WO2021216402A1 - Procédés et compositions pour le traitement d'infections virales et de détresse respiratoire - Google Patents

Procédés et compositions pour le traitement d'infections virales et de détresse respiratoire Download PDF

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WO2021216402A1
WO2021216402A1 PCT/US2021/027885 US2021027885W WO2021216402A1 WO 2021216402 A1 WO2021216402 A1 WO 2021216402A1 US 2021027885 W US2021027885 W US 2021027885W WO 2021216402 A1 WO2021216402 A1 WO 2021216402A1
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fluorocarbon
pharmaceutical composition
vol
ards
respiratory
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PCT/US2021/027885
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English (en)
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Evan C. Unger
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Nuvox Pharma Llc
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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
    • A61K31/02—Halogenated hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • This invention relates to pharmaceutical compositions and methods of their preparation and therapeutic use. More particularly, the invention relates to pharmaceutical compositions and dosage forms of fluorocarbon emulsions that are useful in treating viral infections and acute respiratory distress syndrome and related diseases and conditions, as well as methods of preparation and use thereof.
  • Viruses may cause pneumonia and affect the lung to cause the acute respiratory distress syndrome (ARDS).
  • influenza viruses such as H5N1 and H1N1 are particularly common.
  • Coronaviruses (CoV) are another class of viruses that may cause pneumonia and ARDS.
  • CoVs are positive-stranded RNA viruses with a crown like appearance on electron microscopy.
  • the subfamily of Orthocoronavirinae of the Coronaviridae family (order Nidrovirales) classifies into four genera of COVs: Alphacoronavirus (alphaCoV), Betacoronavirus (betaCoV), Deltacoronavirus (deltaCoV), and Gammacoronavirus (gammaCoV).
  • Common human CoVs HCoV-OC43, and HCoV-HKUl (betaCoVs of the A lineage); HCoV-229E, and HCoV-NL63 (alphaCoVs). These common A lineage CoVs can cause common colds and self-limiting upper respiratory infections in immunocompetent individuals. In immunocompromised subjects and the elderly, however, lower respiratory tract infections can occur.
  • Other human CoVs include SARS-CoV, SARS-CoV-2, and MERS-CoV (betaCoVs of the B and C lineage, respectively). These CoV viruses of the B and C lineage can cause epidemics with potentially severe respiratory and extra-respiratory syptoms.
  • SARS-CoV-2 the causative agent of COVID-19, belongs to the betaCoVs category. Although it has a lower mortality than SARS-CoV and MERS-CoV, it is more readily transmissible than these other betaCoV category viruses and because of its much wider spread is responsible for more deaths than SARS-CoV or MERS-CoV.
  • Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) are two viruses that can cause nosocomial infections and also can evolve into ARDS. Additional viruses that may be implicated in pulmonary infections include Adenovirus, Human metapneumovirus (HmPV), Parainfluenza and Respiratory syncytial virus (RSV).
  • HmPV Human metapneumovirus
  • RSV Respiratory syncytial virus
  • the Ebola virus is another virus with high lethality.
  • ARDS is a serious complication of viral infection, e.g. with COVID-19. Different forms of ARDS are distinguished based on the degree of hypoxia.
  • the reference parameter is the Pa0 2 /Fi0 2 : Mild ARDS is defined as Pa0 2 /Fi0 2 between 200 mm and 300 mm Hg, in non- ventilated patients or in patients treated with non-invasive ventilation (NIV) by using positive end-expiratory pressure (PEEP) or a continuous positive airway pressure (CPAP) > 5 cm H2O.
  • Moderate ARDS is defined as Pa0 2 /Fi0 2 between 100 and 200 mmHg.
  • Severe ARDS is defined as Pa0 2 /Fi0 2 less than or equal to 100 mm Hg.
  • the death rate As low as 25% but some reports have been as high as from 50% to 98% mortality.
  • COVID-19 patients have shown low oxygen levels similar to altitude sickness and poor oxygen uptake as one form of disease pathology. (Muacevic, et al. Cureus.
  • VTE venous thromboembolism
  • VTE Venous thromboembolism
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • thrombosis has been reported in the aorta, the coronary arteries, the brain and other organs in COVID-19 patients (Snell, J., SARS-CoV-2 infection and its association with thrombosis and ischemic stroke: a review. The American journal of emergency medicine, 2021. 40: p. 188-192).
  • the invention is based in part on the unexpected discovery of pharmaceutical compositions of certain fluorocarbons that exhibit therapeutic properties and can be safely and reliably used for treating viral infections and ARDS.
  • low doses of fluorocarbon materials with boiling points between about -34°C to about 100°C, for example, dodecafluoropentane emulsion (DDFPe) have been discovered to improve survival and outcomes in patients with viral infections and ARDS caused, for example, by COVID-19 infections.
  • DDFPe dodecafluoropentane emulsion
  • the invention also provides oxygenation to tissues with compromised blood flow due to macro and microthombi.
  • the unique pharmaceutical compositions and methods of use disclosed herein enable timely and substantial restoration of critical oxygen supply to affected organs, thus leading to reduced organ and tissue damages and improved treatment outcome.
  • the invention generally relates to a method for treating a respiratory infection, or a related disease or condition thereof, comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective dosage of a fluorocarbon having a boiling point between about -36°C to about 100°C, and a pharmaceutically acceptable carrier or excipient.
  • the invention generally relates to a unit dosage form of a pharmaceutical composition in the form of an emulsion comprising a dosage of a fluorocarbon having a boiling point between about -36 °C and about +100 °C therapeutically effective to treat respiratory infection, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable carrier or excipient.
  • the invention generally relates to use of a fluorocarbon for treating a respiratory infection, or a related disease or condition thereof, wherein the fluorocarbon has a boiling point between about -36°C to about 100°C.
  • the invention generally relates to use of a fluorocarbon for the manufacture of a medicament for treating a respiratory infection, or a related disease or condition thereof, wherein the fluorocarbon has a boiling point between about -36°C to about 100°C.
  • FIG. 1 illustrates an exemplary embodiment of an in vitro oxygenation experimental set-up.
  • FIG. 2 shows exemplary results on average oxygen offloading curves.
  • FIG. 3 shows exemplary results on net oxygen offloaded.
  • FIG. 4 shows exemplary results from LPS model of ARDS in mice, administration of
  • FIG. 5 shows exemplary lung histology specimens of normal tissue (left), LPS exposed mouse treated with saline placebo (center) and LPS exposed mouse treated with Nan02 (right).
  • emulsion refers to a suspension or emulsion of nanodroplets or microbubbles in aqueous media.
  • Nanodroplets refers to submicron droplets comprising a liquid fluorocarbon, e.g., ranging from 4 carbon to 8 carbons in length.
  • administration encompasses the delivery to a subject of a pharmaceutical composition using any suitable formulation or route of administration, as discussed herein.
  • the terms "effective amount” or “therapeutically effective amount” refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended benefit including, but not limited to, disease treatment, as illustrated herein.
  • the therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art.
  • the specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred.
  • Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology.
  • treatment herein may achieve an increase in a subject’s oxygen saturation level or an improvement or restoration of oxygen supply
  • Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder.
  • the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • the term "therapeutic effect” refers to a therapeutic benefit and/or a prophylactic benefit as described herein.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the term “pharmaceutically acceptable” excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • the term “subject” refers to any animal ( e.g ., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
  • the “low dosage” refers to at least 5% less ( e.g ., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition. For example, a low dosage of an agent that reduces glucose levels and that is formulated for administration by inhalation will differ from a low dosage of the same agent formulated for oral administration.
  • the “high dosage” is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dosage of a particular compound for treatment of any human disease or condition.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.
  • the invention provides compositions of certain fluorocarbons that exhibit exceptional therapeutic properties and can be safely and reliably used for treating viral infections and ARDS caused, for example, by COVID-19.
  • the unique pharmaceutical compositions and methods of use disclosed herein enable timely intervention and timely restoration of critical oxygen supply to affected organs, thus leading to reduced ischemic tissue damage and improved treatment outcome.
  • the invention generally relates to a method for treating a respiratory infection, or a related disease or condition thereof, comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective dosage of a fluorocarbon having a boiling point between about -36°C to about 100°C, and a pharmaceutically acceptable carrier or excipient.
  • the fluorocarbon is preferably stabilized in the form of an emulsion.
  • the pharmaceutical composition is an emulsion, e.g., a homogenized emulsion.
  • the fluorocarbon may be present as nanodroplets or in microbubbles in the emulsion.
  • the emulsions comprise particles having sizes in the range from about 0.1 pm to about 5 pm ( e.g ., about 0.1 pm to about 1 pm, 0.1 pm to about 1.5 pm, about 0.1 pm to about 2.5 pm, about 0.5 pm to about 2.5 pm).
  • the emulsions comprise particles (nanodroplets or microbubbles) having sizes less than about 1 pm in size.
  • the emulsions comprise particles having sizes less than about 500 nm.
  • the emulsions comprise particles having sizes less than about 250 nm.
  • the boiling point of the fluorocarbon used is preferably between about -4 °C and about 100 °C. In certain embodiments, the boiling point of the fluorocarbon used is preferably between about -4 °C and about 60 °C. In certain embodiments, the boiling point of the fluorocarbon used is preferably between about 28 °C and about 60 °C. [0041] In certain embodiments, the fluorocarbon used preferably has 4, 5, 6, 7 or 8 linear and/or branched carbon atoms with from about 10 to about 18 fluorine atoms.
  • Fluorocarbons useful in the invention include perfluorobutane, perfluoropentane, perfluorohexane, perfluoroheptane and perfluorooctane, or a mixture of two of more thereof.
  • the pharmaceutical composition utilizes perfluorohexane and/or perfluoropentane.
  • the pharmaceutical composition utilizes perfluoropentane.
  • Perfluoropentane may comprise isomers of dodecafluoro-n-pentane (dodecafluoropentane) and dodecafluoro-iso-pentane.
  • the fluorocarbon is dodecafluoropentane.
  • the fluorocarbon accounts for a concentration in the emulsion from about 0.1% w/vol to about 50% w/vol. In certain embodiments, the fluorocarbon accounts for a concentration in the emulsion from about 0.1% w/vol to about 10% w/vol.
  • the emulsion has from about 0.5 to about 20 % w/vol of fluorocarbon. In certain embodiments, the emulsion has between about 1 and about 10 % w/vol fluorocarbon. In certain embodiments, the emulsion has between about 1 and about 5 % w/vol fluorocarbon. In certain embodiments, the emulsion has between about 3 and about 7 % w/vol fluorocarbon. In certain embodiments, the emulsion has from about 0.5 to about 2% w/vol of fluorocarbon. In certain embodiments, the emulsion has between about 1 and about 3% w/vol fluorocarbon. In certain embodiments, the emulsion has between about 2 and about 4% w/vol fluorocarbon. In certain embodiments, the emulsion has between about 3 and about 5% w/vol fluorocarbon.
  • the pharmaceutical composition comprises one or more phospholipids having carbon chains ranging from about 12 carbons to about 18 carbons in length.
  • the emulsion is stabilized by one or more surfactants.
  • the preferred surfactants comprise fluorosurfactants and phospholipids.
  • the phospholipids accounts for a weight percent in the pharmaceutical composition from about 0.10% to about 7.5% (e.g., from about 0.10% to about 1%, from about 1% to about 2.5%, from about 2.5% to about 7.5%).
  • concentration of phospholipids may range from about 0.1 to about 2.0 % weight volume with a range of from around 0.3% to around 0.6% preferred.
  • a preferred composition of phospholipids in the emulsion comprises three separate phospholipids, a phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylethanolamine-PEG (PE-PEG).
  • the lipids may be saturated or unsaturated and range in chain length from 12 carbons to 20 carbons. More preferably the lipids are 16 or 18 carbons in length. Most preferably the lipids are saturated.
  • MW of the PEG 5,000.
  • PC comprises most of the lipid, generally over 70 mole percent and the PE about 5-15 mole percent and the PE-PEG about 5-15 mole percent.
  • a preferred lipid composition comprises about 82 mole percent PC, about 10 mole percent PE and about 8 mole percent PE-PEG.
  • the fluorocarbon is stabilized by one or more surfactants.
  • surfactants may be one or more fluorosurfactants such as PEG-Telomer-B, CAPSTONE, diacylglycerophospholipids, cholesterol, and/or other surfactants known in the art.
  • Fluorosurfactants may comprise mono or di-alkyl moieties.
  • a particularly preferred surfactant is PEG-Telomer-B (PTB).
  • the concentration of the surfactant may vary depending upon the concentration of the fluorocarbon.
  • the concentration of PTB may vary from around 0.1% weight/volume to about 0.6% weight/volume with a preferred concentration of about 0.3% weight/volume. As one skilled in the art would recognize, the concentration of PTB would either increase or decrease proportionally as the active fluorocarbon, e.g. DDFP, is increased or decreased in the product.
  • DDFP dodecafluoropentane
  • the surfactant(s) utilized comprise one or more fluorosurfactants and one or more phospholipids.
  • the surfactant(s) is incorporated into the emulsion in amounts ranging from about 0.1% weight volume to about 10% weight volume.
  • the surfactant(s) is incorporated into the emulsion in amounts ranging from about 0.2% weight volume to about 5% weight volume.
  • the surfactant(s) is incorporated into the emulsion in amounts ranging from about 0.2% w/vol to about 2% w/vol.
  • the pharmaceutical composition is administered intravenously.
  • the pharmaceutical composition may be administered as an IV bolus.
  • the pharmaceutical composition may be administered by sustained IV infusion.
  • the pharmaceutical composition is injected intravenously via bolus or slow IV push over about 3 to about 5 minutes at doses ranging from about 0.2 mg/kg to about 20 mg/kg (e.g., about 0.2 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 5 mg/kg, about 0.2 mg/kg to about 2 mg/kg, about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 20 mg/kg, about 10 mg/kg to about 20 mg/kg).
  • the pharmaceutical composition is injected intravenously as a sustained IV infusion at a rate of from about 0.5 mg/kg/hour up to about 7.0 mg/kg/hour (e.g., about 0.5 mg/kg/hour up to about 5.0 mg/kg/hour, about 0.5 mg/kg/hour up to about 3.0 mg/kg/hour, about 0.5 mg/kg/hour up to about 2.0 mg/kg/hour, about 1 mg/kg/hour up to about 7.0 mg/kg/hour, about 2 mg/kg/hour up to about 7.0 mg/kg/hour, about 3 mg/kg/hour up to about 7.0 mg/kg/hour).
  • the concentration of fluorocarbon in the emulsion can be increased, for example, up to about 60% weight/vol if desired, to minimize the volume injected.
  • the pharmaceutical composition is administered as an IV infusion at a rate of from about 0.2 mg/kg to about 40 mg/kg per hour (e.g ., about 0.2 mg/kg to about 20 mg/kg per hour, about 0.2 mg/kg to about 10 mg/kg per hour, about 0.2 mg/kg to about 5 mg/kg per hour, about 0.2 mg/kg to about 2 mg/kg per hour, about 1 mg/kg to about 40 mg/kg per hour, about 5 mg/kg to about 40 mg/kg per hour, about 10 mg/kg to about 40 mg/kg per hour, about 1 mg/kg to about 10 mg/kg per hour, about 5 mg/kg to about 20 mg/kg per hour).
  • a dose of the pharmaceutical composition is repeated as needed, for example from 1 to about 50 times (e.g., about from 1 to about 25 times, from 1 to about 10 times, from 1 to about 5 times, from 1 to about 3 times, from 2 to about 10 times).
  • the method comprises administering the subject a second therapeutic agent, before, during or after the administration of the fluorocarbon containing pharmaceutical composition.
  • the fluorocarbon emulsions of the invention may be co administered with one or more other suitable second agents, or one or more such second agents may be incorporated into the fluorocarbon emulsion.
  • the second therapeutic agent is an antiviral agent.
  • the second therapeutic agent is an antibiotic agent.
  • the second therapeutic agent is an anti-inflammatory agent.
  • Exemplary second therapeutic agents include, but not limited to chloroquine, hydroxychloroquine, tolicizumab or sarilumab (humanized IgGl monoclonal antibodies directed against the IL-6 receptor), IL-1 receptor antagonist (anakinra), remdesivir (GS5734) - an inhibitor of RNA polymerase with in vitro activity against multiple RNA viruses, lopinavir/ritonavir, alpha-interferon, dexamethasone and methylprednisolone.
  • Therapeutic agents which may be useful for administration with the oxygen therapeutic include inhibitors of the kinin-kallikrein system such as Firazyr® (icatabibant) and Berinert® (human plasma-derived Cl esterase/kallikrein Inhibitor).
  • the oxygen therapeutic may be co-administered with the anti- influenza drugs oseltamivir phosphate (available as a generic version or under the trade name Tamiflu®), zanamivir (trade name Relenza®), peramivir (trade name Rapivab®), and baloxavir marboxil (trade name Xofluza®).
  • compositions and methods of the invention are useful in treating respiratory infections, or a related disease or condition thereof.
  • the compositions and methods of the invention are useful in treating respiratory distress, including ARDS.
  • the respiratory infection, or a related disease or condition thereof is associated with COVID-19 infection.
  • the respiratory distress comprises mild ARDS.
  • the respiratory distress comprises moderate ARDS.
  • the respiratory distress comprises severe ARDS.
  • the invention generally relates to a unit dosage form of a pharmaceutical composition in the form of an emulsion comprising a dosage of a fluorocarbon having a boiling point between about -36 °C and about +100 °C therapeutically effective to treat respiratory infection, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable carrier or excipient.
  • the invention generally relates to use of a fluorocarbon for treating a respiratory infection, or a related disease or condition thereof, wherein the fluorocarbon has a boiling point between about -36°C to about 100°C.
  • the invention generally relates to use of a fluorocarbon for the manufacture of a medicament for treating a respiratory infection, or a related disease or condition thereof, wherein the fluorocarbon has a boiling point between about -36°C to about 100°C.
  • fluorocarbons useful in the invention include perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluoroheptane and perfluorooctane, or a mixture of two of more thereof.
  • the pharmaceutical composition utilizes perfluorohexane and/or perfluoropentane.
  • the pharmaceutical composition utilizes perfluoropentane.
  • Perfluoropentane may comprise isomers of dodecafluoro- n-pentane (dodecafluoropentane) and dodecafluoro-iso-pentane.
  • the fluorocarbon is dodecafluoropentane. In certain embodiments of the unit dosage form, the fluorocarbon is dodecafluoropentane.
  • Any suitable therapeutically effective unit dosage form may be employed, for example, comprising about 1% to about 10% w/vol of the fluorocarbon. In certain embodiments, the unit dosage form comprises about 2% to about 7% w/vol of the fluorocarbon.
  • the unit dosage form comprises from about 1 mg/kg body weight to about 7 mg/kg (e.g ., about 1 mg/kg body weight to about 5 mg/kg, about 1 mg/kg body weight to about 3 mg/kg, about 2 mg/kg body weight to about 7 mg/kg, about 3 mg/kg body weight to about 7 mg/kg) body weight of fluorocarbon.
  • Antioxidants may also be used in the invention to improve the activity of the fluorocarbon.
  • useful antioxidants include n-acetylcysteine, ascorbic acid, and a- tocopherol.
  • n-acetylcysteine can be administered at 150 mg/Kg for 30 min then 20 mg/Kg/h plus bolus doses of 1 g ascorbic acid and 400 mg a-tocopherol.
  • Table 1 below shows fluorocarbons useful in the invention.
  • fully fluorinated fluorocarbons ranging in molecular weight from about 188 to about 438 grams/mole are useful in the invention.
  • the fluorocarbons may be linear or branched or cyclic but have boiling points ranging from about -37°C to about 100°C. More preferably the boiling point of the fluorocarbon is close to the physiologic temperature in the human body, or slightly less than the temperature in the human body or that of a mammal.
  • fluorocarbon perfluoropentane which may exist as n-perfluoropentane, the linear isomer, or the branched isomers of iso-perfluoropentane or neo-perfluoropentane.
  • the fluorocarbon is stabilized in an emulsion.
  • the emulsified suspension of nanodroplets of fluorocarbon represents a liquid in liquid suspension, although with the lower boiling point fluorocarbons such as perfluoropropane or perfluorobutane the product may represent a suspension of microbubbles of fluorocarbon in liquid.
  • the product comprises a liquid in liquid suspension.
  • the size of the nanodroplets in the liquid in liquid suspension ranges from about lnm to about 1,000 nm and more preferably from about 50 to about 500 nm and still more preferably from about 100 nm to about 250 nm.
  • the mean size of the microbubbles ranges from about 0.2 to about 5 microns and more preferably around 1 micron.
  • one or more surfactants are used to stabilize the emulsion.
  • Useful surfactants include fluorosurfactants, e.g., PEG-telomer-B (PTB), and/or phospholipids.
  • a preferred product in the invention is DDFPe.
  • a typical DDFPe may comprise 2% w/vol DDFP with 0.3% w/vol PTB in a saline solution with 30% w/vol sucrose with phosphate buffered saline at near neutral pH also referred to as NanC TM.
  • concentrations of DDFP and surfactant By adjusting the concentrations of DDFP and surfactant, however, formulations may be prepared ranging from about 0.1% w/vol DDFP up to 100% w/vol DDFP.
  • the concentration of the DDFP ranges from about 1% w/vol DDFP to about 50% w/vol DDFP and more preferably from about 1% w/vol DDFP to about 10% w/vol DDFP. Most preferred is the 2% w/vol DDFP concentration in NanC .
  • NanC comprises a mixture of the isomers of 99% n-perfluoropentane and 1% iso-perfluoropentane but the invention may comprise one or more of the n-, iso- or neo-perfluoropentane isomers.
  • the volumes administered to treat the viral infections will vary depending upon the concentration of DDFP in the formulation. For the examples below, the volumes are based upon the 2% w/vol formulation and the gram amount of DDFP administered is listed.
  • the preferred route of administration of the fluorocarbon is intravenous (IV), via bolus, slow IV push or sustained infusion. Other routes of administration such as inhalation, intraperitoneal and oral may also be practiced.
  • the dose of DDFPe for treatment of complications of viral infections in general ranges from about 0.01 mL/kg (0.2 mg DDFPe/kg) to about 1.0 mL/kg (20 mg DDFPe/kg) for the 2% w/vol emulsion. More preferably the dose is between about 0.05 mL/kg (1.0 mg DDFPe/kg) and about 0.35 mL/kg (7.0 mg DDFPe/kg).
  • a dose of DDFPe may be administered once or multiple times. In general, when multiple doses are administered, they are administered between about 10 minutes and about 120 minutes apart, more preferably 60 to 120 minutes apart.
  • the material When administered as a sustained IV infusion the material may be administered using a syringe infusion pump generally at rates from between about 0.01 mL/kg (0.2 mg DDFPe/kg) to about 2.0 mL/kg (40 mg DDFPe/kg) per hour or more preferably at rates from between about 0.05 mL/kg (1.0 mg DDFPe/kg) and about 0.35 mL/kg (7.0 mg DDFPe/kg) per hour.
  • a syringe infusion pump generally at rates from between about 0.01 mL/kg (0.2 mg DDFPe/kg) to about 2.0 mL/kg (40 mg DDFPe/kg) per hour or more preferably at rates from between about 0.05 mL/kg (1.0 mg DDFPe/kg) and about 0.35 mL/kg (7.0 mg DDFPe/kg) per hour.
  • the fluorocarbon administered in the invention to treat viral infections or ARDS may be co-administered with one or more additional therapeutic compounds.
  • Useful therapeutic compounds include chloroquine, hydroxychloroquine, tolicizumab (a humanized IgGl monoclonal antibody directed against the IL-6 receptor), remdesivir (GS5734) — an inhibitor of RNA polymerase with in vitro activity against multiple RNA viruses, lopinavir/ritonavir, Alpha- interferon and methylprednisolone.
  • the in vitro oxygenation experimental set-up was designed to simulate the oxygen uptake by the blood in the lungs, the transport of oxygen by the blood to the tissues, and finally, the uptake of oxygen by the tissues from the blood.
  • the fluid reservoir acts as the lungs where oxygen uptake occurs
  • the gas exchange vessel acts as the hypoxic (low oxygen) tissue or site of oxygen offloading.
  • SilasticTM tubing used to simulate the circulatory system of the body was weaved through polymer netting to maximize the surface area and placed inside the gas exchange vessel. Both the reservoir and the vessel were filled with a 0.9% saline solution.
  • nitrogen gas was bubbled into the saline in the gas exchange vessel used to lower the dissolved oxygen concentration to approximately 1.75mg/L (simulating a hypoxic environment).
  • the DDFPe (experimental) or saline (control) was then injected via the IV-Y site, combined with the 80mL of saline in the fluid reservoir and circulated through the SilasticTM tubing.
  • the dissolved oxygen concentration within the gas exchange vessel was continuously monitored through an external circuit in which the fluid oxygen concentration was sampled using a dissolved oxygen probe.
  • ARDS was induced by a combination of intratracheal lipopolysaccharide (LPS) injection and ventilator-induced lung injury (VILI).
  • LPS intratracheal lipopolysaccharide
  • VILI ventilator-induced lung injury
  • RSI rapid sequence intubation
  • RSI is needed so that these patients can undergo mechanical ventilation.
  • the patients are hypoxic. It is usually not known for sure if they have COVID-19 infection or not as the RT-PCR test usually takes a couple of days for the results. But symptoms of fever and clinical presentation are highly suggestive of COVID-19 infection.
  • high flow oxygenation methods are used to pre-oxygenate the patient prior to induction and intubation. However, these high flow oxygenation methods can cause aerosols and spread the virus to the health care workers and are therefore discouraged.
  • the patient Prior to intubation the patient is paralyzed pharmacologically, and the intubation procedure may take several minutes. During this period the patient may be exposed to profound hypoxia. Clinical experience with COVID-19 patients undergoing intubation has shown that these patients experience, in general, more profound hypoxia than usually seen in other ARDS patients undergoing this procedure. During this critical pre/peri-intubation period they are susceptible to refractory hypoxemia, vascular collapse, cardiac arrest and death.
  • Secondary Objectives include: incidence of cardiac arrest within 1 hour of intubation procedure, incidence of 28-day all-cause mortality, to determine the safety of Nan02 administered prior to intubation in subjects with moderate to severe ARDS and to determine the proportion of subjects that have severe hemoglobin oxygen desaturation levels ⁇ 70% within 5-minutes post intubation.
  • Exploratory Objectives include: to assess the effects of Nan0 2 on arterial blood gas measurements, if possible, Number of days spent in the ICU, Number of ventilator-free days and Duration of Nan0 2 oxygenation response up to 120 minutes post intubation. Note that because of logistical issues is may not be possible to get arterial blood gasses (the respiratory technician who runs the samples has to put on protective clothing, mask, etc. and change this each time the sample is run).
  • a patient with COVID-19 and mild ARDS has a Pa02/Fi02 between 200 and 300 mm Hg.
  • the patient receives a loading dose of 2.0 mg DDFPe/kg via slow IV push over 3-5 minutes. Then the patient is administered repeated doses of 1.0 mg DDFPe/kg via slow IV push each over 3-5 minutes, each dose 90 minutes apart.
  • the patient is treated with non-invasive ventilation (NIV) by using positive end-expiratory pressure (PEEP) or a continuous positive airway pressure (CPAP) > 5 cmEEO.
  • NMV non-invasive ventilation
  • PEEP positive end-expiratory pressure
  • CPAP continuous positive airway pressure
  • the patient gradually improves and the PaCk/FiCk increases to a level of 400 mm Hg. Because of the administration of NanCk there is no need for mechanical ventilation in this patient.
  • An IV infusion of NanCk is commenced.
  • the patient receives an initial loading dose of 2.0 mg DDFPe/kg via slow IV push over 3-5 minutes and then sustained IV infusion of 1.0 mg DDFPe/kg per hour.
  • a patient with Ebola virus presents to a rural clinic in Africa with pharyngitis, fever, diarrhea and vomiting and progressive respiratory distress.
  • the patient receives an IV loading dose of 0.17 mL/kg of NanCk (2% w/vol emulsion) and repeated IV doses of 0.1 mL/kg every 90 minutes over 24 hours. The patient improves during this time period. In the clinic that this patient was treated, mechanical ventilation was not available. Administration of Nan02 thereby avoided the need for mechanical ventilation which was unavailable.
  • the patient is administered Firazyr® (icatibant acetate 30 mg (3.0 mL of 10 mg/mL solution)) via subcutaneous injections in the abdominal area administered at intervals of 8 h for 4 days plus standard care in addition to DDFPe.
  • Firazyr® icatibant acetate 30 mg (3.0 mL of 10 mg/mL solution
  • Berinert® human plasma-derived Cl esterase/kallikrein Inhibitor
  • a dose of 20 IU/kg body weight on day 1 shortly after hospitalization and on day 4 (each vial contains 500 IU of Cl esterase/kallikrein inhibitor as a lyophilized product for reconstitution with 10 mL of sterile water for injection).

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Abstract

L'invention concerne des compositions pharmaceutiques et des formes posologiques d'émulsions de fluorocarbone qui sont utiles pour traiter des infections virales et le syndrome de détresse respiratoire aiguë et des maladies et affections associées, ainsi que des procédés de préparation et d'utilisation de celles-ci.
PCT/US2021/027885 2020-04-20 2021-04-19 Procédés et compositions pour le traitement d'infections virales et de détresse respiratoire WO2021216402A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024086531A1 (fr) * 2022-10-17 2024-04-25 University Of Florida Research Foundation, Incorporated Émulsion de nano2 dodécafluoropentane utilisée en tant qu'agent thérapeutique contre l'arrêt cardiaque

Citations (4)

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Publication number Priority date Publication date Assignee Title
US20140004099A1 (en) * 2011-03-04 2014-01-02 The Board Of Trustees Of The University Of Arkansas Dodecafluoropentane emulsion as a stroke and ischemia therapy
US20150231177A1 (en) * 2006-05-15 2015-08-20 Virginia Commonwealth University Methods and Compositions for Controlled and Sustained Production and Delivery of Peroxides and/or Oxygen for Biological and Industrial Applications
US20160243237A1 (en) * 2009-04-15 2016-08-25 Tenax Therapeutics, Inc. Emulsions of perfluorocarbons
US20180153824A1 (en) * 2015-05-27 2018-06-07 Nuvox Pharma Llc Treatment of acute complications of sickle cell disease

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150231177A1 (en) * 2006-05-15 2015-08-20 Virginia Commonwealth University Methods and Compositions for Controlled and Sustained Production and Delivery of Peroxides and/or Oxygen for Biological and Industrial Applications
US20160243237A1 (en) * 2009-04-15 2016-08-25 Tenax Therapeutics, Inc. Emulsions of perfluorocarbons
US20140004099A1 (en) * 2011-03-04 2014-01-02 The Board Of Trustees Of The University Of Arkansas Dodecafluoropentane emulsion as a stroke and ischemia therapy
US20180153824A1 (en) * 2015-05-27 2018-06-07 Nuvox Pharma Llc Treatment of acute complications of sickle cell disease

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024086531A1 (fr) * 2022-10-17 2024-04-25 University Of Florida Research Foundation, Incorporated Émulsion de nano2 dodécafluoropentane utilisée en tant qu'agent thérapeutique contre l'arrêt cardiaque

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