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EP4580598A1 - Composition de poudre sèche pharmaceutique et méthodes de traitement d'infections des voies respiratoires - Google Patents

Composition de poudre sèche pharmaceutique et méthodes de traitement d'infections des voies respiratoires

Info

Publication number
EP4580598A1
EP4580598A1 EP22765926.5A EP22765926A EP4580598A1 EP 4580598 A1 EP4580598 A1 EP 4580598A1 EP 22765926 A EP22765926 A EP 22765926A EP 4580598 A1 EP4580598 A1 EP 4580598A1
Authority
EP
European Patent Office
Prior art keywords
dry powder
composition
powder composition
use according
naci
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP22765926.5A
Other languages
German (de)
English (en)
Inventor
Suzana Erico Tanni MINAMOTO
Martin Ohrt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Liita Care Aps
Original Assignee
Liita Care Aps
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
Application filed by Liita Care Aps filed Critical Liita Care Aps
Publication of EP4580598A1 publication Critical patent/EP4580598A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0086—Inhalation chambers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/02—Inhalators with activated or ionised fluids, e.g. electrohydrodynamic [EHD] or electrostatic devices; Ozone-inhalators with radioactive tagged particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/08—Inhaling devices inserted into the nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0091—Inhalators mechanically breath-triggered
    • A61M15/0096—Hindering inhalation before activation of the dispenser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • TITLE Pharmaceutical dry powder composition and methods for treating respiratory tract infections
  • the present invention concerns a pharmaceutical composition for use in treating, preventing and/or ameliorating viral infection in airways of a mammal, such as a human subject.
  • the present invention further concerns a pharmaceutical composition for use in treating and/or ameliorating cough of a mammal, such as a human subject, such as cough caused by a viral infection in the airways of the subject.
  • the human subject to be treated with the pharmaceutical composition may be a subject infected with SARS-CoV- 2 and/or diagnosed with COVID-19 infection.
  • the pharmaceutical composition of the present invention is a dry powder composition comprising micronized sodium salt as the main component and primary therapeutic agent. The pharmaceutical composition is administered by dry powder inhalation.
  • Respiratory tract infections are common infections of the upper respiratory tract (e.g., nose, ears, sinuses, and throat) and the lower respiratory tract (e.g., trachea, bronchial tubes, and lungs).
  • Symptoms of upper respiratory tract infections include runny or stuffy nose, irritability, restlessness, poor appetite, decreased activity level, coughing, and fever.
  • Viral infections of the upper respiratory tract cause, or are associated with, for example, sore throats, colds, croup, and the flu.
  • Clinical manifestations of a lower respiratory tract infection include shallow coughing that produces sputum in the lungs, fever, and difficulty breathing.
  • Respiratory viral infections cause an enormous disease burden in infants, children and adults. In persons with underlying cardiopulmonary disease conditions the clinical impact of common infections is even greater.
  • Current therapies for viral respiratory tract infections involve the administration of anti-viral agents for the treatment, prevention, or amelioration.
  • SARSr-CoV Severe acute respiratory syndrome-related coronavirus
  • SARSr-CoV Severe acute respiratory syndrome-related coronavirus
  • SARS Betacoronavirus The morphology of the SARS-related coronavirus is characteristic of the coronavirus family as a whole.
  • SARS-related coronavirus follows the replication strategy typical of all coronaviruses. Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus 1 (SARS-CoV or SARS-CoV-1), which caused the 2002-2004 outbreak of severe acute respiratory syndrome (SARS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing the ongoing pandemic of COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus 1
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • Viral infections are frequently highly contagious, especially when spread by respiration.
  • the recent pandemics caused by severe acute respiratory syndrome-related coronavirus are proof of how rapidly an infection can spread worldwide.
  • the virus can be spread in many ways.
  • Corona virus may cause both upper and lower respiratory tract infections.
  • the present invention encompasses methods to reduce virus growth, infectivity, burden, shed, and development of antiviral resistance, and to enhance the efficacy of traditional anti-viral therapies.
  • the present invention provides a dry powder composition
  • a dry powder composition comprising at least 50 wt%, such as at least 60 wt%, such as at least 70 wt%, such as at least 80 wt%, such as at least 90 wt% NaCI for use in preventing and/or treating a viral respiratory tract infection, such as coronavirus, such as SARS-CoV-2, wherein said composition is administered to a mammalian subject by dry powder inhalation, such as by using a dry powder inhaler.
  • the dry powder composition of the present invention reduces the time for resolution of one or more symptoms, such as cough, caused by the viral respiratory tract infection.
  • the dry powder composition of the present invention has a particle size distribution of at least 80 % of the particles being in the range 1-10 pm.
  • the dry powder composition of the present invention further comprises an anti-agglomerating agent, such as a carbohydrate or carbohydrate derivative, such as lactose, mannitol, and maltodextrin, preferably lactose.
  • an anti-agglomerating agent such as a carbohydrate or carbohydrate derivative, such as lactose, mannitol, and maltodextrin, preferably lactose.
  • the dry powder composition of the present invention substantially consists of NaCI and lactose.
  • the NaCI to lactose ratio is between 99: 1 and 75:25 based on wt%.
  • the dry powder composition of the present invention is administered in a daily dosage of between 0.5-200 mg. In one embodiment, the daily dosage is divided into 1-10 daily sessions of 4-10 mg per session.
  • the dry powder composition of the present invention is administered orally and/or nasally. In one embodiment, the dry powder composition of the present invention is administered to a human subject.
  • the dry powder composition of the present invention reduces the time for resolution of cough of the mammalian subject by at least 30% compared to a mammalian subject not being treated with the dry powder composition.
  • the NaCI of dry powder composition of the present invention is provided by a composition obtained from the Hvornum Salt Diapir (N56 36.834 E009 42.070) in Denmark. DESCRIPTION OF THE INVENTION
  • Figure 1 Average reduction (%) of SARS-CoV-2 viral RNA (y-axis) in the supernatant of CCL-81 VERO cells under treatment with different concentrations of BREATHOX® POWDER (x-axis). Vero cells were pretreated with different concentrations of BREATHOX® POWDER for 1 hour prior to virus infection, followed by incubation with virus for 1 hour in the presence of the BREATHOX® POWDER.
  • Figure 2 Luciferase assay, measuring intracellular ATP concentration via luminescence production, in cells treated with different concentrations of BREATHOX® POWDER after Ih, 24h and 72h.
  • Figure 3 Indirect measure of total cellular ATP concentration.
  • FIG. 4 Mitochondrial status of cultured Vero cells (40 000 cells/well) treated with different concentrations of BREATHOX® POWDER (0, 0.2, 0.4, 0.8, 0.9, 1.1, 1.2, 1.4% wt/vol).
  • A The oxygen consumption rate, OCR and
  • B Extracellular acidification rate, ECAR were measured using Seahorse technology with the Mito Stress Test kit. Sequential injections of oligomycin , carbonyl cyanide 3- chlorophenylhydrazone (CCCP), and rotenone plus antimycin A of the cultured cells are indicated. The ECAR rate was verified by application of the glycolysis stress test kit (Agilent Technologies).
  • the data are representative of three independent experiments and shown as mean values ⁇ SEM; two-way ANOVA (*p ⁇ 0.05).
  • C The correlation between OCR and ECAR is plotted as an energy map.
  • D General illustration of mitochondrial respiration evaluation under four different conditions: (i) basal respiration (corresponding to the cell basal consumed oxygen); (ii) proton leak (after oligomycin addition (ATP-synthase blocker)); (iii) uncoupled (after addition of the respiratory chain uncoupler FCCP, where the oxygen consumed reflects the maximal respiration rate, irreversibly uncoupling from ATP synthesis); and (iv) inhibited, through complex I and complex III total inhibition by rotenone and antimycin A, respectively.
  • FIG. 5 Intracellular Na+ concentration variation (A[Na+]i) in Vero cells.
  • Vero cells cultured in a medium comprising 0.6% NaCI were incubated with Natrium Green (llpM) and Pluronic Acid (0.07%) for 45 min.
  • BREATHOX® POWDER was added to the cell cultures in different concentrations. . Changes in Na+ concentration were recorded by inverted fluorescence microscope Nikon Eclipse Ti coupled to an Andor CCD camera.
  • A Response lines of cells representing the cellular sodium inward flow detected by the natrium green dye over time, for three different BREATHOX® POWDER concentrations (0.4, 0.8, 1.1% wt/vol). The arrow indicates the time point of BREATHOX® POWDER application.
  • B Data from (A) plotted as averages with standard error bars of 70 cells/ 2 replicates.
  • Figure 6 Real time PCR assay of AtolBl mRNA encoding Na+/K+ ATPase channel protein in Vero cells after 72 hours of BREATHOX® POWDER incubation.
  • Figure 7 Study design for testing BREATHOX® antiviral effects in COVID-19 patients.
  • Figure 9 Inhaler suitable for administering the dry powder composition of the present invention.
  • A a cross-sectional top view of the inhaler in 'CLOSED' position and in 'OPEN' position
  • B a perspective side view of the inhaler in the 'CLOSED' position and in the 'OPEN' position
  • C an exploded view of the inhaler.
  • respiratory tract includes the upper respiratory tract (e.g., nasal passages, nasal cavity, throat, pharynx), respiratory airways (e.g., larynx, tranchea, bronchi, bronchioles) and lungs (e.g., respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli).
  • respiratory airways e.g., larynx, tranchea, bronchi, bronchioles
  • lungs e.g., respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli.
  • respiratory tract infection is a term of art that refers to upper respiratory tract infections (e.g., infections of the nasal cavity, pharynx, larynx) and lower respiratory tract infections (e.g., infections of the trachea, primary bronchi, lungs) and combinations thereof.
  • Typical symptoms associated with respiratory tract infections include nasal congestion, cough, running nose, sore throat, fever, facial pressure, sneezing, chest pain and difficulty breathing.
  • dry powder refers to a composition containing finely dispersed respirable dry particles that are capable of being dispersed in an inhalation device and subsequently inhaled by a subject. Such dry powder(s) or dry particle(s) is substantially free of water or other solvent, or is anhydrous (i.e. no water present), to avoid agglomeration.
  • the dry powder of the present invention may be referred to as "NaCI powder", which should be understood as a dry powder composition comprising NaCI according to the disclosures herein.
  • micronized a used herein in relation to a dry powder composition refers to a dry powder having particles of a size suitable for inhalation through the airways of a mammal, such as a human. Typically, such particle size is between 0.1 pm and 20 pm.
  • micronized is not limited to the micronization process as such.
  • aerosol refers to any preparation of a fine cloud of particles.
  • non-liquid particles - i.e. dry powders make up the aerosol.
  • the fine cloud of particles in the aerosol have a volume median geometric diameter of about 0.1 to about 30 microns or a mass median aerodynamic diameter of between about 0.5 and about 10 microns.
  • excipient means any suitable compound for supporting and/or increasing/improving the dryness and/or flowability of the sodium chloride powder.
  • anti-agglomeration agent means a compound that prevents agglomeration of the dry powder composition and in particular the sodium chloride, such as sugars, in particular micronized sugars, in particular lactose.
  • viral infection means any clinical manifestation or symptom caused by the entry of viruses that are inhaled into the airways of a mammal, such as a human.
  • the viral particles may be deposited in the nasal or oral cavity, pharynx, trachea, primary bronchi, secondary bronchi, terminal bronchi, and/or the alveoli.
  • standard care of treatment refers to paracetamol.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the dry powder composition of the present invention to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein "prevention” is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the dry powder composition of the present invention to prevent the onset of the symptoms or complications.
  • the present invention concerns a pharmaceutical composition for use in treating, preventing and/or ameliorating viral infection in airways of a mammal, such as a human subject.
  • a mammal such as a human subject.
  • the human subject to be treated with the pharmaceutical composition is a subject infected with SARS-CoV-2 and/or diagnosed with COVID-19 infection.
  • the present invention more specifically relates to an inhalable dry composition comprising sodium chloride (NaCI) for use in therapy.
  • NaCI sodium chloride
  • Use of the composition facilitates the prevention or reduction of viral growth, and the inhibition of viral replication in the airways of a mammal, such as human.
  • the present invention further relates to an inhalable dry composition comprising sodium chloride (NaCI) for use in reducing of duration of symptoms in viral infections.
  • Typical symptoms are selected form one or more of fever, shortness of breath, nasal blockage, cough, sore throat, runny nose, sneezing, fever, fatigue, body ache, and chest pain.
  • the dry composition comprising sodium chloride facilitates reduction of post-covid symptoms.
  • the composition may be inhalable through oral and/or nasal route - hence the dry powder composition comprises inhalable particles of sodium chloride of a size suitable for getting into the airways of a mammal.
  • the dry powder of sodium chloride is a micronized dry powder.
  • Inhalation therapy is capable of providing a drug delivery system that is easy and safe to use in an inpatient or outpatient setting.
  • the present invention can preferably replace treatments using nebulized formulations, which thereby ultimately protects healthcare workers and other subjects in close proximity to the patient, as nebulization can potentially expose others to contaminated aerosols.
  • the present invention provides a pharmaceutical inhalable dry powder formulation comprising NaCI as its main component.
  • NaCI is the main component of the pharmaceutical dry powder formulation.
  • the present inventors have found that sodium chloride decreases intracellular ATP concentration; this being one mechanism to explain how the dry powder composition of the present invention decreases replication of SARS- CoV-2 in mammalian cells. Treating Vero cells with BREATHOX® POWDER in presence or absence of Ouabain (Na+/K+ATPase transporter inhibit), it was found that the reduced level of ATP was caused by the increased activity of the cells Na+/ K+ ATPase transporter (see Example 2).
  • the amount of sodium chloride in the dry powder composition is at least 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69 weight%, preferably at least 70, 71, 72, 73, 74, 75, 76, 77, 78, or 79 weight%, more preferably at least 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89 weight%, most preferably at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 weight%.
  • the amount of sodium chloride in the dry powder composition is between 70-99 weight%, between 71-99 weight%, between 72-99 weight%, between 73-99 weight%, between 74-99 weight%, between 75-99 weight%, between 76-99 weight%, between 77-99 weight%, between 78-99 weight%, between 79-99 weight%, between 80-99 weight%, between 81-99 weight%, between 82-99 weight%, between 83-99 weight%, between 84-99 weight%, between 85-99 weight%, between 86-99 weight%, between 87-99 weight%, between 88-99 weight%, between 89-99 weight%, between 90-99 weight%, between 91-99 weight%, between 92-99 weight%, between 93-99 weight%, between 94-99 weight%, between 95-99 weight%, between 96-99 weight%, between 97-99 weight%, or between 98-99 weight%.
  • a high weight% of NaCI in the dry powder composition ensures delivery of a high concentration of NaCI locally at a point of interest, such as within the respiratory tract, as disclosed in greater detail herein.
  • a targeted delivery of high concentrations of NaCI is advantageous because the higher the concentration of NaCI, the greater the osmotic power of the compound.
  • Example 1 it was also shown that as the concentration of BREATHOX® POWDER increased, SARS-CoV-2 replication was reduced in proportion to the concentration of BREATHOX®. The higher the concentration of BREATHOX® POWDER, the greater the reduction in viral replication.
  • the sodium chloride has pharmaceutical quality, such as SANAL® P+ (available from Dansk Salt A/S).
  • the sodium chloride is SANAL® (Permian raw salt manufactured according to GMP-ICH Q7).
  • the sodium chloride is extracted from the Hvornum Salt Diapir (N56 36.834 E009 42.070), Denmark; such as the sodium chloride is extracted from the Danish underground by Maricogen A/S and/or by Nouryon. Salt compositions from the Hvornum Salt Diapir are known for their very high purity - this is of relevance as salt in its purest form and without additives plays an essential role in the pharmaceutical industry.
  • the NaCI of the dry powder composition of the present invention is provided by a composition obtained from the Hvornum Salt Diapir (N56 36.834 E009 42.070) in Denmark.
  • the sodium chloride can be manufactured in compliance with the Monograph Sodium Chloride's current version no. 193 of the European Pharmacopoeia.
  • Micronized sodium chloride is the main component of the pharmaceutical dry powder formulation.
  • the inhalable dry powder composition may contain further powders, preferably micronized powders, of other salts and/or minerals and/or excipients in minor amounts.
  • Excipient carrier particles can be part of the pharmaceutical formulation and be codelivered with the therapeutic aerosol to aid in achieving efficient aerosolization among other possible benefits.
  • the dry powder composition comprises an excipient.
  • the excipient is an anti-agglomeration agent.
  • the excipient is an anti-agglomeration agent is a carbohydrate.
  • the excipient is an anti-agglomeration agent is a sugar or sugar derivative.
  • the excipient is an anti-agglomeration agent selected from a disaccharide, a sugar alcohol, and a polysaccharide.
  • the anti-agglomeration agent selected from different amino acids.
  • the anti-agglomeration agent is selected from lactose, mannitol and maltodextrin.
  • An anti-agglomerization agent such as lactose, amino acids (e.g. leucin) and manitol, are added to enhance the dry powder's flowability, reduce the salt particles' agglomeration due to external factors, and partially act as a carrier.
  • the amount of anti-agglomeration agent, such as lactose, in the dry powder composition is at most 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, or 31 weight%, preferably at most 30, 29, 28, 27 , 26, 25, 24, 23, 22, or 21 weight%, more preferably at most 20, 19, 18, 17, 16, 15, 14, 13, 12, or 11 weight%, even more preferably at most 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 weight%.
  • the amount of anti-agglomeration agent, such as lactose, in the dry powder composition is between 1-10%, 2-8%, 3-7%, 4-6% or preferably around 5 weight%.
  • the preferred volume median geometric diameter for aerosol particles is about 5 microns.
  • the aerosol can contain particles that have a volume median geometric diameter between about 0.1 and about 30 microns, between about 0.5 and about 20 microns, between about 0.5 and about 10 microns, between about 1.0 and about 5.0 microns, or between about 2.0 and 5.0 microns.
  • all the dry powder particles have a particle size (i.e. mean diameter) less than 20, 19, 18, 17, 16, 15, 14, 13, 12, or 11 microns, preferably less than 10, 9, 8, 7, or 6 microns, more preferably all the dry particles have a particle size around 5 microns.
  • the dry powder composition has a particle size distribution of at least 50 % of the particles being in the range 1-10 pm. In a preferred embodiment, the dry powder composition has a particle size distribution of at least 60 % of the particles being in the range 1-10 pm. In a more preferred embodiment, the dry powder composition has a particle size distribution of at least 70 % of the particles being in the range 1-10 pm. In a most preferred embodiment, the dry powder composition has a particle size distribution of at least 80 % of the particles being in the range 1-10 pm. In a still further preferred embodiment, the dry powder composition has a particle size distribution of at least 90 % of the particles being in the range 1-10 pm, more preferably at least 95 % of the particles being in the range 1-10 pm.
  • compositions that are dry powders may be produced by any of spray drying, freeze drying, jet milling, single and double emulsion solvent evaporation, and super-critical fluids.
  • dry powder formulations are produced by jet milling,. Jet milling is a particle size reduction method in which un-milled powder(s) are fed into a milling chamber. Inside the chamber compressed air and/or nitrogen, usually in a vortex motion, promotes particle-to-particle collisions. Typically jet mills are designed to output particles below a certain size while continuing to mill particles above that size, resulting in a narrow size distribution of the resulting product. Jet milled powders that contain salt according to the present invention, such as sodium salt, can be readily prepared using conventional methods.
  • salt according to the present invention such as sodium salt
  • Dry powder formulations can also be prepared by blending individual components into the final pharmaceutical formulation.
  • a first dry powder that contains a salt can be blended with additional dry powders that contain excipients (e.g., lactose) to be included in the blend.
  • the blend can contain any desired relative amounts or ratios of salt, excipients and optionally other additional ingredients, according to the teachings of the present invention.
  • An aspect of the invention provides a pharmaceutical composition as described herein for use as a medicament, wherein said pharmaceutical composition is administered by dry powder inhalation to a mammal in need thereof.
  • the mammal may be a human, a primate, a mouse, a rat, a dog, a cat, a horse, as well as livestock or animals grown for food consumption, e.g., cattle, sheep, pigs, chickens, and goats.
  • the mammal is a human.
  • the invention provides a pharmaceutical composition as described herein for use in treating and/or preventing infectious diseases of the respiratory tract, preferably viral infections of the respiratory tract, wherein said composition is administered by dry powder inhalation.
  • the invention further provides methods for treatment (including prophylactic treatment) of infectious diseases of the respiratory tract, such as viral infections of the respiratory tract.
  • the invention provides a method for treating (including prophylactically treating) an individual with a viral infection of the respiratory tract, an individual exhibiting symptoms of a viral infection of the respiratory tract, or an individual at risk of contracting a viral infection of the respiratory tract, comprising administering to the respiratory tract of the individual an effective amount of a pharmaceutical formulation as described herein.
  • the viral infection is caused by a virus selected from the group consisting of influenza virus (e.g., Influenza virus A, Influenza virus B), respiratory syncytial virus, adenovirus, metapneumovirus, cytomegalovirus, parainfluenza virus (e.g., hPIV-l, hPIV-2, hPIV-3, hPIV-4), rhinovirus, adenovirus, coxsackie virus, echo virus, herpes simplex virus, poxvirus (e.g. smallpox), enterovirus, and corona virus.
  • influenza virus e.g., Influenza virus A, Influenza virus B
  • respiratory syncytial virus e.g., Influenza virus A, Influenza virus B
  • adenovirus e.g., Influenza virus A, Influenza virus B
  • respiratory syncytial virus e.g., Influenza virus A, Influenza virus B
  • adenovirus e.g., Influenza virus A
  • the invention provides a pharmaceutical composition as described herein for use in treating and/or preventing a viral respiratory tract infection caused by coronavirus, wherein said composition is administered to a mammalian subject by dry powder inhalation.
  • the invention provides a pharmaceutical composition as described herein for use in treating and/or preventing a viral respiratory tract infection caused by SARS-CoV-2, wherein said composition is administered to a mammalian subject by dry powder inhalation.
  • the invention provides a pharmaceutical composition as described herein for use in treating and/or preventing infectious diseases of the respiratory tract, preferably viral infections of the respiratory tract, wherein said composition is administered by dry powder inhalation, and wherein the composition reduces symptoms of the viral respiratory tract infection.
  • the pharmaceutical composition of the present invention reduces cough, such as dry cough, caused by viral respiratory tract infection.
  • the pharmaceutical composition of the present invention reduces the frequency of cough caused by viral respiratory tract infection, as compared to a person not treated with the composition.
  • at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or at least 95% reduction in frequency of cough is achieved after 5 days of treatment, as compared to an untreated patient.
  • at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or at least 95% reduction in frequency of cough is achieved after 10 days of treatment, as compared to an untreated patient.
  • Cough frequency is typically measured by patient self-assessment, such as by the St. George's Respiratory Questionnaire (SGRQ) by American Toracic Scociety. This is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease.
  • SGRQ Respiratory Questionnaire
  • use of a composition according to the present invention facilities a significant reduction in recovery time in a patient suffering from a viral infection, compared to if the same patient had not been treated using such composition.
  • the dry powder composition of the present invention reduces the time for resolution of one or more symptoms caused by the viral respiratory tract infection.
  • the average recovery time from cough e.g. as a symptom of Covid- 19 affecting the airways
  • recovery time and “time for resolution” are used herein synonymously.
  • an average of 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or even 70% of corona virus patients treated with the dry powder composition of the present invention recover from cough within 10 days of onset.
  • the term "recover from cough” covers complete cessation of cough in a patient or reduction of cough to a patient's normal cough level when the patient does not suffer from said viral respiratory tract infection.
  • an average of 60, 62, 64, 66, 68, 70, 72, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or even by 90% of corona virus patients treated with the dry powder composition of the present invention recover from cough within 18 days of onset.
  • corona virus patients treated with a dry powder composition of the present invention has 30-40% faster recovery of COVID- 19-induced cough than a control group not receiving the treatment.
  • the present invention provides a dry powder composition as disclosed herein for use in treatment of one or more symptoms of the viral respiratory tract infection, wherein the time for resolution of the one or more symptoms in a patient is on average improved by at least 10, 12, 14, 16, 18, or 20% compared to a control group not receiving the treatment, such as improved by at least 22, 24, 26, 28, or 30 % compared to the control group not receiving the treatment, such as improved by at least 32, 34, 36, 38, or 40% compared to the control group not receiving the treatment, such as improved by at least 42, 44, 46, 48, or 50% compared to the control group not receiving the treatment.
  • the invention provides a pharmaceutical composition as described herein for use in treating and/or preventing a pulmonary disease (i.e. a type of disease that affects the lungs and other parts of the respiratory system), wherein said composition is administered by dry powder inhalation.
  • a pulmonary disease i.e. a type of disease that affects the lungs and other parts of the respiratory system
  • the invention provides a dry powder composition as disclosed herein for use in preventing and/or treating a viral respiratory tract infection caused by coronavirus, such as SARS-CoV-2, wherein said composition is administered to a mammalian subject by dry powder inhalation.
  • the dry powder composition comprises at least 80, 85, or 90 weight% sodium chloride, or more preferably around 95 weight% sodium chloride.
  • the pharmaceutical formulation used for treating (including prophylactically treating) a respiratory tract infection preferably comprises a sodium chloride salt and lactose, preferably in a ratio of NaCI salt to lactose of about 95:5 (wt/wt).
  • the invention provides a dry powder composition as disclosed herein for use in treating and/or ameliorating cough caused by viral respiratory tract infection, wherein said composition is administered to a mammalian subject by dry powder inhalation.
  • the dry powder composition comprises at least 80, 85, or 90 weight% sodium chloride, or more preferably around 95 weight% sodium chloride.
  • the pharmaceutical formulation used for treating and/or ameliorating cough preferably comprises a sodium chloride salt and lactose, preferably in a ratio of NaCI salt to lactose of about 95:5 (wt/wt). III Administration of the pharmaceutical dry powder formulation
  • the dry powder composition is administered by dry powder inhalation.
  • the present invention thereby provides a NaCI particle inhalation therapy which has a huge advantage over the use of standard nebulized solutions, both for patients and healthcare workers, considering the safety aspect of minimized viral contamination of the aerosols.
  • the geometry of the airways is an important consideration when selecting a suitable method for producing and delivering aerosols of pharmaceutical formulations to the respiratory tract.
  • the lungs are designed to entrap particles of foreign matter that are breathed in, such as dust.
  • dry powder inhalation with the appropriate particle size is selected for preferential delivery to the desired region of the respiratory tract. Particles between 0.6-5 microns in diameter generally reach the deep lungs, while particles about 3 microns or larger diameter generally stay in the upper airway.
  • the pharmaceutical formulations as described herein are intended for administration to the respiratory tract (e.g., to the mucosal surface of the respiratory tract) in dry powder form.
  • a pharmaceutical formulation as described herein is aerosolized for administration.
  • Many suitable methods and devices that are conventional and wellknown in the art can be used to dry powder aerosolize the formulation, such as a dry power inhaler.
  • the dry powder inhaler is suitable for nasal inhalation. In another embodiment the dry powder inhaler is suitable for oral inhalation. In yet another embodiment, the dry powder composition is orally and nasally inhalable.
  • DPI breath-activated dry powder inhaler
  • the dry powder inhaler is as described in W02015004227 (US 10,583,261 B2), the entireties of which are incorporated by reference herein.
  • a pharmaceutical formulation is administered once, twice, three, four, five, six or more times a day, as needed. Suitable intervals between doses that provide the desired therapeutic effect may be determined based on the severity of the condition (e.g. infection).
  • composition of the present invention is non-toxic to a human subject, and most mammals. Dosing may be based on the desired amount of salt to be delivered to the respiratory tract. The daily dosage administered may depend on the concentration of viral particles in the airways and the frequency of such viral particles as inhaled.
  • the total daily dosage administered is from 4.5 to 60 mg, corresponding to 1 to 10 sessions per day, such as when using the BREATHOX® device.
  • the total daily dosage of the composition of the present invention administered to a human subject is between 0.5-200 mg, between 1-180 mg, between 2-150 mg, between 3-120, between 4-90 mg, or preferably between 5-60 mg, such as between 10-55 mg, between 20-50 mg, between 30-45 mg, such as approximately 40 mg; such as between 5-55 mg, between 5-50 mg, between 5-45 mg, between 5-40 mg, between 5-35 mg, between 5-30 mg, between 5-25 mg, between 5-20 mg, between 5- 15 mg, or between 5-10 mg; such as between 55-60 mg, between 50-60 mg, between 45-60 mg, between 40-60 mg, between 35-60 mg, between 30-60 mg, between 25-60 mg, between 20-60 mg, between 15-60 mg, or between 10-60 mg.
  • These daily dosages are particularly preferred for treatment and/or prevention of corona virus, such as treatment and/or prevention of COVID-19.
  • the total daily dosage of the composition of the present invention administered to a human subject is from 0.005-5 mg/kg body weight, from 0.005-4 mg/kg body weight, from 0.005-3 mg/kg body weight, from 0.005-2 mg/kg body weight, from 0.005-1 mg/kg body weight, from 0.005-0.5 mg/kg body weight, from 0.005-0.2 mg/kg body weight, from 0.005-0.1 mg/kg body weight, or from 0.005- 0.05 mg/kg body weight, such as from 4-5 mg/kg body weight, from 3-5 mg/kg body weight, from 2-5 mg/kg body weight, from 1-5 mg/kg body weight, from 0.5-5 mg/kg body weight, from 0.2-5 mg/kg body weight, from 0.1-5 mg/kg body weight, or from 0.05-5 mg/kg body weight, such as from 0.05-4 mg/kg body weight, from 0.1-3 mg/kg body weight, from 0.2-2 mg/kg body weight, or from 0.5-1 mg/kg body weight.
  • the total daily dosage of NaCI administered to a human subject is from 0.005-5 mg/kg body weight, from 0.005-4 mg/kg body weight, from 0.005-3 mg/kg body weight, from 0.005-2 mg/kg body weight, from 0.005-1 mg/kg body weight, from 0.005-0.5 mg/kg body weight, from 0.005-0.2 mg/kg body weight, from 0.005-0.1 mg/kg body weight, or from 0.005-0.05 mg/kg body weight, such as from 4-5 mg/kg body weight, from 3-5 mg/kg body weight, from 2-5 mg/kg body weight, from 1-5 mg/kg body weight, from 0.5-5 mg/kg body weight, from 0.2-5 mg/kg body weight, from 0.1-5 mg/kg body weight, or from 0.05-5 mg/kg body weight, such as from 0.05-4 mg/kg body weight, from 0.1-3 mg/kg body weight, from 0.2-2 mg/kg body weight, or from 0.5-1 mg/kg body weight.
  • the dry powder composition is administered to the patient once a day.
  • the dry powder composition of the present invention is administered to the patient several times a day, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times each day, such that the total daily dosage is spread out over several unit doses. This may also be referred to as administered in several sessions throughout the day.
  • the dry powder composition is administered to the patient 1- 10 times each day, 1-9 times each day, 1-8 times each day, 1-7 times each day, 1-6 times each day, 1-5 times each day, 1-4 times each day, 1-3 times each day, or 1-2 times each day.
  • the dry powder composition is administered to the patient 2-10 times each day, 3-10 times each day, 4-10 times each day, 5-10 times each day, 6-10 times each day, 7-10 times each day, 8-10 times each day, or 9-10 times each day.
  • the dry powder composition is administered to the patient preferably 1-5 times each day, such as 2-5 times each day, such as 2-4 times each day, such as 3 times each day.
  • a mammal such as a human
  • inhales one dose of the dry powder composition such dose is considered a unit dose.
  • the unit dose will depend on the type of dry powder inhaler used.
  • One administering session may comprise multiples inhalations - i.e. multiple dose units, such as 2, 3, 4, 5, 6 or more dose units per session.
  • a dry powder inhaler is set so that the amount inhaled in one inhalation is from 0.25 to 25 mg, such as from 0.25 to 4 mg.
  • the inhaler delivers 1.5 to 2 mg dry powder in one inhalation.
  • a unit dosage administered to a patient is from 0.25 to 25 mg, such as from 0.25 to 4 mg. In a most preferred embodiment, the unit dosage administered to a patient is from 1.5 to 2 mg dry powder.
  • the dry powder composition is administered successive or simultaneous with one or moreother medicine(s) or drug(s).
  • compositions of the present invention may be used in combination with or to enhance the activity of other antimicrobial agents, or to effectuate a synergism between the multiple agents such that the combination is more effective than the sum of the efficacy of either agent considered independently.
  • Combinations with other agents may also be useful to allow such other agents to be used at lower doses, thereby reducing concerns over toxicity.
  • the combination may inhibit microbe replication, reduce symptoms, shorten the duration of infection, and/or reduce microbe burden in the patient.
  • the dry powder composition of the present invention is administered together with a different drug to treat, ameliorate and/or prevent the same disease, disorder or condition. In other embodiments, dry powder composition is used in combination with a different drug to treat, ameliorate and/or prevent a comorbidity.
  • the combination therapy involves administering both agents/therapies at the same time. This may be achieved by administering a single composition or pharmacological formulation that includes both agents, or by administering two distinct compositions or formulations at the same time, where each composition contains one agent.
  • the treatment using the dry powder composition of the present invention may precede or follow the "other" treatment by intervals ranging from minutes to weeks.
  • the present invention envisages the use of one or more traditional antiviral therapies in combination with the dry powder composition of the present invention.
  • the dry powder composition is administered together with and/or before and/or after treatment with an antiviral drug.
  • the dry powder composition is administered prior to, successive or simultaneous with a lung medicine, such as inhaled corticosteroid.
  • the invention provides methods for reducing transmission or spread of a viral respiratory tract infection, comprising administering to the respiratory tract (e.g., lungs, nasal cavity) of an individual infected with a virus that causes a respiratory tract infection, exhibiting symptoms of a respiratory tract infection, or at risk of contracting a respiratory tract infection by a virus, an effective amount of a pharmaceutical formulation as described herein.
  • a viral respiratory tract infection e.g., lungs, nasal cavity
  • the BREATHOX® device contains BREATHOX® POWDER, which comprises 95 wt% NaCI and 5 wt% lactose.
  • the NaCI is obtained from Hvornum Salt Diapir, Denmark.
  • the NaCI is mixed and micronised with alpha-lactose monohydrate.
  • the NaCI : lactose ratio of the powder is 95% : 5% (on weight basis), with ⁇ 2% tolerance. This is also referred to as the 'NaCI powder'.
  • NaCI is of pharmaceutical grade, manufactured in compliance with the Monograph Sodium Chloride's current version no. 193 of the European Pharmacopoeia. Alphalactose monohydrate of pharmaceutical grade and conforms with Ph. Eur.
  • the BREATHOX® POWDER is micronised to a respirable particle size range of 1-10 pm and is considered a medicinal substance.
  • One inhalation i.e. one unit dose
  • Vero cells cell lineage derived from kidney epithelial cells extracted from an African green monkey; ATCC CCL-81-VHG) and Calu-3 cells (human non-small-cell lung cancer cell line that grows in adherent culture and displays epithelial morphology; ATCC Calu- 3-HTB-55) were maintained in DMEM containing 0.6% NaCI, in a humidified atmosphere containing 5% CO2 at 37°C.
  • Virus titer was determined by plaque forming units per milliliter.
  • RNA samples were removed, and cells were cultured with the same concentrations of BREATHOX® POWDER containing medium until the end of the experiment.
  • MOI multiplicity of infection
  • hpi 72 h post-infection
  • RT-qPCR real time qPCR
  • a luciferase assay was performed. Changes of the total concentration of ATP in Vero cells exposed to increasing concentrations of NaCI for 1 or 72 h was determined by plate microfluorimetry recordings with the FlexStation III microplate reader and the ATP Assay Kit (SIGMA-ALDRICH) following the manufacturer's instructions.
  • the kit provides extremely sensitive results, detecting ATP release of 10- 100 mammalian cells/well, based on the firefly luciferase-catalyzed oxidation of D- luciferin in the presence of ATP, which the amount of ATP is quantified by the amount of light (hv) produced. Recordings of the luminescence intensity of 5xl0 4 cells in black clear bottom of 96 wells plates were acquired at rest (point 0 h), 1 h, 24 h and 72 h after NaCI challenge (depolarizing agent).
  • the mitochondrial status was measured after every treatment condition (different BREATHOX® POWDER concentrations).
  • the Vero cells were tested by the Seahorse assay that measures the mitochondrial metabolism. Intact Vero cells were assessed with a high-resolution respirometry assay. Two parameters were evaluated: oxygen consumption rate (OCR) and extracellular acidification rate (ECAR).
  • OCR oxygen consumption rate
  • ECAR extracellular acidification rate
  • Mitochondrial respiration was evaluated at four different conditions: (i) basal respiration, corresponding to the cell basal oxygen consumption, without the addition of substrates or inhibitors; (ii) proton leak, after oligomycin (ATP- synthase blocker) addition, where oxygen consumption occurs due to mitochondrial inner membrane proton leak; (iii) uncoupled, after the addition of respiratory chain uncoupler carbonyl cyanide 3- chlorophenylhydrazone (CCCP), where the oxygen consumed reflects the maximal respiration rate (uncoupled to ATP synthesis); and (iv) inhibited, with the addition of rotenone (complex I blocker), and antimycin (complex III blocker), where the oxygen consumption reflects non-mitochondrial activity.
  • the ECAR rate was verified through application of the glycolysis stress test kit (Agilent Technologies).
  • Vero cells were treated with 0.4, 0.8 and 1.1% of BREATHOX® POWDER in presence or absence of 5pM ouabain (Na+/K+ ATPase transporter inhibitor). Changes in total ATP concentration in Vero cells exposed to increasing concentrations of BREATHOX® POWDER with or without 5pM ouabain for 1 hour was determined by plate microfl uorimetry recordings with the FlexStation III microplate reader and the ATP Assay Kit (SIGMA-Aldrich) following the manufacturer's instructions.
  • the SIGMA-Aldrich ATP Assay Kit provides sensitive results, detecting ATP release of 10-100 mammalian cells/well, based on the firefly luciferase-catalyzed oxidation of D-luciferin in the presence of ATP, in which the amount of ATP is quantified by the amount of light (hv) produced. Recordings of the luminescence intensity of 5 x 10 4 cells in black clear-bottom 96-well plates were acquired at rest (point 0 h) and 1 h after BREATHOX® POWDER challenge (depolarizing agent).
  • Time kinetics were obtained by measuring at 1.52 s intervals for 120 s after 10 s of monitoring basal fluorescence intensity, which is the luminescence emission rate prior to addition of the ATP-releasing agent. Responses were calculated as the peak luminescence minus the basal luminescence, using the SoftMax2Pro software (Molecular Devices). From the results obtained, Figure 3 shows that the decrease in ATP level was significantly reversed with ouabain treatment.
  • the mitochondrial status was also measured after every treatment condition, in order to assess the effect on ATP production.
  • the Vero cells were tested by the Seahorse assay that measures the mitochondrial metabolism. Intact Vero cells were assessed with a high-resolution respirometry assay. For this, two parameters were evaluated: oxygen consumption rate (OCR; Figure 4A) and extracellular acidification rate (ECAR; Figure 4B).
  • OCR oxygen consumption rate
  • ECAR extracellular acidification rate
  • Figure 4D glycolytic enzymes enhance their activity to compensate for ATP production
  • Figure 4D shows oxygen consumption in four states: (i) basal, (II) proton leak, (iii) uncoupled, and (iv) inhibited.
  • Basal indicates normal cell respiration values; proton leak reflects mitochondrial inner membrane integrity; uncoupled indicates respiratory chain activity of complex I to IV (i.e., maximal respiratory capacity); and inhibited reflects non-mitochondrial processes that consume oxygen.
  • a further objective was to evaluate the influx of Na-i- upon BREATHOX® POWDER treatment by fluorescence microscopy. Vero cells were stained using the intracellular sodium indicator Natrium Green and challenged with NaCI (3%) for the method calibration. Once the methodological conditions were established (45 min incubation in the presence of lluM Natrium Green), the cells were after challenged with BREATHOX® POWDER (0.4, 0.8 and 1.1%) and the Na+ influx measured for 100 seconds, as seen in figures 5AB and 5B.
  • BREATHOX® POWDER corresponds to 0.6% NaCI concentration and 1.7% BREATHOX® POWDER corresponds to 2.1% NaCI, because BREATHOX® POWDER was diluted in cell culture medium containing 0.6% NaCI (HOmM NaCI).
  • BREATHOX® POWDER Due to its ability to increase Na+/K+ ATPase transporter activity, BREATHOX® POWDER can induce a significant reduction in ATP level. Since SARS-CoV-2 requires ATP for its replication, the experiments provided herein showed that BREATHOX® POWDER has significant properties in viral inhibition (replication inhibition) of SARS-CoV-2.
  • the purpose of the study was to demonstrate the benefits of using BREATHOX® POWDER for reducing the severity of COVID-19 symptoms and preventing the deterioration and onset of further symptoms, based on the observed antiviral effects in the pre-clinical, in vitro study.
  • the study provides evidence of the feasibility of a full-scale trial of the effects of BREATHOX® POWDER in COVID-19 patients.
  • the primary objective of the study was to determine the efficacy of using BREATHOX® comprising a NaCI dry powder composition of the present invention (BREATHOX® POWDER), as a dry powder inhaler therapy for clinical improvement in symptomatic, COVID-19 patients compared to standard of care (only treating/alleviating symptoms with paracetamol).
  • Secondary objectives were to evaluate the efficacy of using BREATHOX® POWDER to reduce the use of health services and to assess the safety of adverse events after discontinuation of treatment within 28 days.
  • an 8-point ordinal scale was used, as recommended by the World Health Organization (WHO) for measuring the health status of COVID-19 patients.
  • Their symptoms must be at least 1 of the following symptoms at inclusion: fever or fever perceived for more than 24 hours, headache, sore throat, cough (e.g.

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Abstract

La présente invention concerne une composition de poudre sèche pharmaceutique destinée à être utilisée dans le traitement, la prévention et/ou l'amélioration d'une infection virale dans les voies respiratoires d'un mammifère, tel qu'un sujet humain, ladite composition comprenant du sel de sodium micronisé en tant que composant principal et agent thérapeutique primaire. La présente invention concerne en outre une composition pharmaceutique destinée à être utilisée dans le traitement et/ou l'amélioration de la toux. Le sujet à traiter avec la composition pharmaceutique peut être infecté par le SARS-CoV-2 et/ou diagnostiqué avec une infection par la COVID-19. La composition pharmaceutique est administrée par inhalation de poudre sèche.
EP22765926.5A 2022-09-02 2022-09-02 Composition de poudre sèche pharmaceutique et méthodes de traitement d'infections des voies respiratoires Pending EP4580598A1 (fr)

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