject in need, wherein the administration is initiated before exposure to a viral infection or after potential exposure to a viral infection. In a specific embodiment, the oral dosage form is administered before potential exposure to a viral infection. In other specific embodiments, the oral dosage form is administered 1 to 10 days after potential exposure to a viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after potential exposure. In a specific embodiment, the oral dosage form is administered less than 5 days after potential exposure, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after potential exposure.

[0093] This disclosure also relates to methods for providing antiviral prophylaxis, wherein the subjects may be considered to have a higher risk of severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with eGFR reduced to <30 mL / min / 1.73 m). 2 (Participants); chronic obstructive pulmonary disease; obesity (body mass index of 30 or higher, where body mass index = weight (kg) / (height (m)) 2 Subjects with: serious heart disease (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes. In one implementation, the subject had not been vaccinated against COVID-19. In another implementation, the subject had been vaccinated against COVID-19.

[0094] Additionally, this disclosure relates to a method for providing antiviral prophylaxis, wherein the method includes administering an oral dosage form to a subject in need, wherein the virus is selected from EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae virus, Paramyxoviridae virus, RSV, influenza A virus, influenza B virus, Filoviridae virus, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In a specific embodiment, the virus is selected from RSV, influenza A virus, influenza B virus, Filoviridae virus, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In a specific embodiment, the virus is selected from influenza A virus and influenza B virus. In a specific embodiment, the virus is selected from human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In a specific embodiment, the virus is SARS-CoV-2.

[0095] In embodiments of the preventive methods disclosed herein, the oral dosage form is administered once daily as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In further aspects, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such aspects reduce the burden of medication, both in size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0096] In embodiments of the preventive methods disclosed herein, the oral dosage form is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, each separate daily dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) to four (4) 400 mg tablets. Such aspects reduce the burden of medication administration, both in size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

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

[0098] This disclosure also relates to a method of providing antiviral prophylaxis, the method comprising administering to a subject in need an oral dosage form as described herein, wherein the oral dosage form is administered twice daily for 1 to 42 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific implementation schemes, the oral dosage form is administered twice daily for 1 to 21 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific implementation schemes, the oral dosage form is administered twice daily for 3 to 14 days, such as 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.

[0099] This disclosure also relates to prevention methods that reduce the risk of hospitalization or death in subjects. In embodiments, the method can result in a reduction in the risk of hospitalization or death in subjects. In specific embodiments, the method can result in a reduction in the risk of hospitalization or death in subjects of about 1% to about 10%, such as about 5% to about 7.5%, or about 6.8%. In further embodiments, the method can result in a relative reduction in the risk of hospitalization or death in subjects of up to about 50%.

[0100] The embodiments provided in this disclosure also include oral dosage forms as described herein, which are used as medicines for treating viral infections. In specific embodiments, the viral infection is an infection caused by a virus selected from: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the virus is selected from Influenza A virus and Influenza B virus. In specific embodiments, the virus is selected from Human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0101] This disclosure also provides an oral dosage form as described herein, which is used as a medicine for treating viral infections, wherein the patient has previously (e.g., within 24 hours) received another dose of treatment, which may be as described above.

[0102] In the implementation scheme, the oral dosage form as described herein, used as a medicine for treating viral infections, is administered once daily as a single dose. In aspects of these implementation schemes, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these implementation schemes, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these implementation schemes, the single dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of medication administration, both in terms of size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0103] In the embodiments, the oral dosage form as described herein, used as a medicine for treating viral infections, is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, each separate dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) to four (4) 400 mg tablets. Such an aspect reduces the burden of medication, both in size and quantity, compared to Compound A being administered twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0104] In one embodiment of the oral dosage form used as a medicine for treating viral infections, the oral dosage form is administered once daily for 1 to 21 days, such as 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 another specific embodiment, the oral dosage form is administered once daily for 3 to 14 days, such as 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 yet another specific embodiment, the oral dosage form is administered once daily for 5 days.

[0105] In one embodiment of the oral dosage form used as a medicine for treating viral infections, the oral dosage form is administered twice daily for 1 to 21 days, such as 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 another specific embodiment, the oral dosage form is administered twice daily for 3 to 14 days, such as 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 yet another specific embodiment, the oral dosage form is administered twice daily for 5 days.

[0106] This disclosure also relates to oral dosage forms for use as medicines for treating viral infections, wherein administration of said oral dosage form is initiated 1 to 10 days after the onset of symptoms of the viral infection, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after the onset of symptoms. In a specific embodiment, the oral dosage form is initiated less than 5 days after the onset of symptoms, such as less than 1, 2, 3, 4, or 5 days after the onset of symptoms. The symptoms of the viral infection may be as described above.

[0107] This disclosure also relates to oral dosage forms of medicines for treating viral infections, wherein tablets are administered to subjects who may be considered to have a higher risk of developing severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of developing severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with eGFR reduced to <30 mL / min / 1.73 m). 2 (Participants); chronic obstructive pulmonary disease; obesity (body mass index of 30 or higher, where body mass index = weight (kg) / (height (m)) 2 Subjects with: serious heart disease (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes. In one implementation, the subject had not been vaccinated against COVID-19. In another implementation, the subject had been vaccinated against COVID-19.

[0108] This disclosure also relates to oral dosage forms used as medicines for treating viral infections, wherein administration of the oral dosage form reduces the risk of hospitalization or death in a subject. In embodiments, administration of the oral dosage form can result in a reduction in the risk of hospitalization or death in a subject. In specific embodiments, administration of the oral dosage form can result in a reduction in the risk of hospitalization or death in a subject of about 1% to about 10%, such as about 5% to about 7.5%, or about 6.8%. In further embodiments, administration of the oral dosage form can result in a relative reduction in the risk of hospitalization or death in a subject of up to about 50%.

[0109] This disclosure also relates to oral dosage forms for use as medicines for preventing viral infections or for providing antiviral prophylaxis, wherein the viral infection to be prevented is caused by viruses selected from: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, influenza A virus, influenza B virus, Filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from RSV, influenza A virus, influenza B virus, Filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the virus is selected from influenza A virus and influenza B virus. In specific embodiments, the virus is selected from human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0110] This disclosure also provides oral dosage forms as described herein, which are used as medicines for the prevention of viral infection or for the provision of antiviral prophylaxis, wherein the patient has previously (e.g., within 24 hours) received another dose of treatment, which may be as described herein.

[0111] In embodiments of oral dosage forms as described herein, used as a medicine for the prevention of viral infection or for providing antiviral prophylaxis, the oral dosage form is administered once daily as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of medication administration, both in terms of size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0112] In embodiments of the oral dosage form described herein, used as a medicine for the prevention of viral infection or for the provision of antiviral prophylaxis, the oral dosage form is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, each separate dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) to four (4) 400 mg tablets. Such an aspect reduces the burden of medication administration, both in terms of size and quantity, compared to Compound A administered twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0113] This disclosure also relates to oral dosage forms for use as medicines for preventing viral infection or for providing antiviral prophylaxis, wherein the oral dosage form is administered once daily for 1 to 42 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific implementation schemes, the oral dosage form is administered once daily for 1 to 21 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific implementation schemes, the oral dosage form is administered once daily for 3 to 14 days, such as 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0114] This disclosure also relates to oral dosage forms for use as medicines for preventing viral infection or for providing antiviral prophylaxis, wherein the oral dosage form is administered twice daily for 1 to 42 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific implementation schemes, the oral dosage form is administered twice daily for 1 to 21 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific implementation schemes, the oral dosage form is administered twice daily for 3 to 14 days, such as 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.

[0115] This disclosure also relates to oral dosage forms of medicines used for the prevention of viral infection or for providing antiviral prophylaxis, wherein treatment is initiated before exposure to a viral infection or after potential exposure to a viral infection. In specific embodiments, the oral dosage form is administered before potential exposure to a viral infection. In other specific embodiments, the oral dosage form is administered 1 to 10 days after potential exposure to a viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after potential exposure. In specific embodiments, the oral dosage form is administered less than 5 days after potential exposure, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after potential exposure.

[0116] This disclosure also relates to oral dosage forms of medicines used for the prevention of viral infection or for the provision of antiviral prophylaxis, wherein the oral dosage form is administered to subjects who may be considered to have a higher risk of severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with eGFR reduced to <30 mL / min / 1.73 m). 2 (Participants); chronic obstructive pulmonary disease; obesity (body mass index of 30 or higher, where body mass index = weight (kg) / (height (m)) 2Subjects with: serious heart disease (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes. In one implementation, the subject had not been vaccinated against COVID-19. In another implementation, the subject had been vaccinated against COVID-19.

[0117] Additionally, this disclosure relates to oral dosage forms of medicines used for preventing viral infection or for providing antiviral prophylaxis, wherein the oral dosage form is administered to a subject who may have been exposed to viruses selected from: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the virus is selected from Influenza A virus and Influenza B virus. In specific embodiments, the virus is selected from Human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0118] In embodiments of the oral dosage form as described herein, used as a medicine for treating viral infections, where the patient has previously (e.g., within 24 hours) received another dose, the oral dosage form is administered once daily as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In further aspects, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of medication administration, both in terms of size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0119] In embodiments where the tablet is used as a drug for treating viral infections, where the patient has previously (e.g., within 24 hours) received another dose, the tablet is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In further aspects, each separate dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) 400 mg tablets. Such aspects reduce the burden of medication administration, both in terms of size and quantity, compared to Compound A administered twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and with a unit dose strength of 200 mg).

[0120] combination therapy In another embodiment, at least one tablet as described herein may be used in combination with one or more other therapeutic agents for the treatment or prevention of viral infection.

[0121] In one embodiment, the additional therapeutic agent is an antiviral agent.

[0122] In another embodiment, the additional therapeutic agent is an immunomodulator, such as an immunosuppressant.

[0123] Therefore, in one embodiment, this disclosure provides a method for treating a viral infection in a subject, the method comprising administering to the subject: (i) an oral dosage form as described herein, and (ii) at least one additional therapeutic agent, wherein the amounts administered together are effective in treating or preventing the viral infection.

[0124] When administering a combination therapy as described herein to a subject, the therapeutic agents in the combination, or one or more pharmaceutical compositions containing therapeutic agents, may be administered in any order, such as, for example, sequentially, in parallel, together, simultaneously, etc. In such a combination therapy, the amounts of various active substances may be different amounts (different dosages) or the same amount (same dosage). Therefore, for the purposes of non-limiting illustration, at least one tablet as described herein and another therapeutic agent may be present in a fixed amount (dosage) in a single dose unit.

[0125] In one implementation, at least one tablet as described herein is administered while another therapeutic agent is exerting its preventive or therapeutic effect, or vice versa.

[0126] In another embodiment, at least one tablet as described herein is administered at a dose typically used when such an agent is used as a monotherapy to treat a viral infection.

[0127] In another embodiment, at least one tablet as described herein and one or more additional therapeutic agents are administered at a lower dose than is typically used when such agents are used as monotherapy to treat viral infections.

[0128] In yet another embodiment, at least one tablet as described herein and one or more additional therapeutic agents act synergistically and are administered at a lower dose than is typically used when such agents are used as monotherapy to treat viral infections.

[0129] Viral infections and virus-related conditions that can be treated or prevented using combination therapies as described in this article include, but are not limited to, those listed above.

[0130] The oral dosage forms described herein can work additively or synergistically with one or more other therapeutic agents. Synergistic combinations allow for the use of lower doses of one or more agents and / or a reduction in the frequency of administration of one or more agents in a combination therapy. Lower doses or less frequent administration of one or more agents can reduce the toxicity of treatment without diminishing its efficacy.

[0131] In one implementation, the administration of an oral dosage form as described herein, along with one or more additional therapeutic agents, can inhibit viral resistance to these agents.

[0132] The therapies disclosed herein can be used in combination with one or more other active agents, including but not limited to antiviral agents for the prevention, treatment, control, improvement of a particular disease or condition (e.g., viral infection) or reduction of its risk. In one embodiment, the compounds disclosed herein are used in combination with one or more other antiviral agents for the prevention, treatment, control, improvement of a particular disease or condition to which the compounds disclosed herein are applicable or reduction of its risk. Such other active agents may be administered concurrently or sequentially with the compounds disclosed herein via the usual route and in the amounts commonly used.

[0133] When the therapies disclosed herein are used concurrently with one or more other active agents, the oral dosage forms described herein may be administered simultaneously with, before, or after one or more other active agents. The oral dosage forms described herein may be administered separately from one or more other agents via the same or different routes of administration, or together with one or more other agents in the same pharmaceutical composition.

[0134] The dosage of the oral dosage forms described herein, as well as one or more other active agents, may vary and will depend on the therapeutically effective dose. Typically, the therapeutically effective dose of each will be used. Combinations including the oral dosage forms described herein with other active agents will generally include a therapeutically effective dose of each active agent. In such combinations, the oral dosage forms described herein and other active agents may be administered separately or in combination. Additionally, the administration of one element may be before, simultaneously with, or after the administration of one or more other agents.

[0135] In one embodiment, this disclosure provides an oral dosage form as described herein, along with at least one other active agent, as a combination formulation for simultaneous, separate, or sequential use in treatment. In one embodiment, the therapy is for the treatment of viral infections, such as infections caused by viruses selected from: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, influenza A virus, influenza B virus, Filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In aspects of this embodiment, the virus is selected from RSV, influenza A virus, influenza B virus, Filoviridae, human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In some specific aspects, the virus is selected from influenza A virus and influenza B virus. In other specific aspects, the virus is selected from human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In even more specific aspects, the virus is SARS-CoV-2.

[0136] In another embodiment, this disclosure provides an oral dosage form as described herein, along with at least one other active agent, as a combination formulation for simultaneous, separate, or sequential use in treatment. In one embodiment, the therapy is antiviral prophylaxis, such as pre-exposure or post-exposure prophylaxis against potential infection caused by viruses selected from: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In aspects of this embodiment, the virus is selected from RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In some specific aspects, the virus is selected from Influenza A virus and Influenza B virus. In other specific aspects, the virus is selected from Human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. Even more specifically, the virus is SARS-CoV-2.

[0137] This disclosure also provides for the use of oral dosage forms, as described herein, for the treatment of viral infections in patients who have previously received another dose (e.g., within 24 hours).

[0138] The additional active agents may be one or more agents selected from the following: antiviral compounds, antigens, adjuvants, anticancer agents, CTLA-4 agonists, LAG-3 agonists, PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothing inhibitors, alkylating agents, antibiotics, antimetabolites, retinoids, steroids, and immunomodulators, including but not limited to antiviral vaccines. It should be understood that the descriptions of the additional active agents above may overlap with those listed below. It should also be understood that treatment combinations can be optimized, and that the optimal combination of antiviral nucleosides with one or more additional active agents will be determined based on individual patient needs.

[0139] Antiviral compounds that can be used in combination with the therapies disclosed herein include direct-acting antiviral agents and antiviral compounds that target the intracellular environment. In particular, antiviral compounds that can be used in combination with the therapies disclosed herein include antiviral agents targeting SARS-CoV-2 virus (and COVID-19 caused by SARS-CoV-2 infection), influenza virus inhibitors, 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. These antiviral compounds include, but are not limited to, 2-DG, 2x-121, AB001, avifavir, AVM-0703, C21, CAL-02, CYTO-201 (naltrexone hydrochloride), conronavir (TL-FVP-t), DW-2008S, DWJ-1248, elsufavirine, emtricitabine, eFT226, HP-163, IML-206, IMU-838, LAU-7b, MAN-19, MMS-019, OBP-2001, and omega 3. Viruxide, OPN-019, OYA-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 (azanavir / dexamethasone), nanofenretinideST-001), necuparanib (M-402), nelfinavir, nitazoxanide, piclidenoson, pixatimod, polyinosinic-polycytidylic acid, proxalutamide, hydrochloroquine, hydroxychloroquine, chloroquine, oseltamivir, oseltamivir phosphate, zanamivir, peramivir, baloxavir marboxil), remdesivir, favilarvir, avifavir, favilarvir / avifavir, vaniprevir, grazoprevir, elbasvir, narlaprevir, nitrozonide, atazanavir, ritonavir, daclatasvir, farunavir, darunavir / cobicistat, saquinavir, indinavir, carfilzomib, ivaltinostat (CG200745), isotretinoin / tamoxifen The following are listed: isotretinoin, tamoxifen, levamisole, prexasertib, ebselen, merimepodib, 1-deoxy-D-glucose prodrug, formoterol, budesonide, rigosertib, erlotinib, silmitasertib, favipiravir, galidesivir, ledipasvir, lopinavir, lopinavir / ritonavir, levovir, tenofovir, and sofosbuvir, as well as combinations thereof.

[0140] Other therapies that may be used in combination with the therapies disclosed herein include, but are not limited to, immunomodulatory agents such as interleukin-6 (IL-6) inhibitors, corticosteroids, TNF inhibitors, and other immune-dependent therapies; antibody therapies such as convalescent plasma therapy, hyperimmunoglobulin therapy, monoclonal antibodies, polyclonal antibodies, and neutralizing antibodies; soluble guanylate cyclase stimulators such as riociguat; cannibidiol; and vaccines. Other therapies under consideration include biological products that are biosimilar to any of the biologics or therapies explicitly listed herein.

[0141] In particular, other therapies that can 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'-disodehydro-4'-deoxy-8'-norvincine, 47D11, 5-fluorouracil, abatacept, abiraterone acetate, ABX464, abibertinib, acalabrutinib, ACE2-Fc, ACE-MAB (STI-4920, CMAB020), acetylsalicylic acid, acetaminophen, ACT-20, Actemra, Actemra / RoActemra, adalimumab, adipose-derived mesenchymal stem cells, AdMSCs (autologous adipose-derived stem cells), ADR-001, and adrecizumab. (HAM8101), ADX-629 / reproxalap, AK-119, Alferon N, Allocetra (leukocyte cell therapy), AlloStim, Allorx stem cells, ALT-100 (enamptcumab), ALT-803, Amnioboost, Ampion, altretamine, amiodarone, Anaferon, Anakinra, AMG-3777, anhydrovinblastine, anti-nCoV nanovirus agent, aprepitant, AP-003 (AntiCovir), APL-9 (Polyethylene glycol-based cyclic peptides), APX-115, AQCH, AR-701, ARO-COV, AS-1411, Ascorbic acid, asunercept, atovaquone / azithromycin, AT-100 (rhSP-D), AT-301, AT-H201, ATI-450, ATR-002, auristatin, avdoralimab (IPH5401), axatilimab, AZD-1061, AZD-7442, alvelestat (AZD-9668), AZD-8895, azvudine, azvudine / tetrandrine, azithromycin, bardoxolone, methylbardoxolonemethyl), baricitinib, BBT-032, bemcentinib, BGE-175, BIO-300, BIOMEDIVR, bevacizumab, bexarotene, bicalutamide, BIO-1106, BLD-2660, BLD-2736, BOLD-100, bomedemstat, brequinar sodium, brilacidin, bromhexine hydrochloride, BTL-TML001, bleomycin, BMS-986253, BMS 184476, BT-086, BT-588, BXCL501, BXT-25, Bucillamine, Budesonide, Cachectin, Acalabrutinib, Camrelizumab, Camrelizumab / Thymosin, Captopril, CardioIRx, Carrimycin, Cavaltinib, Camostat, Camostat Mesylate, Canakinumab, CAP-1002, Carboplatin, Carmustine, CB5064 Analog, CD24Fc (Recombinant fusion protein), cepharanthine, cemadotin, cenicriviroc, canthaquine, CERC-002, chlorambucil, chloropromazine, cholecalciferol, ciclesonide, cisplatin, ci-trimoxazole, CK-0802, clazakizumab, clarithromycin, CLBS-119, CM4620-IE, colchicine, CorLiCyte (umbilical cord lining stem cells), COVID-19 aptamer therapy, COVID-19 human mAb, COVID-19 neutralizing antibody, COVID-19siRNA therapy, COVID-HIG, COVID-EIG, spike glycoproteins, CoviGlobulin, COVI-GUARD (STI-1499), CPI-006, crizanlizumab, cryptophycin, CSL-324, CT-P59, CTAP-101, CV-15, CVL-218, cyclosporine, cell replacement therapy, cyclophosphamide, CYNK-001, cytarabine, dacarbazine, dactolisib, actinomycin D (dactinomycin), dalargin, DAS-181, dapagliflozin, dapansurtrile, daunorubicin, decitabine, dexamethasone, DNL758 (SAR443122, RIPK1 inhibitor), dipyridamole, DMX-200, DS-2319, deupirfenidone, duvelisib, DV-890, DWRX-2003, docetaxel, dolastatin, doxetaxel, doxorubicin (doxorubicin) (adriamycin), DP-710, EB-05, EB-201, ebastine, eculizumab, EDP-1815, efineptakin alfa, emapalumab, emtricitabine, ensimifentrine, ENU-200, enoxaparin, enzalutamide, epaspire, etanercept, etoposide, eravacycline, famotidine, finasteride, fingolimod, flebogamma (IGIV31), fluvoxamine, foalumab (NI-0401, TZLS-401), fostamatinib, flutamide(flutamide), FSD-201, FW1022, FT516, Gamunex (IGIV-C), ganestepib, GC-376, Giapreza, GLS-1200, garadacimab, GC-5131A (hyperimmunoglobulin), GIGA-2050 rCIG, gimsilumab, GNS561, GP1681, GSK-2586881 / APN-1, GSK-4182136, GTB-3550 (Trike 161533), haNK:CD-16, HB-adMSCs, HFB30132A, HLCM-051, heparin, hydrocortisone, hydroxyurea, ibuprofen, ibudilast (MN-166), ethyl eicosapentaenoate (icosapentaenoate). ethyl), IC14, IDB-003, IFX-1 / BDB-1, IgY-110, IMM101, IMS001, IMS002, ifosfamide, imatinib, infliximab, INM-005, interferon α, interferon α 1B, interferon α 2B, interferon β 1A, interferon β 1B, interleukin-6, interleukin-7, isoquercetin, itanapraced (CHF-5074), itolizumab, ivermectin, IVIG, JS012 (Monoclonal antibody, LY-CoV016), jaktinib, kagocel, KB109, sarilumab, K-NK-ID101, KTH-222, lactoferrin, LAM-002A (apimod mesylate), lanadelumab, lamellasome, LB-1148, larazotide, leflunomide, lenzilumab, leronlimab (monoclonal antibody), levilimab (BCD-089), levamisole, liarozole, linagliptin, lipocurc, losartan, livilimab, lomustine (CCNU), londamine, losmapimod, losartan(lostartan), LY-CoV555 (LY-3819253), LY-3127804, mannitol, maraviroc, mastinib, mavrilimumab, MDV3100, mechlorethamine, MEDI-3506, melatonin, melphalan, meplazumab, merimepodib, mesencure (cell replacement), metablok (anti-inflammatory), metformin, methotrexate, methylprednisolone, mivobulin isethionate, mosedipimod (EC-18), MP-0420, MP-0423, MRx4DP0004, N-acetylcysteine, N,N-dimethyl-L-valine-L-valine-N-methyl-L-valine-L-prolyl-1-L-proline-tert-butylamide, namilumab (IZN-101), nangibotide, narsoplimab, nebulized dornase alfa, NED-260, Niagen (nicotinamide ribose, vitamin B3), NK cell therapy, niclosamide, nilutamide, nintedanib, nitric oxide, nivolumab, NL-CVX1, NLP-21, NP-02, N-120 (ifenprodil), novaferon, NT-17 (efineptakin) alfa), NTR-441, octagam, olokizumab, omeprazole, onapristone, opaganib, OP-101, OT-101 (trabedersen), otilimab, ozanimod, paclitaxel, pacritinib, panaphix, pamrevlumab, paracetamol, PB1046, PTC299, pegylated interferon α, pegylated interferon α2b. Pegylated interferon λ, 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 β1 agonists, RECC327, REGN-COV2 (antibody cocktail therapy), reparixin, rintatolimod (ampligen), RLF-100 (aviptadil), RLS-0071, STI-5656 (abivertinib), Rhu-pGSN (gelsolin), rhizoxin, RPR109881, RoActemra, RUCONEST (conestat alfa), ruxolitinib, SAB-185, SAR443122, SARS-CoV-2 antibody, SARS-CoV-2 monoclonal antibody, SARS-CoV-2 polyclonal antibody, SARS-CoV-2 neutralizing antibody, SCTA01, Leukine (sargramostim), selenexor, sevoflurane, sertenef, siltuximab, sildenafil citate, silymarin, simvastatin, sirolimus, sirukumab, SIWA-318, solnatide, SNG-001, ST-266, stem cell education therapy, STI-1499, STI-2020dna (COVI-MAB), STI-4398 (Covidtrap), stramustinePhosphate), streptozocin, T-cell therapy (TargNaturTa), TAK-671, TAK-888, TATX-36, TATX-99, TCB-007, TJ003234 / TJM-2, TP508, TRV027, TD-0903, TLC19, tekrurna, tafenoquine, tamoxifen, tasonermin, taxanes, taxol, tetradrine, thalidomide, thimerosal, thymalfasin, tinzaparin, tocilizumab, tofacitinib, toremifene, tranexamic acid (acid), sodium crocetinate (TSC), tramadol, tretinoin, TXA127 (angiotensin-(1-7) peptide), TY027, TZLS-501, UNI-911, ulinastatin, upamostat, vafidemstat, valsartan, ethyl eicosapentaenoic acid, vazegepant, VBI-S, VERU-111, VHH72-Fc, vinblastine, vincristine, vindesinesulfate, 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.

[0142] Vaccine therapies that can be used in combination with the therapies disclosed herein include, but are not limited to, inactivated vaccines, live attenuated vaccines, recombinant vaccines, replication-defective 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. Specifically, vaccine therapies that can 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-defective viral vector vaccine (adenovirus from chimpanzees)), 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, and ChAd-SARS-CoV-2-S. (Adenovirus-based vaccines, 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 vaccines, CoBepiT, CVnCoV (mRNA-based vaccine), DPX-COVID-19, DS-5670, E-6020, ELI-005, EpiVacCorona, EPV-CoV19, Flowvax, GC-004 / Covax-19, GRAd-COV2 (adenovirus-based vaccine), GX-19 (DNA vaccine), HaloVax (self-assembled 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-COVV19 (ARCT-021, Self-replicating RNA vaccines, 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-COVIDTM (intranasal vaccine), TaliCoVax-19, TerraCoV2, Tertomotide (GV-1001), Tiba-pitt RNA vaccine, TNX-1800, TNX-1810, TNX-1820, TNX-2300, T-VIVA-19, V-590 (recombinant vaccine (vesicular stomatitis virus)), V-591 (measles vector vaccine), VBI-2900, VBI-2901, VBI-2902, VLA2001, Vivagel (SPL-7013), YF17D vector, ZIP-1642, and ZyCoV-D (DNA vaccine (plasmid)) and combinations thereof.

[0143] use This disclosure also relates to the use of the oral dosage forms described herein for treating viral infections in subjects in need of treatment, wherein the viral infection is an infection caused by a virus selected from the following: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In a second aspect of these embodiments, the virus is selected from RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In a specific aspect, the virus is selected from Influenza A virus and Influenza B virus. In a further specific aspect, the virus is selected from Human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In a specific embodiment, the virus is SARS-CoV-2.

[0144] In embodiments of the uses disclosed herein, the oral dosage form is administered once daily as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of medication administration, both in terms of size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0145] In embodiments of the uses disclosed herein, the oral dosage form is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, each separate dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of administration, both in size and quantity, compared to Compound A administered twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and with a unit dose strength of 200 mg).

[0146] In embodiments of the uses disclosed herein, the oral dosage form is administered once daily for 1 to 21 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific embodiments, the oral dosage form is administered once daily for 3 to 14 days, such as 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In specific embodiments, the oral dosage form is administered once daily for 3 to 6 days, such as 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered once daily for 5 days.

[0147] In embodiments of the uses disclosed herein, the oral dosage form is administered twice daily for 1 to 21 days, such as 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, such as 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, such as 3 days, 4 days, 5 days, or 6 days. In another specific embodiment, the oral dosage form is administered twice daily for 5 days.

[0148] This disclosure also relates to the use of the oral dosage form described herein for treating a viral infection in a subject in need of such treatment, wherein the use is initiated from 1 to 10 days after the onset of symptoms of the viral infection, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after the onset of symptoms. In a specific embodiment, the oral dosage form is administered less than 5 days after the onset of symptoms, such as less than 1, 2, 3, 4, or 5 days after the onset of symptoms. Symptoms of a viral infection may include one or more of cough, sore throat, nasal congestion, runny nose, shortness of breath or difficulty breathing, muscle or body aches, fatigue / weakness, fever / feeling of heat, chills, headache, nausea, vomiting, and diarrhea, but 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 / weakness, fever / feeling of heat, chills, headache, nausea, vomiting, diarrhea, loss of taste, and loss of smell.

[0149] This disclosure also relates to the aforementioned uses, wherein the subjects may be considered or have been identified as having a higher risk of developing severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of developing severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with eGFR reduced to <30 mL / min / 1.73 m). 2 (Participants); chronic obstructive pulmonary disease; obesity (body mass index of 30 or higher, where body mass index = weight (kg) / (height (m)) 2 Subjects with: serious heart disease (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes. In one implementation, the subject had not been vaccinated against COVID-19. In another implementation, the subject had been vaccinated against COVID-19.

[0150] This disclosure also relates to the aforementioned uses, wherein said uses reduce the risk of hospitalization or death in a subject. In embodiments, said uses can result in a reduction in the risk of hospitalization or death in a subject. In specific embodiments, said uses can result in a reduction in the risk of hospitalization or death in a subject of about 1% to about 10%, such as about 5% to about 7.5%, or about 6.8%. In further embodiments, said uses can result in a relative reduction in the risk of hospitalization or death in a subject of up to about 50%.

[0151] Additionally, this disclosure relates to the use of the oral dosage forms described herein for the prevention of viral infection or for the provision of antiviral prophylaxis in subjects in need (hereinafter, "prophylactic use"), wherein the viral infection is an infection caused by a virus selected from: EEEV, WEEV, VEEV, CHIK, Ross River virus, Orthomyxoviridae, Paramyxoviridae, RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, and Zika virus. In specific embodiments, the virus is selected from RSV, Influenza A virus, Influenza B virus, Filoviridae, Human coronavirus, SARS-CoV-1, MERS-CoV, SARS-CoV-2, and Ebola virus. In specific embodiments, the virus is selected from Influenza A virus and Influenza B virus. In specific embodiments, the virus is selected from Human coronavirus, SARS-CoV-1, MERS-CoV, and SARS-CoV-2. In specific embodiments, the virus is SARS-CoV-2.

[0152] In the embodiments disclosed herein for prophylactic use, the oral dosage form is administered once daily as a single dose. In aspects of these embodiments, the single dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, the single dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, the single dose may be provided as one (1) 800 mg tablet. In another particular aspect of these embodiments, the single dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of medication, both in size and quantity, compared to administering an 800 mg dose of Compound A twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule being 21.7 mm x 7.6 mm and having a unit dose strength of 200 mg).

[0153] In the embodiments disclosed herein for prophylactic use, the oral dosage form is administered twice daily as two separate doses. In aspects of these embodiments, each separate dose may be provided as a single tablet or as two or more tablets, such as two to four tablets. In a further aspect, each separate daily dose may be provided as an 800 mg tablet, a 400 mg tablet, a 200 mg tablet, a 100 mg tablet, or a 50 mg tablet. In a particular aspect of these embodiments, each separate dose may be provided as two (2) 800 mg tablets. In another particular aspect of these embodiments, each separate dose may be provided as two (2) 400 mg tablets. Such an aspect reduces the burden of administration, both in size and quantity, compared to Compound A administered twice daily for five consecutive days in the form of four (4) size 0 capsules (each capsule measuring 21.7 mm x 7.6 mm and with a unit dose strength of 200 mg).

[0154] This disclosure also relates to preventative use, wherein the oral dosage form is administered once daily for 1 to 42 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific implementation schemes, the oral dosage form is administered once daily for 1 to 21 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific implementation schemes, the oral dosage form is administered once daily for 3 to 14 days, such as 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0155] This disclosure also relates to preventative use, wherein the oral dosage form is administered twice daily for 1 to 42 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In specific implementation schemes, the oral dosage form is administered twice daily for 1 to 21 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In specific implementation schemes, the oral dosage form is administered twice daily for 3 to 14 days, such as 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.

[0156] This disclosure also relates to preventative use, wherein said use is initiated before exposure to a viral infection or after potential exposure to a viral infection. In specific embodiments, the oral dosage form is administered before potential exposure to a viral infection. In other specific embodiments, the oral dosage form is administered 1 to 10 days after potential exposure to a viral infection, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days after potential exposure. In specific embodiments, the oral dosage form is administered less than 5 days after potential exposure, such as less than 1 day, 2 days, 3 days, 4 days, or 5 days after potential exposure.

[0157] This disclosure also relates to the aforementioned preventative use, where the subjects may be considered to have a higher risk of developing severe COVID-19. Such individuals may have one or more underlying conditions associated with a higher risk of developing severe COVID-19, such as: age over 60 years; active cancer (excluding minor cancers not associated with immunosuppression or significant morbidity / mortality (e.g., basal cell carcinoma)); chronic kidney disease (excluding those undergoing dialysis or with eGFR reduced to <30 mL / min / 1.73 m). 2 (Participants); chronic obstructive pulmonary disease; obesity (body mass index of 30 or higher, where body mass index = weight (kg) / (height (m)) 2 Subjects with: serious heart disease (heart failure, coronary artery disease, or cardiomyopathy); and / or diabetes. In one implementation, the subject had not been vaccinated against COVID-19. In another implementation, the subject had been vaccinated against COVID-19.

[0158] This disclosure relates to preventative uses as described above, wherein the method reduces the risk of hospitalization or death in a subject. In embodiments, the method can result in a reduction in the risk of hospitalization or death in a subject. In specific embodiments, the method can result in a reduction in the risk of hospitalization or death in a subject of about 1% to about 10%, such as about 5% to about 7.5%, or about 6.8%. In further embodiments, the method can result in a relative reduction in the risk of hospitalization or death in a subject of up to about 50%.

[0159] Many COVID-19 patients recover with little or no medical intervention. However, clinical progression to severe illness severely impacts patients and the healthcare system, increasing not only the risk of mechanical ventilation and death but also potentially overwhelming hospital capacity and existing medical resources during COVID-19 surges. Therefore, reducing the number of COVID-19 patients requiring hospitalization is crucial. Vaccination remains the most important medical intervention currently available to reduce the risk of hospitalization or death due to COVID-19. However, early treatment after symptom onset has also proven effective. Direct-acting oral medications, such as those described in this article, that can be administered at home after diagnosis may be more practical for non-hospitalized patients and will become an important new tool for treating viral infections and diseases, including COVID-19 caused by SARS-CoV-2.

[0160] Other embodiments of this disclosure include the pharmaceutical compositions, combinations, uses, and methods described above, wherein it should be understood that each embodiment may be combined with one or more other embodiments to the extent that the combination of embodiments is consistent with the description of the embodiments. It should also be understood that the embodiments provided above are to be understood as including all embodiments, including such embodiments as those resulting from combinations of embodiments.

[0161] Example The following embodiments are exemplary and should not be construed as limiting further. The accompanying drawings, as well as all references, patents, and published patent applications cited throughout this application, are expressly incorporated herein by reference.

[0162] Comparative Example: Compound A Capsule Formulation The capsule formulation of compound A uses a mixture of wet-granulated materials, which is then filled into 0-size hydroxypropyl methylcellulose capsules with a unit dose strength of 200 mg (fill weight 285.7 mg). The composition of the capsule formulation is shown in Table 2.

[0163] Table 2

[0164] Example 1: Compound A tablet formulation: High-shear wet granulation, roller pressing and direct compaction methods Tablets were prepared using different tableting methods to determine whether the tableting process used affected size and achievable drug loading, and to evaluate the processing performance of different formulations. Each tablet had a unit dose strength of 400.0 mg.

[0165] Tablets of formulation A are prepared using a high-shear wet granulation (HSWG) process, in which compound A, hydroxypropyl cellulose, and sodium lauryl sulfate are dispensed into the feed bowl of a high-shear wet granulator. These components are granulated with water. The wet granules are depolymerized, fluidized bed dried, and ground. The granules are then blended with the extragranule components and lubricated with magnesium stearate.

[0166] Tablets of formulation D are prepared using a high-shear wet granulation (HSWG) process, wherein compound A, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium are dispensed into the feed bowl of a high-shear wet granulator. These components are granulated with water. The wet granules are depolymerized, fluidized bed dried, and ground. The granules are then blended with the extragranule components and lubricated with magnesium stearate.

[0167] Tablets are prepared using a rolling (RC) process, in which compound A, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, tricalcium phosphate, and sodium lauryl sulfate are dispensed into a blending container in the following proportions. These components are then blended. The blend is granulated by rolling. The granules are added to a blending container containing magnesium stearate, and the components are blended again. Subsequently, the blend is compressed into tablets. This process is used to prepare formulation B.

[0168] Tablets are prepared using a direct compression (DC) process, in which compound A and tricalcium phosphate are dispensed into a blending container in the following proportions. These components are pre-blended to improve flow. Then, compound A is dispensed into a blender with the tricalcium phosphate blend, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate, and these components are blended. Subsequently, the blend is compressed into tablets. This process is used to prepare formulation C.

[0169] Example 2: Comparison of tablet formulations with similar drug loading Prepare tablet formulations A, B, C, and D according to the processes and proportions indicated in Table 3.

[0170] Table 3

[0171] To reduce the burden of medication administration and achieve the tablet mechanical strength required for blister packs and film coatings, a variety of formulations and processes have been developed, covering roller compression, direct compression, and high-shear wet granulation (HSWG) platforms. Figure 1Tablet formation profiles for compound A granules and powder blends prepared using different techniques are shown, specifically formulations A, B, and C. The same formulations were selected for processing via RC and DC, while different formulation compositions were chosen for HSWG (Table 3). Granules (HSWG and RC) and DC blends were tableted under different stresses, and the tensile strength of each tablet was determined. Tablet strength is affected by the manufacturing process. At a similar drug loading of 50% (400.0 mg) and a core weight of 800.0 mg, the HSWG formulation (formulation A) produced tablets with the best mechanical strength, while the tablets prepared via RC (formulation B) had the weakest mechanical strength. Granules produced by roll forming showed a loss of tablet formation, while the DC tablets (formulation C) exhibited improved tablet formation due to the lack of granulation of the formulation. The tablets produced via HSWG (formulation A) had the best tensile strength. Figure 1 ).

[0172] Compared to the RC tablets of formulation B, the HSWG tablets of formulation D exhibit improved strength, as indicated by better friability. Figure 2 This will improve the robustness of downstream operations such as film coating and packaging. The superior strength of the HSWG tablets in Formulation D compared to the RC tablets of Formulation B can likely be attributed to the flexibility of the HSWG process, which allows for the use of significant levels of extra-particle compression adjuvants / fillers (see Formulations A and D in Table 3) to improve tablet formation while maintaining excellent processability. Figure 3 ).

[0173] Notably, each tablet formulation contains 400 mg of compound A in a single tablet, which is equivalent to the amount of compound A in two capsules of the approved marketed formulation shown in the comparative examples.

[0174] Example 3: Effect of sodium lauryl sulfate on the in vitro tablet dissolution of HSWG formulation of compound A Tablet formulations E, F, G, and H were prepared using the HSWG process by dispensing the following components into the bowl of a high-shear wet granulator in the proportions indicated in Table 4. These components were granulated with water. The wet granules were deagglomerated, fluidized bed dried, and ground. The granules were blended with the extragranule components indicated in Table 4 and lubricated with magnesium stearate. Sodium lauryl sulfate (SLS) was added to formulations E, F, and G in an intragranule manner at levels of 1.00% (6.000 mg), 0.75% (4.500 mg), and 0.25% (1.500 mg), respectively, while SLS was added to formulation H in an extragranule manner at a level of 0.50% (3.000 mg).

[0175] Table 4

[0176] These samples were evaluated using the 100 RPM USP I (20 mesh) dissolution method. The dissolution medium consisted of 500 mL of 0.1 N HCl. After dissolution, the samples were analyzed using a gradient reversed-phase HPLC method. When SLS was added intraparticlely (formulations E, F, and G), the dissolution rate of the tablets increased with increasing SLS levels. Figure 4 The dissolution characteristics of these formulations are shown. While compound A exhibits good water solubility at 37°C (>10 mg / mL in water), it demonstrates poor wetting properties in aqueous media. Intragranular SLS addition improves wetting properties and enhances contact between the tablet surface and the dissolution medium, leading to rapid tablet disintegration and dissolution. In contrast, the slowest dissolution rate was observed with ex-granular SLS addition (formulation H), indicating that SLS needs to be in close proximity (tightly mixed) with compound A to significantly influence the dissolution rate.

[0177] Example 4: Effect of extraparticulate components on in vitro tablet dissolution of HSWG formulation of compound A For HSWG formulations of compound A, and in the absence of surfactants, excipients can be used to modulate the release of compound A from the formulation. The type of excipient used, the quantitative level of the excipient, and the excipient placement (in-particle or out-of-particle) can all affect the release of compound A. The effect of excipients on the release of compound A was evaluated using the 50 RPM USP II dissolution method, with 0.1 N HCl as the dissolution medium and a container filling volume of 500 mL. After dissolution, the samples were analyzed using a gradient reversed-phase HPLC method. Increased out-of-particle levels of water-soluble tableting adjuvants and disintegrants (lactose monohydrate and croscarmellose sodium, respectively) led to an increased dissolution rate of the HSWG tablets. Compared to the slow-release variant formulation I, formulation D released compound A more rapidly (Table 5 and...). Figure 5 Crosslinked sodium carboxymethyl cellulose promotes the rapid release of compound A from the tablet due to its inherent wicking and swelling capabilities when exposed to water. Lactose monohydrate, being water-soluble and hydrophilic, promotes gel formation and shortens the time it takes for the dissolution medium to penetrate into the tablet matrix.

[0178] Table 5

[0179] Example 5: Absorption, systemic pharmacokinetics and bioequivalence of compound A To characterize the human absorption of compound A and the systemic pharmacokinetics (PK) of NHC, and to evaluate the bioequivalence of the capsule formulation (comparative example) and tablet formulation (formulation D), a physiological biopharmaceutics model (PBBM) was established using dissolution methods according to FDA guidance. This model has been validated using multiple clinically observed PK results (see Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR, Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2, 65(5) ANTIMICROB. AGENTS CHEMOTHER 1-14 (May 2021); available at doi.org / 10.1128 / AAC.02428-20 65:e02428-20. In short, physiologically based biopharmaceutical models are a relatively new tool that can be used throughout the entire drug product development process and after approval, and with the release of a draft guidance, their use at the FDA has become more widespread (see US FOOD AND DRUG ADMINISTRATION. DRAFT GUIDANCE FOR INDUSTRY: THE USE OF PHYSIOLOGICALLY BASED PHARMACOKINETIC ANALYSES—BIOPHARMACEUTICS APPLICATIONS FOR ORAL DRUG PRODUCT DEVELOPMENT, MANUFACTURING CHANGES, AND CONTROLS). (Available from: www.fda.gov / regulatory-information / searchfda-guidance-documents / use-physiologically-based-pharmacokinetic-analyses-biopharmaceutics-applications-oral-drug-product). PBBM focuses on generating mechanistic understanding of how drug product quality attributes interact with physiological functions to affect drug performance and pharmacokinetics in vivo. PBBM allows for the establishment of a dissolution bioequivalence safety space; dissolution profiles within this safety space will result in... max Pharmacokinetics with bioequivalence in terms of AUC. SeeWu F, ShahH, Li M, Duan P, Zhao P, Suarez S, Raines K, Zhao Y, Wang M, Lin HP, Duan J,Yu L, Seo P, Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the US Food and Drug Administration for New Drugs , 23(31) The AAPS J. (February 2021); available from doi: 10.1208 / s12248-021-00564-2. PMID: 33619657).

[0180] Dissolution profiles of compound A were obtained for capsule and tablet formulations D using the USP 2 method. Dissolution profiles are key input data for PBBM and are used in conjunction with in vitro dissolution conditions (volume, solubility in the dissolution medium, and dosage). Then, based on data from Takano et al. (Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, Yamashita S, ...), Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test ,23(6) PHARM RES. 1144-1156 (June 2006); available from doi: 10.1007 / s11095-006-0162-4. Epub May 25, 2006. PMID: 16715363.), a study modeled the dissolution data of compound A to calculate the z-factor. Using the z-factor calculation tool in GastroPlus, the z-factor results obtained from in vitro data were used for simulation by setting the dissolution model to a z-factor model in GastroPlus (see Wu D, Li M, Current State and Challenges of Physiologically Based Biopharmaceutics Modeling (PBBM) in Oral Drug Product Development , 40(2) PHARM RES. 321-336 (Feb. 2023, publishedonline 8 Sep. 2022); available at doi: 10.1007 / s11095-022-03373-0; see also Kollipara, S., Bhattiprolu, AK, Boddu, R., Ahmed T., Chachad S., Best Practices for Integration of Dissolution Data into Physiologically Based Biopharmaceutics Models (PBBM): A Biopharmaceutics Modeling Scientist Perspective, 24(59) AAPS PHARMSCITECH (Feb. 2023); available at doi.org / 10.1208 / s12249-023-02521-y).

[0181] Overall, the lower limit of the bioequivalence safety space is Q = 80% dissolved within 37 minutes in 0.1N HCl dissolution medium (see [reference needed]). Figure 6 Based on the dissolution safety margin (shaded area), the capsule formulation of compound A is bioequivalent to the tablet formulation of formulation D in terms of dissolution. For illustrative purposes, the dissolution profile of the slow-release variant formulation I, which is outside the bioequivalence safety margin, is shown. Formulation I is expected to be bioequivalent or nearly bioequivalent to the capsule formulations of formulation D and the comparative examples.

[0182] It should be understood that the various features and functions discussed above, as well as other features and functions or alternatives thereof, can be combined into many other different systems or applications as needed. It should also be understood that those skilled in the art may subsequently make various substitutions, modifications, variations, or improvements, which are also intended to be covered by the following claims.

Claims

1. An oral dosage form comprising an antiviral nucleoside and one or more excipients, wherein... (a) The antiviral nucleoside is selected from β-D- N (4)-Hydroxycytidine The prodrug, or a pharmaceutically acceptable salt or tautomer thereof, in an amount from about 25 mg to about 800 mg, and (b) The oral dosage form is a tablet having a maximum length equal to or greater than about 5.00 mm ± 0.15 mm.

2. The oral dosage form according to claim 1, wherein the antiviral nucleoside is 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: Compound A Or its pharmaceutically acceptable salt, tautomer, or prodrug.

3. The oral dosage form according to claim 2, wherein the antiviral nucleoside is 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: Compound A Or its tautomers.

4. The oral dosage form according to claim 2, wherein the antiviral nucleoside is 2-methylpropionic acid {(2 R ,3 S 4 R 5 R )-3,4-dihydroxy-5-[4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2 H [2-yl]oxacyclopentane-2-yl methyl ester: Compound A The prodrug or its pharmaceutically acceptable salt or tautomer.

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

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

7. The oral dosage form according to any one of claims 1 to 6, wherein the one or more excipients are selected from tableting aids, diluents, disintegrants, lubricants, flow aids, surfactants or wetting agents, granulation solutions or granulation solvents, binders and fillers, and combinations thereof.

8. The oral dosage form according to claim 7, wherein the one or more excipients include one or more tableting aids, the tableting aids being selected from starch, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, spray-crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microcellulose and microcrystalline cellulose that can be directly tableted.

9. The oral dosage form according to claim 8, wherein the one or more tableting adjuvants are present in an amount of about 6,000 mg to about 1,440 mg.

10. The oral dosage form according to claim 8, wherein the one or more excipients include one or more diluents selected from starch that can be directly compressed into tablets, dicalcium phosphate, spray-dried lactose, anhydrous lactose, spray-crystallized maltose, spray-crystallized dextrose, crystalline sorbitol, mannitol, sucrose, microcellulose and microcrystalline cellulose.

11. The oral dosage form of claim 10, wherein the one or more diluents are present in an amount of about 6,000 mg to about 1,440 mg.

12. The oral dosage form according to claim 8, wherein the one or more excipients comprise one or more disintegrants selected from calcium alginate, sodium calcium alginate, calcium carboxymethyl cellulose, calcium cellulose glycolate, calcium carboxymethyl cellulose, 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 glycolate starch, and crospovidone carboxymethyl cellulose.

13. The oral dosage form of claim 12, wherein the one or more disintegrants are present in an amount of about 0.000 mg to about 240.0 mg.

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

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

16. The oral dosage form according to claim 8, wherein the one or more excipients include one or more flow aids selected from corn starch, talc, colloidal silica and tricalcium phosphate.

17. The oral dosage form of claim 16, wherein the one or more gliding agents are present in an amount of about 0.000 mg to about 80.00 mg.

18. The oral dosage form according to claim 8, wherein the one or more excipients comprise one or more surfactants or wetting agents, said surfactants or wetting agents being selected from polysorbate, poloxamer, 2-[4-(2,4,4-trimethylpentyl-2-yl)phenoxy]ethanol, sodium octyl glycoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, Cocamidopropyl betaine, linoleamide-propyl betaine, myristamidopropyl betaine, palmitamidopropyl betaine, isostearamidopropyl betaine, myristamidopropyl dimethylamine, palmitamidopropyl dimethylamine, isostearamidopropyl dimethylamine, sodium stearate, sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium cholate, hexadecyltrimethylammonium bromide, dodecylpyridine chloride, heptadecyl glycol monohexadecyl ether, n-dodecyl alanine, lecithin, sodium methylcocoyl taurate, disodium methyloleoyl taurate, polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol.

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

20. The oral dosage form according to claim 8, wherein the one or more excipients comprise one or more granulation solutions or granulation solvents selected from water, organic solvents, and combinations thereof.

21. The oral dosage form of claim 20, wherein the one or more granulating agents are present in an amount of about 10% by weight to about 80% by weight relative to the total weight of the tablets.

22. The oral dosage form according to claim 8, wherein the one or more excipients comprise one or more binders and / or fillers selected from starch, cellulose and its derivatives, polyvinylpyrrolidone, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch and mixtures thereof.

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

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

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

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

27. The oral dosage form according to any one of claims 1 to 26, wherein the oral dosage form has a dissolution rate of about 80% in a 0.1N HCl dissolution medium sufficient to dissolve the oral dosage form within about 37 minutes.

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