Treatment of respiratory symptoms

Abstract

The present invention relates to a hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease in a patient, preferably a mammal, more preferably a human. The present invention also relates to a hypochlorite solution for use in the prevention or treatment of an inflammatory or autoimmune response, condition or disease in a patient, preferably a mammal, more preferably a human, wherein the administration of the hypochlorite solution is by inhalation of the hypochlorite solution. The hypochlorite solution contains hypochlorite in a concentration range of about 0.005-0.2% by weight (about 50-2000 ppm by weight).

Description

[Technical field]

[0001] The present invention relates to a new approach to the prevention and treatment of respiratory conditions in patients (e.g., mammals, particularly humans) through the use of hypochlorite solutions. The present invention also relates to a new approach to the prevention and treatment of inflammation in patients (e.g., mammals, particularly humans) through the inhalation of hypochlorite solutions. [Background technology]

[0002] Respiratory conditions pose a significant challenge to human health worldwide. A recent WHO report (The Global Impact of Respiratory Disease-2017) highlights: An estimated 65 million people have moderate to severe chronic obstructive pulmonary disease (COPD), of which approximately 3 million die each year. This makes it the third leading cause of death worldwide. Moreover, the number of people with COPD is increasing. Approximately 334 million people suffer from asthma, making it the most common chronic disease of childhood, affecting 14% of children worldwide. The number of children with asthma is also increasing. Acute lower respiratory tract infections are among the top three causes of death and disability in children and adults. Respiratory tract infections caused by influenza, for example, are responsible for 250,000-500,000 deaths each year. Tuberculosis (TB) is another respiratory disease that has historically been a challenge. In 2015, 10.4 million people developed TB. Of these, 1.4 million people died from TB.

[0003] In particular, the unprecedented COVID-19 pandemic has placed enormous pressure on healthcare facilities around the world.

[0004] Thus, there is an urgent need to develop new treatments for respiratory conditions.

[0005] The use of aqueous chlorine in healthcare has been described previously in the context of surface and wound disinfection (see, e.g., Bashford et al, Lancet 1917, 2:595-597; Bunyan, Brit Med J. 1941, 4002-7; and Century Pharmaceuticals Inc., Dakin's solutions product information and material safety data sheet, 2011, http: / / www.dakins.net / index.html).

[0006] However, any such use has been limited by the general knowledge that toxicity associated with the use of aqueous chlorine in health care is problematic, especially for respiratory tissues which may be more sensitive compared to skin tissue.

[0007] The present invention addresses this need by providing a new approach to the prevention and treatment of respiratory conditions in patients (e.g., mammals, particularly humans) by using hypochlorite solutions.The present invention also provides a new approach to the prevention and treatment of inflammation in patients (e.g., mammals, particularly humans) by inhaling hypochlorite solutions.Surprisingly, it has been found that the hypochlorite solutions described herein can be safely administered by inhalation and used to treat the conditions described herein. Summary of the Invention

[0008] According to one aspect of the present invention, there is provided a hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease in a patient, preferably a mammal, more preferably a human. In particular, there is provided a hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease in a patient, preferably a mammal, more preferably a human, the hypochlorite solution comprising hypochlorite in a concentration range of about 0.005-0.2% by weight (about 50-2000 ppm by weight).

[0009] In one embodiment, the respiratory condition or disease may be acute respiratory distress syndrome (ARDS), asthma; bronchitis; chronic obstructive pulmonary disease (COPD); the common cold; a coronavirus disease, e.g., severe acute respiratory syndrome (SARS), COVID-19; cystic fibrosis; influenza; Middle East respiratory syndrome (MERS); pneumonia, e.g., viral pneumonia, bacterial pneumonia and ventilator-associated pneumonia; pulmonary fibrosis; rhinoviral disease; sarcoidosis (e.g., affecting the lungs); tuberculosis; or inflammation of the lung tissue.

[0010] In one embodiment, the respiratory condition or disease can be an acute respiratory condition or disease.

[0011] In one embodiment, administration may be by inhalation of a hypochlorite solution.

[0012] According to another aspect of the present invention, there is provided a hypochlorite solution for use in the prevention or treatment of inflammation or autoimmune response, symptoms or diseases in a patient, preferably a mammal, more preferably a human, and the administration of the hypochlorite solution is by inhalation of the hypochlorite solution.In particular, there is provided a hypochlorite solution for use in the prevention or treatment of inflammation or autoimmune response, symptoms or diseases in a patient, preferably a mammal, more preferably a human, and the hypochlorite solution comprises a hypochlorite concentration range of about 0.005-0.2 wt% (about 50-2000 wtppm).

[0013] In one embodiment, the inflammatory or autoimmune response, condition or disease can be arthritis, such as osteoarthritis; pancreatitis; Sjogren's syndrome; or myasthenia gravis.

[0014] In one embodiment, the inflammatory or autoimmune response, condition or disease may be an acute inflammatory or autoimmune response, condition or disease.

[0015] In one embodiment, administration of the hypochlorite solution by inhalation may be via a nebulizer or inhaler.

[0016] In one embodiment, the hypochlorite may be sodium hypochlorite.

[0017] In one embodiment, the hypochlorite may be in a concentration range of about 0.005 to 0.2% by weight (about 50 to 2000 ppm by weight), more preferably about 0.01 to 0.1% by weight (about 100 to 1000 ppm by weight), even more preferably about 0.015 to 0.075% by weight (about 150 to 750 ppm by weight), even more preferably about 0.025 to 0.075% by weight (about 250 to 750 ppm by weight), and most preferably about 0.04 to 0.06% by weight (about 400 to 600 ppm by weight).

[0018] In one embodiment, the hypochlorite solution may further include sodium chloride.

[0019] In one embodiment, sodium chloride may be in a concentration range of about 0.5-3.0% by weight, more preferably 0.5-1.5% by weight, even more preferably about 0.6-1.3% by weight, even more preferably about 0.7-1.2% by weight, and most preferably about 0.8-1.0% by weight.

[0020] In one embodiment, the hypochlorite solution may have a pH of about 5-11, preferably about 6-10, more preferably about 7-9, and even more preferably about 7-8.

[0021] In one embodiment, the hypochlorite solution may be unbuffered.

[0022] In one embodiment, the hypochlorite solution may be buffered to a pH of about 5-11, preferably about 6-10, more preferably about 7-9, and even more preferably about 7-8.

[0023] In one embodiment, the buffer may be selected from the group consisting of phosphate / phosphate buffer, borate / borate buffer and citrate / citric acid buffer.

[0024] The hypochlorite solution may be an aqueous sodium hypochlorite solution containing sodium hypochlorite, sodium chloride, and the balance water. Preferably, the hypochlorite solution contains 0.005-0.2 wt% sodium hypochlorite (about 50-2000 wt ppm); 0.5-3.0 wt% sodium chloride; and the balance water. The concentrations of sodium hypochlorite and sodium chloride may be as described above.

[0025] The hypochlorite solution may be an aqueous solution of sodium hypochlorite consisting of 0.005-0.2% by weight sodium hypochlorite (about 50-2000 ppm by weight); 0.5-3.0% by weight sodium chloride; and the balance water. The concentrations of sodium hypochlorite and sodium chloride may be in accordance with the above concentrations.

[0026] According to another aspect of the present invention there is provided a method of preventing or treating a respiratory condition or disease comprising administering to a patient in need thereof a therapeutically effective amount of a hypochlorite solution as defined herein.

[0027] According to another aspect of the present invention there is provided a method of preventing or treating an inflammatory or autoimmune response, condition or disease comprising administering to a patient in need thereof a therapeutically effective amount of a hypochlorite solution as defined herein.

[0028] According to another aspect of the present invention there is provided the use of a hypochlorite solution as defined herein in the preparation of a medicament for preventing or treating a respiratory condition or disease in a patient.

[0029] According to another aspect of the invention there is provided use of a hypochlorite solution as defined herein in the preparation of a medicament for preventing or treating an inflammatory or autoimmune response, condition or disease in a patient, wherein administration of the hypochlorite solution is by inhalation of the hypochlorite solution.

[0030] According to another aspect of the present invention there is provided a kit comprising a hypochlorite solution as defined herein and a nebulizer or inhaler.

[0031] According to another aspect of the present invention, there is provided a pharmaceutical composition for use in preventing or treating respiratory symptoms or diseases in patients, preferably mammals, more preferably humans, said pharmaceutical composition comprising hypochlorite solution as described herein and can be administered by inhalation.The pharmaceutical composition can comprise a propellant.The pharmaceutical composition can be a medicinal aerosol composition suitable for inhalation.

[0032] According to another aspect of the present invention, a pharmaceutical container is provided for use with an inhalation device, the pharmaceutical container comprising the hypochlorite solution described herein and optionally a propellant.The inhalation device can be an inhaler.The inhalation device can be a nebulizer.The pharmaceutical container can be a pressurized pharmaceutical container, for example a pressurized pharmaceutical container suitable for use with an inhaler.

[0033] The present invention provides new and effective treatment options for respiratory, inflammatory and / or autoimmune conditions.

[0034] The invention is further illustrated in the following non-limiting figures. [Brief description of the drawings]

[0035] [Figure 1] Shown are IL-6 cells of Example 1 dialyzed against a control saline solution (0.85% by weight) to determine cytokine functionality. [Diagram 2] IL-6 cells of Example 1 were dialyzed against a solution of Composition 1 to determine cytokine functionality. [Diagram 3] IL-6 cells of Example 1 dialyzed against a solution of Composition 2 to determine cytokine functionality. [Figure 4] Shown are IL-10 cells of Example 2 dialyzed against a control saline solution (0.85% by weight) to determine cytokine functionality. [Diagram 5] IL-10 cells of Example 2 dialyzed against a solution of Composition 1 to determine cytokine functionality. [Figure 6] IL-10 cells of Example 2 dialyzed against a solution of Composition 2 to determine cytokine functionality. [Figure 7] MC9 cell survival following exposure to IL-10 is shown for A (Composition 1) and B (Composition 2). [Figure 8] Shows survival of B9 cells following exposure to IL-6 for A (composition 1) and B (composition 2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Detailed Description of the Invention The following embodiments apply to all aspects of the present invention.

[0037] The present invention will now be further described. In the following sections, different aspects of the present invention are defined in more detail. Each aspect so defined can be combined with any other aspect(s) or embodiment(s) unless expressly indicated otherwise. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature(s) indicated as being preferred or advantageous.

[0038] In this application, a number of general terms and phrases are used, which should be interpreted as follows.

[0039] The term "treat" as used herein, unless otherwise specified, means to reverse, attenuate, alleviate or inhibit the progression of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treat as used herein can also include prophylactic treatment, i.e., treatment designed to prevent the occurrence of a condition or minimize the likelihood of the occurrence of a condition.

[0040] A "patient" includes humans, non-human mammals (eg, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.), and non-mammals (eg, birds, etc.).

[0041] The term "acute", as used herein, unless otherwise specified, means a condition or disease that lasts for a few days (e.g., about 1, 2, 3, 4, 5, 6, or 7 days) to several weeks (e.g., about 1, 2, 3, or 4 weeks). Acute conditions or diseases are typically associated with an acute phase inflammatory response, or a predominance of acute inflammatory cells (e.g., neutrophils) and acute inflammatory exudate.

[0042] The term "chronic," as used herein, unless otherwise specified, means a condition or disease that lasts for a few months (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) to several years (e.g., about 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 years). Chronic conditions or diseases are typically associated with a chronic inflammatory response with the presence of macrophages, monocytes, lymphocytes, and proliferation of blood vessels and connective tissue.

[0043] Acute symptoms or diseases typically occur suddenly and last for a shorter period of time compared to chronic symptoms or diseases.For example, acute symptoms or diseases can be acute phase responses, acute responses mediated by the innate immune system, or systemic acute inflammatory responses.The hypochlorite solution of the present invention is particularly suitable for treating such acute symptoms or diseases, since it has been found that the desired therapeutic effect of the hypochlorite solution is immediate (e.g., within a few minutes to a few hours).Treatment can also be discontinued immediately.

[0044] The hypochlorite solution of the present invention can be used to prevent or treat respiratory symptoms or diseases.Preferably, the respiratory symptoms or diseases are acute respiratory distress syndrome (ARDS); asthma; bronchitis; chronic obstructive pulmonary disease (COPD); cold; coronavirus diseases, such as severe acute respiratory syndrome (SARS), COVID-19; cystic fibrosis; influenza; Middle East respiratory syndrome (MERS); pneumonia, such as viral pneumonia, bacterial pneumonia and ventilator-associated pneumonia; pulmonary fibrosis; rhinovirus disease; sarcoidosis (e.g., affecting the lungs); tuberculosis; or inflammation of lung tissue.

[0045] COVID-19 includes long-term effects and symptoms of COVID-19, referred to herein as "long COVID-19." A "long COVID-19" patient is one who has not fully recovered from COVID-19. A "long COVID-19" patient continues to experience long-term effects or symptoms of the disease for weeks, months, or even years (e.g., at least one month) after contracting COVID-19. A "long COVID-19" patient experiences these long-term effects and symptoms despite the apparent absence of COVID-19 viral load.

[0046] The hypochlorite solution of the present invention can be used to prevent or treat a respiratory condition or disease selected from chronic obstructive pulmonary disease (COPD); pneumonia, such as viral pneumonia, bacterial pneumonia and ventilator-associated pneumonia; and COVID-19.

[0047] Preferably, the respiratory condition or disease is an acute respiratory condition or disease.

[0048] Preferably, administration is by inhalation of the hypochlorite solution, for example, inhalation may be via the nose and / or mouth.

[0049] The hypochlorite solution of the present invention can be used to prevent or treat inflammation or autoimmune response, symptoms or diseases in patients, preferably mammals, more preferably humans, and the administration of the hypochlorite solution is by inhalation of the hypochlorite solution.For example, inhalation can be via nose and / or mouth.Preferably, the inflammation or autoimmune response, symptoms or diseases is arthritis, such as osteoarthritis; pancreatitis; Sjogren's syndrome; or myasthenia gravis.

[0050] Preferably, the inflammatory or autoimmune response, condition or disease is an acute inflammatory or autoimmune response, condition or disease.

[0051] Without wishing to be bound by theory, it is believed that the hypochlorite solution of the present invention acts on known initiators, mediators and regulators of inflammation in epithelial tissues, such as airway epithelium.The solution of the present invention is believed to inhibit the release of inflammatory agents (e.g., cytokines and chemokines) from platelets, but does not prevent platelet aggregation.The solution is also believed to attenuate the effects of cytokines, chemokines and other inflammatory mediators.The proof of concept that such effects can be utilized in the treatment of respiratory symptoms or diseases, and / or inflammatory or autoimmune responses, symptoms or diseases via inhalation is demonstrated in the examples described herein.It has also been found that such effects can be brought about without significant safety issues, as demonstrated in the examples described herein.

[0052] The inventors have surprisingly and unexpectedly discovered that the hypochlorite solution described herein can selectively affect the function of certain anti-inflammatory cytokines.The data described herein demonstrates that the hypochlorite solution described herein causes the loss of IL-6 function in vitro.On the contrary, the hypochlorite solution described herein does not cause significant changes in IL-10 function in vitro.

[0053] Thus, the hypochlorite solution of the present invention can disrupt normal cytokine activity in vitro, thus providing a means of controlling cytokine-dependent cell signaling pathways.IL-6 is known to have pro-inflammatory activity.IL-10 is known to have anti-inflammatory activity.Without wishing to be bound by theory, these data show that the use of hypochlorite solution causes the loss of IL-6 function while maintaining IL-10 function, signaling a net anti-inflammatory effect.

[0054] The inventors have further demonstrated for the first time that inhalation of the hypochlorite solution described herein provides significant relief to patients suffering from several respiratory conditions and diseases.For example, the inventors have demonstrated that inhalation of the hypochlorite solution described herein is an effective treatment for chronic obstructive pulmonary disease (COPD); pneumonia, COVID-19 and long COVID-19.This is believed to be due to the net anti-inflammatory effect described above.

[0055] The hypochlorite solution for use in preventing or treating respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases is preferably administered by inhalation through a nebulizer.The type of nebulizer is not particularly limited as long as it can break the hypochlorite solution into aerosol droplets for inhalation.The nebulizer may be connected to an outlet configured to deliver the hypochlorite solution to the patient through the nose and / or mouth.For example, the outlet may be a mouthpiece or a face mask.

[0056] Non-limiting examples of nebulizers include jet nebulizers (e.g., a nebulizer connected to a source of compressed air or oxygen where the flow of compressed air or oxygen through a solution causes the generation of an aerosol), ultrasonic nebulizers (e.g., a nebulizer connected to a piezoelectric transducer where vibrations from the piezoelectric transducer cause the generation of an aerosol), and mesh nebulizers (e.g., a nebulizer with a membrane with fine pores where forcing the solution through the membrane causes the generation of an aerosol).

[0057] The hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune response, symptoms or diseases is preferably administered by inhalation through an inhaler.For example, the inhaler can be a metered dose inhaler.The metered dose inhaler can be configured to deliver a set dose of hypochlorite solution at each actuation of the metered dose inhaler.

[0058] The hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may be provided in a pharmaceutical container suitable for use with an inhalation device.The pharmaceutical container may include a cartridge or canister suitable for use with an inhalation device, such as an inhaler or nebulizer.

[0059] A hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may be packaged in a cartridge containing a propellant, thus forming a cartridge containing the hypochlorite solution and the propellant.Similarly, a hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may be packaged in a propellant in a canister container, thus forming a canister containing the hypochlorite solution and the propellant.

[0060] The propellant may be a chlorofluorocarbon or a hydrofluoroalkane, or the like.

[0061] The cartridge or canister may be used with an inhaler. The cartridge or canister may be removable from the inhaler. The cartridge or canister may be attached to the inhaler prior to use.

[0062] The hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease and / or an inflammatory or autoimmune response, condition or disease is preferably an aqueous solution.

[0063] The hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease and / or an inflammatory or autoimmune response, condition or disease is preferably a dilute sodium hypochlorite solution.

[0064] The hypochlorite solution may be a hypochlorite solution formulated to optimize therapeutic effects while avoiding adverse effects, which may be accomplished by dilution of the solution to provide a dilute hypochlorite solution.

[0065] Preferably, the hypochlorite solution contains hypochlorite in a concentration range of about 0.005-0.2% by weight (about 50-2000 ppm by weight), more preferably about 0.01-0.1% by weight (about 100-1000 ppm by weight), even more preferably about 0.015-0.075% by weight (about 150-750 ppm by weight), even more preferably about 0.025-0.075% by weight (about 250-750 ppm by weight), and most preferably about 0.04-0.06% by weight (about 400-600 ppm by weight). For example, the hypochlorite solution contains hypochlorite at about 0.05% by weight (about 500 ppm by weight).

[0066] A hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease and / or an inflammatory or autoimmune response, condition or disease may further comprise sodium chloride, preferably in a concentration range of about 0.5-3.0% by weight, more preferably in a concentration range of about 0.5-1.5% by weight, even more preferably in a concentration range of about 0.6-1.3% by weight, still more preferably in a concentration range of about 0.7-1.2% by weight, and most preferably in a concentration range of about 0.8-1.0% by weight.

[0067] A hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease and / or an inflammatory or autoimmune response, condition or disease may be buffered to a pH of about 5 to 11, preferably about 6 to 10, more preferably about 7 to 9, even more preferably about 7 to 8. In some embodiments, the pH may be about 5 to 6, about 6 to 7, about 8 to 9, about 9 to 10, or about 10 to 11. In embodiments, the pH of the hypochlorite solution is greater than 7.5. For example, in embodiments, the pH of the hypochlorite solution is 10 to 11. Hypochlorite ion (ClO - An alkaline pH is generally preferred to ensure the presence of hypochlorite. Acidification of hypochlorite produces hypochlorous acid, a different chemical entity.

[0068] Typically, when used, the pH of the hypochlorite solution is within the range encountered in normal physiology and disease processes, since the hypochlorite solution is preferably pH autoregulating.

[0069] The hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may not be buffered. In a preferred embodiment, the hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases is not buffered. In other words, the hypochlorite solution does not contain a buffering agent. This allows the pH of the hypochlorite solution to be automatically adjusted at the site where it is administered. In an embodiment of the present invention, the composition is such that the pH of the hypochlorite solution is automatically adjusted at the site where it is administered.

[0070] Alternatively, the hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease and / or an inflammatory or autoimmune response, condition or disease may be buffered to a pH of about 5 to 11, preferably about 6 to 10, more preferably about 7 to 9, even more preferably about 7 to 8. In some embodiments, the pH may be about 5 to 6, about 6 to 7, about 8 to 9, about 9 to 10, or about 10 to 11. The buffer may be any suitable buffer conventionally used in the pharmaceutical field, and is preferably selected from the group consisting of phosphate / phosphate buffer, borate / borate buffer, and citrate / citric acid buffer.

[0071] The hypochlorite solution for use in the prevention or treatment of a respiratory condition or disease and / or an inflammatory or autoimmune response, condition or disease is preferably free of a stabiliser.

[0072] The hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may be administered continuously.For example, such continuous administration may be applied to patients on mechanical ventilation, patients in hospital environments, patients in a sedated state, or patients in a coma or induced coma.In some cases, administration may be for a period of about 30 seconds to about 90 minutes. Preferably, the hypochlorite solution is administered for a period of about 1 minute to about 90 minutes, about 5 minutes to about 90 minutes, about 10 minutes to about 90 minutes, about 15 minutes to about 90 minutes, about 20 minutes to about 90 minutes, about 30 minutes to about 90 minutes, about 45 minutes to about 90 minutes, about 60 minutes to about 90 minutes, about 30 seconds to about 60 minutes, about 30 seconds to about 45 minutes, about 30 seconds to about 30 minutes, about 30 seconds to about 20 minutes, about 30 seconds to about 15 minutes, about 30 seconds to about 10 minutes, about 30 seconds to about 5 minutes, or about 30 seconds to about 1 minute.

[0073] The hypochlorite solution for use in preventing or treating respiratory conditions or diseases and / or inflammation or autoimmune responses, conditions or diseases may be administered once, twice, three or four times a day. Preferably, the hypochlorite solution is administered once a day.

[0074] The hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may be administered in a cycle that includes a treatment period of administration of hypochlorite solution once, twice, three or four times a day for a period of several days (e.g., about 1, 2, 3, 4, 5, 6 or 7 days) to several weeks (e.g., about 1, 2, 3 or 4 weeks), followed by a period of several days (e.g., about 1, 2, 3, 4, 5, 6 or 7 days) to several weeks (e.g., about 1, 2, 3 or 4 weeks) during which no hypochlorite solution is administered. The cycle may be repeated at least twice. For example, the cycle may be repeated 2, 3, 4, 5, 6, 7, 8, 9, 10 times, etc.

[0075] The beneficial effects for the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases are particularly pronounced when the patient is treated with a solution having a sodium hypochlorite concentration range of about 0.005-0.2% by weight (about 50-2000 ppm by weight), still more preferably about 0.01-0.1% by weight (about 100-1000 ppm by weight), even more preferably about 0.025-0.075% by weight (about 250-750 ppm by weight); sodium chloride concentration range of about 0.5-1.5% by weight, preferably about 0.6-1.3% by weight, more preferably about 0.7-1.2% by weight, and most preferably about 0.8-1.0% by weight (the solution is not buffered). Even more preferably, the solution comprises sodium hypochlorite at about 0.005-0.2% by weight (about 50-2000 ppm by weight), even more preferably about 0.01-0.1% by weight (about 100-1000 ppm by weight), even more preferably about 0.025-0.075% by weight (about 250-750 ppm by weight); sodium chloride at a concentration range of about 0.5-1.5% by weight, preferably about 0.6-1.3% by weight, more preferably about 0.7-1.2% by weight, and most preferably about 0.8-1.0% by weight; and the solution is not buffered.

[0076] The beneficial effects for the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases are particularly pronounced when the patient is treated with a solution having a concentration range of sodium hypochlorite of about 0.005-0.2% by weight (about 50-2000 ppm by weight), still more preferably about 0.01-0.1% by weight (about 100-1000 ppm by weight), even more preferably about 0.025-0.075% by weight (about 250-750 ppm by weight); sodium chloride of about 0.5-1.5% by weight, preferably about 0.6-1.3% by weight, more preferably about 0.7-1.2% by weight, and most preferably about 0.8-1.0% by weight (the solution is buffered to a pH of about 5-11, preferably about 6-10).

[0077] For example, a solution containing 0.85% sodium chloride and 0.05% (500 ppm) sodium hypochlorite (w / w) has been found to be highly beneficial in preventing and treating respiratory symptoms or diseases and / or inflammatory or autoimmune responses, symptoms or diseases in patients, preferably mammals, more preferably humans. This concentration range has previously been considered in the medical literature to be toxic, particularly to respiratory tissues.

[0078] The hypochlorite should be very pure, for example, ideally produced by electrolysis to ensure its purity as well as its safety and effectiveness.

[0079] The hypochlorite solution for use in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases may be produced from a concentrated hypochlorite solution that is diluted before use in respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases.Preferably, the concentrated hypochlorite solution that is diluted before use is a concentrated sodium hypochlorite solution.When diluted to a suitable diluent to obtain hypochlorite solution, the concentrated hypochlorite solution can be used in the prevention or treatment of respiratory symptoms or diseases and / or inflammation or autoimmune responses, symptoms or diseases.These are as discussed and exemplified above.

[0080] The concentration of hypochlorite in the concentrated hypochlorite solution may range from about 0.5 to 3% by weight. Additionally, the concentrated hypochlorite solution may be buffered to a pH of about 9 to 15, preferably about 11 to 13. Alternatively, the concentrated hypochlorite solution may be unbuffered.

[0081] The concentrated hypochlorite solution may be a stabilized sodium hypochlorite solution at 1% or 2% sodium hypochlorite, for example the disinfectant known as "Milton's solution" containing sodium chloride. The diluted hypochlorite solution may be a 2.5% to 10% solution of Milton's solution diluted in water (the disinfectant solution is 2% sodium hypochlorite). The sodium chloride in the solution is typically at a concentration of 16.5%. The volume ratio of the hypochlorite solution to water may therefore range between 1-10 and 1-40. Alternatively, the diluted hypochlorite solution may be a 5% to 20% solution of Milton's solution diluted in water (the disinfectant solution is 1% sodium hypochlorite). In this case, the volume ratio of the hypochlorite solution to water may range between 1-5 and 1-20.

[0082] In both cases, the amount of water and the amount of sodium hypochlorite solution may be such that the diluted disinfectant solution may be a stabilized sodium hypochlorite solution (sodium hypochlorite is in a concentration range of about 0.005-0.2% by weight (about 50-2000 ppm by weight), more preferably about 0.01-0.1% by weight (about 100-1000 ppm by weight), and even more preferably about 0.025-0.075% by weight (about 250-750 ppm by weight) of sodium hypochlorite). The action of the sodium hypochlorite solution may result in stabilization of the diluted disinfectant solution.

[0083] A suitable device for preparing a hypochlorite solution for use in the present invention is described in WO-A-2011 / 128862.

[0084] Various embodiments and optional features have been described above, it being understood that these embodiments and features can be combined in all practicable permutations.

[0085] Although the above disclosure provides a general description of the subject matter encompassed within the scope of the present invention, including how to make and use the invention and its best mode, the following examples are provided to further enable those skilled in the art to practice the invention and provide a complete written description thereof. However, those skilled in the art will understand that the details of these examples should not be read as limiting the invention, the scope of which should be understood from the claims appended to this disclosure and their equivalents. Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in light of the present disclosure. EXAMPLES

[0086] Examples 1 and 2 - In vitro studies of cytokine function material: Solution of composition 1 - 0.85% by weight saline solution, 0.005% by weight hypochlorite Solution of composition 2 - 0.8% by weight of saline solution, 0.01% by weight of hypochlorite IL-6-dependent cell line B9 (Cat. No. 12121201, murine B cell hybridoma) IL-10-dependent cell line MC9 (ARCC® CRL-8306™, mouse hepatic mast cells) PrestoBlue® (a cell-permeable fluorescent compound for use in cell viability assays)

[0087] Methods: Plasma samples were obtained from volunteers and cells were separated from the plasma. Plasma samples were placed in dialysis tubing with a pore size less than the molecular weight of the cytokine. This was placed in a 1000-fold excess (i.e., 1 ml in 1 L, 2 ml in 2 L, etc.) of dialysis medium.

[0088] The dialysis media were either in saline solution (0.85% by weight) as a control, composition 1 or composition 2, extracted after 5, 15, 30, 45 and 60 minutes and then analyzed, thus determining the functionality of the cytokines.

[0089] Cytokine Function: Functional cellular assays were performed using patient plasma to investigate the ability to support survival of cytokine-dependent cell lines.

[0090] Serum was spiked with human recombinant cytokines: heat-inactivated fetal bovine serum was used and spiked with 100 ng / ml human recombinant IL-6 and IL-10.

[0091] Serum samples were dialysed against either 0.85% by weight saline solution, Composition 1 or Composition 2 as described above.

[0092] IL-6 function was assessed by determining its ability to sustain proliferation of the IL-6-dependent cell line, B9.

[0093] IL-10 function was assessed by determining its ability to sustain proliferation of the IL-10-dependent cell line, MC9.

[0094] Cell viability was measured using fluorescence. A cell-permeable non-fluorescent compound was added to the assay. Live cells maintain a reducing environment that reduces the fluorescent compound, resulting in a color change that fluoresces at 560 nm.

[0095] The degree of fluorescence is measured and directly correlates with the number of viable cells, and the results are shown in Figures 1 to 8.

[0096] In some experiments, high levels of cytokines (i.e., 10 ng / ml) caused a decrease in cell viability. Without wishing to be bound by theory, we hypothesize that this may be due to a prozone-like effect at high cytokine levels and / or that high levels of cytokines may cause cell death or inhibition of cell metabolism in this system.

[0097] Example 1 -IL6 1-3 show the results of cell viability assays of IL-6 spiked serum samples dialyzed against a control saline solution (FIG. 1), composition 1 (FIG. 2) and composition 2 (FIG. 3).

[0098] In these graphs, the positive / negative boundary line represents the mean of the negative control wells (no cytokines added, n=16) plus 3 standard deviations above this mean, anything above this value is considered positive.

[0099] Figures 2 and 3 show that dialysis of serum samples with Composition 1 or Composition 2 of the present invention results in a loss of function of the IL-6 molecule as measured by a cell viability assay.

[0100] Example 2 -IL10 Figures 4-6 show the results of cell viability assays of IL-10 spiked serum samples dialyzed against a control saline solution (Figure 4), composition 1 (Figure 5) and composition 2 (Figure 6).

[0101] In these graphs, the positive / negative boundary line represents the mean of the negative control wells (no cytokines added, n=16) plus 3 standard deviations above this mean, anything above this value is considered positive.

[0102] Experimental data suggests that dialysis of serum samples with Compositions 1 or 2 results in a small loss of function of the IL-10 molecule as measured by cell viability assays, yet IL-10 remains functional. Thus, IL-10 remains functional as the loss of function is within the expected range of in vitro analysis to preserve net survival.

[0103] To further evaluate this, the data was analyzed to examine the cell survival seen after exposure to Composition 1 or Composition 2 as a percentage of that achieved by the same amount of cytokine after dialysis of a 0.85 wt% saline solution (Figure 7) and the results were compared to those obtained for IL-6 analyzed in the same manner (Figure 8).

[0104] From Figure 7, it can be seen that IL-10 receptor binding is preserved, ensuring survival of MC9 cells. In contrast, in Figure 8, after 15 minutes of exposure to Composition 1 or Composition 2, there is almost complete loss of IL-6 function. With complete loss of IL-6 function and negligible effect on IL-10 function, the combined effect is significantly anti-inflammatory. This includes the elimination of pro-inflammatory cytokine effects and the relative increase in anti-inflammatory cytokine effects. Thus, the net effect is anti-inflammatory.

[0105] Examples 3-7 - In vivo patient efficacy studies Treatment involved administration of an aqueous solution of sodium hypochlorite in saline (NaOCl: 0.05% by weight (500 ppm), NaCl: 0.85% by weight - referred to as Composition 3 in Examples 3-7) delivered by a nebulizer.

[0106] Example 3 Male. In his 40s. Pneumonia of viral and bacterial etiology. Pneumonia onset is initially viral and then secondarily bacterial. Treated with composition 3 inhaled 2 x 60 min over 4 days. Diagnosis and resolution of consolidation in the left and right lungs was confirmed by the physician. Recovery was accelerated by continuing administration of nebulized composition 3 for 4 weeks. Return to work (clinical practice) was possible. Effect of composition 3 on viral and bacterial infections and inflammatory responses in the lungs. It was hypothesized that the rapid recovery was due to improved resolution of the innate inflammatory response and resolution of exudates.

[0107] Example 4 Male in his 30s. Treatment for relief of pain / ache and discomfort from chronic pancreatitis (inflammatory disease of the internal organs). Treatment with Composition 3 inhaled from a nebulizer for 20 minutes daily. Resolution of symptoms over 14 days and patient was able to discontinue prescription medications for retrosternal and back pain. Pain symptoms recurred when pulmonary administration of Composition 3 was stopped and resolved with re-administration of nebulized Composition 3. Pathophysiology unknown but may be a systemic manifestation of pulmonary administration of Composition 3.

[0108] Example 5 Female in her 80s. Treatment for prevention of acute episodes in chronic obstructive pulmonary disease. Increase / improvement was observed in blood oxygen saturation. The patient was a long-term COPD patient with increasing frequency of hospitalizations for acute lung / chest infections. Administration of nebulized Composition 3 was initiated for 20 minutes twice daily. The frequency of acute episodes decreased from weekly to every 6 weeks. Improvement was observed in capillary blood oxygenation. The decrease in frequency of acute episodes and increase in blood oxygen saturation are consistent with a decrease in exudate, a decrease in microbial load and improved diffusion across the alveolar membrane.

[0109] Example 6 Female in her 80s. Treatment for pain associated with inflammatory joint disease (osteoarthritis) and pain associated with autoimmune disease (myasthenia gravis). The patient was taking diclofenac sodium (50mg BD) and co-codamol (paracetamol codeine) PRN for morning pain when walking to the toilet to urinate. The pain was in the lower back and hip joints, identified with osteoarthritis and myasthenia gravis. Administration of composition 3 twice daily for 20 minutes, inhaled via nebulizer. After 4 days, the patient was free of morning pain and no longer taking diclofenac sodium 50mg BD. This has been maintained. Hypothesized effect of composition 3 on autoimmune disease and pain.

[0110] Example 7 A woman in her 80s with Sjögren's syndrome, confirmed by a rheumatologist. The primary complaint was dry mouth and severe pain in the mouth and throat. The pain was so severe that eating food was too painful and resulted in weight loss.

[0111] Sjögren's is an autoimmune disease, and the condition results in antibodies targeting the body's own moisture-producing glands. These include the salivary and tear glands, with other effects on the lungs, kidneys and nervous system. Muscle fatigue, effects on thyroid function and numbness in the arms and legs have also been reported.

[0112] Administration of Composition 3 was via a nebulizer to produce a vapor of the formulation as well as the oral fluid. Administration was for 20-30 minutes every 6 hours.

[0113] The symptoms of pain and dry mouth have been resolved to the extent that it allows pain-free and non-dry mouth eating of all food types and consistencies, including spicy recipes that are normally associated with prolonged acute pain and worsening symptoms. Other common symptoms have improved, and movement and sitting are more comfortable.

[0114] During the study, treatment was discontinued and symptoms of pain and feeling ill returned. Medication was reintroduced and symptoms resolved successfully within 5 days.

[0115] Prior to treatment, the patient had unsuccessfully tried corticosteroids prescribed by an oral medicine specialist.

[0116] Example 8 - In vivo patient safety study Treatment involved administration of an aqueous solution of sodium hypochlorite in saline (NaOCl: 0.05% by weight (500 ppm), NaCl: 0.85% by weight - referred to as Composition 3 in Example 8) delivered by a nebulizer.

[0117] Overall Research Plan The study was designed as a phase 1, open-label, escalation study in approximately 18 healthy volunteers aged 2 to 80 years. Three exposure cohorts were planned.

[0118] Cohort 1 consisted of two adults: Initially, one healthy volunteer. Inhalation of composition 3 via a nebulizer. Monitoring of oxygen saturation, pulse rate, blood pressure and coordination test performance. Inhalation program 30 seconds, followed by 30 minutes of observation. 1 minute, followed by 30 minutes of observation. The observation period was kept at 30 minutes, and the administration period was increased to 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes. The following days, the administration period was increased to 45 minutes and 90 minutes.

[0119] This program was repeated with additional healthy volunteers after a 7-day observation period with the first volunteer.

[0120] Both volunteers were followed for six months without further inhalation and monitored for adverse reactions and long-term effects.

[0121] Cohort 2 consisted of Cohort 1 plus 4 additional adults: The program was then extended to additional groups of healthy volunteers and after induction periods of 30 seconds, 1 minute, 5 minutes, 10 minutes, then 15 minutes of administration, a 20 minute daily administration time was recommended based on the assumption of a 15 minute Il-6 neutralization time with composition 3 seen in the mechanistic study and a 4-5 minute circulation time for systemic blood circulation.

[0122] One week after administration, the observed healthy volunteers self-administered during a three-month observation period and were followed over a two-year period, monitoring for adverse reactions and any long-term effects.

[0123] Cohort 3 consisted of 12 adults and children: The program was then extended to additional groups of healthy volunteers at the extreme ages, followed by an induction period of 5, 10, then 15, and 20 minute daily administration times. Healthy volunteers self-administered during a 3 month observation period and were followed over a 3 month period.

[0124] Selection of population Selection criteria: - Written, signed informed consent, or, for participants under 18 years of age, written informed consent by a parent or legal guardian, was provided after the nature of the study was explained to them and before any research-related procedures were performed. - Agreed to comply with all study procedures. - They were in generally good health as evidenced by physical examination.

[0125] Exclusion criteria: - Receiving blood or plasma within 30 days prior to study drug administration. - Use of any over-the-counter (OTC) medications, including vitamins, within 7 days prior to administration of study drug without evaluation and approval by the investigator. - Use of any prescription medication within 14 days prior to administration of study drug without evaluation and approval by the investigator. - Any uncontrolled pulmonary symptoms.

[0126] treatment Subjects (or their legally authorized representatives) could withdraw consent to participate in the study at any time without retaliation. The investigator was to withdraw from the study any subject who requested to do so. A subject's participation in the study was to be discontinued at any time at the investigator's discretion and according to the investigator's clinical judgment.

[0127] If a subject did not return for a scheduled visit, a written effort would be made to determine the reason. If the subject could not be contacted by phone within 7 days, a certified letter would be sent to the subject (or, where appropriate, the subject's legally authorized representative) requesting that the investigator be contacted. This information would be recorded in the study records.

[0128] Cohort 1: - Inhalation of composition 3 via a nebulizer. -Inhalation program for 30 seconds, followed by 30 minutes of observation. -1 minute, followed by 30 minutes of observation. - The observation period was kept at 30 minutes and the administration period was increased to 5, 10, 15, 20, and 30 minutes. -The next day, administration duration was increased to 45 and 90 minutes. -After a further 7-day observation period, the same schedule was repeated on a second volunteer.

[0129] Cohort 2: -Induction periods of 30 seconds, 1 minute, 5 minutes, 10 minutes, then 15 minutes of administration, each followed by a 30 minute observation period. -Then, starting on day 2, administration time of 20 minutes per day.

[0130] Cohort 3: -Induction periods of 5, 10, then 15 minutes each, followed by an observation period of 30 minutes. -Then, starting on day 2, administration time of 20 minutes per day.

[0131] Composition 3 was supplied as a sterile aqueous solution. Composition 3 was nebulized at a concentration of 500 ppm.

[0132] This was an open-label study; no randomization was used to assign subjects to each cohort.

[0133] All prescription and over-the-counter medications taken by subjects during the 30 days prior to screening were to be recorded on the designated CRF. Investigators were allowed to prescribe additional medications during the study, unless the prescribed medication was prohibited by the protocol. In emergency events, necessary medications could be prescribed without prior authorization, but the sponsor's medical monitor had to be notified of the use of contraindicated medications immediately thereafter. Any concomitant medications added or discontinued during the study were to be recorded on the CRF.

[0134] Use of other investigational drugs or investigational medical devices was prohibited within 30 days prior to screening and until all scheduled study evaluations were completed.

[0135] OTC medications and vitamins were prohibited within 7 days prior to Day 1 (study administration) and until all scheduled study evaluations were completed without investigator review and approval.

[0136] Use of prescription medications was prohibited within 14 days prior to Day 1 and until all scheduled study evaluations were completed without investigator evaluation and approval.

[0137] All used and unused drug containers were to be kept by the investigator. Amounts dispensed, returned, used, lost, etc. were to be recorded in the dispensing log provided for the study.

[0138] The PI was responsible for maintaining accurate records (including dates and amounts) of study drug administered, subjects to whom study drug was issued (administration-specific totals per subject), and any loss or accidental or intentional destruction of study drug. Investigators were to retain all unused or expired study drug until the accountability data was reviewed by the study monitor.

[0139] Unused study drug could be destroyed at the site, per the site's standard operating procedures, only after the sponsor gave approval for drug destruction. The monitor was accountable for all study drug in a formal reconciliation process prior to study drug destruction. All study drug destroyed at the site was to be recorded. Documentation was to be provided to the sponsor and maintained in the investigator's study file. If a site was unable to properly destroy study drug, the site could return unused study drug to the sponsor upon request. Return of study drug or study drug materials was accountable to the sponsor.

[0140] Safety and tolerability variables Safety was to be assessed by examining the incidence of all treatment-emergent adverse events (hereafter referred to as AEs) and clinically significant changes in vital signs reported during the study period.

[0141] Vital signs were measured after 5 min of rest and included sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured in mmHg, heart rate (beats / min), respiratory rate (breaths / min) and oxygen saturation.

[0142] According to the ICH definition, an adverse event (or adverse experience) is "any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product, not necessarily having a causal relationship to this treatment. Thus, an AE may be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease associated in time with the use of a medicinal (investigational) product, whether or not considered related to the IP."

[0143] An Adverse Drug Reaction (ADR) is described by the ICH as "any untoward and unintended response to a medicinal product related to any dose."[1] This means that a causal relationship between the medicinal product and the AE is at least reasonably possible, i.e., the relationship cannot be excluded.

[0144] AEs could include concomitant illnesses or injuries that represented an exacerbation (increase in frequency, severity, or specificity) of a pre-existing condition (e.g., exacerbation of asthma). Whenever possible, it was preferred to record the diagnosis as an AE term rather than a series of terms related to the diagnosis.

[0145] The reporting period for nonserious AEs was from the first dose of study drug to Week 26 or early termination. If a nonserious AE remained unresolved at study completion, the PI and sponsor's medical monitor were to conduct a joint clinical assessment as to whether continued follow-up of the AE was necessary and to document the results of this assessment. Resolution was to be defined as return to baseline (screening) status or stabilization of symptoms that were expected to remain chronic.

[0146] Investigators were to assess AEs for severity, relationship to study drug, and whether the event met one or more of the definitions of an SAE.

[0147] The investigator was to determine the severity of each AE and record it on the source document and AE CRF using the categories defined below.

[0148] Statistical Planning Due to the exploratory nature of this study and the overall small sample size, formal statistical tests of inference were not conducted. Inferential statistics were to be used for descriptive purposes only. All summaries were to consist of standard descriptive statistics unless otherwise specified. Standard descriptive statistics were to include the following: -For continuous parameters: number of observations (or subjects), mean, standard deviation, median, minimum, and maximum. -For categorical parameters: frequency and percentage of observations in each category.

[0149] Both efficacy and safety data will be summarized for individual cohorts and for all cohorts combined.

[0150] Sample Size Determination: A total of 18 subjects treated in three cohorts were planned for this study. A total cohort size of 18 subjects equally balanced by gender and broad age range was considered sufficient to meet the objectives of this study.

[0151] No formal sample size calculations or power determinations were performed.

[0152] Planned Analyses: All subjects who received any amount of study drug and had post-dose safety data were to be included in the safety analysis.

[0153] Treatment of dropouts and missing data: All analyses were presented based on observed data only.

[0154] Data Monitoring Committee: A DMC will be used in this study to monitor the safety of subjects in this initial clinical study of Composition 3. Planned reviews will be conducted after the completion of the induction period for each cohort, and at the end of the dosing and follow-up period for each cohort.

[0155] Safety Analysis: Safety was to be assessed by examining the incidence of all AEs reported during the study period and clinically significant changes in vital signs.

[0156] Only AEs reported during the study period were to be included in the AE summary. An AE was to be defined as any AE that was new, increased in frequency, or worsening in severity after study drug administration. An AE was to be considered treatment-emergent if the onset of the AE was missing and the resolution of the AE was either after the day of administration or missing. AEs judged by the investigator to be possibly or probably related to the study drug were to be considered drug-related. AEs were to be considered drug-related if the relationship to study drug was missing.

[0157] For all AEs and all drug-related AEs, the incidence and severity of AEs were to be summarized by system organ class (SOC), preferred term, and severity. For AEs that occurred more than once during the study, AEs were to be summarized by severity using the maximum severity. Subjects reporting multiple events coded to a common preferred term or SOC were to be counted only once per preferred term or SOC.

[0158] AEs assessed by the investigator as possibly or probably related to the study drug were to be summarized by SOC, preferred term, and maximum severity. Drug-related AEs were to be summarized similarly to AEs.

[0159] Changes in the conduct of research or analyses that have been panned Of the 18 subjects enrolled in the study, all met the eligibility criteria defined by the protocol and received appropriate treatment with the appropriate titration schedule for their cohort.

[0160] Research Subjects TIFF2024525752000002.tif66170

[0161] Safety assessment Extent of Exposure: All subjects were exposed to Composition 3 according to their cohort.

[0162] Adverse Events: Four subjects reported adverse events (Cohorts 1 and 2, mild cough or urge to cough) during the first part of the induction phase of treatment and none on subsequent exposures. Patients in Cohort 3 were advised to be aware of this possibility and none reported any.

[0163] One subject with underlying asthma reported sensations similar to asthma symptoms, no wheezing, and no decline in PEFR; treatment was suspended for 1 week and reintroduced without return of sensation.

[0164] All subjects experienced increased sputum production following dosing.

[0165] No other adverse events occurred during the immediate post-procedure 1-hour period.

[0166] No adverse events considered to be related to treatment occurred during the follow-up period.

[0167] List of serious adverse events: There were no SAEs during the treatment period or subsequent phases of this study. TIFF2024525752000003.tif29170

[0168] Safety Study Overview Summary of Results from a Phase 1 Open-Label, Ascending Exposure Study to Evaluate the Safety and Tolerability of Nebulized Composition 3 in Healthy Volunteers: i. Sample size n=18 ii. Serious adverse events - 0 iii. Adverse events during induction - 4 (all grade 1 events) iv. Adverse events during the procedure or during the immediate 1 hour period after the procedure - 18 (all grade 1 events) v. Other adverse events considered to be related to the procedure - 0 vi. Age range: 3 to 80 years vii. Maximum duration of continuous administration - 90 minutes viii. Continuous administration mode duration - 20 minutes ix. Maximum duration of repeated administration for 20 minutes per day - 4 years or more

[0169] Overall, the present invention has demonstrated that the hypochlorite composition according to the present invention is safe and well tolerated when administered via inhalation route.The present invention has also demonstrated that the hypochlorite composition according to the present invention provides in vivo clinical improvement in patients with respiratory, inflammatory and / or autoimmune conditions, with in vitro data demonstrating anti-inflammatory properties.The present invention provides a new and effective treatment option for respiratory, inflammatory and / or autoimmune conditions.

[0170] Example 9 - COVID-19 In Vivo Patient Treatment Study Treatment involved administration of an aqueous solution of sodium hypochlorite in saline (NaOCl: 0.05% by weight (500 ppm), NaCl: 0.85% by weight - referred to as Composition 3 in Example 9) delivered by a nebulizer.

[0171] Each enrolled patient tested positive for COVID-19 and exhibited symptoms of COVID-19 prior to entering the study. Composition 3 was administered to each patient by nebulizer for the period shown in the table below. Inhalation frequency is shown as (number of times per day x duration of each treatment session). When administration was 4 times per day, Composition 3 was administered every 6 hours. When administration was 3 times per day, Composition 3 was administered every 8 hours.

[0172] Treatments were administered at the indicated frequency on consecutive days until negative lateral flow test results were obtained. TIFF2024525752000004.tif104170

[0173] Each enrolled patient became symptom-free within 2-4 days from the date Composition 3 was first administered (i.e., from the date Dose 1 of Composition 3 was administered). Each patient was asymptomatic prior to receiving a negative lateral flow test (LFT). These data indicate that Composition 3 administered via inhalation is an effective treatment for COVID-19 symptoms and reduces recovery time.

[0174] Example 10 - "Long" COVID-19 In Vivo Patient Treatment Study Treatment involved administration of an aqueous solution of sodium hypochlorite in saline (NaOCl: 0.05% by weight (500 ppm), NaCl: 0.85% by weight - referred to as Composition 3 in Example 10) delivered by a nebulizer.

[0175] Each enrolled patient had previously tested positive for COVID-19 and had been symptomatic for "Long COVID-19" for at least one month from the date of the COVID-19 positive test. Composition 3 was administered to each patient by nebulizer for the period shown in the table below. The inhalation frequency is shown as (number of times per day x duration of each treatment session). When administration was four times per day, Composition 3 was administered every 6 hours. When administration was three times per day, Composition 3 was administered every 8 hours.

[0176] Treatment was administered at the indicated frequency on consecutive days until the patient reported no symptoms. TIFF2024525752000005.tif59170

[0177] With the exception of two patients who partially recovered, Long COVID-19 symptoms were alleviated in the patients. Two patients fully recovered from Long COVID-19, and one patient recovered almost completely (90%) with mild residual asthma symptoms. These data indicate that Composition 3 administered via inhalation is an effective treatment for Long COVID-19 symptoms and improves the level of recovery achieved.

Claims

1. A sodium hypochlorite solution for use in preventing or treating respiratory symptoms or diseases in a patient, the sodium hypochlorite solution containing sodium hypochlorite in a concentration range of about 0.015 to 0.075% by weight (about 150 to 750 ppm by weight) and having a pH of about 7 to 11.

2. The sodium hypochlorite solution for use according to claim 1, wherein the respiratory symptom or disease is acute respiratory distress syndrome (ARDS); asthma; bronchitis; chronic obstructive pulmonary disease (COPD); cold; coronavirus disease, such as severe acute respiratory syndrome (SARS), COVID-19; cystic fibrosis; influenza; Middle East respiratory syndrome (MERS); pneumonia, such as viral pneumonia, bacterial pneumonia and ventilator-associated pneumonia; pulmonary fibrosis; rhinovirus disease; sarcoidosis (e.g., affecting the lungs); tuberculosis; or inflammation of lung tissue.

3. The sodium hypochlorite solution for use according to claim 1 or 2, wherein the respiratory symptom or disease is an acute respiratory symptom or disease.

4. A sodium hypochlorite solution for use according to claim 1 or 2, wherein the administration is by inhalation of the sodium hypochlorite solution.

5. A sodium hypochlorite solution for use in preventing or treating inflammation or autoimmune response, symptoms or diseases in a patient, the sodium hypochlorite solution containing sodium hypochlorite in a concentration range of about 0.015 to 0.075% by weight (about 150 to 750 ppm by weight), having a pH of about 7 to 11, and the administration of the sodium hypochlorite solution being by inhalation of the sodium hypochlorite solution.

6. The sodium hypochlorite solution for use according to claim 5, wherein the inflammation or autoimmune response, symptoms or disease is arthritis, such as osteoarthritis; pancreatitis; Sjogren's syndrome; or myasthenia gravis.

7. The sodium hypochlorite solution for use according to claim 5 or 6, wherein the inflammation or autoimmune response, symptoms or disease is an acute inflammation or autoimmune response, symptoms or disease.

8. The sodium hypochlorite solution for use according to claim 1 or 5, wherein the sodium hypochlorite is in a concentration range of 0.025 to 0.075% by weight (about 250 to 750 ppm by weight).

9. A sodium hypochlorite solution for use according to claim 1 or 5, further comprising sodium chloride.

10. A sodium hypochlorite solution for use according to claim 9, wherein the sodium chloride is in a concentration range of about 0.5 to 3.0% by weight.

11. A sodium hypochlorite solution for use according to claim 1 or 5, which is an aqueous sodium hypochlorite solution containing sodium hypochlorite, sodium chloride, and water for balance.

12. A sodium hypochlorite solution for use according to claim 1 or 5, having a pH of about 7 to 10.

13. A sodium hypochlorite solution for use according to claim 1 or 5, which is not buffered.

14. A kit comprising a sodium hypochlorite solution according to claim 1 or 5, and a nebulizer or inhaler.

15. A pharmaceutical container for use with an inhalation device, the pharmaceutical container comprising a sodium hypochlorite solution according to claim 1 or 5, and optionally a propellant.

16. A pharmaceutical composition for use in preventing or treating respiratory symptoms or diseases in a patient, the pharmaceutical composition comprising a sodium hypochlorite solution according to claim 1 or 5, and being administrable by inhalation.

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