Pharmaceutical compositions and methods for inhibiting acid-sensing ion channels

Abstract

Provided are cimetidine, famotidine and famotidine-related compounds, pharmaceutical compositions comprising famotidine as well as methods and uses therefor. In particular, the present disclosure relates to the methods and uses of such compounds or pharmaceutical compositions in the treatment of ASIC-related diseases.

Description

[0001] PHARMACEUTICAL COMPOSITIONSAND METHODS FOR INHIBITING ACID-SENSING ION CHANNELS

[0002] FIELD

[0003] The invention relates to famotidine, famotidine-related compounds and cimetidine, their pharmaceutical formulations and their use in medicine. Specifically, the invention provides compounds, compositions and methods for inhibiting acid-sensing ion channels (ASICs), such as ASIC1 {e.g. ASICIa), using specific repurposed H2 receptor antagonists such as cimetidine and famotidine, in addition to famotidine-related impurities, which are known as famotidine-related compounds. Diseases and disorders associated with ASIC dysfunction include, but are not limited to, ischemic diseases (e.g. ischemic stroke) and neurological disorders. Additionally, the invention relates to high-concentration injectable compositions of famotidine solubilised with ascorbic acid effective to enable administration at high concentration, and suitable for use in applications involving ASIC (such as ASIC1, e.g. ASICIa) inhibition and neuroprotection.

[0004] BACKGROUND

[0005] Acid-sensing ion channels (ASICs) are a group of ion channels that are activated by extracellular protons and are involved in various physiological and pathological processes. These channels are predominantly expressed in the central and peripheral nervous systems and play a crucial role in the pain sensation, particularly in conditions where tissue acidosis occurs, such as inflammation, ischemia, and certain neurological disorders. ASICs have been implicated in the pathophysiology of several conditions, including pain, stroke, heart failure, pulmonary diseases, psychological disorders, and neurodegenerative diseases, making them a target of interest for therapeutic intervention. These channels are particularly significant in the context of neurological and cardiovascular health. During events such as ischemic stroke or myocardial infarction, the body experiences a drop in pH levels, leading to acidosis, which in turn activates ASICs. This activation can result in increased calcium influx into cells, exacerbating neuronal injury and contributing to cell death. Consequently, ASICs have been identified as potential therapeutic targets for conditions where acidosis plays a critical role, such as stroke and neurodegenerative diseases. ASICIa has become an important target in cerebrovascular and cardiac ischemic injuries. However, there is still no successful ASIC-inhibiting medication in the clinic which inhibits ASICs such as ASIC1, e.g. ASICIa.

[0006] Current treatments for conditions associated with ASIC dysfunction often involve the use of analgesics and anti-inflammatory drugs, which may not specifically target the underlying ion channel dysfunction and can have significant side effects. There is a growing need for more targeted therapies that can modulate ASIC activity without affecting other physiologicalprocesses. The development of such therapies could provide significant benefits in terms of efficacy and safety for patients suffering from ASIC-related conditions. Exploring existing drugs with known safety profiles, such as famotidine, for new therapeutic applications represents a promising approach in searching for effective ASIC inhibitors.

[0007] The challenge in targeting ASICs lies in developing inhibitors that can effectively modulate these channels without causing adverse effects. Current treatments for stroke and myocardial infarction are limited, with thrombolytic drugs like Alteplase being the primary option, which do not address the underlying biochemical pathways leading to tissue damage. Moreover, the development of ASIC inhibitors has been complicated by the need for molecules that can act quickly and maintain efficacy over a prolonged period. Small-molecule inhibitors, such as amiloride and diminazene aceturate, often have a narrow therapeutic window due to the rapid recovery of the receptor. In contrast, large-sized peptide inhibitors, such as Psalmotoxin-1 (PcTxl), Mambalgine-1 (Mambal), and Hila toxins, face challenges in production, crossing the blood-brain barrier and potential pharmacological interactions.

[0008] Therefore, there is an ongoing need for innovative solutions that can provide rapid action and a broad therapeutic window to improve outcomes in patients suffering from ASIC-related diseases.

[0009] SUMMARY OF THE INVENTION

[0010] The present disclosure relates to famotidine, famotidine-related compounds, cimetidine, and pharmaceutically acceptable salts thereof. The famotidine, famotidine-related compounds, and cimetidine, and their pharmaceutically acceptable salts, have surprisingly been found to possess activity as inhibitors of acid-sensing ion channels (ASICs), optionally acid-sensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). This unexpected activity allows such compounds to be used for inhibition of ASICs, including ASCII (such as ASICIa) including under conditions relevant to ASIC-related diseases such as ischemia.

[0011] The present invention provides a pharmaceutical composition comprising (a) famotidine, or a pharmaceutically acceptable salt thereof; (b) ascorbic acid; and (c) an aqueous solvent, wherein: (i) the composition comprises famotidine, or a pharmaceutically acceptable salt thereof, in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1 to 1:2.5 of the free base of famotidine relative to ascorbic acid; and (ii)the composition comprises famotidine, or a pharmaceutically acceptable salt thereof, in a concentration which corresponds to at least 70 mg / mL of the free base.

[0012] The pharmaceutical composition of the invention may comprise famotidine, or a pharmaceutically acceptable salt thereof, in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1 : 1.5 to 1 :2.0 of the free base of famotidine relative to ascorbicacid. The pharmaceutical composition of the invention may comprise famotidine, or a pharmaceutically acceptable salt thereof, in a concentration which corresponds to at least 80 mg / mL, at least 85 mg / mL, at least 90 mg / mL, at least 95 mg / mL or at least 100 mg / mL of the free base. The pharmaceutical composition of the invention may have a pH between about 4.0 and about 7.0. The pharmaceutical composition of the invention may have a pH of 4.5. The pharmaceutical composition of the invention may be substantially free of (a) polyethylene glycol; (b) nicotinic acids; (c) water-soluble amides; (d) cyclodextrins; (e) riboflavin or salts or esters thereof; and / or (f) surfactants.

[0013] The invention further provides a famotidine-related compound or a pharmaceutically acceptable salt thereof for use as a medicament. The famotidine-related compound may be selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, H, I, or J, e.g. famotidine-related compounds A, B, and E, and pharmaceutically acceptable salts thereof.

[0014] The invention further provides a pharmaceutical composition of the invention for use as a medicament.

[0015] The invention further provides famotidine or a famotidine-related compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of an ASIC-related disease in a subject. The ASIC-related disease may be selected from neurological disorders, neurodegenerative diseases, psychological disorders, sexual disorders, cardiovascular diseases, respiratory diseases, inflammatory diseases, renal diseases, gastrointestinal diseases, metabolic disorders, cancer, and addiction, e.g. smoking addiction. The ASIC-related disease may be an ASIC1-related disease, e.g. an ASICIa-related disease. The neurological disorder may be selected from the group consisting of ischemic stroke, cerebral ischemia, traumatic brain injury, spinal cord injury, neuropathic pain, and epilepsy. The neurodegenerative disease may be selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. The psychological disorder may be selected from the group consisting of anxiety, depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), and addiction. The cardiovascular disease may be selected from the group consisting of myocardial infarction, heart failure, arrhythmia, and hypertension. The respiratory disease may be selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). The inflammatory disease may be selected from the group consisting of rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. The renal disease may be selected from the group consisting of acute kidney injury, chronic kidney disease, and renal fibrosis. The gastrointestinal disease may be selected from the group consisting of gastroesophageal reflux disease (GERD), peptic ulcer disease, and irritable bowel syndrome (IBS). The metabolic disorder may be selected from thegroup consisting of diabetes, obesity, and metabolic syndrome. The cancer may be selected from the group consisting of glioblastoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer. The addiction may be smoking addiction. The ASIC-related disease may be an acute disease, optionally ischemic stroke, cerebral ischemia, myocardial ischemia, or myocardial infarction. Treatment may comprise administering famotidine or a famotidine-related compound, or a pharmaceutically acceptable salt thereof, to the subject within about 12 hours of the onset of at least one symptom of the acute disease, optionally within about 4 hours to about 6 hours of the onset of at least one symptom of the acute disease, famotidine or a famotidine-related compound, or a pharmaceutically acceptable salt thereof, may be administered to the subject via oral, subcutaneous, or intravenous administration, optionally via intravenous administration. The treatment may comprise administering famotidine or a famotidine-related compound, or a pharmaceutically acceptable salt thereof, to the subject in an amount corresponding to a dosage higher than 80 mg of the free base, preferably from about 200 mg to about 500 mg of the free base of famotidine or the famotidine-related compound. Famotidine or a famotidine-related compound, or a pharmaceutically acceptable salt thereof, may be administered to the subject in a composition of the invention.

[0016] The invention further provides a method of treatment comprising administering famotidine or a famotidine-related compound, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. The method of treatment may be a method of treating an ASIC-related disease in a subject, such as an ASIC1 -related disease, e.g. an ASICIa-related disease. The method of treatment may comprise administering famotidine, a famotidine-related compound, or a pharmaceutically acceptable salt thereof, to the subject in a composition of the invention.

[0017] The invention further provides the use of a pharmaceutical composition of the invention or a famotidine-related compound or pharmaceutically acceptable salt thereof in the manufacture of a medicament. The famotidine-related compound may be selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, H, I, and J, e.g. famotidine-related compounds A, B, and E. The medicament may be for the treatment of an ASIC-related disease in a subject, such as an ASIC1-related disease, e.g. an ASICIa-related disease.

[0018] The invention further provides the use of famotidine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ASIC-related disease in a subject, such as an ASIC1 -related disease, e.g. an ASICIa-related disease.

[0019] The invention further provides a kit of parts comprising (a) a first vial containing famotidine or a pharmaceutically acceptable salt thereof; (b) a second vial containing ascorbic acid; wherein the famotidine, or a pharmaceutically acceptable salt thereof, is provided in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1 to 1:2.5 of thefree base of famotidine relative to ascorbic acid; and (c) a third vial containing an aqueous solvent. The kit may further comprise an injection syringe and / or instructions for administration.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The following figures represent the results of the compounds of the invention by way of non-limiting examples.

[0022] Figure 1: Dose-response analysis of the effect of cimetidine co-application pH 6.5-evoked currents normalized to control pH 6.5-evoked response from endogenous hASICIa in HEK cells. Data fit to the Hill equation gave an IC50 of 655 zM (95% Cl: 551 - 771 zM). All data shown are the mean ± SEM (n = 4-10, depending on dose).

[0023] Figure 2: Dose-response analysis of the effect of famotidine co-application pH 6.5-evoked currents normalized to control pH 6.5-evoked response from endogenous hASICIa in HEK cells. Data fit to the Hill equation gave an IC50 of 214.8 zM (95% Cl: 174 -260 zM). All data shown are the mean ± SEM (n = 4-10, depending on dose).

[0024] Figure 3: Dose-response analysis of the effect of famotidine-related compound A coapplication pH 6.5-evoked currents normalized to control pH 6.5-evoked response from endogenous hASICIa in HEK cells. Data fit to the Hill equation gave an IC50 of 114.5 zM (95% Cl: 103 - 128 zM). All data shown are the mean ± SEM (n = 4-6, depending on dose).

[0025] Figure 4: Dose-response analysis of the effect of famotidine-related compound B coapplication pH 6.5-evoked currents normalized to control pH 6.5-evoked response from endogenous hASICIa in HEK cells. Data fit to the Hill equation gave an IC50 of 92.4 zM (95% Cl: 84 - 101 zM). All data shown are the mean ± SEM (n = 4).

[0026] Figure 5: Dose-response analysis of the effect of famotidine-related compound E coapplication pH 6.5-evoked currents normalized to control pH 6.5-evoked response from endogenous hASICIa in HEK cells. Data fit to the Hill equation gave an IC50 of 4.3 zM (95% Cl: 3.4- 5.3 zM). All data shown are the mean ± SEM (n = 4-10, depending on dose).

[0027] Figure 6: Representative automated patch-clamp current traces show the effect of cimetidine (1 mM) on pH 6.5-activated endogenous hASICIa in HEK 293 cells. Co-application (3 s) with cimetidine 1 mM in pH 6.5 solution resulted in ~ 75% inhibition relative to control traces, (3 s) pH 6.5 application before cimetidine induced 5.5 nA currents, as did (3 s) pH 6.5 application after cimetidine (5.5 nA), indicating rapid and complete recovery from inhibition. Representative current traces at - 70 mV.

[0028] Figure 7: Representative automated patch-clamp current traces show the effect of famotidine (250 pM) on pH 6.5-activated currents from endogenous hASICIa in HEK 293 cells. Co-application (3 s) of famotidine 250 pM in pH 6.5 solution resulted in ~ 50% inhibition relative to control traces, (3 s) application of pH 6.5 before famotidine application induces 11.5nA currents and again after famotidine application induces 11 nA currents, indicating rapid and complete recovery from inhibition. Representative current traces at - 70 mV.

[0029] Figure 8: Representative luminescent assay data measuring ATP levels in HEK-293 cells after 24 hours at pH 7.5, pH 5.5, and pH 5.5 with the application of famotidine (200 pM). This demonstrates that famotidine preserves cellular ATP levels under acidic stress, preventing acidosis-induced mitochondrial energy failure.

[0030] Figure 9: Representative automated patch-clamp current traces show the coapplication of famotidine A (150 pM) effect on pH 6.5-activated endogenous hASICIa in HEK 293 cells. Co-application (3 s) of 150 pM famotidine A with pH 6.5 solution resulted in ~ 70% inhibition relative to control traces, (3 s) with pH 6.5 before famotidine A application, (6 nA currents) and after famotidine A application ( 5.5 nA currents), rapid and almost complete recovery. Representative current traces at - 70 mV.

[0031] Figure 10: Representative automated patch-clamp current traces show the effect of famotidine B (100 pM) at pH 6.5 on the endogenous hASICIa in HEK 293 cells. Treatment (3 s) with famotidine A 100 pM in pH 6.5 solution resulted in ~ 50% inhibition. Treatment (3 s) with pH 6.5 before famotidine B application induce 9 nA currents. Treatment (3 s) with pH 6.5 after famotidine B application induce 9 nA currents in HEK 293 cells. Representative current traces at - 70 mV.

[0032] Figure 11: Effect of famotidine E (10 and 20 pM) at pH 6.5 on the endogenous hASICIa in HEK 293 cells. Treatment (3 s) with famotidine E 10 and 20 pM in pH 6.5 solution resulted in ~ 50% and 65% inhibition, respectively. Treatment (3 s) with pH 6.5 before famotidine E application induce 8 nA currents. Treatment (3 s) with pH 6.5 after famotidine E application induce 6.5 nA currents in HEK 293 cells. Representative current traces at - 70 mV.

[0033] Figure 12: (A) Patch-clamp current traces show the effect of co-applying Famotidine (100 pM) alone (grey traces) and 100 pM Famotidine + 5 mM Aspartic acid (Red traces) on the pH 6.5-induced currents (Black traces). Aspartic acid abolished the inhibitory effect of the famotidine and instead potentiated the pH 6.5 evoked currents (n = 3). Representative current traces at - 70 mV. (B) Patch-clamp current traces show the effect of co-applying Famotidine (100 pM) alone (grey traces) and 100 pM Famotidine + 5mM Ascorbic acid (Red traces) on the pH 6.5-induced currents (Black traces). Ascorbic acid did not influence the inhibitory effect of the famotidine (n = 4). Representative current traces at - 70 mV.

[0034] DESCRIPTION

[0035] Definitions

[0036] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, theuse of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0037] The section headings used herein are for organisational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated-by-reference for the portions of the document discussed herein, as well as in their entirety.

[0038] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure.

[0039] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognise. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts described herein to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0040] As used herein, the term "capable of” when used with a verb, encompasses or means the action of the corresponding verb. For example, "capable of interacting" also means interacting, "capable of inhibiting" also means inhibits, "capable of binding" also means binds and "capable of specifically targeting..." also means specifically targets.Numeric ranges are inclusive of the numbers defining the range. Thus, for example, ranges identified as “between” two end points or “from ... to ...”, i.e. ranges in the form “between x and y” or “from x to y”, should be understood to include those end points x and y. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure.

[0041] As used herein, the articles "a" and “an” may refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting.

[0042] “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. As used herein, the term “about” shall be understood to refer to a value of plus or minus (±) 10% relative to the stated value, unless otherwise specified. Optionally, the term “about” shall be understood herein as plus or minus (±) 5%, further optionally ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the number with which it is being used.

[0043] The term "consisting of" refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the disclosure.

[0044] As used herein the term "consisting essentially of" refers to those elements required for a given disclosure. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that disclosure (i.e., inactive or non-immunogenic ingredients).

[0045] As used herein the term "substantially free of" refers to those components not required for a given disclosure. The term permits the limited presence of components that do not materially affect the functional characteristic(s) of that disclosure. Exemplary degrees of limited presence of components are less than about 0.1 w / v%, and more typically, less than about 0.05 w / v%, or less than about 100 w / v parts per million (ppm) of a given composition ofthe disclosure. Typically, the components referred to when using the term "substantially free of" are considered impurities and are not desired in the composition of the disclosure.

[0046] Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of” and / or “consisting essentially of” such features.

[0047] Concentrations, amounts, volumes, percentages and other numerical values may be presented herein in a range format. It is also to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

[0048] The terms “decrease” "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition (i.e. , abrogation) as compared to a reference level.

[0049] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1.5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4- fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10-fold or greater as compared to a reference level.

[0050] As used herein, compounds of the disclosure may be used to inhibit ASIC, e.g. ASIC1, and in particular ASIC1 a. As used herein, compounds of the disclosure may also be used to monitor the presence and activity of ASIC ex vivo and / or in vivo, e.g. ASIC1, and in particular ASICIa. As used herein, compounds of the disclosure may also be used to treat and / or prevent ASIC-related disorders in patients in need thereof, e.g. ASIC1 -related disorders, and in particular ASIC 1a-related disorders. As used herein, compounds of the disclosure may alsobe used to treat ASIC-related disorders in patients in need thereof, e.g. ASIC1-related disorders and in particular ASICIa-related disorders. As used herein, compounds of the disclosure may also be used to treat acute ASIC-related disorders in patients in need thereof, e.g. acute ASIC1-related disorders and in particular acute ASICIa-related disorders. As used herein, compounds of the disclosure may also be used to prevent ASIC-related disorders in patients in need thereof, e.g. ASIC1-related disorders and in particular ASICIa-related disorders.

[0051] As used herein “acute disorder”, “acute condition” or “acute disease” means a disorder, condition or disease, which is sudden, develops rapidly, causes severe or intense symptoms, and lasts for a short duration. Such “acute disorder”, “acute condition” or “acute disease” may be due to underlying chronic disease.

[0052] A "salt" as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH4+ or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionisable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be "pharmaceutically-acceptable salts. " The term "pharmaceutically-acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. For example, the term “pharmaceutically acceptable” may refer to salts, excipients, carriers, diluents, etc. approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia.

[0053] Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.

[0054] Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, p-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.

[0055] Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I). The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and / or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217.

[0056] Since compounds of the disclosure are bases, then they will readily form salts in which the compounds of the disclosure are protonated and having an anionic counterion. Suitable anionic ions are described above.

[0057] A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e. , a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.

[0058] A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.As used herein, “pharmaceutical composition” or “pharmaceutical formulation” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

[0059] As used herein, a “stable” composition is a composition in which the active ingredient shows no significant degradation for at least 72 hours at ambient (room) temperature, e.g. temperatures in the range of about 20 to 25 °C.

[0060] As used herein, “treating” means improving a subject’s disease or condition by administering a compound described herein. In certain embodiments, treating a subject improves a symptom relative to the same symptom in the absence of the treatment. In certain embodiments, treatment reduces in the severity or frequency of a symptom, or delays the onset of a symptom, slows the progression of a symptom, or slows the severity or frequency of a symptom.

[0061] As used herein, “preventing” means inhibiting or delaying the onset or reoccurrence of a subject’s disease or condition (or a symptom thereof) by administering a compound described herein. In some embodiments, “preventing” means preventing the onset or reoccurrence of subject’s disease or condition (or a symptom thereof) entirely. In some embodiments, “preventing” means either lessening the likelihood of the onset of a subject’s disease or condition (or a symptom thereof).

[0062] As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent or composition that has been observed to provide a therapeutic benefit to an animal. For example, a therapeutically effective amount may be observed to improve a symptom of a disease in an animal. Typically, a “therapeutically effective amount” means an amount of a pharmaceutical agent or composition that has been observed to provide a therapeutic benefit to a human. For example, a therapeutically effective amount may be observed to improve a symptom of a disease in a human.

[0063] The terms "individual,” "subject,” and "patient,” are used interchangeably herein to refer to a mammalian subject for whom diagnosis, prognosis, disease monitoring, treatment, therapy, and / or therapy optimisation is desired. The mammal can be (without limitation) a human, non-human primate, mouse, rat, dog, cat, horse, or cow. The individual, subject, or patient may be a human. An “individual” may be an adult, juvenile or infant. An “individual” may be male or female.

[0064] A "subject in need" of treatment for a particular condition can be an individual having that condition, diagnosed as having that condition, or at risk of developing that condition.

[0065] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications or symptomsrelated to such a condition, and optionally, have already undergone treatment for a condition as defined herein or the one or more complications or symptoms related to said condition. Alternatively, a subject can also be one who has not been previously diagnosed as having a condition as defined herein or one or more or symptoms or complications related to said condition. For example, a subject can be one who exhibits one or more risk factors for a condition, or one or more or symptoms or complications related to said condition or a subject who does not exhibit risk factors.

[0066] As used herein, the term “healthy individual” refers to an individual or group of individuals who are in a healthy state, e.g., individuals who have not shown any symptoms of the disease, have not been diagnosed with the disease and / or are not likely to develop the disease e.g., a thrombotic event. Optionally said healthy individual(s) is not on medication affecting haemostasis and has not been diagnosed with any other disease. The one or more healthy individuals may have a similar sex, age, and / or body mass index (BMI) as compared with the test individual. Application of standard statistical methods used in medicine permits determination of normal levels of expression in healthy individuals, and significant deviations from such normal levels.

[0067] As used herein, an “injectable” composition is a composition which can be administered via a 27-gauge (27G) needle or smaller, without precipitation of any components therein. A 27G needle typically has an outer diameter of 0.413 mm and an inner diameter of 0.21 mm.

[0068] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. All documents cited herein are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents.

[0069] Acid-Sensing Ion Channels (ASICs)

[0070] Acid-sensing ion channels (ASICs) are ligand-gated cation channels and members of the vast degenerin / epithelial sodium channel (DEG / ENaC) family. ASICs are activated by extracellular acidosis and are involved in many physiological and pathophysiological processes. Inhibiting these channels has shown significant efficacy in alleviating nociception, cancer, and ischemic stroke.

[0071] There are four genes of ASICs, namely ASIC1, ASIC2, ASIC3, and ASIC4, and these four genes encode at least six different subunits, ASICIa, ASICIb, ASIC2a, ASIC2b, ASIC3, and ASIC4. Functional ASICs can be homo-trimeric or hetero-trimeric. The functional homotrimeric channels can be formed by ASICIa, ASICIb, ASIC2a, andASIC3, and these channels can be activated with different ranges of acidic pH, with different pHso (pH of half-maximalactivation). The pHso of ASICIa is 6.45, then ASIC3 (pHso ~ 6.5), while ASIC2a is the least sensitive one with pHso ~ 4.7.

[0072] AS / Cs in pathology

[0073] ASICs are essential in chemo-sensing and mechano-sensing and are expressed in different body systems, including the cardiovascular system. ASICs are expressed in the skin, muscles, and gastrointestinal tract (GIT). ASICIa is the most abundant in the CNS but is also expressed in other tissues, including the tongue, intestine, peripheral tissues, arteries, urinary bladder, and kidney. ASICIa has been reported to modulate both the colonic mechanoreceptor and gastroesophageal mechanoreceptor. Knocking outthe ASICIa gene increased the activity of both mesenteric and Serosal afferents, as well as increasing the activity of both Mucosal and tension receptors.

[0074] ASICIa maintains the density of dendritic spines in the postsynaptic terminals. ASIC2a channels can increase the localization of ASICIa channels in the dendritic spines through an interaction between the ASIC2a channels and the PSD-95 (postsynaptic density-95) protein. Moreover, ASICIa-dependent acidosis has been shown to significantly decrease the length and density of dendritic spines.

[0075] Recently, ASICs became a receptor of interest in nociception. ASICs are expressed in the nociceptive sensory neurons, and ASICIa, ASIC2b, and ASIC3 are overexpressed in inflammation. Several studies demonstrated that nociception could be achieved by activating ASICs, specifically ASICIa and ASIC3. This activation has been achieved using selective ASICs activators like GMQ and MitTx. Moreover, several studies showed that blocking ASICs by different selective inhibitors can result in anti-nociception. Several studies showed the implication of ASIC3 in pain, allodynia and fibromyalgia.

[0076] The involvement of membrane proteins in cancer metastases has recently become an important topic. For instance, ASICIa is involved in maintaining the acidic tumour microenvironment to pH 6.5. In 2017, it was shown that ASICIa is significantly involved in liver cancer proliferation and tumorigenicity in both in vitro and in vivo models, and knocking out the ASICIa gene in liver cancer cells inhibits LEF-TCF (lymphoid enhancer factor / T cell factor), resulting in cell cycle arrest. Moreover, the ASICIa gene knockout significantly suppressed the 7-catenin / LEF-TCF, one of the critical pathways to cancer cell migration, adhesion, and proliferation. A more recent study showed that ASICIa is overexpressed in breast cancer and enhance cancer cell migration, invasion, and proliferation, and that inhibition of the ASICIa by the selective inhibitor “PcTxl” or downregulation of the ASICIa gene could significantly decrease tumour migration, invasion, and proliferation. Another recent study showed that inhibiting ASICIa in glioma cells by mambalgin-2 toxin can possess an antitumor effect via cell cycle arrest and apoptosis mechanisms.Tissue acidosis is a significant challenge in ischemic stroke and one of the leading causes of brain neuronal injury. Tissue acidosis results from substantial elevation in brain lactate concentrations, at which extracellular pH has been reported to drop to pH 6. This drop in the extracellular pH is enough to activate ASICs, leading to lower Ca2+permeability and neuronal injury. Moreover, acidosis can induce Ca2+-dependent neuronal injury, which ASIC blockers inhibit.

[0077] Famotidine

[0078] Famotidine is a known histamine H2 receptor antagonist traditionally used for gastrointestinal disorders. Famotidine decreases stomach acid production. It is known to be used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. Famotidine has the structure:

[0079]

[0080] As referred herein, “famotidine and pharmaceutically acceptable salts thereof’ also include solvates and hydrates of the same.

[0081] The inventors of the present invention showed that famotidine is an inhibitor of acid-sensing ion channels (ASICs), optionally acid-sensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). Famotidine inhibits ASICs at an IC50 more than 20 times higher than its known effect as a histamine blocker.

[0082] Without being bound by theory, the inventors of the present invention believe that the presence in the molecule of the guanidinyl and / or thiazolyl-containing heterocycle moieties is mainly responsible for the inhibitory properties of famotidine on ASICs.

[0083] As such famotidine may be for use in the treatment of an ASIC-related disease in a subject, famotidine may be formulated in any of the pharmaceutical compositions of the disclosure described herein.

[0084] In accordance with embodiments, a method is provided for inhibiting acid-sensing ion channels (ASICs) by administering famotidine to a subject in need thereof at an intravenous dosage higher than 80 mg of the free base and oral doses higher than 160 mg of the free base. The famotidine inhibits the ASICs at an IC50 of 215 micromolar under acidic conditions.

[0085] Famotidine-related Compounds

[0086] Famotidine-related compounds are derivatives of famotidine which are often present as impurities. However, no famotidine-related compounds are being clinically used as a H2receptor antagonist or for any other clinical purpose. Several of them are employed simply as analytical reference standards e.g. for the determination of the purity of famotidine, but no clinical uses have been reported. Famotidine-related compounds include those named as famotidine-related compounds A, B, C, D, E, F, G H, I and J as found in the European Pharmacopoeia (Ph. Eur.). References in the present disclosure to famotidine-related compounds include all such famotidine-related compounds A, B, C, D, E, F, G, H, I and J. These are sometimes also referred to in the art by terms such as “Famotidine EP Impurities” or “Famotidine impurities” with the same lettering as given above, such that e.g. famotidine-related compound A may also be referred to as famotidine EP impurity A or famotidine impurity A, and likewise for the other famotidine-related compounds. The terms “famotidine-related compound”, “famotidine impurity”, and “famotidine EP impurity” may therefore be employed interchangeably and with the same meaning.

[0087] The structures of famotidine-related compounds A through to J are shown in Table 1 below. It will be noted that each of these compounds comprises structural motifs in common with famotidine, and in particular each comprises guanidinyl and thiazolyl moieties corresponding to those of famotidine. As noted above, and without wishing to be bound by theory, the inventor believes that it is the guanidinyl and / or thiazolyl moieties which are responsible for the ASIC-inhibitory properties of famotidine. Accordingly, famotidine-related compound having such moieties in common with famotidine, including A, B, C, D, E, F, G, H, I and J, are also suitable for use according to the invention.

[0088] Table 1: structures of famotidine-related compounds A-J

[0089] Famotidine-related compound Structure

[0090] A H2N

[0091] 1 / rsv

[0092] NH2

[0093] NH2

[0094] B ov,o

[0095] N N J H 1

[0096] s'

[0097] SCN NS= / S

[0098] N«(NH2

[0099] H2N NH2

[0100]

[0101] Famotidine-related compound Structure

[0102] C o oK

[0103] 1 v

[0104] KI yzZ^ N \ N - / / H NH2H2N-~^ >^ \ / /

[0105] \S- NH2

[0106] D 0

[0107] N.

[0108] _ _ ^ jfS NHzH2N^_^ \ / /

[0109] \ S -J

[0110] NH2

[0111] E H2N

[0112] .S -21 ,

[0113] 2.. S

[0114] H N~~y^ \ / / N

[0115] NH2

[0116] F o

[0117] hk

[0118] _ _ < / / / S°HH2N~^_^ \ / /

[0119] \ 'S-J

[0120] NH2

[0121] G NH

[0122] N. \ / CN^~~~^ IfSH

[0123] \ / /

[0124] \S" -J

[0125] NH2

[0126] H HN

[0127] N^> / ff NH2

[0128] H2N-^^' \ / /

[0129] \s—J

[0130] NH2

[0131] 1 fl Ov1 V N if $ HNH2H2N^ Z^ \ / / II

[0132] \ s -1 0

[0133] NH2

[0134]

[0135] Famotidine-related compound Structure

[0136] J o

[0137] l\L

[0138] 2If

[0139] H N~^^ \ / / s 0

[0140] \s-J

[0141] NH2

[0142]

[0143] The famotidine-related compound for use according to the invention may thus be selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, H, I and J. The famotidine-related compound may be famotidine-related compound A. The famotidine-related compound may be famotidine-related compound B. The famotidine-related compound may be famotidine-related compound C. The famotidine-related compound may be famotidine-related compound D. The famotidine-related compound may be famotidine-related compound E. The famotidine-related compound may be famotidine-related compound F. The famotidine-related compound may be famotidine-related compound G. The famotidine-related compound may be famotidine-related compound H. The famotidine-related compound may be famotidine-related compound I. The famotidine-related compound may be famotidine-related compound J.

[0144] In embodiments, the famotidine-related compound for use according to the invention may be selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G and H. In embodiments, the famotidine-related compound for use according to the invention may be selected from the group consisting of famotidine-related compounds A, B and E. The famotidine-related compound may be famotidine-related compound A. The famotidine-related compound may be famotidine-related compound B. The famotidine-related compound may be famotidine-related compound E.

[0145] As referred to herein, “famotidine-related compounds and pharmaceutically acceptable salts thereof” also include solvates and hydrates of the same.

[0146] The inventors of the present invention showed that famotidine-related compounds are an inhibitor of acid-sensing ion channels (ASICs), optionally acid-sensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). The inventors of the present invention showed that famotidine-related compounds A, B and E are an inhibitor of acid-sensing ion channels (ASICs), optionally acidsensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa).

[0147] As such famotidine-related compounds may be for use in the treatment of an ASIC-related disease in a subject. Famotidine-related compounds may be formulated in any of the pharmaceutical compositions of the disclosure described herein.As such famotidine-related compounds A, B, C, D, E, F, G, H, I and / or J (such as famotidine-related compounds A, B, C, D, E, F, G and / or H, e.g. famotidine-related compounds A, B and / or E) may be for use in the treatment of an ASIC-related disease in a subject. Famotidine-related compounds A, B, C, D, E, F, G, H, I and / or J (such as famotidine-related compounds A, B, C, D, E, F, G and / or H, e.g. famotidine-related compounds A, B and / or E) may be formulated in any of the pharmaceutical compositions of the disclosure described herein.

[0148] In accordance with embodiments, a method is provided for inhibiting acid-sensing ion channels (ASICs) by administering one of the famotidine-related compounds (A, B, C, D, E, F, G, H, I and / or J, such as famotidine-related compounds A, B, C, D, E, F, G and / or H, e.g. famotidine-related compounds A, B and / or E) to a subject in need thereof at a dosage where it inhibits the ASICs at an IC50 range of 1 to 200 micromolar under acidic conditions.

[0149] Cimetidine

[0150] Cimetidine is a known histamine H2 receptor antagonist that inhibits stomach acid production. It is known to be used in the treatment of heartburn and peptic ulcers. Cimetidine has the structure:

[0151]

[0152] As referred herein, “cimetidine and pharmaceutically acceptable salts thereof’ also include solvates and hydrates of the same.

[0153] The inventors of the present invention have now, surprisingly, shown that cimetidine is an inhibitor of acid-sensing ion channels (ASICs), optionally acid-sensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). Cimetidine inhibits the ASICs at an IC50 more than 100 times higher than its known effect as a histamine blocker.

[0154] Without being bound by theory, the inventors of the present invention believe that the presence of the guanidinyl and / or imidazolyl moieties in the cimetidine molecule is mainly responsible for the inhibitory properties of cimetidine in relation to ASICs.

[0155] As such cimetidine may be for use in the treatment of an ASIC-related disease in a subject.

[0156] In accordance with some embodiments, the present invention provides a method for inhibiting acid-sensing ion channels (ASICs) by administering cimetidine or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dosage greater than 80 mg of the free base, and preferably a dosage greater than about 300 mg of the free base, such as at anintravenous dosage higher than about 300 mg of the free base or an oral dosage higher than about 800 mg of the free base. The cimetidine inhibits the ASICs at an IC50 of 655 micromolar under acidic conditions.

[0157] In accordance with other embodiments, the method involves administering cimetidine, famotidine, or famotidine-related compounds either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

[0158] In yet other embodiments, the cimetidine, famotidine, or famotidine-related compounds are administered in a dosage form selected from tablets, capsules, solutions, injections, suspensions, emulsions, and gels, optionally a dosage form selected from tablets, capsules, solutions, and injections, and preferably solutions or injections.

[0159] Pharmaceutical Compositions

[0160] Famotidine, famotidine-related compounds and cimetidine, and their pharmaceutically acceptable salts, may be formulated according to pharmaceutical compositions described herein.

[0161] In embodiments, the invention therefore provides a pharmaceutical composition comprising famotidine, a famotidine-related compound, or cimetidine, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipient, diluent, or carrier.

[0162] In embodiments, the pharmaceutical composition comprises famotidine or a pharmaceutically acceptable salt thereof.

[0163] In embodiments, the pharmaceutical composition comprises a famotidine-related compound or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound is selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, H, I and J, and pharmaceutically acceptable salts thereof. In embodiments, the famotidine-related compound is selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, and H, and pharmaceutically acceptable salts thereof. In embodiments, the famotidine-related compound is selected from the group consisting of famotidine-related compounds A, B, and E, and pharmaceutically acceptable salts thereof. In embodiments, the famotidine-related compound may be famotidine-related compound A or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound B or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound C or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound D or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound E or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compoundmay be famotidine-related compound F or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound G or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound H or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound I or a pharmaceutically acceptable salt thereof. In embodiments, the famotidine-related compound may be famotidine-related compound J or a pharmaceutically acceptable salt thereof.

[0164] Pharmaceutical compositions of famotidine with ascorbic acid Famotidine is poorly soluble at physiological pH and unstable in aqueous solutions at high concentrations. Previously-described famotidine formulations, such as those disclosed in US7094414, utilise PEGs, nicotinic acid amides, surfactants and / or other solubilisers such as riboflavin or salts or esters thereof to improve aqueous solubility and stability for IV or IM administration at doses up to 40 mg. However, high aqueous concentrations of famotidine (such as concentrations >70 mg / mL) have not previously been achieved. The present inventors have now surprisingly found that such concentrations can be stably achieved by coformulation of famotidine with ascorbic acid, without requiring the presence of additional solubilising excipients such as PEGs, nicotinic acid amides, or other solubilisers such as riboflavin or salts or esters thereof. Such additional solubilising excipients are undesirable as they can lead to increased viscosity rendering formulations unsuitable for injection; require chemical modification; and / or interfere with the pharmacology of ASIC inhibition by famotidine.

[0165] While the use of ascorbic acid as an antioxidant has been described in formulations of various active pharmaceutical ingredients, the formulations disclosed herein employ ascorbic acid in ratios relative to the API which far exceed ratios associated with its use as an antioxidant.

[0166] Recent evidence demonstrates that certain endogenous and formulation-derived acidic amino acids, including aspartic acid, can potentiate acid-sensing ion channel 1a (ASICIa) activity under acidic conditions, thereby functionally counteracting ASIC1 a inhibition. This pharmacological interaction has not previously been considered in the formulation of famotidine. For example, US 2004 / 0067993 A1 and JP 2003-261449A describe formulations of famotidine comprising aspartic acid as a stabilizing or salt- or complex-forming agent together with nicotinic acid amide as a solubilizing agent.

[0167] The inventors have now surprisingly identified that formulations containing aspartic acid and other pharmaceutically acceptable organic acids are unsuitable for preserving famotidine-mediated ASICIa inhibition under acidic conditions relevant to e.g. ischemia,whereas ascorbic acid does not interfere with famotidine-mediated ASICIa inhibition under such conditions. These effects have not previously been described or recognised in the art.

[0168] The present inventors are the first to show in comparative electrophysiological studies that co-application of aspartic acid (a common excipient) with famotidine under acidic conditions eliminates famotidine-mediated ASICIa inhibition and instead potentiates ASICIa currents, whereas co-application with ascorbic acid at the famotidine:ascorbic acid ratios described herein preserves or even enhances the inhibitory activity of famotidine. Therefore, the present inventors postulate that combination of famotidine with ascorbic acid is beneficial for famotidine-mediated ASICIa inhibition.

[0169] Thus, a pharmaceutical composition of the disclosure may comprise famotidine or a pharmaceutically acceptable salt thereof, ascorbic acid and an aqueous solvent. In embodiments the aqueous solvent is water, e.g. water for injection, such as sterile water for injection. In embodiments the aqueous solvent may comprise a buffer, e.g. phosphate-buffered saline (PBS). The buffer may be provided in an amount or concentration suitable to attain a pH of 4.0 to 7.0 as described elsewhere herein.

[0170] The present inventors are also the first to observe that specific molar ratios of the free base of famotidine relative to ascorbic acid are beneficial for solvating famotidine or a pharmaceutically acceptable salt thereof at high concentrations while avoiding potentiation of ASICs as described above with other acidic compounds. In particular, it has surprisingly been found that ascorbic acid contributes to the observed high solubility and stability of the famotidine formulations described herein when ascorbic acid is provided in relatively high levels relative to famotidine, when compared to the levels of ascorbic acid employed in the art as an antioxidant.

[0171] Famotidine or a pharmaceutically acceptable salt thereof may be in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1 to 1:2.5 of the free base of famotidine relative to ascorbic acid, such as a molar ratio of 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4 or 1:2.5 of the free base of famotidine relative to ascorbic acid. In some embodiments, famotidine or a pharmaceutically acceptable salt thereof may be in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1.5 to 1:2.2 of the free base of famotidine relative to ascorbic acid, such as a molar ratio of 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, or 1:2.2, of the free base of famotidine relative to ascorbic acid. In some embodiments, famotidine or a pharmaceutically acceptable salt thereof may be in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1.7 to 1:2.2 of the free base of famotidine relative to ascorbic acid, e.g. a molar ratio of 1:1.8 to 1:2.0. For instance, a molar ratio of 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1 or 1:2.2 of the free base of famotidine relative to ascorbic acid may be employed. In some embodiments, famotidine or a pharmaceutically acceptable salt thereof may be in a molar ratiorelative to ascorbic acid which corresponds to a molar ratio of about 1:1.9 of the free base of famotidine relative to ascorbic acid, e.g. a molar ratio of 1:1.9.

[0172] In embodiments, famotidine or a pharmaceutically acceptable salt thereof may be in a weight ratio relative to ascorbic acid which corresponds to a weight ratio of 1:0.78 to 1:1.30 of the free base of famotidine relative to ascorbic acid, e.g. a weight ratio of 1:0.89 to 1:1.16, such as 1:0.89 to 1:1.05, for example a weight ratio of about 1:1.0 of the free base of famotidine relative to ascorbic acid.

[0173] The concentration of famotidine or a pharmaceutically acceptable salt thereof exceeds 50 mg / mL and may be at least 70 mg / mL of the free base. By way of non-limiting example, the concentration of famotidine or a pharmaceutically acceptable salt thereof may be at least 70 mg / mL, at least 75 mg / mL, at least 80 mg / mL, at least 85 mg / mL, at least 90 mg / mL, at least 95 mg / mL or at least 100 mg / mL of the free base. Optionally the concentration of famotidine or a pharmaceutically acceptable salt thereof may be at least 80 mg / mL, at least 85 mg / mL, at least 90 mg / mL, at least 95 mg / mL or at least 100 mg / mL of the free base. Further optionally the concentration of famotidine or a pharmaceutically acceptable salt thereof may be at least 100 mg / mL of the free base.

[0174] The pH of the pharmaceutical composition of the disclosure may be in the range 4.0 < pH < 7.0. By way of non-limiting example, the pH of the pharmaceutical composition of the disclosure may be 4.0, about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5. Optionally the pH of the pharmaceutical composition of the disclosure may be about 4.5.

[0175] The present inventors are the first to show that according to the specific molar ratios of the free base of famotidine relative to ascorbic acid as described herein are sufficient to solubilise famotidine or pharmaceutically acceptable salts thereof in water at a high concentration, while retaining a suitable viscosity for administration through injection, e.g. injection through 27-gauge (27G) needles or smaller without precipitation. Such properties are usually achieved in the art by adding further excipients to the pharmaceutical composition, which the pharmaceutical composition of the disclosure does not require.

[0176] The pharmaceutical composition of the disclosure may therefore be substantially free of (e.g. free of) (a) polyethylene glycol; (b) nicotinic acids; (c) water-soluble amides; (d) cyclodextrins; (e) riboflavin or salts or esters thereof; and / or (f) surfactants. The composition may be considered substantially free of any of the excipient listed herein by measuring their presence and / or quantity with analytical methods known by the person skilled in the art, such as Liquid Chromatography coupled to Mass-Spectroscopy. A pharmaceutical composition of the invention is substantially free of the excipient listed herein when either it is not present, or it is present in less than 0.5 w / v% of the pharmaceutical composition of the invention, optionally less than 0.1 w / v %, less than 0.05 w / v%, less than about 100 w / v ppm. By way of non-limiting example, the person skilled in the art will appreciate that polyethylene-glycol maybe present in trace amounts in sterile filters and therefore that some may end up in the injectable pharmaceutical composition in trace amounts, i.e. in lower amounts than 0.5 w / v%, 0.1 w / v%. 0 / 05 w / v% or 100 w / v ppm.

[0177] Pharmaceutical compositions of the present disclosure therefore have low viscosity and are suitable for injection. Further, the compositions are stable at room temperature for at least 72 hours, e.g. maintaining >85% of their initial famotidine content and / or >90% of their initial ascorbic acid content and without any precipitation occurring upon dilution. In embodiments, the compositions of the present disclosure may be prepared extemporaneously, e.g. for acute administration to a subject such as within about 12 hours, preferably within about 4 to 6 hours, of the onset of at least one symptom of an ASIC-related disease such as ischemic stroke, brain ischemia (cerebral ischemia) or myocardial ischemia.

[0178] The present disclosure thus further provides a process for preparing a pharmaceutical composition described herein, comprising dissolving famotidine, or a pharmaceutically acceptable salt thereof, and ascorbic acid in an aqueous solvent in a weight ratio or molar ratio as described herein; and optionally adjusting the pH to a value between about 4.0 and about 7.0 as described herein. In embodiments the aqueous solvent is water, e.g. water for injection, such as sterile water for injection. Where the pH is adjusted, this may be done using any suitable buffer known to those skilled in the art, such as phosphate-buffered saline (PBS).

[0179] Therapeutic Applications

[0180] Any references of method of treatment, method of therapy, compound for use in therapy or use of compound in the manufacture of a medicament for therapy are to be used interchangeably.

[0181] The present inventors show for the first time that cimetidine or pharmaceutically acceptable salts thereof, are inhibitors of acid-sensing ion channels (ASICs), optionally acidsensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). The disclosure therefore provides cimetidine and its pharmaceutically acceptable salts thereof for use in the treatment of ASIC- related disease.

[0182] The present inventors show for the first time that famotidine or pharmaceutically acceptable salts thereof, are inhibitors of acid-sensing ion channels (ASICs), optionally acidsensing ion channel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). The disclosure therefore provides famotidine, and its pharmaceutically acceptable salts thereof for use in the treatment of ASIC- related disease.

[0183] famotidine-related compounds have not been shown to be effective nor useful in any conditions while being known impurities of famotidine. However, the present disclosure shows for the first time that famotidine-related compounds or pharmaceutically acceptable salts thereof are inhibitors of acid-sensing ion channels (ASICs), optionally acid-sensing ionchannel 1 (ASIC1) such as acid-sensing ion channel 1a (ASICIa), e.g. human acid-sensing ion channel 1a (hASICIa). The disclosure therefore provides famotidine-related compounds or pharmaceutically acceptable salts thereof for use as a medicament. The disclosure also provides famotidine-related compounds or pharmaceutically acceptable salts thereof for use in the treatment of ASIC-related disease.

[0184] The present disclosure further provides a pharmaceutical composition of the disclosure for use as a medicament. The present disclosure further provides a pharmaceutical composition of the disclosure for use in the treatment of ASIC-related disease.

[0185] The disclosure therefore provides cimetidine and its pharmaceutically acceptable salts thereof for use in the prevention of ASIC-related disease.

[0186] The disclosure therefore provides famotidine, and its pharmaceutically acceptable salts thereof for use in the prevention of ASIC-related disease.

[0187] The disclosure also provides famotidine-related compounds or pharmaceutically acceptable salts thereof for use in the prevention of ASIC-related disease.

[0188] The present disclosure further provides a pharmaceutical composition of the disclosure for use in the prevention of ASIC-related disease.

[0189] The present disclosure further provides a method of treatment of ASIC-related disease comprising administering a therapeutically effective amount of cimetidine or pharmaceutically acceptable salts thereof to a subject in need thereof.

[0190] The present disclosure further provides a method of treatment of ASIC-related disease comprising administering a therapeutically effective amount of famotidine or pharmaceutically acceptable salts thereof to a subject in need thereof.

[0191] The present invention further provides a method of treatment comprising administering a therapeutically effective amount of famotidine-related compound or pharmaceutically acceptable salts thereof to a subject in need thereof. The present disclosure further provides a method of treatment of ASIC-related disease comprising administering a therapeutically effective amount of famotidine-related compounds or pharmaceutically acceptable salts thereof to a subject in need thereof.

[0192] The present invention further provides a method of treatment comprising administering a therapeutically effective amount of a pharmaceutical composition of the disclosure to a subject in need thereof. The present disclosure further provides a method of treatment of ASIC-related disease comprising administering a therapeutically effective amount of a pharmaceutical composition of the disclosure to a subject in need thereof.

[0193] The present disclosure further provides a method of prevention of ASIC-related disease comprising administering a therapeutically effective amount of cimetidine or pharmaceutically acceptable salts thereof to a subject in need thereof.The present disclosure further provides a method of prevention of ASIC-related disease comprising administering a therapeutically effective amount of famotidine or pharmaceutically acceptable salts thereof to a subject in need thereof.

[0194] The present disclosure further provides a method of prevention comprising administering a therapeutically effective amount of famotidine-related compound or pharmaceutically acceptable salts thereof to a subject in need thereof. The present disclosure further provides a method of prevention of ASIC-related disease comprising administering a therapeutically effective amount of famotidine-related compounds or pharmaceutically acceptable salts thereof to a subject in need thereof.

[0195] The present disclosure further provides a method of prevention comprising administering a therapeutically effective amount of a pharmaceutical composition of the disclosure to a subject in need thereof. The present disclosure further provides a method of prevention of ASIC-related disease comprising administering a therapeutically effective amount of a pharmaceutical composition of the disclosure to a subject in need thereof.

[0196] The disclosure provides the use of cimetidine or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of ASIC-related disease.

[0197] The disclosure provides the use of famotidine or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of ASIC-related disease.

[0198] The disclosure provides the use of famotidine-related compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament. The disclosure provides the use of famotidine-related compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of ASIC-related disease.

[0199] The disclosure provides the use of pharmaceutical composition of the disclosure in the manufacture of a medicament. The disclosure provides the use of pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of ASIC-related disease.

[0200] The disclosure provides the use of cimetidine or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention of ASIC-related disease.

[0201] The disclosure provides the use of famotidine or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention of ASIC-related disease.

[0202] The disclosure provides the use of famotidine-related compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament. The disclosure provides the use of famotidine-related compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention of ASIC-related disease.

[0203] The disclosure provides the use of pharmaceutical composition of the disclosure in the manufacture of a medicament. The disclosure provides the use of pharmaceutical compositionof the disclosure in the manufacture of a medicament for the prevention of ASIC-related disease.

[0204] ASIC-related disease may be selected from neurological disorders, neurodegenerative diseases, psychological disorders, sexual disorders, cardiovascular diseases, respiratory diseases, inflammatory diseases, renal diseases, gastrointestinal diseases, metabolic disorders, cancer, and addiction, e.g. smoking addiction. The ASIC-related disease may be an ASIC1-related disease, e.g. an ASICIa-related disease or hASICIa.

[0205] The ASIC-related disease may be selected from neurological disorders, neurodegenerative diseases, psychological disorders, sexual disorders, cardiovascular diseases, respiratory diseases, inflammatory diseases, renal diseases, gastrointestinal diseases, metabolic disorders, cancer, and addiction, e.g. smoking addiction. The ASIC-related disease may be an ASIC1-related disease, e.g. an ASICIa-related disease. The neurological disorder may be selected from the group consisting of ischemic stroke, cerebral ischemia, traumatic brain injury, spinal cord injury, neuropathic pain, and epilepsy. The neurodegenerative disease may be selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. The psychological disorder may be selected from the group consisting of anxiety, depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), and addiction. The cardiovascular disease may be selected from the group consisting of myocardial infarction, heart failure, arrhythmia, and hypertension. The respiratory disease may be selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). The inflammatory disease may be selected from the group consisting of rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. The renal disease may be selected from the group consisting of acute kidney injury, chronic kidney disease, and renal fibrosis. The gastrointestinal disease may be selected from the group consisting of gastroesophageal reflux disease (GERD), peptic ulcer disease, and irritable bowel syndrome (IBS). The metabolic disorder may be selected from the group consisting of diabetes, obesity, and metabolic syndrome. The cancer may be selected from the group consisting of glioblastoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer. The addiction may be smoking addiction.

[0206] The ASIC-related disease may be an acute disease. An ASIC-related disease which is an acute disease may be ischemic stroke, cerebral ischemia, myocardial ischemia, or myocardial infarction.

[0207] Administration may be via oral, subcutaneous, intravenous, parenteral, or topical administration, optionally via oral, subcutaneous or intravenous administration, preferably by intravenous administration.The dosage for treatment with cimetidine, famotidine, famotidine-related compounds or pharmaceutically acceptable salt thereof or pharmaceutical composition of the invention may be a dosage greater than 80 mg of the free base, a dosage greater than 160 mg of the free base, a dosage greater than about 200 mg of the free base, a dosage greater than about 300 mg of the free base, a dosage greater than about 500 mg of the free base, or a dosage greater than about 800 mg of the free base. . By way of non-limiting example, the dosage for treatment may be a dosage corresponding to about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg. In embodiments where famotidine, a famotidine-related compound or a pharmaceutically acceptable salt thereof is administered intravenously, suitable dosages may be greater than 80 mg of the free base and in particular from about 200 to about 500 mg of the free base. For example, the intravenous dosage of famotidine, a famotidine-related compound or a pharmaceutically acceptable salt thereof may correspond to a dosage of greater than 80 mg, from about 160 to about 500 mg, from about 200 to about 500 mg, from about 250 to about 450 mg, from about 250 to about 350 mg, or from about 300 to about 350 mg of the free base, such as about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg of the free base.

[0208] In embodiments where famotidine, a famotidine-related compound or a pharmaceutically acceptable salt thereof is administered orally, suitable dosages may be greater than 160 mg of the free base, and in particular from about 200 to about 500 mg of the free base. For example, the oral dosage of famotidine, a famotidine-related compound or a pharmaceutically acceptable salt thereof may correspond to a dosage of greater than 160 mg, from about 160 to about 500 mg, from about 200 to about 500 mg, from about 250 to about 450 mg, from about 250 to about 350 mg, or from about 300 to about 350 mg of the free base, such as about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg of the free base.

[0209] In embodiments where cimetidine or a pharmaceutically acceptable salt thereof is to be administered, suitable dosages may be greater than about 300 mg of the free base, greater than about 500 mg of the free base or greater than about 800 mg of the free base. Suitable dosages for intravenous administration may be greater than about 300 mg of the free base, such as from about 300 to about 800 mg, from about 350 to about 750 mg, from about 400 to about 700 mg, from about 450 to about 650 mg, from about 450 to about 600 mg, or from about 550 to about 650 mg of the free base. Suitable dosages for oral administration may be greater than about 800 mg of the free base.

[0210] The cimetidine, famotidine, famotidine-related compounds or pharmaceutically acceptable salt thereof or pharmaceutical composition of the invention may be administered within about 12 hours of the onset of at least one symptom of the acute disease. By way ofnon-limiting example, cimetidine, famotidine, famotidine-related compounds or pharmaceutically acceptable salt thereof or pharmaceutical composition of the invention may be administered within about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours or about 2 hours of the onset of at least one symptom of the acute disease. Optionally cimetidine, famotidine, famotidine-related compounds or pharmaceutically acceptable salt thereof or pharmaceutical composition of the invention may be administered within about 4 hours to about 6 hours of the onset of at least one symptom of the acute disease. Exemplary symptoms of ischemic stroke and cerebral ischemia include weakness or paralysis (e.g. hemiplegia or hemiparesis); aphasia; dysarthria; facial drooping; sudden worsening or loss of vision (e.g. blurred vision or double vision), hearing, smell, taste and / or touch; ataxia; dizziness; vertigo; loss of balance; nausea or vomiting; neck stiffness; confusion; seizure; amnesia; headache; fainting or unconsciousness. Exemplary symptoms of myocardial ischemia and myocardial infarction include angina pectoris; pain or discomfort in the upper body; shortness of breath or difficulty breathing; cold sweat; nausea or vomiting; dizziness; tachycardia or irregular heartbeat; anxiety.

[0211] Kit of parts

[0212] The present disclosure further provides a kit of parts a kit of parts comprising (a) a first vial containing famotidine, or a pharmaceutically acceptable salt thereof; (b) a second vial containing ascorbic acid; wherein the famotidine, or a pharmaceutically acceptable salt thereof, is provided in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1 to 1:2.5 of the free base of famotidine relative to ascorbic acid; and (c) a third vial containing an aqueous solvent. The kit may further comprise an injection syringe and / or instructions for administration.

[0213] Famotidine, or a pharmaceutically acceptable salt thereof, is provided in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1 to 1:2.5 of the free base of famotidine relative to ascorbic acid. Any suitable molar ratio or weight ratio of famotidine (or a pharmaceutically acceptable salt thereof) and ascorbic acid may be employed in line with the ratios described elsewhere herein in connection with the pharmaceutical compositions of the disclosure. Thus in some embodiments the famotidine or pharmaceutically acceptable salt thereof in vial (a) and the ascorbic acid in vial (b) are provided in amounts corresponding to a molar ratio of 1:1.5 to 1:2.2, 1:1.7 to 1:2.2, or 1:1.8 to 1:2.0 of the free base of famotidine relative to ascorbic acid, e.g. a molar ratio of 1 : 1.7, 1:1.8, 1:1.9, 1 :2.0, 1 :2.1 or 1.2.2, such as about 1:1.9 (e.g. 1:1.9). In some embodiments the famotidine or pharmaceutically acceptable salt thereof in vial (a) and the ascorbic acid in vial (b) are provided in amounts corresponding to a weight ratio of 1 :0.78 to 1 : 1.30 of the free base of famotidine relative to ascorbic acid, e.g.a weight ratio of 1:0.89 to 1:1.16, such as 1:0.89 to 1:1.05, for example a weight ratio of about 1 : 1.0 of the free base of famotidine relative to ascorbic acid.

[0214] In embodiments the aqueous solvent in vial (c) is water, e.g. water for injection, such as sterile water for injection. Optionally the solvent may comprise an aqueous buffer, e.g. phosphate-buffered saline, which is suitable to attain a pH at a value in the range 4.0 < pH < 7.0 (such as 4.0, about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5; preferably about 4.5) when the famotidine or pharmaceutically acceptable salt thereof and the ascorbic acid are dissolved in the solvent.

[0215] The kit of parts of the disclosure may be used to make a pharmaceutical composition by dissolving the content of the first and second vial with the content of the third vial. Optionally, the content of the first vial may be dissolved with the content of the third vial and the resulting solution may be used to dissolve the content of the second vial. Optionally, the content of the second vial may be dissolved with the content of the third vial and the resulting solution may be used to dissolve the content of the first vial.

[0216] Such kit of parts is particularly useful in the event of developing symptoms in an acute disease to make a pharmaceutical composition of the disclosure and administer the resulting pharmaceutical composition to the patient in need thereof. As the components are not stored in solution they stay stable for a longer time and are ready to be used in a pharmaceutical composition of the invention when needed.

[0217] FURTHER EMBODIMENTS OF THE INVENTION

[0218] Additional embodiments include, but are not limited to, those described in clauses 1 to 20 below:

[0219] 1. A method for inhibiting acid-sensing ion channels (ASICs) comprising: Administering cimetidine to a subject in need thereof at an intravenous dosage exceeding 300 mg and oral doses exceeding 800 mg, wherein the cimetidine inhibits the ASICs at an IC50 of 655 micromolar in a pH-independent manner.

[0220] 2. A method for inhibiting acid-sensing ion channels (ASICs) comprising: Administering famotidine to a subject in need thereof at an intravenous dosage exceeding 80 mg and oral doses exceeding 160 mg, wherein the famotidine inhibits the ASICs at an IC50 of 215 micromolar in a pH-independent manner.

[0221] 3. A method for inhibiting acid-sensing ion channels (ASICs) comprising: Administering a famotidine-related compound A, B, C, D, E, F, G, and / or H to a subject in need thereof, wherein the famotidine-related compound inhibits the ASICs at an IC50 range of 1 to 200 micromolar in a pH-independent manner.4. The method, according to clauses 1, 2, and 3, wherein the compound is administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

[0222] 5. The method, according to clauses 1, 2, and 3, wherein the compound is administered in a dosage form selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, and gels.

[0223] 6. A method for inhibiting acid-sensing ion channels (ASICs) comprising: Administering a composition comprising famotidine and ascorbic acid to a subject in need thereof, wherein the famotidine inhibits the ASICs at an IC50 of 215 micromolar in a pH- independent manner and wherein the ascorbic acid is present in a 1:1 ratio with the famotidine and at a dosage of more than 80 mg, thereby achieving drug solubility. 7. The method, according to clause 6, wherein the famotidine inhibits the ASICs at an IC50 more than 20 times higher than its known effect as a histamine blocker.

[0224] 8. The method, according to clause 6, wherein the ascorbic acid is present at a therapeutic dose rather than a formulation dose.

[0225] 9. The method, according to clauses 1, 2, 3, and 4, wherein the composition is administered orally.

[0226] 10. The method, according to clauses 1, 2, 3, and 4, wherein the composition is administered parenterally.

[0227] 11. The method, according to clauses 1, 2, 3, and 4, wherein the composition is administered topically.

[0228] 12. The method, according to clauses 1, 2, 3, and 4, wherein the composition is administered in a dosage form selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, and gels.

[0229] 13. The method, according to clauses 1, 2, 3, and 4, wherein the subject suffers from a condition associated with ASIC dysfunction.

[0230] 14. The method, according to clause 13, wherein the condition is selected from the group consisting of pain, inflammation, neurological disorders, psychological disorders, sexual dysfunction, pulmonary and respiratory disease, ear disease, heart failure, ischemia, and stroke.

[0231] 15. The method, according to clause 14, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, and nociceptive pain.16. The method, according to clause 14, wherein the neurological disorder is selected from the group consisting of stroke, traumatic brain injury, and neurodegenerative diseases.

[0232] 17. According to clauses 1, 2, 3, and 4, the method provides pulmonary protection, cardioprotection, neuroprotection, and pain relief to the subject.

[0233] 18. The method, according to clauses 1, 2, 3, and 4, wherein the composition further comprises at least one pharmaceutically acceptable carrier, excipient, or diluent. 19. The method, according to clause 6, wherein the composition is administered in a single dosage form comprising both the compound and the ascorbic acid.

[0234] 20. The method, according to clause 6, wherein the composition is administered in separate dosage forms, one comprising the compound and the other comprising the ascorbic acid, wherein the separate dosage forms are administered simultaneously or sequentially.

[0235] The invention is now further illustrated by way of the following non-limiting Examples.

[0236] EXAMPLES

[0237] General Methods

[0238] Mammalian cell culture

[0239] Wild-type Human Embryonic Kidney (HEK 293) cells were obtained from Abeam. Cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% (v / v) foetal bovine serum, 2 mM glutamine, 100 ll / rnl penicillin, and 0.1 mg / ml streptomycin at 37°C and 5% CO2 in a humidified incubator.

[0240] Electrophysiological recording from HEK 293 cells endogenously expressing ASICIa by Automated patch clamp

[0241] Electrophysiological recordings were performed utilizing ensemble microfluidic plates on the lonFlux-16TM System (Fluxion Biosciences, USA) (Golden etal., 2011; Spencer eta / ., 2012; Chen et al., 2012), allowing simultaneous measurement of 16 currents as duplicates from 2 ‘traps’ under varying experimental conditions. Using ‘ensemble’ plates, recording total whole-cell current from up to 20 cells for each recording. Precise solution changes were achieved via pneumatically controlled microfluidics, resulting in exchange times of under 50 ms. A continuous pH 7.5 extracellular solution (ECS) flowed over patch-clamped cells during experiments. HEK 293 cells were washed with PBS, detached with TrypLE or Cell-Stripper for 3 mins, centrifuged at 1000 rpm for 2 min, and resuspended in ECS (in mM: NaC1 138, KCI 4, MgCI2 1, CaCI2 1.8, HEPES 10, glucose 5.6) at 1.5x106 cells / mL for experiments. For ECS with pH <6.5, MES buffer replaced HEPES, resulting in ECS-MES at pH 4.03. ECS pH 7.5aliquots were adjusted to pH 6.5, 6.0, 5.5, and 5.0 by blending ECS (MES) and ECS (HEPES). The pH of the test compound was verified post-reconstitution in control solutions, and adjustments were made as necessary with NaOH or HCI. A 250 pL volume of resuspended cells was transferred to each “Inlet’ well of 8 experimental patterns on lonFlux plates, preloaded with these solutions: Trap wells 1 and 2 with 250 pL intracellular solution (ICS) (in mM: NaCI 15, KCI 60, KF 70, EGTA 5, HEPES 5, pH 7.25), Compound well 8 (C8) with ECS. Other solutions, including ECS with pH 6 or 6.5 for C1 , and test compounds with pH 6 or 6.5, were added to wells C2-C7 for specified period applications. In pre-incubation protocols, compounds were added at pH 7.5, followed by direct application of acidic pH. Whole-cell currents from populations of up to 20 cells, voltage-clamped at -70 mV, were recorded. pH alterations lasted 3 s, with 2- to 3-minute ECS (pH 7.5) washes between applications. All recordings were carried out at room temperature (22-25°C).

[0242] Electrophysiological recording from HEK 293 cells endogenously expressing ASICIa by Manual patch clamp

[0243] Recordings were performed using a HEKA EPC 10 USB amplifier with built-in LIH 8+8 data acquisition, controlled via PatchMaster NEXT software. The setup included an Olympus IX73 inverted microscope, a SENSAPEX uMp micromanipulator for precision pipette positioning, and a TMC CleanBench, anti-vibration table enclosed in a Faraday cage to minimize electrical noise. Patch pipettes were fabricated using a Sutter P-1000 pipette puller and polished with a Warner MFG-5 microforge. Cells were recorded in a Warner RC-26G recording chamber mounted on a Warner PM-1 platform and maintained at room temperature (22-25 °C). HEK 293 cells were cultured under standard conditions and maintained as adherent monolayers on glass-bottom dishes or 12-mm poly-D-lysine-coated coverslips, placed in Petri dishes. On the day of recording, culture media were gently aspirated, and cells were washed twice and then continuously perfused with extracellular solution (ECS) at room temperature (22-25 °C) during the experiment. Both ECS and ICS (Pipette solution) compositions were the same as for the automated patch clamp. Patch pipettes with a resistance of 2-4 MQ were filled with ICS and used to obtain whole-cell configuration under visual control via the Olympus IX73 microscope. Cells were continuously perfused with ECS (pH 7.5) using a Warner VCS-6 perfusion system to maintain baseline conditions. Acidic ECS (pH 6.5 or 6.0) or compound-containing solutions were rapidly applied using a Warner SH-27B in-line heater with perfusion lines connected to a VC3-8 valve controller, allowing for fast and reproducible exchange (<50 ms). Each acidic application was applied for 3 seconds, followed by a 2-10 minutes washout with ECS (pH 7.5). Where indicated, test compounds were pre-applied in ECS pH 7.5 for a designated time before acid application.Data analysis and quantification

[0244] For automated patch clamp, whole-cell currents were analysed using lonFlux Data Analyzer software. Further analysis was performed using GraphPad Prism for EC50 calculations, employing nonlinear regression curve-fitting to the Hill equation. To present representative time-course data, sweeps were filtered using the data analyzer and then exported to Clampfit software. Using Clampfit, baselines were adjusted and annotated using Microsoft PowerPoint. On the other hand, Clampfit software was used for the manual patch clamp. Peak currents were exported to Microsoft Excel for averaging and calculation purposes.

[0245] Example 1: Cimetidine inhibits hASICIa in HEK-293 cells

[0246] H EK-293 cells were voltage-clamped at -70 mV, and acid-evoked currents were recorded in response to extracellular pH of 6.5.

[0247] Co-application (3 s) with cimetidine 1 mM in pH 6.5 solution resulted in ~ 75% inhibition relative to control traces, (3 s) pH 6.5 application before cimetidine induced 5.5 nA currents, as did (3 s) pH 6.5 application after cimetidine (5.5 nA), indicating rapid and complete recovery from inhibition. The representative patch-clamp traces are presented in Figure 6.

[0248] Then, cimetidine was applied extracellularly at concentrations ranging from 5.0 pM to 2000 pM, 2-3 minutes prior to the pH drop. 4 to 10 replicate recordings were obtained at each concentration measured. Data fit to the Hill equation gave an IC50 of 655 zM (95% Cl: 551 -771 zM). Results are shown in Figure 1.

[0249] Cimetidine therefore shows an inhibitory effect to hASICIa in vitro.

[0250] Example 2: Famotidine inhibits hASICIa in HEK-293 cells

[0251] HEK-293 cells were voltage-clamped at -70 mV, and acid-evoked currents were recorded in response to extracellular pH of 6.5.

[0252] Co-application (3 s) of famotidine 250 pM in pH 6.5 solution resulted in ~ 50% inhibition relative to control traces, (3 s) application of pH 6.5 before famotidine application induces 11.5 nA currents and again after famotidine application induces 11 nA currents, indicating rapid and complete recovery from inhibition. The representative patch-clamp traces is presented in Figure 7.

[0253] Then, famotidine was applied extracellularly at concentrations ranging from 0.5 pM to 1000 pM, 2-3 minutes prior to the pH drop. Data fit to the Hill equation gave an IC50 of 214.8 pM (95% Cl: 174 - 260 pM). 4 to 10 replicate recordings were obtained at each concentration measured. Results are shown in Figure 2.Famotidine therefore shows an inhibitory effect against hASICIa in vitro about 3 times more potent than the inhibitory effect of cimetidine.

[0254] A second experiment was performed analogously with application of 200 pM famotidine. Approximately 50% inhibition of hASICIa was observed in HEK-293 cells. This was found to be reversible, as >95% recovery of acid-evoked currents was observed after two minutes of washing following inhibition. Approximately 50% inhibition of hASICIa was also observed in an analogous experiment at an extracellular pH of 6.0.

[0255] Example 3: Famotidine preserves cellular ATP levels under acidic stress in HEK-293 cells

[0256] ATP content of HEK-293 cells was quantified by a luminescence assay after 24 hours of treatment under the following conditions:

[0257] (a) physiological pH, i.e. pH 7.5;

[0258] (b) pH 5.5;

[0259] (c) pH 5.5 with application of 200 pM famotidine.

[0260] Acidic exposure alone (condition (b)) caused a marked reduction at the p < 0.01 level in ATP levels compared to physiological pH (condition (a)). In contrast, co-application of famotidine (condition (c)) was found to preserve near-physiological ATP levels (p < 0.05, oneway ANOVA with Tukey post-hoc analysis). Representative results are shown in Figure 8 based on mean ± SEM from three independent experiments, normalized to the pH 7.5 measurements.

[0261] These results indicate that ASICIa inhibition by famotidine should prevent acidosis-induced mitochondrial energy failure, maintaining intracellular ATP levels.

[0262] Example 3: Famotidine-related compound A inhibits hASICIa in HEK-293 cells

[0263] HEK-293 cells were voltage-clamped at -70 mV, and acid-evoked currents were recorded in response to extracellular pH of 6.5.

[0264] Co-application (3 s) of 150 pM famotidine-related compound A with pH 6.5 solution resulted in ~ 70% inhibition relative to control traces, (3 s) with pH 6.5 before famotidine-related compound A application (6 nA currents) and after famotidine-related compound A application (5.5 nA currents), rapid and almost complete recovery. The representative patchclamp traces is presented in Figure 9.

[0265] Then, famotidine-related compound A was applied extracellularly at concentrations ranging from 30.0 pM to 700 pM, 2-3 minutes prior to the pH drop. Data fit to the Hill equationgave an IC50 of 114.5 zM (95% Cl: 103 - 128 zM). 4 to 6 replicate recordings were obtained at each concentration measured. Results are shown in Figure 3.

[0266] Famotidine-related compound A therefore shows inhibitory effect to hASICIa in vitro about 2 times superior to famotidine.

[0267] Example 4: Famotidine-related compound B inhibits hASICIa in HEK-293 cells

[0268] HEK-293 cells were voltage-clamped at -70 mV, and acid-evoked currents were recorded in response to extracellular pH of 6.5.

[0269] Co-application (3 s) of 100 pM famotidine-related compound B with pH 6.5 solution resulted in ~ 50% inhibition relative to control traces, (3 s) with pH 6.5 before famotidine-related compound B application (9 nA currents) and after famotidine-related compound B application (9 nA currents), rapid and almost complete recovery. The representative patchclamp traces is presented in Figure 10.

[0270] Famotidine-related compound B was applied extracellularly at concentrations ranging from 50.0 pM to 500 pM, 2-3 minutes prior to the pH drop. Data fit to the Hill equation gave an IC50 of 92.4 zM (95% Cl: 84 - 101 zM). 4 replicate recordings were obtained at each concentration measured. Results are shown in Figure 4. An analogous experiment performed at an extracellular pH of 6.0 demonstrated similar inhibitory effects (data not shown).

[0271] Famotidine-related compound B therefore shows inhibitory effect to hASICIa in vitro about 2 times superior to famotidine.

[0272] Example 5: Famotidine-related compound E inhibits hASICIa in HEK-293 cells

[0273] HEK-293 cells were voltage-clamped at -70 mV, and acid-evoked currents were recorded in response to extracellular pH of 6.5.

[0274] Co-application (3 s) of 10 pM famotidine-related compound E with pH 6.5 solution resulted in ~ 50% inhibition relative to control traces, (3 s) with pH 6.5 before famotidine-related compound E application (8 nA currents) and after famotidine-related compound E application (6.5 nA currents), rapid and almost complete recovery. The representative patchclamp traces is presented in Figure 11.

[0275] Co-application (3 s) of 20 pM famotidine-related compound E with pH 6.5 solution resulted in ~ 65% inhibition relative to control traces, (3 s) with pH 6.5 before famotidine-related compound E application (8 nA currents) and after famotidine-related compound E application (6.5 nA currents), rapid and almost complete recovery. The representative patchclamp traces is presented in Figure 11.Famotidine-related compound E was applied extracellularly at concentrations ranging from 0.50 pM to 70 pM, 2-3 minutes prior to the pH drop. Data fit to the Hill equation gave an IC50 of 4.3 zM (95% Cl: 3.4- 5.3 zM). 4 to 10 replicate recordings were obtained at each concentration measured. Results are shown in Figure 5.

[0276] Famotidine-related compound E therefore shows inhibitory effect to hASICIa in vitro about 25 times superior to famotidine-related compounds A and B.

[0277] Example 6: Comparison of inhibitory activities of compounds

[0278] Table 2, below, summarises the IC50 values for ASICIa inhibition as measured in HEK-293 cells for the compounds tested in Examples 1-5 using the assay methods described herein.Table 2

[0279] Compound Structure ICso / pM Cimetidine 655.0

[0280] V

[0281] I >

[0282] Famotidine 214.8

[0283] Famotidine- 114.5 related

[0284] compound A

[0285] Famotidine- O p 92.4 related

[0286] compound B N-O ?! ' N '■ Is

[0287] Hp -pHO.p NH2

[0288] ~ Hghi

[0289] Famotidine- 4.3 related H

[0290] compound E

[0291]

[0292] Each of famotidine-related compounds A, B and E is a more potent ASIC inhibitor than famotidine. It is noted that famotidine-related compound A is related to famotidine through the removal of a sulfoxide moiety, while famotidine-related compound B is derived from famotidine by dimerization, with the sulfoxide moiety at the centre of the dimer. Famotidine-related compound E may be regarded as deriving from dimerization of a famotidine fragment lacking the terminal amidinyl-sulfonamide moiety, and is approximately 25 times more potent as an ASIC inhibitor than either famotidine-related compound A or B. Without wishing to be bound by theory, it is believed that these results indicate that the guanidinyl and / or thiazolyl moieties common to famotidine and famotidine-related compounds A, B and E may be responsible fortheir ASIC inhibitory activity whereas the sulfonamide and amidinyl groups (shown on the righthand side of the famotidine molecule in the above representation) are not essential for such activity.

[0293] Cimetidine was found to have approximately one-third of the potency of famotidine as an inhibitor of ASIC. Without wishing to be bound by theory, it is hypothesised that this may be explained by one or more of (i) the greater distance between the guanidinyl and imidazolyl moieties in cimetidine than between the guanidinyl and thiazolyl moieties in famotidine; (ii) the switch from a thiazolyl moiety in famotidine and the famotidine-related compounds to an imidazolyl moiety in cimetidine; and / or (iii) the fact that the guanidinyl moiety in cimetidine is substituted with methyl and cyano groups whereas the guanidinyl moiety in famotidine lacks such substituents. One or more of these differences, hypothetically, lead to differences in the ASIC binding affinity of cimetidine and famotidine.

[0294] Example 7: Comparative effect of Aspartic acid and Ascorbic acid on ASICIa

[0295] H EK-293 cells were voltage-clamped at -70 mV, and acid-evoked currents were recorded in response to extracellular pH of 6.5.

[0296] Co-application (3 s) of famotidine 100 pM in pH 6.5 solution resulted in ~ 50% inhibition relative to control traces. However, co-application (3 s) of famotidine 100 pM with 5 mM of aspartic acid in pH 6.5 solution resulted in slight potentiation relative to the control trace (Figure 12A).

[0297] On the other hand co-application (3 s) of famotidine 100 pM with 5 mM of ascorbic acid in pH 6.5 solution resulted in ~ 50% inhibition relative to control traces which is equivalent to the inhibition of famotidine alone.

[0298] Aspartic acid therefore is for the first time identified as ASIC potentiating and is therefore not desirable in compositions comprising ASIC inhibitors such as famotidine. Ascorbic acid is shown, however, to have no significant effect on the potentiation of ASIC when in combination with ASIC inhibitor such as famotidine.

[0299] Example 8: Stability assessment of a famotidine formulation with ascorbic acid

[0300] 500 mg was prepared of a dry powder mixture of famotidine and ascorbic acid in a 1 : 1 weight ratio. This was used to prepare a solution containing 100 mg / mLfamotidine and 100 mg / mL ascorbic acid, employing water for injection as the solvent. This weight ratio corresponded to a molar ratio of approximately 1:1.9 of famotidine free base to ascorbic acid.

[0301] Separate solutions were prepared of (i) 100 pg / mL ascorbic acid in water; and (ii) 100 pg / mL famotidine in water. These were employed as analytical standards.HPLC assays were carried out in order to determine the stability of the 1 :1 solution of famotidine:ascorbic acid during storage at room temperature for 7, 12, 24, 48, and 72 hours. HPLC measurement was performed according to the following parameters shown in Table 3:

[0302] Table 3

[0303] Instrument Waters 2690 Alliance HPLC system with Waters 996 photodiode array detector

[0304] Mobile phase 0.1M sodium acetate (pH 3) : methanol, 98:2 v / v Column Kromasil CN (4.6 x 250 mm, 5 pm)

[0305] Column temperature 35 °C

[0306] Autosampler temperature 5 °C

[0307] Flow rate 1 mL / minute

[0308] Wavelength 268 nm

[0309] Injection volume 20 pL

[0310] Run time 15 minutes

[0311]

[0312] Stability measurements were obtained across three separate samples, with mean assay % measurements as follows in Table 4:

[0313] Table 4

[0314] Time interval (hours) Famotidine assay % Ascorbic acid assay %

[0315] 0 86.12 99.44

[0316] 7 86.01 98.23

[0317] 12 85.29 97.21

[0318] 24 85.24 93.37

[0319] 48 85.76 93.29

[0320] 72 84.36 91.11

[0321]

[0322] The absolute assay value observed for famotidine at T = 0 (86.12%) reflects purity of the famotidine starting material, rather than degradation of the active ingredient. The stability of the formulation is therefore assessed based on the minimal variation in assay values overtime, which indicates that no significant degradation occurs during storage under the tested conditions.

[0323] No degradation products were observed and no precipitation was observed upon dilution. The viscosity of the samples remained acceptable for use in an injectable formulation e.g. for injection via a 27G needle.

[0324] pH was also monitored during storage with the following results shown in Table 5:

[0325] Table 5

[0326] Time interval (hours) pH

[0327] 0 4.30

[0328] 7 4.27

[0329] 12 4.26

[0330] 24 4.21

[0331] 48 4.15

[0332] 72 4.00

[0333]

[0334] The colour of the solution was clear at 0 hours and changed gradually to a pale yellow at 72 hours. The clear colour was maintained for at least the first 24 hours with colour change to yellow being observed between 48 and 72 hours.

[0335] Overall these results demonstrated that high aqueous concentrations of famotidine could be attained by coformulation with ascorbic acid. The solutions retained a good level of stability for up to at least 72 hours at room temperature, with no significant degradation of the active ingredient, famotidine, being observed under these conditions. The changes in famotidine %, pH and colour were especially limited during the first 24-48 hours. These properties support the suitability of the formulations of the present disclosure for extemporaneous preparation in order to deliver high doses of famotidine for acute treatment of patients.

[0336] Example 9: Further famotidine formulations with ascorbic acid Formulations of famotidine and ascorbic acid are prepared by dissolving dry powders of famotidine and ascorbic acid in water for injection as a solvent in amounts suitable to attain the following ratios shown in Table 6.Table 6

[0337] Famotidine:ascorbic acid Famotidine:ascorbic acid mg of ascorbic acid per molar ratio weight ratio 100 mg famotidine

[0338] 1:1.7 1:0.89 89 mg

[0339] 1:1.9 1:1.00 100 mg

[0340] 1:2.0 1:1.05 105 mg

[0341] 1:2.2 1:1.16 116 mg

[0342]

[0343] The formulation with a molar ratio of 1:1.9 famotidine:ascorbic acid corresponds to the ratio employed in the formulation of Example 8.

[0344] Formulations with ratios exemplified in Table 6 exhibit good aqueous solubility of famotidine even at high concentrations e.g. when dissolved in water for injection at a concentration of about 100 mg / mL famotidine. Such formulations are suitable for exerting an inhibitory effect on ASIC, e.g. ASICIa.

Claims

CLAIMS1. A pharmaceutical composition comprising:(a) famotidine or a pharmaceutically acceptable salt thereof;(b) ascorbic acid; and(c) an aqueous solvent,wherein:(i) the composition comprises famotidine or a pharmaceutically acceptable salt thereof in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1:1 to 1:2.5 of the free base of famotidine relative to ascorbic acid; and (ii) the composition comprises famotidine or a pharmaceutically acceptable salt thereof in a concentration which corresponds to at least 70 mg / mL of the free base.

2. The pharmaceutical composition according to claim 1, wherein the composition comprises famotidine or a pharmaceutically acceptable salt thereof in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1 : 1.5 to 1 :2.0 of the free base of famotidine relative to ascorbic acid, optionally a molar ratio of 1:1.7 to 1:2.0, 1:1.8 to 1:2.0, or 1:1.9.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein the composition comprises famotidine or a pharmaceutically acceptable salt thereof in a concentration which corresponds to at least 80 mg / mL, at least 85 mg / mL, at least 90 mg / mL, at least 95 mg / mL or at least 100 mg / mL of the free base.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the pH of the composition is between about 4.0 and about 7.0, optionally wherein the pH is about 4.5.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is substantially free of:(a) polyethylene glycol;(b) nicotinic acids;(c) water-soluble amides;(d) cyclodextrins;(e) riboflavin or salts or esters thereof; and / or(f) surfactants.

6. A famotidine-related compound or a pharmaceutically acceptable salt thereof for use as a medicament.

7. A famotidine-related compound or a pharmaceutically acceptable salt thereof for use according to claim 6, wherein the famotidine-related compound is selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, H, I, or J, e.g. famotidine-related compounds A, B, C, D, E, F, G or H, such as famotidine-related compounds A, B, and E; and pharmaceutically acceptable salts thereof.

8. The pharmaceutical composition according to any of claims 1 to 5 for use as a medicament.

9. Famotidine, a famotidine-related compound, or cimetidine, or a pharmaceutically acceptable salt thereof, for use in the treatment of an ASIC-related disease in a subject.

10. Famotidine, a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to claim 9, wherein the ASIC-related disease is selected from neurological disorders, neurodegenerative diseases, psychological disorders, sexual disorders, cardiovascular diseases, respiratory diseases, inflammatory diseases, renal diseases, gastrointestinal diseases, metabolic disorders, cancer, and addiction, e.g. smoking addiction.

11. Famotidine, a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to claim 9 or claim 10, wherein the ASIC- related disease is an ASIC1-related disease, e.g. an ASICIa-related disease.

12. Famotidine, a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to claim 10 or claim 11, wherein:(a) the neurological disorder is selected from the group consisting of ischemic stroke, cerebral ischemia, traumatic brain injury, spinal cord injury, neuropathic pain, and epilepsy;(b) the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis;(c) the psychological disorder is selected from the group consisting of anxiety, depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), and addiction;(d) the cardiovascular disease is selected from the group consisting of myocardial infarction, heart failure, arrhythmia, and hypertension;(e) the respiratory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS);(f) the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis;(g) the renal disease is selected from the group consisting of acute kidney injury, chronic kidney disease, and renal fibrosis;(h) the gastrointestinal disease is selected from the group consisting of gastroesophageal reflux disease (GERD), peptic ulcer disease, and irritable bowel syndrome (IBS);(i) the metabolic disorder is selected from the group consisting of diabetes, obesity, and metabolic syndrome;(j) the cancer is selected from the group consisting of glioblastoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer; and / or(k) the addiction is smoking addiction.

13. Famotidine or a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 9 to 12, wherein the ASIC-related disease is an acute disease, optionally ischemic stroke, cerebral ischemia, myocardial ischemia, or myocardial infarction.

14. Famotidine or a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to claim 13 wherein treatment comprises administering famotidine or a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, to the subject within about 12 hours of the onset of at least one symptom of the acute disease, optionally within about 4 hours to about 6 hours of the onset of at least one symptom of the acute disease.

15. Famotidine or a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 9 to 14, wherein famotidine or a famotidine-related compound, cimetidine, or a pharmaceuticallyacceptable salt thereof, is administered to the subject via oral, subcutaneous, or intravenous administration, optionally via intravenous administration.

16. Famotidine or a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 9 to 15 wherein treatment comprises administering famotidine or a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, to the subject in an amount corresponding to a dosage of greater than 80 mg, such as a dosage from about 200 mg to about 500 mg, of the free base of famotidine or the famotidine-related compound or cimetidine.

17. Famotidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 9 to 16, wherein famotidine or a pharmaceutically acceptable salt thereof is administered to the subject in a composition according to any one of claims 1 to 5.

18. A method of treatment comprising administering famotidine, a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

19. The method of treatment according to claim 18, wherein the method of treatment is a method of treating an ASIC-related disease in a subject, such as an ASIC1-related disease, e.g. an ASICIa-related disease.

20. The method of treatment according to claim 18 or19, wherein the method of treatment comprises administering famotidine, a famotidine-related compound, or a pharmaceutically acceptable salt thereof, to the subject in a composition according to any one of claims 1 to 5.

21. Use of a pharmaceutical composition according to any one of claims 1 to 5 or a famotidine-related compound or pharmaceutically acceptable salt thereof in the manufacture of a medicament, optionally wherein the famotidine-related compound is selected from the group consisting of famotidine-related compounds A, B, C, D, E, F, G, H, I, and J, e.g. famotidine-related compounds A, B, and E.

22. The use according to claim 21, wherein the medicament is for the treatment of an ASIC-related disease in a subject, such as an ASIC1-related disease, e.g. an ASICIa- related disease.

23. Use of famotidine, a famotidine-related compound, cimetidine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ASIC-related disease in a subject, such as an ASIC1-related disease, e.g. an ASICIa- related disease.

24. A kit of parts comprising:(a) a first vial containing famotidine or a pharmaceutically acceptable salt thereof; (b) a second vial containing ascorbic acid;wherein the famotidine or pharmaceutically acceptable salt thereof is provided in a molar ratio relative to ascorbic acid which corresponds to a molar ratio of 1 : 1 to 1 :2.5 of the free base of famotidine relative to ascorbic acid;(c) a third vial containing an aqueous solvent;(d) optionally an injection syringe; and(e) optionally instructions for administration.

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