WO2022147499A1 - Method of treating viral infections with a combination of niclosamide and gemcabene - Google Patents

Method of treating viral infections with a combination of niclosamide and gemcabene Download PDF

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Publication number
WO2022147499A1
WO2022147499A1 PCT/US2022/011033 US2022011033W WO2022147499A1 WO 2022147499 A1 WO2022147499 A1 WO 2022147499A1 US 2022011033 W US2022011033 W US 2022011033W WO 2022147499 A1 WO2022147499 A1 WO 2022147499A1
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virus
day
pharmaceutically acceptable
acceptable salt
weight
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PCT/US2022/011033
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French (fr)
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Richard J. KANG
Seth RENO
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Neurobo Pharmaceuticals, Inc.
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Publication of WO2022147499A1 publication Critical patent/WO2022147499A1/en

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    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • 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

Definitions

  • compositions comprising the compounds.
  • Influenza is the most common respiratory illness and, while generally seasonal, spreads rapidly and globally, affecting all age groups. Seasonal influenza accounts for greater than 200,000 hospitalizations and greater than 30,000 deaths per year in the United States. More recently, a previously unknown respiratory illnesss, SARS-CoV-2 quickly reached pandemic status and as of December 5, 2020, has caused more than 1.53 million deaths worldwide.
  • Vaccination is the most effective manner to control virus-induced outbreaks and avoid complications which result from infection.
  • the difficulty to prepare, distribute and immunize the world population against an epidemic or pandemic there is a clear and apparent need to develop more efficient methods to reduce the severity of viral infections.
  • the present disclosure provides a method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof.
  • the viral infection is caused by an RNA virus.
  • the virus has a filamentous, isometric, enveloped, or a head and tail conformation.
  • the RNA virus is a positive-strand RNA virus.
  • the positive-strand RNA virus belongs to the family of Picornaviridae, Astroviridae, Caliciviridae, Hepeviridae Flaviviridae, Togaviridae, Arteriviridae, or Coronaviridae.
  • the positive-strand RNA virus belongs to the family of Coronaviridae.
  • the Coronaviridae virus is selected from Bat coronavirus CDPHE15, Bat coronavirus HKU10, Rhinolophus ferrumequinum alphacoronavirus HuB-2013, Human coronavirus 229E, Lucheng Rn rat coronavirus, Ferret coronavirus, Mink coronavirus 1, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Myotis ricketti alphacoronavirus Sax-2011, Nyctalus velutinus alphacoronavirus SC-2013, Porcine epidemic diarrhea virus, Scotophilus bat coronavirus 512, Rhinolophus bat coronavirus HKU2, Human coronavirus NL63, NL63-related bat coronavirus strain BtKYNL63-9b, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus - type species, Bat Hp-betacor
  • the Coronaviridae virus is Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • the Coronaviridae virus is selected from HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, SARS CoV-2, a mutated strain thereof, and any combination thereof.
  • the RNA virus is a negative- strand RNA virus.
  • the negative- strand RNA virus belongs to the family of Orthomyxoviridae, Paramyxoviridae, Rhabdoviridiae, Filoviruses, or Arenaviruses.
  • the negative- strand virus is selected from Influenza virus, Sendai virus, Human parainfluenza virus 1 (hPIVl), Simian virus 5 (SV5, PIV5), Mumps virus, Newcastle disease virus (NDV), Measles virus, Rinderpest virus , Respiratory syncytial virus (RSV), Vesicular stomatitis virus (VSV), Rabies virus, Ebola virus, Marburg virus, Lymphocytic choriomeningitis virus (LCMV), Junin virus, and Lassa fever virus.
  • the virus is a retrovirus.
  • the retrovirus is selected from a Lenti virus, Alpharetrovirus, Betaretrovirus, Deltaretrovirus, Gammaretrovirus, and a Epsilonretrovirus.
  • the retrovirus is a Simian immunodeficiency virus (SIV), Human immunodeficiency virus-1 (HIV-1), HIV-2, Feline immunodeficiency virus (FIV), Equine infectious anemia virus (EIAV), Mouse mammary tumor-like virus (MMTV), Mason-Pfizer monkey virus (MPMV), Respiratory syncytial virus RSV, bovine leukemia virus (BLV), Human T- cell leukemia virus-1 (HTLV-1), HTLV-2, Murine leukemia virus (MuLV), Gibbon ape leukemia virus (GALV), and any combination thereof.
  • SIV Simian immunodeficiency virus
  • HV-1 Human immunodeficiency virus-1
  • HIV-2 HIV-2
  • EIAV Equine infectious anemia virus
  • MMTV
  • the viral infection is caused by a DNA virus.
  • the DNA virus is Adenovirus, infectious canine hepatitis virus, Papillomavirus, polyomaviridae, simian vacuolating virus, Parvovirus Bl 9, canine parvovirus, Herpes simplex virus, varicellazoster virus, cytomegalovirus, Epstein-Barr virus, Smallpox virus, cow pox virus, sheep pox virus, monkey pox virus, vaccinia virus, Torque teno virus, or any combination thereof.
  • the subject has a medical condition that increases risk of a poor prognosis without treatment or an increased risk of a severe immune response to the infection.
  • the subject has an impaired or reduced immune response.
  • the subject is immunocompromised.
  • the subject is undergoing or has undergone one or more of an immunosuppressive therapy, presenting a sign or symptom of a second medical disease or disorder or a subject of a past, present or future medical intervention.
  • the second medical disease or disorder comprises an infection, an HIV infection, an onset of Acquired Immunodeficiency Syndrome (AIDS), a proliferative disorder, a cancer, asthma, or an autoimmune condition.
  • AIDS Acquired Immunodeficiency Syndrome
  • the immunosuppressive therapy comprises one or more of an ablation of bone marrow or circulating blood cell types, a radiation therapy, a therapy for a proliferative or malignant disease, a monoclonal antibody therapy, a blood transfusion, a bone marrow transplant, or removal of a lymph node.
  • the medical intervention comprises one or more of a surgery, a graft, a tissue or organ transplant, a wound or bum debridement, a setting of a bone, a replacement of a bone, a replacement of a joint, a cardiac bypass, a vascular stent placement, a spinal tap, an organ resection, or a cardiac pacemaker placement or replacement.
  • the subject presents a sign or symptom of hypertension or cardiac disease. In some aspects, the subject has been diagnosed with hypertension or cardiac disease. In some aspects, the subject presents a sign or symptom of a metabolic disorder. In some aspects, the subject has been diagnosed with the metabolic disorder. In certain aspects, the metabolic disorder comprises insulin resistance, pre-diabetes, or diabetes. In some aspects, the subject presents a sign or symptom of a clotting or vascular disorder. In some aspects, the subject has been diagnosed with the clotting or vascular disorder. In certain asepcts, the subject is at risk of forming a clot or suffering from a stroke.
  • the subject has not received a vaccine for the vims prior to contacting the vims or presenting the viral infection.
  • the subject is a neonatal subject.
  • the mother of the subject is a carrier of the vims or infected by the vims.
  • the subject is under 18 years of age.
  • the subject is between 18 years of age and 29 years of age, inclusive of the endpoints.
  • the subject is between 30 years of age and 49 years of age, inclusive of the endpoints.
  • the subject is between 50 years of age and 69 years of age, inclusive of the endpoints.
  • the subject is over 70 years of age.
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered at an effective amount of from about 25 mg/day to about 900 mg/day.
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered at about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 450 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 750 mg/day, about 800 mg/day, or about 900 mg/day.
  • the niclosamide, or the pharmaceutically acceptable salt thereof is administered at an effective amount of from about 0.1 mg/day and about 5 g/day. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 0.1 mg/day, about 0.25 mg/day, about 0.50 mg/day, about 0.75 mg/day, about 1.0 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 250 mg/day, about 500 mg/day, about 750 mg/day, about 1 g/day, about 1.5 g/day, about 2 g/day, about 2.5 g/day, about 3 g/day, about 3.5 g/day, about 4 g/day, about 4.5 g/day, or about 5 g/day. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about
  • the niclosamide, or the pharmaceutically acceptable salt thereof is administered simulataneously with the gemcabene, or the pharmaceutically acceptable salt thereof. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof, are co-formulated. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered before the gemcabene, or the pharmaceutically acceptable salt thereof.
  • the niclosamide, or the pharmaceutically acceptable salt thereof is administered after the gemcabene, or the pharmaceutically acceptable salt thereof. In certain aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a capsule. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a tablet. [0016] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof are administered for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7 to about 14 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
  • the pharmaceutical composition comprises the monocalcium salt of gemcabene.
  • the niclosamide is administered as a formulation comprising:
  • mannitol comprising about 8% to about 9% weight by weight of the formulation
  • hydroxypropyl cellulose comprising about 5% weight by weight of the formulation
  • the niclosamide is administered as a formulation comprising:
  • hydroxypropyl cellulose comprising about 5% weight by weight of the formulation
  • colloidal silicon dioxide comprising about 0.5% weight by weight of the formulation
  • the niclosamide is administered as a formulation comprising:
  • the gemcabene is administered as a formulation comprising:
  • the gemcabene or the pharmaceutically acceptable salt thereof, has a PSD90 ranging from 40 pm to about 75 pm as measured by laser light diffraction.
  • the present disclosure provides a kit comprising gemcabene, or a pharmaceutically acceptable salt thereof, for administering gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof, to a subject having a viral infection.
  • the present disclosure provides methods of treating or preventing viral infections with a combination of niclosamide, or a pharmaceutically acceptable salt thereof, and gemcabene, or a pharmaceutically acceptable salt thereof.
  • the term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). In some aspects of the formulations of the disclosure, the term “about” encompasses a deviation from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses an increase from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses a decrease from the recited value of between 0.001% and 10%, inclusive of the endpoints.
  • administration refers to introducing a composition, such as gemcabene and/or niclosamide, of the present disclosure, into a subject via a pharmaceutically acceptable route.
  • the introduction of a composition of the present disclosure into a subject is by any suitable route, including intratumorally, orally, pulmonarily, intranasally, parenterally (intravenously, intra-arterially, intramuscularly, intraperitoneally, or subcutaneously), rectally, intralymphatically, intrathecally, periocularly or topically.
  • Administration includes self-administration and the administration by another.
  • a suitable route of administration allows the composition or the agent to perform its intended function. For example, if a suitable route is intravenous, the composition is administered by introducing the composition or agent into a vein of the subj ect.
  • a “subject” includes any human or nonhuman animal.
  • the term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some aspects, the subject is a human.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the term “effective amount” refers to an amount of an agent (e.g., gemcabene and/or niclosamide) that provides the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an agent e.g., gemcabene and/or niclosamide
  • That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an agent e.g., gemcabene and/or niclosamide
  • That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of
  • An effective amount can be administered in one dosage or can be dividied into multiple dosages, the total of such dosages being the effective amount.
  • an effective amount can be provided in two separate administrations over a period of time, that in aggregate, provide the effective amount of the formulation.
  • an “effective amount” is the amount of gemcabene and/or niclosamide that decreases or reduces one or more of a viral load, a number (absolute or relative) of viral particles or infected cells, reduces a severity of a sign or symptom of the infection, and/or improves one or more aspects of a prognosis for the subject.
  • the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of the drug to decreases or reduce one or more of a viral load, a number (absolute or relative) of viral particles or infected cells, reduce a severity of a sign or symptom of the infection, and/or improve one or more aspects of a prognosis for the subject.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the present disclosure provides methods of treating viral infections using niclosamide, or a pharmaceutically acceptable salt thereof, in combination with gemcabene, or a pharmaceutically acceptable salt thereof.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered orally, intravenously, intramuscularly, subcutaneously, peritoneally, intrathecally, intracranially, topically, vaginally, rectally, or any combination thereof.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof is administered orally.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof is administered as a tablet. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, is administered as a capsule.
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered at an effective amount for the method. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at from about 50 mg to about 900 mg, about 150 mg to about 600 mg, or about 150 mg to about 300 mg.
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered at about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered at about 50 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 150 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 300 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 600 mg.
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered at an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, or any amount ranging from and to these values.
  • the niclosamide, or the pharmaceutically acceptable salt thereof is administered from about 0.1 mg to about 5 g, or about 0.1 mg to about 2 g, or about 0.5 mg to about 1 g. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, of the present disclosure can be administered from 1 to 10 times a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered from 1 to 5 times a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered once a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day.
  • the subject that can be treated with the combination of gemcabene, or the pharmaceutically acceptable salt thereof, and niclosamide, or the pharmaceutically acceptable salt thereof is a nonhuman mammal. In some aspects, the subject that can be treated is a human.
  • the combination of gemcabene, or the pharmaceutically acceptable salt thereof, and niclosamide, or the pharmaceutically acceptable salt thereof can be used to treat a viral infection.
  • the viral infection can be caused by an RNA virus or a DNA virus.
  • the virus has a filamentous, isometric, enveloped, or a head and tail conformation.
  • the viral infection can be caused by a postivie-strand RNA virus.
  • the positive-strand RNA virus can belong to the family of Picornaviridae, Astroviridae, Caliciviridae, Hepeviridae Flaviviridae, Togaviridae, Arteriviridae, or Coronaviridae.
  • the positive-strand RNA virus belongs to the family Coronaviridae and is Bat coronavirus CDPHE15, Bat coronavirus HKU10, Rhinolophus ferrumequinum alphacoronavirus HuB-2013, Human coronavirus 229E, Lucheng Rn rat coronavirus, Ferret coronavirus, Mink coronavirus 1, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Myotis ricketti alphacoronavirus Sax-2011, Nyctalus velutinus alphacoronavirus SC-2013, Porcine epidemic diarrhea virus, Scotophilus bat coronavirus 512, Rhinolophus bat coronavirus HKU2, Human coronavirus NL63, NL63 -related bat coronavirus strain BtKYNL63-9b, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus - type species
  • the Coronaviridae virus comprises Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • the Coronviridae virus comprises HCoV 229E, HCoV OC43, HCoVNL63, HCoV HKUl, SARS CoV, MERS CoV, SARS CoV-2, a mutated strain thereof, or any combination thereof.
  • the viral infection comprises an infection by a negative-strand RNA virus.
  • the negative-strand virus belongs to the family of Orthomyxoviridae, Paramyxoviridae, Rhabdoviridiae, Filoviruses, or Arenaviruses.
  • the negativestrand virus comprises Influenza virus (including, but not limited to, influenza A, influenza B and its subtypes), Sendai virus, Human parainfluenza virus 1 (hPIVl), Simian virus 5 (SV5, PIV5), Mumps virus, Newcastle disease virus (NDV), Measles virus, Rinderpest virus, Respiratory syncytial virus (RSV), Vesicular stomatitis virus (VSV), Rabies virus, Ebola virus, Marburg virus, Lymphocytic choriomeningitis virus (LCMV), Junin virus, Lassa fever virus, or a combination thereof.
  • Influenza virus including, but not limited to, influenza A, influenza B and its subtypes
  • Sendai virus including, but not limited to, influenza A, influenza B and its subtypes
  • Sendai virus Human parainfluenza virus 1 (hPIVl), Simian virus 5 (SV5, PIV5)
  • Mumps virus Newcastle disease virus (NDV), Measles virus, Rinderpest
  • the virus comprises a retrovirus.
  • the retrovirus comprises a Lentivirus, Alpharetrovirus, Betaretrovirus, Deltaretrovirus, Gammaretrovirus, Epsilonretrovirus, or any combination thereof.
  • the retrovirus comprises a Simian immunodeficiency virus (SIV), Human immunodeficiency virus-1 (HIV-1), HIV-2, Feline immunodeficiency virus (FIV), Equine infectious anemia virus (EIAV), Mouse mammary tumorlike virus (MMTV), Mason-Pfizer monkey virus (MPMV), Respiratory syncytial virus RSV, bovine leukemia virus (BLV), Human T- cell leukemia virus-1 (HTLV-1), HTLV-2, Murine leukemia virus (MuLV), Gibbon ape leukemia virus (GALV), or a combination thereof.
  • SIV Simian immunodeficiency virus
  • HV-1 Human immunodeficiency virus-1
  • HIV-2 Feline immunodeficiency virus
  • EIAV Equine infectious anemia virus
  • MMTV Mouse mammary tumorlike virus
  • MPMV Mason-Pfizer monkey virus
  • RSV Respiratory syncytial virus
  • BLV bovine leukemia virus
  • HTLV-1 Human T
  • the viral infection is caused by a DNA virus.
  • the DNA virus comprises Adenovirus, infectious canine hepatitis virus, Papillomavirus, polyomaviridae, simian vacuolating virus, Parvovirus Bl 9, canine parvovirus, Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, Smallpox virus, cow pox virus, sheep pox virus, monkey pox virus, vaccinia virus, Torque teno virus, or any combination thereof.
  • the DNA virus comprises CMV, BKV, HSV, VZV, EBV, as well as mutations thereof.
  • the DNA virus comprises hepatitis B virus, hepatitis C virus, human cytomegalovirus, herpes simplex virus type 1, or any combination thereof.
  • the DNA virus comprises hepatitis C virus.
  • the subject can have medical condition that increases risk of a poor prognosis without treatment or an increased risk of a severe immune response to the infection.
  • the subject has an impaired or reduced immune response.
  • the subject is immunocompromised.
  • the subject is undergoing or has undergone one or more of an immunosuppressive therapy, presenting a sign or symptom of a second medical disease or disorder or a subject of a past, present or future medical intervention.
  • the second medical disease or disorder comprises an infection, an HIV infection, an onset of Acquired Immunodeficiency Syndrome (AIDS), a proliferative disorder, a cancer, asthma, and/or an autoimmune condition.
  • AIDS Acquired Immunodeficiency Syndrome
  • the immunosuppressive therapy comprises one or more of an ablation of bone marrow or circulating blood cell types, a radiation therapy, a therapy for a proliferative or malignant disease, a monoclonal antibody therapy, a blood transfusion, a bone marrow transplant, or removal of a lymph node.
  • the medical intervention comprises one or more of a surgery, a graft, a tissue or organ transplant, a wound or bum debridement, a setting of a bone, a replacement of a bone, a replacement of a joint, a cardiac bypass, a vascular stent placement, a spinal tap, an organ resection, or a cardiac pacemaker placement or replacement.
  • the subject presents a sign or a symptom of hypertension or cardiac disease. In some aspects, the subject presents a sign or symptom of a metabolic disorder. In certain aspects, the subject has been diagnosed with a metabolic disease. In some aspects, the subject has been diagnosed with a metabolic disorder that comprises insulin resistance, pre-diabetes, or diabetes.
  • the subject can have type 1, type 2 and/or gestational diabetes, familial hypercholesterolemia, elevated triglycerides, above normal BMI, a BMI >40, cystic fibrosis, a history of smoking, idiopathic pulmonary fibrosis, idiopathic respiratory distress syndrome, non-alcoholic fatty liver disease (NAFLD), Non-Alcoholic Steatohepatitis (NASH), liver disease, cirrhosis, hypertension, familial partial lipodystrophy, compromised respiratory function, asthma, chronic lung disease, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, chronic kidney disease, one or more hemoglobin disorders, sickle cell anemia, thalassemia, anemia, a compromised immune system due to cancer treatment, an autoimmune disease, an age over 65, cardiovascular disease, a heart condition ⁇ heart failure, coronary artery disease, congenital heart disease, cardiomyopathies, and pulmonary hypertension
  • the subject suitable for the present method presents a sign or symptom of a clotting or vascular disorder.
  • the subject has been diagnosed with the clotting or vascular diagnosis.
  • the subject is at risk of forming a clot or suffering from a stroke.
  • the subject has not received a vaccine for the virus prior to contacting the virus or presenting the viral infection.
  • the subject can be a neonatal subject.
  • the mother of the subject is a carrier of the virus or infected by the virus.
  • the subject is less than 18 years old, less than 30 years old, less than 50 years old, less than 60 years old, less than 75 years old, less than 80 years old, less than 85 years old, less than 90 years old, less than 95 years old, or less than 100 years old.
  • the subject can be pediatric.
  • the subject can be over the age of 50, 55, 60, 65, 70, 75, 80, 85, or 90 years old.
  • the subject is between 18 years of age and 29 years of age, inclusive of the endpoints.
  • the subject is between 30 years of age and 49 years of age, inclusive of the endpoints. In some aspects, the subject is between 50 years of age and 69 years of age, inclusive of the endpoints. In certain aspects, the subject is over 70 years of age.
  • the combination of gemcabene, or the pharmaceutically acceptable salt thereof, and niclosamide, or the pharmaceutically acceptable salt thereof can be used in combination with one or more additional therapeutic agents.
  • a method of treating a viral infection as disclosed herein comprises administering gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.
  • Non-limiting examples of antiviral agents that can be used in the present methods include acyclovir, famcyclovir, ganciclovir, idoxuridine, foscamet, fomivirsen, molnupiravir, remdesivir, favipiravir, sofosbuvir, AT-527, boceprevir, GC376, ebselen, PF-00835231, PF-07304814, pencyclovir, trifluridine, tromantadine, valacyclovir, valgancyclovir, vidarbine, cidofavir, docosanol, amantadine, oseltamivir, peramivir, rimantadine, zanamivir, fomivirsen, enfuvirtide, imiquimod, interferon, ribavirin, viramidine, ziduvidine, didanosine, stauvidine, zalcitabine,
  • gemcabene or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof can be used in combination with one or more anti-inflammatory agents, such that multiple aspects of an inflammatory response can be targeted.
  • anti-inflammatory agents that can be used in the present methods include aspirin, sodium salycilate, fenoprofen, diflunixal, ibuprofen, ketoprofen, naproxen, flurbiprofen, diclofenac, ketorolac, tolmetin, etodolac, indomethacin, sulindac, aceclofenac, mefenamic acid, meclofenamic acid, tolfenamic acid, piroxicam, phenylbutazone, nabumetone, tenoxicam, indomethacin, sulindac, minisulide, nimesulide, meloxicam, etoricoxi
  • the niclosamide, or the pharmaceutically acceptable salt thereof can be administered to the subject prior to or after the administration of the gemcabene, or the pharmaceutically acceptable salt thereof.
  • the niclosamide, or the pharmaceutically acceptable salt thereof can be administered to the subject concurrently with the gemcabene, or the pharmaceutically acceptable salt thereof.
  • the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof can be administered concurrently as a single composition in a pharmaceutically acceptable carrier.
  • the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof are administered concurrently as separate compositions.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered for a period of from about 7 days to 6 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 3 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 2 months.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered for a period of from about 7 days to about 45 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for about 7 to about 14 days.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered once a day for a period of from about 7 days to 6 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for a period of from about 7 days to 3 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 2 months.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered for a period of from about 7 days to about 45 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for about 7 to about 14 days.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered once a day for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered twice a day for a period of from about 7 days to 6 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for a period of from about 7 days to 3 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 2 months.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered for a period of from about 7 days to about 45 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for about 7 to about 14 days.
  • the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof can be administered twice a day for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
  • subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof experience a shorter recovery time than those receiving other treatments or no treatment.
  • subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof experience a higher survival rate than those receiving other treatments or no treatment.
  • subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof are less likely to require respirator therapy than those receiving other treatments or no treatment.
  • Niclosamide can also be in the form of other pharmaceutically acceptable salts.
  • such salts can be derived from inorganic or organic acids or bases.
  • the present disclosure provides methods of treating viral infections using gemcabene, or a pharmaceutically acceptable salt thereof, in combination with niclosamide, or a pharmaceutically acceptable salt thereof.
  • Gemcabene has been previously described, e.g., in U.S. Patent No. 5,648,387, which is hereby incorporated by reference in its entirety.
  • the compound is also known as 6-(5-carboxy-5-methylhexyloxy)-2,2-dimethyl-hexanoic acid and is represented by the structure shown below:
  • the present disclosure provides methods of treating an antiviral infection using a pharmaceutically acceptable salt of gemcabene.
  • the pharmaceutically acceptable salt can comprise the monocalcium salt of gemcabene, represented by the structure shown below:
  • Various gemcabene calcium salt hydrates have been previously described, e.g., in U.S. patent No. 6,861,555, which is hereby incorporated by reference in its entirety.
  • Gemcabene can also be in the form of other pharmaceutically acceptable salts.
  • such salts can be derived from inorganic or organic acids or bases.
  • the compounds described herein can be in the form of pharmaceutically acceptable salts.
  • such salts are derived from inorganic or organic acids or bases.
  • Suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl -propionate, picrate, pivalate, propionate, succinate
  • suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, 7V-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, and the like.
  • compositions comprising gemcabene and/or niclosamide can also comprise suitable carriers, excipients, and auxiliaries that may differ depending on the mode of administration.
  • the pharmaceutically acceptable carrier or vehicle comprises a binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, coloring agent, dye-migration inhibitor, sweetening agent, flavoring agent, or a combination thereof.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as com starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Pan war gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxy
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, or mixtures thereof.
  • the binder can comprise hydroxypropyl cellulose.
  • the binder or filler can be present from about 2% to about 49% by weight of the compositions of the disclosure provided herein or any range within these values. In some aspects, the binder or filler can be present in the composition of the disclosure from about 5% to about 15% by weight.
  • the binder or filler can be present in the composition of the disclosure at about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11 %, 12%, 13%, 14%, or 15% by weight or any range within any of these values.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and/or powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the diluent can comprise lactose monohydrate.
  • the diluent can comprise lactose monohydrate Fast-Flo 316 NF.
  • compositions of the disclosure can comprise from about 5% to about 49% of a diluent by weight of composition or any range between any of these values.
  • the diluent can be present in the compositions of the disclosure from about 15% to about 30% by weight.
  • the diluent can be present in the composition of the disclosure at about 15%, 16%, 17%, 18%, 19%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight or any range within any of these values.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cationexchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; or mixtures thereof.
  • the amount of disintegrant in the compositions of the disclosure can vary.
  • the disintegrant can comprise croscarmellose sodium
  • the disintegrant can comprise croscarmellose sodium NF (Ac-Di-Sol).
  • compositions of the disclosure can comprise from about 0.5% to about 15% or from about 1% to about 10% by weight of a disintegrant.
  • the compositions of the disclosure can comprise a disintegrant in an amount of about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11 %, 12%, 13%, 14%, or 15% by weight of the composition or in any range within any of these values.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R.
  • the lubricant can comprise magnesium stearate.
  • the compositions can of the disclosure can comprise about 0.1 to about 5% by weight of a lubricant.
  • compositions of the disclosure comprise a lubricant in an amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.8%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%, by weight of the composition or in any range within any of these values.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL® (Cabot Co. of Boston, MA), talc, including asbestos-free talc, or mixtures thereof.
  • Coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, or color lakes, or mixtures thereof.
  • Flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that provide a pleasant taste sensation, such as peppermint or methyl salicylate, or mixtures thereof.
  • Sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, sucralose; artificial sweeteners, such as saccharin or aspartame; or mixtures thereof.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite; surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), or triethanolamine oleate; or mixtures thereof.
  • Suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrolidone, or mixtures thereof.
  • Preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate, alcohol, or mixtures thereof.
  • Wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether, or mixtures thereof.
  • Solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, syrup, or mixtures thereof.
  • non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil, cottonseed oil, a or nd mixtures thereof.
  • Organic acids include, but are not limited to, citric acid, tartaric acid, or mixtures thereof.
  • Sources of carbon dioxide include, but are not limited to, sodium bicarbonate, sodium carbonate, or combinations thereof.
  • the compounds of the disclosure and the compositions of the disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
  • compositions of the disclosure can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compositions of the disclosure can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds of the disclosure and the compositions of the disclosure can be formulated as a preparation suitable for implantation or injection.
  • pharmaceutically acceptable salt of gemcabene and the compositions of the disclosure can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
  • ion exchange resins e.g., as a sparingly soluble salt
  • sparingly soluble derivatives e.g., as a sparingly soluble salt
  • suitable vehicle e.g., sterile pyrogen-free water
  • compositions of the disclosure are suitable for oral administration.
  • These compositions can comprise solid, semisolid, gelmatrix or liquid dosage forms suitable for oral administration.
  • oral administration includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, without limitation, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups or any combination thereof.
  • compositions of the disclosure suitable for oral administration are in the form of a tablet or a capsule.
  • the composition of the disclosure can be in the form of a tablet.
  • the composition of the disclosure can be in the form of a capsule.
  • the compound of the disclosure can be in the form of a capsule.
  • capsules can be immediate release capsules.
  • a non-limiting example of a capsule is a CONI-SNAP® hard gelatin capsule.
  • compositions of the disclosure can be in the form of compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and/or cellulose acetate phthalate.
  • a film coating can impart the same general characteristics as a sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the coating can comprise a film coating.
  • the film coating can comprise Opadry White and simethicone emulsion 30% USP.
  • the compound of the disclosure can be in the form of a tablet. In some aspects, the compound of the disclosure can be in the form of a compressed tablet. In some aspects, the compound of the disclosure can be in the form of a film-coated compressed tablet. In some aspects, the compositions of the disclosure can be in the form of film-coated compressed tablets.
  • compositions of the disclosure can be prepared by fluid bed granulation of the compound of the disclosure with one or more pharmaceutically acceptable carriers, vehicles, and/or excipients.
  • the compositions of the disclosure can be prepared by fluid bed granulation process and can provide a tablet formulation with good flowability, good compressibility, fast dissolution, good stability, and/or minimal to no cracking.
  • the fluid bed granulation process can allow preparation of formulations having high drug loading, such as over 70% or over 75% of a compound of the disclosure.
  • compositions of the disclosure can be in the form of soft or hard capsules, which can be made from gelatin, methylcellulose, starch, and/or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • tsoft gelatin shells can contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives include, but are not limited to, those as described herein, including methyl- and propyl-parabens, sorbic acid, and combinations thereof.
  • the liquid, semisolid, and solid dosage forms provided herein can be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils, triglycerides, and combinations thereof.
  • Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules can also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions of the disclosure can be in liquid or semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • the emulsion can be a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions can include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
  • Suspensions can include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions can include a pharmaceutically acceptable acetal, such as a di-(lower alkyl)acetal of a lower alkyl aldehyde (the term “lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs can be clear, sweetened, and hydroalcoholic solutions.
  • Syrups can be concentrated aqueous solutions of a sugar, for example, sucrose, and can comprise a preservative.
  • a solution in a polyethylene glycol can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • the compositions of the disclosure for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Miccellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions of the disclosure can be provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders can include, but are not limited to, diluents, sweeteners, wetting agents, and mixtures thereof.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders can include, but are not limited to, organic acids, a source of carbon dioxide, and mixtures thereof.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • flavoring and sweetening agents can be especially useful in the formation of chewable tablets and lozenges.
  • compositions of the disclosure can be formulated as immediate or modified release dosage forms, including delayed-, extended, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions of the disclosure can comprise another active ingredient that does not impair the composition's therapeutic or prophylactic efficacy and/or can comprise a substance that augments or supplements the composition's efficacy.
  • the tablet dosage forms can comprise a pharmaceutically acceptable salt of gemcabene in powdered, crystalline, or granular form, and can further comprise one or more carriers and/or one or more vehicles described herein, including binders, disintegrants, controlled- release polymers, lubricants, diluents, and/or colorants.
  • niclosamide, or the pharmaceutically acceptable salt thereof is administered orally. In some asepcts, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a capsule. In some asepcts, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
  • the gemcabene, or the pharmaceutically acceptable salt thereof is administered orally. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
  • the gemcabene, or the pharmaceutically acceptable salt thereof can be formulated as described in WO 2018/195163, published October 25, 2018. In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, can have a PSD90 ranging from 40 pm to about 75 pm as measured by laser light diffraction. In certain aspects, the gemcabene is a calcum salt. In some embodiments, the pharmaceutically acceptable salt of gemcabene comprises water in 3% w/w to 5% w/w of the pharmaceutically acceptable salt as determined by Karl-Fisher analysis. In some aspects, the pharmaceutically acceptable salt of gemcabene comprises isobutyric acid in 0.07% w/w or less of the pharmaceutically acceptable salt as determined by ion chromatography.
  • the pharmaceutically acceptable of gemcabene comprises 2.5 ppm or less of bis-(4-chlorobutyl)ether as determined by gas chromatography. In some aspects, the pharmaceutically acceptable salt of gemcabene comprises 2.5 ppm or less of 6-(4-chlorobutoxy)-2,2-dimethyl-hexanoic acid as determined by gas chromatography. In certain aspects, the pharmaceutically acceptable salt of gemcabene comprises 2.5 ppm or less of l-chloro-4-hydroxy butane as determined by gas chromatography. In some aspects, the compositions of the disclosure comprising gemcabene can comprise from about 50 mg to about 900 mg, about 150 mg to about 600 mg, or about 150 mg to about 300 mg of a compound of the disclosure.
  • compositions of the disclosure can comprise a compound of the disclosure in an amount of about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about
  • compositions of the disclosure can comprise about 50 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise about 150 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise about 300 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise about 600 mg of a compound of the disclosure. [0112] In some aspects, the gemcabene compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 25 mg to about 900 mg, about 150 mg to about 600 mg, or about 150 mg to about 300 mg of gemcabene.
  • the gemcabene compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 25 mg, about 30 mg, about 40 mg, 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about
  • compositions of the disclosure can comprise a pharmaceutically acceptable salt of gemcabene or a pharmaceutically acceptable salt thereof, in an amount that is a molar equivalent to about 50 mg. In some aspects, the compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 150 mg of he disclosure in an amount that is a molar equivalent to about 300 mg. In some aspects, the compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 600 mg.
  • the gemcabene compositions of the disclosure can comprise gemcabene, or a pharmaceutically acceptable aslt thereof, in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, or any amount ranging from and to these values.
  • compositions of the disclosure comprising niclosamide, or a pharmaceutically acceptable salt thereof can comprise from about 0.1 mg to about 5 g, or about 0.1 mg to about 2 g, or about 0.5 mg to about 1 g of niclosamide, or a pharmaceutically acceptable salt thereof.
  • the niclosamide compositions can comprise about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg.
  • the gemcabene and/or niclosamide compositions of the present disclosure can be administered from 1 to 10 times a day. In some aspects, the compositions of the present disclosure can be administered from 1 to 5 times a day. In some aspects, the compositions of the present disclosure can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In some aspects, the compositions of the present disclosure can be administered once a day. In some aspects, the compositions of the present disclosure can be administered twice a day.
  • niclosamide in some aspects, can be formulated in a composition comprising one or more of mannitol, microcrystalline cellulose (MCC), sodium lauryl sulfate (SLS), sodium starch glycolate, hydroxypropyl cellulose (HPC), colloidal silicon dioxide, and sodium stearyl fumarate.
  • MCC microcrystalline cellulose
  • SLS sodium lauryl sulfate
  • HPC hydroxypropyl cellulose
  • colloidal silicon dioxide sodium stearyl fumarate
  • the niclosamide comprises between about 50% and about 60% weight by weight of the formulation. In some aspects, the niclosamide comprises between about 54% and about 57% weight by weight of the formulation. In some aspects, the niclosamide comprises between about 55% and about 56% weight by weight of the formulation. In some aspects, the niclosamide comprises about 55% weight by weight of the formulation.
  • the niclosamide comprises about 55.6% weight by weight of the formulation.
  • the formulation comprises mannitol and wherein the mannitol comprises between about 4% and about 12% weight by weight of the formulation.
  • the formulation comprises mannitol and wherein the mannitol comprises between about 6% and about 10% weight by weight of the formulation.
  • the formulation comprises mannitol and wherein the mannitol comprises about 8% weight by weight of the formulation.
  • the formulation comprises mannitol and wherein the mannitol comprises about 8.8% weight by weight of the formulation.
  • the formulation comprises MCC and wherein the MCC comprises between about 12% and about 18% weight by weight of the formulation.
  • the formulation comprises MCC and wherein the MCC comprises between about 14% and about 16% weight by weight of the formulation. In some aspects, the formulation comprises MCC and wherein the MCC comprises about 15% weight by weight of the formulation. In some aspects, the formulation comprises MCC and wherein the MCC comprises about 15.1% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises at least about 3% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises between about 3% and about 7% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises between about 4% and about 6% weight by weight of the formulation.
  • the formulation comprises SLS and wherein the SLS comprises about 5% weight by weight of the formulation.
  • the formulation comprises sodium starch glycolate and wherein the sodium starch glycolate comprises between about 4% and about 12% weight by weight of the formulation.
  • the formulation comprises sodium starch glycolate and wherein the sodium starch glycolate comprises between about 7% and about 9% weight by weight of the formulation.
  • the formulation comprises sodium starch glycolate and wherein the sodium starch glycolate comprises about 8% weight by weight of the formulation.
  • the formulation comprises HPC and wherein the HPC comprises between about 3% and about 7% weight by weight of the formulation.
  • the formulation comprises HPC and wherein the HPC comprises between about 4% and about 6% weight by weight of the formulation. In some aspects, the formulation comprises HPC and wherein the HPC comprises about 5% weight by weight of the formulation. In some aspects, the formulation comprises colloidal silicon dioxide and wherein the colloidal silicon dioxide comprises between about 0.1% and about 0.9% weight by weight of the formulation. In some aspects, the formulation comprises colloidal silicon dioxide and wherein the colloidal silicon dioxide comprises between about 0.4% and about 0.6% weight by weight of the formulation. In some aspects, the formulation comprises colloidal silicon dioxide and wherein the colloidal silicon dioxide comprises about 0.5% weight by weight of the formulation.
  • the formulation comprises sodium stearyl fumarate and wherein the sodium stearyl fumarate comprises between about 0.1% and about 4% weight by weight of the formulation. In some aspects, the formulation comprises sodium stearyl fumarate and wherein the sodium stearyl fumarate comprises between about 1% and about 3% weight by weight of the formulation. In some aspects, the formulation comprises sodium stearyl fumarate and wherein the sodium stearyl fumarate comprises about 2% weight by weight of the formulation.
  • the disclosure provides a formulation comprising (a) niclosamide, comprising 55% weight by weight of the formulation; (b) mannitol, comprising 8% weight by weight of the formulation; (c) MCC, comprising 15% weight by weight of the formulation; (d) SLS, comprising 5% weight by weight of the formulation; (e) sodium starch hlycolate, comprising 8% weight by weight of the formulation; (f) hydroxypropyl cellulose (HPC), comprising 5% weight by weight of the formulation; (g) colloidal silicon dioxide, comprising 0.5% weight by weight of the formulation; and (h) Sodium Stearyl Fumarate, comprising 2% weight by weight of the formulation.
  • niclosamide, or a pharmaceutically acceptable salt thereof can be formulated as descibred in US Patent No. 10,292,951, issued May 21, 2019.
  • niclosamide, or a pharmaceutically acceptable salt thereof is formulated as a solid pharmaceutical composition, which comprises: an inner phase which is a wet granulated solid preparation comprising niclosamide, or a pharmaceutically acceptable salt thereof; one or more disintegrants; one or more diluents; and one or more binders; and an external phase comprising one or more glidants and/or one or more lubricants.
  • niclosamide, or a pharmaceutically acceptable salt thereof can be formulated as descibred in US Patent Publication No. 2019/0151231, published May 23, 2019.
  • niclosamide, or a pharmaceutically acceptable salt thereof is formulated as a nonaqueous topical composition comprising: (i) niclosamide a pharmaceutically acceptable salt or hydrate thereof; and (ii) greater than 60% by weight of a polyethylene glycol (PEG), wherein the average molecular weight of the PEG is 600 or less.
  • PEG polyethylene glycol
  • niclosamide, or a pharmaceutically acceptable salt thereof can be formulated as descibred in US Patent No. 8,524,280, issued September 3, 2013.
  • niclosamide, or a pharmaceutically acceptable salt thereof is formulated as microparticles comprising niclosamide obtained by (a) dissolving, melting, or suspending niclosamide in at least one fatty acid, conjugated fatty acid, or combinations thereof to form a mixture, and (b) mixing the mixture of step (a) with a liquid hydrophilic or lipophilic carrier to form the microparticles having a diameter from 100 nm to 25 microns, and wherein the microparticles and carrier are encapsulated in a soft or hard, gelatin, or non-gelatin capsule.
  • niclosamide, or a pharmaceutically acceptable salt thereof can be formulated as described in US Patent No. 10,653,784, issued May 19, 2020. In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated as descibred in US Patent Publication No. 2020/0268894, published as August 27, 2020.
  • Antiviral assay This reverse genetic system allows manipulation of the viral genome at any nucleotide position and engineering foreign into the virus (see, Xie et al., 2020).
  • a nano luciferase gene was engineered into the open- reading-frame 7 (ORF7) of the SARS-CoV-2 genome.
  • ORF7 open- reading-frame 7
  • the cells When cells were infected with such reporter virus, the cells expressed luciferase that could be quantified to indicate viral replication. Increasing amounts of luciferase signals were detected in Vero E6 cells after infected with the reporter virus from 1 to 36 h post-infection.
  • luciferase signal could be used as a surrogate to test antiviral inhibitors.
  • Niclosamide activity is an antiparasitic agent that has broad spectrum of antiviral activity.
  • niclosamide powder was dissolved in 100% DMSO at 10 mM. The antiviral assay was performed in a 96-well plate. Approximately 1.5 x lO 4 Vero E6 cells were seeded to each well the night before viral infection. Different concentrations of niclosamide were added to cells together with reporter SARS-CoV-2 (MOI of 0.1). At each tested condition, the cell medium contained a final concentration of 0.5% DMSO.
  • Subjects diagnosed with Covid-19 are administered 300 mg - 900 mg/day of gemcabene in combination with 100 mg - 4 g/day of niclosamide for a period of 7 to 28 days to reduce the viral load and/or symptoms. Subjects are monitored for improvement.
  • Subjects diagnosed with a viral infection who meet high risk criteria are administered 300 mg - 900 mg/day of gemcabene in combination with 100 mg - 4 g/day of niclosamide for a period of 7 to 28 days to reduce the risk of progessing to respiratory failure. Subjects are monitored for improvement in symptoms.
  • Subjects having influenza virus are administered 300 mg - 900 mg/day of gemcabene in combination with 100 mg - 4 g/day of niclosamide for a period of 7 to 28 days to reduce the viral load and/or symptoms. Subjects are monitored for improvement.

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Abstract

The present disclosure provides methods of treating viral infections with a combination of niclosamide and gemcabene. Also provided are compositions comprising the compounds.

Description

METHOD OF TREATING VIRAL INFECTIONS WITH A COMBINATION OF NICLOSAMIDE AND GEMCABENE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of U.S. Provisional Application No. 63/133,650 filed January 4, 2021, which is incorporated herein by reference in its entirety.
FIELD
[0002] The present disclosure provides methods of treating viral infections with a combination of niclosamide and gemcabene. Also provided are compositions comprising the compounds.
BACKGROUND
[0003] Influenza is the most common respiratory illness and, while generally seasonal, spreads rapidly and globally, affecting all age groups. Seasonal influenza accounts for greater than 200,000 hospitalizations and greater than 30,000 deaths per year in the United States. More recently, a previously unknown respiratory illnesss, SARS-CoV-2 quickly reached pandemic status and as of December 5, 2020, has caused more than 1.53 million deaths worldwide.
[0004] Vaccination is the most effective manner to control virus-induced outbreaks and avoid complications which result from infection. However, in view of the difficulty to prepare, distribute and immunize the world population against an epidemic or pandemic, there is a clear and apparent need to develop more efficient methods to reduce the severity of viral infections.
SUMMARY
[0005] The present disclosure provides a method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof. In some aspects, the viral infection is caused by an RNA virus. In some aspects, the virus has a filamentous, isometric, enveloped, or a head and tail conformation.
[0006] In some aspects, the RNA virus is a positive-strand RNA virus. In some aspects, the positive-strand RNA virus belongs to the family of Picornaviridae, Astroviridae, Caliciviridae, Hepeviridae Flaviviridae, Togaviridae, Arteriviridae, or Coronaviridae. In certain aspects, the positive-strand RNA virus belongs to the family of Coronaviridae. In some aspects, the Coronaviridae virus is selected from Bat coronavirus CDPHE15, Bat coronavirus HKU10, Rhinolophus ferrumequinum alphacoronavirus HuB-2013, Human coronavirus 229E, Lucheng Rn rat coronavirus, Ferret coronavirus, Mink coronavirus 1, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Myotis ricketti alphacoronavirus Sax-2011, Nyctalus velutinus alphacoronavirus SC-2013, Porcine epidemic diarrhea virus, Scotophilus bat coronavirus 512, Rhinolophus bat coronavirus HKU2, Human coronavirus NL63, NL63-related bat coronavirus strain BtKYNL63-9b, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus - type species, Bat Hp-betacoronavirus Zhejiang2013, Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4, Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome- related coronavirus, Wigeon coronavirus HKU20, Bulbul coronavirus HKU11 - type species, Porcine coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night heron coronavirus HKU19, Common moorhen coronavirus HKU21, Beluga whale coronavirus SW1, and Avian coronavirus - type species. In some aspects, the Coronaviridae virus is Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In certain aspects, the Coronaviridae virus is selected from HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, SARS CoV-2, a mutated strain thereof, and any combination thereof.
[0007] In certain asepcts, the RNA virus is a negative- strand RNA virus. In some aspects, the negative- strand RNA virus belongs to the family of Orthomyxoviridae, Paramyxoviridae, Rhabdoviridiae, Filoviruses, or Arenaviruses. In some aspects, the negative- strand virus is selected from Influenza virus, Sendai virus, Human parainfluenza virus 1 (hPIVl), Simian virus 5 (SV5, PIV5), Mumps virus, Newcastle disease virus (NDV), Measles virus, Rinderpest virus , Respiratory syncytial virus (RSV), Vesicular stomatitis virus (VSV), Rabies virus, Ebola virus, Marburg virus, Lymphocytic choriomeningitis virus (LCMV), Junin virus, and Lassa fever virus. [0008] In some aspects, the virus is a retrovirus. In certain aspects, the retrovirus is selected from a Lenti virus, Alpharetrovirus, Betaretrovirus, Deltaretrovirus, Gammaretrovirus, and a Epsilonretrovirus. In some aspects, the retrovirus is a Simian immunodeficiency virus (SIV), Human immunodeficiency virus-1 (HIV-1), HIV-2, Feline immunodeficiency virus (FIV), Equine infectious anemia virus (EIAV), Mouse mammary tumor-like virus (MMTV), Mason-Pfizer monkey virus (MPMV), Respiratory syncytial virus RSV, bovine leukemia virus (BLV), Human T- cell leukemia virus-1 (HTLV-1), HTLV-2, Murine leukemia virus (MuLV), Gibbon ape leukemia virus (GALV), and any combination thereof.
[0009] In certain aspects, the viral infection is caused by a DNA virus. In some aspects, the DNA virus is Adenovirus, infectious canine hepatitis virus, Papillomavirus, polyomaviridae, simian vacuolating virus, Parvovirus Bl 9, canine parvovirus, Herpes simplex virus, varicellazoster virus, cytomegalovirus, Epstein-Barr virus, Smallpox virus, cow pox virus, sheep pox virus, monkey pox virus, vaccinia virus, Torque teno virus, or any combination thereof.
[0010] In certain aspects, the subject has a medical condition that increases risk of a poor prognosis without treatment or an increased risk of a severe immune response to the infection. In some aspects, the subject has an impaired or reduced immune response. In some aspects, the subject is immunocompromised. In some aspects, the subject is undergoing or has undergone one or more of an immunosuppressive therapy, presenting a sign or symptom of a second medical disease or disorder or a subject of a past, present or future medical intervention. In certain asepcts, the second medical disease or disorder comprises an infection, an HIV infection, an onset of Acquired Immunodeficiency Syndrome (AIDS), a proliferative disorder, a cancer, asthma, or an autoimmune condition. In some aspects, the immunosuppressive therapy comprises one or more of an ablation of bone marrow or circulating blood cell types, a radiation therapy, a therapy for a proliferative or malignant disease, a monoclonal antibody therapy, a blood transfusion, a bone marrow transplant, or removal of a lymph node. In some aspects, the medical intervention comprises one or more of a surgery, a graft, a tissue or organ transplant, a wound or bum debridement, a setting of a bone, a replacement of a bone, a replacement of a joint, a cardiac bypass, a vascular stent placement, a spinal tap, an organ resection, or a cardiac pacemaker placement or replacement. In certain aspects, the subject presents a sign or symptom of hypertension or cardiac disease. In some aspects, the subject has been diagnosed with hypertension or cardiac disease. In some aspects, the subject presents a sign or symptom of a metabolic disorder. In some aspects, the subject has been diagnosed with the metabolic disorder. In certain aspects, the metabolic disorder comprises insulin resistance, pre-diabetes, or diabetes. In some aspects, the subject presents a sign or symptom of a clotting or vascular disorder. In some aspects, the subject has been diagnosed with the clotting or vascular disorder. In certain asepcts, the subject is at risk of forming a clot or suffering from a stroke.
[0011] In certain aspects, the subject has not received a vaccine for the vims prior to contacting the vims or presenting the viral infection. In some aspects, the subject is a neonatal subject. In certain aspects, the mother of the subject is a carrier of the vims or infected by the vims. In some aspects, the subject is under 18 years of age. In some aspects, the subject is between 18 years of age and 29 years of age, inclusive of the endpoints. In some aspects, the subject is between 30 years of age and 49 years of age, inclusive of the endpoints. In some aspects, the subject is between 50 years of age and 69 years of age, inclusive of the endpoints. In some aspects, the subject is over 70 years of age.
[0012] In certain asepcts, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at an effective amount of from about 25 mg/day to about 900 mg/day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 450 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 750 mg/day, about 800 mg/day, or about 900 mg/day.
[0013] In certain aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at an effective amount of from about 0.1 mg/day and about 5 g/day. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 0.1 mg/day, about 0.25 mg/day, about 0.50 mg/day, about 0.75 mg/day, about 1.0 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 250 mg/day, about 500 mg/day, about 750 mg/day, about 1 g/day, about 1.5 g/day, about 2 g/day, about 2.5 g/day, about 3 g/day, about 3.5 g/day, about 4 g/day, about 4.5 g/day, or about 5 g/day. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 2 g/day.
[0014] In certain aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered simulataneously with the gemcabene, or the pharmaceutically acceptable salt thereof. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof, are co-formulated. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered before the gemcabene, or the pharmaceutically acceptable salt thereof.
[0015] In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered after the gemcabene, or the pharmaceutically acceptable salt thereof. In certain aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a capsule. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a tablet. [0016] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
[0017] In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7 to about 14 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
[0018] In certain aspects, the pharmaceutical composition comprises the monocalcium salt of gemcabene.
[0019] In certain aspects, the niclosamide is administered as a formulation comprising:
(a) niclosamide, comprising about 55% to about 56% weight by weight of the formulation;
(b) mannitol, comprising about 8% to about 9% weight by weight of the formulation;
(c) MCC, comprising about 15% to about 16% weight by weight of the formulation;
(d) SLS, comprising about 5% weight by weight of the formulation;
(e) sodium starch glycolate, comprising about 8% weight by weight of the formulation;
(f) hydroxypropyl cellulose (HPC), comprising about 5% weight by weight of the formulation;
(g) colloidal silicon dioxide, comprising about 0.5% weight by weight of the formulation; and
(h) sodium stearyl fumarate, comprising about 2% weight by weight of the formulation. [0020] In certain aspects, the niclosamide is administered as a formulation comprising:
(a) niclosamide, comprising about 55.5% weight by weight of the formulation;
(b) mannitol, comprising about 8.8% weight by weight of the formulation;
(c) MCC, comprising about 15.1% weight by weight of the formulation;
(d) SLS, comprising about 5% weight by weight of the formulation;
(e) sodium starch glycolate, comprising about 8% weight by weight of the formulation;
(f) hydroxypropyl cellulose (HPC), comprising about 5% weight by weight of the formulation; (g) colloidal silicon dioxide, comprising about 0.5% weight by weight of the formulation; and
(h) sodium stearyl fumarate, comprising about 2% weight by weight of the formulation.
[0021] In certain asepcts, the niclosamide is administered as a formulation comprising:
(a) about 250 mg of niclosamide;
(b) about 39.6 mg of mannitol,
(c) about 68.1 mg of MCC;
(d) about 22.5 mg of SLS;
(e) about 36 mg of sodium starch glycolate;
(f) about 22.5 mg of hydroxypropyl cellulose (HPC);
(g) about 2.3 mg of colloidal silicon dioxide; and
(h) about 9 mg of sodium stearyl fumarate.
[0022] In certain aspects, the gemcabene is administered as a formulation comprising:
(a) about 250 mg of niclosamide;
(b) about 39.6 mg of mannitol,
(c) about 68.1 mg of MCC;
(d) about 22.5 mg of SLS;
(e) about 36 mg of sodium starch glycolate;
(f) about 22.5 mg of hydroxypropyl cellulose (HPC);
(g) about 2.3 mg of colloidal silicon dioxide; and
(h) about 9 mg of sodium stearyl fumarate.
[0023] In certain asepcts, the gemcabene, or the pharmaceutically acceptable salt thereof, has a PSD90 ranging from 40 pm to about 75 pm as measured by laser light diffraction.
[0024] In certain aspects, the present disclosure provides a kit comprising gemcabene, or a pharmaceutically acceptable salt thereof, for administering gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof, to a subject having a viral infection.
DETAILED DESCRIPTION
[0025] The present disclosure provides methods of treating or preventing viral infections with a combination of niclosamide, or a pharmaceutically acceptable salt thereof, and gemcabene, or a pharmaceutically acceptable salt thereof. I. Definitions.
[0026] In order that the present description can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.
[0027] It is to be noted that the term “a” or “an” entity refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein. It is further noted that the claims can be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a negative limitation.
[0028] Furthermore, “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
[0029] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and/or “consisting essentially of’ are also provided.
[0030] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
[0031] Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the disclosure. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of a disclosure is disclosed as having a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.
[0032] The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). In some aspects of the formulations of the disclosure, the term “about” encompasses a deviation from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses an increase from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses a decrease from the recited value of between 0.001% and 10%, inclusive of the endpoints.
[0033] The terms “administration,” “administering,” and grammatical variants thereof refer to introducing a composition, such as gemcabene and/or niclosamide, of the present disclosure, into a subject via a pharmaceutically acceptable route. The introduction of a composition of the present disclosure into a subject is by any suitable route, including intratumorally, orally, pulmonarily, intranasally, parenterally (intravenously, intra-arterially, intramuscularly, intraperitoneally, or subcutaneously), rectally, intralymphatically, intrathecally, periocularly or topically. Administration includes self-administration and the administration by another. A suitable route of administration allows the composition or the agent to perform its intended function. For example, if a suitable route is intravenous, the composition is administered by introducing the composition or agent into a vein of the subj ect.
[0034] A “subject” includes any human or nonhuman animal. The term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some aspects, the subject is a human. The terms “subject” and “patient” are used interchangeably herein.
[0035] The term “effective amount” refers to an amount of an agent (e.g., gemcabene and/or niclosamide) that provides the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. An effective amount can be administered in one dosage or can be dividied into multiple dosages, the total of such dosages being the effective amount. For example, an effective amount can be provided in two separate administrations over a period of time, that in aggregate, provide the effective amount of the formulation.
[0036] In some aspects, an “effective amount” is the amount of gemcabene and/or niclosamide that decreases or reduces one or more of a viral load, a number (absolute or relative) of viral particles or infected cells, reduces a severity of a sign or symptom of the infection, and/or improves one or more aspects of a prognosis for the subject.
[0037] The terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to decreases or reduce one or more of a viral load, a number (absolute or relative) of viral particles or infected cells, reduce a severity of a sign or symptom of the infection, and/or improve one or more aspects of a prognosis for the subject. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
[0038] The terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
IL Methods of Treatment
[0039] The present disclosure provides methods of treating viral infections using niclosamide, or a pharmaceutically acceptable salt thereof, in combination with gemcabene, or a pharmaceutically acceptable salt thereof. [0040] In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered orally, intravenously, intramuscularly, subcutaneously, peritoneally, intrathecally, intracranially, topically, vaginally, rectally, or any combination thereof. In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, is administered as a tablet. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, is administered as a capsule.
[0041] In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at an effective amount for the method. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at from about 50 mg to about 900 mg, about 150 mg to about 600 mg, or about 150 mg to about 300 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, or an amount ranging from and to any of these values. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 50 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 150 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 300 mg. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 600 mg.
[0042] In other aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, or any amount ranging from and to these values.
[0043] In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered from about 0.1 mg to about 5 g, or about 0.1 mg to about 2 g, or about 0.5 mg to about 1 g. In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg. about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, or about 5 g.
[0044] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, of the present disclosure can be administered from 1 to 10 times a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered from 1 to 5 times a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day.
[0045] In some aspects, the subject that can be treated with the combination of gemcabene, or the pharmaceutically acceptable salt thereof, and niclosamide, or the pharmaceutically acceptable salt thereof, is a nonhuman mammal. In some aspects, the subject that can be treated is a human.
[0046] In some aspects, the combination of gemcabene, or the pharmaceutically acceptable salt thereof, and niclosamide, or the pharmaceutically acceptable salt thereof, can be used to treat a viral infection. In certain aspects the viral infection can be caused by an RNA virus or a DNA virus. In certain aspects, the virus has a filamentous, isometric, enveloped, or a head and tail conformation.
[0047] In some asapects, the viral infection can be caused by a postivie-strand RNA virus. In some aspcets, the positive-strand RNA virus can belong to the family of Picornaviridae, Astroviridae, Caliciviridae, Hepeviridae Flaviviridae, Togaviridae, Arteriviridae, or Coronaviridae. In certain aspects, the positive-strand RNA virus belongs to the family Coronaviridae and is Bat coronavirus CDPHE15, Bat coronavirus HKU10, Rhinolophus ferrumequinum alphacoronavirus HuB-2013, Human coronavirus 229E, Lucheng Rn rat coronavirus, Ferret coronavirus, Mink coronavirus 1, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Myotis ricketti alphacoronavirus Sax-2011, Nyctalus velutinus alphacoronavirus SC-2013, Porcine epidemic diarrhea virus, Scotophilus bat coronavirus 512, Rhinolophus bat coronavirus HKU2, Human coronavirus NL63, NL63 -related bat coronavirus strain BtKYNL63-9b, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus - type species, Bat Hp-betacoronavirus Zhejiang2013, Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4, Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus, Wigeon coronavirus HKU20, Bulbul coronavirus HKU11 - type species, Porcine coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night heron coronavirus HKU19, Common moorhen coronavirus HKU21, Beluga whale coronavirus SW1, Avian coronavirus - type species, or any combination thereof. In certain aspects the Coronaviridae virus comprises Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In certain aspects, the Coronviridae virus comprises HCoV 229E, HCoV OC43, HCoVNL63, HCoV HKUl, SARS CoV, MERS CoV, SARS CoV-2, a mutated strain thereof, or any combination thereof.
[0048] In certain aspects, the viral infection comprises an infection by a negative-strand RNA virus. In some aspects, the negative-strand virus belongs to the family of Orthomyxoviridae, Paramyxoviridae, Rhabdoviridiae, Filoviruses, or Arenaviruses. In some aspects the negativestrand virus comprises Influenza virus (including, but not limited to, influenza A, influenza B and its subtypes), Sendai virus, Human parainfluenza virus 1 (hPIVl), Simian virus 5 (SV5, PIV5), Mumps virus, Newcastle disease virus (NDV), Measles virus, Rinderpest virus, Respiratory syncytial virus (RSV), Vesicular stomatitis virus (VSV), Rabies virus, Ebola virus, Marburg virus, Lymphocytic choriomeningitis virus (LCMV), Junin virus, Lassa fever virus, or a combination thereof.
[0049] In some aspects, the virus comprises a retrovirus. In certain aspects, the retrovirus comprises a Lentivirus, Alpharetrovirus, Betaretrovirus, Deltaretrovirus, Gammaretrovirus, Epsilonretrovirus, or any combination thereof. In some aspects, the retrovirus comprises a Simian immunodeficiency virus (SIV), Human immunodeficiency virus-1 (HIV-1), HIV-2, Feline immunodeficiency virus (FIV), Equine infectious anemia virus (EIAV), Mouse mammary tumorlike virus (MMTV), Mason-Pfizer monkey virus (MPMV), Respiratory syncytial virus RSV, bovine leukemia virus (BLV), Human T- cell leukemia virus-1 (HTLV-1), HTLV-2, Murine leukemia virus (MuLV), Gibbon ape leukemia virus (GALV), or a combination thereof.
[0050] In certain aspects, the viral infection is caused by a DNA virus. In some aspects, the DNA virus comprises Adenovirus, infectious canine hepatitis virus, Papillomavirus, polyomaviridae, simian vacuolating virus, Parvovirus Bl 9, canine parvovirus, Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, Smallpox virus, cow pox virus, sheep pox virus, monkey pox virus, vaccinia virus, Torque teno virus, or any combination thereof. In certain aspects the DNA virus comprises CMV, BKV, HSV, VZV, EBV, as well as mutations thereof. In some aspects, the DNA virus comprises hepatitis B virus, hepatitis C virus, human cytomegalovirus, herpes simplex virus type 1, or any combination thereof. In some aspects, the DNA virus comprises hepatitis C virus.
[0051] In certain aspects, the subject can have medical condition that increases risk of a poor prognosis without treatment or an increased risk of a severe immune response to the infection. In some aspects, the subject has an impaired or reduced immune response. In certain aspects, the subject is immunocompromised. In some aspects, the subject is undergoing or has undergone one or more of an immunosuppressive therapy, presenting a sign or symptom of a second medical disease or disorder or a subject of a past, present or future medical intervention. In some aspects, the second medical disease or disorder comprises an infection, an HIV infection, an onset of Acquired Immunodeficiency Syndrome (AIDS), a proliferative disorder, a cancer, asthma, and/or an autoimmune condition. In some aspects, the immunosuppressive therapy comprises one or more of an ablation of bone marrow or circulating blood cell types, a radiation therapy, a therapy for a proliferative or malignant disease, a monoclonal antibody therapy, a blood transfusion, a bone marrow transplant, or removal of a lymph node. In some aspects, the medical intervention comprises one or more of a surgery, a graft, a tissue or organ transplant, a wound or bum debridement, a setting of a bone, a replacement of a bone, a replacement of a joint, a cardiac bypass, a vascular stent placement, a spinal tap, an organ resection, or a cardiac pacemaker placement or replacement.
[0052] In some aspects, the subject presents a sign or a symptom of hypertension or cardiac disease. In some aspects, the subject presents a sign or symptom of a metabolic disorder. In certain aspects, the subject has been diagnosed with a metabolic disease. In some aspects, the subject has been diagnosed with a metabolic disorder that comprises insulin resistance, pre-diabetes, or diabetes.
[0053] In some aspects, the subject can have type 1, type 2 and/or gestational diabetes, familial hypercholesterolemia, elevated triglycerides, above normal BMI, a BMI >40, cystic fibrosis, a history of smoking, idiopathic pulmonary fibrosis, idiopathic respiratory distress syndrome, non-alcoholic fatty liver disease (NAFLD), Non-Alcoholic Steatohepatitis (NASH), liver disease, cirrhosis, hypertension, familial partial lipodystrophy, compromised respiratory function, asthma, chronic lung disease, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, chronic kidney disease, one or more hemoglobin disorders, sickle cell anemia, thalassemia, anemia, a compromised immune system due to cancer treatment, an autoimmune disease, an age over 65, cardiovascular disease, a heart condition^ heart failure, coronary artery disease, congenital heart disease, cardiomyopathies, and pulmonary hypertension, vitamin D deficiency, or any combination thereof. In some aspects, a subject that has a condition that makes him/her more likely to experiencee a cytokine storm can be treated prophylactically with the compounds and/or compositions of the present disclosure.
[0054] In certain aspects, the subject suitable for the present method presents a sign or symptom of a clotting or vascular disorder. In some aspects, the subject has been diagnosed with the clotting or vascular diagnosis. In some aspects, the subject is at risk of forming a clot or suffering from a stroke.
[0055] In certain asepcts, the subject has not received a vaccine for the virus prior to contacting the virus or presenting the viral infection.
[0056] In certain aspects, the subject can be a neonatal subject. In certain aspects, the mother of the subject is a carrier of the virus or infected by the virus. In some aspects, the subject is less than 18 years old, less than 30 years old, less than 50 years old, less than 60 years old, less than 75 years old, less than 80 years old, less than 85 years old, less than 90 years old, less than 95 years old, or less than 100 years old. In some aspects, the subject can be pediatric. In some aspects, the subject can be over the age of 50, 55, 60, 65, 70, 75, 80, 85, or 90 years old. In certain aspects, the subject is between 18 years of age and 29 years of age, inclusive of the endpoints. In some aspects, the subject is between 30 years of age and 49 years of age, inclusive of the endpoints. In some aspects, the subject is between 50 years of age and 69 years of age, inclusive of the endpoints. In certain aspects, the subject is over 70 years of age.
[0057] In some aspects, the combination of gemcabene, or the pharmaceutically acceptable salt thereof, and niclosamide, or the pharmaceutically acceptable salt thereof, can be used in combination with one or more additional therapeutic agents. Accordingly, in certain aspects, a method of treating a viral infection as disclosed herein comprises administering gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. Non-limiting examples of antiviral agents that can be used in the present methods include acyclovir, famcyclovir, ganciclovir, idoxuridine, foscamet, fomivirsen, molnupiravir, remdesivir, favipiravir, sofosbuvir, AT-527, boceprevir, GC376, ebselen, PF-00835231, PF-07304814, pencyclovir, trifluridine, tromantadine, valacyclovir, valgancyclovir, vidarbine, cidofavir, docosanol, amantadine, oseltamivir, peramivir, rimantadine, zanamivir, fomivirsen, enfuvirtide, imiquimod, interferon, ribavirin, viramidine, ziduvidine, didanosine, stauvidine, zalcitabine, lamivudine, abacavir, tenofovir, nevirapine, efavirenz, delavirdine, saquinavir, indinavir, atazanavir, ritonavir, nelfinavir, amprenavir, lopinavir, tipranavir, or combinations thereof.
[0058] In some aspects, gemcabene or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof, can be used in combination with one or more anti-inflammatory agents, such that multiple aspects of an inflammatory response can be targeted. Non-limiting examples of anti-inflammatory agents that can be used in the present methods include aspirin, sodium salycilate, fenoprofen, diflunixal, ibuprofen, ketoprofen, naproxen, flurbiprofen, diclofenac, ketorolac, tolmetin, etodolac, indomethacin, sulindac, aceclofenac, mefenamic acid, meclofenamic acid, tolfenamic acid, piroxicam, phenylbutazone, nabumetone, tenoxicam, indomethacin, sulindac, minisulide, nimesulide, meloxicam, etoricoxib, valdecoxib, parecoxib, paracetamol, nefopam, cortisol, cortisone, hydrocortisone, dexamethasone, fludrocortisone, methylprednisolone, prednisolone, or combinations thereof.
[0059] In some aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered to the subject prior to or after the administration of the gemcabene, or the pharmaceutically acceptable salt thereof. In other aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered to the subject concurrently with the gemcabene, or the pharmaceutically acceptable salt thereof. In certain aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof, can be administered concurrently as a single composition in a pharmaceutically acceptable carrier. In other aspects, the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof, are administered concurrently as separate compositions.
[0060] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to 6 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 3 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 2 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 45 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for about 7 to about 14 days. In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
[0061] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for a period of from about 7 days to 6 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for a period of from about 7 days to 3 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 2 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 45 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for about 7 to about 14 days. In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered once a day for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
[0062] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for a period of from about 7 days to 6 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for a period of from about 7 days to 3 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 2 months. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered for a period of from about 7 days to about 45 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for about 7 to about 28 days. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for about 7 to about 14 days. In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, can be administered twice a day for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
[0063] In certain aspects, subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, experience a shorter recovery time than those receiving other treatments or no treatment. In some aspects, subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, experience a higher survival rate than those receiving other treatments or no treatment. In some aspects, subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, are less likely to require respirator therapy than those receiving other treatments or no treatment. In some aspects, subjects who are treated with the gemcabene, or the pharmaceutically acceptable salt thereof, and/or the niclosamide, or the pharmaceutically acceptable salt thereof, experience fewer secondary complications resulting from the viral infection than those receiving other treatments or no treatment. a. Niclosamide
[0064] Niclosamide has been previously described in the art. The compound is also known as 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide and is represented by the structure shown below:
Figure imgf000020_0001
[0065] Niclosamide can also be in the form of other pharmaceutically acceptable salts. In some aspects, such salts can be derived from inorganic or organic acids or bases. b. Gemcabene
[0066] The present disclosure provides methods of treating viral infections using gemcabene, or a pharmaceutically acceptable salt thereof, in combination with niclosamide, or a pharmaceutically acceptable salt thereof. Gemcabene has been previously described, e.g., in U.S. Patent No. 5,648,387, which is hereby incorporated by reference in its entirety. The compound is also known as 6-(5-carboxy-5-methylhexyloxy)-2,2-dimethyl-hexanoic acid and is represented by the structure shown below:
Figure imgf000020_0002
[0067] In some aspects, the present disclosure provides methods of treating an antiviral infection using a pharmaceutically acceptable salt of gemcabene. In some aspects, the pharmaceutically acceptable salt can comprise the monocalcium salt of gemcabene, represented by the structure shown below:
Figure imgf000020_0003
Various gemcabene calcium salt hydrates have been previously described, e.g., in U.S. patent No. 6,861,555, which is hereby incorporated by reference in its entirety.
[0068] Gemcabene can also be in the form of other pharmaceutically acceptable salts. In some aspects, such salts can be derived from inorganic or organic acids or bases.
III. Compositions
[0069] The compounds described herein can be in the form of pharmaceutically acceptable salts. In some aspects, such salts are derived from inorganic or organic acids or bases.
[0070] Examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl -propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
[0071] Examples of suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, 7V-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, and the like.
[0072] For example, Berge lists the following FDA-approved commercially marketed salts: anions acetate, besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide, calcium edetate (ethylenediaminetetraacetate), camsylate (camphorsulfonate), carbonate, chloride, citrate, dihydrochloride, edetate (ethylenediaminetetraacetate), edisylate (1,2-ethanedisulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycollylarsanilate (glycollamidophenylarsonate), hexylresorcinate, hydrabamine (A,A'-di(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate (2-hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate (methanesulfonate), methylbromide, methylnitrate, methyl sulfate, mucate, napsylate (2-naphthalenesulfonate), nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate) and triethiodide; organic cations benzathine (M-V'-dibenzylethylenediamine), chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (7V-m ethylglucamine) and procaine; and metallic cations aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
[0073] Berge additionally lists the following non-FDA-approved commercially marketed (outside the United States) salts: anions adipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline, aspartate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), napadisylate (1,5-naphthalenedisulfonate), oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate and undecanoate; organic cations benethamine (A-benzylphenethylamine), clemizole (l-/?-chlorobenzyl-2-pyrrolildine- l'-ylmethylbenzimidazole), di ethylamine, piperazine and tromethamine (tris(hydroxymethyl)aminomethane); and metallic cations barium and bismuth.
[0074] Pharmaceutical compositions comprising gemcabene and/or niclosamide can also comprise suitable carriers, excipients, and auxiliaries that may differ depending on the mode of administration.
[0075] In some aspects, the pharmaceutically acceptable carrier or vehicle, comprises a binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, coloring agent, dye-migration inhibitor, sweetening agent, flavoring agent, or a combination thereof.
[0076] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as com starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Pan war gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC- 581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); or mixtures thereof.
[0077] Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, or mixtures thereof. In some aspects, the binder can comprise hydroxypropyl cellulose. [0078] The binder or filler can be present from about 2% to about 49% by weight of the compositions of the disclosure provided herein or any range within these values. In some aspects, the binder or filler can be present in the composition of the disclosure from about 5% to about 15% by weight. In some aspects, the binder or filler can be present in the composition of the disclosure at about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11 %, 12%, 13%, 14%, or 15% by weight or any range within any of these values.
[0079] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and/or powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. In some aspects, the diluent can comprise lactose monohydrate. In another aspect, the diluent can comprise lactose monohydrate Fast-Flo 316 NF.
[0080] The compositions of the disclosure can comprise from about 5% to about 49% of a diluent by weight of composition or any range between any of these values. In some aspects, the diluent can be present in the compositions of the disclosure from about 15% to about 30% by weight. In some aspects, the diluent can be present in the composition of the disclosure at about 15%, 16%, 17%, 18%, 19%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight or any range within any of these values.
[0081] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cationexchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; or mixtures thereof. The amount of disintegrant in the compositions of the disclosure can vary. In some aspects, the disintegrant can comprise croscarmellose sodium In some aspects, the disintegrant can comprise croscarmellose sodium NF (Ac-Di-Sol).
[0082] The compositions of the disclosure can comprise from about 0.5% to about 15% or from about 1% to about 10% by weight of a disintegrant. In some aspects, the compositions of the disclosure can comprise a disintegrant in an amount of about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11 %, 12%, 13%, 14%, or 15% by weight of the composition or in any range within any of these values. [0083] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); or mixtures thereof. In some aspects, the lubricant can comprise magnesium stearate. [0084] The compositions can of the disclosure can comprise about 0.1 to about 5% by weight of a lubricant. In some aspects, the compositions of the disclosure comprise a lubricant in an amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.8%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0%, by weight of the composition or in any range within any of these values.
[0085] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL® (Cabot Co. of Boston, MA), talc, including asbestos-free talc, or mixtures thereof.
[0086] Coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, or color lakes, or mixtures thereof.
[0087] Flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that provide a pleasant taste sensation, such as peppermint or methyl salicylate, or mixtures thereof.
[0088] Sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, sucralose; artificial sweeteners, such as saccharin or aspartame; or mixtures thereof.
[0089] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite; surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), or triethanolamine oleate; or mixtures thereof. Suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrolidone, or mixtures thereof. Preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate, alcohol, or mixtures thereof. Wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether, or mixtures thereof. [0090] Solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, syrup, or mixtures thereof.
[0091] Examples of non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil, cottonseed oil, a or nd mixtures thereof. Organic acids include, but are not limited to, citric acid, tartaric acid, or mixtures thereof. Sources of carbon dioxide include, but are not limited to, sodium bicarbonate, sodium carbonate, or combinations thereof.
[0092] It should be understood that many carriers and excipients can serve several functions, even within the same formulation.
[0093] The compounds of the disclosure and the compositions of the disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term “parenteral” as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
[0094] The compounds of the disclosure and the compositions of the disclosure can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compositions of the disclosure can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compounds of the disclosure and the compositions of the disclosure can be formulated as a preparation suitable for implantation or injection. Thus, for example, pharmaceutically acceptable salt of gemcabene and the compositions of the disclosure can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). The compounds of the disclosure and the compositions of the disclosure can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA
[0095] In some aspects, the compositions of the disclosure are suitable for oral administration. These compositions can comprise solid, semisolid, gelmatrix or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, without limitation, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups or any combination thereof. In some aspects, compositions of the disclosure suitable for oral administration are in the form of a tablet or a capsule. In some aspects, the composition of the disclosure can be in the form of a tablet. In some aspects, the composition of the disclosure can be in the form of a capsule. In some aspects, the compound of the disclosure can be in the form of a capsule.
[0096] In some aspects, capsules can be immediate release capsules. A non-limiting example of a capsule is a CONI-SNAP® hard gelatin capsule.
[0097] The compositions of the disclosure can be in the form of compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and/or cellulose acetate phthalate. A film coating can impart the same general characteristics as a sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
[0098] In some aspects, the coating can comprise a film coating. In some aspects, the film coating can comprise Opadry White and simethicone emulsion 30% USP.
[0099] In some aspects, the compound of the disclosure can be in the form of a tablet. In some aspects, the compound of the disclosure can be in the form of a compressed tablet. In some aspects, the compound of the disclosure can be in the form of a film-coated compressed tablet. In some aspects, the compositions of the disclosure can be in the form of film-coated compressed tablets.
[0100] In some aspects, the compositions of the disclosure can be prepared by fluid bed granulation of the compound of the disclosure with one or more pharmaceutically acceptable carriers, vehicles, and/or excipients. In some aspects, the compositions of the disclosure can be prepared by fluid bed granulation process and can provide a tablet formulation with good flowability, good compressibility, fast dissolution, good stability, and/or minimal to no cracking. In some aspects, the fluid bed granulation process can allow preparation of formulations having high drug loading, such as over 70% or over 75% of a compound of the disclosure.
[0101] The compositions of the disclosure can be in the form of soft or hard capsules, which can be made from gelatin, methylcellulose, starch, and/or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), can comprise two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. In some aspects, tsoft gelatin shells can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, those as described herein, including methyl- and propyl-parabens, sorbic acid, and combinations thereof. The liquid, semisolid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils, triglycerides, and combinations thereof. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules can also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
[0102] The compositions of the disclosure can be in liquid or semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. In some aspects, the emulsion can be a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions can include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions can include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions can include a pharmaceutically acceptable acetal, such as a di-(lower alkyl)acetal of a lower alkyl aldehyde (the term “lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs can be clear, sweetened, and hydroalcoholic solutions. Syrups can be concentrated aqueous solutions of a sugar, for example, sucrose, and can comprise a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration. [0103] The compositions of the disclosure for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Miccellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
[0104] The compositions of the disclosure can be provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders can include, but are not limited to, diluents, sweeteners, wetting agents, and mixtures thereof. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders can include, but are not limited to, organic acids, a source of carbon dioxide, and mixtures thereof.
[0105] Coloring and flavoring agents can be used in all of the above dosage forms. In addition, flavoring and sweetening agents can be especially useful in the formation of chewable tablets and lozenges.
[0106] The compositions of the disclosure can be formulated as immediate or modified release dosage forms, including delayed-, extended, pulsed-, controlled, targeted-, and programmed-release forms.
[0107] The compositions of the disclosure can comprise another active ingredient that does not impair the composition's therapeutic or prophylactic efficacy and/or can comprise a substance that augments or supplements the composition's efficacy.
[0108] The tablet dosage forms can comprise a pharmaceutically acceptable salt of gemcabene in powdered, crystalline, or granular form, and can further comprise one or more carriers and/or one or more vehicles described herein, including binders, disintegrants, controlled- release polymers, lubricants, diluents, and/or colorants.
[0109] In certain aspects, niclosamide, or the pharmaceutically acceptable salt thereof, is administered orally. In some asepcts, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a capsule. In some asepcts, the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
[0110] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
[OHl] In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, can be formulated as described in WO 2018/195163, published October 25, 2018. In certain aspects, the gemcabene, or the pharmaceutically acceptable salt thereof, can have a PSD90 ranging from 40 pm to about 75 pm as measured by laser light diffraction. In certain aspects, the gemcabene is a calcum salt. In some embodiments, the pharmaceutically acceptable salt of gemcabene comprises water in 3% w/w to 5% w/w of the pharmaceutically acceptable salt as determined by Karl-Fisher analysis. In some aspects, the pharmaceutically acceptable salt of gemcabene comprises isobutyric acid in 0.07% w/w or less of the pharmaceutically acceptable salt as determined by ion chromatography. In some aspects, the pharmaceutically acceptable of gemcabene comprises 2.5 ppm or less of bis-(4-chlorobutyl)ether as determined by gas chromatography. In some aspects, the pharmaceutically acceptable salt of gemcabene comprises 2.5 ppm or less of 6-(4-chlorobutoxy)-2,2-dimethyl-hexanoic acid as determined by gas chromatography. In certain aspects, the pharmaceutically acceptable salt of gemcabene comprises 2.5 ppm or less of l-chloro-4-hydroxy butane as determined by gas chromatography. In some aspects, the compositions of the disclosure comprising gemcabene can comprise from about 50 mg to about 900 mg, about 150 mg to about 600 mg, or about 150 mg to about 300 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise a compound of the disclosure in an amount of about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, or an amount ranging from and to any of these values. In some aspects, the compositions of the disclosure can comprise about 50 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise about 150 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise about 300 mg of a compound of the disclosure. In some aspects, the compositions of the disclosure can comprise about 600 mg of a compound of the disclosure. [0112] In some aspects, the gemcabene compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 25 mg to about 900 mg, about 150 mg to about 600 mg, or about 150 mg to about 300 mg of gemcabene. In some aspects, the gemcabene compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 25 mg, about 30 mg, about 40 mg, 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg gemcabene or a pharmaceutically acceptable salt thereof, or an amount ranging from and to any of these values. In some aspects, the compositions of the disclosure can comprise a pharmaceutically acceptable salt of gemcabene or a pharmaceutically acceptable salt thereof, in an amount that is a molar equivalent to about 50 mg. In some aspects, the compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 150 mg of he disclosure in an amount that is a molar equivalent to about 300 mg. In some aspects, the compositions of the disclosure can comprise a compound of the disclosure in an amount that is a molar equivalent to about 600 mg.
[0113] In other aspects, the gemcabene compositions of the disclosure can comprise gemcabene, or a pharmaceutically acceptable aslt thereof, in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, or any amount ranging from and to these values.
[0114] In some aspects, the compositions of the disclosure comprising niclosamide, or a pharmaceutically acceptable salt thereof, can comprise from about 0.1 mg to about 5 g, or about 0.1 mg to about 2 g, or about 0.5 mg to about 1 g of niclosamide, or a pharmaceutically acceptable salt thereof. In some aspects, the niclosamide compositions can comprise about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg. about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, or about 5 g of niclosamide, or a pharmaceutically acceptable salt thereof.
[0115] In certain aspects, the gemcabene and/or niclosamide compositions of the present disclosure can be administered from 1 to 10 times a day. In some aspects, the compositions of the present disclosure can be administered from 1 to 5 times a day. In some aspects, the compositions of the present disclosure can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In some aspects, the compositions of the present disclosure can be administered once a day. In some aspects, the compositions of the present disclosure can be administered twice a day.
[0116] In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated in a composition comprising one or more of mannitol, microcrystalline cellulose (MCC), sodium lauryl sulfate (SLS), sodium starch glycolate, hydroxypropyl cellulose (HPC), colloidal silicon dioxide, and sodium stearyl fumarate. In some aspects, the niclosamide comprises between about 50% and about 60% weight by weight of the formulation. In some aspects, the niclosamide comprises between about 54% and about 57% weight by weight of the formulation. In some aspects, the niclosamide comprises between about 55% and about 56% weight by weight of the formulation. In some aspects, the niclosamide comprises about 55% weight by weight of the formulation. In some aspects, the niclosamide comprises about 55.6% weight by weight of the formulation. In some aspects, the formulation comprises mannitol and wherein the mannitol comprises between about 4% and about 12% weight by weight of the formulation. In some aspects, the formulation comprises mannitol and wherein the mannitol comprises between about 6% and about 10% weight by weight of the formulation. In some aspects, the formulation comprises mannitol and wherein the mannitol comprises about 8% weight by weight of the formulation. In some aspects, the formulation comprises mannitol and wherein the mannitol comprises about 8.8% weight by weight of the formulation. In some aspects, the formulation comprises MCC and wherein the MCC comprises between about 12% and about 18% weight by weight of the formulation. In some aspects, the formulation comprises MCC and wherein the MCC comprises between about 14% and about 16% weight by weight of the formulation. In some aspects, the formulation comprises MCC and wherein the MCC comprises about 15% weight by weight of the formulation. In some aspects, the formulation comprises MCC and wherein the MCC comprises about 15.1% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises at least about 3% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises between about 3% and about 7% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises between about 4% and about 6% weight by weight of the formulation. In some aspects, the formulation comprises SLS and wherein the SLS comprises about 5% weight by weight of the formulation. In some aspects, the formulation comprises sodium starch glycolate and wherein the sodium starch glycolate comprises between about 4% and about 12% weight by weight of the formulation. In some aspects, the formulation comprises sodium starch glycolate and wherein the sodium starch glycolate comprises between about 7% and about 9% weight by weight of the formulation. In some aspects, the formulation comprises sodium starch glycolate and wherein the sodium starch glycolate comprises about 8% weight by weight of the formulation. In some aspects, the formulation comprises HPC and wherein the HPC comprises between about 3% and about 7% weight by weight of the formulation. In some aspects, the formulation comprises HPC and wherein the HPC comprises between about 4% and about 6% weight by weight of the formulation. In some aspects, the formulation comprises HPC and wherein the HPC comprises about 5% weight by weight of the formulation. In some aspects, the formulation comprises colloidal silicon dioxide and wherein the colloidal silicon dioxide comprises between about 0.1% and about 0.9% weight by weight of the formulation. In some aspects, the formulation comprises colloidal silicon dioxide and wherein the colloidal silicon dioxide comprises between about 0.4% and about 0.6% weight by weight of the formulation. In some aspects, the formulation comprises colloidal silicon dioxide and wherein the colloidal silicon dioxide comprises about 0.5% weight by weight of the formulation. In some aspects, the formulation comprises sodium stearyl fumarate and wherein the sodium stearyl fumarate comprises between about 0.1% and about 4% weight by weight of the formulation. In some aspects, the formulation comprises sodium stearyl fumarate and wherein the sodium stearyl fumarate comprises between about 1% and about 3% weight by weight of the formulation. In some aspects, the formulation comprises sodium stearyl fumarate and wherein the sodium stearyl fumarate comprises about 2% weight by weight of the formulation.
[0117] The disclosure provides a formulation comprising (a) niclosamide, comprising 55% weight by weight of the formulation; (b) mannitol, comprising 8% weight by weight of the formulation; (c) MCC, comprising 15% weight by weight of the formulation; (d) SLS, comprising 5% weight by weight of the formulation; (e) sodium starch hlycolate, comprising 8% weight by weight of the formulation; (f) hydroxypropyl cellulose (HPC), comprising 5% weight by weight of the formulation; (g) colloidal silicon dioxide, comprising 0.5% weight by weight of the formulation; and (h) Sodium Stearyl Fumarate, comprising 2% weight by weight of the formulation.
[0118] In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated as descibred in US Patent No. 10,292,951, issued May 21, 2019. In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, is formulated as a solid pharmaceutical composition, which comprises: an inner phase which is a wet granulated solid preparation comprising niclosamide, or a pharmaceutically acceptable salt thereof; one or more disintegrants; one or more diluents; and one or more binders; and an external phase comprising one or more glidants and/or one or more lubricants.
[0119] In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated as descibred in US Patent Publication No. 2019/0151231, published May 23, 2019. In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, is formulated as a nonaqueous topical composition comprising: (i) niclosamide a pharmaceutically acceptable salt or hydrate thereof; and (ii) greater than 60% by weight of a polyethylene glycol (PEG), wherein the average molecular weight of the PEG is 600 or less.
[0120] In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated as descibred in US Patent No. 8,524,280, issued September 3, 2013. In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, is formulated as microparticles comprising niclosamide obtained by (a) dissolving, melting, or suspending niclosamide in at least one fatty acid, conjugated fatty acid, or combinations thereof to form a mixture, and (b) mixing the mixture of step (a) with a liquid hydrophilic or lipophilic carrier to form the microparticles having a diameter from 100 nm to 25 microns, and wherein the microparticles and carrier are encapsulated in a soft or hard, gelatin, or non-gelatin capsule.
[0121] In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated as described in US Patent No. 10,653,784, issued May 19, 2020. In some aspects, niclosamide, or a pharmaceutically acceptable salt thereof, can be formulated as descibred in US Patent Publication No. 2020/0268894, published as August 27, 2020.
Examples
Example 1
[0122] Antiviral assay. This reverse genetic system allows manipulation of the viral genome at any nucleotide position and engineering foreign into the virus (see, Xie et al., 2020). To facilitate high-throughput antiviral testing, a nano luciferase gene was engineered into the open- reading-frame 7 (ORF7) of the SARS-CoV-2 genome. When cells were infected with such reporter virus, the cells expressed luciferase that could be quantified to indicate viral replication. Increasing amounts of luciferase signals were detected in Vero E6 cells after infected with the reporter virus from 1 to 36 h post-infection. At 36 h post-infection, viral infection-induced cytopathic effect was observed, leading to a decrease of luciferase signal at 48 h post-infection. The results suggest that luciferase signal could be used as a surrogate to test antiviral inhibitors.
[0123] Niclosamide activity. Niclosamide is an antiparasitic agent that has broad spectrum of antiviral activity. To test its activity against SARS-CoV-2, niclosamide powder was dissolved in 100% DMSO at 10 mM. The antiviral assay was performed in a 96-well plate. Approximately 1.5 x lO4 Vero E6 cells were seeded to each well the night before viral infection. Different concentrations of niclosamide were added to cells together with reporter SARS-CoV-2 (MOI of 0.1). At each tested condition, the cell medium contained a final concentration of 0.5% DMSO. After 24 h post-infection, the infected cells were assayed for luciferase activity using Nano-Gio Luciferase System following the manufacture’s protocol (Promega). The ECso value was derived from the luciferase curve. Niclosamide showed a potent antiviral ECso of 150 nM. Example 2
Treatment of Covid-19 Patients with Gemcabene and Niclosamide
[0124] Subjects diagnosed with Covid-19 are administered 300 mg - 900 mg/day of gemcabene in combination with 100 mg - 4 g/day of niclosamide for a period of 7 to 28 days to reduce the viral load and/or symptoms. Subjects are monitored for improvement.
Example 3
Treatment of Patients Suffering Viral-Induced Cytokine Storm with Gemcabene and Niclosamide
[0125] Subjects diagnosed with a viral infection who meet high risk criteria are administered 300 mg - 900 mg/day of gemcabene in combination with 100 mg - 4 g/day of niclosamide for a period of 7 to 28 days to reduce the risk of progessing to respiratory failure. Subjects are monitored for improvement in symptoms.
Example 4
Treatment of Patients having Influenza Virus with Gemcabene and Niclosamide
[0126] Subjects having influenza virus are administered 300 mg - 900 mg/day of gemcabene in combination with 100 mg - 4 g/day of niclosamide for a period of 7 to 28 days to reduce the viral load and/or symptoms. Subjects are monitored for improvement.
[0127] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and thus, are not intended to limit the present disclosure and the appended claims in any way.
[0128] The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.
[0129] The foregoing description of the specific aspects will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.
[0130] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

- 36 - WHAT IS CLAIMED IS:
1. A method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the viral infection is caused by an RNA or DNA virus.
3. The method of claim 2, wherein the virus has a filamentous, isometric, enveloped, or a head and tail conformation.
4. The method of any one of claims 1 to 3, wherein the viral infection is caused by an RNA virus.
5. The method of claim 4, wherein the RNA virus is a positive-strand RNA virus.
6. The method of claim 5, wherein the positive-strand RNA virus belongs to the family of Picornaviridae, Astroviridae, Caliciviridae, Hepeviridae Flaviviridae, Togaviridae, Arteriviridae, or Coronaviridae.
7. The method of claim 6, wherein the positive-strand RNA virus belongs to the family of Coronaviridae.
8. The method of claim 7, wherein the Coronaviridae virus is selected from Bat coronavirus CDPHE15, Bat coronavirus HKU10, Rhinolophus ferrumequinum alphacoronavirus HuB-2013, Human coronavirus 229E, Lucheng Rn rat coronavirus, Ferret coronavirus, Mink coronavirus 1, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Myotis ricketti alphacoronavirus Sax-2011, Nyctalus velutinus alphacoronavirus SC-2013, Porcine epidemic diarrhea virus, Scotophilus bat coronavirus 512, Rhinolophus bat coronavirus HKU2, Human coronavirus NL63, NL63 -related bat coronavirus strain BtKYNL63-9b, Human coronavirus OC43, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus - type species, Bat Hp-betacoronavirus Zhejiang2013, Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus (MERS-CoV), Pipistrellus bat coronavirus HKU5, Tylonycteris bat - 37 - coronavirus HKU4, Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus, Wigeon coronavirus HKU20, Bulbul coronavirus HKU11 - type species, Porcine coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU 16, Night heron coronavirus HKU 19, Common moorhen coronavirus HKU21, Beluga whale coronavirus SW1, and Avian coronavirus - type species.
9. The method of any one of claims 6 to 8, wherein the Coronaviridae virus is Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
10. The method of any one of claims 6 to 8, wherein the Coronaviridae virus is selected from HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, SARS CoV-2, a mutated strain thereof, and any combination thereof.
11. The method of claim 4, wherein the RNA virus is a negative- strand RNA virus.
12. The method of claim 11, wherein the negative- strand RNA virus belongs to the family of Orthomyxoviridae, Paramyxoviridae, Rhabdoviridiae, Filoviruses, or Arenaviruses.
13. The method of claim 11 or 12, wherein the negative-strand virus is selected from Influenza virus, Sendai virus, Human parainfluenza virus 1 (hPIVl), Simian virus 5 (SV5, PIV5), Mumps virus, Newcastle disease virus (NDV), Measles virus, Rinderpest virus , Respiratory syncytial virus (RSV), Vesicular stomatitis virus (VSV), Rabies virus, Ebola virus, Marburg virus, Lymphocytic choriomeningitis virus (LCMV), Junin virus, and Lassa fever virus.
14. The method of any one of claims 1 to 3, wherein the virus is a retrovirus.
15. The method of claim 14, wherein the retrovirus is selected from a Lentivirus, Alpharetrovirus, Betaretrovirus, Deltaretrovirus, Gammaretrovirus, and a Epsilonretrovirus.
16. The method of claim 14, wherein the retrovirus is a Simian immunodeficiency virus (SIV), Human immunodeficiency virus-1 (HIV-1), HIV-2, Feline immunodeficiency virus (FIV), Equine infectious anemia virus (EIAV), Mouse mammary tumor-like virus (MMTV), Mason-Pfizer monkey virus (MPMV), Respiratory syncytial virus RSV, bovine leukemia virus (BLV), Human T- cell leukemia virus-1 (HTLV-1), HTLV-2, Murine leukemia virus (MuLV), Gibbon ape leukemia virus (GALV), and any combination thereof.
17. The method of any one of claims 1 to 3, wherein the viral infection is caused by a DNA virus.
18. The method of claim 17, wherein the DNA virus is Adenovirus, infectious canine hepatitis virus, Papillomavirus, polyomaviridae, simian vacuolating virus, Parvovirus Bl 9, canine parvovirus, Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, Smallpox virus, cow pox virus, sheep pox virus, monkey pox virus, vaccinia virus, Torque teno virus, or any combination thereof.
19. The method of any one of claims 1 to 18, wherein the subject has a medical condition that increases risk of a poor prognosis without treatment or an increased risk of a severe immune response to the infection.
20. The method of claim 19, wherein the subject has an impaired or reduced immune response.
21. The method of claim 20, wherein the subject is immunocompromised.
22. The method of claim 20 or 21, wherein the subject is undergoing or has undergone one or more of an immunosuppressive therapy, presenting a sign or symptom of a second medical disease or disorder or a subject of a past, present or future medical intervention.
23. The method of claim 22, wherein the second medical disease or disorder comprises an infection, an HIV infection, an onset of Acquired Immunodeficiency Syndrome (AIDS), a proliferative disorder, a cancer, asthma, or an autoimmune condition.
24. The formulation of claim 22, wherein the immunosuppressive therapy comprises one or more of an ablation of bone marrow or circulating blood cell types, a radiation therapy, a therapy for a proliferative or malignant disease, a monoclonal antibody therapy, a blood transfusion, a bone marrow transplant, or removal of a lymph node.
25. The method of claim 22, wherein the medical intervention comprises one or more of a surgery, a graft, a tissue or organ transplant, a wound or burn debridement, a setting of a bone, a replacement of a bone, a replacement of a joint, a cardiac bypass, a vascular stent placement, a spinal tap, an organ resection, or a cardiac pacemaker placement or replacement.
26. The method of any one of claims 19 to 25, wherein the subject presents a sign or symptom of hypertension or cardiac disease.
27. The method of claim 26, wherein the subject has been diagnosed with hypertension or cardiac disease.
28. The method of any one of claims 19 to 27, wherein the subject presents a sign or symptom of a metabolic disorder.
29. The method of claim 28, wherein the subject has been diagnosed with the metabolic disorder.
30. The method of claim 28 or 29, wherein the metabolic disorder comprises insulin resistance, pre-diabetes, or diabetes.
31. The method of any one of claims 19 to 30, wherein the subject presents a sign or symptom of a clotting or vascular disorder.
32. The method of claim 31, wherein the subject has been diagnosed with the clotting or vascular disorder.
33. The method of claim 31 or 32, wherein the subject is at risk of forming a clot or suffering from a stroke.
34. The method of any one of claims 1 to 33, wherein the subject has not received a vaccine for the virus prior to contacting the virus or presenting the viral infection.
35. The method of any one of claims 1 to 34, wherein the subject is a neonatal subject.
36. The method of claim 35, wherein the mother of the subject is a carrier of the virus or infected by the virus.
37. The method of any one of claims 1 to 34, wherein the subject is under 18 years of age.
38. The method of any one of claims 1 to 34, wherein the subject is between 18 years of age and 29 years of age, inclusive of the endpoints.
39. The method of any one of claims 1 to 34, wherein the subject is between 30 years of age and 49 years of age, inclusive of the endpoints.
40. The formulation of any one of claims 1 to 34, wherein the subject is between 50 years of age and 69 years of age, inclusive of the endpoints.
41. The formulation of any one of claims 1 to 34, wherein the subject is over 70 years of age.
42. The method of any one of claims 1 to 41, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at an effective amount of from about 25 mg/day to about 900 mg/day.
43. The method of any one of claims 1 to 42, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, is administered at about 25 mg/day, about 50 mg/day, about 75 mgday, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 450 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 750 mg/day, about 800 mg/day, or about 900 mg/day.
44. The method of any one of claims 1 to 43, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at an effective amount of from about 0.1 mg/day and about 5 g/day.
45. The method of any one of claims 1 to 44, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 0.1 mg/day, about 0.25 mg/day, about 0.50 mg/day, - 41 - about 0.75 mg/day, about 1.0 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 250 mg/day, about 500 mg/day, about 750 mg/day, about 1 g/day, about 1.5 g/day, about 2 g/day, about 2.5 g/day, about 3 g/day, about 3.5 g/day, about 4 g/day, about 4.5 g/day, or about 5 g/day.
46. The method of any one of claims 1 to 45, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered at about 2 g/day.
47. The method of any one of claims 1 to 46, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered simulataneously with the gemcabene, or the pharmaceutically acceptable salt thereof.
48. The method of any one of claims 1 to 47, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, and the gemcabene, or the pharmaceutically acceptable salt thereof, are coformulated.
49. The method of any one of claims 1 to 46, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered before the gemcabene, or the pharmaceutically acceptable salt thereof.
50. The method of any one of claims 1 to 46, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered after the gemcabene, or the pharmaceutically acceptable salt thereof.
51. The method of any one of claims 1 to 50, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered orally.
52. The method of any one of claims 1 to 51, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a capsule.
53. The method of any one of claims 1 to 51 , wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is administered in a tablet. - 42 -
54. The method of any one of claims 1 to 53, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, is administered orally.
55. The method of any one of claims 1 to 54, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, is administered in a tablet.
56. The method of any one of claims 1 to 55, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7 to about 28 days.
57. The method of any one of claims 1 to 56, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7 to about 14 days.
58. The method of any one of claims 1 to 57, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, and the niclosamide, or the pharmaceutically acceptable salt thereof, are administered for about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 days.
59. The method of any one of claims 1 to 58, wherein the pharmaceutical composition comprises the monocalcium salt of gemcabene.
60. The method of any one of claims 1 to 59, wherein the niclosamide is administered as a formulation comprising:
(a) niclosamide, comprising about 55% to about 56% weight by weight of the formulation;
(b) mannitol, comprising about 8% to about 9% weight by weight of the formulation;
(c) MCC, comprising about 15% to about 16% weight by weight of the formulation;
(d) SLS, comprising about 5% weight by weight of the formulation;
(e) sodium starch glycolate, comprising about 8% weight by weight of the formulation;
(f) hydroxypropyl cellulose (HPC), comprising about 5% weight by weight of the formulation; - 43 -
(g) colloidal silicon dioxide, comprising about 0.5% weight by weight of the formulation; and
(h) sodium stearyl fumarate, comprising about 2% weight by weight of the formulation.
61. The method of any one of claims 1 to 60, wherein the niclosamide is administered as a formulation comprising:
(a) niclosamide, comprising about 55.5% weight by weight of the formulation;
(b) mannitol, comprising about 8.8% weight by weight of the formulation;
(c) MCC, comprising about 15.1% weight by weight of the formulation;
(d) SLS, comprising about 5% weight by weight of the formulation;
(e) sodium starch glycolate, comprising about 8% weight by weight of the formulation;
(f) hydroxypropyl cellulose (HPC), comprising about 5% weight by weight of the formulation;
(g) colloidal silicon dioxide, comprising about 0.5% weight by weight of the formulation; and
(h) sodium stearyl fumarate, comprising about 2% weight by weight of the formulation.
62. The method of any one of claims 1 to 61, wherein the niclosamide is administered as a formulation comprising:
(a) about 250 mg of niclosamide;
(b) about 39.6 mg of mannitol,
(c) about 68.1 mg of MCC;
(d) about 22.5 mg of SLS;
(e) about 36 mg of sodium starch glycolate;
(f) about 22.5 mg of hydroxypropyl cellulose (HPC);
(g) about 2.3 mg of colloidal silicon dioxide; and
(h) about 9 mg of sodium stearyl fumarate.
63. The method of any one of claims 1 to 62, wherein the gemcabene is administered as a formulation comprising:
(a) about 250 mg of niclosamide;
(b) about 39.6 mg of mannitol,
(c) about 68.1 mg of MCC; - 44 -
(d) about 22.5 mg of SLS;
(e) about 36 mg of sodium starch glycolate;
(f) about 22.5 mg of hydroxypropyl cellulose (HPC);
(g) about 2.3 mg of colloidal silicon dioxide; and
(h) about 9 mg of sodium stearyl fumarate.
64. The method of any one of claims 1 to 63, wherein the gemcabene, or the pharmaceutically acceptable salt thereof, has a PSD90 ranging from 40 pm to about 75 pm as measured by laser light diffraction.
65. A kit comprising gemcabene, or a pharmaceutically acceptable salt thereof, for administering gemcabene, or a pharmaceutically acceptable salt thereof, and niclosamide, or a pharmaceutically acceptable salt thereof, to a subject having a viral infection.
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