WO2019136196A1 - Composition thérapeutique - Google Patents

Composition thérapeutique Download PDF

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Publication number
WO2019136196A1
WO2019136196A1 PCT/US2019/012256 US2019012256W WO2019136196A1 WO 2019136196 A1 WO2019136196 A1 WO 2019136196A1 US 2019012256 W US2019012256 W US 2019012256W WO 2019136196 A1 WO2019136196 A1 WO 2019136196A1
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WO
WIPO (PCT)
Prior art keywords
topical gel
gel formulation
furosemide
formulation
pharmaceutical topical
Prior art date
Application number
PCT/US2019/012256
Other languages
English (en)
Inventor
Linda M. Mahoney
Anne T. Moore
Gary Lee Feiss
Danielle N. Ringhoff
Original Assignee
Dermarc LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/864,155 external-priority patent/US20180133239A1/en
Application filed by Dermarc LLC filed Critical Dermarc LLC
Publication of WO2019136196A1 publication Critical patent/WO2019136196A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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

Definitions

  • This invention relates to a topical composition for prevention and treatment of viral infections.
  • Ionic Contra-Viral Therapy was described in 2006 as a novel approach to the treatment of D A viruses by local application of certain compounds that inhibit the transport of sodium and potassium across cellular membranes (Hartley, Ionic Contra-Viral Therapy (ICVT); a new approach to the treatment of DNA virus infections. Archives of Virology. December 2006, Volume 151 , Issue 12, pp 2495-2501).
  • the disturbances in the intracellular environment created by this inhibition are believed to compromise the ability of viruses to proliferate, as intracellular K+ is necessary for viral DNA synthesis (Hartley, The effects of lithium and potassium on macromolecular synthesis in herpes simplex virus-infected cells.
  • ICVT Intracellular K+ in DNA virus-infected host cells
  • ICVT is envisioned to have potential clinical utility in indications which are caused by or related to, for example, human papillomavirus, including cutaneous warts.
  • ICVT represents an opportunity to utilize the contra-viral activity of digoxin and/or furosemide as found in non-clinical and in vitro studies against HPV as a potentially effective treatment for, for example, cutaneous warts.
  • the invention provides a pharmaceutical topical gel formulation comprising: at least one diuretic; alkylene glycol in the range of about 20-60 % w/w; ethanol in the range of about 20 -60 % w/w; at least one thickener in the range of about 0.5% to 5% w/w; a buffer which maintains the formulation pH at about pH 3 to about pH 8; and optionally, polyalkylene glycol in the range of about 0-20 % w/w; q.s. with water, wherein the concentrations are based on the total weight of the formulation, further wherein the topical gel formulation is anti-viral.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is storage stable at room temperature.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is in the range of about 2 - 15 % w/w.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is capable of cutaneous and/or dermal delivery.
  • the invention provides a pharmaceutical topical gel formulation wherein the diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide, piretanide, tripamide, chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metozalone, cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazolamide, methazolamide, ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide, hydroflumethiazide, trichlormethiazide, polythiazide, benzothiazide, and combinations thereof.
  • the diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide,
  • the invention provides a pharmaceutical topical gel formulation wherein the diuretic is furosemide.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is present at range of about 0.01 - 10 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein the alkylene glycol is propylene glycol.
  • the invention provides a pharmaceutical topical gel formulation capable of transcutaneous delivery of said diuretic through the stratum corneum to the basal epidermis.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is capable of percutaneous absorption.
  • the invention provides a pharmaceutical topical gel formulation in combination with an occlusive dressing, coating or other layer.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is a buffer system selected from the group consisting of citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid oases ana tneir acids; arginine and arginine HC1; lysine and lysine HC1; tartaric acid and sodium tartrate; tartaric acid and potassium tartrate; adipic acid and sodium adipate; adipic acid and potassium adipate; malic acid and sodium malate; malic acid and potassium malate; sodium phosphate monobasic and sodium phosphate dibasic; and combinations thereof.
  • the buffer is a buffer system selected from the group consisting of citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid oases ana tneir acids; arginine and
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is a buffering agent selected from the group consisting of sodium hydroxide, potassium hydroxide, and combinations thereof.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is citrate buffer.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is citric acid and sodium citrate.
  • the invention provides a pharmaceutical topical gel formulation further comprising at least one excipient which is skin-tolerant and/or keratolytic.
  • the invention provides a pharmaceutical topical gel formulation in which the gel carrier medium comprises a cosolvent mix.
  • the invention provides a pharmaceutical topical gel formulation in which the pH is less than 7.
  • the invention provides a pharmaceutical topical gel formulation in which the pH is about 6.3 to about 6.8.
  • the invention provides a pharmaceutical topical gel formulation in which the thickener comprises one or more of the following: Carbomers, cellulose derivatives, or hydroxyalkylcellulose.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 1 to 5% by weight based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 3% by weight based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation comprising a thickener in an amount of 0.5 to 5% by weight, based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation further including at least one of the following: an emulsifier, antioxidant, propellant, colour, buffer, preservative, or adhesive.
  • the invention provides a pharmaceutical topical gel formulation for use in the treatment of conditions selected from the group consisting of DNA viral infections and RNA viral infections.
  • the invention provides a pharmaceutical topical gel formulation for use in the prevention and/or treatment of DNA viral infections selected from viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, influenza virus, VIN (vulvar intraepithelial neoplasia), CIN (cervical intraepithelial neoplasia), and combinations thereof.
  • DNA viral infections selected from viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epider
  • the invention provides a pharmaceutical topical gel formulation for use in WO 2019/136196 . . . , _ . . . , PCT/US2019/012256 me treatment or actinic keratoses.
  • the invention provides a pharmaceutical topical gel formulation for use in the topical treatment of warts.
  • the invention provides a pharmaceutical topical gel formulation for use in the reduction or prevention of viral replications by reduction or depletion of intracellular potassium ions.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in treating a DNA viral infection.
  • the invention provides a pharmaceutical topical gel formulation in which the DNA virus is human papilloma virus.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in topical application to warts.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in reducing or depleting intracellular potassium ions.
  • the invention provides a pharmaceutical topical gel formulation comprising about 0.125% w/w furosemide, about 38.75 %w/w ethanol, about 48.44% w/w propylene glycol, about 3.00 % w/w hydroxypropylcellulose, about 9.69 % w/w citrate buffer, and q.s. water.
  • the invention provides a method for treating or preventing a disease or condition in a patient, wherein the disease or condition is selected from the group consisting of viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1 ), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (H1V), adenovirus, influenza virus, V1N (vulvar intraepithelial neoplasia), CIN (cervical intraepithelial neoplasia), and combinations thereof, wherein said method comprises: selecting a patient in need of treating or preventing said disease or condition; administering to the patient the composition of the invention in a therapeutically effective amount, thereby treating or preventing said disease in said patient
  • the invention provides a pharmaceutical topical gel formulation comprising: at least one cardiac glycoside; alkylene glycol in the range of about 20-60 % w/w; ethanol in the range of about 20 -60 % w/w; at least one thickener in the range of about 0.5% to 5% w/w; a buffer which maintains the formulation pH at about pH 3 to about pH 8; and optionally, polyalkylene glycol in the range of about 0-20 % w/w; q.s. with water, wherein the concentrations are based on the total weight of the formulation, further wherein the topical gel formulation is anti-viral.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is storage stable at room temperature.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is in the range of about 2 - 15 % w/w.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is capable of cutaneous and/or dermal delivery.
  • the invention provides a pharmaceutical topical gel formulation wherein the cardiac glycoside comprises one or more of the following: digoxin, digitoxin, methyl digoxin, lanatoside C, proscillaridin, k strophantin, peruvoside and ouabain.
  • the invention provides a pharmaceutical topical gel formulation wherein the cardiac glycoside is digoxin.
  • the invention provides a pharmaceutical topical gel formulation wherein said cardiac glycoside is present at range of about 0.01 - 10 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein the alkylene glycol is propylene glycol.
  • the invention provides a pharmaceutical topical gel formulation, capable of transcutaneous delivery of said glycoside through the stratum corneum to the basal epidermis.
  • the invention provides a pharmaceutical topical gel formulation wherein said glycoside is capable of percutaneous absorption.
  • the invention provides a pharmaceutical topical gel formulation in combination with an occlusive dressing, coating or other layer.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is a buffer system selected from the group consisting of citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid bases and their acids; arginine and arginine HC1; lysine and lysine HC1; tartaric acid and sodium tartrate; tartaric acid and potassium tartrate; adipic acid and sodium adipate; adipic acid and potassium adipate; malic acid and sodium malate; malic acid and potassium malate; sodium phosphate monobasic and sodium phosphate dibasic; and combinations thereof.
  • the buffer is a buffer system selected from the group consisting of citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid bases and their acids; arginine and arginine HC1; lysine and lysine
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is a buffering agent selected from the group consisting of sodium hydroxide, potassium hydroxide, and combinations thereof.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is citrate buffer.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is citric acid and sodium citrate.
  • the invention provides a pharmaceutical topical gel formulation further comprising at least one excipient which is skin-tolerant and/or lceratolytic.
  • the invention provides a pharmaceutical topical gel formulation, in which the gel carrier medium comprises a cosolvent mix.
  • the invention provides a pharmaceutical topical gel formulation in which the pH is less than 7.
  • the invention provides a pharmaceutical topical gel formulation in which the pH is about 6.3 to about 6.8.
  • the invention provides a pharmaceutical topical gel formulation in which the thickener comprises one or more of the following: Carbomers, cellulose derivatives, or hydroxyalky!cellulose.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 1 to 5% by weight based WO 2019/136196 . , , und , . . PCT/US2019/012256 on tne total weight or the formulation.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 3% by weight based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation comprising a thickener in an amount of 0.5 to 5% by weight, based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation further including at least one of the following: an emulsifier, antioxidant, propellant, colour, buffer, preservative, or adhesive.
  • the invention provides a pharmaceutical topical gel formulation for use in the treatment of conditions selected from the group consisting of DNA viral infections and RNA viral infections.
  • the invention provides a pharmaceutical topical gel formulation for use in the prevention and/or treatment of DNA viral infections selected from viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, influenza virus, VIN (vulvar intraepithelial neoplasia), CIN (cervical intraepithelial neoplasia), and combinations thereof.
  • DNA viral infections selected from viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epider
  • the invention provides a pharmaceutical topical gel formulation for use in the treatment of actinic keratoses.
  • the invention provides a pharmaceutical topical gel formulation for use in the topical treatment of warts.
  • the invention provides a pharmaceutical topical gel formulation for use in the reduction or prevention of viral replications by reduction or depletion of intracellular potassium ions.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in treating a DNA viral infection.
  • the invention provides a pharmaceutical topical gel formulation in which the DNA virus is human papilloma virus.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in topical application to warts.
  • the invention provides a pharmaceutical topical gel formulation, for use in the preparation of a medicament for use in reducing or depleting intracellular potassium ions.
  • the invention provides a pharmaceutical topical gel formulation comprising about 0.125% w/w digoxin, about 38.75 %w/w ethanol, about 48.44% w/w propylene glycol, about 3.00 % w/w hydroxypropylcellulose, about 9.69 % w/w citrate buffer, and q.s. water.
  • the invention provides a method for treating or preventing a disease or condition in a patient, wherein the disease or condition is selected from the group consisting of viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV injection, KNA viral infections, herpes simplex viral infections, actinic keratosis,
  • the invention provides a pharmaceutical topical gel formulation comprising: at least one diuretic; at least one cardiac glycoside; alkylene glycol in the range of about 20-60 % w/w; ethanol in the range of about 20 - 60% w/w; at least one thickener in the range of about 0.5% to 5% w/w; a buffer which maintains the formulation pH at about pH 3 to about pH 8; and optionally, polyalkylene glycol in the range of about 0-20 % w/w; q.s. with water, wherein the concentrations are based on the total weight of the formulation further wherein the topical gel formulation is anti-viral.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is stable at room temperature.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is in the range of about 2 - 15 % w/w.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is capable of cutaneous and/or dermal delivery.
  • the invention provides a pharmaceutical topical gel formulation wherein the cardiac glycoside is digoxin.
  • the invention provides a pharmaceutical topical gel formulation wherein the diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide, piretanide, tripamide, chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metozalone, cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazolamide, methazolamide, ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide, hydroflumethiazide, trich!ormethiazide, polythiazide, benzothiazide, and
  • the invention provides a pharmaceutical topical gel formulation wherein at least one loop diuretic is present in combination with at least one cardiac glycoside.
  • the invention provides a pharmaceutical topical gel formulation wherein the cardiac glycoside comprises one or more of the following: digoxin, digitoxin, methyl digoxin, lanatoside C, proscillaridin, k strophantin, peruvoside and ouabain.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is present at range of about 0.01 - 10 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein said cardiac glycoside is present at range of about 0.01 - 10 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein a molar ratio of cardiac glycoside: loop diuretic is in the range of about 0.5 to 2.5: 20 to 0.5.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is a buffer system selected from the group consisting of citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid bases and their acids; arginine and arginine HC1; lysine and lysine HC1; tartaric acid and sodium tartrate; tartaric acid and potassium tartrate; adipic acid and sodium adipate; adipic acid and potassium adipate; malic acid and sodium malate, malic acid and potassium malate; sodium phosphate monobasic and sodium phosphate dibasic; and combinations thereof.
  • the buffer is a buffer system selected from the group consisting of citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid bases and their acids; arginine and arginine HC1; lysine and lysine
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is a buffering agent selected from the group consisting of sodium hydroxide, potassium hydroxide, and combinations thereof.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is citrate buffer.
  • the invention provides a pharmaceutical topical gel formulation wherein the pH is less than 7.
  • the invention provides a pharmaceutical topical gel formulation in which the pH is about 6.5 to about 6.8.
  • the invention provides a pharmaceutical topical gel formulation in which the pH is about 5.5.
  • the invention provides a pharmaceutical topical gel formulation in which the thickener comprises one or more of the following: Carbomers, cellulose derivatives, hydroxyalkylcelluloses, or hydroxypropylcellulose.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 1 to about 5% by weight based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 3% by weight based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation further comprising at least one excipient which is skin-tolerant and/or keratolytic.
  • the invention provides a pharmaceutical topical gel formulation comprising about 0.125% w/w digoxin, about 0.125% w/w furosemide, about 38.70 %w/w ethanol, about 48.38% w/w propylene glycol, about 3.00 % w/w hydroxypropylcellulose, about 9.68 % w/w citrate buffer, and q.s. water.
  • the invention provides a pharmaceutical topical gel formulation for use in the prevention and/or treatment of conditions selected from the group consisting of viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1 ), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, influenza virus, VIN (vulvar intraepithelial neoplasia), CIN (cervical intraepithelial neoplasia), and combinations thereof.
  • the invention provides a pharmaceutical topical gel formulation for use in the topical treatment of warts.
  • the invention provides a pharmaceutical topical gel formulation for use in the reduction or prevention of viral replications by reduction or depletion of intracellular potassium ions.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in treating a DNA virus.
  • the invention provides a pharmaceutical topical gel formulation in which the DNA virus is human papilloma virus.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in topical application to warts.
  • the invention provides a pharmaceutical topical gel formulation for use in the preparation of a medicament for use in reducing or depleting intracellular potassium ions.
  • a method for treating or preventing a disease or condition in a patient wherein the disease or condition is selected from the group consisting of viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, influenza virus, VIN (vulvar intraepithelial neoplasia), CIN (cervical intraepithelial neoplasia), and combinations thereof, wherein said method comprises: selecting a patient in need of treating or preventing said disease or condition; administering to the patient the composition of the invention in a therapeutically effective amount, thereby treating or preventing said disease in said patient.
  • the disease or condition is
  • the invention provides a pharmaceutical topical gel formulation comprising: at least one diuretic; alkylene glycol in the range of about 20-60% w/w; ethanol in the range of about 20- 60% w/w; at least one thickener in the range of about 0.5% to 5% w/w; a buffer which maintains the formulation pH at about pH 3 to about pH 8; and optionally, polyalkylene glycol in the range of about 0-20% w/w; q.s. with water, wherein the concentrations are based on the total weight of the formulation, further wherein the topical gel formulation is anti-viral.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is storage stable at room temperature.
  • the invention provides a pharmaceutical topical gel formulation wherein the topical gel formulation is capable of cutaneous and/or dermal delivery.
  • the invention provides a pharmaceutical topical gel formulation wherein the diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide, piretanide, tripamide, chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metozalone, cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazol amide, methazola ide, ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide, hydroflumethiazide, trichlormethiazide, polythiazide, benzothiazide, and combinations thereof.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is present at range of about about 1.15 to about 2 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is present at range of about 1.15% to about 1.3%.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is present at about 1.25 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is furosemide and is present at range of about 1 .15 to about 2 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is furosemide and is present at range of about 1.15% to about 1.3%.
  • the invention provides a pharmaceutical topical gel formulation wherein said diuretic is furosemide and is present at about 1.25 w/w %.
  • the invention provides a pharmaceutical topical gel formulation wherein the buffer is citric acid and sodium citrate.
  • the invention provides a pharmaceutical topical gel formulation wherein the thickener comprises hydroxypropylcellulose, in an amount of about 1 to 5% by weight based on the total weight of the formulation.
  • the invention provides a pharmaceutical topical gel formulation for use in the prevention and/or treatment of DNA viral infections selected from viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1 ), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, influenza virus, VIN (vulvar intraepithelial neoplasia), CIN (cervical intraepithelial neoplasia), and combinations thereof.
  • DNA viral infections selected from viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epi
  • the invention provides a method for treating or preventing a disease or condition in a patient, wherein the disease or condition is selected from the group consisting of viral infections, human papilloma virus infection, latent HPV infection, sub-clinical HPV infection, clinical HPV infection, RNA viral infections, herpes simplex viral infections, actinic keratosis, Epidermodysplasia verruciformis, human T-lymphotropic virus type I (HTLV-1), EBV, CMV, SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, influenza virus, VIN (vulvar intraepithelial neoplasia), CI (cervical intraepithelial neoplasia), and combinations thereof, wherein said method comprises: selecting a patient in need of treating or WO 2019/136196 , . , . PCT/US2019/012256 preventing said disease or condition; administering to the patient a pharmaceutical topic
  • Figure 1 shows the In-vitro anti-viral activity of Ionic Contra-Viral Therapy; Summary of in vitro efficacy against F1PV18 in Hela cell culture; % Reduction in HPV DNA. Single and combined drug 48 hour treatment experiment.
  • Figure 2 shows the In-vitro anti-viral activity of Ionic Contra-Viral Therapy; Summary of in vitro efficacy against HPV18 in Hela cell culture; % Reduction in Relative Quantification. Single and combined drug 48 hour treatment experiment.
  • FIG 3 shows the Pharmacodynamics of All Treated Warts ITT least squares means (LSM) Diameter.
  • FIG 4 shows the Pharmacodynamics of All Treated Warts ITT least squares means (LSM) Diameter (3D).
  • Figure 5 shows the least squares means (LSM) change from baseline graph of any HPV in swabs from primary warts (% change) with 95% Cl as error bars.
  • Figure 6 shows the Mean Plasma Furosemide Concentration vs. Time Profile Following Oral Dosing (20 mg) (Flaegeli et al., 2007).
  • Figure 7 shows the Representation of a One-Compartment Model with Extravascular Absorption (Ka) and Linear Elimination (Ke).
  • Figure 8 shows the One-Compartment Model Fit for Furosemide after Extravascular Dosing of 20 mg.
  • Figure 13 shows the Model Predicted Furosemide Concentration vs. Time Profile after a
  • the invention is directed to the use of, for example, a topical formulation, for treating or preventing viral infections.
  • the term "effective amount” refers to the amount of a therapy that is sufficient to result in the prevention of the development, recurrence, or onset of a disease or condition, such as neoplasia or infection, and one or more symptoms thereof, to enhance or improve the prophylactic effect(s) of another therapy, reduce the severity, the duration of a disease or condition, such as neoplasia or infection, ameliorate one or more symptoms of a disease or condition such as warts or HPV infection, prevent the advancement or recurrence of a disease or condition, such as warts or HPV infection, cause regression of a disease or condition, such as warts or HPV infection, and/or enhance or improve the therapeutic effect(s) of another therapy.
  • pharmaceutically acceptable such as in the recitation of a “pharmaceutically acceptable carrier,” or a “pharmaceutically acceptable derivative,” is meant a compound that is not biologically or otherwise undesirable, i.e., the compound may be incorporated into a topical formulation of the invention and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
  • pharmacologically active refers to an active agent as defined above, or to an analog or derivative thereof having the same type of pharmacological activity as the parent compound.
  • pharmaceutically acceptable means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.
  • the terms "prevent,” “preventing” and “prevention” in the context of the administration of a therapy to a subject refer to the prevention or inhibition of the recurrence, onset, and/or development of a disease or condition, such as warts or HPV infection, or a symptom thereof in a subject resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent), or a combination of therapies (e.g., a combination of prophylactic or therapeutic agents).
  • a therapy e.g., a prophylactic or therapeutic agent
  • a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • the terms “subject” and “patient” are used interchangeably.
  • the term “patient” refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkey and human), and most preterabiy a human.
  • the subject is a non-human animal such as a farm animal (e.g., a horse, pig, or cow) or a pet (e.g., a dog or cat).
  • the subject is an elderly human.
  • the subject is a human adult.
  • the subject is a human child.
  • the subject is a human infant.
  • therapies and “therapy” can refer to any method(s), composition(s), and/or agent(s) that can be used in the prevention, treatment and/or management of a disease or condition, such as neoplasia or infection, or one or more symptoms thereof.
  • the terms “treat,” “treatment,” and “treating” in the context of the administration of a therapy to a subject refer to the reduction or inhibition of the progression and/or duration of a disease or condition, such as warts or HPV infection, the reduction or amelioration of the severity of a disease or condition, such as neoplasia or infection, and/or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.
  • the terms “treating” and “treatment” as used herein refer to actions that reduce the severity and/or frequency of symptoms, eliminate symptoms and/or their underlying cause, prevent the occurrence of symptoms and/or their underlying cause, and improve or remediate damage.
  • the present method of "treating" a patient thus encompasses both prevention of warts in a predisposed individual and treatment of warts in a clinically symptomatic individual.
  • topical administration is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosal tissue, as in, for example, the treatment of warts.
  • papillomavirus disease refers to any kind of infection or disorder caused by the virus, including cancers and warts. Thus, the term includes symptoms and side effect of any papillomavirus infection, including latent, persistent and sub-clinical infections, whether or not the infection is clinically apparent.
  • the term "about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1 %, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
  • ranges can be expressed as from “about” one particular value, and/or to "about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to WO 2019/136196 plague , , C , . .. . , . PCT/US2019/012256 me vaiue ltseii. For example, IT the value l O is disclosed, then about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if l O and 15 are disclosed, then 1 1 , 12, 13, and M are also disclosed.
  • the term “storage stable” and/ or“storage stability” means stable for greater than 18 months at room temperature, wherein stable is defined as maintaining >90% of the targeted active concentration. Stable may also refer to a degradation profile limited to low levels ( ⁇ 5% degradation) and no toxic degradants.
  • HPV Human papillomavirus
  • HPV Human papillomavirus
  • the current classification system which is based on similarities in genomic sequences, generally correlates with the 3 clinical categories applied to HPV: anogenital or mucosal, nongenital cutaneous, and epidermodysplasia verruciformis (EV).
  • EV epidermodysplasia verruciformis
  • Mucosal HPV infections are further classified as latent (asymptomatic), subclinical, and clinical.
  • HPV infections are grossly apparent, whereas latent infections are detected only with tests for viral DNA. Subclinical lesions are identified by application of 3-5% acetic acid and inspection under magnification. Most HPV infections are latent; clinically apparent infections usually result in warts rather than malignancies. However, infections due to HPV are common and lead to a wide variety of clinical manifestations; certain types of HVP (6, 1 1 , 16, and G8) can place patients at a high risk for anogenital cancer. HPVs 5, 8, 15, 20, 24, and 26 are associated with actinic keratosis and development of squamous cel! carcinoma. HPVs 16 and 18 are classified as high risk for cervical cancer. The HPV genotypes associated with various diseases are presented in the following tables (source emedicine.medscape.com/article/2l9l 10- overview).
  • HPV HPV is spread via skin or from surface contact. Infection via the environment is more likely to occur if the skin is macerated and in contact with roughened surfaces - conditions which are common in swimming pools and communal washing areas (Sterling, 2001 ). There are very few precise epidemiological data on viral warts. Most prevalence surveys have tended to use selected subsets of the population such as dermatology outpatients or school children. In the general population, viral warts are uncommon in infancy, increasingly common in childhood (reaching a peak in the teenage years) and sharply declining in prevalence thereafter (Gibbs, 2009). Human papillomavirus and Cutaneous Warts
  • Cutaneous wart diagnosis is generally based on clinical examination, but can be suggested by histological appearances of epidermis with papillomatosis, hyperkaratosis, and parakeratosis. Dermal capillary vessels may be prominent and thrombosed. There may be large keratinocytes with eccentric pyknotic nuclei surrounded by a perinuclear halo. HPV-infected cells can have small eosinophilic granules and diffuse clumps of basophilic keratohyline granules - these are not HPV particles. Plantar warts must be distinguished from callosities and corns. Flat warts have less acanthosis and hyperkeratosis and do not have parakeratosis or papillomatosis. A published report in March 2012 examined the prevalence of cutaneous wart-associated
  • HPV types and their relation with patient characteristics were taken from 250 patients, age range 4 to 50 years that had one or more new cutaneous warts. HPV 27, 57, 2 and 1 were the most prevalent types; in only 14% of warts were other HPV types detected. In 74% of patients with multiple warts, one HPV type was shared in all warts of that patient. It is suggested that a co-infection of single cells with multiple HPV types could be responsible for the development of some warts with multiple types. If specific HPV infections prove to be associated with clearance or response to specific treatment, HPV genotyping or HPV type assessment based on clinical profiles may become relevant for daily practice (Bruggink, 2012).
  • Diseases which may be prevented and/or treated by the processes and compositions of this invention are those caused by the etiological agent, papillomavirus, and may be the result of clinical or sub-clinical PV infections.
  • diseases include, for example, epithelial malignancies, anogenital malignancies, such as cervical cancer, malignant lesions, benign lesions, papillomacarcinomas, papilloadenocystomas, papilloma neurophathicum, papillomatosis, cutaneous and mucosal papillomas, condylomas, oral, pharyngeal, laryngeal, and tongue papillomas, fibroblastic tumors and other pathological conditions associated with papillomavirus.
  • the composition of this invention may also be used to treat epithelial and internal fibropapillomas in animals.
  • warts are found on human skin and are caused by the human papillomavirus (HPV).
  • HPV human papillomavirus
  • common warts verruca vulgaris
  • plantar warts palmar warts
  • planar warts verruca plana
  • mosaic warts and venereal warts (condyloma accuminatum).
  • Genital warts also referred to as venereal warts and condylomata acuminata
  • venereal warts and condylomata acuminata are one of the most serious manifestations of HPV infection.
  • the seriousness of genital warts is underlined by the finding that HPV DNA can be found in all grades of cervical intraepithelial neoplasia (CIN I III) and that a specific subset of HPV types can be found in carcinoma in situ of the cervix.
  • VfN vulvar intraepithelial neoplasia
  • a method of treating a patient having WO 2019/136196 . , . PCT/US2019/012256 one or more genital warts comprises the administration or a pharmaceutical of the invention so as to inhibit growth of the wart.
  • the wart(s), or other PV-containing cells are contacted directly with the pharmaceutical composition.
  • the subject method can be used to treat, e.g., condyloma acuminata and/or flat cervical warts.
  • Laryngeal papillomas are benign epithelial tumors of the larynx. Two PV types, HPV-6 and HPV-l l , are most commonly associated with laryngeal papillomas. According to the method of the present invention, laryngeal papillomas are treated administrating a pharmaceutical composition of the invention, so as to inhibit growth of the papillomas.
  • Common warts generally contain HPV types 1 , 2, 3, 4 or 10. These warts typically occur on the soles of feet, plantar warts, or on the hands. Common skin warts are most often found in children and young adults. Later in life the incidence of common warts decreases presumably due to immunologic and physiologic changes. Plantar warts can often be debilitating and require surgical removal and they frequently reoccur after surgery. As above, patients suffering from common warts can be treated by the administration of a effective amount of an E2 peptidomimetic according to the present invention, or a gene therapy construct which encodes the therapeutic E2 peptide.
  • the peptide or gene construct are applied, in the appropriate formulations, directly to the area of the skin afflicted with the wart(s). Similar methods and compositions may be useful in the treatment if epidermodysplasia verruciformis (EV), a rare genetically transmitted disease which is characterized by disseminated flat warts that appear as small reddish macules.
  • EV epidermodysplasia verruciformis
  • compositions may be used to treat lesions resulting from cellular transformation for which HPV is a etiological agent, e.g., in the treatment of cervical cancer.
  • HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. There is currently no specific treatment for HPV infection.
  • the method of the present invention can be used to treat viral infection in an individual caused by human papillomavirus (HPV), human T-Iymphotropic virus type I (HTLV-1), herpes virus (e.g., EBV or CMV), SV40-like virus, hepatitis virus, human immunodeficiency virus (HIV), adenovirus, or influenza virus.
  • HPV human papillomavirus
  • HTLV-1 human T-Iymphotropic virus type I
  • herpes virus e.g., EBV or CMV
  • SV40-like virus e.g., hepatitis virus
  • human immunodeficiency virus HIV
  • adenovirus e.g., adenovirus, or influenza virus.
  • the present method can also be used to treat infections caused by other viruses that are responsive to treatment by artemisinin or artemisinin derivatives, such as DNA viruses and RNA viruses. Such viruses may or may not cause cancer.
  • Herpes simplex virus is a double stranded DNA virus and can enter into target organisms through the mouth, respiratory passage, genital tract mucosa, damaged skin and many other channels. It is a quite common infection among humans and the infection rate is as high as 80-90%. Typical symptoms include clusters of blisters on certain parts of the mucosa and skin, while occasionally serious systemic disease may occur and do harm to the internal organs.
  • HSV-1 and HSV-2 might separately be related to lip cancer, vulva cancer and cervix cancer and lots of attentions have been drawn to them (Sunhe, China practical gynaecology and obstetrics journal, 2001 , 17 (7):407-409).
  • drugs for treating HSV infection include idoxuridine, cytosine arabinoside, vidarabine, bromovinyl, uridine, acyclovir and so on. But the treatment time of these drugs are quite long, about 5-7 days.
  • MC virus is a member of the poxvirus group. It is a large double stranded DNA virus that replicates in the cytoplasm of infected cells. Skin lesions caused by MC have an incidence of approximately 1/200 children by the age of 10 in the United States. While the disease may be epidemic in children, it occurs in people of all ages and is worldwide in distribution. In adults, the infection may be spread by sexual contact. Skin lesions caused by MC are characterized by the appearance on the body surface of small, discreet, lobulated epidermal outgrowths or lesions that occur throughout the body.
  • lesions which are the result of excessive cellular proliferation stimulated in the keratinocyte layer by virus that has entered through the skin, are discrete pearly white or flesh colored papules that may persist for up to three years.
  • the lesions may have a central pore, which contains within its center dead skin cells and numerous virus particles.
  • the virus is resistant to the commonly used anti-viral agents which are effective in treating other viral infections and the disease is treated only by surgical removal of the lesions, e.g., cryotherapy, or tissue destruction by chemical or physical means. This can be painful and distressing, particularly for children, and does not prevent the reappearance of fresh lesions.
  • compositions described herein typically comprise at least one cardiac glycoside.
  • the cardiac glycoside compositions may comprise other compounds as well.
  • the cardiac glycoside may comprise a mixture of cardiac glycosides, a mixture of a cardiac glycoside and one or more pharmaceutically acceptable excipients, or a mixture of a cardiac glycoside with other compounds having useful or desirable properties.
  • the composition of the invention may comprise at least one cardiac glycoside and at least one diuretic.
  • the cardiac glycoside composition of the invention may comprise a cardiac glycoside as the only active agent.
  • the cardiac glycoside is digoxin.
  • the composition of the invention may comprise at least one cardiac glycoside and at least one other active agent.
  • Digoxin also known as digitalis, is a purified cardiac glycoside extracted from the foxglove plant, Digitalis lanata.
  • the systematic name for this compound is (3b,5b, 12b)-3-[(0- 2,6-dideoxy-P-D-ribo-hexopyranosyl-(l ® 4)-0- 2,6-dideoxy ⁇ -D-ribo-hexopyranosyl-(l ®4)- 2,6 dideoxy-B D-nbo-hexopyranosyl)oxy]- 12, 14-dihydroxycard-20(22)-enolide,
  • Digitoxin is a cardiac glycoside which is the corresponding aglycone of digoxin. Thus, it has the systematic name: ⁇ )-3-[(0-2,6-dideoxy ⁇ -D-ribo-hexapyranosyl-(l->4)-2,6- dideoxy ⁇ -D-ribo-hexopyranosyl)oxy]- 14-hydroxycard-20(22)-enolide.
  • Methyl digoxin is a cardiac glycoside related to digoxin and digitoxin with the systematic name: (3b,5b, 12b)-3- ⁇ P ⁇ -dideoxy ⁇ -O-methyl-P-D-z ⁇ o-hexopyranosy ⁇ d ⁇ b-dideoxy ⁇ -D-nTw- hexopyranosyl-(l 4)-2,6-dideoxy ⁇ -D-r/Z 0-hexopyranosyl]oxy ⁇ - 12, 14-dihydiOxycard-2O(22)- enolide.
  • Lanatoside C is a cardiac glycoside with the systematic name: [(3b,5b, 12b)-3- ⁇ [b- ⁇ - Glucopyranosyl-(l ->4)-3-0-acetyl-2,6-dideoxy ⁇ -D-ribo-hexopyranosyl-(l ->4)-2,6-dideoxy ⁇ - D-p bo-hexopyranosyI-( 1 ->4)-2,6-d ideoxy-p-D-ribo-hexopyranosyl]oxy ⁇ - 12 , 14-d ihydroxycard-
  • Prosci llaridin is a bufanolide cardiac glycoside obtainable from plants of the genus Scilla. The systematic name of this compound is: 3P-Rhamnosido-14p-hydroxybufa 4, 20, 22 trienolide.
  • K-strophanthin refers to a cardiac glycoside or mixture of glycosides obtained from a tropical plant (Strophanthus kombe) of the dogbane family.
  • Peruvoside refers to a cardiac glycoside with the systematic name: (3p,5P)-3-[(6-Deoxy-3-0-methyl-a-L-glucopyranosyl)oxy]- 14-hydroxy- 19-oxocard-20(22)-enolide
  • Ouabain, also known as g-strophanthin is a cardiac glycoside found in the ripe seeds of the African plants Strophanthus gratus and Acokanthera ouabaio.
  • the systematic name of this compound is: 1b,3b,5b, 1 l a, 14, 19-Hexahydroxycard- 20(22)-enolide 3-(6-deoxy- a -L-mannopyranoside).
  • Other embodiments of cardiac glycosides include oleander and extracts and isolates thereof.
  • cardiac glycoside refers to a class of pharmacological agents including those that have been used to treat congestive heart failure and heart arrhythmias by inhibiting the Na+/K+ pump in cells. Inhibition of the Na+/K + pump by cardiac glycosides leads to increased Na + levels, which in turn slows down the extrusion of Ca +2 via the Na + /Ca +2 exchange pump. Many cardiac glycosides are natural products which share a common molecular motif comprising a steroid nucleus containing an unsaturated lactone ring at the C ] 7 position and one or more glycosidic residues at C3.
  • cardiac glycosides include, but are not limited to, ouabain, oleandrin, g/k/e-strophanthin, digoxin, digitoxin, proscillaridine A, which are plant derived, and bufalin, marinobufagenin and bufadienolides, which are derived from frog poisons.
  • Cardiac glycosides comprise two structural features, a sugar (glycoside) and a non-sugar (aglycone) steroid moiety.
  • the pharmaceutical composition of the invention may comprise about 0.125%, about 0.250%, about 0.50%, about 0.75%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% w/w of the cardiac glycoside.
  • the pharmaceutical composition of the invention may comprise about 0.125% to about 1 0%, about 0.125% to about 5%, or about 0.125% to about 3% w/w of the cardiac glycoside.
  • compositions described herein typically comprise at least one diuretic compound.
  • the diuretic compositions may comprise other compounds as well.
  • the diuretic composition may comprise a mixture of diuretic compounds, a mixture of a diuretic compound and a pharmaceutically acceptable excipient, or a mixture of a diuretic compound with other compounds having useful or desirable properties.
  • the composition of the invention may comprise at least one cardiac glycoside and at least one diuretic.
  • the diuretic composition may comprise a pure diuretic compound as the only active agent.
  • the composition of the invention may comprise at least one cardiac glycoside and at least one other active agent.
  • the diuretic is furosemide: 4-Chloro-2-[(furan-2-ylmethyl)amino]-5- sulphamoylbenzoic acid (Ph. Eur.) Chemical Abstracts Service (CAS) registry number CAS 54-
  • Furosemide occurs as a white or almost white crystalline powder. It is practically insoluble in water; sparingly soluble in ethanol (96%); soluble in acetone and dilute alkali solutions. Furosemide has a melting point of approximately 210°C with decomposition. Furosemide is known to have several polymorphic forms. They can be differentiated by means of X-ray diffraction patterns. The applied manufacturing process leads to the (commercial) polymorphic form I, which is the thermodynamically stable modification. Furosemide has no chiral center. The pKa value for Furosemide was found to be 3.9.
  • any suitable diuretic compound may be used.
  • Classes ofdiuretics suitable for use with the described methods and formulations include the carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics, thiazide and thiazide-like diuretics, potassium sparing diuretics, and aldosterone antagonists.
  • Exemplary diuretic compounds within these classes include bumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone, torsemide, triamterene, tripamide, BG 9928 (Bicyclo[2,2,2]octane-l -propanoic acid, 4-(2,3,6,7-tetrahydro- 2,6-dioxo- 1 ,3-dipropyl- 1 H-purin-8yl)-(9CI)), and BG 9719 (l H-Purine-2,6-dione, 3,7-dihydro- 8-(3-oxatricyclo[3,2, l ,02,4]oct-6-yl)- 1 ,3-dipropyl-[ 1 S-(l a,2b,4b,5a,6b)], and pharmaceutically acceptable analogs and equivalents thereof.
  • the diuretic is selected from the group consisting of high-ceiling diuretics, furosemide, bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide, piretanide, tripamide, chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metozalone, cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazolamide, methazolamide, ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide, hydroflumethiazide, trichlormethiazide, polythiazide and benzothiazide.
  • the pharmaceutical composition or the invention may comprise about 0.01 %, about 0.125%, about 0.250%, about 0.50%, about 0.75%, about 1 %, about 1 .10%, about 1 .2%, about 1 .25%, about 1 .3%, about 1 .4%, about 1 .5% about 1 .75%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% w/w of the diuretic.
  • the pharmaceutical composition of the invention may comprise about 0.01 % to about 10%, about 0.125% to about 10%, about 0.125% to about 5%, about 0.125% to about 3% w/w of the diuretic, about 1 % to about 5%, about 1 % to about 3%, or about 1 . 1 5% to about 2%, about 1 . 15% to about 2.5%, about 1.15% to about 1 .3%.
  • Buffering Agents are examples of the pharmaceutical composition of the invention.
  • the normal pH of the skin is between about 4 and about 6.5, though it varies in people of different skin types.
  • the compositions of the invention may be formulated in such a manner so as to reduce the effects that the actual application of the composition has on the pH barrier of the skin and/or may be formulated in a manner so as to increase the penetration of the active agent.
  • the typical pH ranges for the compositions of the invention include a pH of about 3 to about 8, of about 4 to about 7, and more typically about 4.5 to about 6.5 or about 5.5.
  • compositions of the invention can be obtained in accordance with practices well known in the art, for instance, by the inclusion of various buffering agents, which should be included in an amount and concentration to optim ize the flux of the active agent through the skin surface and into the dermal layer of skin, while minimizing any possibility of skin irritation due to a change in the pH of the skin.
  • a conventional buffering agent such as a mixture of citric acid and trisodium citrate, may be added to stabilize the desired pH.
  • Other buffering agents include, but are not limited to, sodium phosphate, monosodium dihydrogen phosphate, and disodium monohydrogen phosphate.
  • a citrate buffer for use in the present invention may be generated by dissolution of free citric acid or preferably a pharmaceutically acceptable salt of citrate, preferably a sodium salt.
  • citrate buffer is present in the formulation at 7.5 mmol/1 to 15 mmol/1 and most preferably at 10mmol/l. Any pharmaceutically acceptable citrate buffer may be used in the present invention but the citrate buffer is preferably sodium citrate. It is more preferable that sodium citrate dihydrate is used and most preferable that the citrate buffer be generated from a mixture of sodium citrate dihydrate and citric acid monohydrate. In the preferred embodiments of the present invention, the formulation contains about 2 mg/ml sodium citrate dihydrate and about 0.6 mg/ml citric acid monohydrate.
  • a citrate buffer for use in the present invention may be generated by dissolution of free citric acid or preferably a pharmaceutically acceptable salt of citrate, preferably a sodium salt.
  • a formulation of the present invention may be generated by adding an amount of citrate buffer necessary to obtain a pH of the solution in the range 5.3 to 7.2.
  • the citrate buffer is preferably present at 5mmol/l to 20mmol/l.
  • the desired pH range is from about pH 4.0 to pH 5.5.
  • These buffering systems can be comprised of a weak acid and the salt of a weak acid and/or a mixture of two acid salts.
  • Suitable buffering systems include, for example, citric acid and sodium citrate; citric acid and potassium citrate; phosphoric acid and sodium phosphate; phosphoric acid and potassium phosphate; amino acid bases and their acids; arginine and arginine HC1; lysine and lysine HC1; tartaric acid and sodium tartrate; tartaric acid and potassium tartrate; adipic acid and sodium adipate; adipic acid and potassium adipate; malic acid and sodium malate, malic acid and potassium malate; sodium phosphate monobasic and sodium phosphate dibasic; and combinations thereof; and the like.
  • the buffering system should be present in an amount of from about 0.05 to 2.0%, preferably from about 0.05 to 1 .0% by weight of the total composition.
  • the citrate buffered formulation of the invention may include an amount of citrate effective to provide a pharmaceutically acceptable pH, e.g., to provide a pH environment of between 5 and 7, preferably between about 5.3, and 6.2.
  • a pharmaceutically acceptable amount of citrate buffer effective to achieve the desired pH suitable amounts of sodium citrate and citric acid can be used.
  • Suitable buffer systems of use in the present invention include, by way of example only, tartaric, fumaric, maleic, phosphoric, and acetic acids and salts.
  • Preferred buffering systems include citric acid and phosphoric acid buffer systems.
  • the citric acid buffer system preferably contains sodium citrate dihydrate USP in combination with citric acid anhydrous USP, available from Haarman & Reimer.
  • Buffering agents can also be added to the formulation to control pH.
  • buffering agents can be any one or more of the following agents, and is not limited to, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, glycine, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate, sodium hydroxide, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate, TR1S and sodium carbonate, 2-Amino-2-methyl-l , 3-propanediol, 2-Amino-2-methyl-l -propanol, L-(+)-Tartaric acid, ACES, ADA, Acetic acid, Ammonium acetate solution, Ammonium bicarbonate, Ammonium citrate dibasic, Ammonium formate, Ammonium oxalate monohydrate, Ammonium phosphate dibasic, Ammonium phosphate monobasic, Ammonium sodium phosphate dibasic tetra
  • compositions of the invention may be, for example, administered topically.
  • the compositions of the invention may be, for example, mixed with pharmaceutically suitable auxiliaries, e.g., as described in the standard reference, Gennaro et al., Remington: The Science and Practice of Pharmacy. 20 th Edition Baltimore:Lippincott Williams & Wilkins, 2000..
  • pharmaceutically suitable liquids the compositions may be applied in the form of, for example, a solution, suspension, gel or emulsion.
  • the compositions may also be formulated in, for example, a patch, ointment or can be enclosed in a device for local administration to the skin.
  • topical as employed herein relates to the use of a compound, derivative or analogue as described herein, incorporated in a suitable pharmaceutical carrier, and applied at the site of, for example, a wart, for exertion of local action. Accordingly, such topical compositions including those forms in which the composition is applied externally by direct contact with the skin surface to be treated.
  • Conventional forms for this purpose include ointments, liniments, creams, shampoos, lotions, pastes, gels, sprays, aerosols, soaps, and the like, and may be applied in patches or impregnated dressings depending on the part of the body to be treated.
  • cream embraces formulations (including creams) having oleaginous, absorption, water-soluble and emulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.
  • oleaginous, absorption, water-soluble and emulsion-type bases e.g., petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.
  • compositions of the invention can be formulated in aqueous solutions, gels, creams, ointments or oils exhibiting physiologically acceptable osmolarity by addition of pharmacologically acceptable buffers and salts.
  • Such formulations may or may not, depending on the dispenser, contain preservatives such as benzalkonium chloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids and phenylmercuric salts such as nitrate, chloride, acetate, and borate, or antioxidants, as well as additives like EDTA, sorbitol, boric acid, etc., as additives.
  • aqueous solutions may contain viscosity increasing agents such as polysaccharides, e.g., methylcellulose, mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate, or polyalcohol, e.g., polyvinylalcohol.
  • viscosity increasing agents such as polysaccharides, e.g., methylcellulose, mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate
  • polyalcohol e.g., polyvinylalcohol.
  • slow releasing gels and matrices may also be employed as well as soluble and insoluble ocular inserts, for instance, based on substances forming in-situ gels.
  • various amounts of the drug and different dose regimens may be employed.
  • compositions of the invention can be advantageously formulated using ointments, gels, creams, liniments or patches as a carrier of the active ingredient.
  • tnese formulations may or may not contain preservatives, depending on the dispenser and nature of use.
  • preservatives include those mentioned above, and methyl-, propyl-, or butyl- parahydroxybenzoic acid, betain, chlorhexidine, benzalkonium chloride, and the like.
  • Various matrices for slow release delivery may also be used.
  • the compositions of the invention may be administered once or several times daily, with or without antioxidants.
  • Non-limiting examples of topical products can include, without limitation, application stick, mascara, eyebrow coloring products, eye shadow or other eye lid coloring products, eyeliner, make-up removal products, antiaging products, facial or body powder, nail polish, mousse, sprays, styling gels, nail conditioner, bath and shower gels, shampoos, conditioners, cream rinses, skin conditioners, sun tanning lotions and creams and sprays, sunscreens and sunblocks, skin conditioners, cold creams, moisturizers, soaps, body scrubs, exfoliants, astringents, depilatories and permanent waving solutions, antidandruff formulations, antisweat and antiperspirant compositions, shaving, preshaving and after shaving products, moisturizers, deodorants, cold creams, cleansers, skin gels, and rinses.
  • topical product can be applied topically, either in unit-dose or multi-use package, through the use of a patch or other applicator or delivery device.
  • Delivery devices can include, but are not limited to, those that can be heated or cooled, as well as those that utilize iontophoresis or ultrasound.
  • the topical composition can be applied, for example, by applying a composition in the form of a skin lotion, clear lotion, milky lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, application stick, pencil, foundation, nail polish, after-shave, or the like which is intended to be left on the skin or other keratinous tissue (i.e., a "leave-on" composition).
  • a composition in the form of a skin lotion, clear lotion, milky lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, application stick, pencil, foundation, nail polish, after-shave, or the like which is intended to be left on the skin or other keratinous tissue (i.e., a "leave-on" composition).
  • keratinous tissue e.g., skin
  • it is left on for a period of at least about 15 minutes, or at least about 30 minutes, or at least about 1
  • the topical product is left on overnight. In another embodiment, the topical product is left on all day. Any part of the external portion of the body can be treated, (e.g., face, lips, under-eye area, eyelids, scalp, neck, torso, arms, legs, chest, hands, legs, feet, toenails, scalp, eyelashes, eyebrows, etc.)
  • any suitable method can be used to apply the topical product, including but not limited to for example using the palms of the hands and/or fingers or a device or implement (e.g., a cotton ball, swab, pad, applicator pen, spray applicator, eyebrow brush, eyebrow brush pencil, pencil, mascara brush, etc.)
  • a device or implement e.g., a cotton ball, swab, pad, applicator pen, spray applicator, eyebrow brush, eyebrow brush pencil, pencil, mascara brush, etc.
  • Another approach to ensure a continuous exposure of the keratinous tissue to at least a minimum level of the topical product is to apply the compound by use of a patch applied, e.g., to the face.
  • the patch can be occlusive, semi-occlusive or non-occlusive, and can be adhesive or non-adhesive.
  • the topical product can be contained within the patch or be applied to the skin prior to application of the patch.
  • the patch can also include additional actives such as chemical initiators for exothermic reactions such as those described in PCT application WO 9701313, and in U.S. Pat. Nos. 5,821 ,250, 5,981 ,547, and 5,972,957 to Wu, et al.
  • the patch can be left on the area to be treated for any suitable period of time. For example, a period of at least about 5 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 1 hour, or at night as a form of night therapy, or in another embodiment all day.
  • the topical product can comprise any suitable desired materials.
  • suitable desired materials can be selected from the group consisting of sugar amines (e.g., N-acetylglucosamine), vitamin B3 compounds, sodium dehydroacetate, dehydroacetic acid and its salts, phytosterols, soy derivaties (e.g., equol and other isoflavones), niacinamide, phytantriol, farnesol, bisabolol, salicylic acid compositions, hexamidines, dialkanoyl hydroxyproline compositions, flavonoids, N-acyl amino acid compositions, retinoids (e.g., retinyl propionate), water-soluble vitamins, ascorbates (e.g., vitamin C, ascorbic acid, ascorbyl glucoside, ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate), particulate materials, sunscreen actives, anti cellulite agents, butyl
  • cationic polymers include cationic polymers, conditioning agents (hydrocarbon oils, fatty esters, silicones), anti-dandruff agents, suspending agents, viscosity modifiers, dyes, nonvolatile solvents or diluents (water soluble and insoluble), pearlescent aids, foam boosters, surfactants, nonionic cosurfactants, pediculocides, pH adjusting agents, perfumes, preservatives, chelants, chelating agents, proteins, UV absorbers, pigments, other amino acids, and other vitamins.
  • conditioning agents hydrocarbon oils, fatty esters, silicones
  • anti-dandruff agents suspending agents, viscosity modifiers, dyes, nonvolatile solvents or diluents (water soluble and insoluble), pearlescent aids, foam boosters, surfactants, nonionic cosurfactants, pediculocides, pH adjusting agents, perfumes, preservatives, chelants, chelating agents, proteins, UV absorbers, pigments,
  • topical products for use herein may comprise one or more vitamins and/or amino acids such as: water soluble vitamins such as vitamin B l , B2, B6, B 12, C, pantothenic acid, pantothenyl ethyl ether, panthenol, biotin, and their derivatives, water soluble amino acids such as asparagine, alanine, indole, glutamic acid and their salts, water insoluble vitamins such as vitamin A, D, E, and their derivatives, water insoluble amino acids such as tyrosine, tryptamine, and their salts.
  • water soluble vitamins such as vitamin B l , B2, B6, B 12, C
  • pantothenic acid pantothenyl ethyl ether
  • panthenol panthenol
  • biotin and their derivatives
  • water soluble amino acids such as asparagine, alanine, indole, glutamic acid and their salts
  • water insoluble vitamins such as vitamin A, D
  • Topical products may also contain one or more pigment materials such as inorganic, nitroso, monoazo, diazo, carotenoid, triphenyl methane, triaryl methane, xanthene, quinoline, oxazine, azine, anthraquinone, indigoid, thionindigoid, quinacridone, phthalocianine, botanical, natural colors, including water soluble components.
  • pigment materials such as inorganic, nitroso, monoazo, diazo, carotenoid, triphenyl methane, triaryl methane, xanthene, quinoline, oxazine, azine, anthraquinone, indigoid, thionindigoid, quinacridone, phthalocianine, botanical, natural colors, including water soluble components.
  • the topical products may also contain antimicrobial agents which are useful as cosmetic biocides and antidandruff agents including: water soluble components such as piroctone olamine, water insoluble components such as 3,4,4'- trichlorocarbanilide (trichlosan), triclocarban and zinc pyrithione.
  • antimicrobial agents which are useful as cosmetic biocides and antidandruff agents including: water soluble components such as piroctone olamine, water insoluble components such as 3,4,4'- trichlorocarbanilide (trichlosan), triclocarban and zinc pyrithione.
  • the composition is chronically applied to the skin.
  • chromenic topical application is meant continued topical application of the composition over an extended period during the subject's lifetime, for example, for a period of at least about one week, or for a period of at least about one month, or for at least about three months, or for at least about six months, or for at least about one year. While benefits are obtainable after various periods of use (e.g., five, ten or twenty years), chronic application can continue throughout the subject's lifetime. Typically applications would be on the order of about once per day over such extended periods, however application rates can vary from about once per week up to about three times per day or more.
  • Regulating keratinous tissue condition can be practiced by applying a composition of the invention in the form of a skin lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, lipstick, foundation, nail polish, after-shave, or the like that is preferably intended to be left on the skin or other keratin structure for some esthetic, prophylactic, therapeutic or other benefit (i.e., a "leave-on" composition).
  • a composition of the invention in the form of a skin lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, lipstick, foundation, nail polish, after-shave, or the like that is preferably intended to be left on the skin or other keratin structure for some esthetic, prophylactic, therapeutic or other benefit (i.e., a "leave-on" composition).
  • the composition After applying the composition to the skin, it can be left on the skin for
  • compositions of the invention may include various other and additional ingredients, which may be active, functional, conventionally used in cosmetic, personal care or topical/transdermal pharmaceutical products or otherwise.
  • additional ingredients may be active, functional, conventionally used in cosmetic, personal care or topical/transdermal pharmaceutical products or otherwise.
  • a decision to include an additional ingredient and the choice of specific additional ingredients depends on the specific application and product formulation.
  • the line of demarcation between an "active" ingredient and an "inactive ingredient” is artificial and dependent on the specific application and product type.
  • a substance that is an "active" ingredient in one application or product may be a "functional” ingredient in another, and vice versa.
  • a particular ingredient might provide substantivity in one formulation, facilitate transdermal application in another, and merely provide proper viscosity in a third. Which of these is functional and which is active is subject to debate. But, regardless of the outcome, the material in question would qualify as an additional ingredient in accordance with the present invention.
  • compositions of the invention may include one or more additional ingredients, which provide some benefit to the object of the composition.
  • additional ingredients may include one or more substances such as, without limitations, cleaning agents, conditioning agents, skin conditioning agents, antidandruff agents, growth promoters, perfumes, sunscreen and/or sunblock compositions, pigments, moisturizers, film formers, colors, make-up agents, detergents, pharmaceuticals, thickening agents, emulsifiers, humectants, emollients, antiseptic agents, deodorant actives, dermatologically acceptable carriers, surfactants, bleaching agents, and combinations thereof.
  • compositions of the present invention generally contain at least one additional ingredient.
  • compositions of the present invention may contain a plurality of additional ingredients as well.
  • CTFA Cosmetic Ingredient Handbook Ninth Edition (2002) describes a wide variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use as additional ingredients in the compositions of the present invention.
  • additional ingredient classes include: abrasives, absorbents, aesthetic components such as fragrances, pigments, colorings/colorants, essential oils, skin sensates, astringents, etc.
  • anti-acne agents e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate
  • anti-acne agents e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate
  • antimicrobial agents e.g., iodopropyl butylcarbamate
  • antioxidants e.g., iodopropyl butylcarbamate
  • binders biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers or materials, e.g., polymers, for aiding the film-forming properties and substantivity of the composition (e.g., copolymer of
  • the additional ingredients useful herein can be categorized by the benefit they provide or by their postulated mode of action.
  • the additional ingredients useful herein can in some Instances provide more than one benefit or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit the additional ingredients to that particular application or applications listed.
  • the invention will be illustrated in more detail with reference to the following Examples, but it should be understood that the present invention is not deemed to be limited thereto.
  • CLS003 The CLS003 drug product is a topical gel containing both digoxin and furosemide each at concentrations of 0.125%w/w.
  • the quantitative formulation is provided below:
  • propylene glycol may be increased.
  • Cidofovir another known antiviral drug for DNA virus, effectively inhibited HPV mRNA but not the viral load at 24 hours.
  • Combined digoxin-furosemide drug treatments showed significant decreases on the HPV viral load and mRNA levels.
  • Hela cells were treated with a different combination of digoxin (0, 0.5, 2 pg/mL) and furosemide (50, 100, 200, 500 pg/mL).
  • non-drug treated and cidofovir 65 pM treated WO 2019/136196 ⁇ , A A n A ⁇ ⁇ .
  • J PCT/US2019/012256 wens wci c aisu included.
  • Combined drug treatments showed synergistic effects on anti-viral activity.
  • the inventors further conducted an in vitro study to test the efficacy of digoxin and furosemide through the examination of viral load.
  • Hela S3 cells were treated with different combinations of digoxin (0, 0.1 , 0.5, 2 pg/mL) and furosemide (0, 50, 100, 200, 500 pg/mL).
  • Non-drug treated (NT) cells and cidofovir (65 pM) treated cells served as controls. The study took place over a total of four days. Anti-viral effects were clearly observed at the 48-hour mark in the treated sample.
  • the inventors further conducted a stability study comparing non-buffered and buffered formulations.
  • the Tables below summarizes the improved stability profile of the buffered formulation as compared to a non-buffered formulation. These are 6 month stressed storage results. In the presence of the buffer, the active potency is maintained, and the number and level of degradation products is significantly reduced.
  • the non-buffered formulation is not commercially viable due to the formulation; whereas, the buffered formulation represents a commercially viable product.
  • Citrate Buffered Formulation appeared to result in higher accumulation in dermis than Unbuffered Formulation.
  • the formulations of the invention have the further benefit of limiting systemic exposure. While the flux (J) of digoxin in the buffered formulation is improved over that of the unbuffered, the digoxin levels are still well within the margin of safety established in the non-clinical mini-pig model.
  • the treated area was 270 cm 2 representing 10% of body surface area (BSA) and the standard dose applied was 2.6 mL
  • the resulting mean ⁇ SD day 7 C max was 1 ,045 ⁇ 1 ,065 pg/mL (1 .045 ⁇ 1 .065 ng/mL).
  • formulation i.e., upper layers of stratum corneum through skin barrier
  • the formulation of the invention exhibits improved stability over previous formulations.
  • the formulation of the invention exhibits improved stability over previous formulations, even in stressed conditions.
  • PK model was developed based on the established pharmacokinetic properties of system ically administered furosemide described in the literature.
  • Concentration vs. time data was digitized from previously published PK data in humans following PO and IV administration and modeling was performed assuming linear pharmacokinetics (Haegeli et ah, 2007; Waller et al., 1985).
  • the peak level data was also used to estimate the topical bioavailability of furosemide (using human IV data as the reference) assuming that there was no influence of digoxin on the rate and extent of topical furosemide absorption.
  • PK data following the topical administration of furosemide gel at 0.125% w/w and 0.25% w/w in rats and minipigs were also used to guide model development.
  • PK model were digitized from Haegeli et ah, 2007 ( Figure 6).
  • PK parameter estimates were derived from serial blood samples at the following time points; pre-dose (0 hour) and at 0.25, 0.5, 0.75, 1 , 1 .25, 1 .5, 1.75, 2, 2.50, 3, 3.50, 4, 6, and 8 hours post-dose following the intravenous and oral dosing of 20 mg furosemide (Haegeli et ah, 2007).
  • NCA non-compartmental
  • ast AUCj n r
  • Model selection was based on the goodness of fit, AIC values, and the CV% values of the individual PK parameter estimates.
  • Key PK parameters including the absorption rate constant (Ka), eli ination rate constant (Ke), lag time Tlag, clearance (CL/F), and the volume of the central compartment (V/F), were then estimated from the data.
  • the observed peak plasma level (91 .1 pg/mL [0.09 ng/mL]) was overlaid on the simulated profiles to identify an F value that resulted in good concordance between the observed and simulated C max values.
  • Step 1 the absolute oral bioavailability of furosemide was calculated based on literature data using non- compartmental analysis.
  • Step 2 a base model was built using compartmental modelling within Phoenix version 6.4 (as described in Section 4.2).
  • Step 3 model-fitted PK parameters (Ka, V/F, CL/F, Tlag) were held constant, and various scenarios were simulated using a range of estimated topical bioavailability (F) values (0.005, 0.1, 0.2, 0.5 and 1.0 following a total dose of 3750 gg (or 3.75 mg) furosemide from one 3 g tube containing Furosemide Topical Gel 0.125% w/w (CLS006). These results were then compared to the peak exposure associated with the observed toxic concentration in human, which is approximately 50,000 ng/mL (Rybak et al., 1982).
  • a fixed amount of gel equivalent to 1250 gg of furosemide was applied over a total combined skin area of approximately 100 cm 2 . Assuming the BSA of an average 70 kg adult is 1.7 m 2 (17,000 cm 2 ), 100 cm 2 represents approximately 0.59% of the total BSA. Based on this application site data, the total theoretical amount of furosemide that could be applied to 100% of the body surface area was then calculated for both adults and children > 12 years of age with a body surface area in the range 13,300 cm2 ⁇ 18,000 cm 2 . The exposure associated with the total theoretical amount of furosemide that could be applied topically was then compared to the peak plasma level exposure following a 20 mg oral dose of furosemide.
  • a one-compartment oral absorption described the pharmacokinetic profile of furosemide.
  • the comparison of the model predicted (solid line) and clinically observed data (symbols) from Haegeli et ah, are given in Figure 8.
  • the absorption rate constant (Ka) was estimated to be 1.28/hr, volume of distribution (V/F) 0.03 L, total body clearance (CL/F) 0.02L/hr, with an estimated lag time of 0.23 hrs (Table 2).
  • the absolute oral bioavailability of furosemide was derived from the PO and IV PK data and estimated to be 0.52 (52%).
  • the predicted Cmax value would only reach 2.6 ng/mL, representing a safety margin of 19,230 fold (worst case). Based on an estimated bioavailability of 0.005 (0.5%), the predicted Cmax is estimated to be approximately 0.012 ng/mL, well below the exposure associated with adverse effects.

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Abstract

Cette invention concerne une composition topique pour la prévention et le traitement d'infections virales.
PCT/US2019/012256 2018-01-08 2019-01-04 Composition thérapeutique WO2019136196A1 (fr)

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CN111588691A (zh) * 2020-07-09 2020-08-28 安徽中医药大学 一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法

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US20170000814A1 (en) * 2015-06-08 2017-01-05 Dermarc LLC Therapeutic composition
US20180133239A1 (en) * 2015-06-08 2018-05-17 Dermarc LLC Therapeutic composition

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Publication number Priority date Publication date Assignee Title
US20170000814A1 (en) * 2015-06-08 2017-01-05 Dermarc LLC Therapeutic composition
US20180133239A1 (en) * 2015-06-08 2018-05-17 Dermarc LLC Therapeutic composition
US10137140B2 (en) * 2015-06-08 2018-11-27 Dermarc LLC Therapeutic composition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111588691A (zh) * 2020-07-09 2020-08-28 安徽中医药大学 一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法
CN111588691B (zh) * 2020-07-09 2022-09-23 安徽中医药大学 一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法

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