WO2024091624A1 - Pharmaceutical formulations and uses thereof - Google Patents
Pharmaceutical formulations and uses thereof Download PDFInfo
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- WO2024091624A1 WO2024091624A1 PCT/US2023/036039 US2023036039W WO2024091624A1 WO 2024091624 A1 WO2024091624 A1 WO 2024091624A1 US 2023036039 W US2023036039 W US 2023036039W WO 2024091624 A1 WO2024091624 A1 WO 2024091624A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- solid oral dosage forms comprising the compound of Formula I, and uses thereof are provided.
- BACKGROUND [0003]
- the compound of Formula I is an antiviral agent
- CN114869893 describes solid dosage forms, in particular tablets, of the compound of Formula I.
- the solid dosage forms disclosed in CN114869893 are obtained by wet granulation process and are characterized by low loading of the compound of Formula I (24.4%).
- the issue of low dose loading, i.e., percent Formula I content of the formulation is not addressed in CN114869893.
- there is a need for developing solid dosage forms e.
- g. tablet/capsule dosage forms comprising higher loading of the compound of Formula I.
- High drug loading enables the tablets/capsules to have suitable size in order to allow the patient to easily swallow 35648-0320WO11455-WO-PCT ⁇ the tablets/capsules.
- Higher drug load also helps minimize the number of tablets/capsules required per dose, which may lead to better patient compliance.
- the overall physical properties and manufacturability of low drug loading formulations is determined predominantly by the inactive ingredients or excipients in the formulation. However, at high drug loading, the contribution of the physical properties of the active pharmaceutical ingredient (“API”) to the manufacturability of a formulation becomes predominant.
- API active pharmaceutical ingredient
- APIs possess the necessary properties with respect to compressibility that are required in order to obtain a high load tablet using a dry granulation process.
- most small molecule API can be formulated in low dose forms because the physical properties of the excipients utilized in the formulations dominate the properties of the solid composition, rather than the physical properties of the API itself.
- drug loading increases the physicochemical characteristics of the drug substance become increasing dominant in the tablet manufacturing process. It is common to include filler excipients in a single formulation that possess brittle characteristics and others that possess ductile/plastic characteristics. The combination of the brittle and plastic type materials in a given formulation are important to the “manufacturability” of that formulation.
- API can have a full spectrum of physical properties and are not selected based on these physical properties, it is not to be expected that a particular API would have the physical properties to favorably contribute to an overall formulation in terms of manufacturability and stability. In fact, it is not infrequent that it is the physical properties of the API that actually present the largest obstacle to creating a workable formulation. It is therefore surprising and unanticipated where it is found that an API can be formulated in a dry granulating manufacturing process with drug loads in excess of 40%. The ability to prepare Formula I tablets at a drug loading in excess of 40%, for example using a dry granulation process, as described below is a surprising observation.
- the present disclosure provides a pharmaceutical formulation, comprising: (i) a compound expressed by formula I: 35648-0320WO11455-WO-PCT ⁇ or a pharmaceutically acceptable a disintegrating agent; and (iv) a lubricant; wherein the compound of Formula I is present in an amount of about 40 wt% to about 70 wt%.
- the pharmaceutical formulation comprises the filler in an amount of about 20 wt% to about 60 wt%; the disintegrating agent in an amount of about 1 wt% to about 10% wt%; and the lubricant in an amount of about 0.5 wt% to about 5% wt%.
- the pharmaceutical formulation comprises the filler in an amount of about 40 wt % to about 50 wt%; the disintegrating agent in an amount of about 1 wt% to about 10 wt%; and the lubricant in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical formulation comprises: (i) the compound of Formula I in an amount of about 45 wt% to about 55 wt%; (ii) the filler in an amount of about 44 wt% to about 46 wt%; (iii) the disintegrating agent in an amount of about 3 wt% to about 5 wt%; and (iv) the lubricant in an amount of about 0.5 wt% to about 2 wt%.
- the pharmaceutical formulation comprises: (i) the compound of Formula I in an amount of about 50 wt%; (ii) the filler in an amount of about 44 wt% to about 46 wt%; (iii) the disintegrating agent in an amount of about 3 wt% to about 5 wt%; and (iv) the lubricant in an amount of about 0.5 wt% to about 2 wt%.
- the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate.
- the filler is microcrystalline cellulose.
- the disintegrating agent is starch, pre-gelatinized starch, hydroxypropyl starch, celluloses, cross- linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium. In some embodiments, the disintegrating agent is crospovidone. In some embodiments, the lubricant is stearic acid, sodium stearyl fumarate, or magnesium stearate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical formulation comprises about 100 mg to about 700 mg of the compound of Formula I. In some embodiments, the pharmaceutical formulation comprises about 100 mg of the compound of Formula I. In some embodiments, the pharmaceutical formulation comprises about 350 mg of the compound of Formula I.
- the pharmaceutical formulation comprises about 500 mg of the compound of Formula I. 35648-0320WO11455-WO-PCT ⁇ [0009]
- the current disclosure provides a tablet comprising: (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof (ii) a filler, (iii) a disintegrating agent, and (iv) a lubricant; wherein the compound of Formula I is present in an amount of about 40 wt% to about 70 wt%.
- the tablet comprises the filler in an amount of about 20 wt% to about 60% wt%, the disintegrating agent in an amount of about 1 wt% to about 10 wt%, and the lubricant in an amount of about 0.5 wt% to about 5% wt%. In some embodiments, the tablet comprises the filler in an amount of about 40 wt% to about 50 wt%, the disintegrating agent in an amount of about 1 wt% to about 10% wt%, and the lubricant in an amount of about 0.5 wt% to about 5 wt%.
- the tablet comprises (i) the compound of Formula I in an amount of about 45 wt% to about 55 wt%, (ii) the filler in an amount of about 44 wt% to about 46 wt%, (iii) the disintegrating agent in an amount of about 3 wt% to about 5 wt%, and (iv) the lubricant in an amount of about 0.5 wt% to about 2 wt%.
- the tablet comprises (i) the compound of Formula I in an amount of about 50 wt%, (ii) the filler in an amount of about 44 wt% to about 46 wt%, (iii) the disintegrating agent in an amount of about 3 wt% to about 5 wt%, and (iv) the lubricant in an amount of about 0.5 wt % to about 2 wt%.
- the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate.
- the filler is microcrystalline cellulose.
- the disintegrating agent is starch, pre-gelatinized starch, hydroxypropyl starch, celluloses, cross- linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium. In some embodiments, the disintegrating agent is crospovidone. In some embodiments, the lubricant is stearic acid, sodium stearyl fumarate, magnesium stearate, or a combination thereof. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the tablet comprises about 100 mg to about 700 mg of the compound of Formula I. In some embodiments, the tablet comprises about 100 mg of the compound of Formula I. In some embodiments, the tablet comprises about 350 mg of the compound of Formula I.
- the tablet comprises about 500 mg of the compound of Formula I.
- the present disclosure provides tablet comprising (i) the compound of Formula I in an amount of about 50-700 mg, (ii) microcrystalline cellulose in an amount of about 50 mg to about 500 mg, (iii) crospovidone in an amount of about 5 mg to 50 mg, and (iv) magnesium stearate in an amount of about 1 mg to about 20 mg.
- the tablet comprises (i) the compound of Formula I in an amount of about 100 mg, (ii) microcrystalline cellulose in an amount of about 89 mg, (iii) crospovidone in an amount of about 8 mg, and (iv) magnesium stearate in an amount of about 3 mg.
- the tablet comprises (i) 35648-0320WO11455-WO-PCT ⁇ the compound of Formula I in an amount of about 500 mg, (ii) microcrystalline cellulose in an amount of about 445 mg, (iii) crospovidone in an amount of about 40 mg; and (iv) magnesium stearate in an amount of about 10 mg.
- the tablet comprises (i) the compound of Formula I in an amount of about 350 mg, (ii) microcrystalline cellulose in an amount of about 315 mg, (iii) crospovidone in an amount of about 28 mg. and (iv) magnesium stearate in an amount of about 7 mg.
- the disclosure provides a tablet comprising (a) a tablet core and (b) a film coat; wherein the tablet core comprises (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof, (ii) a filler, (iii) a disintegrating agent; and (iv) a lubricant; wherein the compound of Formula I is present in an amount of about 40 wt% to about 70 wt%.
- the tablet comprises the filler in an amount of about 20 wt% to about 60 wt%; the disintegrating agent in an amount of about 1 wt% to about 10 wt%; and the lubricant in an amount of about 0.5 wt% to about 5 wt%.
- the tablet core comprises the filler in an amount of about 40% to about 50% by weight, the disintegrating agent in an amount of about 1% to about 10% by weight (wt%), and the lubricant in an amount of about 0.5% to about 5% by weight (wt%).
- the tablet core comprises (i) the compound of Formula I in an amount of about 45-55 wt%, (ii) the filler in an amount of about 44% to about 46% by weight, (iii) the disintegrating agent in an amount of about 3% to about 5% by weight (wt%), (iii) the lubricant in an amount of about 0.5 wt% to about 2 wt%.
- the tablet core comprises (i) the compound of Formula I in an amount of about 50 wt%, (ii) the filler in an amount of about 44 wt% to about 46 wt%, (iii) the disintegrating agent in an amount of about 3 wt% to about 5 wt%; and (iv) the lubricant in an amount of about 0.5 wt% to about 2 wt%.
- the film coat comprises Opadry® II.
- the film coat comprises Opadry® QX.
- the film coat comprises Opadry® II purple.
- the film coat comprises Opadry® II yellow.
- the film coat comprises Opadry® QX yellow.
- the film coat comprises titanium free variants of Opadry®.
- the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate.
- the filler is microcrystalline cellulose.
- the disintegrating agent is starch, pre-gelatinized starch, hydroxypropyl starch, celluloses, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium.
- the disintegrating agent is crospovidone.
- the lubricant is stearic acid, sodium stearyl fumarate, or magnesium stearate. In some embodiments, the lubricant is magnesium stearate.
- the tablet comprises 35648-0320WO11455-WO-PCT ⁇ about 100 mg to about 700 mg of the compound of Formula I. In some embodiments, about 100 mg of the compound of Formula I. In some embodiments, the tablet comprises about 350 mg of the compound of Formula I. In some embodiments, the tablet comprises about 500 mg of the compound of Formula I. [0012]
- the disclosure provides a method of treating a viral infection in a patient in need thereof, the method comprising administering to the human a pharmaceutical formulation or a tablet provided herein. In some embodiments, the method comprises administering to the human at least one additional therapeutic or prophylactic agent. In some embodiments, the viral infection is a coronavirus infection.
- the viral infection is a zoonotic coronavirus infection.
- the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.
- the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.
- the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is selected form the group consisting of 229E virus infection, NL63 virus infection, OC43 virus infection, and HKU1 virus infection. In some embodiments, the viral infection is SARS-CoV-2 infection (COVID-19).
- the viral infection is a SARS-CoV virus infection. In some embodiments, the viral infection is a MERS-CoV virus infection. In some embodiments, the viral infection is a pneumoviridae virus infection. In some embodiments, the pneumoviridae virus infection is respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is human metapneumovirus infection. In some embodiments, the viral infection is a picornaviridae virus infection. In some embodiments, the viral infection is an enterovirus infection.
- the viral infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.
- the picornaviridae virus infection is human rhinovirus infection (HRV).
- the picornaviridae virus infection is HRV-A, HRV-B, or HRV-C infection.
- the viral infection is a flaviviridae virus 35648-0320WO11455-WO-PCT ⁇ infection.
- the flaviviridae virus infection is a dengue virus infection, yellow fever virus infection, West Nile virus infection, tick borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, zika virus infection, or a HCV infection.
- the viral infection is a filoviridae virus infection.
- the filoviridae virus infection is an ebola virus infection or a Marburg virus infection.
- the viral infection is an orthomyxovirus infection.
- the viral infection is an influenza virus infection.
- the viral infection is an influenza A virus infection or influenza B virus infection.
- the viral infection is a paramyxoviridae virus infection. In some embodiments, the viral infection is a human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection. [0013] In one aspect, the disclosure provides a method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, characterized in that a pharmaceutical formulation provided herein is used. [0014] In one aspect, the disclosure provides a use of the pharmaceutical formulation provided herein for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof. In some embodiments, the medicament is used with at least one additional therapeutic or prophylactic agent.
- the disclosure provides a pharmaceutical formulation or a tablet disclosed herein for use in treatment or prevention of a viral infection in a human in need thereof.
- the pharmaceutical formulation or the tablet for use with at least one additional therapeutic agent.
- Figure 1 shows a flow diagram illustrating exemplary preparation of the solid oral dosage forms disclosed herein.
- Figure 2 shows the results of the stability studies carried out on exemplary formulations disclosed herein.
- Figure 3 shows the results of the stability studies carried out on exemplary formulations disclosed herein. 35648-0320WO11455-WO-PCT ⁇
- Figure 4 shows results of stability studies carried out on Formulation 8.
- FIG. 1 shows results of stability studies carried out on Formulation 8.
- Figure 6 shows results of stability studies carried out on Formulation 8.
- DETAILED DESCRIPTION [0022] Described herein are pharmaceutical formulations, in particular solid dosage forms (e.g., tablets and capsules) of the compound of Formula I: [0023] The compound of Formula I was disclosed in WO 2022/047065 as Compound 15. The IUPAC name of the compound of Formula I is ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate.
- the compounds described herein, exemplified by Formula I have chiral centers, e.g., chiral carbon.
- the pharmaceutical formulations, for example the solid oral dosage forms (e.g. tablets) disclosed herein thus include embodiments, where the compound having the chemical structure of Formula I is present as a racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
- the pharmaceutical formulations, for example the solid oral dosage forms (e.g., tablets) disclosed herein include embodiments wherein the compound of Formula I is enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
- the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
- Pharmaceutical formulations for example the solid oral dosage forms (e.g., tablets) comprising racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
- the racemic mixtures are separated into their individual, substantially optically pure isomers through appropriate techniques such as, for 35648-0320WO11455-WO-PCT ⁇ example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
- the compound of Formula I is a substantially pure enantiomer.
- Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York.
- Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
- a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
- the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- the compound of Formula I may also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
- ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
- Any formula or structure given herein, including compounds of Formula I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
- isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
- isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes 35648-0320WO11455-WO-PCT ⁇ such as 3 H, 13 C and 14 C are incorporated.
- Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- the pharmaceutical formulations for example the solid oral dosage forms (e.g., tablets) of disclosure also include embodiments, wherein the pharmaceutical formulations comprise compounds of the chemical structure of Formula I, but in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the compound of Formula I.
- Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of the compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984).
- such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
- the pharmaceutical formulations disclosed herein comprise the compound of Formula . [0029] or used in the pharmaceutical formulations, for example solid oral dosage forms (e.g.
- tablets disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
- An 18 F labeled compound may be useful for PET or SPECT studies.
- Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled 35648-0320WO11455-WO-PCT ⁇ reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I. [0030] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
- any atom specifically designated as a deuterium (D) is meant to represent deuterium.
- the “X-ray powder diffraction pattern” or “XRPD pattern” as described herein preferably refers to the X-ray powder diffraction pattern obtained using CuK ⁇ radiation.
- “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results.
- Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
- a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
- compositions may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
- excipient or “excipients” is intended to refer to inter alia basifying agents, solubilisers, glidants, fillers, binders, lubricant, diluents, preservatives, surface active agents, dispersing agents and the like.
- the term also comprises agents such as sweetening 35648-0320WO11455-WO-PCT ⁇ agents, flavoring agents, coloring agents, preserving agents, and coating agents. Such components will generally be present in admixture within the solid oral dosage forms (e.g., tablets).
- “mild renal impairment,” used in reference to a patient means that the patient has mild kidney damage.
- Mild renal impairment can also be referred to as “mild CKD.”
- a patient can be classified as having mild renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient’s population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 60 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 can indicate mild renal impairment. [0036] As used herein, “moderate renal impairment,” used in reference to a patient, means that the patient has moderate kidney damage.
- Moderate renal impairment can also be referred to as “moderate CKD.”
- a patient can be classified as having moderate renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient’s population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 30 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 can indicate moderate renal impairment. [0037] As used herein, “severe renal impairment,” used in reference to a patient, means that the patient has severe kidney damage.
- Severe renal impairment can also be referred to as “severe CKD.”
- a patient can be classified as having severe renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient’s population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 15 mL/min/1.73 m 2 to less than 30 mL/min/1.73 m 2 can indicate severe renal impairment.
- dn refers to particle size distribution by volume where n is between 0 and 100.
- d 90 of less than 800 ⁇ m means 90% of the particles by volume are smaller than 800 ⁇ m.
- PHARMACEUTICAL FORMULATIONS [0039] All pharmaceutical formulations described here comprise the compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- the pharmaceutical formulations disclosed herein comprise the compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more components selected from a filler, a lubricant, and a disintegrating agent.
- the pharmaceutical formulations disclosed herein comprise (i) the compound of Formula I, or a pharmaceutically acceptable salt thereof, (ii) a filler, (iii) a lubricant, and (iv) a disintegrating agent.
- the pharmaceutical formulations disclosed herein are a solid dosage form.
- the solid dosage form disclosed herein will include one or more excipients. Excipients should be compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. Examples of suitable excipients may be found e.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.
- the pharmaceutical formulations disclosed herein are for oral administration to a subject (for e.g., a human).
- solid oral dosage forms of the compound of Formula I for oral administration (“solid oral dosage forms”).
- the solid oral dosage forms disclosed herein comprise one or more excipients selected from (i) a filler, (ii) a disintegrating agent, and (iii) a lubricant.
- the solid oral dosage forms disclosed herein comprise (i) a filler, (ii) a disintegrating agent, and (iii) a lubricant.
- pharmaceutical compositions may have desirable properties for medical or pharmaceutical use.
- compositions may provide advantages such as improving the manufacturing process of the compound, improving the stability or storability of a drug product form of the compound, or improving drug loading of the compound.
- the compound of Formula I [0043]
- the solid oral dosage forms disclosed herein may comprise any suitable amount of the compound of Formula I, for example about 0.1 mg to about 1000 mg of the compound of Formula I.
- the solid oral dosage forms disclosed herein comprise about 10 mg to about 800 mg, about 10 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 10 mg to about 50 35648-0320WO11455-WO-PCT ⁇ mg, about 10 mg to about 30 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 600 mg, about 50 mg to about 400 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 300 mg to about 1000 mg, about 300 mg to about 800 mg, about 300 mg to about 600 mg, about 300 mg to about 400 mg, about 400 mg to about 1000 mg, about 300 mg to about
- the solid oral dosage forms disclosed herein comprise about 50 to about 800 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 100 to about 700 mg of the compound of Formula I, for example from about 100 mg, about 350 mg, about 500 mg, or about 700 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 100 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 350 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 500 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 700 mg of the compound of Formula I.
- the solid oral dosage forms disclosed herein comprise about 175 mg of the compound of Formula I.
- the solid oral dosage forms disclosed herein may comprise any suitable amount of the compound of Formula I, for example about 1 mg to about 1000 mg of the compound of Formula I.
- the compound of Formula I can be used in any suitable form.
- the compound of Formula I can be amorphous or crystalline.
- the compound of Formula I is amorphous.
- the compound of Formula I is crystalline.
- the compound of Formula I is the freebase form.
- the compound of Formula I can be crystalline freebase Form I, freebase Form II, freebase Form III, xinafoate material A, HCl salt Form I, HCl salt material A, HCl salt material B, HCl salt material C as described in WO 2022/047065, or a combination thereof.
- the compound of Formula I is crystalline.
- the %wt of Formula I would be adjusted accordingly based on salt correction factor.
- the salt correction factor is calculated by taking the molar mass of the pharmaceutically acceptable salt of the compound of Formula I and dividing it by the molar mass of the freebase form of the compound of Formula I. For example, for the hydrochloride salt of the compound of Formula I, the salt correction factor is 1.10. Therefore, the %wt of the hydrochloride salt of Formula I will be 1.10 multiplied by the %wt specified for the compound of Formula I.
- the compound of Formula I is crystalline freebase Form III as described in International Patent Application Publication No. WO 2022/047065.
- crystalline compound of Formula I is characterized by an X-ray powder diffraction (XRPD) pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 16.0°, and 25.4°.
- XRPD X-ray powder diffraction
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 16.0°, and 25.4°, and one, two or three of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.2°, 19.1°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 16.0°, and 25.4°, and one or two of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.2°, 19.1°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 16.0°, and 25.4°, and one of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.2°, 19.1°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 16.0°, and 25.4°, and two of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.2°, 19.1°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern 35648-0320WO11455-WO-PCT ⁇ comprising any three of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and one, two or three of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.4°, 19.8°, and 20.7°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and one or two of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.4°, 19.8°, and 20.7°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ - reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and one of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.4°, 19.8°, and 20.7°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and two of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 10.4°, 19.8°, and 20.7°.
- crystalline compound of Formula I has an XRPD pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°.
- crystalline compound of Formula I has an XRPD pattern comprising any three of the degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°.
- the compound of Formula I can have any suitable purity.
- the compound of Formula I can have a purity of at least about 90%, or at least about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or at least about 99.9%.
- the compound of Formula I has a purity of at least about 99.1%.
- the compound of Formula I has a purity of at least about 99.3%.
- the compound of Formula I has a purity of at least about 99.5%.
- the compound of Formula I has a purity of at least about 99.7%. In some embodiments, the compound of Formula I has a purity of at least about 99.5%. In some embodiments, the compound of Formula I has a purity of at least about 99.9%. [0051] In some embodiments, the compound of Formula I has a d 90 of less than about 800 ⁇ m.
- the form has a d90 of less than about 750 ⁇ m, about 700 ⁇ m, about 650 ⁇ m, about 600 ⁇ m, about 550 ⁇ m, about 500 ⁇ m, about 450 ⁇ m, about 400 ⁇ m, about 350 ⁇ m, about 300 35648-0320WO11455-WO-PCT ⁇ ⁇ m, about 250 ⁇ m, about 200 ⁇ m, about 150 ⁇ m, about 100 ⁇ m, about 50 ⁇ m, about 40 ⁇ m, about 30 ⁇ m, about 20 ⁇ m or about 10 ⁇ m.
- the form has a d90 of about 10 ⁇ m- 500 ⁇ m, for example, about 10 ⁇ m-450 ⁇ m, about 10 ⁇ m-400 ⁇ m, about 10 ⁇ m-350 ⁇ m, about 10 ⁇ m-300 ⁇ m, about 10 ⁇ m-250 ⁇ m, about 10 ⁇ m-200 ⁇ m, about 10 ⁇ m-150 ⁇ m, about 10 ⁇ m- 100 ⁇ m, about 40 ⁇ m-800 ⁇ m, about 40 ⁇ m-750 ⁇ m, about 40 ⁇ m-700 ⁇ m, about 40 ⁇ m-650 ⁇ m, about 40 ⁇ m-600 ⁇ m, about 40 ⁇ m-550 ⁇ m, about 40 ⁇ m-500 ⁇ m, about 40 ⁇ m-450 ⁇ m, about 40 ⁇ m-400 ⁇ m, about 40 ⁇ m-350 ⁇ m, about 40 ⁇ m-300 ⁇ m, about 40 ⁇ m-250 ⁇ m, about 40 ⁇ m- 200
- the form has a d90 of about 10 ⁇ m-500 ⁇ m, for example about 40 ⁇ m-500 ⁇ m, or about 100 ⁇ m-500 ⁇ m.
- the compound of Formula I has a d50 of less than about 300 ⁇ m.
- the compound of Formula I has a d 50 of less than about 250 ⁇ m, about 200 ⁇ m, about 150 ⁇ m, about 100 ⁇ m, about 90 ⁇ m, about 80 ⁇ m, about 70 ⁇ m, about 60 ⁇ m, about 50 ⁇ m, about 40 ⁇ m, about 35 ⁇ m, about 30 ⁇ m, about 25 ⁇ m, about 20 ⁇ m, about 15 ⁇ m, about 10 ⁇ m, about 9 ⁇ m, about 8 ⁇ m, about 7 ⁇ m, about 6 ⁇ m, about 5 ⁇ m, about 4 ⁇ m, about 3 ⁇ m, about 2 ⁇ m, or about 1 ⁇ m.
- the compound of Formula I has a d 50 of about 0.1 ⁇ m- 300 ⁇ m. In some embodiments, the form has a d50 of about 1 ⁇ m-300 ⁇ m. In some embodiments, the compound of Formula I has a d 50 of about 10 ⁇ m-300 ⁇ m. In some embodiments, the form has a d50 of about 10 ⁇ m-2500 ⁇ m. [0053] In some embodiments, the compound of Formula I form has a d 10 of less than about 100 ⁇ m.
- the compound of Formula I has a d10 of less than 95 ⁇ m, 90 ⁇ m, 85 ⁇ m, 80 ⁇ m, 75 ⁇ m, 70 ⁇ m, 65 ⁇ m, 60 ⁇ m, 55 ⁇ m, 50 ⁇ m, 45 ⁇ m, 40 ⁇ m, 35 ⁇ m, 30 ⁇ m, 25 ⁇ m, 20 ⁇ m, 15 ⁇ m, 10 ⁇ m, 9 ⁇ m, 8 ⁇ m, 7 ⁇ m, 6 ⁇ m, 5 ⁇ m, 4 ⁇ m, 3 ⁇ m, 2 ⁇ m, or 1 ⁇ m, 0.5 ⁇ m, 0.4 ⁇ m, 0.3 ⁇ m, 0.2 ⁇ m, or 0.1 ⁇ m.
- the form has a d 10 of about 0.1 ⁇ m-90 ⁇ m, for example, about 1 ⁇ m-90 ⁇ m, 1 ⁇ m-80 ⁇ m, 1 ⁇ m-70 ⁇ m, 1 ⁇ m-60 ⁇ m, 1 ⁇ m-50 ⁇ m, 1 ⁇ m-40 ⁇ m, 1 ⁇ m-30 ⁇ m, about 1 ⁇ m-20 ⁇ m, 1 ⁇ m-15 ⁇ m, 1 ⁇ m-10 ⁇ m, 1 ⁇ m-9 ⁇ m, 1 ⁇ m-8 ⁇ m, 1 ⁇ m-7 ⁇ m, 1 ⁇ m-6 ⁇ m, 1 ⁇ m-5 ⁇ m, 1 ⁇ m-4 ⁇ m, 1 ⁇ m-3 ⁇ m, 1 ⁇ m-2 ⁇ m, 0.1 ⁇ m-15 ⁇ m, 0.1 ⁇ m-10 ⁇ m, 0.1 ⁇ m-9 ⁇ m, 0.1 ⁇ m-8 ⁇ m, 0.1 ⁇ m-7 ⁇ m, 0.1 ⁇ m-6 ⁇ m,
- the form has a d10 of about 1 ⁇ m-60 ⁇ m.
- the compound of Formula I is micronized. 35648-0320WO11455-WO-PCT ⁇ Lubricant [0055]
- lubricants that can be used in the solid oral dosage forms disclosed herein include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide, carnauba wax, polyethylene glycol, and talc powder.
- the lubricant is selected from the group consisting of stearic acid, sodium stearyl fumarate, magnesium stearate, and combinations thereof. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. [0056]
- the amount of lubricant in the solid oral dosage forms disclosed herein is generally between about 0.5 to about 5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 4.5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 4.0% by weight.
- the amount of lubricant is about 0.5 to about 3.5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 3.0% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 2.5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 2.0% by weight. In some embodiments, the amount of lubricant is about 0.5% by weight. In some embodiments, the amount of lubricant is about 1.0% by weight. In some embodiments, the amount of lubricant is about 1.5% by weight. In some embodiments, the amount of lubricant is about 2% by weight. In some embodiments, the amount of lubricant is about 2.5% by weight.
- the amount of lubricant is about 3.0% by weight. In some embodiments, the amount of lubricant is about 3.5% by weight. In some embodiments, the amount of lubricant is about 4.0% by weight. In some embodiments, the amount of lubricant is about 4.5% by weight. In some embodiments, the amount of lubricant is about 5.0% by weight. In some embodiments, the amount of lubricant in a tablet is about 1.0% to about 1.5% by weight. In some embodiments, the amount of lubricant in a tablet is about 1.0% by weight. In some embodiments, the amount of lubricant in a tablet is about 1.5% by weight.
- the solid oral dosage form comprises less than about 100 mg of lubricant.
- the solid oral dosage form comprises about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, or less than about 10 mg of lubricant.
- the solid oral dosage form comprises about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 35648-0320WO11455-WO-PCT ⁇ 1 mg to about 80 mg, about 1 mg to about 70 mg of lubricant, or about 1 mg to about 60 mg of lubricant.
- the solid oral dosage form comprises about 1 mg to about 50 mg of lubricant, about 1 mg to about 40 mg, 1 mg to about 30 mg, 1 mg to about 20 mg, or about 1 mg to about 10 mg of lubricant.
- the tablet comprises about 1 mg to about 20 mg lubricant.
- the solid oral dosage forms disclosed herein comprise magnesium stearate.
- the amount of magnesium stearate in a solid oral dosage form is about 1.0% to about 1.5% by weight.
- the amount of magnesium stearate in a solid oral dosage form is about 1.0% by weight.
- the amount of magnesium stearate in a solid oral dosage form is about 1.5% by weight.
- the solid oral dosage form comprises less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, or less than about 10 mg magnesium stearate. In some embodiments, the solid oral dosage form comprises about 1 mg to about 50 mg lubricant, or about 1 mg to about 40 mg, 1 mg to about 30 mg, 1 mg to about 20 mg, or about 1 mg to about 10 mg of magnesium stearate. In some embodiments, the solid oral dosage form comprises about 1 mg to about 20 mg magnesium stearate. [0059] In some embodiments, the solid oral dosage form comprises 100 mg of the compound of Formula I and about 0.5 mg to about 5 mg of the lubricant.
- the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 0.5 mg to about 5 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 1 to about 4 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 3 mg of the lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet. [0060] In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 1.8 mg to about 18 mg of the lubricant.
- the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 5 mg to about 10 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 6 mg to about 8 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I 35648-0320WO11455-WO-PCT ⁇ and about 7 mg of the lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet. [0061] In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 2.5 mg to about 25 mg of the lubricant.
- the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 5 mg to about 15 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 1 to about 8 mg to about 12 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 10 mg of the lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet. [0062] In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 3.6 mg to about 36 mg of the lubricant.
- the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 10 mg to about 20 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 12 mg to about 16 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 14 mg of the lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet. [0063] In some embodiments, the solid oral dosage form comprises 175 mg of the compound of Formula I and about 0.5 mg to about 5 mg of the lubricant.
- the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 2 to about 4 mg of the lubricant. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 3.5 mg of the lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet.
- Disintegrating agent disintegrating agent
- disintegrating agents that can be used in the solid oral dosage forms described herein include, but are not limited to, starches, pre-gelatinized starch, hydroxypropyl starch, celluloses (e.g., microcrystalline cellulose and low substituted hydroxypropyl cellulose), cross-linked PVP (crospovidone), sodium starch glycolate, croscarmellose sodium, etc.
- the disintegrating agent is croscarmellose sodium.
- the disintegrating agent is starch.
- the disintegrating agent is pre-gelatinized 35648-0320WO11455-WO-PCT ⁇ starch.
- the disintegrating agent is cellulose.
- the disintegrating agent is microcrystalline cellulose. In some embodiments, the disintegrating agent is low substituted hydroxypropyl cellulose. In some embodiments, the disintegrating agent is cross-linked PVP (crospovidone). In some embodiments, the disintegrating agent is sodium starch glycolate. In some embodiments, the disintegrating agent is croscarmellose sodium. [0065] In some embodiments, the lubricant is magnesium stearate and the disintegrating agent is crospovidone. [0066] In some embodiments, the disintegrating agent is polyplasdoneTM xl-10 crospovidone. [0067] In some embodiments, the amount of disintegrating agent in a solid oral dosage form is about 1% to about 10% by weight.
- the amount of disintegrating agent in a tablet is about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 10%, 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%, about 4% to about 9%,
- the amount of disintegrating agent in a solid oral dosage forms is about 3% to about 5% by weight.
- the solid oral dosage form comprises about 5 mg to about 200 mg of disintegrating agent.
- the solid oral dosage form comprises about 5 mg to about 190 mg, 5 mg to about 180 mg, 5 mg to about 170 mg, 5 mg to about 160 mg, 5 mg to about 150 mg, 5 mg to about 140 mg, 5 mg to about 130 mg, 5 mg to about 120 mg, 5 mg to about 110 mg, 5 mg to about 100 mg, 5 mg to about 90 mg, 5 mg to about 80 mg, 5 mg to about 70 mg, 5 mg to about 60 mg, 5 mg to about 50 mg, 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 20 mg to 35648-0320WO11455-WO-PC
- the solid oral dosage form comprises about 5 mg to about 50 mg of disintegrating agent. In some embodiments, the solid oral dosage form comprises about 40 mg to about 50 mg of disintegrating agent. [0069] In some embodiments, the disintegrating agent is crospovidone. In some embodiments, the amount of crospovidone in a solid oral dosage form is about 1% to about 10% by weight.
- the amount of crospovidone in a solid oral dosage form is about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 10%, 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 3% to about 5%, about 3% to about 4%, about 4% to about 10%, about 4% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4% to about 6%, about 4% to about 5%, about 5% to about 10%
- the amount of crospovidone in a solid oral dosage form is about 3% to about 5%.
- solid oral dosage form is a tablet.
- the solid oral dosage form comprises about 5 mg to about 50 mg of crospovidone.
- the solid oral dosage form comprises about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, or about 40 mg to about 50 mg of crospovidone.
- solid oral dosage form is a tablet.
- the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 1 to about 10 mg of the disintegrating agent.
- the solid oral dosage form comprises about 100 mg of the compound of Formula I 35648-0320WO11455-WO-PCT ⁇ and about 5 to about 10 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 8 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 1 to about 10 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 5 to about 10 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 8 mg of crospovidone. In some embodiments, solid oral dosage form is a tablet.
- the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 5 to about 50 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 25 to about 50 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 40 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 5 to about 50 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 25 to about 50 mg of crospovidone.
- the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 40 mg of crospovidone. In some embodiments, solid oral dosage form is a tablet. [0073] In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 3.5 to about 35 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 18 to about 35 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises 350 mg of the compound of Formula I and about 28 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 3.5 to about 35 mg of crospovidone.
- the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 18 to about 35 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 28 mg of crospovidone. In some embodiments, solid oral dosage form is a tablet. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 7 to about 70 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 700 mg 35648-0320WO11455-WO-PCT ⁇ of the compound of Formula I and about 36 to about 70 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises 700 mg of the compound of Formula I and about 56 mg of the disintegrating agent.
- the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 7 to about 70 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 36 to about 70 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 56 mg of crospovidone. In some embodiments, solid oral dosage form is a tablet. [0075] In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 2 to about 18 mg of the disintegrating agent. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 9 to about 18 mg of the disintegrating agent.
- the solid oral dosage form comprises 175 mg of the compound of Formula I and about 14 mg of the disintegrating agent. [0076] In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 2 to about 18 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 9 to about 18 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 14 mg of crospovidone. In some embodiments, solid oral dosage form is a tablet.
- fillers also known as bulking agents or diluents
- examples of fillers that can be used in the solid oral dosage forms disclosed herein include, but are not limited to, starches, maltodextrins, polyols (such as lactose), and celluloses.
- the filler is microcrystalline cellulose.
- the filler is lactose.
- the filler is mannitol.
- the filler is dicalcium phosphate.
- the amount of filler in a solid oral dosage form is about 20% to about 60% by weight.
- the amount of filler in a solid oral dosage form is about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 60% 35648-0320WO11455-WO-PCT ⁇ by weight, about 30% to about 50%, about 30% to about 40%, about 40% to about 60%, or about 40% to about 50% by weight. [0079] In some embodiments, the amount of filler in a solid oral dosage form is about 40% to about 50% by weight.
- the amount of filler in a solid oral dosage form is about 40% to about 48%, about 40% to about 46%, about 40% to about 44%, about 40% to about 42%, about 42% to about 50%, about 42% to about 48%, about 42% to about 46%, about 42% to about 44%, about 44% to about 50%, about 44% to about 48%, about 44% to about 46%, about 46% to about 50%, about 46% to about 48%, or about 48% to about 50%.
- the amount of filler in a solid oral dosage form is about 44% to about 46% by weight. [0080]
- the amount of filler in a solid oral dosage form is about 50 mg to about 1000 mg.
- the amount of filler in a solid oral dosage form is about 50 mg to about 950 mg, about 50 mg to about 900 mg, about 50 mg to about 850 mg, about 50 mg to about 800 mg, about 50 mg to about 750 mg, about 50 mg to about 700 mg, about 50 mg to about 650 mg, about 50 mg to about 600 mg, about 50 mg to about 550 mg, about 50 mg to about 500 mg, about 50 mg to about 450 mg, about 50 mg to about 400 mg, about 50 mg to about 350 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 500 mg, about 150 mg to about 450 mg, about 100 mg to about 400 mg,
- the amount of filler in a solid oral dosage form is about 50 mg to about 500 mg. 35648-0320WO11455-WO-PCT ⁇ [0081]
- the filler is microcrystalline cellulose.
- the amount of microcrystalline cellulose in a solid dosage form is about 40% to about 50% by weight.
- the amount of microcrystalline cellulose in a solid dosage form is about 40% to about 48%, about 40% to about 46%, about 40% to about 44%, about 40% to about 42%, about 42% to about 50%, about 42% to about 48%, about 42% to about 46%, about 42% to about 44%, about 44% to about 50%, about 44% to about 48%, about 44% to about 46%, about 46% to about 50%, about 46% to about 48%, or about 48% to about 50%.
- the amount of microcrystalline cellulose in a solid dosage form is about 44% to about 46% by weight. [0082]
- the amount of microcrystalline cellulose in a solid dosage form is about 50 mg to about 1000 mg.
- the amount of microcrystalline cellulose in a solid dosage form is about 50 mg to about 950 mg, about 50 mg to about 900 mg, about 50 mg to about 850 mg, about 50 mg to about 800 mg, about 50 mg to about 750 mg, about 50 mg to about 700 mg, about 50 mg to about 650 mg, about 50 mg to about 600 mg, about 50 mg to about 550 mg, about 50 mg to about 500 mg, 50 mg to about 450 mg, about 50 mg to about 400 mg, about 50 mg to about 350 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 500 mg, about 150 mg to about 450 mg, about 100 mg to about 400 mg,
- the amount of microcrystalline cellulose in a solid dosage form is about 50 mg to about 500 mg.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 40 mg to about 120 mg of the filler.
- the solid dosage 35648-0320WO11455-WO-PCT ⁇ form comprises about 100 mg of the compound of Formula I and about 80 mg to about 100 mg of the filler.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 85 mg to about 95 mg of the filler.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 89 mg of the filler.
- the solid dosage form is a tablet.
- the solid dosage form comprises about 500 mg of the compound of Formula I and about 200 mg to about 600 mg of the filler. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 400 mg to about 500 mg of the filler. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 425 mg to about 475 mg of the filler. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 450 mg of the filler. In some embodiments, the solid dosage form is a tablet. [0085] In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 140 mg to about 420 mg of the filler.
- the solid dosage form comprises about 350 mg of the compound of Formula I and about 280 mg to about 350 mg of the filler. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 298 mg to about 333 mg of the filler. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 315 mg of the filler. In some embodiments, the solid dosage form is a tablet. [0086] In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 70 mg to about 210 mg of the filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 140 mg to about 175 mg of the filler.
- the solid dosage form comprises about 175 mg of the compound of Formula I and about 149 mg to about 167 mg of the filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 157.5 mg of the filler. In some embodiments, the solid dosage form is a tablet. [0087] In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 280 mg to about 840 mg of the filler. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 560 mg to about 700 mg of the filler. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 600 mg to about 670 mg of the filler.
- the solid dosage form comprises about 700 mg of the compound of Formula I and about 630 mg of the filler.
- the solid dosage form is a tablet.
- the filler is microcrystalline cellulose.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 40 mg to about 120 mg of microcrystalline cellulose.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 80 mg to about 100 mg of microcrystalline cellulose.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 85 mg to about 95 mg of microcrystalline cellulose.
- the solid dosage form comprises about 100 mg of the compound of Formula I and about 89 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet. [0089] In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 200 mg to about 600 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 400 mg to about 500 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 425 mg to about 475 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 450 mg of microcrystalline cellulose.
- the solid dosage form is a tablet. [0090] In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 140 mg to about 420 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 280 mg to about 350 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 298 mg to about 333 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 315 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.
- the solid dosage form comprises about 700 mg of the compound of Formula I and about 280 mg to about 840 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 560 mg to about 700 mg of microcrystalline cellulose. In some embodiments, the solid dosage form 35648-0320WO11455-WO-PCT ⁇ comprises about 700 mg of the compound of Formula I and about 600 mg to about 670 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 630 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.
- the solid dosage form comprises about 175 mg of the compound of Formula I and about 70 mg to about 210 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 140 mg to about 175 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 150 mg to about 168 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 149 mg to about 167 mg of the filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 157.5 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.
- solid dosage forms (e.g. tablets) provided herein are uncoated.
- solid dosage forms (e.g. tablets) provided herein are coated (in which case they include a coating).
- uncoated solid dosage forms e.g. tablets
- Film coatings can be composed of hydrophilic polymer materials, but are not limited to, polysaccharide materials, such as hydroxypropylmethyl cellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinylalcohol-co-ethylene glycol) and other water soluble polymers.
- HPMC hydroxypropylmethyl cellulose
- HEC hydroxyethyl cellulose
- HPC hydroxypropyl cellulose
- poly(vinylalcohol-co-ethylene glycol) other water soluble polymers.
- the water soluble material included in the film coating of the embodiments disclosed herein comprises a single polymer material, in certain other embodiments it is formed using a mixture of more than one polymer.
- the coating is yellow or purple.
- Suitable coatings include, but are not limited to, polymeric film coatings such as those comprising polyvinyl alcohol e.g.
- ‘Opadry® II’ (which comprises part-hydrolysed PVA, titanium dioxide, macrogol 3350 (PEG) and talc, with optional coloring such as iron oxide (e.g., iron oxide red or iron oxide black) or indigo carmine or iron oxide yellow or FD&C yellow #6) and Opadry® QX (which comprises polyethylene 35648-0320WO11455-WO-PCT ⁇ glycol/macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl mono and dicaprylocaprate (glyceryl monocaprylocaprate type I), polyvinyl alcohol, and with optional coloring such as iron oxide (e.g., iron oxide red or iron oxide black) or indigo carmine or iron oxide yellow or FD&C yellow #6).
- iron oxide e.g., iron oxide red or iron oxide black
- Opadry® QX which comprises polyethylene 35648-
- the film coating is Opadry® II purple or yellow. In some embodiments, the film coating is Opadry® QX yellow. The amount of coating is generally between about 2-4% of the tablet core weight. In some embodiments, the amount of the coating is about 3% by weight (based on the tablet core weight). [0095] In some embodiments, the film coating is white. In some embodiments, the coating is Opadry® QX white. The amount of coating is generally between about 2-4% of the tablet core weight. In some embodiments, the amount of the coating is about 3% by weight (based on the tablet core weight). [0096] In some embodiments, the film coating does not comprise TiO 2 . In some embodiments, the film coating comprises CaCO3.
- the film coating comprises a TiO2 free variant of Opadry®.
- a reference to % weight is calculated with respect to the tablet core weight.
- the “tablet core weight” as calculated herein is the sum total of (i) the compound of Formula I, (ii) the filler, (iii) the disintegrating agent, and (iv) the lubricant.
- the core tablet weight does not include the weight of the film coating.
- the “tablet weight” as calculated herein is the sum total of (i) the compound of Formula I, (ii) the filler, (iii) the disintegrating agent, (iv) the lubricant, and (v) the film coating.
- the solid dosage form comprises: In redient %w/w 35648-0320WO11455-WO-PCT ⁇ Film Coat 3% [0101]
- omprising Ingredient %w/w
- te so osage orm comprses Ingredient %w/w
- the solid dosage form is a tablet comprising: Ingredient %w/w [0104]
- e so osage o co p ses Ingredient %w/w Amount (mg)
- the solid oral dosage form is a tablet comprising: Ingredient %w/w Amount (mg) [0106] In some embo diments, the solid dosage form comprises: Ingredient %w/w Amount (mg) 35648-0320WO11455-WO-PCT ⁇ [0107] In some embodiments, the solid dosage form is a tablet comprising: Ingredient %w/w Amount (mg) [0108] In some embodiments, the solid dosage form is a tablet comprising: Ingredient %w/w Amount (mg) 35648-0320WO11455-WO-PCT ⁇ [0109] In some embodiments, the solid dosage form comprises: Ingredient %w/w Amount (mg) [0110] In some embodiments, the solid dosage form comprises: Ingredient %w/w Amount (mg) 35648-0320WO11455-WO-PCT ⁇ [0111] In some embodiments, the solid oral dosage form is a tablet comprising: Ingredient %w/w Amount (mg) [0
- the tablet comprises: Ingredient %w/w Amount (mg)
- the tablet comprises: Ingredient %w/w Amount (mg) [0121] In some embodiments, the tablet comprises: Ingredient %w/w Amount (mg) 35648-0320WO11455-WO-PCT ⁇ Extragranular [0122] In some embodiments, the tablet comprises: Ingredient %w/w Amount (mg) 35648-0320WO11455-WO-PCT ⁇ [0123] In some embodiments, the tablet comprises: Ingredient %w/w Amount (mg) [0124] In some embodiments, the tablet comprises: Ingredient %w/w Amount (mg) 35648-0320WO11455-WO-PCT ⁇ Lubricant (magnesium stearate) 0.5% 1.75 mg [0125] In some , g p g the compound of Formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and a film coat.
- the solid dosage form comprises 175 mg of the compound of Formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry® QX White. [0126] In some embodiments, the solid dosage form comprises 350 mg of the compound of Formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and a film coat. In some embodiments, the solid dosage form comprises 350 mg of the compound of Formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry® QX Yellow.
- compositions and tablets [0127]
- the application also provides pharmaceutical compositions, in particular tablets, that comprise a compound expressed by formula I or a pharmaceutically acceptable salt thereof in which the compound of Formula I is present in an amount of about 40 wt% to 70 wt%.
- the compound is present in an amount of about 45 wt% to about 70 wt%.
- the compound is present in an amount of about 45 wt% to about 55 wt%.
- the compound is present in an amount of about 50 wt%.
- the application also provides pharmaceutical compositions, in particular tablets, that comprise a compound expressed by formula I or a pharmaceutically acceptable salt thereof in which the drug loading of the compound of Formula I in the pharmaceutical composition (e.g., tablet) is greater than 40%.
- the drug loading of the compound of Formula I in the pharmaceutical composition or tablet is equal to or less than 70%.
- the drug loading of the compound of Formula I in the pharmaceutical composition or tablet is greater than 40% and equal to or less than 70%.
- the drug loading of the compound of Formula I in the pharmaceutical composition or tablet is equal to or greater than 45% and equal to or less than 70%.
- the drug loading of the compound of 35648-0320WO11455-WO-PCT ⁇ Formula I in the pharmaceutical composition or tablet is greater than 45%. In certain embodiments, the drug loading of the compound of Formula I in the pharmaceutical composition or tablet is equal to or less than 55%. In certain embodiments, the drug loading of the compound of Formula I in the pharmaceutical composition or tablet is equal to or greater than 45% and equal to or less than 55%. In certain embodiments, the drug loading of the compound of Formula I in the pharmaceutical composition or tablet is about 50%. [0129] In certain embodiments, the compound is the freebase form of the compound of Formula I.
- the compound is the crystalline freebase form characterized by an X-ray powder diffraction (XRPD) pattern comprising degree 2 ⁇ -reflections (+/- 0.2 degrees 2 ⁇ ) at 9.8°, 16.0°, and 25.4°.
- the pharmaceutical composition or tablet may further comprise a filler.
- the filler is present in an amount of about 20 to about 60 wt%. In certain embodiments, the filler is present in an amount of about 40 to about 50 wt%. In certain embodiments, the filler is present in an amount of about 44 to about 46 wt%.
- the filler is microcrystalline cellulose.
- the pharmaceutical composition comprises microcrystalline cellulose in an amount of about 20 to about 60 wt%. In certain embodiments, the microcrystalline cellulose is present in an amount of about 40 to about 50 wt%. In certain embodiments, the microcrystalline cellulose is present in an amount of about 44 to about 46 wt%. [0132] In certain embodiments, the pharmaceutical composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to 70 wt% and microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%.
- the pharmaceutical composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 45 wt% to 70 wt% and microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%.
- the pharmaceutical composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 45 wt% to 55 wt% and microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%.
- the pharmaceutical composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to 70 wt% and microcrystalline cellulose in an amount of about 40 wt% to about 50 wt%.
- the pharmaceutical composition comprises the compound of Formula I or a pharmaceutically 35648-0320WO11455-WO-PCT ⁇ acceptable salt thereof in an amount of about 45 wt% to 55 wt% and microcrystalline cellulose in an amount of about 40 wt% to about 50 wt%.
- the pharmaceutical composition or tablet may further comprise a disintegrating agent.
- the disintegrating agent is present in an amount of about 1 wt% to about 10 wt%.
- the disintegrating agent is present in an amount of about 3 wt% to about 5 wt%.
- the disintegrating agent is crospovidone.
- the pharmaceutical composition comprises crospovidone in an amount of about 1 wt% to about 10 wt%. In certain embodiments, the pharmaceutical composition comprises crospovidone in an amount of about 3 wt% to about 5 wt%.
- the pharmaceutical composition or tablet may further comprise a lubricant. In certain embodiments, the lubricant is present in an amount of about 0.5 wt% to about 5 wt%. In certain embodiments, the lubricant is present in an amount of about 0.5 wt% to about 2 wt%. [0136] In certain embodiments, the lubricant is magnesium stearate.
- the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5 wt% to about 5 wt%. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5 wt% to about 2 wt%.
- the pharmaceutical composition or tablet may comprise the compound of Formula I or a pharmaceutically acceptable salt thereof, a filler, a disintegrating agent and a lubricant.
- the filler is microcrystalline cellulose and the disintegrating agent is crospovidone.
- the filler is microcrystalline cellulose and the lubricant is magnesium stearate.
- the disintegrating agent is crospovidone and the lubricant is magnesium stearate.
- the filler is microcrystalline cellulose
- the disintegrating agent is crospovidone and the lubricant is magnesium stearate.
- the compound is the freebase form of the compound of Formula I
- the filler is microcrystalline cellulose
- the disintegrating agent is crospovidone
- the lubricant is magnesium stearate.
- the pharmaceutical composition or tablet may comprise (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in 35648-0320WO11455-WO-PCT ⁇ an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical composition or tablet may comprise (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 45 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical composition or tablet may comprise (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 45 wt% to about 55 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical composition or tablet may comprise (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 50 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical composition or tablet comprises (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 40 wt% to about 50 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical composition or tablet may comprise (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 44 wt% to about 66 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical composition or tablet comprises (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in an amount of about 3 wt% to about 5 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.
- the pharmaceutical 35648-0320WO11455-WO-PCT ⁇ composition or tablet may comprise (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 2 wt%.
- the pharmaceutical composition or tablet is manufactured by dry granulation. In certain embodiments, the dry granulation is carried out using a roller compaction process.
- a single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In certain embodiments, a single dose can be administered once every week.
- a single dose can also be administered once every month.
- a compound described herein is administered once daily in a method described herein.
- a compound described herein is administered twice daily in a method described herein.
- a compound described herein is administered three times daily in a method described herein.
- the pharmaceutical formulations, for example a solid dosage form (e.g., tablet) described herein comprises 350 mg of the compound of Formula I and is administered twice daily.
- the pharmaceutical formulations, for example a solid dosage form (e.g., tablet) described herein comprises 700 mg of the compound of Formula I and is administered once daily.
- the pharmaceutical formulations for example a solid dosage form (e.g., tablet) described herein comprises 500 mg of the compound of Formula I and is administered once daily. In some embodiments, the pharmaceutical formulations, for example a solid dosage form (e.g., tablet) described herein comprises 175 mg of the compound of Formula I and is administered twice daily. 35648-0320WO11455-WO-PCT ⁇ [0145] In some embodiments, the pharmaceutical formulations, for example a solid dosage form (e.g. tablet) described herein comprises 175 mg of the compound of Formula I and is administered twice daily on day one and then once daily on days 2, 3, 4, and 5. In some embodiments, the pharmaceutical formulations, for example a solid dosage form (e.g.
- the tablet) described herein comprises 350 mg of the compound of Formula I and is administered one daily for day 1, 2, 3, 4, and 5.
- the pharmaceutical formulations described herein are administered to a patient, wherein the patient has mild kidney impairment, moderate kidney impairment, or severe kidney impairment.
- the patient has mild kidney impairment, and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered twice daily.
- the patient has mild kidney impairment, and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered twice daily for five days.
- the patient has moderate kidney impairment, and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily.
- the patient has moderate kidney impairment, and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily for five days.
- the patient has severe kidney impairment, and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily.
- the patient has severe kidney impairment, and the pharmaceutical formulation comprises 175 mg of the compound of Formula I and is administered once daily.
- the patient has severe kidney impairment, and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily for one day.
- the patient has severe kidney impairment, and the pharmaceutical formulation comprises 175 mg of the compound of Formula I and is administered once daily for four days.
- a tablet can be made by compression or molding, optionally with one or more excipients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients.
- the pharmaceutical composition or tablet is manufactured using a method comprising dry granulation.
- the dry granulation may be carried out by roller compaction.
- the dry granulation may be performed on a blend of the compound of Formula I, the filler, the disintegrating agent and the lubricant.
- the composition comprises microcrystalline cellulose as a filler, crospovidone as a disintegrating agent and magnesium stearate as a lubricant.
- the manufacturing method includes the following steps: 1. blend the compound of Formula I, filler and disintegrating agent; 2. add lubricant and blend; and 3. dry granulate the resulting blend.
- Also provided herein is a method of manufacturing a tablet comprising: 1.
- the method comprises mixing the drug substance with the excipients.
- the manufacturing process comprises co-blending and lubricating the compound of Formula I with intragranular excipients.
- the method further comprises roller compaction and/or milling.
- the resulting Formula I granules are 35648-0320WO11455-WO-PCT ⁇ then blended with extragranular excipients. The resulting mixture is then compressed into core tablets.
- the tablets are further coated with a film coat.
- An exemplary manufacturing process is shown in Figure 1.
- the pharmaceutical formulations, for e.g. the solid oral dosage forms (e.g. tablets) disclosed herein are used for treatment of viral infections.
- the solid oral dosage forms (e.g. tablets) disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of viral infections.
- PrEP pre-exposure prophylaxis
- methods for treating a viral infection in a subject comprising administering a solid oral dosage form disclosed herein to the subject.
- a solid oral dosage form is provided for use in such treatment methods.
- a solid oral dosage form in the manufacture of an oral dosage form disclosed herein for treatment of viral infections.
- the solid oral dosage forms disclosed herein are used for pre- exposure prophylaxis (PrEP) to reduce the risk viral infections.
- PrEP pre-expo prophylaxis
- methods for preventing infection in a subject at risk of infection comprising administering a solid oral dosage form disclosed herein to the subject.
- a solid oral dosage form disclosed herein is provided for use in such treatment methods.
- the invention also provides the use of a solid oral dosage form in the manufacture of an oral dosage form disclosed herein for prevention of viral infection in a subject at risk for infection.
- the methods involve administering a solid oral dosage form disclosed herein to the subject, typically a human, and will generally involve repeated administrations, typically once daily or twice. In some embodiments, the administration is once daily. In some embodiments, the administration is twice daily.
- the treatment may be prophylactic or therapeutic treatment.
- the viral infection is a paramyxoviridae virus infection.
- the present disclosure provides methods for treating a paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a solid oral dosage form (in particular a tablet) disclosed herein.
- Paramyxoviridae viruses include, but are not limited to Nipah virus, Hendra virus, measles, mumps, and parainfluenze virus. 35648-0320WO11455-WO-PCT ⁇
- the viral infection is a human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.
- the viral infection is a pneumoviridae virus infection.
- the present disclosure provides a method of treating a pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (in particular a tablet) provided herein.
- Pneumoviridae viruses include, but are not limited to, respiratory snycytial virus and human metapneumovirus.
- the pneumoviridae virus infection is a respiratory syncytial virus infection.
- the pneumoviridae virus infection is human metapneumovirus infection.
- the present disclosure provides a solid oral dosage form (in particular a tablet) disclosed herein, for use in the treatment of a pneumoviridae virus infection in a human in need thereof.
- the pneumoviridae virus infection is a respiratory syncytial virus infection.
- the pneumoviridae virus infection is human metapneumovirus infection.
- the present disclosure provides methods for treating a RSV infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (in particular a tablet) provided herein.
- the human is suffering from a chronic respiratory syncytial viral infection.
- the human is acutely infected with RSV.
- a method of inhibiting RSV replication is provided, wherein the method comprises administering to a human in need thereof, a solid oral dosage form (in particular a tablet) disclosed herein, wherein the administration is by inhalation.
- the present disclosure provides a method for reducing the viral load associated with RSV infection, wherein the method comprises administering to a human infected with RSV a solid oral dosage form (in particular a tablet) disclosed herein.
- the viral infection is a picornaviridae virus infection.
- the present disclosure provides a method of treating a picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (in particular a tablet) of the present disclosure.
- Picornaviridae viruses are eneteroviruses causing a heterogeneous group of infections including herpangina, aseptic 35648-0320WO11455-WO-PCT ⁇ meningitis, a common-cold-like syndrome (human rhinovirus infection), a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot-mouth syndrome, pediatric and adult pancreatitis and serious myocarditis.
- the Picornaviridae virus infection is human rhinovirus infection (HRV).
- the Picornaviridae virus infection is HRV-A, HRV-B, or HRV-C infection.
- the viral infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.
- the present disclosure provides a solid oral dosage form (in particular a tablet), for use in the treatment of a picornaviridae virus infection in a human in need thereof.
- the picornaviridae virus infection is human rhinovirus infection.
- the viral infection is a flaviviridae virus infection.
- the present disclosure provides a method of treating a flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (in particular a tablet) described herein.
- Representative flaviviridae viruses include, but are not limited to, dengue, Yellow fever, West Nile, Zika, Japanese encephalitis virus, and Hepatitis C (HCV).
- the flaviviridae virus infection is a dengue virus infection.
- the flaviviridae virus infection is a yellow fever virus infection.
- the flaviviridae virus infection is a West Nile virus infection.
- the flaviviridae virus infection is a zika virus infection. In some embodiments, the flaviviridae virus infection is a Japanese ensephalitis virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection. [0172] In some embodiments, the flaviviridae virus infection is a dengue virus infection, yellow fever virus infection, West Nile virus infection, tick borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, zika virus infection, or a HCV infection.
- the present disclosure provides use of a solid oral dosage form (in particular a tablet) disclosed herein for treatment of a flaviviridae virus infection in a human in need thereof.
- the flaviviridae virus infection is a dengue virus infection. 35648-0320WO11455-WO-PCT ⁇
- the flaviviridae virus infection is a yellow fever virus infection.
- the flaviviridae virus infection is a West Nile virus infection.
- the flaviviridae virus infection is a zika virus infection.
- the flaviviridae virus infection is a hepatitis C virus infection.
- the viral infection is a filoviridae virus infection.
- a method of treating a filoviridae virus infection in a human in need thereof comprising administering to the human a solid oral dosage form (in particular a tablet) disclosed herein.
- Representative filoviridae viruses include, but are not limited to, ebola (variants Zaire, Bundibugio, Sudan, Tai forest, or Reston) and marburg.
- the filoviridae virus infection is an ebola virus infection.
- the filoviridae virus infection is a marburg virus infection.
- the present disclosure provides a solid oral dosage form (in particular a tablet) for use in the treatment of a filoviridae virus infection in a human in need thereof.
- the filoviridae virus infection is an ebola virus infection.
- the filoviridae virus infection is a marburg virus infection.
- the viral infection is a coronavirus infection.
- provided herein is a method of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering to the human a solid oral dosage form (in particular a tablet) provided herein.
- the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS-CoV) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections.
- the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection.
- the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection.
- the viral infection is SARS- CoV-2 infection.
- the viral infection is a zoonotic coronavirus infection
- the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.
- the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.
- the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.
- the viral infection is caused by a variant of SARS-CoV-2, for example by the B.1.1.7 variant (the UK variant), B.1.351 variant (the South African variant), P.1 variant (the Brazil variant), B.1.1.7 with E484K variant, B.1.1.207 variant, B.1.1.317 variant, B.1.1.318 variant, B.1.429 variant, B.1.525 variant, or P.3 variant.
- the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2.
- the viral infection is caused by the B.1.351 variant of SARS-CoV-2.
- the viral infection is caused by the P.1 variant of SARS-CoV-2.
- the present disclosure provides a solid oral dosage form (in particular a tablet) for use in the treatment of a coronavirus virus infection in a human in need thereof.
- the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, and zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections.
- the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection.
- the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection.
- the viral infection is SARS-CoV-2 infection (COVID19).
- the viral infection is an arenaviridae virus infection.
- the disclosure provides a method of treating an arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (in particular a tablet) disclosed herein.
- the arenaviridae virus infection is a Lassa infection or a Junin infection.
- the present disclosure provides a compound for use in the treatment of an arenaviridae virus infection in a human in need thereof.
- the arenaviridae virus infection is a Lassa infection or a Junin infection. 35648-0320WO11455-WO-PCT ⁇
- the viral infection is an orthomyxovirus infection, for example, an influenza virus infection.
- the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.
- the solid oral dosage form (in particular a tablet) described herein can be administered with one or more additional therapeutic agent(s) to an individual (e.g., a human) infected with a viral infection.
- the additional therapeutic agent(s) can be administered to the infected individual at the same time as the compound of the present disclosure or before or after administration of the compound of the present disclosure.
- COMBINATION THERAPY [0183]
- the pharmaceutical formulation for example the solid oral dosage forms described herein, can also be used in combination with one or more additional therapeutic agents.
- the methods comprise administering to the subject a solid oral dosage form disclosed therein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.
- the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.
- the additional therapeutic agent a 2,5-Oligoadenylate synthetase stimulator, 5-HT 2a receptor antagonist, 5-Lipoxygenase inhibitor, ABL family tyrosine kinase inhibitor, Abl tyrosine kinase inhibitor, Acetaldehyde dehydrogenase inhibitor, Acetyl CoA carboxylase inhibitor, Actin antagonist, Actin modulator, Activity-dependent neuroprotector modulator, Adenosine A3 receptor agonist, Adrenergic receptor antagonist, Adrenomedullin ligand, Adrenomedullin ligand inhibitor, Advanced glycosylation product receptor antagonist, Advanced glycosylation product receptor modulator, AKT protein kinase inhibitor, Alanine proline rich secreted protein stimulator, Aldose reductase inhibitor, Alkaline phosphatase stimulator, Alpha 2 adrenoceptor antagonist, Alpha 2B adrenoceptor agonist, AMP activated protein kin
- the solid oral dosage forms of the present disclosure may be administered in combination with a Sars-Cov-2 treatment, such as parenteral fluids (including dextrose saline and Ringer’s lactate), nutrition, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, R-327 and cephalosporin antibiotics, such as ceftriaxone and cefuroxime), antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin K, vitamin D, cholecalciferol, vitamin C and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as dexamethasone, methylprednisolone, prednisone, mometas
- the additional therapeutic agent is an Abl tyrosine kinase inhibitor, such as radotinib or imatinib.
- the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629.
- the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.
- the additional therapeutic agent is an adrenomedullin ligand such as adrenomedullin.
- the additional therapeutic agent is a p38 MAPK + PPAR gamma agonist/insulin sensitizer such as KIN-001.
- the additional therapeutic agent is a PPAR alpha agonist such as DWTC-5101 (fenofibrate choline). 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a cyclophilin inhibitor such as rencofilstat.
- the additional therapeutic is a p38 MAP kinase inhibitor such as PRX-201 or Gen-1124.
- the additional therapeutic agent is an aldose reductase inhibitor, such as caficrestat.
- the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.
- the additional therapeutic agent is an annexin A5 stimulator, such as AP-01 or SY-005.
- the additional therapeutic agent is an apelin receptor agonist, such as CB-5064MM.
- the additional therapeutic agent is an anti-coagulant, such as heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux.
- the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide, or pruxelutamide (proxalutamide).
- the additional therapeutic agent is anti-hypoxic, such as trans- sodium crocetinate.
- the additional therapeutic agent is an anti-thrombotic, such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.
- the additional therapeutic agent is an antihistamine, such as cloroperastine or clemastine.
- the additional therapeutic agent is an apolipoprotein A1 agonist, such as CER-001.
- the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapent ethyl.
- the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as bemcentinib.
- the additional therapeutic agent is a corticosteroid/beta 2 adrenoceptor agonist, such as budesonide + formoterol fumarate.
- the additional therapeutic agent is a BET bromodomain inhibitor/APOA1 gene stimulator such as apabetalone.
- the additional therapeutic agent is a blood clotting modulator, such as lanadelumab.
- the additional therapeutic agent is a bradykinin B2 receptor antagonist, such as icatibant.
- the additional therapeutic agent is an EGFR gene inhibitor/Btk tyrosine kinase inhibitor, such as abivertinib.
- the additional therapeutic agent is a Btk tyrosine kinase inhibitor, such as ibrutinib or zanubrutinib.
- the additional therapeutic agent is a calpain-I/II/IX inhibitor, such as BLD-2660.
- the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as onternabez or PPP-003.
- the additional therapeutic agent is a Ca2+ release activated Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).
- the additional therapeutic agent is an ATR inhibitor, such as berzosertib.
- the additional therapeutic agent is a cadherin-5 modulator, such as FX-06.
- the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.
- the additional therapeutic agent is a caspase inhibitor, such as emricasan.
- the additional therapeutic agent is a catalase stimulator/superoxide dismutase stimulator, such as MP-1032.
- the additional therapeutic agent is a CCR2 chemokine antagonist/ CCR5 chemokine antagonist such as cenicriviroc.
- the additional therapeutic agent is a CCR5 chemokine antagonist, such as maraviroc or leronlimab.
- the additional therapeutic agent is a CD122 agonist/IL-2 receptor agonist, such as bempegaldesleukin.
- the additional therapeutic agent is a CD73 agonist/interferon beta ligand, such as FP-1201.
- the additional therapeutic agent is a cholesterol ester transfer protein inhibitor, such as dalcetrapib.
- the additional therapeutic agent is a Mannan-binding lectin serine protease/complement C1s subcomponent inhibitor/myeloperoxidase inhibitor, such as RLS-0071.
- the additional therapeutic agent is a complement C5 factor inhibitor/ leukotriene BLT receptor antagonist, such as nomacopan.
- the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, STSA-1002, zilucoplan.
- the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motixafortide.
- the additional therapeutic agent is a cytochrome P450 3A4 inhibitor/ peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a cysteine protease inhibitor, such as SLV-213.
- the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, or emvododstat.
- the additional therapeutic agent is a dehydropeptidase-1 modulator, such as Metablok.
- the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor/IL-17 antagonist, such as vidofludimus.
- the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.
- the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.
- the additional therapeutic agent is a NET inhibitor, such as NTR- 441.
- the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor/sphingosine kinase 2 inhibitor, such as opaganib.
- the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azacytidine.
- the additional therapeutic agent is an LXR antagonist, such as larsucosterol.
- the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brensocatib.
- the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.
- the additional therapeutic agent is an elongation factor 1 alpha 2 modulator, such as plitidepsin. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a eukaryotic initiation factor 4A- I inhibitor, such as zotatifin.
- the additional therapeutic agent is an exo-alpha sialidase modulator, such as DAS-181.
- the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor.
- the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.
- the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor/IL-12 receptor antagonist/IL-23 antagonist, such as apilimod dimesylate.
- the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone.
- the additional therapeutic agent is a glucocorticoid receptor agonist, such as ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.
- the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim.
- the additional therapeutic agent is a GPCR agonist, such as esuberaprost sodium.
- the additional therapeutic agent is a Griffithsin modulator, such as Q-Griffithsin.
- the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.
- the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, levocetirizine dihydrochloride.
- the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.
- the additional therapeutic agent is a heat shock protein stimulator/insulin sensitizer/PARP inhibitor, such as BGP-15.
- the additional therapeutic agent is a histone inhibitor, such as STC- 3141.
- the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506.
- the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, such as desidustat.
- the additional therapeutic agent is an HIF prolyl hydroxylase inhibitor, such as vadadustat.
- the additional therapeutic agent is an IL-8 receptor antagonist, such as reparixin.
- the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.
- the additional therapeutic agent is an IL-7 receptor agonist/interleukin-7 ligand, such as efineptakin alfa.
- the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa.
- the additional therapeutic agent is an IL-22 agonist/interleukin 22 ligand, such as F-652.
- the additional therapeutic agent is targeted to IL-33, such as tozorakimab.
- the additional therapeutic is an IL-15 agonist such as nogapendekin alfa.
- the additional therapeutic agent is an integrin alpha-V/beta-1 antagonist/ integrin alpha-V/beta-6 antagonist, such as bexotegrast. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is an interferon alpha 2 ligand, such as interferon alfa-2b or Virafin.
- the additional therapeutic agent is an interferon beta ligand, such as interferon beta-1a follow-on biologic, interferon beta-1b, or SNG-001.
- the additional therapeutic agent is an interferon receptor modulator, such as peginterferon lambda-1a.
- the additional therapeutic agent is an interleukin-2 ligand, such as aldesleukin.
- the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as zimlovisertib.
- the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, jaktinib, tofacitinib, or nezulcitinib (TD- 0903).
- the additional therapeutic agent is a neutrophil elastase inhibitor, such as alvelestat.
- the additional therapeutic agent is a lung surfactant associated protein D modulator, such as AT-100.
- the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen.
- the additional therapeutic agent is a lysine specific histone demethylase 1/MAO B inhibitor, such as vafidemstat.
- the additional therapeutic agent is a Mannan-binding lectin serine protease inhibitor, such as conestat alfa.
- the additional therapeutic agent is a maxi K potassium channel inhibitor, such as ENA-001. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a MEK protein kinase inhibitor, such as zapnometinib.
- the additional therapeutic agent is a MEK-1 protein kinase inhibitor/Ras gene inhibitor, such as antroquinonol.
- the additional therapeutic agent is a melanocortin MC1 receptor agonist, such as PL-8177.
- the additional therapeutic agent is a melanocortin MC1/MC3 receptor agonist, such as resomelagon acetate.
- the additional therapeutic agent is a matrix metalloprotease-12 inhibitor, such as FP-025.
- the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.
- the additional therapeutic agent is a NADPH oxidase inhibitor, such as isuzinaxib.
- the additional therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.
- the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tradipitant.
- the additional therapeutic agent is an NMDA receptor antagonist, such as transcrocetin or ifenprodil.
- the additional therapeutic agent is a nuclear factor kappa B inhibitor/p38 MAP kinase inhibitor, such as zenuzolac.
- the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.
- the additional therapeutic agent is an opioid receptor sigma antagonist 1, such as MR-309. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a PGD2 antagonist, such as asapiprant.
- the additional therapeutic agent is a PDGF receptor antagonist/ TGF beta receptor antagonist/ p38 MAP kinase inhibitor, such as deupirfenidone.
- the additional therapeutic agent is a phospholipase A2 inhibitor, such as varespladib methyl.
- the additional therapeutic agent is a phosphoinositide 3-kinase inhibitor/ mTOR complex inhibitor, such as dactolisib.
- the additional therapeutic agent is a mTOR inhibitor, such as sirolimus.
- the additional therapeutic agent is a phosphoinositide-3 kinase delta/gamma inhibitor, such as duvelisib.
- the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such as TM-5614.
- the additional therapeutic agent is a protein tyrosine phosphatase beta inhibitor, such as razuprotafib.
- the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758 or SIR-0365.
- the additional therapeutic agent is a Rev protein modulator, such as obefazimod.
- the additional therapeutic agent is an S phase kinase associated protein 2 inhibitor, such as niclosamide, SCAI-502 or DWRX-2003.
- the additional therapeutic agent is a signal transducer CD24 stimulator, such as EXO-CD24.
- the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propanediol. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a sodium channel stimulator, such as solnatide.
- the additional therapeutic agent is a sphingosine-1-phosphate receptor-1 agonist/sphingosine-1-phosphate receptor-5 agonist, such as ozanimod.
- the additional therapeutic agent is a non-steroidal anti- inflammatory drug, such as Ampion.
- the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese.
- the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as fostamatinib disodium.
- the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.
- the additional therapeutic agent is a TGFB2 gene inhibitor, such as trabedersen.
- the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.
- the additional therapeutic agent is a TLR-3 agonist, such as rintatolimod.
- the additional therapeutic agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or eritoran.
- the additional therapeutic agent is a TLR-7/8 antagonist, such as enpatoran.
- the additional therapeutic agent is a TLR-2/6 agonist, such as INNA-051.
- the additional therapeutic agent is a TLR-7 agonist, such as PRTX- 007 or APR-002. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is a TLR agonist, such as PUL- 042.
- the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.
- the additional therapeutic agent is a TLR-2/4 antagonist, such as VB-201.
- the additional therapeutic agent is a TNF alpha ligand inhibitor, such as pegipanermin.
- the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra.
- the additional therapeutic agent is a TREM receptor 1 antagonist, such as nangibotide.
- the additional therapeutic agent is a trypsin inhibitor, such as ulinastatin.
- the additional therapeutic agent is a tubulin inhibitor such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole, entasobulin, SAR-132885, or ON- 24160.
- the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.
- the additional therapeutic agent is a xanthine oxidase inhibitor, such as oxypurinol.
- the additional therapeutic agent is a vasodilator, such as iloprost, epoprostenol (VentaProst), zavegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.
- the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.
- the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate.
- the additional therapeutic agent is a synthetic retinoid derivative, such as fenretinide.
- the additional therapeutic agent is a glucose metabolism inhibitor such as WP-1122 or WP-1096.
- the additional therapeutic agent is adalimumab, AT-H201, 2- deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, belapectin, bitespiramycin, bucillamine, budesonide, CNM-AgZn-17, Codivir, CT-38, danicopan, didodecyl methotrexate, DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazolyl ethanamide pentandioic acid, IMM-101, MAS-825, MRG- 001, Nasitrol, Nylexa, olverembatinib, OP-101, OPN-019, Orynotide rhesus theta defensin-1,
- the additional therapeutic agent is a CD73 antagonist, such as AK- 119. [0338] In some embodiments, the additional therapeutic agent is a CD95 protein fusion, such as asunercept. [0339] In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117. [0340] In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as AMY-101 or NGM-621. [0341] In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor, such as EB-06.
- the additional therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is an anti-S. Aureus antibody, such as tosatoxumab.
- the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.
- the additional therapeutic agent is an adrenomedullin ligand inhibitor, such as enibarcimab.
- the additional therapeutic agent is a basigin inhibitor, such as meplazumab.
- the additional therapeutic agent is a CD3 antagonist, such as foralumab.
- the additional therapeutic agent is a connective tissue growth factor ligand inhibitor, such as PRS-220, pamrevlumab.
- the additional therapeutic agent is a complement C5a factor inhibitor, such as BDB-1 or vilobelimab.
- the additional therapeutic agent is a complement C5 factor inhibitor, such as ravulizumab.
- the additional therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor, such as narsoplimab.
- the additional therapeutic agent is a GM-CSF modulator, such as STSA-1005, gimsilumab, namilumab, plonmarlimab, otilimab, or lenzilumab.
- the additional therapeutic agent is a heat shock protein inhibitor/IL- 6 receptor antagonist, such as siltuximab.
- the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, levilimab, olokizumab, tocilizumab, or sirukumab.
- the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253. 35648-0320WO11455-WO-PCT ⁇
- the additional therapeutic agent is an interleukin-1 beta ligand inhibitor, such as canakinumab.
- the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.
- the additional therapeutic agent is an anti-ILT7 antibody, such as daxdilimab.
- the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibuclimab.
- the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanadelumab.
- the additional therapeutic agent is a platelet glycoprotein VI inhibitor, such as glenzocimab.
- the additional therapeutic agent is a T-cell differentiation antigen CD6 inhibitor, such as itolizumab.
- the additional therapeutic agent is a TNF alpha ligand inhibitor/TNF binding agent, such as infliximab.
- the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.
- the additional therapeutic agent is IMC-2 (valacyclovir + celecoxib), or AXA-1125.
- the additional therapeutic agent is COVID-HIG.
- the solid dosage forms of the disclosure are co-administered with one or more agents useful for the treatment and/or prophylaxis of COVID-19.
- Non-limiting examples of such agents include corticosteroids, such as dexamethasone, hydrocortisone, methylprednisolone, or prednisone; interleukin-6 (IL-6) receptor blockers, such 35648-0320WO11455-WO-PCT ⁇ as tocilizumab or sarilumab; Janus kinase (JAK) inhibitors, such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents, such as molnupiravir, sotrovimab, or remdesivir.
- corticosteroids such as dexamethasone, hydrocortisone, methylprednisolone, or prednisone
- IL-6 receptor blockers such 35648-0320WO11455-WO-PCT ⁇ as tocilizumab or sarilumab
- Janus kinase (JAK) inhibitors such as bar
- the solid oral dosage forms of the disclosure are co-administered with two or more agents useful for the treatment of COVID-19.
- Agents useful for the treatment and/or prophylaxis of COVID-19 include but are not limited to nirmatrelvir and ritonavir, casirivimab and imdevimab, or ruxolitinib and tofacitinib.
- the additional therapeutic agent is an antiviral agent.
- the antiviral agent is an entry inhibitor.
- the antiviral agent is a protease inhibitor.
- the antiviral agent is an RNA polymerase inhibitor.
- the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.
- the antiviral agent is selected from angiotensin converting enzyme 2 inhibitors, angiotensin converting enzyme 2 modulators, angiotensin converting enzyme 2 stimulators, angiotensin II AT-2 receptor agonists, angiotensin II AT-2 receptor antagonists, angiotensin II receptor modulators, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, SARS-CoV-2 envelope small membrane protein inhibitors, SARS- CoV-2 envelope small membrane protein modulators, SARS-CoV-2 MPro inhibitors, SARS- CoV-2 non-structural protein 8 modulators, SARS-CoV-2 nucleoprotein inhibitors, SARS-CoV- 2 nucleoprotein modulators, SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replica
- SARS-CoV-2 replicas
- the additional therapeutic agent is an entry inhibitor.
- the additional therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.
- the additional therapeutic agent is an angiotensin converting enzyme 2 inhibitor, such as SBK-001.
- the additional therapeutic agent is an angiotensin converting enzyme 2 modulator, such as neumifil or JN-2019.
- the additional therapeutic agent is an entry inhibitor such as MU- UNMC-1.
- the additional therapeutic agent is an angiotensin converting enzyme 2 stimulator, such as alunacedase alfa.
- the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01.
- the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600.
- the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.
- the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201.
- the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.
- the additional therapeutic agent is a RNAi agent such as ARO- COV or SNS-812.
- the additional therapeutic agent is a vaccine.
- the additional therapeutic agent is a DNA vaccine, RNA vaccine, live-attenuated vaccine, inactivated vaccine (i.e., inactivated SARS-CoV-2 vaccine), therapeutic vaccine, 35648-0320WO11455-WO-PCT ⁇ prophylactic vaccine, protein-based vaccine, viral vector vaccine, cellular vaccine, or dendritic cell vaccine.
- the additional therapeutic agent is a vaccine such as tozinameran, NVX-CoV2373, elasomeran, KD-414, Ad26.COV2-S, Vaxzevria, SCB-2019, AKS-452, VLA- 2001, HDT-301, S-268019, MVC-COV1901, mRNA-1273.214, mRNA-1273.213, mRNA- 1273.222, NVX-CoV2515, Covaxin, BBIBP-CorV, GBP-510, mRNA-1273.351 + mRNA- 1273.617 (SARS-CoV-2 multivalent mRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNA vaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283, Omicron-based COVID-19 vaccine, SARS-CoV-2 Protein Subunit Recombin
- the additional therapeutic agent is a protease inhibitor.
- the additional therapeutic agent is a 3C-like cysteine protease inhibitor (3CLpro, also called Main protease, Mpro), a papain-like protease inhibitor (PLpro), serine protease inhibitor, or transmembrane serine protease 2 inhibitor (TMPRSS2).
- 3CLpro also called Main protease, Mpro
- PLpro papain-like protease inhibitor
- TMPRSS2 transmembrane serine protease 2 inhibitor
- the additional therapeutic agent is a 3CLpro/Mpro inhibitor, such as CDI-873, GC-373, GC-376, PBI-0451, UCI-1, bofutrelvir (FB-2001, DC-402234), DC- 402267, GDI-4405, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, 35648-0320WO11455-WO-PCT ⁇ nirmatrelvir, ensitrelvir, ASC-11, EDDC-2214, SIM-0417, CDI-45205, COR-803, ALG-097111, TJC-642, CVD-0013943, eravacycline, cynarine, or prexasertib.
- 3CLpro/Mpro inhibitor such as CDI-873, GC-373, GC-376, PBI-0451, UCI-1, bofutrelvir (FB-2001, DC-402234
- the additional therapeutic agent is a papain-like protease inhibitor (PLpro), such as SBFM-PL4 or GRL-0617.
- PLpro papain-like protease inhibitor
- the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor, such as EIS-4363.
- the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor, such as TO-507.
- the additional therapeutic agent is a SARS-CoV-2 spike (S) and protease modulator, such as ENU-200.
- the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.
- the additional therapeutic agent is a serine protease inhibitor, such as upamostat, nafamostat, camostat mesylate, nafamostat mesylate, or camostat.
- the additional therapeutic agent is a 3CLpro/transmembrane serine protease 2 inhibitor, such as SNB-01 (pentarlandir) or SNB-02.
- the additional therapeutic agent is a viral protease inhibitor, such as Pan-Corona, Cov-X, or bepridil.
- the additional therapeutic agent is an RNA polymerase inhibitor.
- the additional therapeutic agent is an RNA polymerase inhibitor, or an RNA-dependent RNA polymerase (RdRp) inhibitor.
- the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, GS-621763, DEP remdesivir, ATV-006, VV-116, LGN-20, CMX-521 and compounds disclosed in WO2022142477, WO2021213288, WO2022047065.
- RdRp RNA-dependent RNA polymerase
- the additional therapeutic agent is an RNA polymerase inhibitor, such as molnupiravir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir.
- the additional therapeutic agent is viral entry inhibitor, such as brilacidin.
- the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS.
- the additional therapeutic agent is an antibody, for example a monoclonal antibody.
- the additional therapeutic agent is an antibody against SARS- CoV-2, neutralizing nanobodies, antibodies that target the SARS-CoV-2 spike protein, fusion proteins, multispecific antibodies, and antibodies that can neutralize SARS-CoV-2 (SARS-CoV- 2 neutralizing antibodies).
- the additional therapeutic agent is an antibody that targets specific sites on ACE2.
- the additional therapeutic agent is a polypeptide targeting SARS-CoV-2 spike protein (S-protein).
- the additional therapeutic agent is a SARS-CoV-2 virus antibody.
- the antibody is ABBV-47D11, COVI-GUARD (STI-1499), C144- LS + C135-LS, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and/or sotrovimab (VIR-7831), casirivimab + imdevimab (REGN-COV2 or REGN10933 + RGN10987), BAT2020, BAT2019, 47D11, YBSW-015, or PA-001.
- the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167 or AR-701 (AR-703 and AR-720).
- the additional therapeutic agent is BRII-196, BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotrovimab (GSK-4182136), tixagevimab + cilgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01, plutavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, anti-SARS- CoV-2 IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibodies (COVI-AMG), 9MW-3311 (MW-33), D
- the additional therapeutic agent is an engineered ACE-2-IgG1-Fc- fusion protein targeting SARS-Cov-2 RBD, such as EU-129, bivalent ACE2-IgG Fc null fusion protein (SI-F019).
- the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.
- the additional therapeutic agent is ensovibep.
- the additional therapeutic agent is SYZJ-001.
- the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir.
- the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as elsulfavirine.
- the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azvudine.
- the additional therapeutic agent is Abbv-990, BAT-2022, NED- 260, ALG-097431, bardoxolone, delcetravir, ESFAM-289, ENOB-CV-01, ENOB-CV-11, EIS- 10700, beta-521, SIM-0417, molnupiravir, Pan-Corona, Tollovir, nirmatrelvir + ritonavir (Paxlovid®), favipiravir, GC-376, upamostat, LeSoleil-01, LeSoleil-02+, benfovir, VV-116, VV- 993, SNB-01, EDP-235, Cov-X, ensitrelvir, MPI-8, masitinib, ALG-097558, ASC-11, PBI
- Solid oral dosage forms disclosed herein with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
- the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
- Co-administration of a solid oral forms disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a the solid oral dosage form disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of Formula I and one or more other active therapeutic agents are both present in the body of the patient.
- Co-administration includes administration of unit dosages of the solid oral dosage forms disclosed herein before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the solid oral dosage forms disclosed herein within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
- a unit dose of a solid oral dosage forms disclosed herein can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
- a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of solid oral dosage forms disclosed herein within seconds or minutes.
- a unit dose of a solid oral dosage forms disclosed herein first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents.
- 35648-0320WO11455-WO-PCT ⁇ [0417]
- the combination therapy may provide “synergy” and “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
- a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
- a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
- an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
- a synergistic anti-viral effect denotes an antiviral effect, which is greater than the predicted purely additive effects of the individual compounds of the combination.
- GENERAL The term "pharmaceutically acceptable” with respect to a substance refers to that substance which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
- “Pharmaceutically acceptable” with regard to excipients includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.
- Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a 35648-0320WO11455-WO-PCT ⁇ metal ion, e.
- ammonium and substituted or quaternized ammonium salts are also included in this definition.
- Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p.732, Table 38-5, both of which are hereby incorporated by reference herein.
- the term “comprise” and variations thereof, such as “comprises” and “comprising”, are to be construed in an open, inclusive sense, that is as “including, but not limited to”.
- % w/w or “wt% means the weight of a component as a percentage of the total weight of e.g. a dosage form in which the component is present.
- a composition comprising “5% w/w X” refers to a composition in which the weight of component X is 5% of the total weight of the composition.
- % weight is calculated with respect to the tablet core weight. It will be appreciated that where ranges of % weight are provided for different components of the composition, the total % weight of the components will add up to 100%. In particular, when the upper limits of each range, when added together, exceed 100%, it will be understood that the actual amounts of components present in the composition will be selected so that the total weight % totals 100% and does not exceed it.
- the “tablet core weight” as calculated herein is the sum total of (i) the compound of Formula I, (ii) the filler, (iii) the disintegrating agent, and (iv) the lubricant.
- the core tablet weight does not include the weight of the film coating.
- the “tablet weight” as calculated herein is the sum total of (i) the compound of Formula I, (ii) the filler, (iii) the disintegrating agent, (iv) the lubricant, and (v) the film coating.
- a tablet comprising 100 mg of the compound of Formula I, 89 mg filler, 8 mg disintegrating agent, 3 mg lubricant, and 6 mg film coat: 35648-0320WO11455-WO-PCT ⁇
- Example 1 Compound of Formula I tablets [0426] Compound of Formula I tablets evaluated were manufactured using a dry granulation / tablet compression / film-coating process train. Dry granulation by roller compaction was selected as the means of combining Formula I with inactive excipients in order to minimize exposure of Formula I to moisture during the granulation process. The overall manufacturing process consisted of co-blending and lubricating Formula I with intragranular excipients, followed by roller compaction and milling. The resulting Formula I granules were then blended and lubricated with extragranular magnesium stearate to produce the Formula I final powder blend, which was compressed into core tablets that were subsequently film-coated (with Opadry® II or QX).
- Example 2 Manufacturing process [0427] The manufacturing/packaging procedure for Formula I tablets is divided into four unit processes: 1. Mixing of Formula I drug substance with intragranular excipients, dry granulation, milling, and blending with extragranular magnesium stearate to yield Formula I final powder blend; 35648-0320WO11455-WO-PCT ⁇ 2. Tablet compression to yield tablet cores; 3. Tablet film-coating to yield film-coated tablets; and 4. Packaging. [0428] The manufacturing process steps to produce the final drug product are detailed below. Formula I Final Powder Blend (Dispensing, Blending, Dry Granulation, Milling, Final Blending) 1. Weigh Formula I drug substance and excipients (microcrystalline cellulose and crospovidone).
- DCF drug content factor
- Average hardness (kP) 35648-0320WO11455-WO-PCT ⁇ Film-coating 7. Prepare a suspension of Opadry® II or QX. Film-coat the tablet cores to achieve the target tablet weight gain of 3% (range 2-4%).
- Example 3 Stability of the Formula I tablets
- Five film coated tablets were packaged in a 45 cc white, HDPE bottle containing polyester coil. Each bottle was capped using a white, continuous thread, child-resistant polypropylene crew cap with an induction-sealed, aluminum-faced liner. Two stability experiments were then carried out: one at 30oC and 75% relative humidity (RH) for nine months and one at 40oC and 75% relative humidity (RH) for six months.
- RH relative humidity
- RH relative humidity
- Formulation F1 (100 mg Formula I, lot 1): 35648-0320WO11455-WO-PCT ⁇ Crospovidone 4.0 Ma nesium Stearate 05 : xtragranu ar MCC: microcrystalline cellulose Formulation F2 (500 mg Formula I, lot 1): g MCC: microcrystalline cellulose Formulation F3 (100 mg Formula I, lot 2): w 35648-0320WO11455-WO-PCT ⁇ MCC 44.5 Cros ovidone 40 MCC: microcrystalline cellulose Formulation F4 (500 mg Formula I, lot 2): w g MCC: microcrystalline cellulose [0433] As shown in Figure 2, three of the impurities found in the tested formulations were compounds GS 441524 (the parent nucleoside of the compound of Formula I) and compounds A and B.
- Example 4 Stability of the Formula I tablets
- the stability of the Formula I tablets was tested when stored in 6 mil Aclar, Non- desiccated Bottle, and Open Condition.. The stability experiment was carried out at 40oC and 75% relative humidity (RH) for one or three months.
- the appearance of the tablets was recorded both at the start and end of the stability experiment.
- the water content of the initial formulations and the formulations after the stability experiments was measured by Karl Fisher titration.
- Initial impurity content and impurities after each of the stability experiments were measured by UPLC.
- Percentage dissolution at 45 minutes for both the initial formulations and the formulations after the stability experiments was measured as follows: 35648-0320WO11455-WO-PCT ⁇ x Formulation F5: dissolution measured using a Type 2 apparatus, 20mM of sodium acetate at a pH of 4.5 with 900mL of 0.5% TWEEN 20 at 75rpm. Dissolution was measured at a temperature of 37 oC.
- x Formulation F6 dissolution measured using a Type 2 apparatus, 25mM of sodium acetate at a pH of 4.5 with 1000mL of 0.25% SLS at 75rpm. Dissolution was measured at a temperature of 37 oC.
- Formulation F7 dissolution measured using a Type 2 apparatus, 20mM of sodium acetate at a pH of 4.5 with 1000mL of 0.5% TWEEN 20 at 75rpm. Dissolution was measured at a temperature of 37 oC.
- Figure 3 The results of the stability experiments are summarized in Figure 3. As seen, Formula I tablets are chemically and physically stable when stored in 6 mil Aclar, non-desiccated bottle, and open condition with less than 0.1% degradation observed. Equilibration to water content of ⁇ 4.5% at 75% RH is observed. Dissolution results demonstrate that Formula I tablets fully release ( ⁇ 97%) by 45 minutes. [0437] The following formulations/lots were tested.
- Formulation F5 w % 35648-0320WO11455-WO-PCT ⁇ EG: Extragranular MCC: microcrystalline cellulose
- Formulation F6 : mcrocrysa ne ce uose
- Formulation F7 w % 35648-0320WO11455-WO-PCT MCC: microcrystalline cellulose
- Example 5 Stability of Formulation F8
- the stability of Formulation F8 was tested when stored at elevated temperatures without a desiccant. The results of the stability experiments are shown in Figures 4-6.
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| CN202380075265.5A CN120112279A (en) | 2022-10-27 | 2023-10-26 | Pharmaceutical preparations and their uses |
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| US12180217B2 (en) | 2022-03-02 | 2024-12-31 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US12404289B2 (en) | 2020-06-24 | 2025-09-02 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021213288A1 (en) | 2020-04-20 | 2021-10-28 | 中国科学院上海药物研究所 | Antiviral application of nucleoside analog or combination formulation containing nucleoside analog |
| WO2022047065A2 (en) | 2020-08-27 | 2022-03-03 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| WO2022142477A1 (en) | 2020-12-30 | 2022-07-07 | Southern University Of Science And Technology | Methods and modified nucleosides for treating coronavirus infections |
| CN114869893A (en) | 2022-04-15 | 2022-08-09 | 苏州旺山旺水生物医药有限公司 | A kind of pharmaceutical composition and its application |
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| WO2021213288A1 (en) | 2020-04-20 | 2021-10-28 | 中国科学院上海药物研究所 | Antiviral application of nucleoside analog or combination formulation containing nucleoside analog |
| WO2022047065A2 (en) | 2020-08-27 | 2022-03-03 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| WO2022142477A1 (en) | 2020-12-30 | 2022-07-07 | Southern University Of Science And Technology | Methods and modified nucleosides for treating coronavirus infections |
| CN114869893A (en) | 2022-04-15 | 2022-08-09 | 苏州旺山旺水生物医药有限公司 | A kind of pharmaceutical composition and its application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12404289B2 (en) | 2020-06-24 | 2025-09-02 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
| US12180217B2 (en) | 2022-03-02 | 2024-12-31 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US12448383B2 (en) | 2022-03-02 | 2025-10-21 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
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| CN120112279A (en) | 2025-06-06 |
| EP4608377A1 (en) | 2025-09-03 |
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