Pharmaceutical dry powder compositions and methods for treating respiratory tract infections

Abstract

The present invention provides a pharmaceutical dry powder composition for use in the treatment, prevention and / or amelioration of viral infections in the airway of a mammal, such as a human subject, said composition comprising a micronized sodium salt as a major component and a major therapeutic agent. The invention also provides a pharmaceutical composition for treating and / or reducing cough. A subject to be treated with the pharmaceutical composition may be infected with SARS-CoV-2 and / or diagnosed as a COVID-19 infection. The pharmaceutical composition is administered by dry powder inhalation.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for treating, preventing and / or alleviating viral infections in the airways of mammals such as human subjects. The present invention also relates to a pharmaceutical composition for treating and / or alleviating cough in mammals such as human subjects, the cough being caused, for example, by viral infections 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 a micronized sodium salt as a main component and a main therapeutic agent. The pharmaceutical composition is administered by dry powder inhalation. Background Art

[0002] Respiratory tract infection is a common infection of the upper respiratory tract (e.g., nose, ears, sinuses, and throat) and lower respiratory tract (e.g., trachea, bronchi, and lungs). Symptoms of upper respiratory tract infection include runny or stuffy nose, irritability, restlessness, loss of appetite, reduced activity, cough, and fever. Viral infections of the upper respiratory tract cause or are associated with, for example, sore throat, colds, laryngitis (croup), and influenza. Clinical manifestations of lower respiratory tract infection include a shallow cough, fever, and dyspnea that produces sputum in the lungs.

[0003] Respiratory viral infections cause a huge disease burden in infants, children and adults. The clinical impact of common infections is even greater in people with underlying cardiopulmonary conditions. Current treatments for viral respiratory infections include the administration of antiviral agents for treatment, prevention or alleviation.

[0004] Some common types of respiratory viruses associated with human illness include: paramyxoviruses, orthomyxoviruses, adenoviruses, picornaviruses, parvoviruses, arenaviruses, herpesviruses, retroviruses, and coronaviruses.

[0005] Severe acute respiratory syndrome-related coronavirus (SARSr-CoV or SARS-CoV) is a virus consisting of many known strains. The SARSr-CoV species is a member of the genus Betacoronavirus and the subgenus Sarbecovirus (genus SARS betacoronavirus). The morphology of SARS-related coronaviruses is characteristic of the entire coronavirus family. These viruses are enveloped, positive-sense single-stranded RNA viruses. SARS-related coronaviruses follow the typical replication strategy of all coronaviruses. Two strains of the virus have caused outbreaks of severe respiratory disease in humans: severe acute respiratory syndrome coronavirus type 1 (SARS-CoV or SARS-CoV-1), which caused the outbreak of severe acute respiratory syndrome (SARS) in 2002-2004; and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which caused the ongoing COVID-19 pandemic.

[0006] Viral infections are often highly contagious, especially when spread through the respiratory tract. The recent pandemic caused by the severe acute respiratory syndrome-related coronavirus is a testament to how quickly an infection can spread around the world.

[0007] Potential ways that the virus can be spread include contact with another person's skin or objects contaminated with infectious droplets, and then contact with your own eyes, nose, or mouth. In addition, airborne infection is also a possible route of virus transmission. It is also possible that the virus can be spread more widely through the air via aerosols, which are composed of mucus droplets originating from the lungs and / or nasal cavity produced when a person or animal coughs or simply breathes. These aerosols may contain the virus, and thus the disease is spread when the exposed subject inhales it.

[0008] Coronaviruses can cause upper and lower respiratory tract infections.

[0009] Although several means of treating and / or preventing viral infections are available, there is a great need for new therapeutic approaches to address growing healthcare problems, such as the emergence of new pathogen strains and the high cost of traditional pharmaceuticals.

[0010] The invention encompasses methods for reducing viral growth, infectivity, burden, shedding, and the development of antiviral resistance, as well as methods for enhancing the efficacy of traditional antiviral therapies. Summary of the invention

[0011] In one aspect, the present invention provides a dry powder composition comprising at least 50 wt % NaCl, such as at least 60 wt %, such as at least 70 wt %, such as at least 80 wt %, such as at least 90 wt % NaCl, for preventing and / or treating viral respiratory infections, such as coronaviruses, such as SARS-CoV-2, wherein the composition is administered to a mammalian subject by dry powder inhalation, such as by using a dry powder inhaler.

[0012] In one embodiment, the dry powder composition of the invention reduces the time for resolution of one or more symptoms (such as cough) caused by a viral respiratory infection.

[0013] In one embodiment, at least 80% of the particles of the dry powder composition of the present invention have a particle size distribution in the range of 1 μm to 10 μm.

[0014] In one embodiment, the dry powder composition of the present invention further comprises an anti-agglomerating agent, such as a carbohydrate or a carbohydrate derivative, such as lactose, mannitol and maltodextrin, preferably lactose.

[0015] In one embodiment, the dry powder composition of the invention consists essentially of NaCl and lactose. In one embodiment, the ratio of NaCl to lactose is between 99:1 and 75:25, based on weight %.

[0016] In one embodiment, the sole therapeutic agent of the dry powder composition of the present invention is NaCl, or a combination of NaCl and an anti-agglomeration agent.

[0017] In one embodiment, the dry powder composition of the present invention is administered at a daily dose of between 0.5 mg and 200 mg. In one embodiment, the daily dose is divided into 1 to 10 times a day, each time 4 mg to 10 mg.

[0018] In one embodiment, the dry powder composition of the invention is administered orally and / or nasally. In one embodiment, the dry powder composition of the invention is administered to a human subject.

[0019] In one embodiment, the dry powder composition of the invention reduces the time to resolution of a cough in a mammalian subject by at least 30% compared to a mammalian subject not treated with the dry powder composition.

[0020] In one embodiment, the NaCl of the dry powder composition of the present invention is provided by a composition obtained from Hvornum Salt Diapir (N56 36.834E009 42.070) in Denmark.

[0021] Description of the invention Description of the drawings:

[0023] Figure 1 : Using different concentrations of The average reduction (%) of SARS-CoV-2 viral RNA in the supernatant of CCL-81VERO cells treated with powder (x-axis) (y-axis). Vero cells were pretreated with the powder for 1 h and then Incubation with the virus in the presence of the powder was continued for 1 hour.

[0024] Figure 2 : Luciferase assay, measured by luminescence production using different concentrations of Intracellular ATP concentration in cells after 1 h, 24 h, and 72 h of powder treatment.

[0025] Figure 3 : Indirect measurement of total cellular ATP concentration. Measured by luciferase assay using increasing concentrations of Total ATP concentration of Vero cells treated with powder for 1 h. In the presence or absence of ouabain (5 μM), The powder was diluted in cell culture medium containing 0.6% NaCl (110 mM NaCl). Data are plotted as mean values ​​with standard error bars based on 12 replicates (*p<0.05). Control (sham) = Cells in the presence of powder (white bars); ouabain = cells in the presence of ouabain and increasing concentrations of Cells in the presence of powder (grey bars).

[0026] Figure 4 : Using different concentrations of Mitochondrial status of cultured Vero cells (40 000 cells / well) treated with powder (0, 0.2, 0.4, 0.8, 0.9, 1.1, 1.2, 1.4% weight / volume). (A) Oxygen consumption rate OCR, and (B) extracellular acidification rate ECAR, measured using Seahorse technology and Mito stress test kit. Cultured cells were sequentially injected with oligomycin, carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and rotenone plus antimycin A as indicated. The ECAR rate was verified by applying the glycolysis stress test kit (Agilent Technologies). Data represent three independent experiments and are expressed as mean ± SEM; two-way ANOVA (*p≤0.05). (C) The correlation between OCR and ECAR is plotted as an energy diagram. (D) Overall representation of mitochondrial respiration assessed under four different conditions: (i) basal respiration (corresponding to the basal consumed oxygen of the cell); (ii) proton leak (after oligomycin addition (ATP-synthase blocker)); (iii) uncoupling (after addition of the respiratory chain uncoupler FCCP, where consumed oxygen reflects the maximal respiration rate, irreversibly uncoupled from ATP synthesis); and (iv) inhibition, total inhibition of complex I and complex III by rotenone and antimycin A, respectively.

[0027] Figure 5 : Changes in intracellular Na+ concentration in Vero cells (Δ[Na+]i). Vero cells cultured in medium containing 0.6% NaCl were incubated with Natrium Green (11 μM) and Pluronic Acid (0.07%) for 45 minutes. The powder was added to the cell culture. The changes in Na+ concentration were recorded by an inverted fluorescence microscope Nikon Eclipse Ti connected to an Andor CCD camera. (A) For three different Powder concentration (0.4, 0.8, 1.1% wt / vol), the cell response line representing the change of cellular sodium influx over time detected by Natrium Green dye. Arrows indicate Time points of powder application. (B) Data from (A) are plotted as mean with standard error bars representing 70 cells / 2 replicates.

[0028] Figure 6 :exist Real-time PCR assay of Ato1B1 mRNA encoding the Na+ / K+ ATPase channel protein in Vero cells after 72 hours of powder incubation.

[0029] Figure 7 : For testing in COVID-19 patients Study design for antiviral effects.

[0030] Figure 8 : Cough as a symptom of Covid-19 affecting the airways. Recovery time from the onset of symptoms in patients treated with 5 times / day for 10 days (Group 1), 10 times / day for 10 days (Group 2), or standard of care treatment (Group 3). 1 time = 4 inhalations. The y-axis shows the proportion of patients who experienced cough at the time indicated on the x-axis (1.00 = 100%). The values ​​below the graph indicate the number of patients in each group who experienced cough at the time indicated on the x-axis in the graph. (A) Data graph for the first 10 days of treatment. (B) Same data as in (A), but extended to show 20 days.

[0031] Fig. 9 : An inhaler suitable for administering the dry powder composition of the present invention. (A) Cross-sectional top view of the inhaler in the "closed" position and the "open" position, (B) Perspective side view of the inhaler in the "closed" position and the "open" position, (C) Exploded view of the inhaler.

[0032] Abbreviations, Terms and Definitions:

[0033] As used herein, the term "respiratory tract" includes the upper respiratory tract (e.g., nasal passages, nasal cavity, throat, pharynx), respiratory airways (e.g., larynx, trachea, bronchi, bronchioles), and lungs (e.g., respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli).

[0034] The term "respiratory tract infection" refers to the term in the art of upper respiratory tract infection (e.g., infection of the nasal cavity, pharynx, larynx) and lower respiratory tract infection (e.g., infection of the trachea, main bronchi, lungs) and combinations thereof. Typical symptoms associated with respiratory tract infection include nasal congestion, cough, runny nose, sore throat, fever, facial pressure, sneezing, chest pain and dyspnea.

[0035] The term "dry powder" as used herein refers to a composition containing finely dispersed respirable dry particles that can be dispersed in an inhalation device and then inhaled by a subject. Such dry powders or dry particles are substantially free of water or other solvents, or are anhydrous (i.e., water is not present) to avoid agglomeration. The dry powder of the present invention can be referred to as "NaCl powder", which should be understood as a dry powder composition containing NaCl according to the disclosure herein.

[0036] The term "micronized" as used herein in relation to dry powder compositions refers to dry powders having particles of a size suitable for inhalation through the airways of a mammal, such as a human. Typically, such particle sizes are between 0.1 μm and 20 μm. The term "micronized" is not limited to the micronization process itself.

[0037] As used herein, the term "aerosol" refers to any preparation of a fine cloud of particles. For the present invention, in particular, non-liquid particles, i.e., dry powders, constitute an aerosol. Typically, the cloud of fine particles in an aerosol has a volume median geometric diameter of about 0.1 microns to about 30 microns, or a mass median aerodynamic diameter of between about 0.5 microns and 10 microns.

[0038] The term "excipient" as used herein means any suitable compound used to support and / or increase / improve the dryness and / or flowability of the sodium chloride powder.

[0039] The term "anti-agglomeration agent" as used herein means a compound, such as sugar, especially micronized sugar, especially lactose, which prevents agglomeration of dry powder compositions and in particular sodium chloride.

[0040] As used herein, the term "viral infection" means any clinical manifestation or symptom caused by the entry of a virus inhaled into the airways of a mammal such as a human. Viral particles may be deposited in the nasal or oral cavity, pharynx, trachea, primary bronchi, secondary bronchi, terminal bronchi and / or alveoli.

[0041] The term "standard of care treatment" as used herein refers to paracetamol.

[0042] As used herein, the terms "treatment" and "treatment" mean the management and care of a patient for the purpose of combating a condition such as a disease or disorder. The term is intended to include all treatments for a given condition that a patient is suffering from, such as the administration of a dry powder composition of the present invention to alleviate symptoms or complications, to delay the progression of a disease, disorder or condition, to alleviate or relieve symptoms and complications, and / or to cure or eliminate a disease, disorder or condition, as well as prevent conditions, wherein "prevention" is understood as the management and care of a patient for the purpose of combating a disease, condition or disorder, and includes the administration of a dry powder composition of the present invention to prevent the onset of symptoms or complications.

[0043] As used in the context of describing the present invention, the terms “a”, “an” and “the” and similar referents should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0044] Unless otherwise indicated herein, ranges of values ​​recited herein are merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. Unless otherwise indicated, all exact values ​​provided herein represent corresponding approximate values ​​(e.g., all exact exemplary values ​​provided with respect to a particular factor or measurement can be considered to also provide the corresponding approximate measurement modified by "about" where appropriate). DETAILED DESCRIPTION OF THE INVENTION

[0046] The present invention relates to a pharmaceutical composition for treating, preventing and / or alleviating viral infections in the airways of mammals such as human subjects. In a preferred embodiment, 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.

[0047] The present invention more particularly relates to an inhalable dry composition comprising sodium chloride (NaCl) for use in therapy. The use of the composition helps prevent or reduce viral growth, as well as inhibit viral replication in the airways of mammals such as humans.

[0048] The present invention also relates to an inhalable dry composition comprising sodium chloride (NaCl) for reducing the duration of symptoms in viral infections. Typical symptoms are selected from one or more of fever, shortness of breath, nasal congestion, cough, sore throat, runny nose, sneezing, fever, fatigue, body aches and chest pain. In another embodiment, the dry composition comprising sodium chloride helps reduce post-covid symptoms.

[0049] The composition may be inhalable by the oral and / or nasal route - the dry powder composition thus comprises inhalable particles of sodium chloride of a size suitable for entry into the airways of a mammal. In a preferred embodiment, the dry powder of sodium chloride is a micronised dry powder.

[0050] Inhalation therapy can provide a drug delivery system that is easy and safe to use in an inpatient or outpatient setting. Preferably, the present invention can replace treatments using nebulized formulations, thereby ultimately protecting healthcare workers and other subjects in close proximity to patients, as nebulization can potentially expose others to contaminated aerosols.

[0051] Various embodiments of the invention are described below. The embodiments should be considered to relate to any aspect described herein as well as any embodiment described herein, unless it is specified that an embodiment relates to one or more specific aspects of the invention.

[0052] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0053] I. Drug dry powder preparations

[0054] In one aspect, the present invention provides a pharmaceutical inhalable dry powder formulation comprising NaCl as its major component.

[0055] II Composition of drug dry powder preparations

[0056] NaCl is the main component of drug dry powder formulations.

[0057] Without wishing to be bound by theory, the inventors have discovered that sodium chloride reduces intracellular ATP concentrations; this is one mechanism to explain how the dry powder compositions of the present invention reduce the replication of SARS-CoV-2 in mammalian cells. Vero cells were treated with the powder and it was found that the decrease in ATP levels was caused by an increase in the activity of the cellular Na+ / K+ ATPase transporter (see Example 2).

[0058] In one embodiment, 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 %.

[0059] In one embodiment, 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 %. In one embodiment, the amount of sodium chloride in the dry powder composition is between 89-99 weight %, between 90-98 weight %, between 91-97 weight %, between 92-97 weight %, between 93-97 weight %, between 94-96 weight %, such as preferably about 95 weight %.

[0060] As disclosed in more detail herein, a high weight % NaCl in a dry powder composition can ensure local delivery of high concentrations of NaCl at a point of interest, such as within the respiratory tract. Targeted delivery of high concentrations of NaCl is advantageous because the higher the NaCl concentration, the greater the osmotic power of the compound. In Example 1, it is also shown that, with As the concentration of the powder increases, the replication of SARS-CoV-2 The concentration decreases proportionally. The higher the concentration of the powder, the greater the reduction in viral replication.

[0061] In one embodiment, the sodium chloride is of pharmaceutical quality, such as P+ (available from Dansk Salt A / S). Typically, sodium chloride is (Permian raw salt produced according to GMP-ICH Q7). Preferably, the sodium chloride is extracted from the Hvornum Salt Diapir (N5636.834E009 42.070) in Denmark; for example, the sodium chloride is extracted from the ground in Denmark by Maricogen A / S and / or by Nouryon. The salt component from the Hvornum Salt Diapir is known for its very high purity - this is related to the vital role that salt in its purest form and without additives plays in the pharmaceutical industry. In a preferred embodiment, the NaCl of the dry powder composition of the present invention is provided by a composition obtained from the Hvornum Salt Diapir (N56 36.834E009 42.070) in Denmark.

[0062] In one embodiment, sodium chloride can be manufactured according to the current version of the sodium chloride monograph of the European Pharmacopoeia, edition 193. Micronized sodium chloride is the main component of the pharmaceutical dry powder formulation. The inhalable dry powder composition may also contain a small amount of other salts and / or minerals and / or excipient powders, preferably micronized powders.

[0063] Excipient carrier particles can be part of a pharmaceutical formulation and delivered together with a therapeutic aerosol to help achieve effective aerosol administration among other possible benefits. In one embodiment, the dry powder composition comprises an excipient. In a particularly preferred embodiment, the excipient is an anti-agglomeration agent. In one embodiment, the excipient is an anti-agglomeration agent and is a carbohydrate. In one embodiment, the excipient is an anti-agglomeration agent and is a sugar or a sugar derivative. In one embodiment, the excipient is an anti-agglomeration agent selected from disaccharides, sugar alcohols and polysaccharides. In one embodiment, the anti-agglomeration agent is selected from different amino acids. In a preferred embodiment, the anti-agglomeration agent is selected from lactose, mannitol and maltodextrin.

[0064] Anti-agglomeration agents, such as lactose, amino acids (eg, leucine), and mannitol are added to enhance the flowability of the dry powder, reduce the agglomeration of salt particles due to external factors, and partially act as a carrier.

[0065] In one embodiment, the amount of anti-agglomeration agents 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% by weight, preferably at most 30, 29, 28, 27, 26, 25, 24, 23, 22 or 21% by weight, more preferably at most 20, 19, 18, 17, 16, 15, 14, 13, 12 or 1% by weight, and more preferably at most 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% by weight. In one embodiment, the amount of anti-agglomeration agents such as lactose in the dry powder composition is between 1-10%, 2-8%, 3-7%, 4-6% or preferably about 5% by weight.

[0066] In a preferred embodiment, the anti-agglomeration agent is lactose. In one embodiment, the lactose is pharmaceutical grade alpha-lactose monohydrate and complies with the European Pharmacopoeia, such as CAS No. 7647-14-5.

[0067] In one embodiment, the dry powder composition is substantially composed of NaCl and lactose. In one embodiment, NaCl and lactose together constitute at least 80,81,82,83,84,85,86,87,88 weight % or at least 89 weight % of the total dry powder composition, preferably at least 90,91,92,93,94 weight % or at least 95 weight % of the total dry powder composition, more preferably at least 95,96,97,98% or at least 99 weight % of the total dry powder composition; such as at least 99.1,99.2,99.3,99.4,99.5,99.6,99.7,99.8,99.9 weight % or even 100 weight % of the total dry powder composition. In one embodiment, the dry powder composition of the present invention is composed of NaCl and lactose.

[0068] In one embodiment, the weight ratio between sodium chloride and an anti-agglomerating agent such as lactose is from 99 / 1 to 50 / 50, 99 / 1 to 55 / 45, 99 / 1 to 60 / 40, 99 / 1 to 65 / 35, or 99 / 1 to 70 / 30, 99 / 1 to 75 / 25, 99 / 1 to 70 / 30, 99 / 1 to 85 / 25, 99 / 1 to 90 / 10, 98 / 2 to 90 / 10, 97 / 3 to 90 / 10, 96 / 4 to 90 / 10, 95 / 5 to 90 / 10, 99 / 1 to 95 / 5, 98 / 2 to 95 / 5, 97 / 3 to 95 / 5, or from 96 / 4 to 95 / 5. Preferably, the weight ratio between sodium chloride and lactose is about 95 / 5.

[0069] In one embodiment, the dry powder composition comprises between 50-99 wt.% NaCl and between 1-50 wt.% lactose, between 60-99 wt.% NaCl and between 1-40 wt.% lactose, or between 70-99 wt.% NaCl and between 1-30 wt.% lactose, such as preferably between 75-99 wt.% NaCl and between 1-25 wt.% lactose, more preferably between 80-99 wt.% NaCl and between 1-20 wt.% lactose, more preferably between 85-99 wt.% NaCl and between 1-25 wt.% lactose, more preferably between 90-99 wt.% NaCl and between 1-10 wt.% lactose; most preferably, the dry powder composition comprises about 95 wt.% NaCl and 5 wt.% lactose.

[0070] In one embodiment, the composition consists essentially of NaCl and lactose, and the weight ratios are as disclosed above.

[0071] In a preferred embodiment, the dry powder composition of the present invention consists essentially of NaCl and lactose in a ratio of about 95:5 on a weight basis. "Consisting essentially of" and "consisting essentially of" mean that only small amounts of impurities are present in the composition, which impurities are considered inert in terms of having a therapeutic effect and are also considered inert in terms of functioning as anti-agglomeration agents.

[0072] As further disclosed herein and apparent from the Examples provided herein, the NaCl in the dry powder composition acts as a therapeutic agent when administered to a mammalian subject. In one embodiment, NaCl is the only therapeutic agent in the pharmaceutical composition, wherein all other components are inert in terms of the therapeutic effect of treating and / or preventing and / or alleviating viral infections in the airways of mammals. In one embodiment, the dry powder composition comprises lactose, and the only therapeutic agents of the composition are NaCl and lactose. In another embodiment, additional therapeutic agents may be present in the composition, such as other antiviral drugs, such as oseltamivir, zanamivir, amantadine, rimantadine, ribavirin, gancyclovir, valgancyclovir, foscavir, (cytomegalovirus immune globulin), pleconaril, rupintrivir, palvizumab, motavizumab, cytarabine, docosin, denotivir, cidofovir, acyclovir, or drugs such as Paxlovid TM(nirmatrelvir and ritonavir) or Lagevrio TM (molnupiravir).

[0073] I.ii Particle size

[0074] Dry powder formulations are prepared to have appropriate particle size and density for topical delivery to selected areas of the respiratory tract. For example, higher density and / or larger particles can be used for upper airway delivery, while lower density and / or smaller particles can be used for lower airway delivery. Similarly, mixtures of particles of different sizes can be administered in one administration to target different areas of the lung.

[0075] For the present invention, delivery to the respiratory tract and airways is preferred, therefore the dry composition of the present invention is preferably micronized to a respirable particle size range of 1 μm to 10 μm.

[0076] The dry powder composition is administered by dry inhalation in the form of an aerosol, i.e., a cloud of fine dry particles. Preferably, the dry powder aerosol for inhalation therapy is generated with an average diameter in the range of 1-10 microns. Preferably, the volume median geometric diameter of the aerosol particles is less than about 10 microns.

[0077] The preferred volume median geometric diameter of the aerosol particles is about 5 microns. For example, the aerosol can contain particles having a volume median geometric diameter between about 0.1 microns and about 30 microns, between about 0.5 microns and about 20 microns, between about 0.5 microns and about 10 microns, between about 1.0 microns and about 5.0 microns, or between about 2.0 microns and 5.0 microns.

[0078] It is preferred that all dry powder particles have a particle size (i.e., average diameter) of less than 20 microns, 19 microns, 18 microns, 17 microns, 16 microns, 15 microns, 14 microns, 13 microns, 12 microns or 11 microns, preferably less than 10 microns, 9 microns, 8 microns, 7 microns or 6 microns, and more preferably all dry particles have a particle size of about 5 microns.

[0079] Malvern particle size analyzers are used to determine and measure particle size distribution, such as the Malvern Mastersizer 3000 instrument. The particle size distribution (PSD) of a powder determines the relative amount of particles present according to particle size.

[0080] In one embodiment, the dry powder composition has a particle size distribution of at least 50% of the particles in the range of 1 μm-10 μm. In a preferred embodiment, the dry powder composition has a particle size distribution of at least 60% of the particles in the range of 1 μm-10 μm. In a more preferred embodiment, the dry powder composition has a particle size distribution of at least 70% of the particles in the range of 1 μm-10 μm. In a most preferred embodiment, the dry powder composition has a particle size distribution of at least 80% of the particles in the range of 1 μm-10 μm. In a further preferred embodiment, the dry powder composition has a particle size distribution of at least 90% of the particles in the range of 1 μm-10 μm, more preferably, at least 95% of the particles in the range of 1 μm-10 μm.

[0081] In one embodiment, the dry powder composition has a particle size distribution of at least 50% of the particles in the range of 2μm-5μm. In a preferred embodiment, the dry powder composition has a particle size distribution of at least 60% of the particles in the range of 2μm-5μm. In a more preferred embodiment, the dry powder composition has a particle size distribution of at least 70% of the particles in the range of 2μm-5μm. In a most preferred embodiment, the dry powder composition has a particle size distribution of at least 80% of the particles in the range of 2μm-5μm. In yet another preferred embodiment, the dry powder composition has a particle size distribution of at least 90% of the particles in the range of 2μm-5μm, more preferably, at least 95% of the particles in the range of 2μm-5μm.

[0082] I.iii Preparation of drug dry powder preparations

[0083] Usually, the pharmaceutical preparation as dry powder can be produced by any one of spray drying, freeze drying, jet milling, single emulsion solvent evaporation and double emulsion solvent evaporation (single and double emulsion solvent evaporation) and supercritical fluid.Preferably, dry powder preparation is produced by jet milling.Jet milling is a method of reducing particle size, wherein unground powder is fed to a grinding chamber.In the chamber, compressed air and / or nitrogen that are usually in eddy motion promote the collision of particles with particles.Usually, jet mill is designed to output particles lower than a certain size, while continuing to grind particles higher than the size, resulting in a final product of narrow size distribution.The powder of the jet milling containing salt (such as sodium salt) according to the present invention can be easily prepared using conventional methods.

[0084] Dry powder formulations can also be prepared by blending the individual components into a final pharmaceutical formulation. For example, a first dry powder containing a salt can be blended with another dry powder containing an excipient (e.g., lactose) to be included in the blend. According to the teachings of the present invention, the blend can contain any desired relative amount or ratio of salt, excipient, and optional other additional ingredients.

[0085] II. Pharmaceutical dry powder compositions for treating and / or preventing viral respiratory infections

[0086] One aspect of the present invention provides a pharmaceutical composition for use as a medicament as described herein, wherein the pharmaceutical composition is administered to a mammal in need thereof by dry powder inhalation. The mammal may be a human, a primate, a mouse, a rat, a dog, a cat, a horse, and livestock or animals bred for food consumption, such as cattle, sheep, pigs, chickens, and goats. In a preferred embodiment, the mammal is a human.

[0087] As demonstrated herein, the pharmaceutical compositions of the present invention can inhibit viral infection, such as reducing the viral load of SARS-CoV-2 (Example 1). As further demonstrated herein, administering the pharmaceutical composition to the respiratory tract of a mammal suffering from a viral infection such as COVID helps to significantly reduce the cough symptoms of the patient (Example 3).

[0088] The present 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 the composition is administered by dry powder inhalation.

[0089] The present invention also provides a method for treating (including prophylactic treatment) infectious diseases of the respiratory tract (such as viral infections of the respiratory tract). In one embodiment, the present invention provides a method for treating (including prophylactic treatment) an individual with viral infections of the respiratory tract, an individual showing symptoms of viral infections of the respiratory tract, or an individual at risk of viral infections of the respiratory tract, the method comprising applying an effective amount of a pharmaceutical formulation as described herein to the respiratory tract of the individual.

[0090] In certain embodiments, 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-1, hPIV-2, hPIV-3, hPIV-4), rhinovirus, adenovirus, coxsackievirus, echo virus, herpes simplex virus, poxvirus (e.g., smallpox), enterovirus, and coronavirus. In a preferred embodiment, the viral infection is a coronavirus, such as a SARS coronavirus. In a further preferred embodiment, the viral infection is a beta coronavirus, such as a Sarbecovirus subgenus (SARS beta coronavirus). In a most preferred embodiment, the viral infection is specifically SARS-CoV-2.

[0091] In a preferred embodiment, the present invention provides a pharmaceutical composition as described herein for use in treating and / or preventing viral respiratory infections caused by coronaviruses, wherein the composition is administered to a mammalian subject by dry powder inhalation. In a preferred embodiment, the present invention provides a pharmaceutical composition as described herein for use in treating and / or preventing viral respiratory infections caused by SARS-CoV-2, wherein the composition is administered to a mammalian subject by dry powder inhalation.

[0092] In one embodiment, the present invention provides a pharmaceutical composition as described herein for treating and / or preventing infectious diseases of the respiratory tract, preferably viral infections of the respiratory tract, wherein the composition is administered by dry powder inhalation, and wherein the composition alleviates the symptoms of viral respiratory tract infections. In some embodiments, the symptoms may be selected from one or more of the following: fever, shortness of breath, nasal congestion, cough (e.g., dry cough), sore throat, runny nose, vomiting, nausea, diarrhea, sneezing, fatigue, body pain, myalgia, taste disorder, anosmia, headache, and chest pain.

[0093] In a preferred embodiment, the pharmaceutical composition of the present invention reduces coughs caused by viral respiratory infections, such as dry coughs. In a preferred embodiment, the pharmaceutical composition of the present invention reduces the frequency of coughs caused by viral respiratory infections compared to people who are not treated with the pharmaceutical composition of the present invention. In one embodiment, compared to untreated patients, after 5 days of treatment, a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or at least 95% of the cough frequency is achieved. In one embodiment, compared to untreated patients, after 10 days of treatment, a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or at least 95% of the cough frequency is achieved. Cough frequency is usually measured by patient self-assessment, such as through the American Thoracic Society's St. George's Respiratory Questionnaire (SGRQ). This is a disease-specific scale designed to measure the impact on overall health, daily life, and perceived well-being of patients with obstructive airway disease. (www.thoracic.org / members / assemblies / assemblies / srn / questionaires / sgrq.php)

[0094] In a preferred embodiment, compared with people who are not treated with the pharmaceutical composition of the present invention, the pharmaceutical composition of the present invention reduces the severity of coughs such as dry coughs caused by viral respiratory infections. In one embodiment, compared with untreated patients, after 5 days of treatment, a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or at least 95% of the severity of coughs is achieved. In one embodiment, compared with untreated patients, after 10 days of treatment, a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or at least 95% of the severity of coughs is achieved. Cough severity is usually measured by patient self-assessment, such as by the St. George's Respiratory Questionnaire.

[0095] In one embodiment, the use of such a composition can significantly reduce the recovery time of the same patient compared to if the patient suffering from viral infection is not treated with a composition according to the present invention. In one embodiment, the dry powder composition of the present invention reduces the time for the disappearance of one or more symptoms caused by viral respiratory tract infection. In one embodiment, the average recovery time from cough (for example, as a symptom of Covid-19 affecting the airway) is significantly improved. The terms "recovery time" and "time to disappear" are used synonymously herein. In one embodiment, 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 patients suffering from viral respiratory tract infection treated with the dry powder composition of the present invention recovered from cough within 10 days of onset. In one embodiment, in the coronavirus patient treated with the dry powder composition of the present invention, 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 the patients recover from cough within 10 days of onset. The term "recovery from cough" includes complete termination of the patient's cough or a reduction in cough to the patient's normal cough level when the patient is not subject to the viral respiratory tract infection.

[0096] In one embodiment, 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 90% of patients suffering from viral respiratory infections treated with the dry powder composition of the present invention recover from cough within 18 days of onset. In one embodiment, 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 90% of coronavirus patients treated with the dry powder composition of the present invention recovered from cough within 18 days of onset.

[0097] As demonstrated herein (Example 2), on average, coronavirus patients treated with the dry powder composition of the present invention had a 30-40% faster recovery from COVID-19-induced cough than untreated controls.

[0098] In one embodiment, the present invention provides a dry powder composition as disclosed herein for use in treating one or more symptoms of a viral respiratory infection, wherein the time to resolution of one or more symptoms in a patient is improved by an average of at least 10%, 12%, 14%, 16%, 18% or 20% compared to an untreated control group, such as by at least 22%, 24%, 26%, 28% or 30% compared to an untreated control group, such as by at least 32%, 34%, 36%, 38% or 40% compared to an untreated control group, such as by at least 42%, 44%, 46%, 48% or 50% compared to an untreated control group.

[0099] In one embodiment, the present invention provides a dry powder composition as disclosed herein for treating a cough caused by a viral respiratory infection, such as a dry cough, wherein the time of resolution of the cough of the patient suffering from the viral respiratory infection is improved by at least 10%, 12%, 14%, 16%, 18% or 20% on average compared to an untreated control group, such as an improvement of at least 22%, 24%, 26%, 28% or 30% compared to an untreated control group, such as an improvement of at least 32%, 34%, 36%, 38% or 40% compared to an untreated control group, such as an improvement of at least 42%, 44%, 46%, 48% or 50% compared to an untreated control group. In a preferred embodiment, the patient's cough is caused by a coronavirus.

[0100] In another aspect, the present invention provides a pharmaceutical composition as described herein for use in the treatment and / or prevention of pulmonary disease (i.e. a class of diseases affecting the lungs and other parts of the respiratory system), wherein the composition is administered by dry powder inhalation.

[0101] In one embodiment, the present invention provides a method of treating (including prophylactically treating) an individual with a lung disease, such as an individual suffering from a lung disease, an individual showing symptoms of a lung disease, or an individual susceptible to a lung disease, the method comprising administering to the respiratory tract of the individual an effective amount of a pharmaceutical formulation according to the present invention by dry powder inhalation.

[0102] Preferably, the present invention provides a dry powder composition as disclosed herein for preventing and / or treating viral respiratory infections caused by coronaviruses such as SARS-CoV-2, wherein the composition is administered to a mammalian subject by dry powder inhalation. Preferably, the dry powder composition comprises at least 80, 85 or 90% by weight of sodium chloride, or more preferably about 95% by weight of sodium chloride. The pharmaceutical preparation for treating (including prophylactic treatment) respiratory infections preferably comprises sodium chloride salt and lactose, preferably the ratio of NaCl salt to lactose is about 95:5 (weight / weight).

[0103] In addition, the present invention provides a dry powder composition as disclosed herein for treating and / or alleviating cough caused by viral respiratory tract infection, wherein the composition is administered to a mammalian subject by dry powder inhalation. Preferably, the dry powder composition comprises at least 80, 85 or 90% by weight of sodium chloride, or more preferably about 95% by weight of sodium chloride. The pharmaceutical preparation for treating and / or alleviating cough preferably comprises sodium chloride salt and lactose, preferably the ratio of NaCl salt to lactose is about 95:5 (weight / weight).

[0104] III. Administration of dry powder formulations of drugs

[0105] The administration of the dry powder composition by dry powder inhalation is an essential feature of the present invention. Therefore, the present invention provides a NaCl particle inhalation therapy which has great advantages for both patients and healthcare workers in terms of safety aspects of minimized viral contamination of aerosols compared to the use of standard nebulized solutions.

[0106] III.i Dry powder inhalation

[0107] When selecting a suitable method for producing an aerosol of a pharmaceutical preparation and delivering it to the respiratory tract, the geometry of the airway is an important consideration. The structure of the lungs enables it to capture inhaled foreign particles, such as dust. As disclosed herein, for administration, dry powder inhalation is selected with a suitable particle size so as to be preferentially delivered to the desired area of ​​the respiratory tract. Particles with a diameter between 0.6-5 microns usually reach the deep lungs, while particles of about 3 microns or larger diameters usually stay in the upper airway.

[0108] Widespread clinical application of dry powder delivery by inhalation has been limited by the difficulties of producing dry powders of suitable particle size, particle density and dispersibility, maintaining dry powders in a dry state for storage, and developing a convenient handheld device that effectively disperses respirable dry particles for inhalation in air.

[0109] Pharmaceutical preparations 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. Preferably, pharmaceutical preparations as described herein are aerosolized for administration. Many conventional and well-known suitable methods and devices in the art, such as dry powder inhalers, can be used to aerosolize dry powder preparations.

[0110] III.ii Dry powder inhaler

[0111] Inhalable dry powders are typically administered to the respiratory tract, which includes the lungs and nasal mucosa, via a dry powder inhaler.

[0112] In one embodiment, 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 oral and nasal. There are several suitable dry powder inhaler devices. Preferably, the composition is administered in a single breath activation step using a breath-activated dry powder inhaler (DPI).

[0113] In a specific embodiment, the dry powder inhaler is as described in WO2015004227 (US10,583,261B2), the entire contents of which are incorporated herein by reference.

[0114] In particular, if Fig. 9 The dry powder inhaler shown in WO2015004227 Figure 1 a. Figure 1 b. Figure 2 a. Figure 2 b and Figure 3A copy of the invention) is a preferred embodiment. Therefore, in a preferred embodiment of the present invention, a dry powder inhaler for applying the dry powder composition of the present invention has a proximal end (P) for insertion into the oral cavity of a user in the axial direction, and a distal end (D) opposite to the proximal end (P), wherein the inhaler comprises an inlet, an outlet arranged at the proximal end (P), an air passage extending from the inlet to the outlet, and a reservoir connected to the air passage through a release orifice, the reservoir containing a dispersible substance, wherein the inhaler has a proximal portion including an outlet and a distal portion connected to the proximal portion, wherein the proximal portion is linearly slidable along the axial direction (A) between an "open" position (where the proximal portion is extended from the distal portion) and a "closed" position (where the proximal portion is retracted toward the distal portion) relative to the distal portion, wherein the inhaler also comprises an inlet valve member, an outlet valve member and a reservoir valve member (reservoir valve member member), wherein the inlet valve member, the outlet valve member and the reservoir valve member are arranged to close the inlet, the outlet and the release hole at the same time when the proximal portion enters the "open" position from the "closed" position; and when the proximal portion enters the "open" position from the "closed" position, the inlet is opened, the outlet is opened, and a certain amount of dispersible substance is delivered from the reservoir to the air channel through the release hole.

[0115] In another preferred embodiment, the dry powder inhaler is an inhaler (1) having a proximal end (P) in an axial direction and a distal end 40 (D) opposite to the proximal end (P), wherein the proximal end (P) is used to be inserted into the oral cavity of a user, wherein the inhaler (1) comprises an inlet (4), an outlet (5) arranged at the proximal end (P), an air passage (10, 11, 12, 13) extending from the inlet (4) to the outlet (5), and a reservoir (8, 9) connected to the air passage (10, 11, 12, 13) through a release hole (6, 7), and the reservoir (8, 9) comprises The inhaler (1) comprises a proximal portion (2) comprising an outlet (5) and a distal portion (3) connected to the proximal portion (2), wherein the proximal portion (2) is linearly slidable in an axial direction (A) relative to the distal portion (3) between an "open" position and a "closed" position, wherein the proximal portion (2) is extended from the distal portion (3) in the "open" position and the proximal portion (2) is retracted toward the distal portion (3) in the "closed" position, wherein the inhaler (1) further comprises an inlet valve member (14) and an outlet valve member (15);

[0116] - wherein the reservoirs (8, 9) are arranged in the proximal part (2);

[0117] - wherein the inlet (4) comprises one or more openings in a peripheral housing wall (20) of the proximal part (2), the one or more openings facing radially outwards away from the axial direction (A), and the inlet valve member (14) is formed by a peripheral housing wall (30) of the distal part (3), the peripheral housing wall (30) covering the openings when the proximal part (2) is in the "closed" position;

[0118] - wherein the outlet (5) comprises an axially oriented aperture;

[0119] wherein the outlet valve member (15) is formed as a plug connected to the distal portion (3), the plug blocking the outlet (5) when the proximal portion (2) is in the "closed" position;

[0120] - wherein the release holes (6, 7) are oriented in an axial direction (A); and

[0121] - wherein the inhaler (1) further comprises a reservoir valve member (16, 17), wherein the reservoir valve member (16, 17) is formed as a peg travelling in the axial direction (A), the peg being fixed to the distal portion (3) via an axially extending rod, wherein the peg blocks the release aperture (6, 7) when the proximal portion (2) is in a "closed" position;

[0122] Thus, the inlet valve member (14), the outlet valve member (15) and the reservoir valve members (16, 17) are arranged such that

[0123] - when the proximal part (2) is retracted from the "open" position in the axial direction towards the distal part to the "closed" position, the inlet (4), the outlet (5) and the release holes (6, 7) are closed simultaneously, and

[0124] -When the proximal portion (2) is expanded from the distal portion in the axial direction from the "closed" position to the "open" position, the inlet (4) is opened simultaneously, the outlet (5) is opened, and a certain amount of dispersible substance from the reservoir (8, 9) is delivered to the air channel (10, 11, 12, 13) through the release hole (6, 7).

[0125] Another preferred embodiment is described in detail in WO2015004227. In a preferred embodiment, the dry powder inhaler for administering the dry powder composition of the present invention is

[0126] The inhaler contains 1000 mg ± 150 mg of dry powder, referred to herein as Powder. The device delivers 90% of the dose within 2.1 ± 0.6 mg per inhalation, and 95% of the dose within the specified critical level of 2.0 ± 1.0 mg. This is equivalent to a minimum of 300 inhalations per device. The 300-dose use period is based on a worst-case scenario where 90% of the dose is 2.7 mg (2.1 + 0.6 mg). 2.7 mg times 300 doses equals 810 mg of salt, which is 40 mg below the minimum filling tolerance (850 mg). 40 mg remains in the device; the probability of having maximum dispensing over the entire use period is very low.

[0127] III.iii Dosage regimen

[0128] The pharmaceutical formulations of the invention can be delivered to the upper respiratory tract (e.g., nasal passages, nasal cavity, throat, pharynx), respiratory airways (e.g., larynx, trachea, bronchi, bronchioles), and / or lungs (e.g., respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli).

[0129] In one aspect, the present invention relates to a dry powder composition as disclosed herein for preventing or reducing viral growth and inhibiting viral replication in the respiratory tract of a mammal such as a human, wherein an effective amount of the dry powder composition is administered to the mammal by dry powder inhalation.

[0130] In another aspect, the present invention relates to a method for preventing or reducing viral growth and inhibiting viral replication in the respiratory tract of a mammal such as a human, wherein an effective amount of a dry powder composition of the present invention is administered to a mammal in need of such treatment by dry powder inhalation.

[0131] An effective amount of a pharmaceutical formulation as described herein is administered to an individual in need thereof, such as an individual with a respiratory tract infection, an individual exhibiting symptoms of a respiratory tract infection, or an individual at risk of contracting a respiratory tract infection. An "effective amount" is an amount sufficient to achieve a desired therapeutic or prophylactic effect, such as an amount sufficient to alleviate the symptoms of an infection.

[0132] Preferably, the inhalation device should be capable of delivering a therapeutically effective amount of the composition described herein in a single inhalation. However, in certain cases, multiple inhalations and / or frequent administration may be required to achieve the desired therapeutic result.

[0133] Typically, the pharmaceutical formulation is administered once, twice, three times, four times, five times, six times or more per day, as needed. Appropriate intervals between administrations to provide the desired therapeutic effect can be determined based on the severity of the condition (e.g., infection).

[0134] The compositions of the present invention are non-toxic to human subjects and most mammals. The dosage can be based on the desired amount of salt to be delivered to the respiratory tract. The daily dosage can depend on the concentration of viral particles in the airways and the frequency of such viral particles being inhaled.

[0135] During the coronavirus trial (Example 3), patients from Group 1 received 5 doses of This is equivalent to 22.5mg to 30mg powder (NaCl powder); patients from group 2 received 10 doses of This is equivalent to 45mg to 60mg Powder (NaCl powder).

[0136] In a preferred embodiment, the total daily dose administered is from 4.5 mg to 60 mg, which is equivalent to 1 to 10 times a day, such as when using When installing.

[0137] In one embodiment, the total daily dose of the composition of the invention administered to a human subject is between 0.5-200 mg, between 1-180 mg, between 2-150 mg, between 3-120 mg, 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 about 40 mg; such as between 5-55 mg, between 5-50 mg, between 5-45 mg, between 5- Between 40mg, between 5-35mg, between 5-30mg, between 5-25mg, between 5-20mg, between 5-15mg or between 5-10mg; such as between 55-60mg, between 50-60mg, between 45-60mg, between 40-60mg, between 35-60mg, between 30-60mg, between 25-60mg, between 20-60mg, between 15-60mg, or between 10-60mg. These daily doses are particularly preferred for treating and / or preventing coronaviruses, such as treating and / or preventing COVID-19.

[0138] In one embodiment, the total daily dose of NaCl administered to a human subject is between 0.5-200 mg, between 1-180 mg, between 2-150 mg, between 3-120 mg, 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 about 40 mg; such as between 5-55 mg, between 5-50 mg, between 5-45 mg, between 5-40 In some embodiments, the present invention relates to an agent that is present in an amount of at least 100 mg to about 200 mg of an amino acid residue in an amount of at least 1 ...

[0139] In a preferred embodiment, the total daily dose of the composition of the present invention administered to a human subject is 0.005-5 mg / kg body weight, 0.005-4 mg / kg body weight, 0.005-3 mg / kg body weight, 0.005-2 mg / kg body weight, 0.005-1 mg / kg body weight, 0.005-0.5 mg / kg body weight, 0.005-0.2 mg / kg body weight, 0.005-0.1 mg / kg body weight, or 0.005- 0.05 mg / kg body weight, such as 4-5 mg / kg body weight, 3-5 mg / kg body weight, 2-5 mg / kg body weight, 1-5 mg / kg body weight, 0.5-5 mg / kg body weight, 0.2-5 mg / kg body weight, 0.1-5 mg / body weight, or 0.05-5 mg / kg body weight, such as 0.05-4 mg / kg body weight, 0.1-3 mg / kg body weight, 0.2-2 mg / kg body weight, or 0.5-1 mg / kg body weight.

[0140] In a preferred embodiment, the total daily dose of NaCl administered to a human subject is 0.005-5 mg / kg body weight, 0.005-4 mg / kg body weight, 0.005-3 mg / kg body weight, 0.005-2 mg / kg body weight, 0.005-1 mg / kg body weight, 0.005-0.5 mg / kg body weight, 0.005-0.2 mg / kg body weight, 0.005-0.1 mg / kg body weight, or 0.005-0.0 5 mg / kg body weight, such as 4-5 mg / kg body weight, 3-5 mg / kg body weight, 2-5 mg / kg body weight, 1-5 mg / kg body weight, 0.5-5 mg / kg body weight, 0.2-5 mg / kg body weight, 0.1-5 mg / kg body weight, or 0.05-5 mg / kg body weight, such as 0.05-4 mg / kg body weight, 0.1-3 mg / kg body weight, 0.2-2 mg / kg body weight, or 0.5-1 mg / kg body weight.

[0141] In one embodiment, the dry powder composition is applied to the patient once a day. In a preferred embodiment, the dry powder composition of the present invention is applied to the patient several times a day, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times a day, so that the daily total dose is split into several unit doses. This can also be referred to as several times of administration in one day. In one embodiment, the dry powder composition is applied to the patient 1-10 times a day, 1-9 times a day, 1-8 times a day, 1-7 times a day, 1-6 times a day, 1-5 times a day, 1-4 times a day, 1-3 times a day, or 1-2 times a day. In one embodiment, the dry powder composition is applied to the patient 2-10 times a day, 3-10 times a day, 4-10 times a day, 5-10 times a day, 6-10 times a day, 7-10 times a day, 8-10 times a day, or 9-10 times a day. In one embodiment, the dry powder composition is preferably administered to the patient 1-5 times per day, such as 2-5 times per day, such as 2-4 times per day, such as 3 times per day.

[0142] When the dry powder composition of a dosage is sucked by a mammal such as the human being, such dosage is considered to be a unit dose.Unit dose will depend on the type of the dry powder inhaler used.Once-use can comprise multiple suctions-i.e. multiple dosage units, such as 2,3,4,5,6 or more dosage units at a time.Usually, the dry powder inhaler is arranged to make the amount sucked in a suction be 0.25mg to 25mg, such as 0.25mg to 4mg.In the most preferred embodiment, the inhaler delivers 1.5mg to 2mg dry powder in a suction.

[0143] As illustrative examples and preferred embodiments, Inhaler contains 1000mg ± 150mg Powder (NaCl powder according to the invention). The device delivers 90% of the dose within 2.1±0.6 mg per inhalation, and 95% of the dose within the specified critical level of 2.0±1.0 mg. This corresponds to a minimum of 300 inhalations per device. The 300 dose life is based on a worst case scenario, i.e. 90% of the dose is 2.7 mg (2.1+0.6 mg). 2.7 mg times 300 doses equals 810 mg of salt, which is 40 mg below the minimum filling tolerance (850 mg). 40 mg remains in the device; the probability of having maximum distribution over the entire life is very low.

[0144] For COVID-19 disease, the optimal and recommended dose was found to be 4 inhalations (2 nasal, 2 oral) 5 times a day until symptoms subside (see Example 3). This is equivalent to about 40 mg of NaCl powder. Users can also inhale as needed (10 times a day is the maximum recommended dose, 1 time = 3 inhalations). Each dose should be inhaled

[0145] In a preferred embodiment, the unit dose administered to a patient is from 0.25 mg to 25 mg, such as from 0.25 mg to 4 mg. In a most preferred embodiment, the unit dose administered to a patient is from 1.5 mg to 2 mg of dry powder.

[0146] In one embodiment, the pharmaceutical dry powder formulation of the present invention is administered to a patient via a dry powder inhaler in an amount of 0.001 mg-0.5 mg dry powder / kg body weight / dose, such as 0.002 mg-0.2 mg dry powder / kg body weight / dose, preferably 0.01 mg-0.04 mg dry powder / kg body weight / dose.

[0147] In other embodiments, dry powder composition and one or more other medicines (medicine) or drugs (drug) are used continuously or simultaneously.It is conceivable that the composition of the present invention can be used in combination with other antimicrobial agents or be used to enhance the activity of other antimicrobial agents, or be used to realize the synergistic effect between multiple medicaments (agents), so that the combination is more effective than the sum of the effectiveness of any medicament considered separately.With the combination of other medicaments, it is also possible to be used for allowing such other agents to be used at a lower dosage, thereby reducing the worry about toxicity.This combination can suppress microbial replication, alleviate symptoms, shorten the duration of infection and / or reduce microbial burden in patients.

[0148] In some embodiments, the dry powder compositions of the present invention are administered together with different drugs to treat, alleviate and / or prevent the same disease, disorder or condition. In other embodiments, the dry powder compositions are used in combination with different drugs to treat, alleviate and / or prevent comorbidity.

[0149] In some embodiments, combination therapy involves the simultaneous administration of two agents / therapies. This can be achieved by administering a single composition or pharmacological formulation comprising both agents, or by administering two different compositions or formulations simultaneously, wherein each composition comprises one agent. Alternatively, treatment using the dry powder composition of the present invention can precede or follow the "other" treatment by an interval ranging from a few minutes to a few weeks.

[0150] In one embodiment, the present invention contemplates the use of one or more conventional antiviral therapies in combination with the dry powder compositions of the present invention. In another embodiment, the dry powder compositions are administered together with and / or before and / or after antiviral drug therapy. In another embodiment, the dry powder compositions are administered before, consecutively with, or simultaneously with pulmonary medications such as inhaled corticosteroids.

[0151] III.iv Reduce the spread or transmission

[0152] Use of dry powder formulations administered by dry powder inhalation may reduce the spread and / or transmission of viral infections compared to, for example, use of a nebulizer.

[0153] In another aspect, the present invention provides a method for reducing the spread or transmission of a viral respiratory infection, the method comprising administering an effective amount of a pharmaceutical formulation as described herein to the respiratory tract (e.g., lungs, nasal cavity) of an individual who is infected with a virus that causes a respiratory infection, exhibits symptoms of a respiratory infection, or is at risk of contracting a respiratory infection caused by a virus. Example

[0154] The present invention is illustrated by the following examples, however, these examples should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and the following examples, whether used alone or in any combination, can be used as constituent elements for implementing various forms of the present invention.

[0155] It is a dry powder inhaler. It is a substance-based, non-sterile, breath-actuated dry particle inhaler consisting of 5 injection-molded acrylonitrile-butadiene-styrene (ABS) plastic polymer parts assembled into a unit. The device is disclosed in WO2015004227A1.

[0156] The device contains A powder containing 95% by weight NaCl and 5% by weight lactose. The NaCl comes from the Hvornum Salt Diapir in Denmark. Sodium chloride is mixed with α-lactose monohydrate and micronized. The powder has a NaCl:lactose ratio of 95%:5% (based on weight) with a tolerance of ±2%. This is also referred to as "NaCl powder".

[0157] NaCl is pharmaceutical grade and complies with the production requirements of the current edition of the European Pharmacopoeia's monograph on sodium chloride, 193rd edition. Pharmaceutical grade alpha-lactose monohydrate complies with European Pharmacopoeia standards.

[0158] The powder is micronized to a respirable particle size range of 1 μm-10 μm and is considered a pharmaceutical substance.

[0159] One inhalation (i.e. one unit dose) will deliver about 1.5mg-2mg of The powder is delivered to the subject.

[0160] Embodiment 1: Antiviral effects of serotype 2—in vitro study design

[0161] The preclinical in vitro studies were conducted in the NB-3 laboratory (biosafety level 3) following all WHO biosafety regulations and adhering to Good Laboratory Practices (GLP). The dry powder composition contained in the device (comprising 95% by weight NaCl and 5% by weight lactose) - namely Powder—Antiviral effect in reducing SARS-CoV-2 viral load.

[0162] Methods: To analyze The antiviral activity of Then the cells were infected and the addition of Powder. The final step is nucleic acid extraction and quantitative real-time qPCR.

[0163] Vero cells (a cell line derived from renal epithelial cells extracted from African green monkeys; ATCC-CCL-81-VHG) and Calu-3 cells (a human non-small cell lung cancer cell line grown in adherent culture and exhibiting an epithelial morphology; ATCC Calu-3-HTB-55) were maintained in DMEM containing 0.6% NaCl in a humidified atmosphere containing 5% CO. 2, 37°C in a humidified atmosphere. Virus titer was determined by plaque forming unit per ml.

[0164] The powder was dissolved in basic-DMEM (free DMEM) (Dulbecco's Modified Eagle's Medium). Seven concentrations of Powders: 0.2%, 0.4%, 0.8%, 0.9%, 1.1%, 1.2% and 1.4% (based on weight / volume). Basal - DMEM contains 110 mM NaCl, so the total NaCl concentration of the seven samples is 135 mM, 160 mM, 185 mM, 210 mM, 235, 260 mM and 285 mM respectively.

[0165] For antiviral activity, there were 4 different time-of-addition experiments. Vero cells were seeded in a 96-well plate with a transparent bottom (5 × 10 4 cells / mL) and incubated at 37°C for 24 h to allow cell adherence. They were then treated with increasing concentrations of Powder treatment. The powder addition times were evaluated, including before virus preincubation (VPI), adsorption (AD), after infection (PI), and after adsorption plus infection, referred to as total time (FT).

[0166] VPI: SARS-CoV-2 variants are injected with increasing concentrations of The powder was pre-incubated for 1 hour. After adsorption, the inoculum was removed and the medium was replaced and maintained until the end of the experiment.

[0167] AD: Before virus infection, different concentrations of The powder was added to the cell monolayer for 1 hour and maintained during 1 hour for the virus attachment process. Then, the virus was replaced with fresh DMEM- powder mixture until the end of the experiment.

[0168] PI: Virus was added to cells to allow infection for 1 hour, and then the virus-containing supernatant was replaced with a different Powder concentration medium until the end of the experiment.

[0169] FT: Before virus infection, different concentrations of Vero cells were pretreated with the powder for 1 hour and then The virus was incubated in the presence of the powder for 1 hour.

[0170] Then, the virus mixture was removed and replaced with The cells were cultured in the powdered medium until the end of the experiment. For all experimental groups, the cells were infected with viruses at a multiplicity of infection (MOI) of 0.02, and the cell supernatant was collected 72 h after infection (hpi) for real-time qPCR (RT-qPCR).

[0171] The supernatant collected after 72h was subjected to real-time RT-PCR for detection and quantification of SARS-CoV-2 viral RNA. Total nucleic acid (RNA and DNA) was extracted using a semi-automatic NucliSENS EASYMAG platform (BioMerieux, Lyon, France) according to the manufacturer's instructions. Quantification of viral RNA was performed using the AgPath-ID one-step RT-PCR kit (Applied Biosystem, Weiterstadt, Germany), on an ABI 7500SDS real-time PCR machine (Applied Biosystems), using published reference primer sequences and probes for the E gene (Corman et al., 2020). RNA copy number / mL was quantified using a specific in vitro transcribed RNA quantification standard.

[0172] Results: RT-qPCR results are expressed as RNA copies / mL, and for each treatment, the percentage of inhibition is presented in Table 1 (VPI), Table 2 (AD), Table 3 (PI), and Table 4 (FT), respectively.

[0173] Table 1. The different concentrations of Quantification of SARS-CoV-2 viral RNA in supernatant CCL-81VERO cells under VPI treatment

[0174]

[0175] Table 2. Different concentrations of Quantification of SARS-CoV-2 viral RNA in supernatant CCL-81VERO cells under AD treatment

[0176]

[0177] Table 3. Different concentrations of Quantification of SARS-CoV-2 viral RNA in supernatant CCL-81VERO cells under PI treatment

[0178]

[0179] Table 4. Different concentrations of Quantification of SARS-CoV-2 viral RNA in supernatant CCL-81VERO cells under FT treatment

[0180]

[0181] Based on the observation of cytopathic effect and comparison of real-time RT-PCR results, we found that any None of the powder concentrations were able to reduce SARS-COV-2 viral titers. However, PI and FT treatments showed the ability to reduce viral load (see for details on FT treatment). Figure 1 The best results for PI were obtained at 0.8% and 0.9% for PI treatment. At 1.3 and 1.6 powder concentrations, they had average percent reductions of 66.17 and 81.76, respectively. However, there was wide variation in the inhibition results for the PI treatments. The inhibition was not consistent, with higher concentrations of The powder showed a lower inhibition percentage. For FT, the best results were at 0.9%, 1.1%, 1.2%, and 1.4%. The average percentage reductions were 73.80, 99.85, 95.36 and 100.00 at 1.1% to 1.4% concentrations, respectively. The FT treatment showed the best results in this experiment. The powder inhibits the manifestation of cytopathic effect without causing any irreversible damage to the cell monolayer.

[0182] in conclusion: The antiviral activity of the powder was confirmed by in vitro study results showing that The powder was available at concentrations of 0.9%, 1.1%, 1.2% and 1.4% (based on weight / volume). The powders had average viral inhibition rates of 73.80%, 99.85%, 95.36% and 100.00%, respectively.

[0183] Embodiment 2: Mechanism of action

[0184] Researched Mechanism of action of the powder in reducing the viral load of SARS-CoV-2. To elucidate the mode of action, different assays were performed.

[0185] First, membrane potential changes were analyzed by microfluorimetry. The changes in membrane potential of Vero cells exposed to increasing concentrations of NaCl were determined by plate microfluorimetry recording using a FlexStation III microplate reader and the FLIPR membrane potential assay kit (Molecular Devices Corp., Sunnyvale, CA) according to the manufacturer's instructions. 5 × 10 50 μL of 5 μg / mL of 96-well plates with a black transparent bottom were obtained at rest (0 h time point) and 1 h, 24 h, and 72 h after NaCl stimulation (depolarizing agent). 4 The fluorescence intensity of each cell was recorded.

[0186] Luciferase assays were then performed to visualize available ATP. The changes in total ATP concentration in Vero cells exposed to increasing concentrations of NaCl for 1 h or 72 h were determined by plate microfluorimetry recording using a FlexStation III microplate reader and an ATP assay kit (SIGMA-ALDRICH) according to the manufacturer's instructions. The kit provides very sensitive results, detecting ATP release from 10-100 mammalian cells / well, based on the oxidation of D-luciferin catalyzed by firefly luciferase in the presence of ATP, where the amount of ATP is quantified by the amount of light produced (hv). 5 × 10 50 μL of ... 4 The luminescence intensity of each cell was recorded.

[0187] To evaluate The effect of the powder on cellular ATP production was observed in each treatment condition (different The mitochondrial state was measured after 50 min of 4% paraformaldehyde (Powder concentration). To this end, Vero cells were tested by the Seahorse assay, which measures mitochondrial metabolism. Intact Vero cells were evaluated using high-resolution respirometry. Two parameters were evaluated: oxygen consumption rate (OCR) and extracellular acidification rate (ECAR).

[0188] Mitochondrial respiration was assessed under four different conditions: (i) basal respiration, corresponding to cellular basal oxygen consumption, without addition of substrates or inhibitors; (ii) proton leak, after oligomycin (ATP synthase blocker) addition, where oxygen consumption occurs due to proton leak from the inner mitochondrial membrane; (iii) uncoupling, after addition of the respiratory chain uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP), where oxygen consumed reflects the maximal respiratory rate (uncoupled from ATP synthesis); (iv) inhibition, in the presence of rotenone (complex I blocker) and antimycin (complex III blocker), where oxygen consumption reflects non-mitochondrial activity. ECAR rates were validated by applying the Glycolysis Stress Test Kit (Agilent Technologies).

[0189] Another aim is to evaluate by fluorescence microscopy Na+ influx into cells after powder treatment. Vero cells were stained with the intracellular sodium indicator Natrium Green and stimulated with NaCl (3%) for method calibration. Once method conditions were established (incubation in the presence of 11 μM Natrium Green for 45 min), Cells were stimulated with 1% MgCl2 powder (0.4%, 0.8% and 1.1% wt / vol) and Na+ influx was measured for 100 s. The changes in Na + concentration after powdering were recorded by a Nikon fluorescence microscope connected to a CCD camera and automatic shutter.

[0190] Luciferase-based assay (protocol to measure ATP concentration via luminescence production - Figure 2 ), significantly higher than 0.9% at 1 hour and more significantly at 72 hours. The concentrations of powder (i.e., 1.1%, 1.2%, and 1.4%) that caused a significant decrease in intracellular ATP concentrations are one mechanism explaining the reduced SARS-CoV-2 replication in Vero cells.

[0191] To test whether the decrease in ATP levels was caused by an increase in the activity of the Na+ / K+ ATPase transporter, 0.4%, 0.8%, and 1.1% of Vero cells were treated with 5 μM ouabain powder. The expression of 5 μM ouabain in the presence or absence of ouabain was determined by plate microfluorimetry using a FlexStation III microplate reader and an ATP assay kit (SIGMA-Aldrich) according to the manufacturer's instructions. Changes in total ATP concentration in Vero cells after 1 hour of powder. The SIGMA-Aldrich ATP Assay Kit provides sensitive results for detecting ATP release from 10-100 mammalian cells / well based on the oxidation of D-luciferin catalyzed by firefly luciferase in the presence of ATP, where the amount of ATP is quantified by the amount of light produced (hv). One hour after the powder stimulation (depolarizing agent), 5 × 10 4 The luminescence intensity of each cell was recorded. After monitoring the basal fluorescence intensity (i.e., the luminescence emission rate before adding the ATP-releasing agent) for 10 seconds, the time kinetics was obtained by measuring at 1.52 second intervals for 120 seconds. Using SoftMax2Pro software (Molecular Devices), the response value was calculated by subtracting the basal luminescence value from the peak luminescence value. From the results obtained, Figure 3 It was shown that the decrease in ATP level was significantly reversed in the case of ouabain treatment.

[0192] Mitochondrial status was also measured after each treatment condition to assess the impact on ATP production. To this end, mitochondrial metabolism of Vero cells was tested using the Seahorse assay. Intact Vero cells were assessed using high-resolution respirometry. For this, two parameters were assessed: oxygen consumption rate (OCR); Figure 4 A) and extracellular acidification rate (ECAR; Figure 4 B) When mitochondrial metabolism is impaired, glycolytic enzymes increase their activity to compensate for ATP production ( Figure 4 D) The final product of this pathway is lactate, and the synthesis and accumulation of lactate leads to acidification of the culture medium. Figure 4 D shows oxygen consumption in four states: (i) basal state, (ii) proton leak state, (iii) uncoupled state, and (iv) inhibited state. The basal state indicates normal cellular respiration values; the proton leak state reflects the integrity of the mitochondrial inner membrane; the uncoupled state indicates the respiratory chain activity of complexes I to IV (i.e., maximal respiration); and the inhibited state reflects non-mitochondrial processes that consume oxygen. After 72h, the powder was found to have a 0.2% Powder can increase the maximum respiration. However, values ​​above 0.8% Powder downregulates breathing ( Figure 4 A). In line with this, the ECAR assessment ( Figure 4B) shows the same pattern. The correlation between OCR and ECAR is plotted in the energy spectrum ( Figure 4 C), which shows 0.2% and 0.4% Powder treatment resulted in an increased energy state, whereas higher concentrations shifted metabolism toward anaerobic pathways. OCR and ECAR results showed that lower concentrations of The powder had a positive effect on the cells' metabolism, while higher doses impaired mitochondrial function in Vero cells. Such results are important for the study of any chemical with therapeutic potential, as it is common to observe mitochondrial damage during the development of new drugs.

[0193] Another aim is to evaluate by fluorescence microscopy Na+ influx after powder treatment. Vero cells were stained with the intracellular sodium indicator Natrium Green and stimulated with NaCl (3%) for method calibration. Once method conditions were established (incubation in the presence of 11 μM Natrium Green for 45 min), Powder (0.4%, 0.8% and 1.1%) stimulated cells and measured Na + influx for 100 seconds, as Figure 5 As seen in A and 5B.

[0194] Δ[Na+]i data show that application The powder induced Na+ influx. The Na+ influx was 0.8% The powder concentration was significantly higher than 0.4% and 1.1% This confirms the data on mitochondrial status, which is above 0.8%. Powder doses are toxic to mitochondria.

[0195] It is worth mentioning that 0% The powder corresponds to a NaCl concentration of 0.6%, and 1.7% The powder corresponds to 2.1% NaCl, because The powder was diluted in cell culture medium containing 0.6% NaCl (110 mM NaCl).

[0196] Gene expression of sodium channels in cell culture was investigated by measuring the relative abundance of mRNA for the Na+ / K+ ATPase (Atp1B1, NCBI Reference Sequence: NM_001677.4); primers were standardized. Figure 6 As seen in the 0.4% concentration In the presence of 0.8% of The doses of ENac were toxic and decreased the expression of Na+ / K+ ATPase channel. No expression of ENac was observed in Vero cells.

[0197] Due to its ability to increase the activity of the Na+ / K+ ATPase transporter, The powder can induce a significant decrease in ATP levels. Since SARS-CoV-2 requires ATP for its replication, the experiments presented in this article show that The powder has significant virostatic properties (replication inhibition) against SARS-CoV-2.

[0198] Example 3: Antiviral effect on COVID-19

[0199] An open-label, randomized, three-arm feasibility study was conducted to evaluate the efficacy of a NaCl dry powder containing Device (particularly as defined herein Powder) in reducing COVID-19-related symptoms and preventing referral to healthcare providers in adult patients diagnosed with COVID-19. Data were collected from 100 COVID-19 patients who were randomized into three treatment groups.

[0200] The purpose of this study is to demonstrate the use of The powder is used to reduce the severity of COVID-19 symptoms as well as to prevent exacerbations and additional symptom onset benefits.

[0201] This study provides evidence that in patients with COVID-19 The main objective of the study is to determine the efficacy of a full-scale trial of the powder composition comprising the NaCl of the present invention compared to standard care (treating / alleviating symptoms with paracetamol alone). ( powder), as a dry powder inhaler therapy for clinical improvement in symptomatic COVID-19 patients. The efficacy of the powder in reducing healthcare service use and the safety of adverse events within 28 days after cessation of treatment were evaluated.

[0202] Outcomes were measured through telemedicine monitoring of participants' vital signs and symptoms, physical examinations, diary data, and daily self-reports. The efficacy of the powder and the development of the health status of the subjects were measured using an 8-level ordinal scale as recommended by the World Health Organization (WHO) to measure the health status of COVID-19 patients. The 100 participants included in the experiment were adult males or females (18 years of age or older) diagnosed with mild to moderate SARS-CoV-2 infection by RT-PCR or swab antigen PCR test. At the time of inclusion, their symptoms had to be at least one of the following: fever or perceived fever for more than 24 hours, headache, sore throat, cough (e.g., dry cough), fatigue, chest pain or choking sensation (without associated respiratory distress), myalgia, anosmia, anosmia, or gastrointestinal symptoms and these symptoms had to appear within 10 days of onset. The included patients were not hospitalized. The subjects were randomly divided into three groups in a 1:1:1 ratio.

[0203] The two experimental treatment groups were Group 1 and Group 2. Group 1 received standard of care treatment combined with 10 doses of This means once every hour during the day for 10 days. Group 2 received standard care combined with 5 times a day Each participant in the two groups received two devices, one for nasal use and one for oral use. By use The device was carried out 4 times The three randomized groups were:

[0204] Group 1: Standard care + hourly (4 inhalations / time), 10 times per day, for 10 days - 33 subjects.

[0205] Group 2: Standard care + every three hours (4 inhalations / time), 5 times per day, 10 days - 33 subjects.

[0206] Group 3: Standard care only (0 )-34 subjects.

[0207] The total duration of the study was 28 days, with a treatment period of 10 days and a treatment cessation period of 18 days. At the first visit, informed consent was collected, vital signs were measured, and a physical examination was performed by a health care professional. After 10 days from the start of the study, patients received a remote visit via telephone or video conversation to assess the use of assigned treatment, adverse events, and the need for unplanned medical care. During this call, a symptom diary was assessed. After the visit, treatment was stopped for the remaining 18 days of the study. At the end of the study (Day 28), a final visit was conducted to assess the presence of adverse events and collect a symptom diary. This post-treatment visit took place virtually. Figure 7 The study design is shown schematically.

[0208] Outcomes were measured based on participants' RT-PCR COVID-19 testing, telemedicine monitoring of vital signs and symptoms, diary data, and daily self-reporting. The principal investigator was responsible for ensuring that visits and follow-up were performed at the correct intervals. An independent safety monitoring committee was established to conduct ongoing review and assessment of clinical efficacy and safety data collected during the study every two weeks.

[0209] This feasibility study included 100 patients to perform the first interim analysis of the efficacy and safety of the trial. All participants were analyzed based on intention-to-treat analysis. The study outcomes were analyzed using analysis of variance (ANOVA) for continuous variables and Kruskal-Wallis test for nonparametric variables. The Chi-square test was used to calculate the proportion of health resource use to hospitalization. Poisson Regression was used to assess the frequency of health resource use.

[0210] After analyzing the data from the clinical trial, using Kaplan-Meier survival analysis, it was observed that during the treatment period (two treatment groups), the use The powder showed significant improvement in symptom recovery compared with the control group. The duration of COVID-19-induced cough was significantly less in the treatment group.

[0211] Figure 8 The number of days required to recover from cough as a symptom of Covid-19 affecting the airways is shown. Only patients who experienced cough symptoms at the start of the trial were included in this dataset. Figure 8 The values ​​reported below the graph in represent the prevalence of the symptom - ie the number of patients in each group experiencing the symptom of cough; whereas in the graph the y-axis shows the proportion of patients in each group experiencing cough at the time indicated on the x-axis (1.00 = 100%).

[0212] like Figure 8 As shown, on the 4th day after the first day of coughing:

[0213] 50% of patients in Group 1 and Group 2 recovered from cough.

[0214] In group 3, only 25% of patients recovered from their cough.

[0215] Compared with patients receiving usual care, Cough symptoms resolved twice as fast in treated patients.

[0216] like Figure 8 As further illustrated in the figure, on the 10th day after the first day of coughing:

[0217] · In Group 1, 75% of patients recovered from cough.

[0218] And in Group 2, 64% of patients recovered from cough.

[0219] In group 3, only 42% of patients recovered from their cough.

[0220] like Figure 8 As further illustrated in the figure, on day 20 after the first day of coughing:

[0221] 88% of patients in Group 1 recovered from cough.

[0222] And in Group 2, 72% of patients recovered from cough.

[0223] In group 3, only 58% of patients recovered from their cough.

[0224] Therefore, compared with standard care, the Proven to reduce recovery time from cough in COVID-19 patients.

[0225] Overall, no adverse events were reported with the use of powder and was well tolerated by patients.

[0226] Conclusion: Thus, the clinical study confirmed the results of the in vitro study shown and found that the use of the NaCl dry powder containing the present invention during the treatment period (two treatment groups) It provided significant (p=0.01) improvement in symptom recovery compared to the control group. The time to resolution of COVID-19-induced cough was significantly shorter in the treatment group. Group 1” recovered 40% faster from COVID-19-induced cough than the control group, and “ Group 2" was 30% faster than the control group (p=0.01).

[0227] Improvements were also observed in the resolution of other COVID-19-induced symptoms, but were not statistically significant due to the small sample size.

Claims

1. A dry powder composition for preventing and / or treating viral respiratory tract infections, the dry powder composition comprising at least 50% by weight of NaCl, wherein: The composition is administered to a mammalian subject by dry powder inhalation.

2. The dry powder composition for use according to claim 1, wherein The viral respiratory infection is caused by a coronavirus.

3. The dry powder composition for use according to claim 1 or 2, wherein The composition reduces the time for resolution of one or more symptoms caused by the viral respiratory infection.

4. The dry powder composition for use according to any one of claims 1 to 3, wherein The one or more symptoms caused by the viral respiratory infection is cough.

5. The dry powder composition for use according to any one of claims 1 to 4, wherein The composition comprises at least 60% NaCl, preferably at least 70% NaCl, more preferably at least 80% NaCl, most preferably at least 90% NaCl.

6. A dry powder composition for use according to any one of claims 1 to 5, wherein At least 80% of the particles of the dry powder composition have a particle size distribution in the range of 1 μm to 10 μm.

7. A dry powder composition for use according to any one of claims 1 to 6, wherein The composition also includes an anti-agglomeration agent.

8. A dry powder composition for use according to any one of claims 1 to 7, wherein The only therapeutic agent in the composition is NaCl.

9. The dry powder composition for use according to claim 7, wherein The only therapeutic agents are NaCl and the anti-agglomeration agent.

10. A dry powder composition for use according to any one of claims 7 to 9, wherein The anti-agglomeration agent is a carbohydrate or a carbohydrate derivative.

11. A dry powder composition for use according to any one of claims 7 to 10, wherein: The anti-agglomeration agent is selected from lactose, mannitol and maltodextrin; preferably, selected from lactose.

12. A dry powder composition for use according to any one of claims 1 to 11, wherein The composition is administered in a daily dose of between 0.5 mg-200 mg.

13. The dry powder composition for use according to claim 12, wherein The daily dose is divided into 1 to 10 times a day, 4 mg to 10 mg each time.

14. A dry powder composition for use according to any one of claims 1 to 13, wherein The composition is administered orally and / or nasally.

15. A dry powder composition for use according to any one of claims 1 to 14, wherein The composition consists essentially of NaCl and lactose.

16. A dry powder composition for use according to any one of claims 1 to 15, wherein The composition comprises lactose, and wherein the ratio of NaCl to lactose is between 99:1 and 75:25 based on weight %.

17. The dry powder composition for use according to claim 16, wherein The ratio of NaCl to lactose was about 95:5 based on weight %.

18. A dry powder composition for use according to any one of claims 2 to 17, wherein The coronavirus is SARS-CoV-2.

19. A dry powder composition for use according to any one of claims 2 to 18, wherein The viral respiratory infection is COVID-19.

20. A dry powder composition for use according to any one of claims 1 to 19, wherein The mammalian subject is a human.

21. A dry powder composition for use according to any one of claims 4 to 20, wherein The composition reduces the time to resolution of a cough in the mammalian subject by at least 30% compared to a mammalian subject not treated with the dry powder composition.

22. A dry powder composition for use according to any one of claims 1 to 21, wherein The NaCl was provided by a composition obtained from a salt diapir in the Hvornum area of ​​Denmark (N56 36.834E009 42.070).

23. A dry powder composition for use according to any one of claims 1 to 22, wherein The composition is administered using a dry powder inhaler.

24. The dry powder composition for use according to claim 23, wherein The dry powder inhaler is an inhaler (1) having a proximal end (P) in an axial direction and a distal end 40 (D) opposite to the proximal end (P), wherein the proximal end (P) is used to be inserted into the oral cavity of a user, wherein the inhaler (1) comprises an inlet (4), an outlet (5) arranged at the proximal end (P), an air passage (10, 11, 12, 13) extending from the inlet (4) to the outlet (5), and a reservoir (8, 9) connected to the air passage (10, 11, 12, 13) through a release hole (6, 7), wherein the reservoir (8, 9) contains a dispersible substance, wherein The inhaler (1) comprises a proximal portion (2) comprising the outlet (5) and a distal portion (3) connected to the proximal portion (2), wherein the proximal portion (2) is linearly slidable in an axial direction (A) relative to the distal portion (3) between an "open" position and a "closed" position, in which the proximal portion (2) is extended from the distal portion (3); and in which the proximal portion (2) is retracted toward the distal portion (3), wherein the inhaler (1) further comprises an inlet valve member (14) and an outlet valve member (15); - wherein the reservoirs (8, 9) are arranged in the proximal portion (2); - wherein the inlet (4) comprises one or more openings in the peripheral wall (20) of the proximal part (2), the one or more openings facing radially outwards away from the axial direction (A), and the inlet valve member (14) is formed by the peripheral wall (30) of the distal part (3), the peripheral wall (30) covering the openings when the proximal part (2) is in the "closed" position; - wherein the outlet (5) comprises an axially oriented hole; wherein the outlet valve member (15) is formed as a plug connected to the distal portion (3), the plug blocking the outlet (5) when the proximal portion (2) is in the "closed" position; - wherein said release holes (6, 7) are oriented in said axial direction (A); and - wherein the inhaler (1) further comprises a reservoir valve member (16, 17), wherein the reservoir valve member (16, 17) is formed as a hook travelling in the axial direction (A), the hook being fixed to the distal portion (3) via an axially extending rod, wherein the hook blocks the release hole (6, 7) when the proximal portion (2) is in the "closed" position; Thus, the inlet valve member (14), the outlet valve member (15) and the reservoir valve members (16, 17) are arranged such that - when the proximal portion (2) is retracted from the "open" position in the axial direction towards the distal portion to the "closed" position, the inlet (4), the outlet (5) and the release holes (6, 7) are closed simultaneously, and -When the proximal portion (2) is unfolded from the distal portion along the axial direction from the "closed" position to the "open" position, the inlet (4) is opened, the outlet (5) is opened, and a certain amount of the dispersible substance from the reservoir (8, 9) is delivered to the air channel (10, 11, 12, 13) through the release hole (6, 7).

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