WO2021038480A1 - Association pour le traitement du virus de la grippe - Google Patents

Association pour le traitement du virus de la grippe Download PDF

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Publication number
WO2021038480A1
WO2021038480A1 PCT/IB2020/058000 IB2020058000W WO2021038480A1 WO 2021038480 A1 WO2021038480 A1 WO 2021038480A1 IB 2020058000 W IB2020058000 W IB 2020058000W WO 2021038480 A1 WO2021038480 A1 WO 2021038480A1
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WO
WIPO (PCT)
Prior art keywords
compound
baloxavir
pharmaceutically acceptable
acceptable salt
dosage form
Prior art date
Application number
PCT/IB2020/058000
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English (en)
Inventor
Jin Wu
Johan Hendrika Jozef Vingerhoets
Dirk André Emmy ROYMANS
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Janssen Pharmaceuticals, Inc.
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Publication date
Application filed by Janssen Pharmaceuticals, Inc. filed Critical Janssen Pharmaceuticals, Inc.
Publication of WO2021038480A1 publication Critical patent/WO2021038480A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention relates to combinations comprising Compound (1) and baloxavir.
  • the present invention also relates to pharmaceutical compositions comprising a combination of Compound (1) and baloxavir, as well as processes for producing the pharmaceutical compositions.
  • the invention further relates to methods of treating influenza virus infection in a subject or biological sample infected with influenza viruses, as well as methods of inhibiting the replication of, or reducing the number of influenza viruses in an in vitro biological sample.
  • Influenza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within 6 feet) infected persons. Transmission might also occur through direct contact or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth.
  • respiratory secretions such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth.
  • Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune systems might be infectious for 10 or more days after onset of symptoms.
  • Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises seven genera: Influenza A virus, Influenza B virus, Influenza C virus, Influenza D virus, ISA virus, Thogoto virus, and Quaranja virus.
  • influenza A virus genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.
  • the type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease.
  • the influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses.
  • H1N1 which caused Spanish influenza in 1918
  • H2N2 which caused Asian Influenza in 1957
  • H3N2 which caused Hong Kong Flu in 1968
  • H5N1 a pandemic threat in the 2007-08 influenza season
  • H7N7 which has unusual zoonotic potential
  • H1N2 endemic in humans and pigs
  • H9N2, H7N2, H7N3 and H10N7 are: H1N1 (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2, H7N3 and H10N7.
  • influenza B virus genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.
  • Influenza C virus genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children.
  • Influenza A, B and C viruses are very similar in structure. The virus particle is
  • the Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2.
  • HA and NA are large glycoproteins on the outside of the viral particles.
  • HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.
  • these proteins have been targets for antiviral drugs.
  • they are antigens to which antibodies can be raised.
  • Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra ) in, for example, H5N1.
  • Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures.
  • influenza In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. Preventative costs are also high. Governments worldwide have spent billions ofU.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.
  • influenza vaccine Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral medications.
  • Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people that have asthma, diabetes, or heart disease.
  • the vaccine is reformulated each season for a few specific influenza strains but cannot possibly include all the strains actively infecting people in the world for that season. It may take six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine may take several weeks to become effective.
  • influenza vaccines are variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.
  • RNA-dependent RNA polymerase of influenza vRNA makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA.
  • nearly every newly-manufactured influenza virus is a mutant — antigenic drift.
  • the separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell.
  • the resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.
  • Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.
  • Compound (1) is a non-nucleotide inhibitor of the PB2 subunit of the influenza A virus polymerase complex and shows potent, antiviral activity against influenza A.
  • Compound (1) has demonstrated antiviral activity in both in vitro and in vivo nonclinical models and has been shown to reduce peak viral load, area under the curve of viral shedding, and influenza-related clinical symptoms in a human challenge model and two Phase nb studies.
  • Compound (1) is in Phase IP clinical development for the treatment of patients at risk of influenza-related complications, including hospitalized patients in the following studies: 63623872FLZ3001 (SAPPHIRE, NCT03376321) and 63623872FLZ3002 (DIAMOND, NCT03381196).
  • FIG. 1 is an image of three different views of a surface graph plot of Synergy/Antagonism for the in-vitro Combination of Compound (1) and baloxavir.
  • FIG. 2A is an image of heatmap plots presenting the raw values for 3 different plates.
  • FIG. 2B is an image of heatmap plots presenting the values for the 3 different plates normalized to % inhibition.
  • FIG. 3 is an image of graphs of the viral control (VC), cell control (CC), medium control (MC), and MC by plate and column.
  • FIG. 4A is an image of multiple plots presenting the raw data for the different doses of each compound.
  • FIG. 4B is an image of multiple plots presenting the raw data for the different doses of each compound.
  • FIG. 5A is an image of multiple plots presenting the normalized data for the different doses of each compound.
  • FIG. 5B is an image of multiple plots presenting the normalized data for the different doses of each compound.
  • FIG. 6 is an image of two graphs showing the activity of Compound (1) and baloxavir for unrestricted parameters of monotherapy fits.
  • FIG. 7A is a contour plot of MaxR for unrestricted parameters of monotherapy fits.
  • FIG. 7B is a 3D plot of MaxR for unrestricted parameters of monotherapy fits.
  • FIG. 8 is an image of two graphs showing the activity of Compound (1) and baloxavir for fixed maximal response and baseline of monotherapy fits.
  • FIG. 9A is a contour plot of MaxR for fixed maximal response and baseline of monotherapy fits.
  • FIG. 9B is a 3D plot of MaxR for fixed maximal response and baseline of monotherapy fits.
  • the invention includes a method for treating influenza virus infection in a subject or biological sample infected with influenza viruses comprising:
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof is prior to, concurrent with, or subsequent to the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • Some implementations further comprise administering to the subject or biological sample a dosage of from about 100 mg to about 1600 mg of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the dosage is administered 1 to 4 times per day during a treatment period.
  • the dosage is from about 200 mg to about 1200 mg of Compound (1) or a pharmaceutically acceptable salt thereof, and the dosage is administered 1 to 3 times per day during the treatment period.
  • the dosage is from about 550 mg to about 650 mg (e.g., about 600 mg), and the dosage is administered twice (i.e., BID) per day during the treatment period.
  • Compound (1) is administered to a subject in a unit dosage form, wherein the unit dosage form comprises from about 100 mg to about 800 mg of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the unit dosage form of Compound (1) is adapted for oral administration.
  • Compound (1) in the unit dosage form is provided as a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the unit dosage form is a tablet comprising from about 200 mg to about 700 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the tablet comprises from about 250 mg to about 650 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the tablet comprises from about
  • At least one tablet is administered to the subject 1 to 3 times per day during the treatment period.
  • the baloxavir or a pharmaceutically acceptable salt or prodrug thereof is administered to the sample or subject in a dosage of from about 10 mg to about
  • the dosage of baloxavir or a pharmaceutically acceptable salt or prodrug thereof is from about 30 mg to about 90 mg.
  • the dosage of baloxavir or a pharmaceutically acceptable salt or prodrug thereof is administered at least once during the treatment period.
  • baloxavir or a pharmaceutically acceptable salt or prodrug thereof is administered to a subject in a unit dosage form, wherein the unit dosage form comprises from about 10 mg to about 100 mg of baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the unit dosage form of baloxavir is adapted for oral administration.
  • baloxavir in the unit dosage form is provided as baloxavir marboxil.
  • the unit dosage form is a tablet or capsule comprising from about 20 mg to about 90 mg of baloxavir marboxil.
  • the tablet or capsule comprises from about 30 mg to about 50 mg of baloxavir marboxil.
  • the tablet or capsule comprises from about 70 mg to about 90 mg of baloxavir marboxil. In some implementations, one tablet or capsule is administered to the subject at least once during the treatment period. [0038] In some implementations, the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof results in a synergistic effect as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone and the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof results in a reduced or no development of virus resistance as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone and the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of oseltamivir or a pharmaceutically acceptable salt thereof results in a reduced or no development of virus resistance as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone and the administration of oseltamivir or a pharmaceutically acceptable salt thereof alone.
  • the administration of oseltamivir or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof results in a reduced or no development of virus resistance as compared with the administration of oseltamivir or a pharmaceutically acceptable salt thereof alone and the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof and in combination with the administration of oseltamivir or a pharmaceutically acceptable salt thereof results in a reduced or no development of virus resistance as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone, the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone and the administration of oseltamivir or a pharmaceutically acceptable salt thereof alone.
  • Another aspect of the present invention provides a pharmaceutical product comprising:
  • a second unit dosage form comprising from about 10 mg to about 100 mg of baloxavir marboxil, wherein the first unit dose and the second unit dose are adapted for oral administration.
  • the second unit dosage form is provided as a single tablet or capsule.
  • the first unit dosage form is provided as one or more tablets, wherein each tablet comprises from about 200 mg to about 800 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the first unit dosage form is provided as one or more tablets, wherein each tablet comprises from about 200 mg to about 400 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • Another aspect of the present invention provides a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O, wherein Compound (1) has the structure: in combination with baloxavir or a pharmaceutically acceptable salt or prodrug thereof for use as a medicament for treating influenza virus infection.
  • the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O is adapted for oral administration.
  • the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O is formulated as a tablet comprising from about 100 mg to about 700 mg of the crystalline HC1 salt.
  • the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O is formulated as a tablet comprising from about 200 mg to about 650 mg of the crystalline HC1 salt.
  • baloxavir is adapted for oral administration.
  • baloxavir is baloxavir marboxil.
  • baloxavir is formulated as a tablet comprising from about 30 mg to about 50 mg or from about 70 mg to about 90 mg of baloxavir marboxil.
  • Another aspect of the present invention provides a method of inhibiting the replication of or reducing the number of influenza viruses in an in vitro biological sample, comprising:
  • baloxavir is administered to give a concentration of from about 0.0018 mM to 0.4400 mM
  • baloxavir is administered to give a concentration of from about 0.003 mM to 0.0750 mM.
  • Compound (1) is administered prior to, concurrently with, or subsequent to the administration of baloxavir.
  • Another aspect of the present invention provides a pharmaceutical composition comprising Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) has the structure baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the composition comprises a single dosage form comprising Compound (1) or a pharmaceutically acceptable salt thereof and baloxavir or a pharmaceutically acceptable salt or prodrug thereof, or separate dosage forms, wherein the separate dosage forms comprise a dosage form of Compound (1) or a pharmaceutically acceptable salt thereof and a separate dosage form of baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the composition comprises a single dosage form comprising Compound (1) or a pharmaceutically acceptable salt thereof and baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the single dosage form comprises a homogenous mixture of Compound (1) or a pharmaceutically acceptable salt thereof and baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the single dosage form comprises 2 or more distinct compositions, wherein each composition comprises Compound (1) or a pharmaceutically acceptable salt thereof or baloxavir or a pharmaceutically acceptable salt or prodrug thereof or a mixture of any combination thereof.
  • the composition comprises separate dosage forms.
  • the separate dosage forms can be administered concurrently or consecutively.
  • the separate dosage forms are administered consecutively as a first dosage form and a second dosage form.
  • the second dosage form is administered from about one minute to about 48 hours after the first dose form.
  • the second dosage form comprises Compound (1) or a pharmaceutically acceptable salt thereof
  • the first dosage form comprises baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the second dosage form comprises baloxavir or a pharmaceutically acceptable salt or prodrug thereof
  • the first dosage form comprises Compound (1) or a pharmaceutically acceptable salt thereof.
  • Compound (1) or a pharmaceutically acceptable salt thereof is present in an amount sufficient to produce a concentration of from about 0.1 nM to about 0.1 mM of Compound (1) in the blood plasma of a patient after administration, and baloxavir or a pharmaceutically acceptable salt or prodrug thereof is present in an amount sufficient to produce a concentration of from about 0.1 nM to about 0.05 mM of baloxavir in the blood plasma of a patient after administration.
  • the therapeutic effect is synergistic compared to the therapeutic effect observed for Compound (1) or a pharmaceutically acceptable salt thereof or baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • Compound (1) is provided in the composition as a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • baloxavir is provided in the composition as baloxavir marboxil.
  • the dosage form of Compound (1) comprises from about 200 mg to about 800 mg of a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the dosage form of baloxavir comprises from about 30 mg to about 90 mg of baloxavir marboxil.
  • the dosage form of Compound (1) and the dosage form of baloxavir are adapted for oral administration.
  • the dosage form of Compound (1) comprises one or more tablets, and the dosage form of baloxavir comprises a single tablet or capsule.
  • Compound (1) is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex.
  • Compound (1) binds the cap-binding domain of the PB2 subunit with a dissociation constant of about 24 nM.
  • Compound (1) is present as the Compound (1) HC1 salt. In some other embodiments,
  • Compound (1) is present as the HC1 salt of Compound (1) hemihydrate. In still some other embodiments, Compound (1) is present as the HC1 salt of Compound (1) hemihydrate having Form A.
  • baloxavir and “baloxavir acid” are used interchangeably and refer to the compound having the structure
  • baloxavir marboxyl refers to a prodrug of baloxavir wherein the prodrug is a compound having the structure
  • oseltamivir refers to an acetamido cyclohexene compound having the structure
  • Oseltamivir is a neuraminidase inhibitor that is sold (in phosphate salt form) under the trade name Tamiflu.
  • an “excipient” is an inactive ingredient in a pharmaceutical composition.
  • excipients include fillers or diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, or the like.
  • a “disintegrant agent” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion.
  • disintegrant agents include sodium croscarmellose, polyplasdone (i.e., cross-linked polyvinylpyrollidone), sodium starch glycolate, or any combination thereof.
  • a “diluent” or “filler” is an excipient that adds bulkiness to a pharmaceutical composition.
  • fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.
  • a “wetting agent” or a “surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.
  • wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., TweenTM), or any combination thereof.
  • a “binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness). Examples of binders include dibasic calcium phosphate, sucrose, com (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).
  • a “glidant” is an excipient that imparts a pharmaceutical compositions with enhanced flow properties. Examples of glidants include colloidal silica and/or talc.
  • a “colorant” is an excipient that imparts a pharmaceutical composition with a desired color. Examples of colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof. Other colorants include commercially available pigments such as FD&C Green #3.
  • a “lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets.
  • the lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press.
  • lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and "March’s Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention, unless only one of the isomers is drawn specifically.
  • a substituent can freely rotate around any rotatable bonds.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Such compounds, especially deuterium (D) analogs can also be therapeutically useful.
  • the term “synergy” or “synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies can permit the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disorder.
  • a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
  • the phrase “therapeutically effective amount” refers to an amount sufficient to elicit the desired biological response.
  • the desired biological response is to inhibit the replication of influenza virus, to reduce the amount of influenza viruses or to reduce or ameliorate the severity, duration, progression, or onset of an influenza virus infection, prevent the advancement of an influenza viruses infection, prevent the recurrence, development, onset or progression of a symptom associated with an influenza virus infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy used against influenza infections.
  • the precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the infection and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs.
  • a “unit dosage form” refers to one or more pharmaceutical drug products in the form in which it is marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration (such as a capsule shell, for example), and apportioned into a particular dose.
  • a “subject” refers to a mammal (e.g., human, monkey, dog, mouse, rat, and the like).
  • the invention includes a method for treating influenza virus infection in a subject or biological sample infected with influenza viruses comprising:
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof is prior to, concurrent with, or subsequent to the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the method further comprises administering to the subject or biological sample a dosage of from about 100 mg to about 1600 mg (e.g., from about
  • the dosage is from about 200 mg to about 1200 mg of Compound (1) or a pharmaceutically acceptable salt thereof, and the dosage is administered 1 to 3 times per day during the treatment period.
  • the dosage is from about 550 mg to about 650 mg (e.g., about 600 mg) of Compound (1) or a pharmaceutically acceptable salt thereof, and the dosage is administered twice (i.e., BID) per day during the treatment period.
  • the dosage is from about 200 mg to about 400 mg (e.g., from about 250 mg to about 375 mg or from about 275 mg to about 350 mg) of Compound (1) or a pharmaceutically acceptable salt thereof, and the dosage is administered 1-3 times per day during the treatment period.
  • Compound (1) is administered to a subject in a unit dosage form, wherein the unit dosage form comprises from about 100 mg to about 800 mg (e.g., from about 100 mg to about 300 mg, from about 150 mg to about 300 mg, or from about 150 mg to about 250 mg) of Compound (1) or a pharmaceutically acceptable salt thereof. And, in some examples, the unit dosage form of Compound (1) is adapted for oral administration.
  • Compound (1) in the unit dosage form is provided as a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O (i.e., the HC1 salt of Compound (1) hemihydrate).
  • the unit dosage form is a tablet comprising from about
  • the tablet comprises from about 250 mg to about 650 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O. In other examples, the tablet comprises from about 300 mg to about 375 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • At least one tablet is administered to the subject 1 to 3 times per day during the treatment period.
  • the baloxavir or a pharmaceutically acceptable salt or prodrug thereof is administered to the sample or subject in a dosage of from about 10 mg to about 100 mg.
  • the dosage of baloxavir or a pharmaceutically acceptable salt or prodrug thereof is from about 20 mg to about 90 mg (e.g., from about 25 mg to about 75 mg, from about 30 mg to about 60 mg, or from about 30 mg to about 50 mg), and the dosage is administered 1-3 times per day during the treatment period.
  • the dosage of baloxavir or a pharmaceutically acceptable salt or prodrug thereof is from about 25 mg to about 50 mg (e.g., from about 35 mg to about 45 mg), and the dosage is administered 1-3 times per day during the treatment period.
  • the dosage of baloxavir or a pharmaceutically acceptable salt or prodrug thereof is administered at least once (e.g., from 1 to 20 times, from 2 to 16 times, or from 2 to 10 times) during the treatment period.
  • baloxavir or a pharmaceutically acceptable salt or prodrug thereof is administered to a subject in a unit dosage form, wherein the unit dosage form comprises from about 10 mg to about 100 mg of baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the unit dosage form of baloxavir is adapted for oral administration.
  • baloxavir in the unit dosage form is provided as a prodrug (e.g., baloxavir marboxil).
  • the unit dosage form is a tablet or capsule comprising from about 20 mg to about 90 mg of baloxavir marboxil.
  • the tablet or capsule comprises from about 30 mg to about SO mg of baloxavir marboxil.
  • the tablet or capsule comprises from about 70 mg to about 90 mg of baloxavir marboxil.
  • one tablet or capsule is administered to the subject at least once (e.g., 1-20 times, 2-18 times, or 4-12 times) during the treatment period.
  • oseltamivir or a pharmaceutically acceptable salt thereof is administered to the sample or subject in a dosage of from about 50 mg to about 100 mg.
  • the dosage of oseltamivir or a pharmaceutically acceptable salt thereof is from about 40 mg to about 90 mg (e.g., from about 50 mg to about 80 mg, from about 55 mg to about 75 mg, or from about 60 mg to about 70 mg), and the dosage is administered 1-3 times per day during the treatment period.
  • oseltamivir is administered in a dosage regimen according to its label. In some specific embodiments, it is administered 75 mg twice a day, or 150 mg once a day.
  • the dosage of oseltamivir or a pharmaceutically acceptable salt thereof is administered at least once (e.g., from 1 to 20 times, from 2 to 16 times, or from 2 to 10 times) during the treatment period.
  • oseltamivir or a pharmaceutically acceptable salt thereof is administered to a subject in a unit dosage form, wherein the unit dosage form comprises from about 50 mg to about 100 mg of oseltamivir or a pharmaceutically acceptable salt thereof.
  • the unit dosage form of oseltamivir is adapted for oral administration.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof results in a synergistic effect as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone and the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof results in a reduced or no development of virus resistance as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone and the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of oseltamivir or a pharmaceutically acceptable salt thereof results in a reduced or no development of virus resistance as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone and the administration of oseltamivir or a pharmaceutically acceptable salt thereof alone.
  • the administration of oseltamivir or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof results in a reduced or no development of virus resistance as compared with the administration of oseltamivir or a pharmaceutically acceptable salt thereof alone and the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • the administration of Compound (1) or a pharmaceutically acceptable salt thereof in combination with the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof and in combination with the administration of oseltamivir or a pharmaceutically acceptable salt thereof results in a reduced or no development of virus resistance as compared with the administration of Compound (1) or a pharmaceutically acceptable salt thereof alone, the administration of baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone and the administration of oseltamivir or a pharmaceutically acceptable salt thereof alone.
  • Another aspect of the present invention provides a pharmaceutical product comprising:
  • a second unit dosage form comprising from about 10 mg to about 100 mg of baloxavir marboxil, wherein the first unit dose and the second unit dose are adapted for oral administration.
  • the second unit dosage form is provided as a single tablet or capsule. In some embodiments, the second unit dosage form is provided as two tablets or capsules.
  • the first unit dosage form is provided as one or more tablets, wherein each tablet comprises from about 200 mg to about 800 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the first unit dosage form is provided as one or more tablets, wherein each tablet comprises from about 200 mg to about 400 mg of the crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the invention includes a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2
  • Compound (1) has the structure: in combination with baloxavir or a pharmaceutically acceptable salt or prodrug thereof for use as a medicament for treating influenza virus infection.
  • the crystalline HC1 salt is adapted for oral administration.
  • the crystalline HC1 salt is formulated as a tablet comprising from about 100 mg to about 700 mg of the crystalline HC1 salt.
  • the crystalline HC1 salt is formulated as a tablet comprising from about 200 mg to about 650 mg of the crystalline HC1 salt.
  • baloxavir is adapted for oral administration.
  • baloxavir is provided as baloxavir marboxil.
  • baloxavir is formulated as a tablet comprising from about 30 mg to about 50 mg or from about 70 mg to about 90 mg of baloxavir marboxil.
  • Another aspect of the present invention provides a method of inhibiting the replication of or reducing the number of influenza viruses in an in vitro biological sample, comprising:
  • Compoumd (1) is administered prior to, concurrently with, or subsequent to the administration of baloxavir.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) has the structure baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the composition comprises
  • the composition comprises a single dosage form comprising Compound (1) or a pharmaceutically acceptable salt thereof and baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the single dosage form comprises a homogenous mixture of Compound (1) or a pharmaceutically acceptable salt thereof and baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the single dosage form comprises 2 or more distinct compositions, wherein each composition comprises Compound (1) or a pharmaceutically acceptable salt thereof or baloxavir or a pharmaceutically acceptable salt or prodrug thereof or a mixture of any combination thereof.
  • the composition comprises separate dosage forms.
  • the separate dosage forms can be administered concurrently or consecutively.
  • the separate dosage forms are administered consecutively as a first dosage form and a second dosage form.
  • the second dosage form is administered from about one minute to about 48 hours after the first dose form.
  • the second dosage form comprises Compound (1) or a pharmaceutically acceptable salt thereof
  • the first dosage form comprises baloxavir or a pharmaceutically acceptable salt or prodrug thereof.
  • the second dosage form comprises baloxavir or a pharmaceutically acceptable salt or prodrug thereof
  • the first dosage form comprises Compound (1) or a pharmaceutically acceptable salt thereof.
  • Compound (1) or a pharmaceutically acceptable salt thereof is present in an amount sufficient to produce a concentration of from about 0.1 nM to about 0.1 mM of Compound (1) in the blood plasma of a patient after administration
  • baloxavir or a pharmaceutically acceptable salt or prodrug thereof is present in an amount sufficient to produce a concentration of from about 0.1 nM to about 0.05 mM of baloxavir in the blood plasma of a patient after administration.
  • the therapeutic effect is synergistic compared to the therapeutic effect observed for Compound (1) or a pharmaceutically acceptable salt thereof or baloxavir or a pharmaceutically acceptable salt or prodrug thereof alone.
  • Compound (1) is provided in the composition as a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • baloxavir is provided in the composition as baloxavir marboxil.
  • the dosage form of Compound (1) comprises from about 200 mg to about 800 mg of a crystalline HC1 salt of Compound (1) ⁇ 1 ⁇ 2 H2O.
  • the dosage form of baloxavir comprises from about 30 mg to about 90 mg of baloxavir marboxil.
  • the dosage form of Compound (1) and the dosage form of baloxavir are adapted for oral administration.
  • the dosage form of Compound (1) comprises one or more tablets, and the dosage form of baloxavir comprises a single tablet or capsule.
  • compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present invention relates to a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present invention is a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • an “effective amount” includes a “therapeutically effective amount” and a “prophylactically effective amount”.
  • therapeutically effective amount refers to an amount effective in treating and/or ameliorating an influenza virus infection in a patient infected with influenza.
  • prophylactically effective amount refers to an amount effective in preventing and/or substantially lessening the chances or the size of influenza virus infection outbreak.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.
  • the pharmaceutically acceptable carrier, adjuvant, or vehicle includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky.
  • Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and
  • compositions described above can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, symps and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compounds may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • opacifying agents may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in
  • 1,3-butanediol 1,3-butanediol.
  • acceptable vehicles and solvents water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include, but are not limited to, lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, specifically, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the compounds for use in the methods of the invention can be formulated in unit dosage form.
  • the term “unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • Example 2 In vitro combination study of Compound (1) and baloxavir [0167] To determine synergy effects of Compound (1) and baloxavir, baloxavir was spotted horizontally and the Compound (1) was spotted vertically to create a matrix of combinations of two compounds at variable concentrations. Compound (1) was spotted 100 nl from 0.045 mM to 0.00019 mM with 3-fold dilution. Baloxavir was spotted 100 nl from 0.075 mM to 0.0003 mM with 2-fold dilution. Plates were stored at -20 °C. Before the experiment, plates were placed at room temperature.
  • the influenza strain A/PR/8/1934(HlNl) virus was dropped to the plates containing test compounds at a concentration to reach a multiplicity of infection (MOI) of 0.01 using infection medium: Ultra MDCK serum free medium containing 0.0002% trypsine.
  • Madin-Darby Canine Kidney (MDCK) cells were plated in assay medium (cat no BE12-749Q, lot no 8MB122, without trypsin) at a density of 6000 cells/well in 384-well white microplates (from Greiner Bio-One Catalog number GREI781098) using Multidrop (from Thermo, equipment id B0046). The assay plates were incubated for three days at incubator with 5% CO2 at 37 °C. At day 3, 40 m ⁇ of reconstituted ATPlite 1 step reagent was added to all wells. Luminescence signal was measured on ViewLux imager (Perkin Elmer), 3x binning and 0.1 s measuring time.
  • Example 3 Synergistic effect of the combination of Compound (1) and baloxavir
  • Plate layout The heatmap plots present the raw (FIG. 2A) and normalized to % inhibition (FIG. 2B) values for the 3 different plates. For the normalized values the CC,
  • FIG. 3 provides graphs of the viral control (VC), cell control (CC), medium control (MC), and MC by plate and column.
  • FIGS. 4 A, 4B, 5 A, and 5B present the normalized and raw data for the different doses of each compound.
  • test-statistics calculated in step 3 are displayed graphically. [0183] Note that the method relies on the assumption that monotherapy dose-response curves follow log-logistic shape (Hill equation).
  • FIG. 6 (2D activity plot) can be used to calculate the EC50 of baloxavir (0.0041569 mM) and Compound (1) (0.0021605 mM).
  • Table 1 presents the dose combinations of baloxavir and Compound (1) that show a synergistic/antagonistic effect. [0190] Table 1.
  • the maximal response level of the monotherapy fits is fixed at 1 (100% inhibition) and the baseline is fixed at 0 (0% inhibition).
  • Table 2 presents the dose combinations of baloxavir and Compound (1) that show a synergistic/antagonistic effect. [0197] Table 2.
  • Step 1 Fluid Bed Granulation Process
  • Binder solution Hydroxypropylmethyl cellulose (HPMC) 2910 15 mPa.s (21.00 mg per unit) and polysorbate 20 (3.00 mg per unit; common commercial brand names include Scattics, Alkest TW 20, and Tween 20) were added to purified water (700.00 mg per unit) and mixed until a clear solution was obtained.
  • HPMC Hydroxypropylmethyl cellulose
  • Granulation Compound (1) HC1 hemihydrate salt Form A (668.40 mg per unit) and crospovidone (20.00 mg per unit) were transferred to a fluid bed granulator, and the resulting mixture was warmed while fluidizing. The binder solution was then sprayed upon the ingredients using standard wet granulation techniques.
  • the granulate was dried while fluidizing, the dried granules collected, and then packed in aluminum bags for later use.
  • Step 2 Blending and Tableting
  • Granules comprising Compound (1) HC1 hemihydrate salt Form A from step 1 and colloidal anhydrous silica are passed through a sieve (0.950 mm sieve size; 0.4 mm wire diameter) and mixed until homogeneous using a high speed blender (10 rpm, 5 min).
  • the resulting blended mixture was then compressed into tablets using a tableting press.
  • the resulting tablets were then collected into aluminum laminated bags in suitable containers.
  • Step 3 Film Coating
  • Coating powder for example Opadry P White 85F 18422
  • purified water amounts specified in a per unit basis in Tables 3 A and 3B below
  • the core tablets from steps 1 and 2 were transferred to a coating pan and sprayed with the coating suspension using the film coating technique, which comprises 1) loading the tablets into the coating pan and allowing them to pre-warm to the required temperature; 2) spraying the tablets with the coating suspension based on the parameters as set in Table 10 until the required weight film coating layer (weight gain) is achieved on the tablets (“the spraying phase”); and 3) drying the tablets at the set inlet and exhaust air temperature for 5 minutes.
  • the dried, film coated tablets were then transferred to aluminum laminated bags in suitable containers.
  • the component compositions of Tablet Compositions 1 - 6 are presented in Tables
  • Table 3a Tablet Compositions 1-3.
  • Table 4 Tablet compression parameters for Compositions 1-6.
  • Table 5 Parameters and results of the film coating process for Compositions 1-6.
  • Example 5 Process for producing Tablet Composition 7 having 300 mg Compound (1) (molar equivalent of the HC1 salt).
  • composition 8 was developed by dose-proportionally reducing the excipients present in the equivalent 600 mg Composition 3 tablet by 50%.
  • Composition 8 is a formulation that is in between Composition 3 and Composition 7, and serves as a bridging composition between the two.
  • Table 6 Tablet Composition 7 and 8.
  • Tables 7 and 8 Parameters and results of the tablet compression process for tablet composition 7 are provided in Tables 7 and 8 below.
  • the tables present results for a single batch of tablet composition 7 at 1) four different sampling intervals during compression (Table 7) and 2) five different sampling intervals during compression (Table 8).
  • Table 9 The conditions for granulation of Tablet Composition 8 are provided in Table 9 below.
  • Table 9 Granulation conditions for tablet composition 8.
  • Table 10 Compression parameters and physical attributes of tablet cores for Tablet Composition 8.
  • Example 6 Process for producing Tablet Composition 9 having 300 mg Compound (1) (molar equivalent of the HC1 salt).
  • SSF Sodium Stearyl Fumarate
  • Table 12a Tablet Composition 9.
  • Table 12b Compression parameters and physical attributes of Composition 9.

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Abstract

La présente invention concerne des associations comprenant le composé (1) et le baloxavir ou un promédicament de celui-ci. La présente invention concerne également des compositions pharmaceutiques comprenant une association du composé (1) et du baloxavir, ainsi que des procédés de production des compositions pharmaceutiques. L'invention concerne en outre des procédés de traitement d'une infection par le virus de la grippe chez un sujet ou un échantillon biologique infecté par des virus de la grippe, ainsi que des procédés d'inhibition de la réplication ou de réduction du nombre de virus de la grippe dans un échantillon biologique in vitro.
PCT/IB2020/058000 2019-08-27 2020-08-27 Association pour le traitement du virus de la grippe WO2021038480A1 (fr)

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US62/892,133 2019-08-27

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WO2021038480A1 true WO2021038480A1 (fr) 2021-03-04

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015073476A1 (fr) * 2013-11-13 2015-05-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
WO2018137670A1 (fr) * 2017-01-24 2018-08-02 苏州科睿思制药有限公司 Forme cristalline du médicament inhibiteur de protéine virale (vx-287), et son procédé de préparation et d'utilisation
WO2018191475A1 (fr) * 2017-04-12 2018-10-18 Vertex Pharmaceuticals Incorporated Polythérapies pour le traitement d'infection par le virus de la grippe
EP3391888A1 (fr) * 2015-12-15 2018-10-24 Shionogi & Co., Ltd. Médicament pour traiter la grippe caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'endonucléase coiffe-dépendante avec un médicament antigrippal
CA3082522A1 (fr) * 2017-11-17 2019-05-23 Shionogi & Co., Ltd. Preparation pharmaceutique presentant d'excellentes proprietes de photostabilite et de liberation de medicament

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015073476A1 (fr) * 2013-11-13 2015-05-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
EP3391888A1 (fr) * 2015-12-15 2018-10-24 Shionogi & Co., Ltd. Médicament pour traiter la grippe caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'endonucléase coiffe-dépendante avec un médicament antigrippal
WO2018137670A1 (fr) * 2017-01-24 2018-08-02 苏州科睿思制药有限公司 Forme cristalline du médicament inhibiteur de protéine virale (vx-287), et son procédé de préparation et d'utilisation
WO2018191475A1 (fr) * 2017-04-12 2018-10-18 Vertex Pharmaceuticals Incorporated Polythérapies pour le traitement d'infection par le virus de la grippe
CA3082522A1 (fr) * 2017-11-17 2019-05-23 Shionogi & Co., Ltd. Preparation pharmaceutique presentant d'excellentes proprietes de photostabilite et de liberation de medicament

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
E. W. MARTIN: "Remington's Pharmaceutical Sciences", 1980, MACK PUBLISHING CO.
NOSHI TAKESHI ET AL: "In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit", ANTIVIRAL RESEARCH, ELSEVIER BV, NL, vol. 160, 11 October 2018 (2018-10-11), pages 109 - 117, XP085534511, ISSN: 0166-3542, DOI: 10.1016/J.ANTIVIRAL.2018.10.008 *
THOMAS SORRELL: "Handbook of Chemistry and Physics", 1999, UNIVERSITY SCIENCE BOOKS

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