WO2022119661A1 - Matériau thérapeutique à faible ph et faible toxicité, actif contre au moins un pathogène pour la prise en charge de patients atteints de maladies respiratoires - Google Patents
Matériau thérapeutique à faible ph et faible toxicité, actif contre au moins un pathogène pour la prise en charge de patients atteints de maladies respiratoires Download PDFInfo
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- WO2022119661A1 WO2022119661A1 PCT/US2021/056001 US2021056001W WO2022119661A1 WO 2022119661 A1 WO2022119661 A1 WO 2022119661A1 US 2021056001 W US2021056001 W US 2021056001W WO 2022119661 A1 WO2022119661 A1 WO 2022119661A1
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- Prior art keywords
- acid
- pharmaceutically acceptable
- fluid
- respiratory
- acceptable fluid
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- the present disclosure is directed to a method and composition for treating and/or preventing a respiratory illness. More particularly, the present disclosure is directed to a method for treating and/or preventing a respiratory illness caused, at least in part by an infectious pathogen.
- infectious pathogens are bacterial pathogens, fungal pathogens and/or viral pathogens.
- viral pathogens include those caused by one of more of coronaviruses, influenzas viruses, parainfluenza viruses, respiratory syncytial viruses, and rhinoviruses.
- 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 spread readily through populations infecting many. This is particularly challenging when large numbers of individuals in the affected population lacks natural or acquired immunities to the given pathogen. It is also challenging in populations with limited or no access to advanced medical treatment. Therefore, rural regions in the developed countries such as the United States as well as many regions in countries in Africa, South America and Asia can find the arrival of novel infectious pathogens, particularly difficult if not devastating.
- Respiratory pathogens such as bacteria, fungi, and viruses including SARS-CoV- 2, kill over five million people annually, (see Forum of International Respiratory Societies.
- a broad- spectrum antimicrobial therapy that offers 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 bacteria strains. Additionally, it is desirable that the therapeutic is easy to administer, demonstrates minimal systemic effects and is broadly available for all patient access, which may enable use as a first-line treatment option for a wide range of respiratory infections prior to or in addition to pathogen- specific drug materials and/or treatment methods.
- a method of treating or preventing a respiratory illness that includes administering at least one dose of a pharmaceutically acceptable fluid having a pH less than 3.0 into contact with at least one region of the respiratory tract of the patient in need thereof.
- the pharmaceutically acceptable fluid can include at least one inorganic acid, at least one organic acid and mixtures thereof.
- a therapeutic composition that includes a fluid carrier and an acidic component that includes a pharmaceutically acceptable acidic component present in an amount sufficient to produce a pH less than 3.0 for use in addressing a respiratory illness in a patient in need thereof.
- the pharmaceutically acceptable acidic component can be at least one inorganic acid, at least one organic acid and mixtures thereof.
- composition having a pH below 3.0 composed of at least one pharmaceutically acceptable acid used as a therapeutic inhalant composition.
- the at least one pharmaceutically acceptable acid can be at least one inorganic acid, at least one organic acid or mixtures thereof.
- kit for use in the treatment or prevention of a respiratory illness comprising a pharmaceutically acceptable fluid which comprises a liquid carrier and at least one compound wherein the pharmaceutically acceptable fluid has a pH less than 3.0 and a container for administering the pharmaceutically acceptable fluid into the respiratory tract of a patient in need thereof.
- Fig. 1 are mass spectra collected in the positive ionization mode for Dilute Sulfuric Acid w/ 400 ppm CaSCU (A), Dilute Sulfuric Acid (B), an embodiment as disclosed herein prepared according to the process outlined in Example LXXII (C), and Reverse Osmosis Water (D);
- Fig. 2 are mass spectra collected in the negative ionization mode for Dilute Sulfuric Acid w/ 400 ppm CaSO4 (A), Dilute Sulfuric Acid (B), and embodiment as disclosed herein prepared according to the process outlined in Example LXXII(C), and Reverse Osmosis Water (D).
- Disclosed herein is a method of and composition for treating or preventing a respiratory illness that includes the step of administering at least one dose of a pharmaceutically acceptable fluid having a pH less than 3.0 into contact with at least one region of the respiratory tract present in the patient in need thereof.
- Respiratory illnesses that can be treated or prevented by the method and/or composition as disclosed herein can include respiratory tract infections caused be one or more a variety of infectious pathogens which can affect humans or animals or both.
- Respiratory illness that can be treated or prevented by the method as disclosed herein can include one or more chronic respiratory conditions.
- Respiratory illnesses that can be treated or prevented can be a combination of one or more chronic respiratory conditions and one or more respiratory infections.
- respiratory tract infections can be either acute infections or chronic infections and can be caused by one or more pathogens. It is also contemplated that respiratory illnesses can be a combination of the chronic respiratory illness(es) and respiratory tract infection(s).
- Chronic respiratory conditions as defined by the United States Center for Disease Control are defined broadly as conditions that last one year or more and require ongoing medical attention or curtail activities of daily living or both.
- Non-limiting examples of chronic respiratory illnesses that can be addressed by the method and/or composition disclose herein include chronic obstructive pulmonary disease, cystic fibrosis, asthma, or respiratory allergies.
- Respiratory tract infections as that term in used in this disclosure is broadly defined as any infectious disease of the upper or lower respiratory tract.
- Upper respiratory tract infections can include, but are not limited to, the common cold, laryngitis, pharyngitis/tonsillitis, rhinitis, rhinosinusitis, and the like.
- Lower respiratory tract infections include bronchitis, bronchiolitis, pneumonia, tracheitis and the like.
- Pathogens responsible for respiratory tract infections can include one or more viral pathogens, one or more bacterial pathogens, one or more fungal pathogens as well as mixed pathogen infections arising from two or more of the classes discussed.
- the viral pathogen can be at least one of a coronavirus, an influenza virus, a parainfluenza virus, a respiratory syncytial virus (RSV), a rhinovirus, an adenovirus as well as combinations of two or more of the foregoing.
- RSV respiratory syncytial virus
- the various viral strains causing infection in a patient can be pure strains or can be mixtures of various strains, types, subtypes and/or mutations.
- Coronaviruses that can be treated by the method and/or composition as disclosed herein include, but are not limited to, alpha coronaviruses, beta coronavirus as well as other emergent types. Coronaviruses, as that term is employed in this disclosure, are understood to be a group of related RNA viruses that cause disease, particularly respiratory tract infections in various mammalian and avian species. Coronaviruses that can be treated by the method and/or composition as disclosed herein include members of the subfamily Orthocoronavirinae in the family Coronaviridea.
- the method and/or composition as disclosed herein can be employed to treat or prevent respiratory infections in which the diseases-causing pathogen is a human coronavirus that is member of the family Coronaviridea selected from the group consisting of SARS-CoV-1 (2003), HCoV NL63(2004), HCoV HKU1 (2004), MERS- CoV (2013) SARS-CoV-2 (2019) and mixtures thereof.
- the coronavirus can be a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and mixtures thereof.
- the method and/or composition as disclosed herein can be employed to treat or prevent respiratory infections in which the diseases- causing pathogen is an enveloped, 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 the method and/or compositions as disclosed herein can be negative-sense RNA viruses such as Orthomyxoviridae such as those from the genera: alphainfluenza, betainfluenza, deltainfluenza, gammainfluenza, thogotovirus and quarajavirus.
- Orthomyxoviridae such as those from the genera: alphainfluenza, betainfluenza, deltainfluenza, gammainfluenza, thogotovirus and quarajavirus.
- influenza virus can be an alphainfluenza that expresses as a serotype such as H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N4, N7N7, H7N9, H9N2, H10N7.
- a serotype such as H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N4, N7N7, H7N9, H9N2, H10N7.
- Other expressions are also contemplated.
- Non-limiting examples of parainfluenza viruses can be single-stranded, enveloped RNA viruses of the Paramyoviridae family.
- Non-limiting examples of human parainfluenza viruses include those in the genus Respirovirus and those in the genus Rubulavirus.
- Non-limiting examples of respiratory syncytial viruses are various medium sized ( ⁇ 150nm) enveloped viruses from the family Pneumvidae such as those in the genus Orthopneumovirus.
- Non-limiting examples of rhinovirus that can be treated by the method and/or composition as disclosed herein include those with single- stranded positive sense RNA genomes that are composed of a capsid containing the viral protein(s).
- Rhinoviruses can be from the family Picovirus and the genus Enterovirus.
- Non-limiting examples of adenoviruses include non-enveloped viruses such as those with an icosahedral nucleocapsid containing nucleic acid such as double stranded DNA.
- Viruses can be from the family Adenoviridae and genera such as Atadenovirus, Mastadenvirus, Siadenovirus, and the like.
- the method and/or composition as disclosed herein can be used to treat respiratory infections caused by bacterial pathogens.
- Non-limiting examples of such bacterial pathogens include Streptoccocus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Streptococcus pyogenes, Mycobacterium tuberculosis, Mycobacterium avium - intracellulare (MAI), Mycobacterium terrae, and mixtures thereof.
- the method and/or composition as disclosed herein can be used to treat respiratory infections caused by fungal pathogens presenting as single-pathogen fungal infections, multi-pathogen fungal infections or general mycosis with respiratory involvement.
- fungal pathogens implicated in respiratory illnesses and infections include certain species from the genus Aspergillus, with A. fumigatus, A. flavus, and A. clavatus being non-limiting examples.
- Other examples of respiratory infections caused by fungal pathogens that can be treated by the method and/or compositions disclosed herein are respiratory infections involving infectious species of Cryptococcus, Rhizopus, Mucor, Pneumocystis, Candida, and the like.
- the method and/or composition as disclosed herein can have a pH 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; less than 1.0 with lower ranges being determined by the lung condition and health of the patient.
- the composition can have a have a pH between 2.8 and 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; less than 1.0 with lower ranges being determined by the lung condition and health of the patient.
- the composition can have a have a pH between
- the pharmaceutically acceptable fluid having a pH below 3.0 can be administered into contact with at least one region of the respiratory tract of the patient in need thereof can be administered by any therapeutically acceptable manner.
- the pharmaceutically acceptable fluid will be administered in a manner that permits or promotes uptake of at least a portion of the composition by patient inhalation.
- the pharmaceutically acceptable fluid can be introduced under pressure in certain embodiments.
- the pharmaceutically acceptable fluid as disclosed herein can be introduced into contact with at least one region in the respiratory tract of the patient in the form of a gas, a fluid or a mixture of the two.
- the pharmaceutically acceptable fluid can also include one or more powders or micronized solids.
- the pharmaceutically acceptable fluid can be introduced into contact with at least a portion of the respiratory tract of the patient in the form a vapor, aerosol, spray, micronized mist, gas or the like. It is also contemplated that the pharmaceutically acceptable fluid can be administered as a gas, as dispersed nanoparticles in a gas, as micronized particles in a gas, as nanoparticles dispersed in a gas or the like.
- the size particulate or droplet material composed of the pharmaceutically acceptable fluid that is introduced into contact with at least one region of the respiratory tract of the patient can be adjusted or tuned to increase contact with the desired region of the respiratory tract.
- the respective regions of the respiratory tract which the pharmaceutically acceptable fluid can contact can include nose, sinuses, throat, pharynx, larynx, epiglottis, sinuses, trachea, bronchi, alveoli, or combinations of any of the foregoing.
- the size distribution of the particles/droplets can be tuned to address the location of greatest pathogen population.
- the at least one dose of a pharmaceutically acceptable fluid can be delivered into contact with the lower respiratory tract such as the bronchi, alveoli and the like in order to address infections localized in that region.
- the at least one dose of a pharmaceutically acceptable fluid can be delivered into contact with the upper respiratory tract such as the nose or nostrils, nasal cavity, mouth, pharynx, larynx and the like to address infections localized in this region.
- the pharmaceutically acceptable fluid as administered can have a particle size between 0.1 and 20.0 microns mean mass aerodynamic diameter (MMAD).
- the particle size can be between 0.5 and 20.0; between 0.75 and 20.0; between 1.0 and 20.0; between 2.0 and 20.0; between 3.0 and 20.0; between 4.0 and 20.0; between 5.0 and 20.0; between 7.0 and 20.0; between 10.0 and 20.0; between 12.0 and 20.0; between 15.0 and 20.0; between 16.0 and 20.0; between 17.0 and 20.0; between 18.0 and 20.0; between 0.1 and 15.0; between 0.5 and 15.0; between 0.75 and 15.0; between 1.0 and 15.0; between 2.0 and 15.0; between 3.0 and 15.0; between 4.0 and 15.0; between 5.0 and 15.0; between 7.0 and 15.0; between 10.0 and 15.0; between 12.0 and 15.0; between 14.0 and 15.0; between 0.1 and 10.0; between 0.5 and 10.0; between 0.75 and 10.0; between 1.0 and 10.0; between 2.0 and 15.0; between 3.
- the pharmaceutically acceptable fluid can be introduced into contact with at least one region of the respiratory tract of the patient at a concentration and in an amount sufficient to reduce pathogen load present in the respiratory tract. It is within the purview of this disclosure that the pharmaceutically acceptable fluid can be introduced continually over a defined interval of minutes, hours or even days. In certain embodiments, the pharmaceutically acceptable fluid can be introduced continuously for an interval of at least 24 hours. In patients presenting with respiratory infections, continuous administration can be discontinued upon reduction in pathogen load either as directly measured or indirectly ascertained by improvement in symptoms such as blood oxygen saturation or the like.
- the pharmaceutically acceptable fluid can be administered in a series of at least two doses introduced at defined intervals.
- the intervals for dosing and number of doses administered will be that sufficient to reduce the pathogen load present in the respiratory tract of the patient either as directly measured or indirectly ascertained by improvement in symptoms such as blood oxygen saturation or the like.
- the reduction in pathogen load can be a partial or complete reduction in the pathogen count in the respiratory tract of the patient to whom the pharmaceutically acceptable fluid is administered. Where less than complete reduction in respiratory tract pathogen count is achieved, it is believed that respiratory tract pathogen count reduction, in at least some instances can be sufficient to permit the patient’s own immune system response to address or overcome the infectious pathogen either alone or with additional supportive or augmented therapy.
- the pharmaceutically acceptable fluid is administered in a plurality of discrete doses
- the pharmaceutically acceptable fluid can be administered over 2 to 10 doses in a 24-hour period, with 3 to 4 doses being contemplated in certain embodiments.
- Each dosing interval can be for a period of 1 second to 120 minutes, with administration intervals between 1 and 60 minutes; 1 and 30 minutes; 1 and 20 minutes; 1 and 10 minutes being contemplated in certain embodiments.
- an additional portion of the pharmaceutically acceptable fluid is introduced over the dosing interval and is brought into contact with the affected portion respiratory tract thereby reducing pathogen load with the continuing addition.
- Direct measurement of the reduction in pathogen load in the respiratory tract of the patient can be accomplished by any suitable mechanism such as by swabbing, sampling or the like.
- the reduction in pathogen load can be defined as at least 1% reduction of pathogen population in at least one region of the respiratory tract of the patient as measured at a time between 1 minute and 24 hours after commencement of administration.
- the reduction in pathogen load can be at least 10% as measured at a time between 1 minute and 24 hours after commencement of administration; at least 25%; at least 50%; at least 75%.
- the pharmaceutically acceptable fluid can be administered prophylactically or therapeutically depending on the physiology and health history of the specific patient.
- a non-limiting example of prophylactic administration can include routine administration of the pharmaceutically acceptable fluid in a suitable dosing regimen to individuals presenting with a chronic condition with increased risk for respiratory tract infection or complications due to a respiratory tract infection.
- Another non-limiting example of prophylactic administration is administration of one or more doses of the pharmaceutically acceptable fluid as disclosed herein after exposure to a contagious pathogen.
- administration of the pharmaceutically acceptable fluid can be accomplished by one or more suitable devices including, but not limited to, nebulizers, cool mist vaporizers, positive pressure inhalers, CPAP units and the like.
- the pharmaceutically acceptable fluid can include at least one acid compound that is present at a concentration sufficient to provide a fluid pH less than 3.0 and within the ranges recited in this disclosure.
- the pharmaceutically acceptable fluid can include at least one acid present in a suitable carrier as desired or required.
- the acid that is employed can be one which is pharmaceutically acceptable, effective, tolerable and non-deleterious to the surrounding tissue present in the respiratory tract of the patient being treated.
- Suitable acid compounds can be selected from the group consisting of Bronsted acids, Lewis acids and mixtures thereof.
- the term “pharmaceutically acceptable” is defined as having suitable pharmacodynamics and pharmacokinetics such that the therapeutic material is active primarily on the surface of the tissue of the respiratory tract with little or no systemic effect. Ideally, the materials employed produce residual products that are recognized by the body as common metabolites that are rapidly absorbed and metabolized. “Effective” as used herein is defined as materials that are to be effective on the targeted pathogen in vivo with the goal of significantly reducing the pathogen load in order to assist and augment the body’s natural defenses. “Tolerable” as defined herein is that the material can be tolerated by the patient at the effective therapeutic concentration without undesirable reactions including, but not limited to, irritation, choking, coughing or the like. “Non-deleterious” as used herein is defined as the material being effective at killing the targeted pathogen with little or no negative effect on the tissue of the respiratory tract of the that is in direct contact with the material present at therapeutic concentration levels.
- the acid compound employed can 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.
- pharmaceutically acceptable fluid will include and can be at least one inorganic acid present in a concentration sufficient to provide a pH at the levels defined herein. Where two or more inorganic acids are employed, the various inorganic acids will present at a ratio sufficient to provide a pH level within the parameters defined in this disclosure. The ratio of respective acids can be modified or altered to meet parameters such as tolerability.
- Non-limiting examples of suitable inorganic acids include an inorganic acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, hypochlorous acid, and mixtures thereof.
- the pharmaceutically acceptable fluid can include sulfuric acid, hydrochloric acid, hydrobromic acid and mixtures thereof.
- the at least one inorganic acid in the pharmaceutically acceptable fluid can be present in whole or in part as a salt or salts of the respective inorganic acid.
- the at least one inorganic acid can be used alone or in combination with other weak or strong organic or inorganic acids or salts thereof in order to obtain the desired pH range.
- the pharmaceutically acceptable fluid can include at least one organic acid present in a concentration sufficient to provide a pH at the levels defined herein.
- the at least one organic acid can be present alone or in combination with one or more inorganic acids. Where two or more organic acids are employed, the various organic acids can be present at a ratio sufficient to provide a pH level within the parameters defined in this disclosure. The ratio of respective acids can be modified or altered to meet parameters such as tolerability.
- Non-limiting examples of organic acids include at least one organic acid selected from the group consisting 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.
- 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.
- the pharmaceutically acceptable fluid can include at least one inorganic acid in combination with at least one organic acid listed above. It is also contemplated that the at least one organic acid or the at least one inorganic acid can be present in combination with at least one amino acid. Non-limiting examples of such combination includes for example an amino acid such as aspartic acid or glutamic acid and at least one inorganic acid such as hydrochloric acid, hydrobromic acid, and sulfuric acid required to provide the proper pH range.
- an acid component present in the pharmaceutically acceptable fluid can include two or more acid compounds in sufficient concentrations to provide the pharmaceutically acceptable fluid with a pH below 3 or in one of the ranges discussed herein.
- the composition can include certain organic and/or inorganic acids that have a pH outside the range levels outlined for the finished composition. It also considered within the purview of this disclosure to include minor amounts of acid compounds at levels which permit them to be tolerated and/or effectively metabolized as needed.
- the pharmaceutically acceptable therapeutic fluid can include a fluid carrier.
- the fluid carrier component can be a liquid gaseous material suitable for administration to a human, more particularly, the fluid carrier can be one that can be administered as an inhalable or introducible material and come into contact with one or more surfaces present in the at least one region of the respiratory tract of a patient.
- the fluid carrier component can be a suitable protic solvent, a suitable aprotic solvent or mixtures thereof.
- the carrier can be a fluid that can be gaseous or can be that can be vaporized, aerosolized or the like by suitable means.
- suitable carriers include water, organic solvents and the like, present alone or in suitable admixture.
- Non-limiting examples of organic solvents include materials selected from the group consisting of C2 to Ce alcohols, pharmaceutically acceptable fluorine compounds, pharmaceutically acceptable siloxane compounds, pharmaceutically acceptable hydrocarbons, pharmaceutically acceptable halogenated hydrocarbons and mixtures thereof.
- free hydrogen present in the pharmaceutically acceptable fluid composition can include one or more suitable acids present in whole or on part in a dissociated state.
- the suitable acid present in a whole or partially dissociated state can 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 can be present in an amount sufficient to act on the pathogen present in the respiratory tract of the patient.
- the acid component can be present in an amount up to 10,000 ppm; between 1000 and 10,000 ppm; between 2000 and 10,000 ppm; between 3000 and 10,000 ppm; between 4000 and 10,000 ppm; between 5000 and 10,000 ppm; between 6000 and 10,000 ppm; between 7000 and 10,000 ppm between 8000 and 10,000 ppm; between 9000 and 10,000 ppm.
- the acid component can be present in the pharmaceutically acceptable material solution in an amount between 100 ppm and 2000 ppm; in certain embodiments the inorganic acid can be present in an amount between 100 ppm and 1700 ppm; between 100 and 1500 ppm; between 100 and 1200 ppm; between 100 and 1000 ppm; between 100 and 900 ppm; between 100 ppm and 800 ppm; between 100 ppm and 700 ppm; and between 100 ppm and 600 ppm.
- acid compound(s) in the pharmaceutically acceptable fluid can function as proton donors which can affect the pathogen(s) present in the at least one region of the respiratory tract of the patient and reduce the pathogen load therein.
- sulfuric acid when employed, it at least a portion dissociates at low concentration primarily into hydrogen ions and hydrogen sulfate (HSO4 ) In its dissociated state sulfuric acid can donate protons to affect pathogens. While this mode of action is mentioned, other modes of action are not precluded by this discussion.
- the water component of the liquid material can be composed of water having a purity greater than primary grade, if desired or required. Water classified as ASTM1 193-96 purified, ASTM1193-96 ultrapure or higher can be used is desired or required.
- the composition can also include between 5 and 2000 ppm of pharmaceutically acceptable Group I ions, pharmaceutically acceptable Group II ions and mixtures thereof. In certain embodiments, ions can be selected from the group consisting of calcium, magnesium, strontium and mixtures thereof.
- the calcium ions can be present as Ca 2+ , CaSO-f 1 , and mixtures thereof.
- the acid compound or compounds that is admixed can be produced by any suitable means that results in a material that has limited to no harmful interaction when introduced into contact with at least one region present in the respiratory tract of the patient.
- the pharmaceutically acceptable fluid can also include at least one active pharmaceutical ingredient present in suitable therapeutic concentrations.
- suitable active pharmaceutical ingredients can be those that have activity that is localized to the region of the respiratory tract to which it is brought into contact. It is also within the purview of this disclosure that suitable active pharmaceutical ingredients can be those which have effect on the larger respiratory system and/or the general systemic effect on the patient.
- the active pharmaceutical ingredient(s) employed can be those which can be administered through the pulmonary system by inhalation or the like.
- the active pharmaceutical ingredient can be administered as part of a usage or treatment regimen using administration methods other than other than inhalation such as orally or intravenously.
- Active Pharmaceutical Ingredient can also include “derivatives” of an Active Pharmaceutical Ingredient, such as, pharmaceutically acceptable salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomers, active metabolites and the like.
- derivatives include prodrugs and active metabolites.
- the various “Active Pharmaceutical Ingredients and derivatives thereof’ are described in various literature articles, patents and published patent applications and are well known to a person skilled in the art.
- the at least one active pharmaceutical ingredient can include one or more suitable compounds from classes such as antimicrobials such as antivirals or antibiotics, adrenergic 2 receptor agonists, steroids, non-steroidal anti-inflammatory compounds, muscarinic antagonists, and the like.
- the pharmaceutically acceptable fluid as disclosed herein can include antiviral compounds with specific or general efficacy against coronaviruses, influenza, and the like to address and treat specific pathogenic infections.
- Nonlimiting examples of antiviral active pharmaceutical ingredient(s) include one or more compounds selected from the group consisting of amantadine, Lopinavir, linebacker and equivir, Arbidol, a nanoviricide, remdesivir, favipiravir, oseltamivir ribavirin, molnupiravir, and derivatives and prodrugs thereof as well as combinations of the foregoing.
- the antiviral active pharmaceutical ingredient(s) can be present in the form that will permit administration via inhalation or other suitable administration into direct or immediate contact with at least a potion of the respiratory tract of the patient.
- the materials such as molnupiravir may be present as a prodrug that could be converted by esterases in the lung to its active metabolite.
- the antiviral drug can be administered as part of a use or treatment regimen.
- Orally or intravenously administered antivirals such as neuraminidase inhibitors, Cap-dependent endonuclease inhibitors and the like can be included in a use or treatment regimen.
- the pharmaceutically acceptable fluid as disclosed herein can include antiviral compounds with specific or general efficacy against coronaviruses, influenza, and the like to address and treat specific pathogenic infections.
- antiviral compounds include remdesivir, molnupiravir and the like.
- the present disclosure contemplates the use of such materials in suitable combination with the pharmaceutically acceptable fluid disclosed herein used prophylactic ally either upon exposure or routinely, as with at risk patient populations such as those with chronic illnesses or recognized co-morbidities.
- the present disclosure also contemplates administration or use of such materials in suitable combination with the pharmaceutically acceptable fluid disclosed herein after confirmed diagnosis to symptomatic or asymptomatic individuals. Without being bound to any theory, it is believed that the treatment with or use of the combination as disclosed can provide an effective therapy regimen to address respiratory illnesses including but not limited to SARS- CoV-2, influenza, and the like.
- the pharmaceutically acceptable fluid can include at least one adrenergic P2 receptor agonist active pharmaceutical ingredient.
- Suitable adrenergic P2 receptor agonists can be those that can be administered by inhalation or other methods of introduction into contact with at least one region of the respiratory tract of the patient. Without being bound to any theory, it is believed that the adrenergic P2 receptor agonists that are employed can act to cause localized smooth muscle dilation that can result in dilation of bronchial passages.
- Non-limiting examples of adrenergic P2 receptor agonist that can be employed in the pharmaceutically acceptable fluid as disclosed herein can include those selected from the group consisting of bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol, arformoterol, bambuterol, clenbuterol, formoterol, salmeterol, abediterol, carmoterol, indacaterol, olodaterol, vilanterol, isoxsuprine, mabuterol, zilpaterol, and mixtures thereof.
- the adrenergic 2 receptor agonist can be administered in a composition in combination with the pharmaceutically acceptable fluid. It is also contemplated the adrenergic 02 receptor agonist can be co-administered with the with the pharmaceutically acceptable fluid disclosed herein.
- the pharmaceutically acceptable fluid can include at least one steroid medication selected from the group consisting of compounds such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and combinations thereof. It is contemplated that, in certain situations, the steroid can be administered in a composition in combination with the pharmaceutically acceptable fluid. It is also contemplated the steroid can be co-administered with the pharmaceutically acceptable fluid disclosed herein.
- the pharmaceutically acceptable fluid can include at least one inhalable non-steroidal medication such as those selected from the group consisting of compounds such as metabisulphite, adenosine, L-aspirin, indomethacin and combinations thereof.
- the non-steroidal medication can be administered in a composition in combination with the pharmaceutically acceptable fluid. It is also contemplated the non-steroidal medication can be co-administered with the pharmaceutically acceptable fluid disclosed herein.
- muscarinic antagonists can be one or more compounds selected from the group consisting of atropine, scopolamine, glycopyrrolate, and ipratropium bromide and the like.
- the method as disclosed herein can be employed as a stand-alone treatment regimen or can be employed in combination with other therapy regimens suitable to address and treat the specific respiratory infection.
- the method can also be used alone or in combination with one or more procedures that can be employed prophylactically to reduce or minimize the risk or symptoms for individuals subsequent to exposure but prior to the onset of symptoms.
- the method as disclosed herein can be employed as a stand-alone treatment regimen for use for individuals at risk for complications or sub-optimal outcomes from respiratory infections.
- Non-limiting examples of such individuals include those with compromised immune systems, compromised pulmonary function, cardiac challenges, as well as co-morbidities such as age, body weight (obesity) and the like.
- the method as disclosed herein can also include the step of administering a composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof into contact with the at least one region the respiratory tract of the patient.
- the administration of hypochlorous acid, hydrogen peroxide and mixtures thereof can occur prior to or contemporaneous with the step in which at least one dose of a pharmaceutically acceptable fluid is brought into contact with the at least one region of the respiratory tract of the patient.
- the composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof can be co-administered with the pharmaceutically acceptable fluid material as disclosed herein.
- the composition comprising hypochlorous acid, hydrogen peroxide and mixtures thereof as dispersed can be configured or sized to contact the same region of the respiratory tract as the pharmaceutically acceptable fluid material or different region.
- the pharmaceutically acceptable fluid can include a compound produced by the process that comprises the steps of: contacting a volume of a concentrated inorganic acid in liquid form having a molarity of at least 7, a density between 22° and 70° baume and a specific gravity between 1.18 and 1.93 in a reaction vessel with an inorganic hydroxide present in a volume sufficient to produce a solid material present in the resulting composition as at least one of a precipitate, a suspended solid, a colloidal suspension; and removing the solid material from the resulting liquid material, wherein the resulting material is a viscous material having a molarity of 200 to 150 M.
- the composition produced by the method as disclosed herein can be formed by the addition of a suitable inorganic hydroxide to a suitable inorganic acid.
- the inorganic acid may have a density between 22° and 70° baume; with specific gravities between about 1.18 and 1.93. In certain embodiments, it is contemplated that the inorganic acid will have a density between 50° and 67° baume; with specific gravities between 1.53 and 1.85.
- the inorganic acid can be either a monoatomic acid or a polyatomic acid.
- the inorganic acid that is employed in the process described can be homogenous or can be a mixture of various acid compounds that fall within the defined parameters. It is also contemplated that the acid may be a mixture that includes one or more acid compounds that fall outside the contemplated parameters but in combination with other materials will provide an average acid composition value in the range specified.
- the inorganic acid or acids employed can be of any suitable grade or purity. In certain instances, tech grade and/or food grade material can be employed successfully in various applications.
- the inorganic acid can be contained in any suitable reaction vessel in liquid form at any suitable volume.
- the reaction vessel can be non-reactive beaker of suitable volume.
- the volume of acid employed can be as small as 50 ml. Larger volumes up to and including 5000 gallons or greater are also considered to be within the purview of this disclosure.
- the inorganic acid employed can be maintained in the reaction vessel at a suitable temperature such as a temperature at or around ambient. It is within the purview of this disclosure to maintain the initial inorganic acid in a range between approximately 23° and about 70°C. However lower temperatures in the range of 15° and about 40°C can also be employed.
- the inorganic acid is agitated by suitable means to impart mechanical energy in a range between approximately 0.5 HP and 3 HP with agitation levels imparting mechanical energy between 1 and 2.5 HP being employed in certain applications of the process.
- Agitation can be imparted by a variety of suitable mechanical means including, but not limited to, DC servo drive, electric impeller, magnetic stirrer, chemical inductor, and the like.
- Agitation can commence at an interval immediately prior to hydroxide addition and can continue for an interval during at least a portion of the hydroxide introduction step.
- the acid material of choice may be a concentrated acid with an average molarity (M) of at least 7 or above. In certain procedures, the average molarity will be at least 10 or above; with an average molarity between 7 and 10 being useful in certain applications.
- the acid material of choice employed may exist as a pure liquid, a liquid slurry or as an aqueous solution of the dissolved acid in essentially concentrated form.
- Suitable acid materials can be either aqueous or non-aqueous materials.
- Nonlimiting examples of suitable acid materials can include one or more of the following: hydrochloric acid, nitric acid, phosphoric acid, chloric acid, perchloric acid, chromic acid, sulfuric acid, permanganic acid, bromic acid, hydrobromic acid, hydrofluoric acid, iodic acid, fluoboric acid, fluosilicic acid, fluotitanic acid.
- the defined volume of a liquid concentrated strong acid employed can be sulfuric acid having a specific gravity between 55° and 67° baume. This material can be placed in the reaction vessel and mechanically agitated at a temperature between 16° and 70°C.
- a measured, defined quantity of suitable hydroxide material can be added to an agitating acid, such as concentrated sulfuric acid, that is present in the non-reactive vessel in a measured, defined amount.
- the amount of hydroxide that is added will be that sufficient to produce a solid material that is present in the composition as a precipitate and/or a suspended solid or colloidal suspension.
- the hydroxide material employed can be a water-soluble or partially water-soluble inorganic hydroxide.
- Partially water-soluble hydroxides employed in the process as disclosed herein will generally be those which exhibit miscibility with the acid material to which they are added.
- suitable partially water-soluble inorganic hydroxides will be those that exhibit at least 50% miscibility in the associated acid.
- the inorganic hydroxide can be either anhydrous or hydrated.
- Non-limiting examples of water-soluble inorganic hydroxides include water soluble alkali metal hydroxides, alkaline earth metal hydroxides and rare earth hydroxides; either alone or in combination with one another. Other hydroxides are also considered to be within the purview of this disclosure.
- Water-solubility as the term is defined in conjunction with the hydroxide material that will be employed is defined as a material exhibiting dissolution characteristics of 75% or greater in water at standard temperature and pressure.
- the hydroxide that is utilized typically is a liquid material that can be introduced into the acid material. The hydroxide can be introduced as a true solution, a suspension or a super- saturated slurry.
- the concentration of the inorganic hydroxide in aqueous solution can be dependent on the concentration of the associated acid to which it is introduced.
- suitable concentrations for the hydroxide material are hydroxide concentrations 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.
- Inorganic hydroxide solutions when employed may have concentration of inorganic hydroxide between 5 and 50% of a 5-mole material, with concentration between 5 and 20% being employed in certain applications.
- the inorganic hydroxide material in certain processes, can be calcium hydroxide in a suitable aqueous solution such as is present as slaked lime.
- the inorganic hydroxide in liquid or fluid form is introduced into the agitating acid material in one or more metered volumes over a defined interval to provide a defined resonance time.
- the resonance time in this process as outlined is considered to be the time interval necessary to promote and provide the environment in which the hydronium ion material as disclosed herein develops.
- the resonance time interval as employed in the process as disclosed herein is typically between 12 and 120 hours with resonance time intervals between 24 and 72 hours and increments therein being utilized in certain applications.
- the inorganic hydroxide is introduced into the acid at the upper surface of the agitating volume in a plurality of metered volumes.
- the total amount of inorganic hydroxide material will be introduced as a plurality of measured portions over the resonance time interval.
- Front-loaded metered addition being employed in many instances. “Front-loaded metered addition”, as the term is used herein, is taken to mean addition of the total hydroxide volume with a greater portion being added during the initial portion of the resonance time. An initial percentage of the desired resonance time -considered to be between the first 25% and 50% of the total resonance time.
- each metered volume that is added can be equal or can vary based on such non-limiting factors as external process conditions, in situ process conditions, specific material characteristics, and the like. It is contemplated that the number of metered volumes can be between 3 and 12.
- the interval between additions of each metered volume can be between 5 and 60 minutes in certain applications of the process as disclosed. The actual addition interval can be between 60 minutes to five hours in certain applications.
- 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 5 metered increments of 2 ml per minute, with or without admixture.
- Addition of the hydroxide material to the sulfuric acid produces a material having increasing liquid turbidity.
- Increasing liquid turbidity is indicative of calcium sulfate solids forming as precipitate.
- the produced calcium sulfate can be removed in a fashion that is coordinated with continued hydroxide addition to provide a coordinated concentration of suspended and dissolved solids.
- the resulting material is subjected to a non-bi-polar magnetic field at a value greater than 2000 gauss; with magnetic fields great than 2 million gauss being employed in certain applications. It is contemplated that a magnetic field between 10,000 and 2 million gauss can be employed in certain situations.
- the magnetic field can be produced by various suitable means.
- a suitable magnetic field generator is found in US 7,122,269 to Wurzburger, the specification of which is incorporated by reference herein.
- Solid material generated during the process and present as precipitate or suspended solids can be removed by any suitable means.
- removal means include, but need not be limited to, the following: gravimetric, forced filtration, centrifuge, reverse osmosis and the like.
- the material produced by the process as disclosed can be present as a shelf-stable viscous liquid that is believed to be stable for at least one year when stored at ambient temperature and between 50 to 75% relative humidity.
- the stable electrolyte composition of matter can be used neat in various end use applications.
- the stable electrolyte composition of matter can have a 1.87 to 1.78 molar material that contains 8 to 9 % of the total moles of acid protons that are not charged balanced.
- the liquid material can contain between 4% and 9% of total moles of acid protons that are charge balanced; between 5% and 9% of total moles of charge balanced acid; between 6% and 9% of total moles of charge balanced acid; between 7% and 9% of total moles of charge balanced acid; between 8% and 9% of total moles of charge balanced acid.
- the resulting material can be further purified as suitable and can be employed as the liquid material in the pharmaceutically acceptable material solution as disclosed herein. It is also within the purview of this disclosure to subject the resulting material to further processing as desired or required. Non-limiting examples of such processing can include subjecting the resulting fluid to as suitable magnetic field or fields.
- the resulting liquid material can be subjected to a non-bi- polar magnetic field at a value greater than 2000 gauss; with magnetic fields greater than 2 million gauss being employed in certain applications. It is contemplated that a magnetic field between 10,000 gauss and 2 million gauss can be employed in certain situations.
- Suitable ranges include between 10,000 gauss and 20,000 gauss; between 10,000 gauss and 30,000 gauss; between 10,000 gauss and 40,000 gauss; between 10,000 gauss and 50,000 gauss; between 10,000 gauss and 60,000 gauss; between 10,000 gauss and 70,000 gauss; between 10,000 gauss and 80,000 gauss; between 10,000 gauss and 90,000 gauss; between 10,000 gauss and 100,000 gauss; between 50,000 gauss and 100,000 gauss; between 50,000 gauss and 150,000 gauss; between 50,000 gauss between 200,000 gauss; between 50,000 gauss and 250,000 gauss; between 100,000 gauss and 200,000 gauss; between 100,000 gauss and 250,000 gauss; between 100,000 gauss and 300,000 gauss; between 100,000 gauss and 350,000 gauss; between 100,000 gauss and
- the material produced by the process disclosed herein has molarity of 200 to 150 M strength, and 187 to 178 M strength in certain instances, when measured titrametrically through hydrogen coulometry and via FTIR spectral analysis.
- the material has a gravimetric range greater than 1.15; with ranges greater than 1.9 in in certain instances.
- the material, when analyzed, is shown to yield up to 1300 volumetric times of orthohydrogen per cubic ml versus hydrogen contained in a mole of water.
- the material produced by this process can be introduced into water to produce the composition employed herein. It is contemplated that the use solution that is produced will contain between 0.5 volume% and 10 volume% of the produce produced in certain embodiments. In certain embodiments, the therapeutic material will contain between 0.5 and 8 volume %; between 0.5 and 7 volume %; between 0.5 and 6 volume %; between 0.5 and 5 volume %; between 0.5 volume %; between 0.5 and 4 volume %; between 0.5 and 3 volume %; between 0.5 and 2 volume %; between 0.5 and 1 volume %; between 1 and 10 volume % 1 and 8 volume %; between 1 and 7 volume %; between 1 and 6 volume %; between 1 and 5 volume %; between 1 volume %; between 1 and 4 volume %; between 1 and 3 volume %; between 1 and 2 volume %; between 2 and 10 volume % 2 and 8 volume %; between 2 and 7 volume %; between 2 and 6 volume %; between 2 and 5 volume %; between 2 and 4 volume %;
- Z is one of a monoatomic ion from Groups 14 through 17 having a charge between -1 and -3 or a poly atomic ion having a charge between -1 and -3.
- monatomic constituents that can be employed as Z include Group 17 halides such as fluoride, chloride, iodide and bromide; Group 15 materials such as nitrides and phosphides and Group 16 materials such as oxides and sulfides.
- Polyatomic constituents include carbonate, hydrogen carbonate, chromate, nitride, nitrate, permanganate, phosphate, sulfate, sulfite, chlorite, perchlorate, hydrobromite, bromite, bromate, iodide, hydrogen sulfate, hydrogen sulfite. It is contemplated that the composition of matter can be composed of a single one to the materials listed above or can be a combination of one or more of the compounds listed.
- x is an integer between 3 and 9, with x being an integer between 3 and 6 in some embodiments.
- y is an integer between 1 and 10; while in other embodiments y is an integer between 1 and 5.
- x is an odd integer between 3 and 12; y is an integer between 1 and 20; and Z is one of a group 14 through 17 monoatomic ion having a charge between -1 and -3 or a poly atomic ion having a charge between -1 and -3 as outlined above, some embodiments having x between 3 and 9 and y being an integer between 1 and 5.
- the ion complex as disclosed herein is believed to be stable and may be capable of functioning as an oxy gen donor in the presence of the environment created to generate the same.
- the material mayhaveany suitable structure and solvation that is generally stable and capable of functioningas an oxygen donor.
- Particular embodiments of the resulting solution will include a concentration of the ion as depicted by the following formula: wherein x is an odd integer > 3.
- hydronium ion complex can be broadly defined as the cluster ofmolecules that surround the cation L 4- where x is an integer greater than or equal to 3.
- the hydronium ion complex may include at least four additional hydrogen molecules and a stoichiometric proportion of oxygen molecules complexed thereto as water molecules.
- hydronium ion complexes will exist as solvated structures of hydronium ions having the formula: H s + (? 2 y+ wherein x is an integer between 1 and 4; and y is an integer between 0 and 2.
- an core is protonated by multiple H2O molecules.
- the hydronium complexes present in the composition of matter as disclosed herein can exist as Eigen complex cations, Zundel complex cations or mixtures of the two.
- the Eigen solvation structure can have the hydronium ion at the center of an H9O4+ structure with the hydronium complex being strongly bonded to three neighboring water molecules.
- the Zundel solvation complex can be an H5O2+ complex in which the proton is shared equally by two water molecules.
- the solvation complexes typically exist in equilibrium between Eigen solvation structure and Zundel solvation structure.
- therespective solvation structure complexes generally existedin an equilibriumstate thatfavorstheZundel solvation structure.
- the inclusion of the material produced by the process as outlined is based, at least in part, on the unexpected discovery that stable materials can be produced in which hydronium ion exists in an equilibrium state that favors the Eigen complex.
- the present disclosure is also predicated on the unexpected discovery that increases in the concentration of the Eigen complex in a process stream can provide a class of novel enhanced oxygen-donor oxonium materials.
- the process stream as disclosed herein can have an Eigen solvation state to Zundel solvation state ratio between 1.2 to 1 and 15 to 1 in certain embodiments; with ratios between 1.2 to 1 and 5 to 1 in other embodiments.
- the novel enhanced oxygen-donor oxonium material as disclosed herein can be generally described as a thermodynamically stable aqueous acid solution that is buffered with an excess of proton ions.
- the excess of protons ions can be in an amount between 10% and 50% excess hydrogen ions as measured by free hydrogen content.
- composition of matter can have the following chemical structure: wherein x is an odd integer between 3-11; y is an integer between 1 and 10; and
- Z is a polyatomic ion or monoatomic ion.
- the polyatomic ion can be derived from an ion derived from an acid having the ability to donate one or more protons.
- the associated acid can be one that would have a pK a values > 1,7 at 23°C.
- the ion employed can be one having a charge of +2 or greater.
- Non-limiting examples of such ions include sulfate, carbonate, phosphate, oxalate, chromate, dichromate, pyrophosphate and mixtures thereof.
- the polyatomic ion can be derived from mixtures that include polyatomic ion mixtures that include ions derived from acids having pK a values ⁇ 1.7.
- the composition of matter is composed of a stoichiometrically balanced chemical composition of at least one of the following: hydrogen (1+), triaqua-p3-oxotri sulfate (1:1); hydrogen (1+), triaqua-p3-oxotri carbonate (1:1), hydrogen (1+), triaqua-p3-oxotri phosphate, (1:1); hydrogen (1+), triaqua-p3-oxotri oxalate (1:1); hydrogen (1+), triaqua-p3-oxotri chromate (1:1) hydrogen (1+), triaqua-p3-oxotri dichromate (1:1), hydrogen (1+), triaqua-p3-oxotri pyrophosphate (1:1), and mixtures thereof in admixture with water.
- fluid material can be nebulized, aerosolized, made into a particulate to facilitate administration.
- Administration of fluid material can be accomplished by direct application as swabbing, spraying, rinsing, emersion, and the like. It is also contemplated that aerosolized or nebulized material can be administered by inhalation if desired or required.
- the pharmaceutically acceptable fluid material(s) can be processed into droplets having a size suitable for inhalation uptake.
- suitable droplet size include droplets having sizes between 0.1 and 20 pm; between 0.1 and 18 pm; between 0.1 and 17 pm; between 0.1 and 16 pm; between 0.1 and 15 pm; between 0.1 and 14 pm; between 0.1 and 13 pm; between 0.1 and 12 pm; between 0.1 and 12 pm; between 0.1 and
- the acid compound(s) employed can be selected based on the pharmacodynamics and/or pharmacokinetics of the acid compound(s).
- the low pH antimicrobial inhalant making up the pharmaceutically acceptable fluid material can include a dilute sulfuric acid formulation due to its desirable pharmacodynamics and pharmacokinetics. It is believed that the sulfuric acid material will undergo a redox reaction to generate protons (H+) to be absorbed in the mucosa while the sulfate anions will be non-specifically biodistributed into the surrounding tissue for immediate clearance.
- Inhaled inorganic acids such as sulfuric acid at the concentrations contemplated in the present disclosure rapidly dissociate within the proximal pulmonary architecture, absorbing the sulfate ions into the bloodstream.
- the half-life of the 35 S radiolabeled sulfuric acid in the dog studies varied significantly depending on the specific respiratory system administration site. Deep-lung sulfuric acid administration demonstrated a 2- 3 minute half-life similar to the rats and guinea pigs.
- the half-life was significantly longer for administration to higher regions within the bronchi and sinus cavities, (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)).
- the therapeutic inhalant demonstrates anti-viral therapeutic potential in the peripheral lung tissues with a half-life of ⁇ 2-3 minutes until absorption. Although sulfuric acid neutralization was not directly measured within the respiratory system, previous in vitro studies predict virus, bacteria, and fungi replication inhibition within 1 minute.
- kits for use in the treatment or prevention of a respiratory illness that includes at least one container for administering the pharmaceutically acceptable fluid into the respiratory tract of a patient in need thereof that is connectable to a respiratory delivery device having at least one chamber.
- the at least one chamber contains at least one dose a pharmaceutically acceptable fluid as disclosed herein.
- the pharmaceutically acceptable fluid includes a liquid carrier and at least one acid compound, wherein the pharmaceutically acceptable fluid has a pH less than 3.0 and a container for administering the pharmaceutically acceptable fluid into the respiratory tract of a patient in need thereof.
- the kit can alco include means for administering the pharmaceutically acceptable fluid to at least a portion of the respiratory tract of the patient in need thereof.
- suitable means for administering the pharmaceutically acceptable fluid to at least a portion of the respiratory tract of the patient in need thereof can include devices like inhalers, metered dose inhalers, nebulizers such as PARI nebulizers and the like.
- the administering means can include at least one mechanism that delivers the fluid in a vaporized, atomized or nebulized state.
- Nebulizer as the term is used herein is a drug delivery device used to administer medication in a form that can be inhaled into the lungs using oxygen, compressed air, ultrasonic power or the like to break up solutions into small aerosol droplets.
- nebulizers that can be used to dispense the pharmaceutically acceptable fluid as disclosed herein can be a jet nebulizer, a soft mist inhaler, an ultrasonic nebulizer or the like.
- PARI nebulizers are commercially available PARI Respiratory Equipment, Inc., Midlothian VA.
- the kit can also include a suitable mask or oral insert to direct material into the oral and/or nasal cavity of the patient.
- a respiratory inhalant device that includes a reservoir having at least one interior chamber and a dispenser in fluid communication with the reservoir.
- the container includes pharmaceutically acceptable fluid as disclosed herein contained in the at least one interior chamber.
- the respiratory inhalant device also includes a dispenser in fluid communication with the reservoir that is configured to dispense a measured portion of the pharmaceutically acceptable fluid from the reservoir into inhalable contact with at least one portion of a respiratory tract of a patient having a respiratory illness.
- the dispenser can include suitable tubing and an outlet member.
- the outlet member can be configured as a mask that can be removably fitted to the patient or pipe-like member that can be removably inserted into the mouth of the patient, in certain embodiments.
- Other delivery members may include nasal cannula, or the like.
- the respiratory illness can be at least one of a viral pathogen, a bacterial pathogen, a fungal pathogen such as a viral pathogen such as one of coronavirus, an influenza virus, a parainfluenza virus, respiratory syncytial virus, a rhinovirus.
- the viral pathogen can be a beta coronavirus selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and mixtures thereof.
- An antimicrobial respiratory inhalant composed of the pharmaceutically acceptable fluid according to the present disclosure was prepared by admixing a pharmaceutically acceptable grade of sulfuric acid with water to provide pH in the various values indicated in the examples as follow.
- patients using an inhalation method such as nebulizer administration would be inhaling the therapeutic material comprising a pharmaceutically acceptable fluid as disclosed herein continuously for several minutes in a specific concentration either continuously or in a series of discrete dose intervals with potentially multiple times per day potentially over multiple days.
- any reduction in pathogen load in vitro may be compounded in vivo to achieve higher efficacy over the treatment period.
- an in vitro efficacy such as that demonstrated in the tests discussed herein that is lower than 1 log may provide an acceptable efficacy in vivo when administered as outlined herein.
- Toxicity studies were performed with a formulation of sulfuric acid solution 50 times more concentrated than an inhalation therapeutic prepared according to the present disclosure. These studies included acute inhalation toxicity, acute oral toxicity, acute dermal toxicity, skin sensitivity, eye sensitivity and Local Lymph Node Assay (LLNA). [00129] All six acute toxicity studies demonstrated little to no toxicity with a 50X concentration version of the therapeutic inhalation formulation. Since this is a respiratory inhalant, the acute inhalation toxicity study is particularly important. This study with 5 male and 5 female rats, demonstrated irregular breathing after dosing, but all 10 rats recovered. The results are summarized in Table 1.
- the as-received pH measurements were of the test materials as received by the test laboratory.
- the ASTM antimicrobial test procedures mix 9 parts test material with 1 part medium containing the pathogen.
- the as-applied pH is the pH after mixing, which is what is seen by the pathogen.
- the test material is neutralized, and the pathogens are counted and compared with the control.
- Albuterol sulfate This comparative example discusses the potential of reformulating one of the world’s most common respiratory inhalants, Albuterol sulfate, in order to provide new antimicrobial properties.
- Albuterol is typically formulated with sulfuric acid as an adduct to enhance stability and shelf-life of the active albuterol ingredient.
- Albuterol sulfate has been used for decades without harmful effects including regularly by asthmatics, a patient population that has higher sensitivity to respiratory irritants.
- the pH of albuterol is typically 3.5.
- composition was composed of sulfuric acid plus albuterol formulation at 3.1 pH that was tested closely matches a commercial albuterol sulfate formulation at the low end of the pH range with this well-established therapeutic.
- Albuterol sulfate as available and administered is not recognized to have any antimicrobial properties.
- Albuterol sulfate tests conducted confirm that albuterol sulfate at its lowest therapeutically approved pH of 3.1 demonstrated no efficacy against S. aureus or P. aeruginosa bacteria as determined by 1 log decrease in pathogen count at one minute.
- Multidrug resistant Pseudomonas aeruginosa has one of the higher mortality rates of any respiratory bacterial infection, particularly in patients with chronic respiratory diseases such as cystic fibrosis and chronic obstructive pulmonary disease. These tests demonstrate that the widely used albuterol sulfate therapeutic, when reformulated with additional sulfuric acid can function as a potential therapeutic against this pathogen and may have particular utility for populations with pre-existing chronic respiratory diseases.
- Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis, and is estimated to have caused approximately 335,000 (240,000- 460,000) deaths in children aged ⁇ 5 years in 2015 globally. Due to the prevalence and mortality of S. pneumoniae a wide range of acid formulations were tested against this common pathogen to determine what variables may affect efficacy. The purpose of the tests performed was to determine what pH is required to achieve Ilog (90%) efficacy in 1 minute against S. pneumoniae using various acid formulations.
- the stronger organic acids including benzenesulfonic acid, trichloroacetic acid, hydroxyacetic acid, monochloroacetic acid and trifluoroacetic acid exhibit higher efficacy than the inorganic acids in the range of 1.9 pH (example 39 and examples 42-44).
- the weaker organic acids when used alone, generally cannot reach the required pH range of ⁇ 2.0 pH required for efficacy. However, these weaker organic acids can be mixed with inorganic acids to meet the desired pH range of ⁇ 2.0, and these mixed acid solutions of a weak organic and inorganic acid can demonstrate better efficacy than the inorganic acid alone at the same pH level.
- Amino acids are weak organic acids that are pharmaceutically acceptable and can be formulated with stronger inorganic acids to provide improved efficacy.
- Two of the more acidic amino acids are aspartic acid and glutamic acid.
- Formulation of aspartic acid or glutamic acid and hydrochloric acid at 1.98 pH exhibit 0.62-0.66 log efficacy while hydrochloric at the same pH level exhibits no little efficacy (examples 45, 42 and 31).
- Adding aspartic acid or glutamic acid to inorganic acids such as sulfuric, hydrochloric and hydrobromic may offer better efficacy in a higher pH formulation with less deleterious effect.
- Acetic acid inhalation has been proposed as a potential adjunctive therapy for non-severe 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 discussed to determine if acetic acid could be used as an acidic antimicrobial inhalant therapeutic. Studies indicate that acetic acid has demonstrated efficacy as a disinfectant on hard surfaces against the SARS-CoV-2 virus with 41og efficacy in 1 minute using a 4% concentration with a 2.68pH. (see J. Yoshimoto, Virucidal effect of acetic acid and vinegar on SARS-CoV-2).
- a 0.35% acetic acid concentration was measured to have a pH of approximately 2.98, and a 0.01% concentration was measured to have a pH of 3.77
- Fungi tested Aspergillus fumigatus ATCC 36607, Rhizopus microspores ATCC 52807, Cryptococcous neoformans ATCC 66031
- the sulfuric acid formulation outlined above demonstrates limited efficacy (0.121og/25%) on Mycobacterium terrae, used as a surrogate for Mycobacterium tuberculosis.
- the 1.9 pH sulfuric acid formulation was effective on Aspergillus fumigatus and Rhizopus microspores demonstrating efficacy against some forms of fungi. It is also noted that R. microsporus is a spore producing fungi, and these results appear to support conclusions of efficacy at killing fungi spores as well as active forms of the fungi.
- Mycobacterium terrae is recognized as a surrogate for Mycobacterium Tuberculosis, which is one of the world’s most deadly pathogens.
- M. tuberculosis killed 1.4 million people, making it the greatest single infectious agent cause of death in the world (prior to COVID- 19).
- Over 10 million new cases of tuberculosis are diagnosed annually with growing percentage having multi-drug 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 demonstrated modest efficacy (0.121og 24.56%) on M. terrae. Even at modest in vitro efficacy this formulation may have therapeutic efficacy due to the compounding efficacy from continuous administration. This may be beneficial for tuberculosis patients, and particularly those suffering with antibiotic resistant strains.
- a more concentrated sulfuric formulation with a pH of 1.6 with or without Aspartic acid added demonstrates a 1 log efficacy against M. terrae in 1 minute.
- Acidic antimicrobial inhalation therapeutics are a promising new therapeutic approach to the global issue of tuberculosis.
- a sulfuric acid formulation with a pH of 1.6 with or without aspartic acid appears promising and may be used alone or as an adjunct therapeutic with established antibiotics.
- the sulfuric acid formulation is anticipated to be equally effective on antibiotic sensitive and antibiotic resistant strains for M. tuberculosis.
- acidic antimicrobial inhalant therapeutic as disclosed herein may have minimal or no side effects and be easy to administer to large patient populations.
- COVID- 19 is a global pandemic caused by the SARS-CoV-2 coronavirus. The purpose of these studies was to determine the efficacy of several inorganic acids against the human coronavirus and ascertain the pH required to achieve Ilog efficacy in 1 minute.
- SARS-CoV-2 is a beta coronavirus.
- An alpha coronavirus was used in these studies since this was the closest virus available at the test laboratory.
- the alpha coronavirus is considered to be representative for efficacy on SARS-CoV-2 for purposes of this investigation.
- Results The test results of these studies are shown in Table 8.
- Virus tested Human Coronavirus, 229E strain, ATCC VR-740; Influenza A (H1N1), A/PR/8/34 Strain;
- the viral medium used was EMEM (Eagle’s Minimum Essential Medium) which has a larger effect at increasing the pH between As Received and As Applied than that demonstrated with the bacteria medium. Due to the larger increase in pH, none of the acids achieved the 1 log efficacy goal.
- the EMEM includes live MRC-5 cells which have significant buffer capacity.
- Lower pH sulfuric acid formulations employed to repeat the efficacy test vs human coronavirus demonstrate 1 log efficacy.
- Virus tested Human Coronavirus, 229E strain, ATCC VR-740; Influenza A (H1N1) A/PR/8/34 Strain; Rhinovirus 37
- a lower 1.72 pH sulfuric acid formulation was selected for First-in-Human Clinical Trials to further reduce patient risk.
- a 1.60 sulfuric acid formulation demonstrated >4 log efficacy against an alpha influenza virus. Influenza A is responsible for seasonal flus and the efficacy against this virus may indicate efficacy against this serious pathogen.
- a 1.66 and 1.90 pH sulfuric acid formulation demonstrated >2 log efficacy against a rhinovirus. The rhinovirus is the most common viral infectious agent in humans and is the predominant cause of the common cold. Efficacy against this virus may indicate efficacy against this common pathogen.
- Coronaviruses, influenza viruses and rhinoviruses are all encapsulated respiratory viruses. These tests demonstrate efficacy against all of the common encapsulated respiratory viruses tested using a sulfuric acid formulation of 1.6pH and below. Based on these results it may be assumed that this formulation would be effective on all encapsulated respiratory viruses in an inhalation setting.
- a pharmaceutically acceptable fluid composition containing the product prepared according to the process outlined in Paragraphs 0069 to 0108 as disclosed herein material is produced by is prepared by placing 50 ml portions of concentrated liquid sulfuric acid having a mass fraction H2 SO4 of 98%, an average molarity(M) above 7 and a specific gravity of 66 0 baume in non-reactive vessels and maintaining each of them at 25°C with agitation by a magnetic stirrer to impart mechanical energy of 1 HP to the liquid.
- the calcium hydroxide material employed is a 20% aqueous solution of 5M calcium hydroxide and is introduced in five metered volumes introduced at a rate of 2 ml per minute over an interval of five hours to provide a resonance time of 24 hours. The introduction interval for each metered volume is 30 minutes.
- Turbidity is produced with addition of calcium hydroxide to the sulfuric acid indicating formation of calcium sulfate solids.
- the solids are permitted to precipitate periodically during the process and the precipitate removed from contact with the reacting solution.
- the resulting product Upon completion of the 24-hour resonance time, the resulting product is exposed to a non-bi-polar magnetic field of 2400 gauss resulting in the production of observable precipitate and suspended solids for an interval of 2 hours. The resulting material is centrifuged and force filtered to isolate the precipitate and suspended solids. [00185] The samples are collected for future use. Test samples are subjected to FTIR spectra analysis and titrated with hydrogen coulometry. The sample material has a molarity ranging from 200 to 150 M strength and 187 to 178 M strength. The material has a gravimetric range greater than 1.15; with ranges greater than 1.9 in in certain instances.
- composition is stable and has a 1.87 to 1.78 molar material that contains 8 to 9 % of the total moles of acid protons that are not charged balanced.
- FTIR analysis indicates that the material has the formula hydrogen (1+), triaqua-p3-oxotri sulfate (1:1).
- the respective samples are diluted to produce 5 volume % of the product in water and are found to be shelf 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.
- the 5 vol % material is diluted with distilled deionized water at a ratio of four parts water to 1 part material and package in 2oz/60ml glass bottles with droppers.
- Example 74 The individuals treated with the composition of Example 74 are evaluated at Day 7 and at least 50% of the individuals demonstrate no respiratory symptoms and are negative for COVID-19. At Day 14, these individuals test negative for COVID-19 based on the standard PCR test.
- a second embodiment of the liquid material discussed in Example 74 as disclosed herein is prepared by introducing 50 ml units of concentrated liquid sulfuric acid having a mass fraction H2SO4 of 98%, an average molarity(M) above 7 and a specific gravity of 66 0 baume into a non-reactive vessel and maintaining each at 25°C with agitation by a magnetic stirrer to impart mechanical energy of 1 HP to each liquid unit.
- the sodium hydroxide material employed is a 20% aqueous solution of 5M calcium hydroxide and is introduced in five metered volumes introduced at a rate of 2 ml per minute over an interval of five hours with to provide a resonance time of 24 hours. The introduction interval for each metered volume is 30 minutes.
- Turbidity is produced with addition of calcium hydroxide to the sulfuric acid indicating formation of calcium sulfate solids.
- the solids in each unit are permitted to precipitate periodically during the process and the precipitate is removed from contact with the reacting solution.
- the resulting material is centrifuged and force filtered to isolate the precipitate and suspended solids from the liquid material and respective resulting material units are collected for further use and analysis.
- a 5 ml portion of the material produced according to this method outlined is admixed in a 5 ml portion of deionized and distilled water at standard temperature and pressure.
- the excess hydrogen ion concentration is measured as greater than 15 % by volume and the pH of the material is determined to be 1.
- samples of the materials are diluted with deionized water to provide material that contains 1 % by volume of the respective material in water. These samples are evaluated against a diluted sulfuric acid solution, a dilute sulfuric acid solution with to which calcium sulfate is added to yield 300 ppm and a dilute sulfuric acid component with 400 ppm calcium sulfate and well as a reverse osmosis water control.
- Each test material is initially prepared by simple dilution in a 5% nitric acid matrix.
- the calibration standards are prepared in the same acid matrix to match the samples. However, this preparation leads to high recoveries for calcium which is believed to be a result of the sulfuric acid present in the samples but not present in the calibration standards.
- the calibration standards are re-prepared with a small amount of sulfuric acid in order to match the samples, and the analysis repeated in order to provide better QC recoveries that approach 100%.
- the samples are each diluted with de-ionized water for analysis. The testing is completed using a Mettler Toledo Seven Excellence Meter with a conductivity probe following EPA method 120.1. Predicted conductivity results are presented in Table 11.
- Respective samples as produced are diluted to produce 5 volume % of the product in water and are found to be shelf 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.
- a 5 volume % material is diluted with distilled deionized water at a ratio of four parts water to Ipart material and package in 2oz/60ml glass bottles with droppers.
- Example 79 The individuals treated with the composition of Example 79 are evaluated at Day 7 and at least 50% of the individuals demonstrate no respiratory symptoms. At Day 14, these individuals test negative for COVID-19 based on the standard PCR test.
- Therapeutic Package Material Various 5 vol% solutions of a pharmaceutically acceptable grade of sulfuric acid alone, hydrochloric acid alone or a 50-50 mixture of sulfuric acid and hydrochloric acid, respectively, are prepared and are diluted with deionized water at a ratio of four parts water to Ipart material and are packaged in 2oz/60ml glass bottles with droppers.
- Material is introduced into a PARI nebulizer to produce a particle size of 2.9 pm Mean Mass Aerodynamic Diameter (MMAD) that can be administered to each respective subject via inhalation though as suitable nebulizer mask.
- MMAD Mean Mass Aerodynamic Diameter
- the 4mL dose is anticipated to produce aerosolized sulfuric acid for about 10 minutes, which is one treatment.
- an additional 100 individuals with confirmed cases of COVID 19 as confirmed by PCR testing and presenting with various respiratory symptoms up to and including Acute Respiratory Distress each receive 4 ml doses, every 3 to 4 hours, 4 times daily (10-minute treatment each) for 7 days via nebulizer.
- subjects are randomized to either Arm A who will receive the therapeutic composition of (67 individuals) while 33 condition and age-matched subjects receive a placebo of normal saline solution.
- Treatment commences immediately upon confirmation of COVID 19 with follow-up visits for 14 days post-treatment; at Weeks 3 and 4 after the completion of treatment; and at Month 3 post-treatment.
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Abstract
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CA3200648A CA3200648A1 (fr) | 2020-12-04 | 2021-10-21 | Materiau therapeutique a faible ph et faible toxicite, actif contre au moins un pathogene pour la prise en charge de patients atteints de maladies respiratoires |
US18/265,214 US20240009161A1 (en) | 2020-05-01 | 2021-10-21 | THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES |
CN202180093092.0A CN116829127A (zh) | 2020-12-04 | 2021-10-21 | 对至少一种病原体有效的低pH值且低毒性的用于治疗呼吸道疾病患者的治疗材料 |
EP21802884.3A EP4255389A1 (fr) | 2020-12-04 | 2021-10-21 | Matériau thérapeutique à faible ph et faible toxicité, actif contre au moins un pathogène pour la prise en charge de patients atteints de maladies respiratoires |
KR1020237022309A KR20230129017A (ko) | 2020-12-04 | 2021-10-21 | 호흡기 병을 갖는 환자를 다루기 위한 적어도 하나의병원균에 활성인 낮은 pH 및 낮은 독성을 갖는 치료 물질 |
JP2023533908A JP2023552389A (ja) | 2020-12-04 | 2021-10-21 | 呼吸器疾病を有する患者に対処するための、少なくとも1種の病原体に対して活性な低pHおよび低毒性を有する治療用材料 |
AU2021390439A AU2021390439A1 (en) | 2020-12-04 | 2021-10-21 | THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES |
IL303404A IL303404A (en) | 2020-12-04 | 2021-10-21 | A therapeutic agent with low pH and low toxicity active against at least one pathogen intended for the treatment of patients with respiratory diseases |
US17/547,712 US11642372B2 (en) | 2020-05-01 | 2021-12-10 | Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses |
US17/547,624 US11826382B2 (en) | 2020-05-01 | 2021-12-10 | Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses |
US17/547,794 US20220133786A1 (en) | 2020-05-01 | 2021-12-10 | THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES |
US18/122,478 US12042514B2 (en) | 2020-05-01 | 2023-03-16 | Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses |
DO2023000110A DOP2023000110A (es) | 2020-12-04 | 2023-06-02 | MATERIAL TERAPÉUTICO CON BAJO pH Y DE BAJA TOXICIDAD ACTIVA CONTRA AL MENOS UN PATÓGENO PARA EL TRATAMIENTO DE PACIENTES CON ENFERMEDADES RESPIRATORIAS |
US18/521,859 US20240091253A1 (en) | 2020-05-01 | 2023-11-28 | THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES |
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US17/547,794 Continuation US20220133786A1 (en) | 2020-05-01 | 2021-12-10 | THERAPEUTIC MATERIAL WITH LOW pH AND LOW TOXICITY ACTIVE AGAINST AT LEAST ONE PATHOGEN FOR ADDRESSING PATIENTS WITH RESPIRATORY ILLNESSES |
US17/547,624 Continuation US11826382B2 (en) | 2020-05-01 | 2021-12-10 | Therapeutic material with low pH and low toxicity active against at least one pathogen for addressing patients with respiratory illnesses |
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WO2021001789A1 (fr) * | 2019-07-03 | 2021-01-07 | Apr Applied Pharma Research, S.A. | Utilisations thérapeutiques de solutions acides oxydantes hypotoniques |
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WO2002038154A1 (fr) * | 2000-11-13 | 2002-05-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Nouvelles compositions de medicaments a base de sels de tiotropium et de sels de salmeterol |
US7122269B1 (en) | 2002-05-30 | 2006-10-17 | Wurzburger Stephen R | Hydronium-oxyanion energy cell |
WO2021001789A1 (fr) * | 2019-07-03 | 2021-01-07 | Apr Applied Pharma Research, S.A. | Utilisations thérapeutiques de solutions acides oxydantes hypotoniques |
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