Methods for reducing symptoms in subjects suffering from bronchiectasis and other pulmonary diseases

Abstract

This application is directed to the method of reducing cough and / or sputum in a patient suffering from a respiratory disease or disorder, comprising administering to the respiratory system of the subject a therapeutically effective amount of glutathione, a glutathione derivative, a glutathione conjugate, or a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and an organic acid, or a pharmaceutically acceptable salt thereof. In certain aspects the application is directed to glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically-acceptable salt thereof; and an organic acid; wherein the molar ratio is about 0.5-1:1. The composition can further comprises a bicarbonate salt, wherein the molar ratio is about 0.1-0.5: 0.5-1:1.

Description

METHODS FOR REDUCING SYMPTOMS IN SUBJECTS SUFFERING FROM BRONCHIECTASIS AND OTHER PULMONARY DISEASESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the priority benefit of U.S. Provisional Application No. 63 / 640,839, filed April 30, 2024, which is hereby incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present invention relates to methods of treating or preventing disorders or diseases of the respiratory system and / or reducing cough and / or sputum and / or symptoms in a patient suffering from a respiratory disease or disorder.BACKGROUND

[0003] Bronchiectasis is characterized by dilated and inflamed airways (bronchi and bronchioles) with thick, viscous mucus resulting in plugging. The structure of the airways and mucus accumulation results in pulmonary infections and neutrophilic airway inflammation that are often challenging to treat and can become chronic. Bronchiectasis can also referred to as non-cystic fibrosis bronchiectasis (NCFBE). Despite a growing number of patients being diagnosed with NCFBE, therapeutic approaches to treating NCFBE remain limited to physical clearance mechanisms (e.g., exercise, vest therapies, oscillation breath devices) and mucolytics / expectorants (e.g., hypertonic saline) to enable more effective cough clearance.

[0004] Chronic cough and sputum production in NCFBE affects the subject's quality of life (QOL) and may eventually lead to exacerbations, with no approved pharmaceutical therapies available. There is an urgent need for new effective therapies that can break the vicious cycle of excess mucus, inflammation, and infection for these patients.

[0005] Currently, there are no approved therapies targeting mucus and symptom burden in individuals with NCFBE, particularly the excess mucus production that impair their quality of life.BRIEF SUMMARY

[0006] Certain aspects of the disclosure are directed to a method of reducing sputum in a subject in need thereof, comprising administering to the subject (e.g., to the subject’s airway) a therapeutically effective amount of a composition comprising: (a) glutathione, a glutathione derivative, a glutathione conjugate, or a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and (b) an organic acid or a pharmaceutically acceptable salt thereof, optionally, (c) bicarbonate, or a pharmaceutically acceptable salt of bicarbonate. In some aspects, compositions comprising (a) glutathione, a glutathione derivative, a glutathione conjugate, or a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and (b) an organic acid, or pharmaceutically acceptable salts thereof, are collectively referred to herein as "Compositions of the Disclosure" or individually as a "Composition of the Disclosure." Compositions of the Disclosure can further comprise (c) bicarbonate, or a pharmaceutically acceptable salt of bicarbonate. See Section II below.

[0007] In some aspects, the Composition of the Disclosure comprises ARINA-1.

[0008] In some aspects, the disclosure provides a method of treating or preventing bronchiectasis, e.g., non-cystic fibrosis bronchiectasis (NCFBE), or a symptom thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0009] In some aspects, the Composition of the Disclosure administered to the subject is nebulized.

[0010] In some aspects, the disclosure provides a method of treating or preventing a symptom of NCFBE in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure. In some aspects, the symptom of NCFBE is excessive sputum production, e.g., mucus, chronic cough, and / or respiratory infection.

[0011] In some aspects, the disclosure provides a method of treating or preventing excessive sputum production in a subject having NCFBE, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0012] In some aspects, the disclosure provides a method of treating or preventing chronic cough in a subject having NCFBE, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0013] In some aspects, the disclosure provides a method of treating or preventing a respiratory infection in a subject having NCFBE, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0014] In some aspects, the subject is at least 18 years of age.

[0015] In some aspects, the subject is at least 21 years of age.

[0016] In some aspects, the subject is at least 24 years of age.

[0017] In some aspects, the Composition of the Disclosure is administered to the subject once a day, twice a day, three times a day, or four times a day.

[0018] In some aspects, the Composition of the Disclosure is administered to the subject BID, i.e., twice a day.

[0019] In some aspects, the Composition of the Disclosure is administered to the subject BID in the morning and in the evening.

[0020] In some aspects, the efficacy of the Composition of the Disclosure is determined by quality of life (QOL), sputum rheological markers, and / or blood inflammatory markers after administration to the subject.

[0021] In some aspects, improvements in the quality of life of the subject after administration of a Composition of the Disclosure are determined by patient-reported outcomes (PROs).

[0022] In some aspects, the PROs are gathered from the Quality of Life-Bronchiectasis (QOL-B) questionnaire after administering the Composition of the Disclosure to the Subject.

[0023] In some aspects, the QOL-B questionnaire is used to assess respiratory domain score in the subject.

[0024] In some aspects, the QOL-B questionnaire is used to assess respiratory physical functioning in the subject.

[0025] In some aspects, the QOL-B questionnaire is used to assess vitality in the subject.

[0026] In some aspects, the QOL-B questionnaire is used to assess role functioning in the subject.

[0027] In some aspects, the QOL-B questionnaire is used to assess health perception in the subject.

[0028] In some aspects, the QOL-B questionnaire is used to assess emotional functioning in the subj ect.

[0029] In some aspects, the QOL-B questionnaire is used to assess social functioning in the subject.

[0030] In some aspects, the QOL-B questionnaire is used to assess treatment burden in the subject.

[0031] In some aspects, the disclosure provides a method of improving the QOL in a subject in need thereof, e.g., a subject having NCFBE, as measured by the QOL-B questionnaire, the method comprising administering a therapeutically effective amount of a Composition of the Disclosure to the subject.

[0032] In some aspects, the PROs are gathered from the St. George’s Respiratory Questionnaire (SGRQ).

[0033] In some aspects, the SGRQ is used to assess a total respiratory domain score in the subject.

[0034] In some aspects, the SGRQ is used to assess respiratory symptoms in the subject.

[0035] In some aspects, the SGRQ is used to assess physical activity in the subject.

[0036] In some aspects, the SGRQ is used to assess the psychosocial impacts in the subject.

[0037] In some aspects, the disclosure provides a method of improving the QOL in a subject in need thereof, e.g., a subject having NCFBE, as measured by SGRQ, the method comprising administering a therapeutically effective amount of a Composition of the Disclosure to the subject.

[0038] In some aspects, the PROs are gathered from the Chronic Airways Assessment Test (CAAT).

[0039] In some aspects, the PROs are gathered from the Ease of Cough and Mucus Clearance Multiple Choice Question (MCQ). In some aspects, the PROs are gathered from an MCQ: Question for Ease of cough and Sputum Clearance. In some aspects, the MCQ was measured in subjects having chronic bronchitis. In some aspects, improvements are shown by decreasing scores using the MCQ. In some aspects, decreasing scores are correlated to improved mucus and cough clearance.

[0040] In some aspects, QOL is measured using the CAAT minimally clinically important difference (MCID).

[0041] In some aspects, quality of life is measured using the St. George’s Respiratory Questionnaire (SGRQ) minimally clinically important difference (MCID).

[0042] In some aspects, exploratory endpoints for assessing bronchiectasis and other pulmonary diseases include sputum biomarkers, particularly changes in sputum elasticity, sputum viscosity, sputum percent solids, neutrophil elastase (sputum inflammatory marker), and C-reactive protein (CRP) (blood inflammatory markers).

[0043] In some aspects, the disclosure provides a method of treating or preventing chronic bronchitis, or a symptom thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0044] In some aspects, the disclosure provides a method of treating or preventing chronic bronchitis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0045] In some aspects, the disclosure provides a method of treating or preventing a symptom of chronic bronchitis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0046] In some aspects, the symptom of chronic bronchitis is a chronic cough.

[0047] In some aspects, the symptom of chronic bronchitis is a chronic productive cough in 3 months of 2 successive years in subjects without another cause of chronic cough.

[0048] In some aspects, a characteristic of chronic bronchitis include airway wall thickening without dilation.

[0049] In some aspects, a characteristic of chronic bronchitis include mucus visualized in the airways.

[0050] In some aspects, characteristics of chronic bronchitis include airway wall thickening without dilation and mucus visualized in the airways.

[0051] In some aspects, the cough severity index represents the patient’s perception of cough.

[0052] In some aspects, the disclosure provides a method of improving cough, improving or reducing sputum production, improving or reducing sputum viscosity, reducing sputumpercent solids, reducing neutrophil elastase, improving sputum elasticity, reducing CAAT total score, reducing SGRQ total score, reducing SGRQ symptoms score, reducing SGRQ activity score, reducing SGRQ impacts score, or reducing cough severity score, or a combination thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Composition of the Disclosure.

[0053] In some aspects, the methods disclosed herein comprise administering to the subject (e.g., to the subject’s airway) a therapeutically effective amount of a composition comprising: (a) glutathione, or a pharmaceutically acceptable salt of glutathione; and (b) ascorbic acid, or a pharmaceutically acceptable salt thereof.

[0054] In some aspects, the molar ratio of (a):(b) is about 0.1-0.5:0.5-1.

[0055] In some aspects, the methods disclosed herein comprise administering to the subject (e.g., to the subject’s airway) a therapeutically effective amount of a composition comprising: (a) glutathione, or a pharmaceutically acceptable salt of glutathione; (b) ascorbic acid, or a pharmaceutically acceptable salt thereof; and (c) bicarbonate, or a pharmaceutically acceptable salt thereof.

[0056] In some aspects, the bicarbonate or a pharmaceutically acceptable salt thereof comprises sodium bicarbonate or calcium bicarbonate.

[0057] In some aspects, the molar ratio of (a):(b):(c) is about 0.1-0.6:0.5-1 : 1; about 0.4- 0.6:0.4-0.6: 1; or about 0.5:0.5: 1. In some aspects, (a):(b):(c) is about 0.1-0.6:0.5-1 : 1; about 0.4-0.6:0.4-0.6: 1; or about 0.5:0.5: 1, wherein (a) is glutathione, (b) is ascorbic acid, and (c) is a pharmaceutically acceptable salt of bicarbonate (e.g., sodium bicarbonate).

[0058] In some aspects, the composition comprises glutathione.

[0059] In some aspects, the organic acid is ascorbic acid, or a pharmaceutically acceptable salt thereof.

[0060] In some aspects, the administration is to the airway via inhalation. In some aspects, the composition is administered to the lungs by an inhalable dosage form.

[0061] In some aspects, the inhalable dosage form is a metered dose inhaler, a dry powder inhaler, or a nebulizer.

[0062] In some aspects, the subject has a chronic airway disease or condition. In some aspects, the chronic airway disease or condition is a pre-existing condition.

[0063] In some aspects, the subject has a pulmonary or airway disease or disorder. In some aspects, the pulmonary or airway disease or disorder is bronchiectasis or non-cysticfibrosis bronchiectasis. In some aspects, the pulmonary or airway disease or disorder is chronic bronchitis and / or non-tuberculous mycobacteria-pulmonary disease (NTM-PD).

[0064] In some aspects, the subject has a pulmonary or airway infection. In some aspects, the infection is caused by one or more bacteria. In some aspects, the one or more bacteria comprises nontuberculous mycobacteria (NTM).

[0065] In some aspects, nontuberculous mycobacteria (NTM) is also known as environmental mycobacteria, atypical mycobacteria, and mycobacteria other than tuberculosis (MOTT).

[0066] In some aspects, the composition comprises: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof; and (b) an organic acid, wherein the molar ratio of (a) to (b) is about 0.5-1 : 1 and the pH of the formulation is at least 5.5. In some aspects, the organic acid is ascorbic acid. In some aspects, the composition further comprises (c) a bicarbonate salt (e.g., sodium bicarbonate or calcium bicarbonate). In some aspects, the composition does not include a bicarbonate salt.

[0067] In some aspects, the molar ratio of (a):(b):(c) is about 0.1-0.5: 0.5-1 : 1, wherein (a) is glutathione, (b) is ascorbic acid, and (c) is a pharmaceutically acceptable salt of bicarbonate (e.g., sodium bicarbonate). In some aspects, the molar ratio of (a) :(b) :(c) is about 0.4-0.5: 0.5-1 : 1, wherein (a) is glutathione, (b) is ascorbic acid, and (c) is a pharmaceutically acceptable salt of bicarbonate (e.g., sodium bicarbonate). In some aspects, the molar ratio of (a):(b):(c) is about 0.4-0.5: 0.5: 1 or 0.4-0.5: 1 : 1, wherein (a) is glutathione, (b) is ascorbic acid, and (c) is a pharmaceutically acceptable salt of bicarbonate (e.g., sodium bicarbonate).

[0068] In some aspects, the composition is an aqueous solution, a dry powder, or lyophilized.

[0069] In some aspects, the composition is an aqueous solution.

[0070] In some aspects, the composition is administered to the lung.BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0071] FIGs. 1 A-1E show measurements (Mean ± Std Err) of elasticity, sputum viscosity, mucus percent solids, neutrophil elastase, and C-reactive protein, respectively, for the ARINA- 1 and placebo treatment groups after 28 days of treatment. (Example 7)

[0072] FIG. 2 shows airway function score as assessed by the Chronic Airways Assessment Test (CAAT) between ARINA-1 and placebo treatment groups after 56 days of treatment. (Example 6)

[0073] FIGs. 3 A-3D show the score for the overall health and perceived well-being in patients in the ARINA- 1 and placebo treatment groups as assessed by the St. George's Respiratory Questionnaire (SGRQ) after 56 days of treatment for the following parameters: total score, symptoms score, activity score, impact score, respectively. (Example 5)

[0074] FIGs. 4A-4H show the quality of life assessment for bronchiectasis patients in the ARINA- 1 and placebo treatment groups after 56 days of treatment for the following parameters: respiratory symptoms, physical functioning, vitality, role functioning, health perceptions, emotional function, social functioning, and treatment burden, respectively. (Example 4)

[0075] FIG. 5 show a plot of the percentage of adverse events of special interest (AESI) and the relative risk with a 95% CI for the ARINA-1 and placebo treatment groups. (Example 3)

[0076] FIG. 6 show a plot of the percentage of adverse events experienced in 5% of participants in the safety population and the relative risk with a 95% CI. (Example 3)

[0077] FIG. 7 show a graph depicting the cough severity score of 1 individual with chronic bronchitis over a period of 6 weeks. (Example 9)

[0078] FIG. 8 shows a plot of MCQ scores indicating improvements in quality of life for subjects having chronic bronchitis and being treated with ARINA- 1.

[0079] FIG. 9 shows a plot of CAAT scores indicating improvements in quality of life for subjects having chronic bronchitis and being treated with ARINA- 1.DETAILED DESCRIPTIONI. Definitions

[0080] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0081] As used in the present disclosure and claims, the singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise.

[0082] The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include both "A and B," "A or B," "A," and "B." Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0083] The term “about” as used herein means approximately ± 10%. When the term "about" is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent, up or down (higher or lower), i.e., ± 10%, unless a different variance is indicated (e.g., ± 30%, ± 20%, ± 5%, ± 1%, etc.).

[0084] "Pharmaceutically acceptable" as used herein means safe and effective for use in humans. For example, a "pharmaceutically acceptable salt", as used herein, means those salts of the compounds disclosed herein that are safe and effective for use in a subject and that possess the desired biological activity of the compound.

[0085] By "subject" or "patient" is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. In certain aspects, the mammal is a human subject. In other aspects, a subject is a human patient. In a particular aspect, a subject is a human patient in need of treatment.

[0086] An "effective amount" of a composition or active agent as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" can be determined empirically and in a routine manner, in relation to the stated purpose.

[0087] The term "therapeutically effective amount" refers to an amount of a Composition of the Disclosure or active agent as disclosed herein effective to "treat" a disease or disorder in a subject.

[0088] The term "ARINA-1" as used herein refers to a composition comprising(a) glutathione or a salt thereof; (b) ascorbic acid or a salt thereof; and (c) a bicarbonate or salt thereof; optionally, the molar ratio of (a): (b) :(c) is about 0.4-0.5:0.5: 1 as disclosed in US Pat. No. 11,497,786. In some aspects, ARINA-1 is nebulized by a subject or patient at home, or optionally, in a healthcare setting. In some aspects, ARINA-1 is nebulized prior to, during, or after an exacerbation.

[0089] As used herein, “nebulize” or “nebulized” refers to converting a liquid to a fine spray, particularly for inhalation.

[0090] As used herein, "treating" or "treatment" refers to any indicia of success in preventing, arresting, or ameliorating a disease of the respiratory system, e.g., bronchiectasis, NTM pulmonary disease, or chronic bronchitis, in a subject, and / or preventing, arresting, or ameliorating any one or more symptoms of a disease of the respiratory system in a subject, including any objective or subjective parameter such as abatement; remission; diminishing, inhibiting, preventing, or eliminating one or more symptoms; making the disease of the respiratory system more tolerable to the subject; slowing in the worsening of the disease of the respiratory system; or improving the physical or mental well-being of the subject in need thereof.

[0091] The terms "treating" or "treatment" also encompasses, e.g., inducing inhibition, regression, rescue, or stasis of a disease of the respiratory system. For example, treatment of a subject in need of treatment for a disease of the respiratory system includes improving, preventing, or reducing a symptom of the disease of the respiratory system in the subject, inducing clinical response, preventing, inhibiting or reducing progression of a disease of the respiratory system, or preventing, inhibiting or reducing a complication of a disease of the respiratory system.

[0092] Preventing, arresting, or ameliorating a disease of the respiratory system, such as preventing, diminishing, inhibiting, or eliminating one or more symptoms of a disease of the respiratory system can be based on objective and / or subjective parameters, including, e.g., the results of genetic testing, physical examination(s), neurological examination(s), and / or psychiatric evaluation(s). The success of treatment for a disease of the respiratory system may be measured or evaluated by, for example, comparing the severity of the disease of the respiratory system, or symptom thereof, before treatment with a Composition of the Disclosure is initiated, with the severity of the disease of the respiratory system, or symptom thereof, following treatment with a Composition of the Disclosure. For example, the severity of disease of the respiratory system, or symptom thereof, may be assessed using a scale, index, rating, or score. In one aspect, the treatment described herein improves such an assessment from a value or degree characteristic of a symptomatic subject to a value or degree characteristic of a non- symptomatic subject. In one aspect, the treatment described herein improves such anassessment compared to a baseline. The baseline may be, for example, the subject's condition before initiating any treatment for the disease of the respiratory system, or symptom thereof, or before initiating treatment for the disease of the respiratory system, or symptom thereof, with a Composition of the Disclosure. Alternatively, the baseline may be, for example, the subject's condition after a certain time period on treatment for the disease. In one aspect, treatment with a Composition of the Disclosure as described herein improves the subject's assessment, e.g., scale, index, rating, or score of objective and / or subjective parameters, compared to a baseline by at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

[0093] A "symptom" of a disease of the respiratory system includes any clinical or laboratory manifestation associated with the disease of the respiratory system and is not limited to what the subject can feel or observe. Symptoms of a disease of the respiratory system include, but are not limited to, excessive sputum production, chronic cough, respiratory infection, or a combination thereof.II. Compositions of the Disclosure

[0094] In some aspects, glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, an organic acid (e.g., ascorbic acid), or any combination thereof can be combined with a pharmaceutical carrier or excipient and, optionally, other components to provide a composition of the present disclosure. In some aspects, glutathione, an organic acid (e.g. ascorbic acid), and bicarbonate salt (e.g., sodium bicarbonate) are formulated to comprise a molar ratio of about 0.4-0.5:0.5: 1. In some aspects, the amount of glutathione, a glutathione derivative, a glutathione conjugate, pharmaceutically acceptable salt thereof, or any combination thereof, e.g., reduced glutathione, in a Composition of the Disclosure is about 30-90% by weight, about 30- 85% by weight, about 30-80% by weight, about 30-75% by weight, about 30-70% by weight, about 30-65% by weight, about 30-60% by weight, about 30-55% by weight, about 30-50% by weight. In some aspects, the amount of glutathione, a glutathione derivative, a glutathione conjugate, pharmaceutically acceptable salt thereof, or any combination thereof, e.g., reduced glutathione, in a Composition of the Disclosure is 30- 50% by weight.

[0095] In some aspects, a Composition of the Disclosure further comprises an organic acid. In some aspects, the organic acid is selected from the group of acids consisting of ascorbic, acetic, adipic, aspartic, benzenesulfonic, benzoic, butyric, camphorsulfonic, camsylic, carbonic, chlorobenzoic, cholic, citric, edetic, edisylic, estolic, ethanesulfonic, formic, fumaric, gluceptic, gluconic, glucuronic, glutamic, glycolic, glycolylarsanilic, hippuric, l-hydroxy-2-naphthoic, isethionic, isobutyric, isonicotinic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, muconic, napthalenesulfonic, nicotinic, oxalic, oleic, orotic, p-nitromethanesulfonic, pamoic, pantothenic, phthalic, polygalactouronic, propionic, saccharic, salicylic, stearic, suberic, succinic, sulfanilic, tannic, tartaric, p-toluenesulfonic and any combination thereof. In some aspects, the organic acid is ascorbic acid or a pharmaceutically acceptable salt thereof.

[0096] In some aspects, the amount of an organic acid, e.g., reduced ascorbic acid, in a Composition of the Disclosure is about 10-90% by weight, about 10-85% by weight, about 10-80% by weight, about 10-75% by weight, about 10-70% by weight, about 10- 65% by weight, about 10-60% by weight, about 10-55% by weight, about 10-50% by weight, about 10-45% by weight, about 10-40% by weight, about 10-35% by weight, about 10-30% by weight, about 1-30% by weight, about 1-20% by weight, or about 1- 10% by weight. In some aspects, the amount of an organic acid, e.g., reduced ascorbic acid, in a Composition of the Disclosure is 25-40% by weight.

[0097] In some aspects, a Composition of the Disclosure further comprises a bicarbonate salt. In some aspects, the bicarbonate salt is sodium bicarbonate. In some aspects, the bicarbonate salt is potassium bicarbonate. In some aspects, the bicarbonate salt is calcium bicarbonate. In some aspects, the bicarbonate salt is magnesium bicarbonate. In some aspects, the bicarbonate salt is ammonium bicarbonate. In some aspects, the bicarbonate salt is caesium bicarbonate. In some aspects, the amount of bicarbonate salt, e.g., sodium bicarbonate, in a Composition of the Disclosure is about 10-90% by weight, about 10-85% by weight, about 10-80% by weight, about 10-75% by weight, about 10- 70% by weight, about 10-65% by weight, about 10-60% by weight, about 10-55% by weight, about 10-50% by weight, about 10-45% by weight, about 10-40% by weight, about 10-35% by weight, about 10-30% by weight, about 1-30% by weight, about 1-20% by weight, or about 1-10% by weight. In some aspects, the amount of bicarbonate salt,e.g., sodium bicarbonate, in a Composition of the Disclosure is about 20-30% by weight. In some aspects, a Composition of the Disclosure does not comprise a bicarbonate salt.

[0098] In some aspects, the pH of a Composition of the Disclosure is about 6.0 to about 8. In some aspects, the pH of a Composition of the Disclosure is greater than 5.5 or at least 6.0. (e.g., 5.6 to 14, 5.7 to 14, 5.8 to 14, 5.9 to 14, 6 to 14, 5.6 to 12, 5.7 to 12, 5.8 to 12, 5.9 to 12, 6 to 12, 5.6 to 10, 5.7 to 10, 5.8 to 10, 5.9 to 10, 6 to 10, 5.6 to 9, 5.7 to 9, 5.8 to 9, 5.9 to 9, 6 to 9, 5.6 to 8, 5.7 to 8, 5.8 to 8, 5.9 to 8, 6 to 8, 5.6 to 7.5, 5.7 to 7.5, 5.8 to 7.5, 5.9 to 7.5, 6 to 7.5, 5.6 to 7, 5.7 to 7, 5.8 to 7, 5.9 to 7, or 6 to 7).

[0099] In some aspects, a Composition of the Disclosure is formulated to maximize formulation stability and minimize oxidation of glutathione. Oxidized glutathione is associated with the generation of protein-carbonyls via glutathionlyation. Glutathionylation occurs when oxidized glutathione dissociates and attaches to proteins. Maintaining the glutathione in the reduced state in solution prior to administration can decrease the risk of glutathionylation products that can result in clinical complications such as bronchiectasis. In some aspects, the oxidized glutathione (e.g., %GSSG) in a Composition of the Disclosure is less than about 20%, less than about 18%, less than about 16%, less than about 15%, less than about 12%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, or less than about 3% by weight of the total glutathione in a Composition of the Disclosure after storage of a Composition of the Disclosure for 4 weeks (e.g., at 5°C in a N2 atmosphere and / or ambient atmosphere). In some aspects, the percentage of oxidized glutathione (e.g., %GSSG) in a Composition of the Disclosure is no more than about 2% to about 20%, about 2% to about 18%, about 2% to about 16%, about 2% to about 16%, about 2% to about 10%, or about 2% to 8% by weight of the total glutathione in a Composition of the Disclosure following 4 weeks of storage (e.g., at 5°C in a N2 atmosphere and / or ambient atmosphere). In some aspects, the percentage of oxidized glutathione (e.g., %GSSG) in a Composition of the Disclosure is less than about 20%, less than about 18%, less than about 16%, or less than about 10% by weight of the total glutathione in a Composition of the Disclosure following 4 weeks of storage (e.g., at 5°C in a N2 atmosphere and / or ambient atmosphere).

[0100] In some aspects, the reduced glutathione in a Composition of the Disclosure is more than about 80%, more than about 82%, more than about 84%, more than about 85%,more than about 88%, more than about 90%, more than about 91%, more than about 92%, more than about 93%, more than about 94%, more than about 95%, more than about 96%, or more than about 97% by weight of the total glutathione in a Composition of the Disclosure after storage of a Composition of the Disclosure for 4 weeks at about 5° C (e.g., in a N2 or ambient atmosphere). In some aspects, the percentage of reduced glutathione in a Composition of the Disclosure is between about 80% to about 100%, between about 80% to about 98%, between about 82% to about 98%, between about 84% to about 98%, between about 86% to about 98%, between about 88% to about 98%, between about 90% to about 98%, or between about 92% to about 98% by weight of the total glutathione in a Composition of the Disclosure following 4 weeks of storage at 5°C (e.g., in a N2 or ambient atmosphere). In some aspects, the percentage of reduced glutathione in a Composition of the Disclosure is at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, or at least 90% by weight of the total glutathione in a Composition of the Disclosure following 4 weeks of storage at 5°C in a N2 or ambient atmosphere.

[0101] In some aspects, a Composition of the Disclosure is further formulated to maximize formulation stability and minimize oxidation of an organic acid, e.g., ascorbic acid, or a pharmaceutically acceptable salt thereof. Additionally, when ascorbic acid is oxidized into dehydroascorbate (DHA), DHA can break down and result in the formation of protein adducts in process called ascorbylation. Maintaining the organic acid, e.g., ascorbic acid, in the reduced state in solution prior to administration can decrease the risk of ascorbylation from the breakdown products of dehydroascorbate. In some aspects, the reduced ascorbic acid (e.g., %ASC) is more than about 80%, more than about 85%, more than about 86%, more than about 87%, more than about 88%, more than about 89%, or more than about 90% by weight of the ascorbic acid in a Composition of the Disclosure after storage of a Composition of the Disclosure for 4 weeks (e.g., at 5°C in a N2 atmosphere and / or ambient atmosphere). In some aspects, the percentage of reduced ascorbic acid (e.g., %ASC) in a Composition of the Disclosure is between about 82% to about 100% or between about 85% to about 95% by weight of the total ascorbic acid in a Composition of the Disclosure following 4 weeks of storage (e.g., at 5°C in aN? atmosphere and / or ambient atmosphere). In some aspects, the percentage of reduced ascorbic acid (e.g., %ASC) in a Composition of the Disclosure is at least 80%, at least85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90% by weight of the total ascorbic acid in a Composition of the Disclosure following 4 weeks of storage (e.g., at 5°C in aN? atmosphere and / or ambient atmosphere).

[0102] In some aspects, the oxidized ascorbic acid in a Composition of the Disclosure is less than about 20%, less than about 18%, less than about 16%, less than about 15%, less than about 12%, less than about 10%, or less than about 9% by weight of the total ascorbic acid in a Composition of the Disclosure after storage of a Composition of the Disclosure for 4 weeks (e.g., at 5°C in a N2 atmosphere and / or ambient atmosphere). In some aspects, the percentage of oxidized ascorbic acid in a Composition of the Disclosure is no more than about 5% to about 20%, about 5% to about 18%, about 5% to about 10%, or about 5% to 9% by weight of the total ascorbic acid in a Composition of the Disclosure following 4 weeks of storage (e.g., at 5°C in aN? atmosphere and / or ambient atmosphere). In some aspects, the percentage of oxidized ascorbic acid in a Composition of the Disclosure is less than about 20%, less than about 18%, less than about 16%, or less than about 10% by weight of the total ascorbic acid in a Composition of the Disclosure following 4 weeks of storage (e.g., at 5°C in a N2 atmosphere and / or ambient atmosphere).

[0103] In certain aspects, the ratios of the components of a Composition of the Disclosure are formulated to maximize formulation stability and minimize oxidation of glutathione and an organic acid, e.g., ascorbic acid, or a pharmaceutically acceptable salt thereof. In some aspects, glutathione and an organic acid (e.g., ascorbic acid) are formulated to comprise molar equivalents in solution, e.g., about 0.5-1 :1, about 0.6-1 :1, 0.7-1 :1, 0.8- 1 : 1, 0.9-1 : 1 or about 1 : 1 molar ratio of glutathione to ascorbic acid. In some aspects, the glutathione and an organic acid (e.g., ascorbic acid) are formulated to comprise a molar excess of an organic acid (e.g., ascorbic acid) relative to glutathione in solution, e.g., about 1 : 1.1, about 1 : 1.2, about 1 :3, about 1 :4, about 1 :5 molar ratio of glutathione to ascorbic acid.

[0104] In some aspects, a Composition of the Disclosure further comprises a bicarbonate salt (e.g., sodium bicarbonate). In some aspects, glutathione, an organic acid (e.g. ascorbic acid), or a pharmaceutically acceptable salt thereof, and bicarbonate salt (e.g., sodium bicarbonate) are formulated in a molar ratio of about 0.4-0.5:0.5:1. In some aspects, glutathione, an organic acid (e.g. ascorbic acid), or a pharmaceutically acceptablesalt thereof, and bicarbonate salt (e.g., sodium bicarbonate) are formulated in a molar ratio of about 0.5:0.5: 1. In some aspects, glutathione, an organic acid (e.g. ascorbic acid), and bicarbonate salt (e.g., sodium bicarbonate) are formulated in a molar ratio of about 0.4-0.5:0.5: 1.

[0105] In some aspects, glutathione, an organic acid (e.g., ascorbic acid), and bicarbonate salt (e.g., sodium bicarbonate) are formulated to comprise a molar ratio of about 0.1-0.5: 0.5-1 : 1, about 0.2-0.5: 0.5-1 : 1, about 0.3-0.5: 0.5-1 : 1, about 0.4-0.5: 0.5-1 : 1, about 0.49: 0.5-1 : 1, about 0.5: 0.5-1 : 1, about 0.1-0.5: 0.6-1 : 1, about 0.2-0.5: 0.6-1 : 1, about 0.3-0.5: 0.6-1 : 1, about 0.4-0.5: 0.6-1 : 1, about 0.49: 0.6-1 : 1, about 0.5: 0.6-1 : 1, about 0.1-0.5: 0.7-1 : 1, about 0.2-0.5: 0.7-1 : 1, about 0.3-0.5: 0.7-1 : 1, about 0.4-0.5: 0.7-1 : 1, about 0.49: 0.7-1 : 1, about 0.5: 0.7-1 : 1, about 0.1-0.5: 0.8-1 : 1, about 0.2-0.5: 0.8-1 : 1, about 0.3-0.5: 0.8-1 : 1, about 0.4-0.5: 0.8-1 : 1, about 0.49: 0.8-1 : 1, about 0.5: 0.8-1 : 1, about 0.1-0.5: 0.9-1 : 1, about 0.2-0.5: 0.9-1 : 1, about 0.3-0.5: 0.9-1 : 1, about 0.4-0.5: 0.9- 1 : 1, about 0.49: 0.9-1 : 1, about 0.5: 0.9-1 : 1, about 0.1 -0.5: 1 : 1, about 0.2-0.5: 1 : 1, about 0.3-0.5: 1 : 1, about 0.4-0.5: 1 : 1, about 0.49: 1 : 1, about 0.5: 1 : 1, molar ratio of glutathione to an organic acid (e.g., ascorbic acid), to bicarbonate salt (e.g., sodium bicarbonate). In some aspects, the molar ratio of glutathione, an organic acid (e.g., ascorbic acid), and bicarbonate salt (e.g., sodium bicarbonate) is 0.1-0.5: 0.5-1 : 1, 0.4-0.5: 0.5-1 : 1, 0.1-0.5: 0.5: 1, 0.1-0.5: 1 : 1, or 0.4-0.5: 1 : 1. In some aspects, the molar ratio of glutathione, an organic acid (e.g., ascorbic acid), and bicarbonate salt (e.g., sodium bicarbonate) is 0.49: 0.5: 1, 0.5: 0.5: 1, 0.49: 1: 1, or 0.5: 1 : 1.

[0106] In some aspects, the bicarbonate salt (e.g., sodium bicarbonate) is less than the combined molar ratio of (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof and (b) an organic acid (e.g., ascorbic acid). In some aspects, the molar ratio of glutathione, an organic acid (e.g., ascorbic acid), and bicarbonate salt (e.g., sodium bicarbonate) is 0.1-0.49: 0.5: 1, 0.2-0.49: 0.5: 1, 0.3-0.49: 0.5: 1, or 0.4-0.49: 0.5: 1.

[0107] In some aspects, a Composition of the Disclosure comprises or consists essentially of (a) a glutathione, a glutathione derivative, a glutathione conjugate, pharmaceutically acceptable salt thereof, or any combination thereof, and (b) an organic acid, wherein the molar ratio of (a) to (b) is about 0.5-1 : 1, about 0.6-1 : 1, 0.7-1 : 1, 0.8-1 : 1, 0.9-1 : 1 or about1 : 1 and the pH of the composition is about 5.5 to 14, about 6 to about 8, 7 ± 1.5, 6 ± 0.5, or about 6.

[0108] In some aspects, a Composition of the Disclosure comprises or consists essentially of (a) a glutathione, a glutathione derivative, a glutathione conjugate, pharmaceutically acceptable salt thereof, or any combination thereof, (b) an organic acid, (c) a bicarbonate salt, wherein the molar ratio of (a) to (b) to (c) is about 0.1-0.5: 0.5-1 : 1, 0.4-0.5: 0.5-1 : 1, 0.1-0.5: 0.5: 1, 0.1-0.5: 1 : 1, 0.4-0.5: 1 : 1, 0.1-0.49: 0.5: 1, 0.2-0.49: 0.5: 1, 0.3-0.49: 0.5: 1, or 0.4-0.49: 0.5: 1 and the pH of the composition is about 5.5 to 14, about 6 to about 8, 7 ± 1.5, 6 ± 0.5, or about 6. Pharmaceutical compositions for use in the present disclosure can be formulated using one or more physiologically acceptable carriers and / or excipients that facilitate administration of an organic acid, glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof to a subject by an intended route, e.g., delivery by inhalation. In some aspects, the pharmaceutical composition is an aqueous solution. In some aspects, the pharmaceutical composition is a dry powder.

[0109] A Composition of the Disclosure can be manufactured by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, spray drying, or lyophilizing processes that are known in the art. The particular formulation depends upon the route of administration chosen. In one aspect, glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof is dissolved in a solvent, e.g., water, for administration to the airway of a subject (e.g., intranasal administration).

[0110] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid (e.g., water), or a solid filler, diluent, excipient, solvent, or encapsulating material. A carrier is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation and suitable for use in humans without toxicity, irritation, allergic response, immunogenicity, or other complications commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of PharmaceuticalAdditives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).[OHl] In some aspects, a Composition of the Disclosure comprises an excipient. In some aspects, the excipient is selected from the group consisting of a pH adjusting agent, a preservative, a chelating agent, and any combination thereof.

[0112] In certain aspects, a Composition of the Disclosure can comprise a pH adjusting agent. pH adjusting agents are known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th edition, A. R Gennaro, Ed., Mack Publishing Company (1990) and Handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000). Suitable examples of pharmaceutically acceptable pH adjusting agents include, but are not limited to, ascorbic acid, citric acid, sodium citrate, sodium bicarbonate, potassium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate, magnesium hydroxide, buffers (e.g., acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, and borate buffers, and any combination thereof), fat-soluble fatty acid esters of ascorbic acid (vitamin C) (e.g., alone or in combination with a-hydroxy acids), oxidation-resistant saturated fatty acid esters of ascorbic acid (e.g., ascorbyllaurate, ascorbyl myristate, ascorbyl palmitate, ascorbyl stearate, and ascorbyl behenate, and any combination thereof), and any combination thereof. In some aspects, esters can be prepared using hydrogenated oils or fats, or fractions thereof, and contain small amounts of another ester. Ascorbyl stearate prepared using canola, for example, can commonly contain about 4% ascorbyl palmitate.

[0113] In one aspect, the pH adjusting agent, e.g., ascorbic acid, or a pharmaceutically acceptable salt thereof, is present in a Composition of the Disclosure in an amount of about 0.01-50% by weight, about 10-90% by weight, about 10-85% by weight, about 10- 80% by weight, about 10-75% by weight, about 10-70% by weight, about 10-65% by weight, about 10-60% by weight, about 10-55% by weight, about 10-50% by weight, about 10-45% by weight, about 10-40% by weight, about 10-35% by weight, about 10- 30% by weight, about 1-30% by weight, about 1-20% by weight, or about 1-10% by weight. In some aspects, the pH adjusting agent is present in a Composition of the Disclosure at an amount of about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% byweight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of the composition.

[0114] In certain aspects, a Composition of the Disclosure can comprise preservatives. Pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents, solvents (e.g., ethanol, propylene glycol, benzyl alcohol and chlorobutanol, and any combination thereof), quaternary ammonium salts (e.g., cetylypridinium chloride, benzalkonium chloride and parabens including, but not limited to, methyl paraben, ethyl paraben and propyl paraben), chlorhexidine, benzoic acid and the salts thereof, parahydroxybenzoic acids and the salts thereof, alkyl esters of parahydroxybenzoic acid and the salts thereof, phenylmercuric salts such as nitrate, chloride, acetate, and borate, antioxidants, EDTA, sorbitol, phenol, boric acid and the salts thereof, sorbic acid and the salts thereof, thimerosal and nitromersol, and any combinations thereof.

[0115] In one aspect, the preservative is present in a Composition of the Disclosure in about 0.01-50% by weight, e.g., about 1-30% by weight, about 1-20% by weight, or about 1-10% by weight, e.g., about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of the composition.

[0116] In certain aspects, a Composition of the Disclosure can comprise a chelating agent. Non-limiting examples of chelating agents include lactic acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, aconitic acid, pimelic acid, sebacic acid, allymalonic acid, ethylmalonic acid, citric acid, malic acid, glyceric acid, tartaric acid, mevaloic acid, oxyglutaric acid, oxaloacetic acid, a-ketoglutaric acid, a- ketomalonic acid, glucuronic acid, galaceturonic acid, mannuronic acid, aspartic acid, glutamic acid, glycine, alanine, lysine, histidine, alginine, cysteine, s-aminocaproic acid, phenylalanine, phenylglycine, p-hydroxyphenylglycine, p-aminophenylalanine, y- carb oxy glutamic acid, iminodiacetic acid, hydroxy ethyliminodiacetic acid, ethylenediaminediacetic acid, ethylenediaminetetraacetic acid, trans-cyclohexane- diaminetetraacetic acid, diethylenediaminepentaacetic acid, alaninediacetic acid, diaminopimelic acid, phthalic acid, terephthalic acid, homophthalic acid, phenylsuccinic acid, phenylmalonic acid, oxanylic acid-o-carboxylic acid, anthralininoacetic acid, 2,4-dihydroxybenzoic acid, p-aminosalicyclic acid, phthaly glutamic acid, kynurenine, 1,2- hyroxybenzene-3,5-disulfonic acid, 4-amino-phenol-2-sulfonic acid, cysteic acid, 2- phosphoglyceric acid, glycero-3 -phosphoric acid, glucose- 1,6-diphosphoric acid, fructose- 1,6- diphosphoric acid and phosphates (e.g., sodium phosphate, sodium aluminum phosphate, sodium acid phosphate, dipotassium phosphate, disodium phosphate, monobasic and sodium hexametaphosphate), and any combination thereof. Chelating agents can be included in the pharmaceutical compositions of this disclosure either as the parent molecule or in the salt form where appropriate. For example, compounds containing an acid function can be used in the protonated form or as a pharmaceutically acceptable inorganic or organic salt which retains the chelating activity of the parent compound

[0117] In one aspect, the chelating agent is present in a Composition of the Disclosure in about 0.01-50% by weight, e.g., about 1-30% by weight, about 1-20% by weight, or about 1-10% by weight, e.g., about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, or about 50% by weight of the composition.

[0118] In certain aspects, a Composition of the Disclosure comprises glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof; a bicarbonate, or a pharmaceutically acceptable salt thereof, (e.g., sodium bicarbonate or potassium bicarbonate), and / or a pH modifier (e.g., ascorbic acid), or a pharmaceutically acceptable salt thereof. In some aspects, a Composition of the Disclosure comprises glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof and / or a pH modifier such as an organic acid (e.g., ascorbic acid), or a pharmaceutically acceptable salt thereof. In some aspects, the present disclosure is directed to a composition disclosed herein, wherein the amount of each component is present such that the amount of ascorbic acid, or a pharmaceutically acceptable salt thereof, is approximately molar equivalent or in molar excess of that of glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0119] In some aspects, a Composition of the Disclosure comprises (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable saltthereof; (b) an organic acid; and (c) a bicarbonate salt. In further aspects, the molar ratio of (a):(b):(c) in a Composition of the Disclosure is 0.1-0.5: 0.5-1 : 1 (e.g., 0.4-0.5: 0.5-1 : 1, 0.1-0.5: 0.5: 1, 0.1-0.5: 1 : 1, 0.4-0.5: 1 : 1, 0.1-0.49: 0.5: 1, 0.2-0.49: 0.5: 1, 0.3-0.49: 0.5: 1, or 0.4-0.49: 0.5: 1).

[0120] In some aspects, the organic acid in a Composition of the Disclosure is ascorbic acid. In some aspects, the bicarbonate salt in a Composition of the Disclosure is sodium bicarbonate. In some aspects, the composition comprises: (a) glutathione; (b) ascorbic acid; and (c) sodium bicarbonate. In certain aspects, the molar ratio of (a):(b):(c) is about 0.1-0.5: 0.5-1 : 1 (e.g., about 0.49 : about 0.50 : about 1). In other aspects, the molar ratio of (a):(b):(c) is about 0.1-0.5: 1 : 1 (e.g., about 0.49 : about 1 : about l).In some aspects, the pH of a Composition of the Disclosure is from about 5.5 to about 14 (e.g. 5.5 to 7.5). In some aspects, the pH of a Composition of the Disclosure is from about 6 to about 14 (e.g., 6 to 7.5). In some aspects, the pH of the composition is 7 ± 1.5, 7 ± 1.4, 7 ± 1.3, 7 ± 1.2, 7 ± 1.1, 6 ± 0.5, 6 ± 0.4, 6 ± 0.3, 6 ± 0.2, 6 ± 0.5, 6 ± 0.1, or about 6.

[0121] In some aspects, a Composition of the Disclosure is storage stable at 2-8°C for at least 72 hours. In some aspects, a Composition of the Disclosure can (a) remain essentially free of precipitation after storage at 2-8°C for at least 72 hours, (b) comprise less than 7%, less than 6%, less than 5%, or less than 4% impurities after storage at 2-8°C for at least 72 hours, (c) have or maintain a pH from about 6 to 7.5 (e.g., 6.0-7.0) after storage at 2-8°C for at least 72 hours, and / or (d) have minimal loss of solubility after storage at 2-8°C for at least 72 hours.

[0122] In some aspects, the molar ratio of (a):(b) is about 0.1-0.5:0.5-1, about 0.1-0.6:0.5- 1, about 0.1-0.7:0.5-1, about 0.1-0.8:0.5-1, about 0.1-0.9:0.5-1, about 0.1-1.0:0.5-1, about 0.1-1.1 :0.5-1, about 0.1-1.2:0.5-1, about 0.1-1.3:0.5-1, about 0.1-1.4:0.5-1, about 0.1- 1.5:0.5-1, about 0.1-1.6:0.5-1, about 0.1-1.7:0.5-1, about 0.1-1.8:0.5-1, about 0.1-1.9:0.5- 1, about 0.1-2.0:0.5-1, about 0.1-0.5:0.5-1.1, about 0.1-0.5:0.5-1.2, about 0.1-0.5:0.5-1.3, about 0.1-0.5:0.5-1.4, about 0.1-0.5:0.5-1.5, about 0.1-0.5:0.5-1.6, about 0.1-0.5:0.5-1.7, about 0.1-0.5:0.5-1.8, about 0.1-0.5:0.5-1.9, about 0.1-0.5:0.5-2.0, or about 1 : 1. In some aspects, the molar ratio of (a):(b) is about 0.1-0.5:0.5-1.

[0123] In some aspects, the composition further comprises (c) bicarbonate or a pharmaceutically acceptable salt thereof. In some aspects, the composition comprises sodium bicarbonate or calcium bicarbonate.

[0124] In some aspects, the molar ratio of (a):(b):(c) is about 0.1-0.6:0.5-1 : 1.

[0125] In some aspects, the molar ratio of (a):(c) is about 0.1-0.5:0.5-1, about 0.1-0.6:0.5- 1, about 0.1-0.7:0.5-1, about 0.1-0.8:0.5-1, about 0.1-0.9:0.5-1, about 0.1-1.0:0.5-1, about 0.1-1.1 :0.5-1, about 0.1-1.2:0.5-1, about 0.1-1.3:0.5-1, about 0.1-1.4:0.5-1, about 0.1- 1.5:0.5-1, about 0.1-1.6:0.5-1, about 0.1-1.7:0.5-1, about 0.1-1.8:0.5-1, about 0.1-1.9:0.5- 1, about 0.1-2.0:0.5-1, about 0.1-0.5:0.5-1.1, about 0.1-0.5:0.5-1.2, about 0.1-0.5:0.5-1.3, about 0.1-0.5:0.5-1.4, about 0.1-0.5:0.5-1.5, about 0.1-0.5:0.5-1.6, about 0.1-0.5:0.5-1.7, about 0.1-0.5:0.5-1.8, about 0.1-0.5:0.5-1.9, or about 0.1-0.5:0.5-2.0.

[0126] In some aspects, the composition comprises glutathione or a pharmaceutically acceptable salt thereof. In some aspects, the composition comprises a glutathione derivative or a pharmaceutically acceptable salt thereof. In some aspects, the composition comprises a glutathione conjugate or a pharmaceutically acceptable salt thereof.

[0127] In some aspects, the organic acid is ascorbic acid or a pharmaceutically acceptable salt thereof.

[0128] In some aspects, the composition is administered to the lungs by an inhalable dosage form. In some aspects, the inhalable dosage form is a metered dose inhaler, a dry powder inhaler, or a nebulizer.

[0129] In some aspects, the subject has a chronic airway disease or condition. In some aspects, the chronic airway disease or condition is a pre-existing condition.

[0130] As used herein, glutathione or "GSH" can refer to a compound having the Formula A:or a zwitterionic form thereof, e.g., a compound having the Formula B:III. Pharmaceutical Preparations

[0131] In some aspects referred to as "Embodiment I," the present disclosure provides a preparation comprising an aqueous solution in a closed container with a headspace, wherein:

[0132] (i) the aqueous solution comprises a salt having Formula I:

[0133] (ii) the atmosphere of the headspace comprises 90% or more carbon dioxide by volume; and

[0134] (iii) M+is Na+, Li+, K+or Cs+.

[0135] In another aspect, the aqueous solution of Embodiment I has a pH of 6.0 ± 0.4 for 24 hours or more at about 5 °C.

[0136] In another aspect, the aqueous solution of Embodiment I has a pH of 6.0 ± 0.3 for 24 hours or more at about 5 °C.

[0137] In another aspect, the aqueous solution of Embodiment I has a pH of 6.0 ± 0.2 for 24 hours or more at about 5 °C.

[0138] In another aspect, the aqueous solution of Embodiment I has a pH of 6.0 ± 0.1 for 24 hours or more at about 5 °C.

[0139] In another aspect, the aqueous solution of Embodiment I further comprises a salt having Formula II:

[0140] In another aspect, the aqueous solution of Embodiment I further comprises a salt having Formula III:

[0141] In another aspect, the atmosphere of the headspace of Embodiment I comprises 80% or more of carbon dioxide by volume.

[0142] In another aspect, the atmosphere of the headspace of Embodiment I comprises 85% or more of carbon dioxide by volume.

[0143] In another aspect, the atmosphere of the headspace of Embodiment I comprises 90% or more of carbon dioxide by volume.

[0144] In another aspect, the atmosphere of the headspace of Embodiment I comprises 95% or more of carbon dioxide by volume.

[0145] In another aspect, the aqueous solution of Embodiment I comprises about 10 wt % to about 20 wt % of the salt having Formula I.

[0146] In another aspect, the aqueous solution of Embodiment I comprises about 13 wt % to about 17 wt % of the salt having Formula I.

[0147] In another aspect, the aqueous solution of Embodiment I comprises about14.7 wt % of the salt having Formula I.

[0148] In another aspect, the aqueous solution of Embodiment I comprises about 5 wt % to about 15 wt % of the salt having Formula II.

[0149] In another aspect, the aqueous solution of Embodiment I comprises about 7 wt % to about 11 wt % of the salt having Formula II

[0150] In another aspect, the aqueous solution of Embodiment I comprises about9.1 wt % of the salt having Formula II.

[0151] In another aspect, the aqueous solution of Embodiment I has a density of about 1.13 g / L.

[0152] In another aspect, the aqueous solution of Embodiment I is frozen.

[0153] In another aspect, M+is Na+in Embodiment I.

[0154] In another aspect, M+is Li+in Embodiment I.

[0155] In another aspect, M+is K+in Embodiment I.

[0156] In another aspect, M+is Cs+in Embodiment I.

[0157] In another embodiment, the preparation of Embodiment I is packaged as a single unit dose. In another aspect, the single unit dose is in a sealed vial.

[0158] In another aspect, the preparation of Embodiment I is marketed, distributed, or administered as part of a pharmaceutical product.

[0159] In some aspects, the preparation of Embodiment I can further comprise any one or more of the further aspects disclosed herein.

[0160] In another aspect referred to as "Embodiment II," the present disclosure provides a method of making the preparation of Embodiment I (or Embodiment I including one or more the further aspects disclosed above), the method comprising:

[0161] (i) dissolving L-glutathione, ascorbic acid, and M+HC03‘, wherein M+is Na+, Li+,K+or Cs+, in water for injection under carbon dioxide to give an aqueous solution;

[0162] (ii) transferring a portion of the aqueous solution to a container;

[0163] (iii) overlaying the aqueous solution with carbon dioxide; and

[0164] (iv) sealing the container with a stopper.

[0165] In another embodiment, about 8 wt % to about 18 wt % of L-glutathione, about3 wt % to about 13 wt % of ascorbic acid, and about 3 wt % to about 13 wt % of M+HC03‘ is dissolved in about 62 wt % to about 82 wt % water for injection to give the aqueous solution of Embodiment II.

[0166] In another aspect, the aqueous solution of Embodiment II has a pH of 6.0 ± 0.4 for 24 hours or more at about 5 °C.

[0167] In another aspect, the aqueous solution of Embodiment II has a pH of 6.0 ± 0.3 for 24 hours or more at about 5 °C.

[0168] In another aspect, the aqueous solution of Embodiment II has a pH of 6.0 ± 0.2 for 24 hours or more at about 5 °C.

[0169] In another aspect, the aqueous solution of Embodiment II has a pH of 6.0 ± 0.1 for 24 hours or more at about 5 °C.

[0170] In another aspect, M+is Na+, i.e., M+HCCh’ is sodium bicarbonate, in Embodiment II.

[0171] In another aspect, M+is Li+, i.e., M+HCCh’ is lithium bicarbonate, in Embodiment II.

[0172] In another aspect, M+is K+, i.e., NfUCCh’ is potassium bicarbonate, in Embodiment II.

[0173] In another aspectt, M+is Cs+, i.e., M+HCCh’ is cesium bicarbonate, in Embodiment II.

[0174] In another aspect, about 11 wt % to about 15 wt % of L-glutathione, about 5 wt % to about 9 wt % of ascorbic acid, and about 5 wt % to about 9 wt % of sodiumbicarbonate is dissolved in about 68 wt % to about 76 wt % water to give the aqueous solution of Embodiment II, wherein M+is Na+.

[0175] In another aspect, about 13.0 wt % of L-glutathione, about 7.6 wt % of ascorbic acid, and about 7.3 wt % of sodium bicarbonate is dissolved in about 72.0 wt % water to give the aqueous solution of Embodiment II, wherein M+is Na+.

[0176] In some aspects, the method of Embodiment II can further comprise any one or more of the further aspects disclosed herein.

[0177] In another aspect referred to as "Embodiment III," the present disclosure provides an aqueous solution comprising a salt having Formula I:prepared by dissolving L-glutathione, ascorbic acid, and M+HC03‘, wherein M+is Na+, Li+, K+or Cs+, in water for injection under an atmosphere of carbon dioxide.

[0178] In another aspect, about 8 wt % to about 18 wt % L-glutathione, about 3 wt % to about 13 wt % of ascorbic acid, and about 3 wt % to about 13 wt % M+HC03‘ is dissolved in about 62 wt % to about 82 wt % water for injection to give the aqueous solution of Embodiment III.

[0179] In another aspect, the aqueous solution of Embodiment III has a pH of 6.0 ± 0.4 for 24 hours or more at about 5 °C.

[0180] In another aspect, the aqueous solution of Embodiment III has a pH of 6.0 ± 0.3 for 24 hours or more at about 5 °C.

[0181] In another aspect, the aqueous solution of Embodiment III has a pH of 6.0 ± 0.2 for 24 hours or more at about 5 °C.

[0182] In another aspect, the aqueous solution of Embodiment III has a pH of 6.0 ± 0.1 for 24 hours or more at about 5 °C.

[0183] In another aspect, the aqueous solution of Embodiment III further comprises a salt having Formula IL

[0184] In another aspect, the aqueous solution of Embodiment III further comprises a salt having Formula III:

[0185] In another aspect, M+is Na+, i.e., M+HC03‘ is sodium bicarbonate, in Embodiment III.

[0186] In another aspect, M+is Li+, i.e., M+HC03' is lithium bicarbonate, in Embodiment III.

[0187] In another aspect, M+is K+, i.e., M+HC03‘ is potassium bicarbonate, in Embodiment III.

[0188] In another aspect, M+is Cs+, i.e., M+HC03‘ is cesium bicarbonate, in EmbodimentIII.

[0189] In another aspect, about 11 wt % to about 15 wt % L-glutathione, about 5 wt % to about 9 wt % of ascorbic acid, and about 5 wt % to about 9 wt % sodium bicarbonate is dissolved in about 68 wt % to about 76 wt % water to give the aqueous solution in Embodiment III.

[0190] In another aspect, about 13.0 wt % L-glutathione, about 7.6 wt % ascorbic acid, and about 7.3 wt % sodium bicarbonate is dissolved in about 72.0 wt % water to give the aqueous solution in Embodiment III.

[0191] In some aspects, the aqueous solution of Embodiment III can further comprise any one or more of the further aspects disclosed herein.

[0192] Glutathione plays a role in the detoxification of xenobiotic compounds and in the antioxidation of reactive oxygen species and free radicals. See, e.g., Bray and Taylor, Canadian Journal of Physiology and Pharmacology 71 :746-751 (1993).

[0193] In individuals with chronic inflammatory airway diseases, such as lung transplant patients or patients having received other transplants (e.g., solid organ, blood, bone marrow), glutathione reserves are depleted.IV. Glutathione Conjugates

[0194] In some aspects, a Composition of the Disclosure comprises a glutathione- containing conjugate or a pharmaceutically acceptable salt thereof. In certain aspects, theglutathione-containing conjugate is metabolized to release glutathione, or a derivative thereof, upon administration to a subject.

[0195] In one aspect, a glutathione conjugate is a compound having Formula I:and the pharmaceutically acceptable salts and solvates thereof, wherein,A1is -OR1; A2is Z1; A3is hydrogen; and A4is R3a; orA1is Z1; A2is -OR2; and A3is hydrogen; and A4is R3a; orA1is -OR1; A2is -OR2; and A3is Z3; and A4is R3a; orA1is Z2; A2is -OR2; and A3is hydrogen; and A4is R3a; orA1is -OR1; A2is Z2; and A3is hydrogen; and A4is R3a; orA1is -OR1; A2is -OR2; A3is hydrogen; and A4is Z3; orA1and A2are each Z1, and A3is hydrogen;Z1is selected from the group consisting of:Z2is selected from the group consisting of:Z3is selected from the group consisting of:R1is selected from the group consisting of hydrogen and optionally substituted alkyl;R2is selected from the group consisting of hydrogen and optionally substituted alkyl;R3a, R3b, and R3care each independently selected from the group consisting of hydrogen and protecting group;X is selected from the group consisting of:-O-;-O(CH2)mO-;-OCH2CH(R4)O-;-OCH(R4)CH2O-; and-O(CH2CH2O)n-;R4is:m is 1, 2, 3, 4, 5, 6, 7, or 8; n is 2, 3, 4, 5, 6, 7, or 8; andR5is selected from the group consisting of hydrogen and optionally substituted alkyl.

[0196] In another aspect, a glutathione conjugate is a compound having Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein m is 2, 3, 4, 5, 6, 7, or 8.

[0197] In another aspect, a glutathione conjugate is a compound having Formula II:or a pharmaceutically acceptable salt or solvate thereof, wherein Rl, R3a, R3b, R3c, and X are as defined in connection with Formula I.

[0198] In another aspect, a glutathione conjugate is enantiomerically enriched.

[0199] In another aspect, the glutathione conjugate is as described in US 11,497,786.V. Methods of Use

[0200] Certain aspects of the disclosure are directed to a method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising glutathione wherein: the disease is bronchiectasis or chronic bronchitis; and the severity and / or rate of progression is determined using one or more of the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire, and / or spirometry.

[0201] Certain aspects of the disclosure are directed to a method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising glutathione wherein: the disease is NTM pulmonary disease, with or without bronchiectasis; and the severity and / or rate of progression is determined using one or more of the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire, and / or spirometry.

[0202] Certain aspects of the disclosure are directed to a method improving or reducing cough and / or sputum associated in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and (b) an organic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0203] In some aspects, the subject suffers from bronchiectasis or chronic bronchitis. In some aspects, the subject suffers from NTM pulmonary disease, with or without bronchiectasis. In some aspects, the subject suffers from NTM pulmonary disease with bronchiectasis. In some aspects, the subject suffers from NTM pulmonary disease without bronchiectasis.

[0204] In some aspects, the bronchiectasis is non-CF bronchiectasis (NCFBE)

[0205] Certain aspects of the disclosure are directed to a method of reducing sputum in a subject in need thereof, comprising administering to the subject (e.g., to the subject’s airway) a therapeutically effective amount of a composition comprising: (a) glutathione, a glutathione derivative, a glutathione conjugate, or a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and (b) an organic acid, or a pharmaceutically acceptable salt thereof.

[0206] In some aspects, the methods disclosed herein comprise administering to the subject (e.g., to the subject’s airway) a therapeutically effective amount of a composition comprising: (a) glutathione or a pharmaceutically acceptable salt of glutathione; and (b) ascorbic acid or a pharmaceutically acceptable salt thereof.

[0207] In some aspects, the molar ratio of (a):(b) is about 0.1-0.5:0.5-1.

[0208] In some aspects, the bicarbonate or a pharmaceutically acceptable salt thereof comprises sodium bicarbonate or calcium bicarbonate.

[0209] In some aspects, the methods disclosed herein comprise administering to the subject (e.g., to the subject’s airway) a therapeutically effective amount of a composition comprising: (a) glutathione or a pharmaceutically acceptable salt of glutathione; (b) ascorbic acid or a pharmaceutically acceptable salt thereof, and (c) bicarbonate, or a pharmaceutically acceptable salt thereof.

[0210] In some aspects, the molar ratio of (a):(b):(c) is about 0.1-0.6:0.5-1 : 1; about 0.4- 0.6:0.4-0.6: 1; about 0.4-0.5:0.5: 1; about 0.49:0.5:1; or about 0.5:0.5: 1.

[0211] In some aspects, the composition comprises glutathione.

[0212] In some aspects, the organic acid is ascorbic acid or a pharmaceutically acceptable salt thereof.

[0213] In some aspects, the administration is to the airway via inhalation. In some aspects, the composition is administered to the lungs by an inhalable dosage form.

[0214] In some aspects, the inhalable dosage form is a metered dose inhaler, a dry powder inhaler, or a nebulizer.

[0215] In some aspects, the subject has a chronic airway disease or condition. In some aspects, the chronic airway disease or condition is a pre-existing condition.

[0216] In some aspects, the subject has a pulmonary or airway disease or disorder. In some aspects, the pulmonary or airway disease or disorder is non-cystic fibrosis bronchiectasis.

[0217] In some aspects, the subject has a pulmonary or airway infection. In some aspects, the infection is caused by one or more bacteria. In some aspects, the bacteria are laboratory isolates or clinical isolates. In some aspects, the infection is caused by one or more bacteria selected from nontuberculous mycobacteria (NTM), Burkholderia cepacia, mucoid Pseudomonas aeruginosa, non-mucoid Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumonia, Actinobacter baumannii, Burkholderia pseudomallei, Enterococcus, Streptococcus, Pneumococcus, and combinations thereof.

[0218] In some aspects, the infection is caused by nontuberculous mycobacteria (NTM). Nontuberculous mycobacteria is also known as environmental mycobacteria, atypical mycobacteria, and mycobacteria other than tuberculosis (MOTT).

[0219] In some aspects, the subject has a pulmonary or airway infection (e.g., an infection caused by nontuberculous mycobacteria (NTM)) and suffers frombronchiectasis. In some aspects, the severity and / or the rate of progression of bronchiectasis is reduced by at least 4 points after administering the composition to the subject as measured by SGRQ. In some aspects, the severity and / or the rate of progression of bronchiectasis is reduced by at least 7 points after administering the composition to the subject as measured by QOL-B. In some aspects, the severity and / or the rate of progression of bronchiectasis is reduced by at least 2 points after administering the composition to the subject as measured by CAAT.

[0220] In some aspects, the severity and / or the rate of progression of bronchiectasis in a subject is reduced by at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points, or at least 7 points, or at least 8 points, or at least 9 points, or at least 10 points, after administering the composition to the subject as measured by SGRQ. In some aspects, the MCID for the SGRQ is -4 (i.e., a reduction of 4 points).

[0221] In some aspects, the severity and / or the rate of progression of bronchiectasis in a subject (e.g., a subject having an infection caused by nontuberculous mycobacteria (NTM)) is reduced by at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points, or at least 7 points, or at least 8 points, or at least 9 points, or at least 10 points, or at least 11 points, or at least 12 points, or at least 13 points, or at least 14 points, or at least 15 points, after administering the composition to the subject as measured by QOL-B.

[0222] In some aspects, the severity and / or the rate of progression of bronchiectasis in a subject (e.g., a subject having an infection caused by nontuberculous mycobacteria (NTM)) is reduced by at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points, or at least 7 points, or at least 8 points, or at least 9 points, or at least 10 points, after administering the composition to the subject as measured by CAAT. In some aspects, the MCID for the CAAT is -2 (i.e., a reduction of 2 points).

[0223] In some aspects, the subject has chronic bronchitis. In some aspects, the severity and / or the rate of progression of chronic bronchitis is reduced by at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points, or at least 7 points, or at least 8 points, or at least 9 points, or at least 10 points, after administering the composition to the subject as measured by MCQ.

[0224] In some aspects, the subject has chronic bronchitis. In some aspects, the severity and / or the rate of progression of chronic bronchitis is reduced by at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points, or at least 7 points, or at least 8 points, or at least 9 points, or at least 10 points, , or at least 11 points, or at least 12 points, or at least 13 points, or at least 15 points after administering the composition to the subject as measured by CAAT.

[0225] In some aspects, the Composition of the Disclosure comprises: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof; and (b) an organic acid, or a pharmaceutically acceptable salt thereof, wherein the molar ratio of (a) to (b) is about 0.5-1 : 1 and the pH of the formulation is at least 5.5. In some aspects, the organic acid is ascorbic acid. In some aspects, the composition further comprises (c) a bicarbonate salt (e.g., sodium bicarbonate or calcium bicarbonate). In some aspects, the composition does not include a bicarbonate salt.

[0226] In some aspects, (b) is ascorbic acid, and the molar ratio of (a):(b):(c) is about 0.1- 0.5: 0.5-1 : 1. In some aspects, the molar ratio of (a):(b):(c) is about 0.4-0.5: 0.5-1 : 1. In some aspects, the molar ratio of (a):(b):(c) is about 0.4-0.5: 0.5: 1 or 0.4-0.5: 1 : 1.

[0227] In some aspects, the composition is an aqueous solution, a dry powder, or lyophilized.

[0228] Certain aspects are directed to a method improving or reducing cough and / or sputum associated in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and (b) an organic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0229] In some aspects, the subject suffers from bronchiectasis or chronic bronchitis.

[0230] In some aspects, the bronchiectasis is non-CF bronchiectasis (NCFBE).

[0231] In some aspects, the subject suffers from chronic bronchitis.

[0232] In some aspects, the subject has a pulmonary or airway infection caused by nontuberculous mycobacteria (NTM). In some aspects, the subject suffers from bronchiectasis and a pulmonary or airway infection caused by nontuberculousmycobacteria (NTM). In some aspects, the subject has non-CF bronchiectasis (NCFBE) and a pulmonary or airway infection caused by nontuberculous mycobacteria (NTM).

[0233] In some aspects, the subject suffers from NTM pulmonary disease with or without bronchiectasis. In some aspects, the subject suffers from NTM pulmonary disease with bronchiectasis. In some aspects, the subject suffers from NTM pulmonary disease without bronchiectasis.

[0234] In some aspects, the composition comprises: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof; and (b) an organic acid, wherein the molar ratio of (a) to (b) is about 0 5-1:1.

[0235] In some aspects, the pH of the formulation is at least 5.5.

[0236] In some aspects, the organic acid is ascorbic acid.

[0237] In some aspects, the composition further comprises (c) a bicarbonate salt (e.g., sodium bicarbonate or calcium bicarbonate).

[0238] In some aspects, the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.1 -0.5: 0.5-1 : 1.

[0239] In some aspects, the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.4-0.5: 0.5-1 : 1.

[0240] In some aspects, the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.4-0.5: 0.5: 1 or 0.4-0.5: 1 : 1.

[0241] In some aspects, the composition is an aqueous solution.

[0242] In some aspects, the composition is administered to the lung.

[0243] In some aspects, the method is directed to improving or reducing cough, reducing sputum, and / or improving or reducing sputum viscosity.VI. Particular Aspects

[0244] The present description also provides the following particular embodiments.

[0245] Aspect 1. A method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising glutathione salt wherein: the disease is bronchiectasis or chronic bronchitis; andthe severity and / or rate of progression is determined using one or more of the Bronchiectasis Severity Index(BSI), Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire, and / or spirometry.

[0246] Aspect 2. The method of Aspect 1, wherein the glutathione salt has the formula of a salt of glutathione having Formula (I):

[0247] wherein:

[0248] (i) M+is Na+, Li+, K+, or Cs+.

[0249] Aspect 3. The method of Aspect 1 or 2 for reducing the severity of the disease in the subject.

[0250] Aspect 4. The method of any one of Aspects 1-3, wherein reducing the severity of the disease is the result of a symptomatic response.

[0251] Aspect 5. The method of Aspect 4, wherein the symptomatic response is reducing the severity of cough in the subject.

[0252] Aspect 6. The method of any one of Aspects 1-5, wherein reducing the severity of the disease is the result of a disease-modifying response in the subject.

[0253] Aspect 7. The method of any one of Aspects 1-6 for reducing the rate of progression of the disease in a subject.

[0254] Aspect 8. The method of any one of Aspects 1-7, wherein reducing the rate of progression of the disease is the result of a symptomatic response.

[0255] Aspect 9. The method of Aspect 8, wherein the symptomatic response is reducing the rate of progression of cough in the subject.

[0256] Aspect 10. The method of any one of Aspects 1-9, wherein reducing the severity of the disease is the result of a disease-modifying response in the subject.

[0257] Aspect 11. The method of any one of Aspects 1-8, wherein the rate of progression is reduced by at least four points after at least four weeks of administering the composition to the subject as compared to the natural history of disease progression in an untreated subject.

[0258] Aspect 12. A method of improving or reducing cough and / or sputum associated in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising:

[0259] (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and

[0260] (b) an organic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0261] Aspect 13. The method of Aspect 10 or 11, wherein the subject suffers from bronchiectasis or chronic bronchitis.

[0262] Aspect 14. The method of any one of Aspects 1-12, wherein the bronchiectasis is non-CF bronchiectasis (NCFBE).

[0263] Aspect 15. The method of any one of Aspects 1-13, wherein the composition comprises: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof; and (b) an organic acid, wherein the molar ratio of (a) to (b) is about 0.5-1 : 1.

[0264] Aspect 16. The method of any one of Aspects 1-14, wherein the pH of the formulation is at least 5.5.

[0265] Aspect 17. The method of any one of Aspects 1-15, wherein the organic acid is ascorbic acid.

[0266] Aspect 18. The method of any one of Aspects 1-16, wherein the composition further comprises (c) a bicarbonate salt (e.g., sodium bicarbonate or calcium bicarbonate).

[0267] Aspect 19. The method of any one of Aspects 1-17, wherein the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.1-0.5: 0.5-1 : 1.

[0268] Aspect 20. The method of any one of Aspects 1-18, wherein the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.4-0.5: 0.5-1 : 1.

[0269] Aspect 21. The method of any one of Aspects 1-19, wherein the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.4-0.5: 0.5: 1 or 0.4-0.5: 1 : 1.

[0270] Aspect 22. The method of any one of Aspects 1-20, wherein the composition is an aqueous solution.

[0271] Aspect 23. The method of any one of Aspects 1-21, wherein the composition is administered to the lung.

[0272] The present description also provides the following particular aspects.

[0273] Aspect 24. A method of treating or preventing a disease, or a symptom thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water, wherein the disease is bronchiectasis, NTM pulmonary disease, or chronic bronchitis.

[0274] Aspect 25. The method of Aspect 24, wherein the disease is bronchiectasis, or a symptom thereof.

[0275] Aspect 26. The method of Aspect 25, wherein the symptom is excessive sputum production, chronic cough, inflammation, respiratory infection, or a combination thereof.

[0276] Aspect 27. The method of any one of Aspects 24-26, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

[0277] Aspect 28. The method of Aspect 24, wherein the disease is chronic bronchitis, or a symptom thereof.

[0278] Aspect 29. The method of Aspect 24, wherein the disease is NTM pulmonary disease, or a symptom thereof.

[0279] Aspect 30. The method of Aspect 28 or 29, wherein the symptom is chronic cough.

[0280] Aspect 31. A method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water, wherein:

[0281] (i) the disease is bronchiectasis or chronic bronchitis; and

[0282] (ii) the severity and / or rate of progression is determined using one or more of the Bronchiectasis Severity Index (BSI), the Quality of Life-Bronchiectasis (QOL-B) questionnaire, the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire (SGRQ), Ease of Cough and Mucus Clearance Multiple Choice Question (MCQ), and / or spirometry.

[0283] Aspect 32. The method of Aspect 31, wherein the disease is bronchiectasis.

[0284] Aspect 33. The method of Aspect 32, wherein the bronchiectasis is NCFBE.

[0285] Aspect 34. The method of Aspect 31, wherein the disease is chronic bronchitis.

[0286] Aspect 35. The method of Aspect 31, wherein the disease is NTM pulmonary disease with or without bronchiectasis.

[0287] Aspect 36. The method of any one of Aspects 31-35 for reducing the severity of the disease in the subject.

[0288] Aspect 37. The method of Aspect 36, wherein reducing the severity of the disease is the result of a symptomatic response.

[0289] Aspect 38. The method of Aspect 37, wherein the symptomatic response is improving or reducing sputum production, reducing the severity or frequency of chronic cough, reducing inflammation, reducing respiratory infection, or a combination thereof, in the subject.

[0290] Aspect 39. The method of Aspect 37, wherein reducing the severity of the disease is the result of a disease-modifying response in the subject.

[0291] Aspect 40. The method of any one of Aspects 31-35 for reducing the rate of progression of the disease in a subject.

[0292] Aspect 41. The method of Aspect 40, wherein reducing the rate of progression of the disease is the result of a symptomatic response.

[0293] Aspect 42. The method of Aspect 41, wherein the symptomatic response is improving or reducing sputum production, reducing the severity or frequency of chronic cough, reducing inflammation, reducing respiratory infection, or a combination thereof, in the subject.

[0294] Aspect 43. The method of Aspect 40, wherein reducing the rate of progression of the disease is the result of a disease-modifying response in the subject.

[0295] Aspect 44. The method of Aspect 33, wherein the severity and / or the rate of progression of NCFBE is reduced by at least 4 points after at least four weeks of administering the composition to the subject as measured by SGRQ.

[0296] Aspect 45. The method of Aspect 33, wherein the severity and / or the rate of progression of NCFBE is reduced by at least 7 points after at least four weeks of administering the composition to the subject as measured by QOL-B.

[0297] Aspect 46. The method of Aspect 33, wherein the severity and / or the rate of progression of NCFBE is reduced by at least 2 points after at least four weeks of administering the composition to the subject as measured by CAAT.

[0298] Aspect 47. A method of improving or reducing cough, improving or reducing sputum production, improving or reducing sputum viscosity, reducing sputum percent solids, improving or reducing sputum elasticity, reducing neutrophil elastase, reducing CAAT total score, reducing SGRQ total score, reducing SGRQ symptoms score, reducing SGRQ activity score, reducing SGRQ impacts score, reducing inflammation, reducing cough severity score, or a combination thereof, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof;(c) bicarbonate, or a salt thereof; and (d) water.

[0299] Aspect 48. The method of Aspect 47, wherein the subject suffers from bronchiectasis, NTM pulmonary disease, or chronic bronchitis.

[0300] Aspect 49. The method of Aspect 48, wherein the subject suffers from bronchiectasis.

[0301] Aspect 50. The method of Aspect 49, wherein the bronchiectasis is NCFBE.

[0302] Aspect 51. The method of Aspect 48, wherein the subject suffers from chronic bronchitis.

[0303] Aspect 52. The method of Aspect 48, wherein the subject suffers from NTM pulmonary disease.

[0304] Aspect 53. The method of any one of Aspects 24-52, wherein the molar ratio of (a):(b):(c) is about 0.1-0.5:0.5-1 : 1.

[0305] Aspect 54. The method of any one of Aspects 24-52, wherein the molar ratio of (a):(b):(c) is about 0.4-0.5:0.5: 1.

[0306] Aspect 55. The method of any one of Aspects 24-52, wherein the molar ratio of (a):(b):(c) is about 0.4-0.5: 1 : 1.

[0307] Aspect 56. The method of any one of Aspects 24-55, wherein the composition comprises a salt of glutathione having Formula I:wherein M+is Na+, Li+, K+, or Cs+.

[0308] Aspect 57. The method of any one of Embodiments Aspects 24-56, wherein the composition comprises a salt of ascorbic acid having Formula II:

[0309] wherein M+is Na+, Li+, K+, or Cs+.

[0310] Aspect 58. The method of any one of Embodiments Aspects 24-57, wherein the composition comprises a salt of glutathione having Formula III:wherein M+is Na+, Li+, K+, or Cs+.

[0311] Aspect 59. The method of any one of Aspects 57-58, wherein M+is Nat

[0312] Aspect 60. The method of any one of Aspects 24-59, wherein the composition is administered to the lung of the subject.

[0313] Aspect 61. The method of Aspect 60, wherein the composition is nebulized by the subject.

[0314] Aspect 62. The method of any one of Aspects 24-61, wherein the subject has a pulmonary or airway infection.

[0315] Aspect 63. The method of Aspect 62, wherein the infection is caused by nontuberculous mycobacteria (NTM).

[0316] Aspect 64. The method of Aspect 63, wherein the subject suffers from bronchiectasis.

[0317] Aspect 65. The method of Aspect 64, wherein the severity and / or the rate of progression of bronchiectasis is reduced by at least 4 points after administering the composition to the subject as measured by SGRQ with an MCID of -4.

[0318] Aspect 66. The method of Aspect 64, wherein the severity and / or the rate of progression of bronchiectasis is reduced by at least 7 points after administering the composition to the subject as measured by QOL-B.

[0319] Aspect 67. The method of Aspect 64, wherein the severity and / or the rate of progression of bronchiectasis is reduced by at least 2 points after administering the composition to the subject as measured by CAAT with an MCID of -2.EXAMPLESExample 1 : Study Population and Randomization

[0320] Study participants were selected based on two primary criteria 1) a previous diagnosis of non-cystic fibrosis bronchiectasis (NCFBE) confirmed by CT scan and 2) significant mucus and cough symptoms. Other inclusion criteria included, but were not limited to, stable disease and medication regimen. A total number of forty participants were randomized (7:3) to receive either ARINA- 1 or control (0.9% isotonic saline) nebulized twice daily for 28 days. Eligible participants included adults with confirmed (NCFBE) and mucus symptoms defined by a Chronic Airways Assessment Test (CAAT) score >10 and >2 on question 2. Patients were followed for an additional 28 days off study drug. A prespecified responder analysis was assessed based on achieving the SGRQ MCID (Example 5). All efficacy data are shown as the mean change (standard deviation) from baseline in the ITT population.Example 2: Clinical study for administration of ARINA-lto individuals with Non- cystic fibrosis bronchiectasis (NCFBE)

[0321] Clinical study was conducted using a double-blinded, placebo-controlled design where participants 18-80 years old were instructed to nebulize the therapy (either ARINA- 1 or Placebo) twice daily (morning and evening). Safety evaluations were completed throughout the study, as well as patient-reported outcomes (PROs) at randomization, day 28, and day 56, including the St. George’s Respiratory Questionnaire and other PROs. The participants also completed a daily diary for compliance and safety, along with a modified clinical global impression questionnaire.

[0322] Efficacy endpoints included quality of life, sputum rheological markers, and blood inflammatory markers. Quality of life will be measured using the following tools: Quality of Life-Bronchiectasis (QOL-B) questionnaire (Example 4), St. George’s Respiratory Questionnaire ((SGRQ); minimally clinically important difference (MCID) -4) (Example 5), Chronic Airways Assessment Test (CAAT (MCID -2) (Example 6).Example 3: Primary Objectives and Efficacy Endpoints

[0323] The primary objective was to evaluate the safety and tolerability of ARINA- 1.The primary endpoints were to (1) compare the incidence of treatment-emergent adverse events (TEAEs) between the two arms (Tables 1-3), and (2) to investigate the proportion of participants that experience each treatment-emergent adverse event (Table 7).

[0324] Forty participants were randomized to ARINA- 1 (72%, n = 29) or control (28%, n=11). Twenty-five (86%) participants in the ARINA-1 arm experienced a TEAE compared to five (45%) in the control arm. All the TEAEs were expected for a nebulized medication, with the most common TEAEs being cough and dyspnea (Tables 4-6). Safety and tolerability were also evaluated by the percentage of adverse events of special interest (AESI) (FIG. 5) and the percentage of adverse events experienced in 5% of participants in the safety population (FIG. 6).

[0325] Treatment-Emergent Adverse Events by Treatment Group is summarized in the table below.

[0326] The Treatment Related Adverse Events (TEAE) by Treatment Group broken down by System Organ Class and Preferred Term is summarized in the table below.Example 4: Secondary Objectives and Efficacy Endpoint: Quality of Life - Bronchiectasis (QOL-B)

[0327] The Quality of Life Scale (QOLS) has been adapted for use in chronic illness groups. It is a valid instrument for measuring quality of life across patient groups and cultures and is conceptually distinct from health status or other causal indicators of quality of life. The QOL-B, a self-administered, patient-reported outcome measure assessing symptoms, functioning and health-related quality of life for patients with non- cystic fibrosis (CF) bronchiectasis, contains 37 items on 6 scales. The effects of ARINA- 1 on quality of life, as measured by the QOL-B were assessed. The results of the respiratory domain score, physical functioning, vitality, role functioning, health perceptions, and emotional functioning are shown in FIGs. 4A-4H).Example 5: Secondary Objectives and Efficacy Endpoints: St. George’s Respiratory Questionnaire (SGRQ)

[0328] St. George’s Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. The SGRQ contains 50 items that fall into three domains (Symptoms, Impacts, and Activities) with a total of 3 categories, as well as a total score.

[0329] The change in quality of life, as measured by St. George’s Respiratory Questionnaire (SGRQ), was assessed. Secondary endpoints included changes in QOL measured using the SGRQ a minimally clinically important difference (MCID) of -4. The results of the SGRQ total score, symptoms score, activity score, impacts score are shown in FIGs. 3 A-3D.

[0330] This change correlated with a positive change in quality of life, as measured by St. George’s Respiratory Questionnaire. Notable improvements in QOL were observed in the treatment arm. The mean changes in the SGRQ total score and subdomains exceeded the MCID at days 28 and 56 of the study. The mean change in the SGRQ total score at day 28 in the ARINA-1 arm was -8.5 (10.75); the control group did not demonstrate an MCID at day 28 [-2.6 (SD 13.63)]. At day 56, the improvement in the treatment arm persisted with a mean of -6.1 (11.64). The control arm remained unchanged with -1.4 (13.18).

[0331] In the pre-specified responder analysis, 62% of the participants in the ARINA-1 arm and 27% of the control arm had an MCID response to the SGRQ. Exploratory analyses at day 28 demonstrated a trend improved mucus viscosity and NE in the ARINA- 1 arm while the control arm remained unchanged.Example 6: Secondary Objectives and Efficacy Endpoints: CAAT

[0332] The Chronic Airways Assessment Test (CAAT) is a patient-reported outcome (PRO) instrument used to assess the overall health status across different lung diseases. The CAAT score, ranging from 0-40, is the sum score of 8 items assessed (scored 0-5). Eligible participants included individuals with confirmed NCFBE and significant mucus and cough symptoms defined by a Chronic Airways Assessment Test (CAAT) score >10 and >2 on question 2. The higher scores indicate worse health status.

[0333] In the treatment arm, the CAAT improved by -3.7 points (5.07) at day 28 but returned to baseline at day 56 [-1.5 (1.07)]. The CAAT scores in the control arm remained unchanged (day 28, -1.3 (4.71); day 56, -0.5 (3.98)]. The result of the questionnaire is shown in FIG. 2.Table 35Summary of Baseline Variables, CAAT Analysis Population: SafetyExample 7 : Exploratory Endpoints

[0334] Exploratory endpoints were evaluated based on sputum biomarkers. Changes particularly in sputum rheology elasticity, viscosity, sputum percent solids, neutrophil elastase (sputum inflammatory markers) and C-reactive protein (CRP) (blood inflammatory markers) were recorded and analyzed. The results are shown in FIGs. 1 A- 1E.

[0335] Induced sputum samples were collected from all participants as specified in the schedule of events (SOE). Biological samples for biomarker research were collected as part of this study and the sputum biomarkers used to evaluate their association with the observed clinical responses, such as quality of life, to ARINA-1. In addition, samples were stored for additional analyses of biomarkers that may play a role in mucus properties, inflammation, or bacterial composition to evaluate their association with observed clinical responses to ARINA-1.Example 8: Summary of ResponderExample 9: Reduction in Cough Severity Score and Symptoms for subjects suffering with chronic bronchitis.

[0336] Chronic bronchitis is characterized by the presence of a chronic productive cough in 3 months of 2 successive years in patients without another cause of chronic cough. Usually, chest CT imaging is performed to exclude bronchiectasis. Characteristic findings include airway wall thickening without dilation, and / or mucus visualized in the airways.

[0337] In the chronic bronchitis study, data (n = 1) was collected between February 28 through April 7. ARINA- 1 was administered on March 6. The cough severity index represents the patient’s perception of cough (FIG. 7), and showed a decline in cough severity, particularly with a sharp drop right after the administration of the drug.

[0338] ARINA- 1 was safe and tolerable for participants after 28 days of use and demonstrated improved quality of life via the MCQ and CAAT (see FIGS. 8 and 9). Exploratory analyses showed a signal toward improved sputum viscosity and NE, which complements previous studies demonstrating ARINA- l’s impact on mucus clearance and potential to improve quality of life.Example 10: Summary of Phase 2 Study

[0339] A randomized, double-blind, placebo-controlled, multi-center, US Phase 2 study to assess the safety, efficacy, and tolerability of ARINA- 1 administered twice daily for 28 days in patients with non-cystic fibrosis bronchiectasis (NCFBE) was conducted. Thestudy was conducted at 9 sites with 40 adult patients diagnosed with NCFBE who indicated that they had mucus symptoms at the time of screening. Patients were randomized 7:3 to receive either ARINA-1 or matching placebo. The primary endpoint was safety at day 28. Secondary endpoints included quality of life measurements at days 28 and 56, and sputum viscosity and neutrophil elastase were measured at day 28.

[0340] This Phase 2 study of ARINA- 1 was in individuals with non-CF bronchiectasis (NCFBE). ARINA-1 was delivered as is a nebulized therapy.

[0341] The study was a randomized double-blind placebo-controlled study to assess the safety and efficacy of ARINA- 1 in NCFBE. The trial was conducted at nine sites across the US. Participants were randomized (7:3, treatmentplacebo), and 40 participants completed the study, with 29 completing in the ARINA- 1 arm and 11 in the placebo (0.9% saline) arm. Topline results from the intention-to-treat (ITT) population demonstrate that ARINA-1 is safe and improves quality of life (QOL) in individuals with NCFBE who experience mucus symptoms.

[0342] These results highlight the effectiveness of ARINA- 1 in the treatment of chronic cough and sputum production in non-CF bronchiectasis patients, which improves affects their QOL.

[0343] ARINA- 1 was well-tolerated in individuals with NCFBE with mucus symptoms. The most common treatment-related AEs (TRAEs) (event rates (95%CI)) in the ARINA- 1 arm (n=29) were cough (0.3, 95%CI 0.1-0.5), dyspnea (0.2, 95%CI 0.1-0.4), and hemoptysis (0.1, 95%CI 0.0-0.3), which are all commonly associated with nebulized therapies and an underlying diagnosis of NCFBE.

[0344] Topline ITT efficacy results from the trial demonstrated that ARINA- 1 improved quality of life in individuals with NCFBE at day 28. The mean change in SGRQ (MCID, - 4) in the ARINA- 1 arm from baseline to day 28 exceeded the MCID for the SGRQ in the total score (-8.5) and all three domains (symptoms, -9.6; activity, -8.5; impact, -7.9). This improvement persisted in the total score persisted to day 56 (-6.1), 28 days after stopping therapy. This demonstrates that ARINA- 1 not only improved quality of life during treatment, but that it also had a durable effect in these patients after stopping ARINA- 1. The placebo group did not achieve an MCID in the total score or any domain of the SGRQ at days 28 (total score, -2.6) or 56 (total score, -1.4). Consistent with the SGRQ, the CAAT (MCID, -2), which is a validated assessment specific for mucus and coughsymptoms, also demonstrated MCID improvements in mean change from baseline to day 28 (-3.7). The placebo group did not reach MCID for the CAAT questionnaire (day 28: - 1.3).

[0345] The topline exploratory analysis of sputum data indicated that ARINA- 1 demonstrated improved mucus viscosity and sputum neutrophil elastase (NE) compared to placebo. Further analyses on the mechanism of action and biomarker data are ongoing.

[0346] ARINA- 1 improved quality of life and also improved mucus biomarkers in people with bronchiectasis.Example 11 : Results of Clinical Study in Patients Having Bronchiectasis and an Infection with Nontuberculous Mycobacteria (NTM).

[0347] A subgroup analysis was performed as part of the bronchiectasis study outlined above. Participants in the analysis had a current or historical diagnosis of NTM pulmonary disease based on identification of an NTM organism (e.g., M. abscessus, M. avium complex).

[0348] The results of this subgroup analysis are shown in FIGS. 8 and 9 and Tables 53-58 below.

[0349] The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0350] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0351] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0352] All patents and publications cited herein are fully incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising glutathione wherein: the disease is bronchiectasis, non-tuberculous mycobacteria pulmonary disease (NTM pulmonary disease), or chronic bronchitis; and the severity and / or rate of progression is determined using one or more of the Bronchiectasis Severity Index (BSI) Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire, Multiple Choice Question (MCQ), and / or spirometry.

2. A method of reducing symptoms of a disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising glutathione wherein: the disease is bronchiectasis, non-tuberculous mycobacteria pulmonary disease (NTM pulmonary disease), or chronic bronchitis; and the severity and / or rate of progression is determined using one or more of the Bronchiectasis Severity Index (BSI) Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire, Ease of Cough and Mucus Clearance Multiple Choice Question (MCQ), and / or spirometry.

3. The method of claim 1 or 2, wherein the glutathione salt has the formula of a salt of glutathione having Formula (I):wherein:(i) M+is Na+, Li+, K+, or Cs+.

4. The method of any one of claims 1-3 for reducing the severity of the disease in the subject.

5. The method of any one of claims 1-4, wherein reducing the severity of the disease is the result of a symptomatic response.

6. The method of claim 5, wherein the symptomatic response is reducing the severity of cough in the subj ect.

7. The method of any one of claims 1 and 3-6, wherein reducing the severity of the disease is the result of a disease-modifying response in the subject.

8. The method of any one of claims 1-7 for reducing the rate of progression of the disease in a subject.

9. The method of any one of claims 1 and 3-7, wherein reducing the rate of progression of the disease is the result of a symptomatic response.

10. The method of 9, wherein the symptomatic response is reducing the rate of progression of cough in the subject.

11. The method of 9, wherein the symptomatic response is improving sputum viscosity, improving sputum elasticity, or a combination thereof.

12. The method of any one of claims 1 and 3-11, wherein reducing the severity of the disease is the result of a disease-modifying response in the subject.

13. The method of any one of claims 1 and 3-9, wherein the rate of progression is reduced by at least four points after at least four weeks of administering the composition to the subject as compared to the natural history of disease progression in an untreated subject.

14. A method of improving or reducing cough and / or sputum associated in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising:(a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt of glutathione, a glutathione derivative, or a glutathione conjugate; and(b) an organic acid, or a pharmaceutically acceptable salt thereof, to the subj ect.

15. The method of claim 14, wherein the subject suffers from bronchiectasis, NTM pulmonary disease, or chronic bronchitis.

16. The method of any one of claims 1-15, wherein the bronchiectasis is non-CF bronchiectasis (NCFBE).

17. The method of any one of claims 1-16, wherein the composition comprises: (a) glutathione, a glutathione derivative, a glutathione conjugate, a pharmaceutically acceptable salt thereof, or any combination thereof; and (b) an organic acid, wherein the molar ratio of (a) to (b) is about 0.5-1 : 1.

18. The method of any one of claims 1-17, wherein the pH of the formulation is at least 5.5.

19. The method of any one of claims 1-18, wherein the organic acid is ascorbic acid.

20. The method of any one of claims 1-19, wherein the composition further comprises (c) a bicarbonate salt (e.g., sodium bicarbonate or calcium bicarbonate).

21. The method of any one of claims 1-20, wherein the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.1-0.5: 0.5-1 : 1.

22. The method of any one of claims 1-21, wherein the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.4-0.5: 0.5-1 : 1.

23. The method of any one of claims 1-22, wherein the molar ratio of (a) glutathione :(b) ascorbic acid :(c) bicarbonate is about 0.4-0.5: 0.5: 1 or 0.4-0.5: 1 : 1.

24. The method of any one of claims 1-23, wherein the composition is an aqueous solution.

25. The method of any one of claims 1-24, wherein the composition is administered to the lung.

26. A method of treating or preventing a disease, or a symptom thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water, wherein the disease is bronchiectasis, NTM pulmonary disease, or chronic bronchitis; and wherein the treatment or preventing of the disease, or a symptom thereof, is determined using one or more of the Bronchiectasis Severity Index (BSI), the Quality of Life-Bronchiectasis (QOL-B) questionnaire, the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire (SGRQ), MCQ, and / or spirometry.

27. The method of claim 26, wherein the disease is bronchiectasis, or a symptom thereof.

28. The method of claim 27, wherein the symptom is excessive sputum production, chronic cough, inflammation, respiratory infection, or a combination thereof.

29. The method of any one of claims 26-28, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

30. The method of claim 26, wherein the disease is chronic bronchitis, or a symptom thereof.

31. The method of claim 30, wherein the symptom is chronic cough.

32. The method of claim 26, wherein the disease is NTM pulmonary disease.

33. A method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water, wherein:(i) the disease is bronchiectasis, chronic bronchitis, or NTM pulmonary disease; and(ii) the severity and / or rate of progression is determined using one or more of the Bronchiectasis Severity Index (BSI), the Quality of Life-Bronchiectasis (QOL-B) questionnaire, the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire (SGRQ), Ease of Cough and Mucus Clearance MCQ, and / or spirometry.

34. The method of claim 33, wherein the disease is bronchiectasis.

35. The method of claim 34, wherein the bronchiectasis is NCFBE.

36. The method of claim 33, wherein the disease is chronic bronchitis.

37. The method of claim 33, wherein the disease is NTM pulmonary disease.

38. The method of any one of claims 33-37 for reducing the severity of the disease in the subject.

39. The method of claim 38, wherein reducing the severity of the disease is the result of a symptomatic response.

40. The method of claim 39, wherein the symptomatic response is improving or reducing sputum production, reducing the severity or frequency of chronic cough, reducing inflammation, reducing respiratory infection, or a combination thereof, in the subject.

41. The method of claim 38, wherein reducing the severity of the disease is the result of a disease-modifying response in the subject.

42. The method of any one of claims 33-37 for reducing the rate of progression of the disease in a subject.

43. The method of claim 42, wherein reducing the rate of progression of the disease is the result of a symptomatic response.

44. The method of claim 43, wherein the symptomatic response is improving or reducing sputum production, reducing the severity or frequency of chronic cough, reducing inflammation, reducing respiratory infection, or a combination thereof, in the subject.

45. The method of claim 42, wherein reducing the rate of progression of the disease is the result of a disease-modifying response in the subject.

46. The method of claim 35, wherein the severity and / or the rate of progression of NCFBE is reduced by at least 4 points after at least four weeks of administering the composition to the subject as measured by SGRQ.

47. The method of claim 35, wherein the severity and / or the rate of progression of NCFBE is reduced by at least 7 points after at least four weeks of administering the composition to the subject as measured by QOL-B.

48. The method of claim 35, wherein the severity and / or the rate of progression of NCFBE is reduced by at least 2 points after at least four weeks of administering the composition to the subject as measured by CAAT.

49. A method of improving or reducing cough, improving or reducing sputum production, improving sputum viscosity, reducing sputum percent solids, reducing neutrophil elastase, reducing CAAT total score, reducing SGRQ total score, reducing SGRQ symptoms score, reducing SGRQ activity score, reducing SGRQ impacts score, reducing inflammation, reducing cough severity score, or a combination thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water.

50. The method of claim 49, wherein the subject suffers from bronchiectasis or chronic bronchitis.

51. The method of claim 50, wherein the subject suffers from bronchiectasis.

52. The method of claim 51, wherein the bronchiectasis is NCFBE.

53. The method of claim 50, wherein the subject suffers from chronic bronchitis.

54. The method of any one of claims 1-20 and 24-53, wherein the molar ratio of (a):(b):(c) is about 0.1-0.5:0.5-1 : 1.

55. The method of any one of claims 1-20 and 24-53, wherein the molar ratio of (a):(b):(c) is about 0.4-0.5:0.5: 1.

56. The method of any one of claims 1-20 and 24-53, wherein the molar ratio of (a):(b):(c) is about 0.4-0.5: 1 : 1.

57. The method of any one of claims 26-56, wherein the composition comprises a salt of glutathione having Formula I:wherein M+is Na+, Li+, K+, or Cs+.

58. The method of any one of claims 1-57, wherein the composition comprises a salt of ascorbic acid having Formula II:wherein M+is Na+, Li+, K+, or Cs+.

59. The method of any one of claims 1-58, wherein the composition comprises a salt of glutathione having Formula III:wherein M+is Na+, Li+, K+, or Cs+.

60. The method of any one of claims 57-59, wherein M+is Na+.

61. The method of any one of claims 1-60, wherein the composition is administered to the lung of the subject.

62. The method of claim 61, wherein the composition is nebulized by the subject.

63. The method of any one of claims 1-62, wherein the subject has a pulmonary or airway infection.

64. The method of claim 63, wherein the infection is caused by nontuberculous mycobacteria (NTM).

65. A method of treating or preventing a disease, or a symptom thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water, wherein the disease is bronchiectasis or chronic bronchitis; and wherein the subject has a pulmonary or airway infection caused by nontuberculous mycobacteria (NTM).

66. The method of claim 65, wherein the treating or preventing of the disease, or a symptom thereof, is determined using one or more of the Bronchiectasis Severity Index (BSI), the Quality of Life-Bronchiectasis (QOL-B) questionnaire, the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire (SGRQ), MCQ, and / or spirometry67. A method of improving or reducing cough, improving or reducing sputum production, improving sputum viscosity, reducing sputum percent solids, reducing neutrophil elastase,reducing CAAT total score, reducing SGRQ total score, reducing SGRQ symptoms score, reducing SGRQ activity score, reducing SGRQ impacts score, reducing inflammation, reducing cough severity score, or a combination thereof, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water; wherein the subject has a pulmonary or airway infection caused by nontuberculous mycobacteria (NTM).

68. A method of reducing severity and / or the rate of progression of a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) glutathione, or a salt thereof; (b) ascorbic acid, or a salt thereof; (c) bicarbonate, or a salt thereof; and (d) water, wherein:(i) the disease is bronchiectasis or chronic bronchitis; and(ii) the subject has a pulmonary or airway infection and / or disease caused by nontuberculous mycobacteria (NTM).

69. The method of claim 68, wherein the severity and / or rate of progression is determined using one or more of the Bronchiectasis Severity Index (BSI), the Quality of Life-Bronchiectasis (QOL- B) questionnaire, the Chronic Airways Assessment Test (CAAT), the St. George’s Respiratory Questionnaire (SGRQ), MCQ, and / or spirometry70. The method of any one of claims 63-69, wherein the subject suffers from bronchiectasis.

71. The method of claim 70, wherein the severity and / or the rate of progression of bronchiectasis is reduced by at least 5 points after administering the composition to the subject as measured by SGRQ with an MCID of -4.

72. The method of claim 70, wherein the severity and / or the rate of progression of bronchiectasis is reduced by at least 7 points after administering the composition to the subject as measured by QOL-B.

73. The method of claim 70, wherein the severity and / or the rate of progression of bronchiectasis is reduced by at least 5 points after administering the composition to the subject as measured by CAAT with an MOD of -2.

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