KR20230129017A - A therapeutic substance with low pH and low toxicity that is active against at least one pathogen for treating patients with respiratory disease - Google Patents

Abstract

Methods and compositions for treating or preventing respiratory illness. The method includes administering at least one dose of a pharmaceutically acceptable fluid having a pH less than 3.0 to contact at least one region of the airways present in a patient in need thereof. Respiratory illnesses that can be treated include COVID-19.

Description

A therapeutic substance with low pH and low toxicity that is active against at least one pathogen for treating patients with respiratory disease

CROSS-REFERENCES OF PENDING APPLICATIONS

This disclosure relates to all pending U.S. Application Serial Nos. 63/121,856, filed on December 4, 2020; US Application No. 63/144,305, filed February 1, 2021; Priority is claimed to U.S. Application No. 63/158,864, filed on March 9, 2021, and U.S. Application No. 63/220,441, filed on July 9, 2021, the disclosures of which are incorporated herein in their entirety. is included This application also claims priority to currently pending application PCT/US2021/030429, filed on May 3, 2021, the specification of which is hereby incorporated by reference.

The present disclosure relates to methods and compositions for treating and/or preventing respiratory illness. More specifically, the present disclosure relates to methods for treating and/or preventing respiratory illnesses caused at least in part by infectious pathogens. Non-limiting examples of such pathogens are bacterial, fungal and/or viral pathogens. Non-limiting examples of viral pathogens include those caused by one or more of coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinovirus.

Infectious respiratory diseases challenge the health, safety and well-being of people of all ages. Various viral and/or bacterial and/or fungal pathogens can readily spread through multi-infecting populations. This is particularly challenging when a large number of individuals in the affected population lack natural or acquired immunity to a given pathogen. It is also challenging in populations with limited or no access to advanced medical treatment. Thus, many areas in countries in Africa, South America and Asia as well as rural areas in developed countries such as the United States may find the arrival of new infectious pathogens difficult, if not particularly catastrophic.

Respiratory pathogens such as bacteria, fungi and viruses, including SARS-CoV-2, kill over 5 million people each year. (See Forum of International Respiratory Societies. The Global Impact of Respiratory Disease - Second Edition. Sheffield, European Respiratory Society, 2017). In the case of emerging pandemic pathogens, such as SARS-CoV-2, disease specific treatments take time to develop. In addition, many endemic pathogens can evolve to become multi-drug resistant, exhibit multiple genotypes, and can rapidly exist without specific diagnostic platforms available until exponential disease transmission occurs. Available therapeutics are usually pathogen specific. The timetable for therapeutic development, from pathogen identification, target validation, and small molecule design to clinical trials, is expensive and can take years to achieve. For example, the SARS-CoV-2 virus mutates into multiple variants to increase its transmission and proliferative infection, and will probably further mutate to avoid recognizing antibodies generated within the vaccinated population.

A broad-spectrum antibacterial treatment that provides efficacy across many viral, bacterial and fungal respiratory pathogens is highly desirable. It is also desirable to provide efficacy against current and emerging SARS-CoV-2 variants as well as current and emerging antibiotic resistant bacterial strains. Additionally, it is desirable that the therapeutic agent is easy to administer, exhibits minimal systemic effects, and is widely available for all patient access, which is suitable for a wide range of respiratory infections prior to or outside of pathogen-specific drug substances and/or therapeutic methods. It can be used as a first-line treatment option for

Medical investigation into inhaled pulmonary antibacterial compounds effective against infectious pathogens capable of multiplying in one or more areas of the respiratory tract began over a century ago as potential treatments for infectious diseases such as tuberculosis and also common cold influenza and others. The investigation was unsuccessful, and its efforts appear to have been overshadowed by the discovery of antibiotics such as penicillin. However, the demand for safe and effective pulmonary antibacterial compounds and compositions continues to become more urgent due to the COVID-19 pandemic. Additionally, an increasing population of patients with pre-existing respiratory diseases that can increase their susceptibility to a wide range of viral, bacterial and fungal respiratory pathogens as well as the proliferation of antibiotic and therapeutic resistant pathogens are also looking for effective pulmonary antibacterial compounds and treatments. clearly show the demand.

Additionally, upper respiratory tract infections and lower respiratory tract infections are often treated with antibiotics and may account for over half of antibiotic prescriptions in industrialized developed countries. This can be costly and over time can increase the emergence of antibiotic resistant strains of the pathogen. Accordingly, it would be desirable to provide compositions and treatments that can be used as treatment in respiratory tract infections either as an alternative to, or at least as an adjunct to, antibiotic treatment.

There is an unmet need for pulmonary disinfectant compounds that are pharmaceutically acceptable, effective, within patient tolerance levels, and non-harmful to host tissues.

Accordingly, it would be desirable to provide an agent or agents capable of acting against one or more pathogens in situ in a patient to reduce or eliminate one or more pathogens associated with respiratory infections. It would also be desirable to provide a method for preventing infection, presenting an infection caused by one or more pathogens, or treating a patient that tests positive for a pathogen that is pharmaceutically acceptable, effective, tolerant, and non-harmful to the host tissue. .

A method of treating or preventing a respiratory illness comprising administering at least one dose of a pharmaceutically acceptable fluid having a pH less than 3.0 to contact at least one region of the respiratory tract of a patient in need thereof is disclosed. there is. A pharmaceutically acceptable fluid may include at least one inorganic acid, at least one organic acid, and mixtures thereof.

A therapeutic composition comprising an acidic component comprising a fluid carrier and a pharmaceutically acceptable acidic component present in an amount sufficient to produce a pH of less than 3.0 for use in treating respiratory illness in a patient in need thereof is provided. Also disclosed. The pharmaceutically acceptable acidic component can be at least one inorganic acid, at least one organic acid, and mixtures thereof.

A composition having a pH less than 3.0 composed of at least one pharmaceutically acceptable acid for use as a therapeutic inhalant composition is also disclosed. The at least one pharmaceutically acceptable acid can be at least one inorganic acid, at least one organic acid or a mixture thereof.

A pharmaceutically acceptable fluid comprising a liquid carrier and at least one compound, wherein the pharmaceutically acceptable fluid has a pH less than 3.0, and administering the pharmaceutically acceptable fluid to the respiratory tract of a patient in need thereof A kit for use in the treatment or prevention of a respiratory illness comprising a container for use is also disclosed.

Various features, advantages and other uses of the methods and/or compositions will become more apparent with reference to the following detailed description and drawings, wherein
Figure 1 shows an embodiment as disclosed herein prepared according to the process outlined in dilute sulfuric acid and 400 ppm CaSO ₄ (A), dilute sulfuric acid (B), Example LXXII (C) and reverse osmosis water (D). is a mass spectrum collected in positive ionization mode for;
Figure 2 shows an embodiment as disclosed herein prepared according to the process outlined in dilute sulfuric acid and 400 ppm CaSO ₄ (A), dilute sulfuric acid (B) and Example LXXII (C) and reverse osmosis water (D). This is a mass spectrum collected in the negative ionization mode for

A method for treating or preventing a respiratory illness comprising administering at least one dose of a pharmaceutically acceptable fluid having a pH less than 3.0 to contact at least one region of the airways present in a patient in need thereof. and compositions disclosed herein.

Respiratory illnesses that may be treated or prevented by the methods and/or compositions as disclosed herein may include airway infections caused by one or more of a variety of infectious pathogens that may affect humans or animals or both. there is. Respiratory diseases that may be treated or prevented by methods as disclosed herein may include one or more chronic respiratory conditions. A respiratory illness that can be treated or prevented can be a combination of one or more chronic respiratory conditions and one or more respiratory infections. In certain embodiments, the respiratory tract infection can be either an acute infection or a chronic infection, and can be caused by one or more pathogens. It is also contemplated that the respiratory illness may be a combination of chronic respiratory illness(es) and respiratory tract infection(s).

A chronic respiratory condition, as defined by the United States Center for Disease Control, is broadly defined as a condition that lasts longer than one year and requires ongoing medical attention, reduces activities of daily living, or both. do. Non-limiting examples of chronic respiratory diseases that can be addressed by the methods and/or compositions disclosed herein include chronic obstructive pulmonary disease, cystic fibrosis, asthma or respiratory allergies.

Respiratory tract infection, as the term is used in this disclosure, is broadly defined as any infectious disease of the upper or lower respiratory tract. Upper respiratory tract infections may include, but are not limited to, the common cold, laryngitis, sore throat/tonsillitis, rhinitis, rhinosinusitis, and others. Lower respiratory tract infections include bronchitis, bronchiolitis, pneumonia, tracheitis and others.

Pathogens responsible for respiratory tract infections treatable by the methods and/or compositions as disclosed herein include one or more viral pathogens, one or more bacterial pathogens, one or more fungal pathogens, as well as mixed pathogens resulting from two or more of the described classes. May include infection. In certain embodiments disclosed herein, the viral pathogen is at least one of a coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus (RSV), rhinovirus, adenovirus, as well as combinations of two or more of the foregoing. can It is also contemplated that the various viral strains that cause infection in a patient may be pure strains or may be a mixture of various strains, types, subtypes and/or mutations.

Coronaviruses that can be treated by the methods and/or compositions as disclosed herein include, but are not limited to, alpha coronaviruses, beta coronaviruses, as well as other emerging types. Coronaviruses, as the term is used in this disclosure, are understood to be a group of related RNA viruses that cause disease, particularly respiratory tract infections, in a variety of mammalian and avian species. Coronaviruses that can be treated by the methods and/or compositions as disclosed herein include members of the subfamily Orthocoronavirinae in the family Coronaviridea . In certain embodiments, methods and/or compositions as disclosed herein may be used to prevent disease-causing pathogens from SARS-CoV-1 (2003), HCoV NL63 (2004), HCoV HKU1 (2004), MERS-CoV (2013) SARS-CoV (2013). CoV-2 (2019) and mixtures thereof. In certain embodiments, the coronavirus may be a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and mixtures thereof. In certain embodiments, the methods and/or compositions as disclosed herein may be used to treat or prevent respiratory infections in which the disease-causing pathogen is an encapsulated, positive-sense, single-stranded RNA virus other than those mentioned.

Non-limiting examples of influenza viruses that can cause respiratory tract infections and can be treated by methods and/or compositions as disclosed herein include negative-sense RNA viruses, such as orthomyxoviridae, such as alphainfluenza, beta It may be from the genera Influenza, Delta Influenza, Gamma Influenza, Togotovirus and Quarajavirus. In certain embodiments, the influenza virus is expressed as a serotype such as H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N4, N7N7, H7N9, H9N2, H10N7 It may be alpha influenza. Other representations are also contemplated.

A non-limiting example of a parainfluenza virus can be a single-stranded, enclosed RNA virus of the family Paramyxoviridae. Non-limiting examples of human parainfluenza viruses include those of the genus Respirovirus and the genus Rubulavirus .

A non-limiting example of a respiratory syncytial virus (RSV) is a variety of medium-sized (about 150 nm) enclosed viruses from the family Pneumvidae , such as the genus Orthopneumovirus .

Non-limiting examples of rhinoviruses that can be treated by methods and/or compositions as disclosed herein include those having a single-stranded positive sense RNA genome composed of a capsid containing viral protein(s). Rhinoviruses can be from the Picovirus family and the Enterovirus genus.

Non-limiting examples of adenoviruses include unencapsulated viruses, such as those having an icosahedral nucleocapsid containing a nucleic acid such as double-stranded DNA. The virus may be from the family Adenoviridae and genera such as Atadenovirus , Mastadenvirus , Siadenovirus and others.

It is also contemplated that the methods and/or compositions as disclosed herein may be used to treat respiratory tract infections caused by bacterial pathogens. Non-limiting examples of such bacterial pathogens include Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Streptococcus blood Ogenes, Mycobacterium tuberculosis, Mycobacterium avium - Intracellulare (MAI), Mycobacterium terrae and mixtures thereof.

The methods and/or compositions as disclosed herein can be used to treat respiratory infections caused by fungal pathogens presenting as mono-pathogen fungal infections, multi-pathogen fungal infections, or common mold fungal infections with respiratory involvement. Non-limiting examples of fungal pathogens implicated in respiratory diseases and infections include certain species from the genus Aspergillus, and A. Fumigatus, a. Flavus and A. Clavatus is a non-limiting example. Other examples of respiratory infections caused by fungal pathogens that can be treated by the methods and/or compositions disclosed herein are respiratory infections involving Cryptococcus, Rhizopus, Mucor, Pneumocystis, Candida, and other infectious species. am.

In certain embodiments, a method and/or composition as disclosed herein has a value of less than 2.8; less than 2.5; less than 2.4; less than 2.0; less than 1.8; less than 1.7; less than 1.6; less than 1.5; It may have a pH less than 1.0, the lower range being determined by the lung condition and health of the patient. In certain embodiments, the composition is 1.4 to 3.0; 1.5 to 3.0; 1.6 to 3.0; 1.7 to 3.0; 1.8 to 3.0; 1.9 to 3.0; 2.0 to 3.0; 2.2 to 3.0; 2.4 to 3.0; 1.4 to 2.5; 1.5 to 2.5; 1.6 to 2.5; 1.7 to 2.5; 1.8 to 2.5; 1.9 to 2.5; 2.0 to 2.5; 2.2 to 2.5; 2.4 to 2.5; 1.4 to 2.4; 1.5 to 2.4; 1.6 to 2.4; 1.7 to 2.4; 1.8 to 2.4; 1.9 to 2.4; 2.0 to 2.4; 2.2 to 2.4; 1.4 to 2.4; 1.5 to 2.2; 1.6 to 2.2; 1.7 to 2.2; 1.8 to 2.2; 1.9 to 2.2; 2.0 to 2.2; 1.4 to 2.0; 1.5 to 2.0; 1.6 to 2.0; 1.7 to 2.0; 1.8 to 2.0; 1.9 to 2.0, 1.4 to 1.9; 1.4 to 1.9; 1.4 to 1.8; 1.4 to 1.7; 1.4 to 1.6; It may have a pH of 1.4 to 1.5.

In methods such as those disclosed herein, a pharmaceutically acceptable fluid having a pH of less than 3.0 can be administered in contact with at least one region of the respiratory tract of a patient in need thereof, and in any therapeutically acceptable manner. can be administered by In certain embodiments, the pharmaceutically acceptable fluid will be administered in a manner that permits or facilitates absorption of at least a portion of the composition by patient inhalation. A pharmaceutically acceptable fluid may be introduced under pressure in certain embodiments.

A pharmaceutically acceptable fluid as disclosed herein may be introduced into contact with at least one area of a patient's respiratory tract in the form of a gas, fluid, or a mixture of the two. In certain embodiments, the pharmaceutically acceptable fluid may also include one or more powders or micronized solids. The pharmaceutically acceptable fluid may be introduced into contact with at least a portion of a patient's respiratory tract in the form of a vapor, aerosol, spray, micronized mist, gas or otherwise. It is also contemplated that the pharmaceutically acceptable fluid may be administered as a gas, as nanoparticles dispersed in a gas, as micronized particles in a gas, as nanoparticles dispersed in a gas, or the like.

The size particulate or droplet material comprised of a pharmaceutically acceptable fluid introduced into contact with at least one area of a patient's airway can be adjusted or tuned to increase contact with a desired airway area. Each airway area that the pharmaceutically acceptable fluid may contact may include the nose, sinuses, throat, pharynx, larynx, epiglottis, sinuses, trachea, bronchi, alveoli, or any combination of the foregoing. The particle/droplet size distribution can be tuned to address the location of the largest pathogen population. In certain embodiments, at least one dose of a pharmaceutically acceptable fluid may be delivered in contact with the lower respiratory tract, such as the bronchi, alveoli, and the like, to treat infection localized in that area. In certain embodiments, at least one dose of a pharmaceutically acceptable fluid is delivered in contact with the upper respiratory tract, such as the nose or nostrils, nasal cavities, mouth, pharynx, larynx, and the like to address infection localized in that area. It can be.

In certain embodiments, the pharmaceutically acceptable fluid as administered may have a particle size with a mean mass aerodynamic diameter (MMAD) of 0.1 to 20.0 microns. In certain embodiments, the particle size is 0.5 to 20.0; 0.75 to 20.0; 1.0 to 20.0; 2.0 to 20.0; 3.0 to 20.0; 4.0 to 20.0; 5.0 to 20.0; 7.0 to 20.0; 10.0 to 20.0; 12.0 to 20.0; 15.0 to 20.0; 16.0 to 20.0; 17.0 to 20.0; 18.0 to 20.0; 0.1 to 15.0; 0.5 to 15.0; 0.75 to 15.0; 1.0 to 15.0; 2.0 to 15.0; 3.0 to 15.0; 4.0 to 15.0; 5.0 to 15.0; 7.0 to 15.0; 10.0 to 15.0; 12.0 to 15.0; 14.0 to 15.0; 0.1 to 10.0; 0.5 to 10.0; 0.75 to 10.0; 1.0 to 10.0; 2.0 to 10.0; 3.0 to 10.0; 4.0 to 10.0; 5.0 to 10.0; 7.0 to 10.0; 8.0 to 10.0; 9.0 to 10.0; 0.1 to 5.0; 0.5 to 5.0; 0.75 to 5.0; 1.0 to 5.0; 2.0 to 5.0; 3.0 to 5.0; 4.0 to 5.0; 0.1 to 4.0; 0.5 to 4.0; 0.75 to 4.0; 1.0 to 4.0; 2.0 to 4.0; 3.0 to 4.0; 0.1 to 3.0; 0.5 to 3.0; 0.75 to 3.0; 1.0 to 3.0; 1.5 to 3.0; 2.0 to 3.0; 0.1 to 2.0; 0.5 to 2.0; 0.75 to 2.0; 1.0 to 2.0; 1.5 to 2.0; 0.1 to 1.0; 0.3 to 1.0; 0.5 to 1.0; 0.75 to 1.0 microns.

The pharmaceutically acceptable fluid may be introduced into contact with at least one region of the airways of a patient in a sufficient concentration and in an amount sufficient to reduce the pathogen load present in the airways. It is within the scope of the present disclosure that a pharmaceutically acceptable fluid may be continuously introduced over defined intervals of minutes, hours or even days. In certain embodiments, the pharmaceutically acceptable fluid may be introduced continuously for an interval of at least 24 hours. In patients presenting with a respiratory infection, continuous administration may be discontinued upon a decrease in the pathogen load, as measured directly or indirectly confirmed by improvement of symptoms such as blood oxygen saturation or otherwise.

It is also within the scope of the present disclosure that a pharmaceutically acceptable fluid may be administered in a series of at least two doses introduced at defined intervals. The dosing interval and number of doses administered will be sufficient to reduce the pathogen load present in the airways of the patient, as measured directly or indirectly confirmed by improvement of symptoms such as blood oxygen saturation or otherwise.

In certain embodiments, the reduction in pathogen load can be a partial or complete reduction in the number of pathogens in the airways of a patient to whom the pharmaceutically acceptable fluid is administered. When a less-than-complete reduction in airway pathogen counts is achieved, the reduction in airway pathogen counts, at least in some instances, alone or by additional supportive or adjuvant therapy, is sufficient to allow the patient's own immune system response to address or overcome the infectious pathogen. is considered to be sufficient for

Where the pharmaceutically acceptable fluid is administered in multiple discrete doses, it is contemplated that the pharmaceutically acceptable fluid may be administered over 2 to 10 doses in a 24 hour period, with 3 to 4 doses being the desired implementation. considered in the form Each dosing interval can be for a period of 1 second to 120 minutes, 1 minute to 60 minutes; 1 minute to 30 minutes; 1 minute to 20 minutes; Dosing intervals of 1 minute to 10 minutes are contemplated in certain embodiments. In certain embodiments, when the pharmaceutically acceptable fluid is administered over a dosing interval, an additional portion of the pharmaceutically acceptable fluid is introduced over the dosing interval and, by continued addition in contact with the affected partial airway, kills the pathogen. reduce the load

Direct measurement of a reduction in pathogen load in a patient's airways can be achieved by any suitable mechanism, such as swabbing, sampling, or the like. In certain embodiments, it is contemplated that a reduction in pathogen load may be defined as a reduction in pathogen population of at least 1% in at least one area of the patient's respiratory tract as measured at a time of 1 minute to 24 hours after start of administration. . In certain embodiments, the reduction in pathogen load is at least 10%; at least 25%; at least 50%; It may be at least 75%.

It is contemplated that pharmaceutically acceptable fluids may be administered prophylactically or therapeutically depending on the physiology and health history of a particular patient. A non-limiting example of prophylactic administration may include the routine administration of a pharmaceutically acceptable fluid in an appropriate dosing regimen to an individual presenting with a chronic condition with an increased risk for airway infection or complications from airway infection. . Another non-limiting example of prophylactic administration is administration of one or more doses of a pharmaceutically acceptable fluid as disclosed herein following exposure to an infectious pathogen.

It is contemplated that administration of pharmaceutically acceptable fluids may be accomplished by one or more suitable devices including, but not limited to, nebulizers, cold mist vaporizers, positive pressure inhalers, CPAP units, and the like.

A pharmaceutically acceptable fluid may include at least one acid compound present in a concentration sufficient to provide a fluid pH less than 3.0 and within the ranges recited in this disclosure. A pharmaceutically acceptable fluid may include at least one acid in a suitable carrier, as desired or required. The acid used may be one that is pharmaceutically acceptable, effective, tolerable, and not harmful to the surrounding tissues present in the airways of the patient being treated. Suitable acid compounds may be selected from the group consisting of Bronsted acids, Lewis acids and mixtures thereof.

As used herein, the term “pharmaceutically acceptable” is defined as having suitable pharmacokinetics and pharmacodynamics such that a therapeutic agent is primarily active at the surface of the tissues of the respiratory tract with little or no systemic effect. Ideally, the materials used produce residual products recognized by the body as common metabolites that are rapidly absorbed and metabolized. As used herein, "effective" is defined as a substance effective against a targeted pathogen in vivo with the goal of significantly reducing the pathogen load to assist and augment the body's natural defenses. "Tolerable", as defined herein, is that a substance can be tolerated by a patient at effective therapeutic concentrations without undesirable reactions including, but not limited to, irritation, choking, coughing, or the like. As used herein, "non-harmful" is defined as a substance that is effective in killing the targeted pathogen with little or no adverse effect on tissues of the respiratory tract in direct contact with the substance present at therapeutic concentration levels.

The acid compound used may be at least one inorganic acid, at least one organic acid or a mixture of at least one inorganic acid and at least one organic acid.

In certain embodiments, the pharmaceutically acceptable fluid will include and can be at least one inorganic acid present in a concentration sufficient to provide a pH at a level defined herein. When two or more inorganic acids are used, the various inorganic acids will be present in a ratio sufficient to provide a pH level within the parameters defined in this disclosure. The ratio of each acid can be modified or altered to meet parameters such as tolerance. Non-limiting examples of suitable inorganic acids include inorganic acids selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid, and mixtures thereof. In certain embodiments, the pharmaceutically acceptable fluid may include sulfuric acid, hydrochloric acid, hydrobromic acid, and mixtures thereof. The present disclosure also contemplates that the at least one inorganic acid in the pharmaceutically acceptable fluid may be wholly or partially present as a salt or salts of the respective inorganic acid. The at least one inorganic acid may be used alone or in combination with other organic or inorganic weak or strong acids or salts thereof to obtain a desired pH range.

In certain embodiments, the pharmaceutically acceptable fluid may include at least one organic acid present in a concentration sufficient to provide a pH at a level defined herein. In certain embodiments, at least one organic acid may be present alone or in combination with one or more inorganic acids. When two or more organic acids are used, the various organic acids may be present in a ratio sufficient to provide a pH level within the parameters defined in this disclosure. The ratio of each acid can be modified or altered to meet parameters such as tolerance. Non-limiting examples of organic acids include acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorbic acid, aspartic acid, glutamic acid, glutaric acid, and mixtures thereof. at least one organic acid selected from the group In certain embodiments, the organic acid can be at least one of trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorbic acid, aspartic acid, glutamic acid, and mixtures thereof.

In certain embodiments, the pharmaceutically acceptable fluid may include at least one inorganic acid in combination with at least one organic acid listed above. It is also contemplated that at least one organic acid or at least one inorganic acid may be present in combination with at least one amino acid. Non-limiting examples of such combinations include, for example, amino acids such as aspartic acid or glutamic acid and at least one inorganic acid necessary to provide an appropriate pH range, such as hydrochloric acid, hydrobromic acid and sulfuric acid.

an acid component present in a pharmaceutically acceptable fluid that may include two or more acid compounds in a concentration sufficient to provide a pharmaceutically acceptable fluid having a pH of less than 3 or in one of the ranges described herein. It is within the scope of this disclosure to provide. Thus, when two or more acid compounds are present in a pharmaceutically acceptable fluid, it is contemplated that the composition may include certain organic and/or inorganic acids having a pH outside the levels outlined for the final composition. . It is also contemplated within the scope of the present disclosure to include small amounts of the acid compound at levels that allow the acid compound to be tolerated as needed and/or metabolized effectively.

A pharmaceutically acceptable therapeutic fluid may include a fluid carrier as desired or necessary. The fluid carrier component can be a liquid gas material suitable for administration to humans, and more specifically, the fluid carrier is administered as an inhalable material or an introducible material and is present on one or more surfaces present in at least one region of the respiratory tract of a patient. It may be something you can contact. The fluid carrier component can be a suitable protic solvent, a suitable aprotic solvent or mixtures thereof. In certain embodiments, the carrier may be a fluid, which may be a gas, or may be a fluid, which may be vaporized, aerosolized, or otherwise by suitable means. Non-limiting examples of suitable carriers include water, organic solvents and others, either alone or in suitable mixtures. Non-limiting examples of organic solvents include C ₂ to C ₆ alcohols, pharmaceutically acceptable fluorine compounds, pharmaceutically acceptable siloxane compounds, pharmaceutically acceptable hydrocarbons, pharmaceutically acceptable halogenated hydrocarbons, and mixtures thereof. It includes a material selected from the group consisting of.

Without wishing to be bound by any theory, it is believed that the free hydrogen present in the pharmaceutically acceptable fluid composition may include one or more suitable acids present in a wholly or partially dissociated state. In certain embodiments, the suitable acid present in a fully or partially dissociated state may be selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, carbonic acid, oxalic acid, pyrophosphoric acid, phosphoric acid, and mixtures thereof.

The acid component may be present in an amount sufficient to act on pathogens present in the patient's respiratory tract. In certain embodiments, the acid component is 10,000 ppm or less; 1000 to 10,000 ppm; 2000 to 10,000 ppm; 3000 to 10,000 ppm; 4000 to 10,000 ppm; 5000 to 10,000 ppm; 6000 to 10,000 ppm; 7000 to 10,000 ppm; 8000 to 10,000 ppm; It may be present in an amount of 9000 to 10,000 ppm. In certain embodiments, the acid component may be present in the pharmaceutically acceptable material solution in an amount of 100 ppm to 2000 ppm; In certain embodiments the inorganic acid is from 100 ppm to 1700 ppm; 100 to 1500 ppm; 100 to 1200 ppm; 100 to 1000 ppm; 100 to 900 ppm; 100 ppm to 800 ppm; 100 ppm to 700 ppm; and 100 ppm to 600 ppm. 500 ppm to 1700 ppm; 500 to 1500 ppm; 500 to 1200 ppm; 500 to 1000 ppm; 500 to 900 ppm; 500 ppm to 800 ppm; 500 ppm to 700 ppm; and 500 ppm to 600 ppm; 1000 ppm to 1700 ppm; 1000 to 1500 ppm; It may be present in an amount of 1000 to 1200 ppm.

Without wishing to be bound by any theory, it is possible that the acid compound(s) in a pharmaceutically acceptable fluid can affect and reduce pathogen load in at least one area of a patient's respiratory tract. It is believed that it can act as a proton donor in For example, when sulfuric acid is used, it dissociates at least partially into mainly hydrogen ions and hydrogen sulfate (HSO ₄ ^- ) at low concentrations. Sulfuric acid can affect pathogens by donating protons in its dissociated state. Although this mode of action is mentioned, other modes of action are not excluded by this description.

The aforementioned compounds may be present in suitable liquid materials. Non-limiting examples of suitable materials include water at a level of purity sufficient to facilitate the availability of the component materials and suitability for the end use application. In certain embodiments, the water component of the liquid material may be a material classified as ASTM D1193-06 primary grade. Where desired or necessary, the water component, which is water, can be any water component including, but not limited to, distillation, double distillation, deionization, demineralization, reverse osmosis, carbon filtration, ultrafiltration, ultraviolet oxidation, microporous filtration, electrodialysis, and the like. It can be purified by a suitable method of. In certain embodiments, water having a conductivity of 0.05 to 2.00 micro Siemens may be used. It is also within the scope of the present disclosure that the water component of the liquid material may consist of water having a greater than primary grade purity if desired or necessary. Water classified as ASTM1193-96 purified, ASTM1193-96 ultrapure water or higher may be used if desired or required.

If desired or necessary, the composition may also contain 5 to 2000 ppm of a pharmaceutically acceptable Group I ion, a pharmaceutically acceptable Group II ion, and mixtures thereof. In certain embodiments, the ion may be selected from the group consisting of calcium, magnesium, strontium, and mixtures thereof. In certain embodiments, the concentration of inorganic ions is 5 to 900 ppm; 5 to 800 ppm; 5 to 700 ppm; 5 to 600 ppm; 5 to 500 ppm; 5 to 400 ppm; 5 to 300 ppm; 5 and 200 ppm; 5 to 100 ppm; 5 to 50 ppm; 5 to 30 ppm; 5 to 20 ppm; 10 to 900 ppm; 10 to 800 ppm; 10 to 700 ppm; 10 to 600 ppm; 10 to 500 ppm; 10 to 400 ppm; 10 to 300 ppm; 10 and 200 ppm; 10 to 100 ppm; 10 to 50 ppm; 10 to 30 ppm; 100 to 900 ppm; 100 to 800 ppm; 100 to 700 ppm; 100 to 600 ppm; 100 to 500 ppm; 100 to 400 ppm; 100 to 300 ppm; 200 to 900 ppm; 200 to 800 ppm; 200 to 700 ppm; 200 to 600 ppm; 200 to 500 ppm; 200 to 400 ppm; 200 to 300 ppm; 300 to 900 ppm; 300 to 800 ppm; 300 to 700 ppm; 300 to 600 ppm; 300 to 500 ppm; 300 to 400 ppm. In certain embodiments, calcium ions may be present as Ca ²⁺ , CaSO ₄ ^-1 and mixtures thereof.

It is contemplated that the mixed acid compound or acid compounds may be prepared by any suitable means that results in a material that has limited to non-harmful interactions when introduced into contact with at least one area present in the respiratory tract of a patient. do.

A pharmaceutically acceptable fluid may also contain at least one active pharmaceutical ingredient present in suitable therapeutic concentrations. A suitable active pharmaceutical ingredient may be one that has activity localized to the area of the respiratory tract with which it comes into contact. It is also within the scope of the present disclosure that suitable active pharmaceutical ingredients may be those that have effects on the greater respiratory system and/or general systemic effects on the patient. In certain embodiments, the active pharmaceutical ingredient(s) used may be one that can be administered via the pulmonary system by inhalation or otherwise. In certain embodiments, it is contemplated that the active pharmaceutical ingredient may be administered as part of a regimen or treatment regimen using routes of administration other than inhalation, such as orally or intravenously.

As used herein, "active pharmaceutical ingredient" also includes pharmaceutically acceptable salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomers, active metabolites, and the like of active pharmaceutical ingredients. "Derivatives" may be included. Preferably, derivatives include prodrugs and active metabolites. Moreover, various "active pharmaceutical ingredients and derivatives thereof" are described in various literature articles, patents and published patent applications, and are well known to those skilled in the art.

In certain embodiments, the at least one active pharmaceutical ingredient is an antimicrobial agent, such as one from the class of antiviral agents or antibiotics, adrenergic _β2 receptor agonists, steroids, non-steroidal anti-inflammatory compounds, muscarinic antagonists, and the like. Any of the above suitable compounds may be included. In certain embodiments, pharmaceutically acceptable fluids such as those disclosed herein may contain antiviral compounds with specific or general efficacy against coronaviruses, influenza and others to address and treat specific pathogenic infections. . Non-limiting examples of antiviral active pharmaceutical ingredient(s) include amantadine, lopinavir, linebacker and equivir, arbidol, nanoviricid, remdesivir, favipiravir, oseltamivir, ribavirin, molnupiravir and one or more compounds selected from the group consisting of derivatives and prodrugs thereof, as well as combinations of the foregoing. In certain circumstances, the antiviral active pharmaceutical ingredient(s) may be present in a form that permits administration via inhalation or other suitable administration to direct or immediate contact with at least a portion of a patient's respiratory tract. Without wishing to be bound by any theory, it is believed that a substance such as molnupiravir may exist as a prodrug that can be converted to its active metabolite by esterases in the lung. The combination with a pharmaceutically acceptable fluid administered in contact with at least one portion of the respiratory tract of a patient in need thereof thereby enhances the bioavailability of materials administered by other methods and/or eliminates one or more side effects. .

It is also contemplated that antiviral drugs may be administered as part of a use or treatment regimen, if desired or necessary. Antiviral agents administered orally or intravenously, such as neuraminidase inhibitors, Cap-dependent endonuclease inhibitors, and others, may be included in the use or treatment regimen.

In certain embodiments, pharmaceutically acceptable fluids such as those disclosed herein may contain antiviral compounds with specific or general efficacy against coronaviruses, influenza and others to address and treat specific pathogenic infections. . Non-limiting examples of such antiviral compounds include remdesivir, molnupiravir and others. The present disclosure relates to the use of such materials in suitable combinations with the pharmaceutically acceptable fluids disclosed herein used routinely prophylactically or upon exposure, such as in at-risk patient populations, such as those with chronic illnesses or recognized comorbidities. consider using The present disclosure also contemplates administration or use of these materials in suitable combination with a pharmaceutically acceptable fluid disclosed herein following a confirmed diagnosis to a symptomatic or asymptomatic individual. Without wishing to be bound by any theory, it is believed that treatment by or use of a combination as disclosed may provide an effective treatment regimen to address respiratory illnesses including, but not limited to, SARS-CoV-2, influenza, and others. It is considered

In certain embodiments, the pharmaceutically acceptable fluid may include at least one adrenergic β ₂ receptor agonist active pharmaceutical ingredient. A suitable adrenergic β ₂ receptor agonist may be one that can be administered by inhalation or other inlet method that brings it into contact with at least one region of the patient's respiratory tract. Without wishing to be bound by any theory, it is believed that the adrenergic β ₂ receptor agonist used may act to cause localized smooth muscle dilation that may dilate the bronchial passages. Non-limiting examples of adrenergic β ₂ receptor agonists that can be used in pharmaceutically acceptable fluids as disclosed herein include bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol , Procaterol, Litodrine, Salbutamol, Terbutaline, Albuterol, Arformoterol, Bambuterol, Clenbuterol, Formoterol, Salmeterol, Abediterol, Carmoterol, Indacaterol , olodaterol, vilanterol, isoxuprine, mabuterol, zilpaterol, and mixtures thereof.

In certain circumstances, it is contemplated that an adrenergic β ₂ receptor agonist may be administered in a composition in combination with a pharmaceutically acceptable fluid. It is also contemplated that an adrenergic β ₂ receptor agonist may be co-administered with a pharmaceutically acceptable fluid disclosed herein.

In certain embodiments, the pharmaceutically acceptable fluid is selected from the group consisting of compounds such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and combinations thereof. It may contain at least one steroid agent. In certain circumstances, it is contemplated that the steroid may be administered in a composition in combination with a pharmaceutically acceptable fluid. It is also contemplated that steroids may be co-administered with the pharmaceutically acceptable fluids disclosed herein.

In certain embodiments, the pharmaceutically acceptable fluid is selected from the group consisting of at least one inhalable non-steroidal drug such as a compound such as metabisulfite, adenosine, L-aspirin, indomethacin, and combinations thereof. may include being

In certain circumstances, it is contemplated that a nonsteroidal agent may be administered in a composition in combination with a pharmaceutically acceptable fluid. It is also contemplated that non-steroidal agents may be co-administered with the pharmaceutically acceptable fluids disclosed herein.

In certain embodiments, the muscarinic antagonist can be one or more compounds selected from the group consisting of atropine, scopolamine, glycopyrrolate and ipratropium bromide and others.

Methods as disclosed herein may be used as a stand-alone treatment regimen or may be used in combination with other treatment regimens suitable for addressing and treating certain respiratory infections. The methods may also be used alone or in combination with one or more procedures that may be used prophylactically to reduce or minimize the risk or symptoms to the subject following exposure but before the onset of symptoms. It is also contemplated that methods as disclosed herein may be used as a stand-alone treatment regimen for use in individuals at risk for complications or suboptimal outcomes from respiratory infections. Non-limiting examples of such individuals include those with compromised immune systems, impaired lung function, cardiac challenge, as well as those with comorbidities such as age, weight (obesity) and others.

Methods as disclosed herein may also include administering a composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof into contact with at least one area of a patient's respiratory tract. Administration of hypochlorous acid, hydrogen peroxide and mixtures thereof may occur prior to or concurrently with contacting at least one dose of the pharmaceutically acceptable fluid with at least one area of the patient's respiratory tract. In certain embodiments, it is contemplated that compositions comprising hypochlorous acid, hydrogen peroxide and mixtures thereof may be co-administered with pharmaceutically acceptable fluid materials such as those disclosed herein. If desired or necessary, compositions comprising hypochlorous acid, hydrogen peroxide, and mixtures thereof, such as dispersed, may be configured or sized to contact the same area of the respiratory tract or to contact different areas of the respiratory tract with the pharmaceutically acceptable fluid material.

In certain embodiments, a pharmaceutically acceptable fluid may include a compound prepared by a process comprising the steps of:

A composition resulting from a volume of concentrated mineral acid in liquid form having a molarity of at least 7, a density of 22° to 70° Baume and a specific gravity of 1.18 to 1.93 in a reaction vessel as at least one of a precipitate, a suspended solid, and a colloidal suspension. contacting an inorganic hydroxide present in a density sufficient to produce a solid material present in the; and

A step of removing a solid material from the resulting liquid material, wherein the resulting material is a viscous material having a molar concentration of 200 to 150 M.

Compositions prepared by methods such as those disclosed herein may be formed by addition of a suitable inorganic hydroxide to a suitable inorganic acid. Inorganic acids may have densities between 22° and 70° Baume; The specific gravity is about 1.18 to 1.93. In certain embodiments, the inorganic acid has a density between 50° and 67° Baume; A specific gravity of 1.53 to 1.85 is considered. Inorganic acids can be either monoatomic acids or polyatomic acids.

The inorganic acid used in the process described can be homogeneous or can be a mixture of various acid compounds falling within defined parameters. It is also contemplated that the acid may be a mixture comprising one or more acid compounds that fall outside the parameters considered, but which, in combination with other materials, provide an average acid composition value in a defined range. The inorganic acid or acids used may be of any suitable grade or purity. In some cases, technical grade materials and/or food grade materials can be successfully used in various fields.

In preparing the products herein, the inorganic acid may be contained in any suitable reaction vessel in liquid form in any suitable volume. In various embodiments, it is contemplated that the reaction vessel may be a non-reactive beaker of suitable volume. The volume of acid used may be as small as 50 ml. Larger volumes, including up to 5000 gallons or more, are also contemplated as being within the scope of this disclosure.

The inorganic acid used may be maintained in the reaction vessel at a suitable temperature, such as at or near ambient temperature. It is within the scope of the present disclosure to maintain the initial inorganic acid in the range of approximately 23° C. to about 70° C. However, lower temperatures in the range of 15° C. to about 40° C. may also be used.

Mineral acids are agitated by suitable means that impart mechanical energy in the range of approximately 0.5 HP to 3 HP, and agitation levels imparting mechanical energy in the range of 1 HP to 2.5 HP are used in certain process applications. Agitation may be imparted by a variety of suitable means including, but not limited to, DC servo drives, electric impellers, magnetic stirrers, chemical inductors, and others.

Agitation may begin at intervals immediately prior to hydroxide addition and may continue for intervals during at least part of the hydroxide introduction step.

In a process such as disclosed herein, the acid material of choice may be a concentrated acid having an average molar concentration (M) of at least 7 or greater. In certain procedures, the average molarity will be at least 10 or greater; An average molar concentration of 7 to 10 is useful in certain applications. The optional acid material used may be present as a pure liquid, liquid slurry or essentially as an aqueous solution of the dissolved acid in concentrated form.

Suitable acid materials may be either aqueous or non-aqueous materials. Non-limiting examples of suitable acid materials include hydrochloric acid, nitric acid, phosphoric acid, chloric acid, perchloric acid, chromic acid, sulfuric acid, permanganic acid, hydrobromic acid, hydrobromic acid, hydrofluoric acid, iodic acid, fluoroboric acid, fluorosilicic acid, fluorotitanic acid. may contain one or more.

In certain embodiments, the defined volume of liquid concentrated strong acid used may be sulfuric acid having a specific gravity between 55° and 67° Baume. This material may be placed in a reaction vessel and mechanically agitated at a temperature of 16° C. to 70° C.

In certain particular aspects of the disclosed method, a measured, defined quantity of a suitable hydroxide material may be added in measured, defined amounts to an agitating acid, such as concentrated sulfuric acid, present in a non-reactive vessel. The amount of hydroxide added will be sufficient to make the solid material present in the composition as a precipitate and/or suspended solid or colloidal suspension. The hydroxide material used may be a water soluble or partially water soluble inorganic hydroxide. Partially water-soluble hydroxides used in processes such as those disclosed herein will generally be those which exhibit miscibility with the acid material to which they are added. A non-limiting example of a suitable partially water soluble inorganic hydroxide would be one that exhibits at least 50% miscibility in the associated acid. Inorganic hydroxides can be anhydrous or hydrated.

Non-limiting examples of water-soluble inorganic hydroxides, alone or in combination with each other, include water-soluble alkali metal hydroxides, alkaline earth metal hydroxides and rare earth hydroxides. Other hydroxides are also considered to be within the scope of this disclosure. “Water solubility,” as defined with the hydroxide material for which the term is used, is defined as a material that exhibits 75% or greater solubility characteristics in water at standard temperature and standard pressure. A commonly used hydroxide is a liquid material that can be introduced as an acid material. The hydroxide may be introduced as a true solution, suspension or supersaturated slurry. In certain embodiments, it is contemplated that the concentration of the inorganic hydroxide in the aqueous solution may vary depending on the concentration of the associated acid into which it is incorporated. A non-limiting example of a suitable concentration for a hydroxide material is a hydroxide concentration of greater than 5% to 50% of a 5 mole material.

Suitable hydroxide materials include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, magnesium hydroxide and/or silver hydroxide. The inorganic hydroxide solution, when used, may have a concentration of inorganic hydroxide of 5% to 50% of the 5 moles of material, with concentrations of 5% to 20% being used in certain applications. The inorganic hydroxide material may be calcium hydroxide in a suitable aqueous solution for the given process, eg present as slaked lime.

In a process such as the one disclosed, an inorganic hydroxide in liquid or fluid form is introduced into the agitating acid material in one or more metered volumes over defined intervals to provide a defined resonance time. The resonance time in this process, as outlined, is believed to be the time interval necessary to promote and provide an environment in which hydronium ionic materials such as those disclosed herein occur. Resonance time intervals as used in processes such as those disclosed herein are typically 12 to 120 hours, and resonant time intervals of 24 to 72 hours and increments therein are used in certain applications.

In various parts of the process, inorganic hydroxide is introduced as an acid at the upper surface of the agitating volume in a plurality of metered volumes. Typically, the total amount of inorganic hydroxide material will be introduced as a plurality of measured portions over the resonant time interval. Front loaded metered additions are used in many cases. "Forward loaded metered addition", as the term is used herein, is taken to mean the addition of the total hydroxide volume, the larger portion being added during the initial portion of the resonance time. The initial percentage of the desired resonance time is considered to be between the initial 25% and 50% of the total resonance time.

It is to be understood that the proportion of each metered volume added may be the same or may vary based on such non-limiting factors as external process conditions, in situ process conditions, specific material characteristics, and others. It is contemplated that the number of metered volumes may be from 3 to 12. The interval between the addition of each metered volume can be from 5 minutes to 60 minutes in certain areas of the process such as those disclosed. The actual interval between additions may be 60 minutes to 5 hours in some applications.

In a given section of the process, a 100 ml volume of 5% weight per volume of calcium hydroxide material is added to 50 ml of 66° Baume concentrated sulfuric acid in five metered increments of 2 ml per minute with or without addition. Addition of the hydroxide material to the sulfuric acid results in a material with increasing liquid turbidity. Increasing liquid turbidity indicates calcium sulfate solids forming as a precipitate. The calcium sulfate produced can be removed in a controlled manner by continued hydroxide addition to provide a controlled concentration of suspended and dissolved solids.

Without wishing to be bound by any theory, it is believed that the addition of calcium hydroxide to sulfuric acid in the manner defined herein results in consumption of the initial hydrogen proton or protons associated with the sulfuric acid to produce hydrogen proton oxygenation such that the proton becomes a hydroxide. Upon addition, it is believed that there is no offgassing as would normally be expected. Instead, the proton or protons recombine with the ionic water molecular component present in the liquid material.

If desired or necessary, after a suitable resonant time as defined has elapsed, the resulting material is subjected to a nonpolar magnetic field with a value greater than 2000 Gauss; Magnetic fields greater than 2,000,000 Gauss are used in certain applications. It is contemplated that magnetic fields of 10,000 to 2,000,000 Gauss may be used in some situations. The magnetic field may be generated by a variety of suitable means. One non-limiting example of a suitable magnetic field generator can be found in US 7,122,269 to Wurzburger, the specification of which is incorporated herein by reference.

Solid material produced during the process and present as a precipitate or suspended solid may be removed by any suitable means. Such removal includes, but is not limited to, weighing, forced filtration, centrifugation, reverse osmosis, and others.

Materials made by processes such as those disclosed can exist as room temperature stable viscous liquids that are believed to be stable for at least one year when stored at ambient temperature and between 50% and 75% relative humidity. The stable electrolyte composition of materials can be used untreated in a variety of end-use applications. A stable electrolyte composition of materials may have 1.87 to 1.78 moles of material containing 8% to 9% total moles of uncharge balanced acid protons. In certain embodiments, the liquid material comprises between 4% and 9% total moles of charge balanced acid protons; 5% to 9% total moles of charge balanced acids; 6% to 9% total moles of charge balanced acids; 7% to 9% total moles of charge balanced acids; may contain between 8% and 9% total moles of charge balanced acids.

It is contemplated that the resulting material may be further purified as appropriate and used as a liquid material in a solution of pharmaceutically acceptable materials such as those disclosed herein. It is also within the scope of the present disclosure to subject the resulting material to further processing as desired or necessary. A non-limiting example of such processing may include subjecting the resulting fluid to a suitable magnetic field or magnetic fields.

In certain embodiments, the resulting liquid material may be subjected to a non-polar magnetic field with a value greater than 2000 Gauss; Magnetic fields greater than 2,000,000 Gauss are used in certain applications. It is contemplated that magnetic fields of 10,000 Gauss to 2,000,000 Gauss may be used in some situations. Other suitable ranges are 10,000 Gauss to 20,000 Gauss; 10,000 Gauss to 30,000 Gauss; 10,000 Gauss to 40,000 Gauss; 10,000 Gauss to 50,000 Gauss; 10,000 Gauss to 60,000 Gauss; 10,000 Gauss to 70,000 Gauss; 10,000 Gauss to 80,000 Gauss; 10,000 Gauss to 90,000 Gauss; 10,000 Gauss to 100,000 Gauss; 50,000 Gauss to 100,000 Gauss; 50,000 Gauss to 150,000 Gauss; 50,000 Gauss to 200,000 Gauss; 50,000 Gauss to 250,000 Gauss; 100,000 Gauss to 200,000 Gauss; 100,000 Gauss to 250,000 Gauss; 100,000 Gauss to 300,000 Gauss; 100,000 Gauss to 350,000 Gauss; 100,000 Gauss to 400,000 Gauss; 100,000 Gauss to 450,000 Gauss; 100,000 Gauss to 500,000 Gauss; 250,000 Gauss to 300,000 Gauss; 250,000 Gauss to 400,000 Gauss; 250,000 Gauss to 500,000 Gauss; 500,000 Gauss to 600,000 Gauss; 500,000 Gauss to 700,000 Gauss; 500,000 Gauss to 800,000 Gauss; 500,000 Gauss to 900,000 Gauss; 500,000 Gauss to 1,000,000 Gauss; 750,000 Gauss to 1,100,000 Gauss; 750,000 Gauss to 1,200,000 Gauss; 750,000 Gauss to 1,250,000 Gauss; 1,000,000 Gauss to 1,100,000 Gauss; 1,100,000 Gauss to 1,200,000 Gauss; 1,200,000 Gauss to 1,300,000 Gauss; 1,300,000 Gauss to 1,400,000 Gauss; 1,400,000 Gauss to 1,500,000 Gauss; 1,500,000 Gauss to 1,600,000 Gauss; 1,600,000 Gauss to 1,700,000 Gauss; 1,800,000 Gauss to 1,900,000 Gauss; 1,900,000 Gauss to 2,000,000 Gauss. The magnetic field may be generated by a variety of suitable means. One non-limiting example of a suitable magnetic field generator can be found in US 7,122,269 to Wurzburger, the specification of which is incorporated herein by reference.

The material produced by the process disclosed herein has a molar concentration of between 200 and 150 M as measured titratively via the hydrogen coulombic method and in some cases between 187 and 178 M as measured via FTIR spectral analysis. have The material has a weighing range greater than 1.15; The range is greater than 1.9 in some cases. The material, when analyzed, appears to produce less than 1300 volumetric multiples of orthohydrogen per square ml relative to the hydrogen contained in one mole of water.

Materials produced by this process may be introduced into water to prepare the compositions used herein. It is contemplated that the prepared use solution will contain from 0.5% to 10% by volume of the product prepared in certain embodiments. In certain embodiments, the therapeutic material is present in an amount of 0.5 to 8% by volume; 0.5 to 7% by volume; 0.5 to 6% by volume; 0.5 to 5% by volume; 0.5% by volume; 0.5 to 4% by volume; 0.5 to 3% by volume; 0.5 to 2% by volume; 0.5 to 1% by volume; 1 to 10% by volume; 1 to 8% by volume; 1 to 7% by volume; 1 to 6% by volume; 1 to 5% by volume; 1% by volume; 1 to 4% by volume; 1 to 3% by volume; 1 to 2% by volume; 2 to 10% by volume; 2 to 8% by volume; 2 to 7% by volume; 2 to 6% by volume; 2 to 5% by volume; 2 to 4% by volume; 2 to 3% by volume; 2 to 10% by volume; 2 to 8% by volume; 2 to 7% by volume; 2 to 6% by volume; 2 to 5% by volume; 2 to 4% by volume; 2 to 3% by volume.

Without wishing to be bound by any theory, it is believed that the processes disclosed herein may produce components having the general formula:

In the above formula, x is an odd integer of 3 or greater;

y is an integer from 1 to 20;

Z is either a monoatomic ion of groups 14 to 17 having a charge of -1 to -3 or a multiatomic ion having a charge of -1 to -3.

Monoatomic constituents that can be used as Z in components as disclosed herein include Group 17 halides such as fluorides, chlorides, iodides and bromides; Group 15 materials, such as nitrides and phostides, and Group 16 materials, such as oxides and sulfides. Polyatomic constituents are carbonate, hydrogen carbonate, chromate, nitride, nitrate, permanganate, phosphate, sulfate, sulfite, chlorite, perchlorate, hydrobromite, bromite, bromate, iodide, hydrogen sulfate , contains hydrogen sulfite. It is contemplated that the composition of materials may consist of a single material relative to the materials listed above, or may be a combination of one or more of the listed compounds.

In certain embodiments, it is also contemplated that x is an integer from 3 to 9, and in some embodiments x is an integer from 3 to 6.

In certain embodiments, y is an integer from 1 to 10; In another embodiment y is an integer from 1 to 5.

In certain embodiments, x is an odd integer from 3 to 12; y is an integer from 1 to 20; Z is either a monoatomic ion of groups 14 to 17 having a charge of -1 to -3 or a polyatomic ion having a charge of -1 to -3, as outlined above, some embodiments having a charge of 3 to 9 has x and y is an integer from 1 to 5;

Ionic complexes, such as those disclosed herein, are considered stable when present and can function as oxygen donors in the presence of the environment created to produce them. The material is generally stable and may have any suitable structure and solvation capable of functioning as an oxygen donor. Certain embodiments of the resulting solution will include concentrations of ions as shown by the equation:

In the formula, x is an odd integer of 3 or greater.

Ionic versions of compounds as disclosed herein are contemplated to exist as unique ionic complexes having more than 7 hydrogen atoms in each individual ionic complex, referred to herein as hydronium ion complexes. As used herein, the term "hydronium ion complex" is broadly can be defined as a cluster of molecules surrounding the cations of where x is an integer greater than or equal to 3. The hydronium ion complex may include a stoichiometric ratio of oxygen molecules complexed with at least four additional hydrogen molecules and water molecules. Thus, a formulaic representation of a non-limiting example of a hydronium ion complex that can be used in the process herein can be depicted by the formula:

In the above formula, x is an odd integer of 3 or greater;

y is an integer from 1 to 20, and in certain embodiments y is an integer from 3 to 9.

In various embodiments disclosed herein, it is contemplated that at least a portion of the hydronium ion complex exists as a solvated structure of hydronium ion having the formula:

In the above formula, x is an integer from 1 to 4;

y is an integer from 0 to 2;

In this structure, The core is protonated by a number of H ₂ O molecules. It is contemplated that a hydronium complex present in a composition of matter as disclosed herein may be present as an Eigen complex cation, a Zundel complex cation, or a mixture of the two. The Eigen solvation structure may have a hydronium ion in the center of the H ₉ O ₄ + structure, and the hydronium complex is strongly bound to three neighboring water molecules. A Jundel solvation complex can be a H ₅ O ₂ + complex in which a proton is shared equally by two water molecules. The solvation complex usually exists in equilibrium between an Eigen solvation structure and a Jundel solvation structure. Previously, each solvation structure complex generally existed in an equilibrium favoring the Jundel solvation structure.

The inclusion of materials made by processes such as those outlined is based, at least in part, on the unexpected discovery that stable materials can be made in which hydronium ions exist in an equilibrium favoring the eigen complex. The present disclosure is also predicated on the unexpected discovery that increasing the concentration of eigen complexes in a process stream can provide a class of new and improved oxygen-donor oxonium materials.

A process stream as disclosed herein may have an Eigen solvation state to Jundel solvation state ratio of from 1.2 to 1 to 15 to 1 in certain embodiments; The ratio is from 1.2 to 1 to 5 to 1 in other embodiments.

The novel and improved oxygen-donor oxonium materials, such as those disclosed herein, can generally be described as thermodynamically stable aqueous acid solutions buffered with an excess of proton ions. In certain embodiments, the excess of proton ions can be an amount of 10% to 50% excess of hydrogen ions, as measured by free hydrogen content.

In certain embodiments, the composition of the material may have the following chemical structure:

In the above formula, x is an odd integer from 3 to 11;

y is an integer from 1 to 10;

Z is a polyatomic ion or a monoatomic ion.

Polyatomic ions can be derived from ions derived from acids that have the ability to donate more than one proton. The associated acid may have a pK _a value of 1.7 or greater at 23°C. The ion used may have a charge of +2 or greater. Non-limiting examples of such ions include sulfate, carbonate, phosphate, oxalate, chromate, dichromate, pyrophosphate, and mixtures thereof. In certain embodiments, it is contemplated that the polyatomic ion may be derived from a mixture comprising a polyatomic ion mixture comprising an ion derived from an acid having a pK _a value of 1.7 or less.

In certain embodiments, the composition of the material is hydrogen(1+), triaqua-μ3-oxotri sulfate (1:1) in admixture with water; hydrogen(1+), triaqua-μ3-oxotricarbonate (1:1), hydrogen(1+), triaqua-μ3-oxotriphosphate, (1:1); hydrogen(1+), triaqua-μ3-oxotrioxalate (1:1); Hydrogen(1+), Triaqua-μ3-oxotrichromate (1:1) Hydrogen(1+), Triaqua-μ3-oxotridichromate(1:1), Hydrogen(1+), Tri and a stoichiometrically balanced chemical composition of at least one of aqua-μ3-oxotripyrophosphate (1:1) and mixtures thereof.

The pharmaceutically acceptable fluid material may be atomized, aerosolized, or formulated into particulates to facilitate administration, if desired or necessary. Administration of fluid materials can be accomplished by direct application as swabs, sprays, washes, emulsions and others. It is also contemplated that aerosolized or nebulized materials may be administered by inhalation if desired or necessary.

When the various materials that make up the pharmaceutically acceptable fluid are aerosolized or nebulized, the pharmaceutically acceptable fluid material(s) can be processed into droplets of a size suitable for inhalation ingestion. Non-limiting examples of suitable droplet sizes are 0.1 to 20 μm; 0.1 to 18 μm; 0.1 to 17 μm; 0.1 to 16 μm; 0.1 to 15 μm; 0.1 to 14 μm; 0.1 to 13 μm; 0.1 to 12 μm; 0.1 to 12 μm; 0.1 to 11 μm; 0.1 to 10 μm; 0.1 to 9 μm; 0.1 to 8 μm; 0.1 to 7 μm; 0.1 to 6 μm; 0.1 to 5 μm; 0.1 to 4 μm; 0.1 to 3 μm; 0.1 to 2 μm; 0.1 to 1 μm; 0.1 to 0.5 μm; 0.5 to 20 μm; 0.5 to 18 μm; 0.5 to 17 μm; 0.5 to 16 μm; 0.5 to 15 μm; 0.5 to 14 μm; 0.5 to 13 μm; 0.5 to 12 μm; 0.5 to 12 μm; 0.5 to 11 μm; 0.5 to 10 μm; 0.5 to 9 μm; 0.5 to 8 μm; 0.5 to 7 μm; 0.5 to 6 μm; 0.5 to 5 μm; 0.5 to 4 μm; 0.5 to 3 μm; 0.5 to 2 μm; 0.5 to 1 μm; 1 to 20 μm; 1 to 18 μm; 1 to 17 μm; 1 to 16 μm; 1 to 15 μm; 1 to 14 μm; 1 to 13 μm; 1 to 12 μm; 1 to 11 μm; 1 to 10 μm; 1 to 9 μm; 1 to 8 μm; 1 to 7 μm; 1 to 6 μm; 1 to 5 μm; 1 to 4 μm; 1 to 3 μm; 1 to 2 μm; 2 to 20 μm; 2 to 18 μm; 2 to 17 μm; 2 to 16 μm; 2 to 15 μm; 2 to 14 μm; 2 to 13 μm; 2 to 12 μm; 2 to 11 μm; 2 to 10 μm; 2 to 9 μm; 2 to 8 μm; 2 to 7 μm; 2 to 6 μm; 2 to 5 μm; 2 to 4 μm; It contains droplets having a size of 2 to 3 μm.

The acid compound(s) used may be selected based on the pharmacokinetics and/or pharmacodynamics of the acid compound(s), if desired or necessary. Certain embodiments of the low pH antibacterial inhalant comprising a pharmaceutically acceptable fluid material may include a dilute sulfuric acid formulation due to its favorable pharmacokinetics and pharmacodynamics. It is believed that the sulfate material undergoes a redox reaction to produce protons (H+) that are absorbed by the mucous membranes, while the sulfate anions will be biodistributed non-specifically to surrounding tissues for immediate clearance. The distribution of negative ions to the body's electrolyte pool is considered negligible provided the exposure is not excessive. Without wishing to be bound by any theory, it is believed that the effect of sulfuric acid is the result of H+ ions (local deposition of H+, pH change) rather than the effect of sulfate ions. Sulfuric acid is not particularly expected to be absorbed or distributed throughout the body. The acid will dissociate quickly and the anion will enter the body electrolyte pool and will not play a specific toxicological role. (See OECD SIDS Sulfuric Acid, 2001, UNEP Publications, p102). As a result, little or no systemic effect is expected from a dilute inhaled sulfuric acid aerosol, and the only effect will be local to the surface of the respiratory system.

The local effect of the emitted protons can inactivate viruses and other pathogens that target the mucosal lining of the lung epithelium and endothelium. A therapeutic concentration of dilute sulfuric acid (about 1.7 pH) provides efficacy in inactivating and/or reducing the concentration of human coronavirus within 1 minute based on an in vitro suspension test.

At the suggested exposure concentrations, the proton levels produced were not toxic to human cells and the pulmonary vasculature, presumably due to the highly buffered tissue microenvironment robust to these short-term changes in interspace pH. This was shown by acute tissue toxicity and cytotoxicity studies conducted within Good Laboratory Practice (GLP) guidelines.

Inhaled inorganic acids such as sulfuric acid at the concentrations contemplated by this disclosure rapidly dissociate within the proximal lung structures and absorb sulfate ions into the bloodstream. Dahl studied uptake of ³⁵ S radiolabeled sulfate in rats, guinea pigs and dogs and found that rat and guinea pig animal models have very similar PK/PD parameters with ³⁵ S half-lives of 170 and 230 seconds. . The half-life of ³⁵ S radiolabeled sulfuric acid in canine studies varied considerably with the specific respiratory site of administration. Deep lung sulfate administration showed a half-life of 2 to 3 minutes similar to rats and guinea pigs. The half-life was significantly longer for administration to the upper regions within the bronchi and sinuses. (See Dahl, Clearance of Sulfuric Acid-Introduced ³⁵ S from the Respiratory Tracks of Rats, Guinea Pigs and Dogs Following Inhalation or Instillation, Fundamental and Applied Toxicology 3:293-297 (1983)).

Therapeutic inhalants demonstrate antiviral therapeutic potential in peripheral lung tissue with a half-life of about 2 to 3 minutes until absorption. Although sulfuric acid neutralization cannot be measured directly within the respiratory system, previous in vitro studies predict inhibition of viral, bacterial and fungal replication within 1 minute.

A kit for use in the treatment or prevention of respiratory illness comprising at least one container for administering a pharmaceutically acceptable fluid to the respiratory tract of a patient in need thereof, connectable to a respiratory delivery device having at least one chamber. are also disclosed herein. At least one chamber contains at least one volume of a pharmaceutically acceptable fluid as disclosed herein. The pharmaceutically acceptable fluid comprises a liquid carrier and at least one acid compound, wherein the pharmaceutically acceptable fluid has a pH less than 3.0 and is a container for administering the pharmaceutically acceptable fluid to the respiratory tract of a patient in need thereof. have

The kit may also include means for administering the pharmaceutically acceptable fluid to at least a portion of the respiratory tract of a patient in need thereof. Non-limiting examples of suitable means for administering pharmaceutically acceptable fluids to at least part of the respiratory tract of a patient in need thereof may include devices such as inhalers, metered dose inhalers, nebulizers such as PARI nebulizers and the like. can The means for administration may include at least one mechanism for delivering the fluid in a vaporized, atomized or nebulized state. "Nebulizer", as that term is used herein, is a drug delivery used to administer a drug in a form that can be inhaled into the lungs using oxygen, compressed air, ultrasonic power, or the like to break the solution into small aerosol droplets. It is a device. Non-limiting examples of nebulizers that may be used to dispense pharmaceutically acceptable fluids such as those disclosed herein may be jet nebulizers, soft mist inhalers, ultrasonic nebulizers, or the like. The PARI nebulizer is a commercially available PARI Respiratory Equipment, Inc. (Midlothian, Va.).

The kit may also include a suitable mask or oral insert for directing materials into the mouth and/or nasal cavity of a patient.

Also disclosed herein is a respiratory inhalant device comprising a reservoir having at least one internal chamber and a dispenser in fluid communication with the reservoir. The container contains a pharmaceutically acceptable fluid as disclosed herein contained in at least one interior chamber.

The respiratory inhalant device also includes a dispenser in fluid communication with the reservoir configured to dispense a metered portion of a pharmaceutically acceptable fluid from the reservoir into respirable contact with at least a portion of the respiratory tract of a patient with a respiratory illness. The pharmaceutically acceptable fluid is dispensed in droplet sizes with mean mass diameters of 0.5 to 5.0 microns. In certain embodiments, the dispenser may include suitable tubing and outlet members. The outlet member may be configured as a mask that can be removably mounted on the patient or, in certain embodiments, as a pipe-like member that can be removably inserted into the patient's mouth. Other delivery members may include nasal cannulas or the like.

The respiratory disease can be at least one of a viral pathogen, a bacterial pathogen, a fungal pathogen, such as a viral pathogen, such as one of a coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinovirus. In certain embodiments, the viral pathogen may be a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and mixtures thereof.

To further illustrate the present disclosure, the following examples are presented. The examples are for illustrative purposes and should not be construed as limiting the present disclosure.

Example 1

Safety Evaluation of Various Ingredients for Use in Antibacterial Inhaled Therapy

Antibacterial respiratory inhalants composed of pharmaceutically acceptable fluids according to the present disclosure were prepared by mixing a pharmaceutically acceptable grade of sulfuric acid with water to provide a pH at various values indicated in the examples as described below.

1. Objective : To test a low pH antibacterial respiratory inhalant using a pharmaceutically acceptable fluid formulation of dilute sulfuric acid and low concentrations of calcium for in vivo safety using acute toxicity studies in animals and later in humans. An in vitro cytotoxicity test was also performed.

An in vitro suspension test using dilute sulfuric acid against human coronavirus was used to assist in determining the minimum concentration needed to demonstrate in vitro efficacy at 1 minute. The 1 minute suspension test is believed to be the most representative in vitro test to simulate in vivo efficacy based on previously described pharmacokinetics. The 1 log or 90% efficacy goal was chosen by consideration of effective concentrations and patient recovery while minimizing potential patient risk. In one contemplated method of administration, such as those described in this disclosure, the material is administered to a patient in need thereof by inhalation with a nebulizer. Using an inhalation method, such as nebulizer administration, a patient can receive a pharmaceutically acceptable dosage as disclosed herein continuously, potentially over multiple days, potentially multiple times per day, or in a series of discrete dosing intervals at a particular concentration for several minutes. It is contemplated to inhale a therapeutic substance comprising an acceptable fluid. As a result, any in vitro pathogen load reduction can be compounded in vivo to achieve higher efficacy over the treatment period. Thus, it is believed that efficacy in vitro as demonstrated in the tests described herein below 1 log may provide acceptable efficacy in vivo when administered as outlined herein.

Sulfuric acid at 1.61 pH was shown to demonstrate 0.75 log (82.11%) in vitro suspension efficacy in 1 minute. A slightly weaker and more conservative 1.72 pH (0.12%) sulfuric acid formulation was chosen to reduce viral load and aid patient recovery from COVID-19.

2. Acute Toxicity In Vivo: GLP (Good Laboratory Practices) reported that acute toxicity studies were conducted with formulations of sulfuric acid solutions that were 50 times more concentrated than inhaled therapeutics prepared according to the present disclosure. The study included acute inhalation toxicity, acute oral toxicity, acute dermal toxicity, skin sensitivity, eye sensitivity and Local Lymph Node Assay (LLNA).

All six acute toxicity studies showed little or no toxicity with the 50X concentration version of the therapeutic inhalation formulation. As this is a respiratory inhalant, acute inhalation toxicity studies are particularly important. This study with 5 male and 5 female rats showed irregular breathing after dosing, but all 10 rats recovered. Results are summarized in Table 1.

A 50-fold concentration formulation with 5.2% sulfuric acid exhibits no acute inhalation toxicity, while a more dilute concentration of 0.12% exhibits in vitro efficacy against human coronaviruses such that this material is a non-limiting example of beta coronaviruses such as It has been shown to exhibit efficacy against respiratory infections caused by human coronaviruses, including SARS-CoV-2, which has encouraged further investigation of its use as a potential antibacterial respiratory inhalant and human-first clinical trials.

3. In vitro cytotoxicity: A GLP Cytotoxic Assay was performed according to ISO 10993-5 on the L929 mouse cell line using 4 different concentrations and the results are summarized in Table 2. All four concentrations, including those at 250% of the therapeutic concentration, showed no signs of biological reactivity grade 0 -- no detectable zone around or under the specimen.

Examples 2 to 17

To evaluate the antibacterial efficacy of various acid compounds and combinations, several potential pharmaceutically acceptable fluid formulations within the scope of this disclosure were evaluated to determine their antibacterial efficacy against common viral, bacterial and fungal pathogens. All of these studies were conducted by an ISO 17025 Accredited and GLP Compliant Laboratory. This in vitro test followed the ASTM (American Society of Testing and Materials) standard suspension test for antibacterial efficacy. All tests were performed with 1 min contact time based on previously described pharmacokinetics.

Efficacy of various proposed antibacterial inhaled therapeutics against antibiotic-resistant microorganisms

Objective : The first set of in vitro efficacy tests were antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa performed on bacteria. These two antibiotic resistant bacterial strains were initially selected as these pathogens represent two broad classes of bacteria. S. aureus is gram-positive, p. Aeruginosa is Gram-negative. Antibiotic-resistant strains of each pathogen are considered to be some of the most lethal respiratory bacterial strains with limited treatment options.

Results: The results of this test are listed in Table 3.

The pH measurements as received were of the test material as received by the testing laboratory. The ASTM antibacterial test procedure mixes 9 parts test material with 1 part pathogen-containing medium. The pH as applied is the pH after mixing that is exhibited by the pathogen. After a test period, which is 1 minute for this test, the test material is neutralized and the pathogens are counted and compared to the control.

Conclusions: None of the formulations at 1.9 or 3.1 pH were S. against the 1 log reduction target adopted for this evaluation . Aureus did not demonstrate a notable effect. All formulations at a pH of 1.9 are antibiotic-resistant blood. Although effective against aeruginosa, none of the 3.1 pH formulations demonstrated efficacy at defined target levels.

To study the antibacterial effect of known APIs when formulated into compositions such as those disclosed herein, samples of test compositions were formulated with albuterol, an established respiratory API at a standard therapeutic concentration of 0.0063 M albuterol. The results are summarized in Table 3 and indicate that the established APIs do not significantly affect the antimicrobial efficacy of the composition.

Example 18

Efficacy of Reformulated Albuterol Inhaled Therapy Against Antibiotic Resistant Microorganisms

Purpose: This comparative example describes the feasibility of reformulating one of the world's most common respiratory inhalants, albuterol sulfate, to provide new antibacterial properties. Albuterol is usually formulated with sulfuric acid as an adduct to improve the stability and shelf life of the active albuterol ingredient. Albuterol sulfate has been used for decades without detrimental effects, including regularly by asthmatics, a group of patients with greater sensitivity to respiratory irritants. The pH of albuterol is usually 3.5.

The composition consisted of an albuterol formulation with sulfuric acid at a tested pH of 3.1 that closely matched commercial albuterol sulfate formulations at the lower end of the pH range by this well-established treatment.

Results: Albuterol sulfate administered as available is not recognized to have any antibacterial properties. The albuterol sulfate test performed showed that albuterol sulfate at its lowest therapeutically acceptable pH of 3.1 was S. as determined by a 1 log pathogen count reduction per minute. aureus or blood. This confirms that efficacy against aeruginosa bacteria has not been demonstrated.

The test also demonstrates that by increasing the concentration of sulfuric acid in the albuterol sulfate treatment, a new antibacterial potency is achieved against antibiotic resistant strains of Pseudomonas aeruginosa, as outlined in Examples 16 and 17.

Conclusions: Multidrug-resistant Pseudomonas aeruginosa has one of the higher mortality rates of any respiratory bacterial infection, especially in patients with chronic respiratory diseases such as cystic fibrosis and chronic obstructive pulmonary disease. This trial demonstrates that the widely used albuterol sulfate treatment can function as a potential treatment for this pathogen when re-formulated with additional sulfuric acid and may have particular utility for populations with pre-existing chronic respiratory disease. do.

Examples 19 to 46

Efficacy of various acid antibacterial inhaled therapies against Streptococcus pneumoniae

Purpose: Streptococcus pneumoniae is a major cause of bacterial pneumonia, meningitis and sepsis, and is estimated to cause approximately 335,000 (240,000 to 460,000) deaths in children under 5 years of age in 2015 worldwide. S. Due to the morbidity and mortality of pneumonia, a wide range of acid preparations have been tested against this common pathogen to determine which variables may affect efficacy. The purpose of the tests performed was to use various acid formulations to prevent S. The goal was to determine what pH would be needed to achieve 1 log (90%) efficacy in 1 minute against pneumoniae.

Results: The results of this test are listed in Tables 4 and 5.

Conclusions: Respiratory APIs such as bronchodilators, steroids and non-steroidal anti-inflammatory drugs did not significantly alter efficacy. This suggests that new formulations of these established APIs can be prepared that provide new antibacterial properties, especially for patient populations that may be susceptible to these pathogens.

Several inorganic acids were tested to determine the effective pH to meet the 1 log potency target. A pH value of 1.91 for sulfuric acid (Example 24) was found to meet this goal. Similarly, a pH value of 1.90 for hydrobromic acid (Example 36); A pH value of approximately 1.87 for hydrochloric acid (Example 35) and a pH value of approximately 1.85 for polyphosphoric acid (Example 41) achieved this goal.

Stronger organic acids, including benzenesulfonic acid, trichloroacetic acid, hydroxyacetic acid, monochloroacetic acid and trifluoroacetic acid, show higher efficacy than inorganic acids in the range of 1.9 pH (Examples 39 and 42- Example 44).

Weaker organic acids, when used alone, generally cannot reach the required pH range of less than 2.0 for efficacy. However, this weaker organic acid can be mixed with an inorganic acid to meet a desired pH range of less than 2.0, and this mixed acid solution of a weak organic acid and an inorganic acid has better efficacy than an inorganic acid alone at the same pH level. can indicate

Amino acids are pharmaceutically acceptable weak organic acids, and may be formulated with stronger inorganic acids to provide improved potency. At least two acidic amino acids are aspartic acid and glutamic acid. Formulations of aspartic or glutamic acid and hydrochloric acid at 1.98 pH show 0.62 to 0.66 log efficacy, while hydrochloric acid at the same pH level shows little efficacy (Example 45, Example 42 and Example 31). Addition of aspartic acid or glutamic acid to inorganic acids such as sulfuric acid, hydrochloric acid and hydrobromic acid may provide better efficacy in higher pH formulations with less detrimental effects.

Comparative Example 1 - Acetic Acid

Acetic acid inhalation has been limited as a potential adjunctive treatment for mild COVID-19. (See L. Pianta, Acetic acid disinfection as a potential adjunctive therapy for non-severe COVID-19, European Archives of Oto-Rhino-Laryngology, May 2020). The results of efficacy and tolerability studies are described to determine whether acetic acid is used as an acidic antibacterial inhalant treatment. The study indicates that acetic acid demonstrates efficacy as a disinfectant against hard surfaces against the SARS-CoV-2 virus with a 4 log potency in 1 minute using a 4% concentration at a pH of 2.68. (See J. Yoshimoto, Virucidal effect of acetic acid and vinegar on SARS-CoV-2).

In the Pianta study, 29 patients inhaled 0.35% acetic acid as adjuvant treatment with hydroxychloroquine. Inhalation was delivered by placing the patient's face over the steaming acid solution and covering the head and bowl with a cloth. Steam mist aerosol size and concentration were not controlled. A 0.35% acetic acid concentration was measured to have a pH of approximately 2.98. An acetic acid concentration of 0.35% above 3.0 pH will not have any antibacterial benefit.

An acetic acid inhalation tolerance study was conducted with 5 male and 5 female healthy volunteers. Nasal discomfort, burning, irritated or runny nose were noted at levels as low as 10 ppm (0.001%) with a 118 minute exposure. (See L. Ernstgard, Acute effects of exposure to vapors of acetic acid human, Toxicology Letters 165 (2006) 22-30).

Conclusion: Disinfectant efficacy studies, therapeutic inhalation studies and inhalation tolerance studies all used different concentrations of acetic acid with different pH values as summarized in Table 6.

The 0.35% acetic acid concentration was measured to have a pH of approximately 2.98, and the 0.01% concentration was measured to have a pH of 3.77.

A high concentration of acetic acid with a pH at 2.68 can be an effective disinfectant to inactivate the SARS-CoV-2 virus. At very low concentrations, with a pH of 3.77, acetic acid presents a patient irritation problem. At the 2.98 pH concentration acetic acid used in the antibacterial treatment study it will not have any antibacterial benefit. Additionally, if acetic acid at this concentration is applied continuously with significant mist density (weighed concentration) it is expected to cause patient irritation.

The material should not cause patient tolerance problems at therapeutic concentrations to be an effective acidic antibacterial agent. Acetic acid does not pass patient tolerance criteria.

Although many factors can affect patient tolerability, various pharmaceutically acceptable acids with poor patient tolerance profiles, such as organic acids such as acetic acid, are used in pharmaceutically acceptable fluids or compositions that are more tolerable to the patient to whom they are administered or It is believed that it may be used in combination with one or more acids or adjuvants having a more acceptable profile to provide this.

Examples 47 to 58

Efficacy against common bacterial and fungal respiratory pathogens

Objective: The purpose of this study was to determine whether effective sulfuric acid is effective against a range of common gram-negative bacterial and fungal respiratory pathogens. Avoid sulfuric acid. Aeruginosa and S. pneumoniae, it is desirable to understand how effectively it can fight other respiratory pathogens and what concentration (pH) is required to achieve a 1 log per minute potency. Three different bacteria and three fungi representing a wide variety of respiratory pathogens were selected.

Results: Results are summarized in Table 7.

Conclusion: It is noted that 1.99 pH sulfuric acid is highly effective against both Klebsiella pneumoniae and Haemophilus influenzae. In a previous study, 1.9 pH sulfate ES. pneumoniae and antibiotic resistant blood. It has been proven effective against aeruginosa. These four bacteria are sometimes considered to be the most common Gram-negative bacterial respiratory pathogens. This supports the conclusion that preparations of sulfuric acid at a pH of 1.9 or less are effective against all gram-negative respiratory bacteria, both antibiotic sensitive and antibiotic resistant.

The sulfuric acid formulation outlined above demonstrates limited efficacy (0.12 log/25%) against M. terrae used as a surrogate against M. tuberculosis.

The 1.9 pH sulfuric acid formulation is effective against Aspergillus fumigatus and Rhizopus microsporus, demonstrating efficacy against some types of fungi. egg. It is also noted that Microsporus is the spore that produces fungi, and this result seems to support the conclusion of efficacy in killing fungal spores as well as active forms of fungi.

Example 59

Efficacy of combined sulfuric acid and aspartic acid inhaled therapy against Mycobacterium terrae

Purpose: Mycobacterium terrae is recognized as a surrogate for Mycobacterium tuberculosis, one of the world's most lethal pathogens. In 2015 M. Tuberculosis kills 1.4 million people, making it the world's largest single cause of death from an infectious agent (prior to COVID-19). More than 10 million new cases of tuberculosis are diagnosed each year with an increasing percentage having multidrug-resistant infections. (See Forum of International Respiratory Societies. The Global Impact of Respiratory Disease - Second Edition. Sheffield, European Respiratory Society, 2017)

Results: The 1.99 pH sulfuric acid formulation was M. Moderate efficacy (0.12 log 24.56%) for Terrae was demonstrated. Even with moderate in vitro efficacy, this agent may have therapeutic efficacy due to the compounding efficacy from sustained administration. This can be beneficial for tuberculosis patients and especially those suffering from antibiotic resistant strains.

Concentrated sulfuric acid formulations with a pH of 1.6 with or without added aspartic acid produced M. Demonstrate 1 log efficacy against Terrae.

Conclusions: Acidic antibacterial inhalation therapy is a promising new therapeutic approach for tuberculosis of global interest. Sulfuric acid formulations with a pH of 1.6 with or without aspartic acid appear promising and can be used alone or as adjuvant treatment with established antibiotics. The sulfuric acid formulation is M M. It is expected to be equally effective against antibiotic sensitive and antibiotic resistant strains of tuberculosis.

Unlike antibiotic treatments known to have significant side effects in some patients with tuberculosis, acidic antibacterial inhalant treatments such as those disclosed herein may have minimal or no side effects and may be easy to administer to a large patient population.

Examples 60 to 67

Efficacy of inorganic acid antibacterial inhalant therapy against human coronavirus

Purpose: COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. The purpose of this study was to determine the potency of several inorganic acids against human coronavirus and to determine the pH required to achieve 1 log potency per minute.

SARS-CoV-2 is a beta coronavirus. Alpha coronavirus was used in this study as it is the closest virus available in testing laboratories. Alpha coronavirus is considered representative of efficacy against SARS-CoV-2 for the purposes of this investigation.

Results: The test results of this study are listed in Table 8.

The viral medium used was EMEM (Eagle Minimum Essential Medium) which had a greater effect in increasing the pH between pH as measured and pH as applied than that exhibited by the bacterial medium. Due to the larger increase in pH, none of the acids achieved the 1 log potency target.

EMEM contains live MRC-5 cells with significant buffering capacity. The lower pH sulfuric acid formulation used to replicate the efficacy test against human coronavirus demonstrates 1 log efficacy.

CONCLUSIONS: The lower as-received pH determined that further virus testing was necessary.

Examples 68 to 79

Efficacy of sulfuric acid antibacterial inhalant therapy against selected respiratory viruses

Purpose : An antibacterial inhalant concentration of sulfuric acid was tested for efficacy against human coronavirus, alpha influenza virus and rhinovirus to determine how effective this material is as a therapeutic inhalant.

Results: The results of this study are listed in Table 9.

Conclusions : Sulfuric acid formulation with 1.62 pH demonstrates 0.75 log or 82.11% efficacy at 1 minute, nearly meeting the 1 log efficacy target against human coronavirus pathogens, similar efficacy predicted against SARS-CoV-2 coronavirus do. As previously described due to sustained inhalation of nebulizer treatment, treatment efficacy over the treatment period is compounded from in vitro efficacy results.

The lower 1.72 pH sulfuric acid formulation was selected for human first clinical trials to further reduce patient risk.

The 1.60 sulfate formulation demonstrated greater than 4 log efficacy against alpha influenza virus. Influenza A is the cause of seasonal flu, and efficacy against this virus may indicate efficacy against this serious pathogen.

The 1.66 and 1.90 pH sulfuric acid formulations demonstrated greater than 2 log efficacy against rhinovirus. Rhinovirus is the most common viral infectious agent in humans and is a major cause of the common cold. Efficacy against this virus may indicate efficacy against this common pathogen.

Coronaviruses, influenza viruses and rhinoviruses are all enclosed respiratory viruses. This test demonstrates efficacy against all common encapsulated respiratory viruses tested using sulfuric acid formulations below a pH of 1.6. Based on these results it can be assumed that this formulation will be effective against all encapsulated respiratory viruses in an inhalation environment.

Example 74

To test the efficacy of a pharmaceutically acceptable fluid composition containing a product prepared according to the process outlined in paragraphs 0069 to 0108 as disclosed herein, a 98% mole ratio H ₂ SO ₄ , 7 in a non-reactive vessel Place 50 ml portions of concentrated liquid sulfuric acid having an average molarity (M) in excess and specific gravity of 66° Baume and heat them at 25° C. by agitation on a magnetic stirrer to impart a mechanical energy of 1 HP to the liquid. The material is prepared by holding each of

When agitation is started, a measured amount of calcium hydroxide is added to the top surface of each portion of the agitating acid material. The calcium hydroxide used is a 20% aqueous solution of 5 M calcium hydroxide and is introduced in 5 measured volumes introduced at a rate of 2 ml per minute over an interval of 5 hours to give a resonance time of 24 hours. The introduction interval for each metered volume is 30 minutes.

Turbidity is produced by the addition of calcium hydroxide to sulfuric acid indicating the formation of calcium sulfate solids. Solids are allowed to precipitate periodically during the process and the precipitate is removed from contact with the reacting solution.

Upon completion of the 24 hour resonance time, the resulting product is exposed to a nonpolar magnetic field of 2400 Gauss to produce an observable precipitate and suspended solids over an interval of 2 hours. The resulting material is centrifuged and force filtered to isolate precipitates and suspended solids.

Collect samples for future use. The test sample was subjected to FTIR spectral analysis and titrated by the hydrogen Coulomb method. The sample material has a molar concentration ranging from 200 to 150 M concentration and from 187 to 178 M concentration. The material has a weighing range greater than 1.15; The range is greater than 1.9 in some cases. The composition is stable and has a 1.87 to 1.78 molar material containing 8% to 9% total moles of uncharge balanced acid protons. FTIR analysis indicates that the material has the formula hydrogen(1+), triaqua-μ3-oxotrisulphate (1:1).

Each sample is diluted to yield 5% product by volume in water and is found to be storage stable for at least 12 to 18 months. The excess hydrogen ion concentration is measured to be greater than 15%, and the pH of the material is determined to be 1.

5% by volume of the material is diluted with distilled deionized water at a ratio of 4 parts water to 1 part material and packaged in 2 oz/60 ml glass bottles with droppers.

Aliquots of each material sample of 4 ml are introduced into each PARI nebulizer set to produce a particle size of 2.5 μm that can be administered to each subject via inhalation as a suitable nebulizer mask for 10 minute dosing intervals. A subset of subjects to whom the material is administered self-report nasal congestion or congestion in the lungs of an acute nature but of unknown origin.

All subjects are tolerant of inhalation of the material. Additional material is administered to subjects reporting nasal congestion or congestion in the lungs at intervals of 10 minutes over a 72-hour period, with no more than 4 administrations occurring on each 24-hour day. Approximately two-thirds of subjects report a marked reduction in congestion after the initial 24 hour interval, and resolution of bleeding symptoms occurs in some subjects after 72 hours.

Example 75

100 subjects presenting with a variety of respiratory symptoms, including acute respiratory distress syndrome (ARDS), with confirmed cases of COVID 19 as confirmed by PCR testing, 4 times daily for 7 days each (10 minutes treatment each) 3 hours Receive a 2 ml dose via nebulizer every 4 to 4 hours. To evaluate the efficacy of materials as disclosed herein, subjects were randomized (67 subjects) into Arm A receiving the composition of Example 76, while 33 conditionally and age-matched subjects received a placebo in normal saline solution. will receive Treatment will begin immediately after confirmation of COVID 19, for 14 days after treatment, at weeks 3 and 4 after completion of treatment, and with follow-up visits at 3 months after treatment.

Subjects treated with the composition of Example 74 are evaluated on day 7, and at least 50% of subjects do not show respiratory symptoms and are negative for COVID-19. On day 14, these subjects are test negative for COVID-19 based on standard PCR tests.

Example 76

A second embodiment of the liquid material described in Example 74 as disclosed herein is a non-reactive container having a molar fraction H ₂ SO ₄ of 98%, an average molar concentration (M) greater than 7 and a specific gravity of 66° Baume. Prepare by introducing 50 ml units of concentrated liquid sulfuric acid and holding each at 25° C. by agitation for a magnetic stirrer to impart a mechanical energy of 1 HP to each liquid unit.

When agitation is initiated, a measured portion of sodium hydroxide is added to the upper surface of the agitating acid material of each liquid unit. The sodium hydroxide used is a 20% aqueous solution of 5 M calcium hydroxide and is introduced in 5 measured volumes introduced at a rate of 2 ml per minute over an interval of 5 hours to give a resonance time of 24 hours. The introduction interval for each metered volume is 30 minutes.

Turbidity is produced by the addition of calcium hydroxide to sulfuric acid indicating the formation of calcium sulfate solids. The solids in each unit are allowed to settle periodically during the process and the precipitate is removed from contact with the reacting solution.

Upon completion of the 24 hour resonance time, the resulting material is centrifuged and force filtered to isolate precipitates and suspended solids from the liquid material, and each unit of resulting material is collected for further use and analysis.

A 5 ml portion of the material prepared according to this method outlined is mixed in a 5 ml portion of deionized and distilled water at standard temperature and pressure. The excess hydrogen ion concentration is measured to be greater than 15% by volume, and the pH of the material is determined to be 1.

To further evaluate the materials produced by this method, samples of the materials are diluted with deionized water to provide materials containing 1% by volume of each material in water. These samples are evaluated for a diluted sulfuric acid solution, a dilute sulfuric acid solution with added calcium sulfate to create 300 ppm, and a dilute sulfuric acid component with 400 ppm calcium sulfate, as well as a reverse osmosis control.

All samples are diluted in nitric acid matrix for analysis. Testing is completed using a Thermo iCAP 6300 Duo ICP-OES for calcium and sulfur content according to EPA method 200.7.

Each test material is initially prepared by simple dilution in a 5% nitric acid matrix. Prepare calibration standards in the same acid matrix to match samples. However, this preparation leads to a high recovery for calcium, which is believed to be a result of sulfuric acid present in the sample but not in the calibration standard. Calibration standards are re-prepared with a small amount of sulfuric acid to match the sample, and the assay is repeated to provide a better QC recovery reaching 100%.

To test for conductivity, samples are diluted with deionized water for each analysis. The test is completed using a Mettler Toledo Seven Excellence Meter as a conductivity probe per EPA Method 120.1. The predicted conductivity results are presented in Table 11.

To evaluate the freezing point, samples are analyzed using a TA Instruments Q100 DSC equipped with an RCS-90 cooling system according to USP <891>. The predicted results are presented in Table 12.

Determine the density and specific gravity of the sample at 20°C using an Anton Paar digital density meter according to EPA method 830.7300. The predicted results are presented in Table 13.

Samples are also titrated for hydrogen ion content, and acidity is determined according to ASTM D1067 - Test Method A to a pH of 8.6. The test is completed using a Metrohm 826 Titrando equipped with a pH probe. The predicted results are presented in Table 14.

The solutions are analyzed by Agilent 1290/G6530 Q-TOF LC-MS using direct injection (no column) and electrospray ionization in positive and negative mode. Representative mass spectra collected in positive and negative ionization modes are shown in Figures 1 and 2 for dilute sulfuric acid and 400 ppm CaSO ₄ (A), dilute sulfuric acid (B), Example 76 (C) and reverse osmosis water (D). 2 is shown.

Each sample, as prepared, is diluted to yield 5% product by volume in water and is found to be storage stable for at least 12 to 18 months. The excess hydrogen ion concentration is measured to be greater than 15%, and the pH of the material is determined to be 1.

Example 77

5% by volume of the material is diluted with distilled deionized water at a ratio of 4 parts water to 1 part material and packaged in 2 oz/60 ml glass bottles with droppers.

4 ml aliquots of each material as outlined in Example 76 are introduced into a PARI nebulizer to produce a particle size of 2.9 μm that can be administered to each respective subject via inhalation through a suitable nebulizer mask. do.

Example 78

100 subjects presenting with various respiratory symptoms, including acute respiratory distress, with confirmed cases of COVID 19 as confirmed by PCR testing, 4 times daily for 7 days each (10 minute treatment each) every 3 to 4 hours Receive a 2 ml dose via a nebulizer. To evaluate the efficacy of materials as disclosed herein, subjects were randomized (67 subjects) into Arm A receiving the composition of Example 79, while 33 conditionally and age-matched subjects received a placebo in normal saline solution. will receive Treatment will begin immediately after confirmation of COVID 19. For 14 days post-treatment, by follow-up visits at weeks 3 and 4 after completion of treatment and at 3 months post-treatment.

Subjects treated with the composition of Example 79 are evaluated on day 7, and at least 50% of subjects do not exhibit respiratory symptoms. On day 14, these subjects are test negative for COVID-19 based on standard PCR tests.

Example 79

Simplified treatment process and preparation for inhalation therapy for individuals presenting with COVID-19

1. Therapeutic package materials : Prepare various 5% by volume solutions of pharmaceutically acceptable grades of sulfuric acid alone, hydrochloric acid alone or a 50-50 mixture of sulfuric acid and hydrochloric acid, respectively, in a ratio of 4 parts water to 1 part material Dilute with deionized water and package in a 2 oz/60 ml glass bottle with dropper.

2. Therapeutic Administration: A particle size of 2.9 μm mean mass aerodynamic diameter (MMAD) where aliquots of 4 ml of therapeutic packaged material can each be administered to each subject via inhalation through a suitable nebulizer mask. is introduced into the PARI nebulizer to produce A dose of 4 ml is expected to produce aerosolized sulfuric acid for about 10 minutes, which is one treatment.

3. Human Clinical Study: 20 subjects presenting with various respiratory symptoms, including acute respiratory distress, who have confirmed cases of COVID 19 as confirmed by PCR testing, were observed daily for 14 days after the start of treatment and thereafter 3 Weeks, 4 weeks, and 3 months follow-up are 4 ml doses via nebulizer every 3 to 4 hours, 4 times daily for 7 days each (10 minute treatment each). Dosing results in a well-tolerated decrease in somatic symptoms after 24 hours in most patients, and a subset of patients test negative for COVID after 72 hours.

For each composition, an additional 100 subjects who had confirmed cases of COVID 19 as confirmed by PCR testing and presenting various respiratory symptoms including acute respiratory distress were given 4 times daily for 7 days each (10 min each treatment). ) Receive a dose of 4 ml via nebulizer every 3 to 4 hours. To evaluate the efficacy of materials as disclosed herein, subjects are randomized (67 subjects) into Arm A to receive a therapeutic composition, while 33 conditionally and age-matched subjects receive a placebo of normal saline solution. Treatment begins immediately after confirmation of COVID 19, for 14 days after treatment, at weeks 3 and 4 after completion of treatment, and with follow-up visits at 3 months after treatment.

A given subject receiving one of the therapeutic compositions experiences a reduction in symptoms that begins following receipt of the first or second dose, as measured by a reduction in blood oxygenation levels and/or chest congestion. This result is not reflected in the control group. A significant proportion of subjects receiving one of the therapeutic compositions are test negative for COVID-19 after 3 to 7 days of treatment as measured by PCR.

While the present invention has been described in connection with what is presently believed to be the most practical and preferred embodiment, the invention is not limited to the disclosed embodiments, but on the contrary, various modifications and equivalent arrangements are included within the spirit and scope of the appended claims. intended to cover, its scope should be construed to be accorded the widest interpretation to include all such modifications and equivalent structures as permitted under law.

Claims (114)

As a method for treating or preventing respiratory diseases,
A method for treating or preventing a respiratory illness comprising administering at least one dose of a pharmaceutically acceptable fluid having a pH less than 3.0 to contact at least one region of the respiratory tract present in a patient in need thereof. . The method of claim 1 , wherein the respiratory disease is a chronic condition. 3. The method of claim 2, wherein the respiratory disease is one of chronic obstructive pulmonary disease, cystic fibrosis, asthma or respiratory allergy. 4. A respiratory illness according to any one of claims 1 to 3, wherein the respiratory illness is an airway infection caused by at least one of viral pathogens, bacterial pathogens, fungal pathogens, and mixtures thereof. 5. The respiratory disease according to claim 4, wherein the viral pathogen is at least one of coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus (RSV), rhinovirus, adenovirus, and mixtures thereof. 6. The respiratory disease according to claim 5, wherein the coronavirus is a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV and mixtures thereof. The method of claim 4, wherein the bacterial pathogen is Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Streptococcus blood A method selected from the group consisting of Ogenes, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare (MAI), Mycobacterium terrae, and mixtures thereof. 5. The method of claim 4, wherein the fungal pathogen is selected from the group consisting of Aspergillus, Cryptococcus, Pneumocystis, Rhizopus, Candida, endemic fungi, and mixtures thereof. The method according to any one of claims 1 to 8, wherein the pharmaceutically acceptable fluid is a carrier and at least one selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid, and mixtures thereof. A method comprising an inorganic acid compound of 10. The method of claim 9, wherein the inorganic acid in the pharmaceutically acceptable fluid is sulfuric acid, hydrochloric acid, hydrobromic acid and mixtures thereof. 11. The method of any one of claims 1 to 10, wherein the pharmaceutically acceptable fluid has a pH less than 2.5. 12. The method of any one of claims 1 to 11, wherein the pharmaceutically acceptable fluid has a pH less than 2.2. 12. The method of any one of claims 1-11, wherein the pharmaceutically acceptable fluid has a pH less than 2.0. 12. The method of any one of claims 1-11, wherein the pharmaceutically acceptable fluid has a pH less than 1.8. 12. The method of any one of claims 1 to 11, wherein the pharmaceutically acceptable fluid has a pH of 1.4 to 3.0. 12. The method of any one of claims 1 to 11, further comprising the step of administering a composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof into contact with respiratory tissue of a patient, wherein hypochlorous acid, hydrogen peroxide and their wherein the administration of the mixture is administered immediately before or concurrently with the administration of at least one dose of the pharmaceutically acceptable fluid brought into contact with tissue in the respiratory tract of the patient. 17. The method of claim 16, wherein the composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof is co-inhaled with a pharmaceutically acceptable fluid. 18. The method according to any one of claims 1 to 11, 16 or 17, wherein the pharmaceutically acceptable fluid is selected from acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, and further comprising an organic acid selected from the group consisting of ascorbic acid, isoascorbic acid, aspartic acid, glutamic acid, glutaric acid, and mixtures thereof. 19. The method of any one of claims 1-11 and 16-18, wherein the pharmaceutically acceptable fluid comprises aspartic acid or glutamic acid and at least one of hydrochloric acid, hydrobromic acid and sulfuric acid. . 20. The method of any one of claims 1-11 and 16-19, wherein the pharmaceutically acceptable fluid comprises a compound having the general formula:

In the above formula, x is an odd integer of 3 or greater;
y is an integer from 1 to 20;
Z is a polyatomic ion or a monoatomic ion. 21. The method of any one of claims 1-11 and 16-20, wherein the pharmaceutically acceptable fluid further comprises Group 1 cations, Group 2 cations and mixtures thereof. 21. The method of any one of claims 1 to 11 and 16 to 20, wherein the pharmaceutically acceptable fluid further comprises at least one antifungal inhibitor, wherein the at least one antifungal inhibitor is sorbic acid, sorbic acid, A method selected from the group consisting of potassium benzoate, potassium benzoate, and mixtures thereof. 23. The method of any one of claims 1-22, wherein the region of the respiratory tract contacted by at least one dose of the pharmaceutically acceptable fluid is the nasal passages, paranasal cavities, throat, pharynx, larynx, epiglottis, paranasal cavities, trachea, bronchi. or in at least one of the alveoli. 24. The method of claim 23, wherein the portion of the airway contacted by the at least one dose of the pharmaceutically acceptable fluid is located in the bronchi and alveoli. 25. The method of any one of claims 1-11 and 16-24, wherein the patient is a human. 25. The method of any one of claims 1-11 and 16-24, wherein the patient is an animal. 27. The method according to any one of claims 1 to 11 and 16 to 26, wherein the administering step is performed to at least one region of the patient's airway and for a time interval sufficient to reduce the pathogen load present in the patient's airway. A method comprising introducing a pharmaceutically acceptable fluid to be brought into contact. 28. The method of claim 27, wherein the administration of the pharmaceutically acceptable fluid brought into contact with at least one area of the patient's respiratory tract is for an interval of 1 second to 120 minutes. 28. The method of claim 27, wherein administration of the pharmaceutically acceptable fluid brought into contact with the patient's respiratory tract is ongoing for an interval of at least 24 hours. 30. The method of any one of claims 27 to 29, wherein the pharmaceutically acceptable fluid is at least one of vapor, aerosol, spray, micronized mist, gas, dispersed nanoparticles, or micronized particles dispersed in a gas to the respiratory tract. and is introduced into contact with at least one portion of the 31. The method according to any one of claims 27 to 30, wherein the pharmaceutically acceptable fluid has a particle size with a mean mass aerodynamic diameter of 0.1 to 5.0 microns. 28. The method of claim 27, wherein the pharmaceutically acceptable fluid is administered in at least one dose in a 24 hour period. 33. The method of any one of claims 24-32, further comprising administering a pharmaceutically acceptable fluid to the respiratory tract of the patient prior to onset of respiratory illness. 34. The method of claim 33, wherein the patient has confirmed exposure to at least one of viral pathogens, bacterial pathogens, fungal pathogens, and mixtures thereof. 35. The method of claim 33 or 34, wherein the patient presents with a chronic illness or comorbidity, the chronic illness is one of chronic obstructive pulmonary disease, cystic fibrosis, asthma, short-term or long-term immunodeficiency, or respiratory allergy, and the comorbidity is medically at least one of condition, age or weight. As a pharmaceutically acceptable therapeutic fluid composition,
fluid carrier; and
A pharmaceutically acceptable acidic component for use in treating respiratory illness in a patient, the pharmaceutically acceptable acidic component comprising at least one inorganic acid, at least one organic acid and mixtures thereof, An acceptable acidic component is a pharmaceutically acceptable acidic component that is present in the carrier in an amount sufficient to produce a pH less than 3.0.
A pharmaceutically acceptable therapeutic fluid composition comprising a. As a pharmaceutically acceptable therapeutic fluid. A pharmaceutically acceptable therapeutic fluid, wherein the pharmaceutically acceptable acidic component is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid, and mixtures thereof. 37. The pharmaceutically acceptable therapeutic fluid composition of claim 36 wherein the pH is less than 2.5. 37. The pharmaceutically acceptable therapeutic fluid composition of claim 36 wherein the pH is less than 2.2. 37. The pharmaceutically acceptable therapeutic fluid composition of claim 36 wherein the pH is less than 2.0. 37. The pharmaceutically acceptable therapeutic fluid composition of claim 36 wherein the pH is less than 1.8. 37. The pharmaceutically acceptable therapeutic fluid composition of claim 36 wherein the pH is between 1.4 and 3.0. 43. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 36 to 42, wherein the acidic component is at least one of sulfuric acid and hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid. 43. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 36 to 42, wherein the acidic component is sulfuric acid or hydrochloric acid. 45. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 36-42 and 44, wherein the acidic component further comprises an organic acid. 46. The method of claim 45, wherein the organic acid consists of acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorbic acid, aspartic acid, glutamic acid, glutaric acid, and mixtures thereof. A pharmaceutically acceptable therapeutic fluid composition selected from the group. 45. The method of any one of claims 36-42 and 44, wherein the acidic component is selected from sulfuric acid and, acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorb A pharmaceutically acceptable therapeutic fluid composition comprising at least one organic acid selected from the group consisting of acid, aspartic acid, glutamic acid, glutaric acid, and mixtures thereof. 45. The method of any one of claims 36-42 and 44, wherein the acidic component is hydrochloric acid and acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorb A pharmaceutically acceptable therapeutic fluid composition comprising at least one organic acid selected from the group consisting of acid, aspartic acid, glutamic acid, glutaric acid, and mixtures thereof. 49. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 36 to 48, wherein the respiratory illness is an infection caused by at least one of a viral infection, a bacterial infection, or a fungal infection. 50. The method of any one of claims 36 to 49, wherein the respiratory illness is caused by a viral infection caused by at least one of coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, rhinovirus. As an acceptable therapeutic fluid composition. 51. The pharmaceutically acceptable therapeutic fluid composition of claim 50, wherein the viral infection is caused by a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV and mixtures thereof. . 50. The method according to any one of claims 36 to 49, wherein the respiratory disease is Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus, caused by at least one of the bacterial pathogens selected from the group consisting of Moraxella catarrhalis, Streptococcus pyogenes, Mycobacterium tuberculosis, Mycobacterium avium-Intracellulare (MAI), and mixtures thereof A pharmaceutically acceptable therapeutic fluid composition that is bacterial infection. 50. The method according to any one of claims 36 to 49, wherein the respiratory disease is a fungal infection caused by at least one fungal pathogen selected from the group consisting of Aspergillus, Cryptococcus, Rhizopus and mixtures thereof. As an acceptable therapeutic fluid composition. 56. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 36 to 55, wherein the pharmaceutically acceptable fluid is administered via inhalation as a vapor, aerosol, spray or micronized mist. The method of any one of claims 36 to 48,
At least one item selected from the group consisting of amantadine, lopinavir, linebacker and equivir, arbidol, nanoviricid, remdesivir, molnupiravir, favipiravir, oseltamivir, ribavirin, and combinations thereof A pharmaceutically acceptable therapeutic fluid composition further comprising a viral agent. The method of any one of claims 36 to 48,
Bitolterol, Fenoterol, Isoprenaline, Levosalbutamol, Orciprenaline, Pirbuterol, Procaterol, Litodrine, Salbutamol, Terbutaline, Albuterol, Ciclesonide, Arformoterol, The group consisting of bambuterol, clenbuterol, formoterol, salmeterol, abediterol, carmoterol, indacaterol, olodaterol, vilanterol, isoxuprine, mabuterol, zilpaterol and mixtures thereof A pharmaceutically acceptable therapeutic fluid composition further comprising at least one adrenergic β ₂ receptor agonist selected from The method of any one of claims 36 to 48,
A pharmaceutically acceptable pharmaceutically acceptable product further comprising at least one steroid agent selected from the group consisting of beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and combinations thereof. Possible therapeutic fluid compositions. The method of any one of claims 36 to 48,
A pharmaceutically acceptable therapeutic fluid composition, further comprising at least one non-steroidal anti-inflammatory agent selected from the group consisting of adenosine, metabisulfite, L-aspirin, indomethacin, and combinations thereof. As a therapeutic fluid composition,
fluid carrier;
An acidic component, wherein the acidic component is selected from the group consisting of at least one inorganic acid, at least one organic acid, or mixtures thereof, wherein the acidic component is present in the composition in an amount sufficient to produce a pH less than 3.0. ingredient; and
at least one active pharmaceutical agent selected from the group consisting of at least one antiviral compound, at least one adrenergic _β2 receptor agonist, at least one steroid, at least one anti-inflammatory agent and mixtures thereof
A therapeutic fluid composition comprising a. 60. The pharmaceutically acceptable therapeutic fluid composition of claim 59, wherein the at least one inorganic acid of the acidic acid component is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid, and mixtures thereof. . 61. The pharmaceutically acceptable therapeutic fluid composition of claim 60, wherein the at least one inorganic acid of the acidic acid component is sulfuric acid, hydrochloric acid and mixtures thereof. 62. The method of claim 60 or 61, wherein the at least one organic acid of the acidic acid component is acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorbic acid, aspartic acid, A pharmaceutically acceptable therapeutic fluid composition selected from the group consisting of glutamic acid, glutaric acid and mixtures thereof. 63. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 59 to 62 wherein the pH is less than 2.5. 63. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 59 to 62 wherein the pH is less than 2.2. 63. The pharmaceutically acceptable therapeutic fluid composition of any one of claims 59-62, wherein the pH is less than 2.0. 63. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 59 to 62 wherein the pH is less than 1.8. 63. A pharmaceutically acceptable therapeutic fluid composition according to any one of claims 59 to 62 wherein the pH is between 1.4 and 3.0. 68. The method of any one of claims 59-67, wherein the at least one antiviral agent is amantadine, lopinavir, linebacker and equivir, arbidol, nanoviricid, remdesivir, molnupiravir, favipyra A pharmaceutically acceptable therapeutic fluid composition selected from the group consisting of vir, oseltamivir, ribavirin, and combinations thereof. 68. The method of any one of claims 59-67, wherein the at least one adrenergic β ₂ receptor agonist is bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procate Lol, Litodrine, Salbutamol, Terbutaline, Albuterol, Arformoterol, Bambuterol, Clenbuterol, Formoterol, Salmeterol, Abediterol, Carmoterol, Indacaterol, Orloda A pharmaceutically acceptable therapeutic fluid composition selected from the group consisting of terol, vilanterol, isoxuprine, mabuterol, zilpaterol, and mixtures thereof. 68. The method of any one of claims 59-67, wherein the at least one steroid agent consists of beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone and combinations thereof. A pharmaceutically acceptable therapeutic fluid composition selected from the group. 68. The therapeutic fluid composition of any one of claims 59-67, wherein the at least one anti-inflammatory agent is selected from the group consisting of metabisulfite, adenosine, L-aspirin, indomethacin, and combinations thereof. . A pharmaceutically acceptable fluid for use in a method of treating or preventing a respiratory disease, the use comprising at least one of said pharmaceutically acceptable fluid brought into contact with at least a portion of the respiratory membrane present in the respiratory tract of a patient in need thereof. A pharmaceutically acceptable fluid for use comprising administering one dose, wherein the pharmaceutically acceptable fluid has a pH of less than 3.0. 73. A pharmaceutically acceptable fluid for use according to claim 72, wherein respiratory disease is a chronic condition. 74. A pharmaceutically acceptable fluid for use according to claim 73, wherein the respiratory illness is one of chronic obstructive pulmonary disease, cystic fibrosis, asthma, or respiratory allergy. 73. A pharmaceutically acceptable fluid for use according to claim 72, wherein respiratory illness is an acute condition. 73. A pharmaceutically acceptable fluid for use according to claim 72, wherein the respiratory illness is an airway infection caused by at least one of viral pathogens, bacterial pathogens, fungal pathogens, and mixtures thereof. 77. The pharmaceutically acceptable fluid for use according to claim 76, wherein the viral pathogen is at least one of coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus (RSV), rhinovirus, adenovirus and mixtures thereof. 78. The pharmaceutically acceptable fluid for use according to claim 77, wherein the coronavirus is a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV and mixtures thereof. 76. The method of claim 75, wherein the bacterial pathogen is Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Streptococcus blood A pharmaceutically acceptable fluid for use, which is selected from the group consisting of Ogenes, Mycobacterium tuberculosis, Mycobacterium avium-Intracellulare (MAI), and mixtures thereof. 76. A pharmaceutically acceptable fluid for use according to claim 75, wherein the fungal pathogen is selected from the group consisting of Aspergillus, Cryptococcus, Pneumocystis, Rhizopus, endemic fungi and mixtures thereof. 73. The method of claim 72, wherein the pharmaceutically acceptable fluid comprises a carrier and at least one inorganic acid compound selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid, and mixtures thereof. Phosphorus, a pharmaceutically acceptable fluid for use. 82. A pharmaceutically acceptable fluid for use according to claim 81, wherein the inorganic acid is sulfuric acid. 83. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 82, wherein the pharmaceutically acceptable fluid has a pH less than 2.5. 82. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 81, wherein the pharmaceutically acceptable fluid has a pH less than 2.2. 82. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 81, wherein the pharmaceutically acceptable fluid has a pH less than 2.0. 82. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 81, wherein the pharmaceutically acceptable fluid has a pH less than 1.8. 82. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 81, wherein the pharmaceutically acceptable fluid has a pH of 1.4 to 3.0. 88. The method of any one of claims 72-87, further comprising the step of administering a composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof in contact with at least one area of the respiratory tract of a patient, wherein hypochlorous acid, The administration of hydrogen peroxide and mixtures thereof is administered immediately prior to or concurrently with the administration of at least one dose of a pharmaceutically acceptable fluid brought into contact with at least one area of the respiratory tract of a patient. acceptable fluid. 89. The method of any one of claims 72-88, wherein the pharmaceutically acceptable fluid is acetic acid, trichloroacetic acid, benzenesulfonic acid, citric acid, propionic acid, formic acid, gluconic acid, lactic acid, ascorbic acid, isoascorbic acid, aspartic acid A pharmaceutically acceptable fluid for use, further comprising an organic acid selected from the group consisting of acid, glutamic acid, glutaric acid and mixtures thereof. 89. A pharmaceutically acceptable fluid for use according to claim 88, wherein the pharmaceutically acceptable fluid comprises hydrochloric acid and aspartic acid. 91. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 90, wherein the pharmaceutically acceptable fluid comprises a compound having the general formula:

In the above formula, x is an odd integer of 3 or greater;
Y is an integer from 1 to 20; Z is a polyatomic ion or a monoatomic ion. 92. A pharmaceutically acceptable fluid for use according to any one of claims 72 to 91, wherein the pharmaceutically acceptable fluid further comprises group 1 cations, group 2 cations and mixtures thereof. 92. The method of any one of claims 72-91, wherein the pharmaceutically acceptable fluid further comprises at least one antifungal inhibitor selected from the group consisting of sorbic acid, potassium sorbate, potassium benzoate and mixtures thereof. A pharmaceutically acceptable fluid for use. 94. The pharmaceutical composition for use according to any one of claims 72 to 93, wherein the portion of the respiratory tract contacted by at least one dose of the pharmaceutically acceptable fluid comprises an epithelium present in the mucous membranes of the respiratory tract. acceptable fluid. 95. The method of any one of claims 72-94, wherein the portion of the airway contacted by at least one dose of the pharmaceutically acceptable fluid is the nasal passages, throat, pharynx, larynx, epiglottis, paranasal sinuses, trachea, bronchi, or alveoli. A pharmaceutically acceptable fluid for use, which is located in at least one of. 95. A pharmaceutically acceptable fluid for use according to claim 94, wherein the portion of the respiratory membrane that the at least one dose of the pharmaceutically acceptable fluid contacts is located in the bronchi and alveoli. 96. A pharmaceutically acceptable fluid for use according to any one of claims 71 to 95, wherein the patient is a human. 96. A pharmaceutically acceptable fluid for use according to any one of claims 71 to 95, wherein the patient is an animal. 99. The method of any one of claims 72-98, wherein the administering is a pharmaceutically acceptable fluid brought into contact with the patient's airways for a time interval sufficient to provide at least a 1% reduction in the pathogen load present in the patient's airways. A pharmaceutically acceptable fluid for use comprising the incorporation of 100. A pharmaceutically acceptable fluid for use according to claim 99, wherein introduction of the pharmaceutically acceptable fluid into contact with the patient's respiratory tract is continuous for an interval of 5 seconds and for an interval of at least 24 hours. 101. A pharmaceutically acceptable fluid for use according to claim 100, wherein introduction of the pharmaceutically acceptable fluid into contact with the respiratory tract of a patient is continuous for an interval of at least 24 hours. 102. The method of any one of claims 99-101, wherein the pharmaceutically acceptable fluid is introduced into the respiratory tract as a vapor, aerosol, spray, micronized mist, gas, micronized solid particles or nanosized solid particles. , a pharmaceutically acceptable fluid for use. 103. A pharmaceutically acceptable fluid for use according to any one of claims 99 to 102, wherein the pharmaceutically acceptable fluid has a particle size of mean mass aerodynamic diameter of 0.1 to 5.0 microns. 104. A pharmaceutically acceptable fluid for use according to any one of claims 99 to 103, wherein the pharmaceutically acceptable fluid is administered in at least one dose in a 24 hour period. 105. The pharmaceutically acceptable fluid for use according to any one of claims 99 to 104, further comprising administering the pharmaceutically acceptable fluid to the respiratory tract of the patient prior to onset of respiratory illness. . As a kit for use in the treatment or prevention of respiratory diseases,
A container connectable to a respiratory delivery device for administering a pharmaceutically acceptable fluid to the respiratory tract of a patient in need thereof, the container having at least one chamber and a pharmaceutically acceptable fluid from the container being transferred to a patient in need thereof. having at least one device for delivery to the airway, wherein the chamber contains at least one volume of a pharmaceutically acceptable fluid comprising a liquid carrier and at least one acid compound, wherein the pharmaceutically acceptable fluid has a concentration of less than 3.0 container having a pH
Including, kit. 107. The kit of claim 106, further comprising a means for administering a pharmaceutically acceptable fluid. 108. The method of claim 107, wherein the means for administering the pharmaceutically acceptable fluid into contact with at least a portion of the patient's respiratory tract comprises at least one mechanism for delivering the fluid in a vaporized, atomized or nebulized state. in kit. 107. The kit of claim 106, wherein the container is an inhaler or nebulizer. 110. The kit of claim 109, wherein the nebulizer is a PARI nebulizer. As a respiratory inhalant device,
a reservoir having at least one inner chamber;
A pharmaceutically acceptable fluid contained in the inner chamber, wherein the pharmaceutically acceptable fluid is
an acid compound selected from the group consisting of at least one organic acid, at least one inorganic acid, and mixtures thereof; and
a pharmaceutically acceptable fluid comprising a carrier, wherein the acid compound is present in an amount sufficient to provide a pH of less than 3.0; and
A dispenser in fluid communication with the reservoir, the dispenser configured to dispense a measured portion of a pharmaceutically acceptable fluid from the reservoir into respirable contact with at least a portion of the respiratory tract of a patient having a respiratory illness, the pharmaceutically The dispenser wherein the acceptable fluid is in a droplet size with a mean mass diameter of 0.5 to 5.0 microns.
A respiratory inhalant device comprising a. 112. The respiratory inhalant device of claim 111, wherein the respiratory illness is an acute respiratory illness caused by at least one of a viral pathogen, a bacterial pathogen, and a fungal pathogen. 113. The respiratory inhalant device of claim 112, wherein the viral pathogen is one of a coronavirus, an influenza virus, a parainfluenza virus, a respiratory syncytial virus, and a rhinovirus. 114. The respiratory inhaler device of claim 113, wherein the viral pathogen is a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and mixtures thereof.