Liquid pharmaceutical formulations of loop diuretics and methods of administration thereof

Abstract

Disclosed herein, in part, are liquid pharmaceutical formulations and unit liquid pharmaceutical formulations comprising a loop diuretic and a pharmaceutically acceptable excipient. In certain embodiments, the formulations comprise a buffer and / or an antioxidant. Methods of treating hyperemia, edema, liquid overload, or hypertension in a patient in need thereof are also provided.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 376,157, filed on September 19, 2022, the content of which is incorporated herein by reference in its entirety. Background of the Invention

[0003] Loop diuretics can be used to treat hypertension, edema, and related conditions, including congestive heart failure. For example, furosemide is commonly used to treat and / or control edema associated with congestive heart failure, liver failure, and kidney disease. H. Bundgaard, T. Norgaard, N. M. Nielsen, “Photodegradation and hydrolysis of furosemide and furosemide esters in aqueous solutions,” International Journal of Pharmaceutics 42, 217 (1988).

[0004] The oral bioavailability and thus the oral efficacy of loop diuretics such as furosemide are generally limited. Furosemide is typically administered parenterally and orally, but due to the combined effects of limited solubility and reduced stability at acidic pH, highly variable oral absorption has been observed. B. Devarakonda, D. P. Otto, A. Judefeind, R. A. Hill, M. M. de Villiers, “Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes,” International Journal of Pharmaceutics 345, 142 (December 10, 2007). Thus, for most patients with congestive heart failure or other forms of more severe edema, furosemide is typically administered intravenously or intramuscularly.

[0005] Administering drugs intravenously (such as loop diuretics) requires trained healthcare professionals to place catheters and administer the drug solution. In contrast, patients or caregivers can administer drugs subcutaneously or by infusion at home with the aid of an auto - injector device and / or a wearable on - body delivery infusion device. Subcutaneous administration of loop diuretics by patients or caregivers can also achieve more optimized therapeutic administration and total dosing to provide more appropriate pharmacokinetic and pharmacodynamic profiles and patient outcomes.

[0006] For subcutaneous administration, discomfort and pain during administration should be minimized to avoid poor patient compliance with the treatment regimen. Factors that can cause pain and discomfort to the patient during, during, or after subcutaneous administration include injection volume, the pH of the formulation, and the osmolarity or tonicity of the formulation. In addition, such a formulation should be stable in solution so that it is ready for use and / or can be pre-loaded into various drug delivery devices.

[0007] Accordingly, there is a need to improve pharmaceutical formulations containing loop diuretics (such as bumetanide, furosemide, or torasemide) that are chemically and physically stable over the shelf life, contain a sufficient concentration of the loop diuretic (such as a therapeutically effective amount in a suitable volume), and have an appropriate pH and weight osmolarity, such as to permit subcutaneous administration of the loop diuretic. Summary of the Invention

[0008] In one aspect, the present invention provides a liquid pharmaceutical formulation of a loop diuretic (such as bumetanide, furosemide, or torasemide), such as a loop diuretic and a pharmaceutically acceptable excipient.

[0009] In various embodiments of the present invention, the liquid pharmaceutical formulation comprises:

[0010] (i) A therapeutically effective amount of a loop diuretic such as furosemide or a pharmaceutically acceptable salt thereof;

[0011] (ii) An antioxidant; and

[0012] (iii) A pharmaceutically acceptable buffer.

[0013] In another aspect, the present invention provides a unit liquid pharmaceutical formulation of a loop diuretic such as furosemide or a pharmaceutically acceptable salt thereof.

[0014] In various embodiments of the present invention, the unit liquid pharmaceutical formulation comprises:

[0015] (i) From about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0016] (ii) From about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or derivatives thereof, vitamin E or derivatives thereof, and any combination thereof;

[0017] (iii) From about 0.05% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, EDTA, and combinations thereof; and

[0018] (iv) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and any combination thereof,

[0019] wherein the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0020] Another aspect of the invention provides a method of treating a patient in need of treatment for congestion, edema, fluid overload, or hypertension, the method comprising administering to the patient the liquid pharmaceutical formulation or unit liquid pharmaceutical formulation described herein.

[0021] Another aspect of the invention provides a kit for treating congestion, edema, fluid overload, or hypertension, the kit comprising the liquid pharmaceutical formulation or unit liquid pharmaceutical formulation described herein and a delivery device (e.g., a pump device, an autoinjector, etc.), and written instructions for use. Detailed Description

[0022] The present invention provides liquid pharmaceutical formulations and unit liquid pharmaceutical formulations containing a loop diuretic (e.g., bumetanide, furosemide, or torasemide), kits containing the same, and methods of using the liquid pharmaceutical formulations and unit liquid pharmaceutical formulations to treat a medical condition (e.g., congestion, edema, fluid overload, or hypertension) in a patient in need thereof. Specifically, the present invention can provide a pharmaceutical formulation of a loop diuretic for administration to a patient, the formulation comprising pharmaceutically acceptable excipients such as antioxidants, pH adjusters, solubilizers, tonicity modifiers, and / or pharmaceutically acceptable buffers.

[0023] Definition

[0024] To facilitate understanding of the present invention, the following defines a number of terms and phrases.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Abbreviations used herein have their conventional meanings in the chemical and biological arts. Chemical structures and chemical formulas shown herein are constructed according to standard rules of chemical valence known in the chemical art.

[0026] As used herein, the term "a / an" means "one or more" and includes the plural, unless the context is inappropriate.

[0027] In the present application, when an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0028] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of the present invention, whether explicitly or implicitly described herein. For example, when a particular compound is mentioned, the compound can be used in various embodiments of the compositions of the present invention and / or the methods of the present invention, unless otherwise understood from the context. In other words, in the present application, the embodiments have been described and depicted in a manner that enables the application to be written and drawn clearly and concisely, but it is intended and will be recognized that the embodiments can be combined or separated in various ways without departing from this teaching and invention. For example, it should be understood that all of the features described and depicted herein are applicable to all aspects of the inventions described and depicted herein.

[0029] It should be understood that, unless otherwise understood from the context and usage, the expression "at least one" includes each of the recited objects individually as well as various combinations of two or more of the recited objects. The expression "and / or" related to three or more of the said objects should be understood to have the same meaning, unless otherwise understood from the context.

[0030] The use of the terms "include (include / includes / including)", "have (have / has / having)", "contain (contain / contains / containing)" (including their grammatical equivalents) should generally be understood as open-ended and non-restrictive, e.g., not excluding additional elements or steps not recited, unless otherwise expressly stated or understood from the context.

[0031] When the term "about" is used before a numerical value, the present invention also includes the specific numerical value itself, unless otherwise expressly stated. The term "about" as used herein refers to a variation of ±10%, ±5%, ±3%, ±2% or ±1% from the nominal value, unless otherwise stated or inferred from the context.

[0032] Throughout different places in this specification, numerical values are disclosed in groups or ranges. This description is specifically intended to include each and every individual sub - combination of such group members and range members. For example, integers within the range of 0 to 40 are specifically intended to be individually disclosed as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers within the range of 1 to 20 are specifically intended to be individually disclosed as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0033] Any and all examples or exemplary language used herein, such as "such as" or "including", are merely for better illustrating the invention and do not limit the scope of the invention unless claimed. The language in this specification should not be construed as indicating any non - claimed element as necessary for practicing the invention.

[0034] As used herein, "compound" (including specifically named compounds such as furosemide, bumetanide, ethacrynic acid, torasemide) refers to the compound itself and its pharmaceutically acceptable salts, unless otherwise understood from the context of the specification or explicitly limited to a particular form of the compound, such as the compound itself or its pharmaceutically acceptable salts.

[0035] As used herein, "furosemide" refers to a compound having the following formula:

[0036]

[0037] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, furosemide sodium salt and furosemide quaternary ammonium salt. Furosemide may have other names, such as frusemide, 5 - (aminosulfonyl) - 4 - chloro - 2 - [(2 - furylmethyl)amino]benzoic acid, or its IUPAC name 4 - chloro - 2 - (furan - 2 - ylmethylamino) - 5 - aminosulfonylbenzoic acid, or its common trade name

[0038] As used herein, "bumetanide" refers to a compound having the following formula:

[0039]

[0040] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, potassium furosemide and sodium furosemide. Bumetanide may have other names, such as bumedyl, bumethanide, or its IUPAC name 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid, or its common trade name and

[0041] As used herein, "ethacrynic acid" refers to a compound having the following formula:

[0042]

[0043] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, sodium ethacrynic acid (also known as sodium etacrynate). Ethacrynic acid may have other names, such as etacrynic acid, or its IUPAC name 2-[2,3-dichloro-4-(2-methylenebutanoyl)phenoxy]acetic acid, or its common trade name Sodium and

[0044] As used herein, "torsemide" refers to a compound having the following formula:

[0045]

[0046] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, sodium torsemide. Torsemide may have other names, such as torasemide, 1-isopropyl-3-((4-(3-methylphenylamino)pyridine)-3-sulfonyl)urea, 1-isopropyl-3-((4-m-tolyl-3-pyridyl)sulfonyl)urea, or its IUPAC name 1-[4-(3-methylanilino)pyridin-3-yl]sulfonyl-3-propan-2-ylurea, or its common trade name

[0047] As used herein, the terms "subject" and "patient" refer to a living organism to be treated by the methods and / or compositions described herein. Such living organisms are preferably mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), more preferably humans (e.g., adult humans).

[0048] As used herein, "buffer solution" refers to an aqueous solution that resists changes in pH. A buffer solution may include a "buffer", such as a weak acid and its salt, or a weak base and its salt, which helps to maintain the stability of pH. Examples of buffer solutions used in pharmaceutical preparations include bicarbonate buffer solution, carbonate buffer solution, citrate buffer solution, histidine buffer solution, phosphate buffer solution, tartrate buffer solution, tris(hydroxymethyl)aminomethane (or 2-amino-2-hydroxymethyl-propane-1,3-diol [(HOCH2)3CNH2]) buffer solution, and combinations thereof. Some of these buffer solutions are suitable for pharmaceutical preparations for subcutaneous administration.

[0049] Tris(hydroxymethyl)aminomethane or tris(hydroxymethyl)aminomethane buffer solution may be referred to as "TRIS", "Tris", "Tris buffer solution", "trimethylolaminomethane", "THAM", "tromethamine" and other names. In addition, many buffer solutions and / or buffer systems may include Tris, or a pharmaceutically acceptable salt thereof, and may be used in the present teachings. For example, Tris-buffered saline ("TBS"), Tris hydrochloride buffer solution ("Tris-HCl"), Tris base (pH 10.6), Tris / borate / ethylenediaminetetraacetate ("EDTA") buffer solution ("TBE") and Tris / acetate / EDTA buffer solution ("TAE"). Tris base is usually used together with Tris-HCl to prepare Tris buffer solution with the desired pH. In addition, the present teachings may include Tris-related compounds that can act as buffer solutions, such as compounds derived from Tris or structurally related to Tris.

[0050] As used herein, "tonicity" refers to the ionic strength or ionic concentration in a solution (such as a pharmaceutical preparation). Tonicity is usually measured in molar concentration ("M"). As used herein, "isotonic solution", "isotonic preparation", "isotonic pharmaceutical preparation" and "isotonic" pharmaceutical preparation refer to a solution or preparation having the same or similar concentration of ions as those found in body fluids.

[0051] As used herein, "physiological pH" refers to a pH of about 7.4.

[0052] As used herein, "osmolality" and "molality" refer to the osmotic pressure of a solution (such as a pharmaceutical preparation). Osmolality is typically measured in terms of osmolarity ("Osm / L" or "OsM") or molality ("Osm / kg"), which are used interchangeably herein. When measuring the freezing point depression, the observed value is the molality of the solution. In contrast to tonicity, osmolality takes into account non-ionized solutes in the solution, and thus when non-ionized solutes are present, the osmolarity or molality of the solution will be higher than its tonicity. The osmolarity of the liquid pharmaceutical preparation described herein can be measured, for example, using the vapor pressure method.

[0053] As used herein, "osmolarity regulator" and "osmotic agent" refer to pharmaceutically acceptable compounds that can be added to the liquid pharmaceutical preparation described herein to adjust the osmolarity of the liquid pharmaceutical preparation.

[0054] As used herein, "pharmaceutically acceptable" refers to substances that are useful for pharmaceutical applications from a toxicological perspective and do not interact adversely with the active ingredient. Thus, pharmaceutically acceptable carriers are those substances that are compatible with the other components in the preparation and are biologically acceptable. In certain embodiments, supplementary active ingredients can also be incorporated into the pharmaceutical composition.

[0055] As used herein, "pharmaceutically acceptable excipient" refers to a substance that aids in the administration and / or absorption of an active agent by a subject and can be included in the compositions and formulations of the present invention without producing significant adverse toxicological effects on the patient. In certain embodiments, the pharmaceutically acceptable excipients described herein can also be used to enhance the stability of the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein. In certain embodiments, the pharmaceutically acceptable excipients described herein can also be used to enhance the solubility of loop diuretics in the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein. Non-limiting examples of pharmaceutically acceptable excipients include liquid vehicles such as water, NaCl, physiological saline solutions, buffers and buffering agents such as phosphate buffered saline solutions, components or compounds of emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and coloring agents, etc. The formulations can be sterilized and, if desired, admixed with auxiliary excipients such as lubricants, preservatives, solubilizers, stabilizers, wetting agents, emulsifying agents, salts affecting osmotic pressure, buffers, coloring substances, and / or aromatic substances that do not react detrimentally with the compounds of the present invention. For examples of excipients and carriers, see Martin, Remington’s Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, PA (1975).

[0056] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier such as buffers (such as phosphate buffered saline solution or tromethamine buffered aqueous solution), water (e.g., water for injection (WFI)), emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The compositions can also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, PA

[1975] .

[0057] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the invention (e.g., a loop diuretic as described herein) that, upon administration to a subject, is capable of providing the compound of the invention or its active metabolite or residue. As is known to those skilled in the art, "salts" of the compounds of the invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, although not pharmaceutically acceptable per se, can be used to prepare salts that can be used as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0058] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of the formula NW4 + wherein W is C 1-4 alkyl, and the like.

[0059] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and the like. Other examples of salts include salts formed by combining an anion of a compound of the invention with a suitable cation such as Na + , NH4 + , NW4 + (wherein W is C 1-4 alkyl), and the like.

[0060] It should be understood herein that unless otherwise indicated, all weights described herein correspond to the weights of the compounds in free acid / free base form (e.g., furosemide, torasemide, bumetanide).

[0061] As used herein, the term "effective amount" refers to the amount of a composition (e.g., a liquid pharmaceutical formulation or a compound as disclosed herein) sufficient to achieve a beneficial or desired result. The effective amount can be administered in one or more administrations, applications, or doses, and is not intended to be limited to a particular formulation or route of administration.

[0062] As used herein, the terms "treat / treating / treatment" include any effect that results in an improvement in a disorder, disease, condition, etc., or an improvement in its symptoms, such as alleviating, reducing, modulating, improving, or eliminating.

[0063] As used herein, the phrase "therapeutically effective amount" refers to the amount of a composition (e.g., a liquid pharmaceutical formulation or a compound disclosed herein) that is capable of effectively producing some desired therapeutic effect in a subject.

[0064] As used herein, the term "congestion" (heart failure) refers to the presence of signs and symptoms of extracellular fluid accumulation, which leads to an increase in cardiac filling pressure, thereby resulting in a decrease in cardiac output. The decrease in cardiac output is further exacerbated by neurohormonal activation, leading to an increased affinity of the kidneys for sodium and water, thereby resulting in an increase in plasma volume.

[0065] As used herein, "fluid overload", "volume overload", and "hypervolemia" may describe a medical condition of having too much fluid in the blood. Excessive fluid (mainly salt and water) may accumulate throughout the body, leading to weight gain.

[0066] Throughout the specification, when a composition and a kit are described as having, including, or containing a specific component, or when a process and a method are described as having, including, or containing a specific step, it is additionally foreseeable that there are compositions and kits of the present invention consisting essentially of or consisting of the recited components, and there are processes and methods according to the present invention consisting essentially of or consisting of the recited processing steps.

[0067] Generally, unless otherwise specified, percentages of compositions are by weight. Additionally, if a variable is not accompanied by a definition, the previous definition of the variable shall apply.

[0068] Liquid pharmaceutical preparation of loop diuretics

[0069] As described herein, in one aspect, the present invention provides a liquid pharmaceutical formulation of a loop diuretic (e.g., a loop diuretic) and a pharmaceutically acceptable excipient.

[0070] In various embodiments, the liquid pharmaceutical formulation generally comprises:

[0071] (i) a therapeutically effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof; and

[0072] (ii) a pharmaceutically acceptable buffer.

[0073] Loop diuretic

[0074] In certain embodiments, the concentration of the loop diuretic or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulations described herein can be from about 0.025 mg / mL to about 250 mg / mL, from about 0.1 mg / mL to about 250 mg / mL, from about 1 mg / mL to about 250 mg / mL, from about 5 mg / mL to about 250 mg / mL, from about 10 mg / mL to about 250 mg / mL, from about 20 mg / mL to about 250 mg / mL, from about 30 mg / mL to about 250 mg / mL, from about 40 mg / mL to about 250 mg / mL, from about 50 mg / mL to about 250 mg / mL, from about 60 mg / mL to about 250 mg / mL, from about 70 mg / mL to about 250 mg / mL, from about 80 mg / mL to about 250 mg / mL, from about 90 mg / mL to about 250 mg / mL, from about 100 mg / mL to about 250 mg / mL, from about 120 mg / mL to about 250 mg / mL, from about 140 mg / mL to about 250 mg / mL, from about 160 mg / mL to about 250 mg / mL, from about 180 mg / mL to about 250 mg / mL, from about 200 mg / mL to about 250 mg / mL, from about 225 mg / mL to about 250 mg / mL, from about 0.025 mg / mL to about 225 mg / mL, from about 0.025 mg / mL to about 200 mg / mL, from about 0.025 mg / mL to about 180 mg / mL, from about 0.025 mg / mL to about 160 mg / mL, from about 0.025 mg / mL to about 140 mg / mL, from about 0.025 mg / mL to about 120 mg / mL, from about 0.025 mg / mL to about 100 mg / mL, from about 0.025 mg / mL to about 90 mg / mL, from about 0.025 mg / mL to about 80 mg / mL, from about 0.025 mg / mL to about 70 mg / mL, from about 0.025 mg / mL to about 60 mg / mL, from about 0.025 mg / mL to about 50 mg / mL, from about 0.025 mg / mL to about 40 mg / mL, from about 0.025 mg / mL to about 30 mg / mL, from about 0.025 mg / mL to about 20 mg / mL, from about 0.025 mg / mL to about 10 mg / mL, from about 0.025 mg / mL to about 5 mg / mL, from about 0.025 mg / mL to about 1 mg / mL, from about 0.025 mg / mL to about 0.1 mg / mL, from about 0.1 mg / mL to about 225 mg / mL, from about 0.1 mg / mL to about 200 mg / mL, from about 0.1 mg / mL to about 180 mg / mL, from about 0.1 mg / mL to about 160 mg / mL, from about 0.1 mg / mL to about 140 mg / mL, from about 0.1 mg / mL to about 120 mg / mL, from about 0.1 mg / mL to about 100 mg / mL, from about 0.1 mg / mL to about 90 mg / mL,From about 0.1 mg / mL to about 80 mg / mL, from about 0.1 mg / mL to about 70 mg / mL, from about 0.1 mg / mL to about 60 mg / mL, from about 0.1 mg / mL to about 50 mg / mL, from about 0.1 mg / mL to about 40 mg / mL, from about 0.1 mg / mL to about 30 mg / mL, from about 0.1 mg / mL to about 20 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, from about 1 mg / mL to about 225 mg / mL, from about 1 mg / mL to about 200 mg / mL, from about 1 mg / mL to about 180 mg / mL, from about 1 mg / mL to about 160 mg / mL, from about 1 mg / mL to about 140 mg / mL, from about 1 mg / mL to about 120 mg / mL, from about 1 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 90 mg / mL, from about 1 mg / mL to about 80 mg / mL, from about 1 mg / mL to about 70 mg / mL, from about 1 mg / mL to about 60 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 1 mg / mL to about 40 mg / mL, from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 20 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 225 mg / mL, from about 5 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 180 mg / mL, from about 5 mg / mL to about 160 mg / mL, from about 5 mg / mL to about 140 mg / mL, from about 5 mg / mL to about 120 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 90 mg / mL, from about 5 mg / mL to about 80 mg / mL, from about 5 mg / mL to about 70 mg / mL, from about 5 mg / mL to about 60 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 225 mg / mL, from about 10 mg / mL to about 200 mg / mL, from about 10 mg / mL to about 180 mg / mL, from about 10 mg / mL to about 160 mg / mL, from about 10 mg / mL to about 140 mg / mL, from about 10 mg / mL to about 120 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 90 mg / mL, from about 10 mg / mL to about 80 mg / mL, from about 10 mg / mL to about 70 mg / mL, from about 10 mg / mL to about 60 mg / mL, from about 10 mg / mL to about 50 mg / mL,From about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 20 mg / mL, from about 20 mg / mL to about 225 mg / mL, from about 20 mg / mL to about 200 mg / mL, from about 20 mg / mL to about 180 mg / mL, from about 20 mg / mL to about 160 mg / mL, from about 20 mg / mL to about 140 mg / mL, from about 20 mg / mL to about 120 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 20 mg / mL to about 70 mg / mL, from about 20 mg / mL to about 60 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 20 mg / mL to about 30 mg / mL, from about 30 mg / mL to about 225 mg / mL, from about 30 mg / mL to about 200 mg / mL, from about 30 mg / mL to about 180 mg / mL, from about 30 mg / mL to about 160 mg / mL, from about 30 mg / mL to about 140 mg / mL, from about 30 mg / mL to about 120 mg / mL, from about 30 mg / mL to about 100 mg / mL, from about 30 mg / mL to about 90 mg / mL, from about 30 mg / mL to about 80 mg / mL, from about 30 mg / mL to about 70 mg / mL, from about 30 mg / mL to about 60 mg / mL, from about 30 mg / mL to about 50 mg / mL, from about 30 mg / mL to about 40 mg / mL, from about 40 mg / mL to about 225 mg / mL, from about 40 mg / mL to about 200 mg / mL, from about 40 mg / mL to about 180 mg / mL, from about 40 mg / mL to about 160 mg / mL, from about 40 mg / mL to about 140 mg / mL, from about 40 mg / mL to about 120 mg / mL, from about 40 mg / mL to about 100 mg / mL, from about 40 mg / mL to about 90 mg / mL, from about 40 mg / mL to about 80 mg / mL, from about 40 mg / mL to about 70 mg / mL, from about 40 mg / mL to about 60 mg / mL, from about 40 mg / mL to about 50 mg / mL, from about 50 mg / mL to about 225 mg / mL, from about 50 mg / mL to about 200 mg / mL, from about 50 mg / mL to about 180 mg / mL, from about 50 mg / mL to about 160 mg / mL, from about 50 mg / mL to about 140 mg / mL, from about 50 mg / mL to about 120 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 90 mg / mL, from about 50 mg / mL to about 80 mg / mL, from about 50 mg / mL to about 70 mg / mL, from about 50 mg / mL to about 60 mg / mL, from about 60 mg / mL to about 225 mg / mL,from about 60 mg / mL to about 200 mg / mL, from about 60 mg / mL to about 180 mg / mL, from about 60 mg / mL to about 160 mg / mL, from about 60 mg / mL to about 140 mg / mL, from about 60 mg / mL to about 120 mg / mL, from about 60 mg / mL to about 100 mg / mL, from about 60 mg / mL to about 90 mg / mL, from about 60 mg / mL to about 80 mg / mL, from about 60 mg / mL to about 70 mg / mL, from about 70 mg / mL to about 225 mg / mL, from about 70 mg / mL to about 200 mg / mL, from about 70 mg / mL to about 180 mg / mL, from about 70 mg / mL to about 160 mg / mL, from about 70 mg / mL to about 140 mg / mL, from about 70 mg / mL to about 120 mg / mL, from about 70 mg / mL to about 100 mg / mL, from about 70 mg / mL to about 90 mg / mL, from about 70 mg / mL to about 80 mg / mL, from about 70 mg / mL to about 225 mg / mL, from about 80 mg / mL to about 200 mg / mL, from about 80 mg / mL to about 180 mg / mL, from about 80 mg / mL to about 160 mg / mL, from about 80 mg / mL to about 140 mg / mL, from about 80 mg / mL to about 120 mg / mL, from about 80 mg / mL to about 100 mg / mL, from about 80 mg / mL to about 90 mg / mL, from about 70 mg / mL to about 225 mg / mL, from about 90 mg / mL to about 200 mg / mL, from about 90 mg / mL to about 180 mg / mL, from about 90 mg / mL to about 160 mg / mL, from about 90 mg / mL to about 140 mg / mL, from about 90 mg / mL to about 120 mg / mL, from about 90 mg / mL to about 100 mg / mL, from about 100 mg / mL to about 225 mg / mL, from about 100 mg / mL to about 200 mg / mL, from about 100 mg / mL to about 180 mg / mL, from about 100 mg / mL to about 160 mg / mL, from about 100 mg / mL to about 140 mg / mL, from about 100 mg / mL to about 120 mg / mL, from about 120 mg / mL to about 225 mg / mL, from about 120 mg / mL to about 200 mg / mL, from about 120 mg / mL to about 180 mg / mL, from about 120 mg / mL to about 160 mg / mL, from about 120 mg / mL to about 140 mg / mL, from about 140 mg / mL to about 225 mg / mL, from about 140 mg / mL to about 200 mg / mL, from about 140 mg / mL to about 180 mg / mL, from about 140 mg / mL to about 160 mg / mL, from about 160 mg / mL to about 225 mg / mL, from about 160 mg / mL to about 200 mg / mL, from about 160 mg / mL to about 180 mg / mL, from about 180 mg / mL to about 225 mg / mLFrom about 180 mg / mL to about 200 mg / mL or from about 200 mg / mL to about 225 mg / mL. In certain embodiments, the concentration of the loop diuretic or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be from about 0.025 mg / mL to about 250 mg / mL.

[0075] In certain embodiments, the concentration of the loop diuretic or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be greater than about 0.025 mg / mL, greater than about 0.1 mg / mL, greater than about 1 mg / mL, greater than about 5 mg / mL, greater than about 10 mg / mL, greater than about 20 mg / mL, greater than about 30 mg / mL, greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, greater than about 100 mg / mL, greater than about 110 mg / mL, greater than about 120 mg / mL, greater than about 130 mg / mL, greater than about 140 mg / mL, greater than about 150 mg / mL, greater than about 160 mg / mL, greater than about 170 mg / mL, greater than about 180 mg / mL, greater than about 190 mg / mL, greater than about 200 mg / mL, greater than about 210 mg / mL, greater than about 220 mg / mL, greater than about 230 mg / mL, greater than about 240 mg / mL or greater than about 250 mg / mL.

[0076] In certain embodiments, the concentration of the loop diuretic or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be about 0.025 mg / mL, about 0.05 mg / mL, about 0.075 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 32 mg / mL, about 34 mg / mL, about 36 mg / mL, about 38 mg / mL, about 40 mg / mL, about 42 mg / mL, about 44 mg / mL, about 46 mg / mL, about 48 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL or about 250 mg / mL.

[0077] In certain embodiments, the loop diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, torasemide or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is furosemide or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is bumetanide or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is ethacrynic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is torasemide or a pharmaceutically acceptable salt thereof.

[0078] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be from about 1 mg / mL to about 250 mg / mL, from about 5 mg / mL to about 250 mg / mL, from about 10 mg / mL to about 250 mg / mL, from about 20 mg / mL to about 250 mg / mL, from about 30 mg / mL to about 250 mg / mL, from about 40 mg / mL to about 250 mg / mL, from about 50 mg / mL to about 250 mg / mL, from about 60 mg / mL to about 250 mg / mL, from about 70 mg / mL to about 250 mg / mL, from about 80 mg / mL to about 250 mg / mL, from about 90 mg / mL to about 250 mg / mL, from about 100 mg / mL to about 250 mg / mL, from about 120 mg / mL to about 250 mg / mL, from about 140 mg / mL to about 250 mg / mL, from about 160 mg / mL to about 250 mg / mL, from about 180 mg / mL to about 250 mg / mL, from about 200 mg / mL to about 250 mg / mL, from about 225 mg / mL to about 250 mg / mL, from about 1 mg / mL to about 225 mg / mL, from about 1 mg / mL to about 200 mg / mL, from about 1 mg / mL to about 180 mg / mL, from about 1 mg / mL to about 160 mg / mL, from about 1 mg / mL to about 140 mg / mL, from about 1 mg / mL to about 120 mg / mL, from about 1 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 90 mg / mL, from about 1 mg / mL to about 80 mg / mL, from about 1 mg / mL to about 70 mg / mL, from about 1 mg / mL to about 60 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 1 mg / mL to about 40 mg / mL, from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 20 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 225 mg / mL, from about 5 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 180 mg / mL, from about 5 mg / mL to about 160 mg / mL, from about 5 mg / mL to about 140 mg / mL, from about 5 mg / mL to about 120 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 90 mg / mL, from about 5 mg / mL to about 80 mg / mL, from about 5 mg / mL to about 70 mg / mL, from about 5 mg / mL to about 60 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 225 mg / mL, from about 10 mg / mL to about 200 mg / mL,From about 10 mg / mL to about 180 mg / mL, from about 10 mg / mL to about 160 mg / mL, from about 10 mg / mL to about 140 mg / mL, from about 10 mg / mL to about 120 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 90 mg / mL, from about 10 mg / mL to about 80 mg / mL, from about 10 mg / mL to about 70 mg / mL, from about 10 mg / mL to about 60 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 20 mg / mL, from about 20 mg / mL to about 225 mg / mL, from about 20 mg / mL to about 200 mg / mL, from about 20 mg / mL to about 180 mg / mL, from about 20 mg / mL to about 160 mg / mL, from about 20 mg / mL to about 140 mg / mL, from about 20 mg / mL to about 120 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 20 mg / mL to about 70 mg / mL, from about 20 mg / mL to about 60 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 20 mg / mL to about 30 mg / mL, from about 30 mg / mL to about 225 mg / mL, from about 30 mg / mL to about 200 mg / mL, from about 30 mg / mL to about 180 mg / mL, from about 30 mg / mL to about 160 mg / mL, from about 30 mg / mL to about 140 mg / mL, from about 30 mg / mL to about 120 mg / mL, from about 30 mg / mL to about 100 mg / mL, from about 30 mg / mL to about 90 mg / mL, from about 30 mg / mL to about 80 mg / mL, from about 30 mg / mL to about 70 mg / mL, from about 30 mg / mL to about 60 mg / mL, from about 30 mg / mL to about 50 mg / mL, from about 30 mg / mL to about 40 mg / mL, from about 40 mg / mL to about 225 mg / mL, from about 40 mg / mL to about 200 mg / mL, from about 40 mg / mL to about 180 mg / mL, from about 40 mg / mL to about 160 mg / mL, from about 40 mg / mL to about 140 mg / mL, from about 40 mg / mL to about 120 mg / mL, from about 40 mg / mL to about 100 mg / mL, from about 40 mg / mL to about 90 mg / mL, from about 40 mg / mL to about 80 mg / mL, from about 40 mg / mL to about 70 mg / mL, from about 40 mg / mL to about 60 mg / mL, from about 40 mg / mL to about 50 mg / mL, from about 50 mg / mL to about 225 mg / mL, from about 50 mg / mL to about 200 mg / mLFrom about 50 mg / mL to about 180 mg / mL, from about 50 mg / mL to about 160 mg / mL, from about 50 mg / mL to about 140 mg / mL, from about 50 mg / mL to about 120 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 90 mg / mL, from about 50 mg / mL to about 80 mg / mL, from about 50 mg / mL to about 70 mg / mL, from about 50 mg / mL to about 60 mg / mL, from about 60 mg / mL to about 225 mg / mL, from about 60 mg / mL to about 200 mg / mL, from about 60 mg / mL to about 180 mg / mL, from about 60 mg / mL to about 160 mg / mL, from about 60 mg / mL to about 140 mg / mL, from about 60 mg / mL to about 120 mg / mL, from about 60 mg / mL to about 100 mg / mL, from about 60 mg / mL to about 90 mg / mL, from about 60 mg / mL to about 80 mg / mL, from about 60 mg / mL to about 70 mg / mL, from about 70 mg / mL to about 225 mg / mL, from about 70 mg / mL to about 200 mg / mL, from about 70 mg / mL to about 180 mg / mL, from about 70 mg / mL to about 160 mg / mL, from about 70 mg / mL to about 140 mg / mL, from about 70 mg / mL to about 120 mg / mL, from about 70 mg / mL to about 100 mg / mL, from about 70 mg / mL to about 90 mg / mL, from about 70 mg / mL to about 80 mg / mL, from about 70 mg / mL to about 225 mg / mL, from about 80 mg / mL to about 200 mg / mL, from about 80 mg / mL to about 180 mg / mL, from about 80 mg / mL to about 160 mg / mL, from about 80 mg / mL to about 140 mg / mL, from about 80 mg / mL to about 120 mg / mL, from about 80 mg / mL to about 100 mg / mL, from about 80 mg / mL to about 90 mg / mL, from about 70 mg / mL to about 225 mg / mL, from about 90 mg / mL to about 200 mg / mL, from about 90 mg / mL to about 180 mg / mL, from about 90 mg / mL to about 160 mg / mL, from about 90 mg / mL to about 140 mg / mL, from about 90 mg / mL to about 120 mg / mL, from about 90 mg / mL to about 100 mg / mL, from about 100 mg / mL to about 225 mg / mL, from about 100 mg / mL to about 200 mg / mL, from about 100 mg / mL to about 180 mg / mL, from about 100 mg / mL to about 160 mg / mL, from about 100 mg / mL to about 140 mg / mL, from about 100 mg / mL to about 120 mg / mL, from about 120 mg / mL to about 225 mg / mL, from about 120 mg / mL to about 200 mg / mL, from about 120 mg / mL to about 180 mg / mLFrom about 120 mg / mL to about 160 mg / mL, from about 120 mg / mL to about 140 mg / mL, from about 140 mg / mL to about 225 mg / mL, from about 140 mg / mL to about 200 mg / mL, from about 140 mg / mL to about 180 mg / mL, from about 140 mg / mL to about 160 mg / mL, from about 160 mg / mL to about 225 mg / mL, from about 160 mg / mL to about 200 mg / mL, from about 160 mg / mL to about 180 mg / mL, from about 180 mg / mL to about 225 mg / mL, from about 180 mg / mL to about 200 mg / mL, or from about 200 mg / mL to about 225 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be from about 1 mg / mL to about 250 mg / mL.

[0079] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be greater than about 1 mg / mL, greater than about 5 mg / mL, greater than about 10 mg / mL, greater than about 20 mg / mL, greater than about 30 mg / mL, greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, greater than about 100 mg / mL, greater than about 110 mg / mL, greater than about 120 mg / mL, greater than about 130 mg / mL, greater than about 140 mg / mL, greater than about 150 mg / mL, greater than about 160 mg / mL, greater than about 170 mg / mL, greater than about 180 mg / mL, greater than about 190 mg / mL, greater than about 200 mg / mL, greater than about 210 mg / mL, greater than about 220 mg / mL, greater than about 230 mg / mL, greater than about 240 mg / mL, or greater than about 250 mg / mL.

[0080] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 32 mg / mL, about 34 mg / mL, about 36 mg / mL, about 38 mg / mL, about 40 mg / mL, about 42 mg / mL, about 44 mg / mL, about 46 mg / mL, about 48 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL or about 250 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be about 80 mg / mL.

[0081] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein can be from about 0.025 mg / mL to about 65 mg / mL, from about 0.1 mg / mL to about 65 mg / mL, from about 0.5 mg / mL to about 65 mg / mL, from about 1 mg / mL to about 65 mg / mL, from about 5 mg / mL to about 65 mg / mL, from about 10 mg / mL to about 65 mg / mL, from about 20 mg / mL to about 65 mg / mL, from about 30 mg / mL to about 65 mg / mL, from about 40 mg / mL to about 65 mg / mL, from about 50 mg / mL to about 65 mg / mL, from about 60 mg / mL to about 65 mg / mL, from about 0.025 mg / mL to about 60 mg / mL, from about 0.025 mg / mL to about 50 mg / mL, from about 0.025 mg / mL to about 40 mg / mL, from about 0.025 mg / mL to about 30 mg / mL, from about 0.025 mg / mL to about 20 mg / mL, from about 0.025 mg / mL to about 10 mg / mL, from about 0.025 mg / mL to about 5 mg / mL, from about 0.025 mg / mL to about 1 mg / mL, from about 0.025 mg / mL to about 0.5 mg / mL, from about 0.025 mg / mL to about 0.1 mg / mL, from about 0.1 mg / mL to about 60 mg / mL, from about 0.1 mg / mL to about 50 mg / mL, from about 0.1 mg / mL to about 40 mg / mL, from about 0.1 mg / mL to about 30 mg / mL, from about 0.1 mg / mL to about 20 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, from about 0.5 mg / mL to about 60 mg / mL, from about 0.5 mg / mL to about 50 mg / mL, from about 0.5 mg / mL to about 40 mg / mL, from about 0.5 mg / mL to about 30 mg / mL, from about 0.5 mg / mL to about 20 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 5 mg / mL, from about 0.from 5 mg / mL to about 1 mg / mL, from about 1 mg / mL to about 60 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 1 mg / mL to about 40 mg / mL, from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 20 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 60 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 60 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 20 mg / mL, from about 20 mg / mL to about 60 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 20 mg / mL to about 30 mg / mL, from about 30 mg / mL to about 60 mg / mL, from about 30 mg / mL to about 50 mg / mL, from about 30 mg / mL to about 40 mg / mL, from about 40 mg / mL to about 60 mg / mL, from about 40 mg / mL to about 50 mg / mL, or from about 50 mg / mL to about 60 mg / mL. In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulation described herein can be from about 0.025 mg / mL to about 65 mg / mL.

[0082] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulation described herein can be greater than about 0.025 mg / mL, greater than about 1 mg / mL, greater than about 5 mg / mL, greater than about 10 mg / mL, greater than about 20 mg / mL, greater than about 30 mg / mL, greater than about 40 mg / mL, greater than about 50 mg / mL, or greater than about 60 mg / mL.

[0083] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein can be about 0.025 mg / mL, about 0.05 mg / mL, about 0.075 mg / mL, about 0.1 mg / mL, about 0.25 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 32 mg / mL, about 34 mg / mL, about 36 mg / mL, about 38 mg / mL, about 40 mg / mL, about 42 mg / mL, about 44 mg / mL, about 46 mg / mL, about 48 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL or about 65 mg / mL.

[0084] In certain embodiments, the concentration of torasemide in the liquid pharmaceutical formulations described herein can be from about 0.5 mg / mL to about 125 mg / mL, from about 1 mg / mL to about 125 mg / mL, from about 5 mg / mL to about 125 mg / mL, from about 10 mg / mL to about 125 mg / mL, from about 20 mg / mL to about 125 mg / mL, from about 30 mg / mL to about 125 mg / mL, from about 40 mg / mL to about 125 mg / mL, from about 50 mg / mL to about 125 mg / mL, from about 75 mg / mL to about 125 mg / mL, from about 100 mg / mL to about 125 mg / mL, from about 0.5 mg / mL to about 100 mg / mL, from about 0.5 mg / mL to about 75 mg / mL, from about 0.5 mg / mL to about 50 mg / mL, from about 0.5 mg / mL to about 40 mg / mL, from about 0.5 mg / mL to about 30 mg / mL, from about 0.5 mg / mL to about 20 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 5 mg / mL, from about 0.from 5 mg / mL to about 1 mg / mL, from about 1 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 75 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 1 mg / mL to about 40 mg / mL, from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 20 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 75 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 75 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 20 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 75 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 20 mg / mL to about 30 mg / mL, from about 30 mg / mL to about 100 mg / mL, from about 30 mg / mL to about 75 mg / mL, from about 30 mg / mL to about 50 mg / mL, from about 30 mg / mL to about 40 mg / mL, from about 40 mg / mL to about 100 mg / mL, from about 40 mg / mL to about 75 mg / mL, from about 40 mg / mL to about 50 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 75 mg / mL or from about 75 mg / mL to about 100 mg / mL.

[0085] In certain embodiments, the concentration of torasemide in the liquid pharmaceutical formulations described herein can be greater than about 0.5 mg / mL, greater than about 1 mg / mL, greater than about 5 mg / mL, greater than about 10 mg / mL, greater than about 20 mg / mL, greater than about 30 mg / mL, greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, greater than about 100 mg / mL or greater than about 125 mg / mL.

[0086] In certain embodiments, the concentration of torasemide in the liquid pharmaceutical formulations described herein can be about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL or about 125 mg / mL.

[0087] pH, buffers and pH regulators

[0088] In certain embodiments, the pH of the liquid pharmaceutical formulations described herein can be from about 5.5 to about 8.5, from about 6 to about 8.5, from about 6.5 to about 8.5, from about 7 to about 8.5, from about 7.5 to about 8.5, from about 8 to about 8.5, from about 5.5 to about 8, from about 5.5 to about 7.5, from about 5.5 to about 7, from about 5.5 to about 6.5, from about 5.5 to about 6, from about 6 to about 8, from about 6 to about 7.5, from about 6 to about 7, from about 6 to about 6.5, from about 6.5 to about 8, from about 6.5 to about 7.5, from about 6.5 to about 7, from about 7 to about 8, from about 7 to about 7.5 or from about 7.5 to about 8. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is from about 6.5 to about 8.5.

[0089] In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be from about 7 to about 8.5, from about 7.1 to about 8.5, from about 7.3 to about 8.5, from about 7.5 to about 8.5, from about 7.7 to about 8.5, from about 7.9 to about 8.5, from about 8.1 to about 8.5, from about 8.3 to about 8.5, from about 7 to about 8.3, from about 7 to about 8.1, from about 7 to about 7.9, from about 7 to about 7.7, from about 7 to about 7.5, from about 7 to about 7.3, from about 7 to about 7.1, from about 7.1 to about 8.3, from about 7.1 to about 8.1, from about 7.1 to about 7.9, from about 7.1 to about 7.7, from about 7.1 to about 7.5, from about 7.1 to about 7.3, from about 7.3 to about 8.3, from about 7.3 to about 8.1, from about 7.3 to about 7.9, from about 7.3 to about 7.7, from about 7.3 to about 7.5, from about 7.5 to about 8.3, from about 7.5 to about 8.1, from about 7.5 to about 7.9, from about 7.5 to about 7.7, from about 7.7 to about 8.3, from about 7.7 to about 8.1, from about 7.7 to about 7.9, from about 7.9 to about 8.3, from about 7.9 to about 8.1 or from about 8.1 to about 8.3.

[0090] In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4 or about 8.5. In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be about 7.4. In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be about 7.7.

[0091] In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be 5.5 ± 0.3, 5.6 ± 0.3, 5.7 ± 0.3, 5.8 ± 0.3, 5.9 ± 0.3, 6 ± 0.3, 6.1 ± 0.3, 6.2 ± 0.3, 6.3 ± 0.3, 6.4 ± 0.3, 6.5 ± 0.3, 6.6 ± 0.3, 6.7 ± 0.3, 6.8 ± 0.3, 6.9 ± 0.3, 7 ± 0.3, 7.1 ± 0.3, 7.2 ± 0.3, 7.3 ± 0.3, 7.4 ± 0.3, 7.5 ± 0.3, 7.6 ± 0.3, 7.7 ± 0.3, 7.8 ± 0.3, 7.9 ± 0.3, 8 ± 0.3, 8.1 ± 0.3, 8.2 ± 0.3, 8.3 ± 0.3, 8.4 ± 0.3 or 8.5 ± 0.3. In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be 7.4 ± 0.3. In certain embodiments, the pH of the liquid pharmaceutical formulation described herein can be 7.7 ± 0.3.

[0092] (i) pharmaceutically acceptable buffer

[0093] In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein can be from about 10 mM to about 500 mM, from about 20 mM to about 500 mM, from about 30 mM to about 500 mM, from about 40 mM to about 500 mM, from about 50 mM to about 500 mM, from about 60 mM to about 500 mM, from about 70 mM to about 500 mM, from about 80 mM to about 500 mM, from about 90 mM to about 500 mM, from about 100 mM to about 500 mM, from about 125 mM to about 500 mM, from about 150 mM to about 500 mM, from about 200 mM to about 500 mM, from about 250 mM to about 500 mM, from about 300 mM to about 500 mM, from about 350 mM to about 500 mM, from about 400 mM to about 500 mM, from about 450 mM to about 500 mM, from about 10 mM to about 450 mM, from about 10 mM to about 400 mM, from about 10 mM to about 350 mM, from about 10 mM to about 300 mM, from about 10 mM to about 250 mM, from about 10 mM to about 200 mM, from about 10 mM to about 150 mM, from about 10 mM to about 125 mM, from about 10 mM to about 100 mM, from about 10 mM to about 90 mM, from about 10 mM to about 80 mM, from about 10 mM to about 70 mM, from about 10 mM to about 60 mM, from about 10 mM to about 50 mM, from about 10 mM to about 40 mM, from about 10 mM to about 30 mM, from about 10 mM to about 20 mM, from about 20 mM to about 450 mM, from about 20 mM to about 400 mM, from about 20 mM to about 350 mM, from about 20 mM to about 300 mM, from about 20 mM to about 250 mM, from about 20 mM to about 200 mM, from about 20 mM to about 150 mM, from about 20 mM to about 100 mM, from about 20 mM to about 90 mM, from about 20 mM to about 80 mM, from about 20 mM to about 70 mM, from about 20 mM to about 60 mM, from about 20 mM to about 50 mM, from about 20 mM to about 40 mM, from about 20 mM to about 30 mM, from about 30 mM to about 450 mM, from about 30 mM to about 400 mM, from about 30 mM to about 350 mM, from about 30 mM to about 300 mM, from about 30 mM to about 250 mM, from about 30 mM to about 200 mM, from about 30 mM to about 150 mM, from about 30 mM to about 125 mM, from about 30 mM to about 100 mM, from about 30 mM to about 90 mM, from about 30 mM to about 80 mM, from about 30 mM to about 70 mM, from about 30 mM to about 60 mM, from about 30 mM to about 50 mM, from about 30 mM to about 40 mM, from about 40 mM to about 450 mM, from about 40 mM to about 400 mM, from about 40 mM to about 350 mM, from about 40 mM to about 300 mM, from about 40 mM to about 250 mM, from about 40 mM to about 200 mM, from about 40 mM to about 150 mM, from about 40 mM to about 125 mM, from about 40 mM to about 100 mM, from about 40 mM to about 90 mM,from about 40 mM to about 80 mM, from about 40 mM to about 70 mM, from about 40 mM to about 60 mM, from about 40 mM to about 50 mM, from about 50 mM to about 450 mM, from about 50 mM to about 400 mM, from about 50 mM to about 350 mM, from about 50 mM to about 300 mM, from about 50 mM to about 250 mM, from about 50 mM to about 200 mM, from about 50 mM to about 150 mM, from about 50 mM to about 125 mM, from about 50 mM to about 100 mM, from about 50 mM to about 90 mM, from about 50 mM to about 80 mM, from about 50 mM to about 70 mM, from about 50 mM to about 60 mM, from about 60 mM to about 450 mM, from about 60 mM to about 400 mM, from about 60 mM to about 350 mM, from about 60 mM to about 300 mM, from about 60 mM to about 250 mM, from about 60 mM to about 200 mM, from about 60 mM to about 150 mM, from about 60 mM to about 125 mM, from about 60 mM to about 100 mM, from about 60 mM to about 90 mM, from about 60 mM to about 80 mM, from about 60 mM to about 70 mM, from about 70 mM to about 450 mM, from about 70 mM to about 400 mM, from about 70 mM to about 350 mM, from about 70 mM to about 300 mM, from about 70 mM to about 250 mM, from about 70 mM to about 200 mM, from about 70 mM to about 150 mM, from about 70 mM to about 100 mM, from about 70 mM to about 90 mM, from about 70 mM to about 80 mM, from about 80 mM to about 450 mM, from about 80 mM to about 400 mM, from about 80 mM to about 350 mM, from about 80 mM to about 300 mM, from about 80 mM to about 250 mM, from about 80 mM to about 200 mM, from about 80 mM to about 150 mM, from about 80 mM to about 100 mM, from about 80 mM to about 90 mM, from about 90 mM to about 450 mM, from about 90 mM to about 400 mM, from about 90 mM to about 350 mM, from about 90 mM to about 300 mM, from about 90 mM to about 250 mM, from about 90 mM to about 200 mM, from about 90 mM to about 150 mM, from about 90 mM to about 100 mM, from about 100 mM to about 450 mM, from about 100 mM to about 400 mM, from about 100 mM to about 350 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 100 mM to about 200 mM, from about 100 mM to about 150 mM, from about 150 mM to about 450 mM, from about 150 mM to about 400 mM, from about 150 mM to about 350 mM, from about 150 mM to about 300 mM, from about 150 mM to about 250 mM, from about 150 mM to about 200 mM, from about 200 mM to about 450 mM, from about 200 mM to about 400 mM, from about 200 mM to about 350 mM, from about 200 mM to about 300 mM, from about 200 mM to about 250 mM, from about 250 mM to about 450 mM, from about 250 mM to about 400 mMFrom about 250 mM to about 350 mM, from about 250 mM to about 300 mM, from about 300 mM to about 450 mM, from about 300 mM to about 400 mM, from about 300 mM to about 350 mM, from about 350 mM to about 450 mM, from about 350 mM to about 400 mM, or from about 400 mM to about 450 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein can be from about 50 mM to about 125 mM.

[0094] In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein can be about 10 mM, about 15 mM, about 20 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 105 mM, about 110 mM, about 115 mM, about 120 mM, about 125 mM, about 130 mM, about 135 mM, about 140 mM, about 145 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 225 mM, about 250 mM, about 275 mM, about 300 mM, about 325 mM, about 350 mM, about 375 mM, about 400 mM, about 425 mM, about 450 mM, about 475 mM, or about 500 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein can be about 50 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein can be about 125 mM.

[0095] In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein can be less than or equal to about 10 mM, less than or equal to about 20 mM, less than or equal to about 30 mM, less than or equal to about 40 mM, less than or equal to about 50 mM, less than or equal to about 60 mM, less than or equal to about 70 mM, less than or equal to about 80 mM, less than or equal to about 90 mM, less than or equal to about 100 mM, less than or equal to about 125 mM, less than or equal to about 150 mM, less than or equal to about 175 mM, less than or equal to about 200 mM, less than or equal to about 225 mM, less than or equal to about 250 mM, less than or equal to about 275 mM, less than or equal to about 300 mM, less than or equal to about 325 mM, less than or equal to about 350 mM, less than or equal to about 375 mM, less than or equal to about 400 mM, less than or equal to about 425 mM, less than or equal to about 450 mM, less than or equal to about 475 mM, or less than or equal to about 500 mM.

[0096] In certain embodiments, the pharmaceutically acceptable buffer comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. In certain embodiments, the buffering agent is histidine. In certain embodiments, the buffering agent is citrate. In certain embodiments, the buffering agent is sodium phosphate. In certain embodiments, the buffering agent is potassium phosphate. In certain embodiments, the buffering agent is tromethamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of tromethamine is tromethamine hydrochloride.

[0097] In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulations described herein can be from about 10 mM to about 250 mM, from about 15 mM to about 250 mM, from about 20 mM to about 250 mM, from about 25 mM to about 250 mM, from about 30 mM to about 250 mM, from about 40 mM to about 250 mM, from about 50 mM to about 250 mM, from about 60 mM to about 250 mM, from about 70 mM to about 250 mM, from about 80 mM to about 250 mM, from about 90 mM to about 250 mM, from about 100 mM to about 250 mM, from about 125 mM to about 250 mM, from about 150 mM to about 250 mM, from about 175 mM to about 250 mM, from about 200 mM to about 250 mM, from about 225 mM to about 250 mM, from about 10 mM to about 225 mM, from about 10 mM to about 200 mM, from about 10 mM to about 175 mM, from about 10 mM to about 150 mM, from about 10 mM to about 125 mM, from about 10 mM to about 100 mM, from about 10 mM to about 90 mM, from about 10 mM to about 80 mM, from about 10 mM to about 70 mM, from about 10 mM to about 60 mM, from about 10 mM to about 50 mM, from about 10 mM to about 40 mM, from about 10 mM to about 30 mM, from about 10 mM to about 25 mM, from about 10 mM to about 20 mM, from about 10 mM to about 15 mM, from about 15 mM to about 225 mM, from about 15 mM to about 200 mM, from about 15 mM to about 175 mM, from about 15 mM to about 150 mM, from about 15 mM to about 125 mM, from about 15 mM to about 100 mM, from about 15 mM to about 90 mM, from about 15 mM to about 80 mM, from about 15 mM to about 70 mM, from about 15 mM to about 60 mM, from about 15 mM to about 50 mM, from about 15 mM to about 40 mM, from about 15 mM to about 30 mM, from about 15 mM to about 25 mM, from about 15 mM to about 20 mM, from about 20 mM to about 225 mM, from about 20 mM to about 200 mM, from about 20 mM to about 175 mM, from about 20 mM to about 150 mM, from about 20 mM to about 125 mM, from about 20 mM to about 100 mM, from about 20 mM to about 90 mM, from about 20 mM to about 80 mM, from about 20 mM to about 70 mM, from about 20 mM to about 60 mM, from about 20 mM to about 50 mM, from about 20 mM to about 40 mM, from about 20 mM to about 30 mM, from about 20 mM to about 25 mM, from about 25 mM to about 225 mM, from about 25 mM to about 200 mM, from about 25 mM to about 175 mM, from about 25 mM to about 150 mM, from about 25 mM to about 125 mM, from about 25 mM to about 100 mM, from about 25 mM to about 90 mM, from about 25 mM to about 80 mM, from about 25 mM to about 70 mM, from about 25 mM to about 60 mM, from about 25 mM to about 50 mM, from about 25 mM to about 40 mM, from about 25 mM to about 30 mM,from about 30 mM to about 225 mM, from about 30 mM to about 200 mM, from about 30 mM to about 175 mM, from about 30 mM to about 150 mM, from about 30 mM to about 125 mM, from about 30 mM to about 100 mM, from about 30 mM to about 90 mM, from about 30 mM to about 80 mM, from about 30 mM to about 70 mM, from about 30 mM to about 60 mM, from about 30 mM to about 50 mM, from about 30 mM to about 40 mM, from about 40 mM to about 225 mM, from about 40 mM to about 200 mM, from about 40 mM to about 175 mM, from about 40 mM to about 150 mM, from about 40 mM to about 125 mM, from about 40 mM to about 100 mM, from about 40 mM to about 90 mM, from about 40 mM to about 80 mM, from about 40 mM to about 70 mM, from about 40 mM to about 60 mM, from about 40 mM to about 50 mM, from about 50 mM to about 225 mM, from about 50 mM to about 200 mM, from about 50 mM to about 175 mM, from about 50 mM to about 150 mM, from about 50 mM to about 125 mM, from about 50 mM to about 100 mM, from about 50 mM to about 90 mM, from about 50 mM to about 80 mM, from about 50 mM to about 70 mM, from about 50 mM to about 60 mM, from about 60 mM to about 225 mM, from about 60 mM to about 200 mM, from about 60 mM to about 175 mM, from about 60 mM to about 150 mM, from about 60 mM to about 125 mM, from about 60 mM to about 100 mM, from about 60 mM to about 90 mM, from about 60 mM to about 80 mM, from about 60 mM to about 70 mM, from about 60 mM to about 60 mM, from about 70 mM to about 225 mM, from about 70 mM to about 200 mM, from about 70 mM to about 175 mM, from about 70 mM to about 150 mM, from about 70 mM to about 125 mM, from about 70 mM to about 100 mM, from about 70 mM to about 90 mM, from about 70 mM to about 80 mM, from about 80 mM to about 225 mM, from about 80 mM to about 200 mM, from about 80 mM to about 175 mM, from about 80 mM to about 150 mM, from about 80 mM to about 125 mM, from about 80 mM to about 100 mM, from about 80 mM to about 90 mM, from about 90 mM to about 225 mM, from about 90 mM to about 200 mM, from about 90 mM to about 175 mM, from about 90 mM to about 150 mM, from about 90 mM to about 125 mM, from about 90 mM to about 100 mM, from about 100 mM to about 225 mM, from about 100 mM to about 200 mM, from about 100 mM to about 175 mM, from about 100 mM to about 150 mM, from about 100 mM to about 125 mM, from about 125 mM to about 225 mM, from about 125 mM to about 200 mM, from about 125 mM to about 175 mM, from about 125 mM to about 150 mM, from about 150 mM to about 225 mM, from about 150 mM to about 200 mM, from about 150 mM to about 175 mM, from about 150 mM to about 250 mMFrom about 175 mM to about 225 mM, from about 175 mM to about 200 mM, or from about 200 mM to about 225 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein is from about 10 mM to about 200 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein is from about 25 mM to about 150 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein is from about 50 mM to about 125 mM.

[0098] In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 32 mM, about 34 mM, about 36 mM, about 38 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 105 mM, about 110 mM, about 115 mM, about 120 mM, about 125 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 225 mM or about 250 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be about 50 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be about 125 mM.

[0099] In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation described herein can be less than or equal to about 10 mM, less than or equal to about 20 mM, less than or equal to about 30 mM, less than or equal to about 40 mM, less than or equal to about 50 mM, less than or equal to about 60 mM, less than or equal to about 70 mM, less than or equal to about 80 mM, less than or equal to about 90 mM, less than or equal to about 100 mM, less than or equal to about 125 mM, less than or equal to about 150 mM, less than or equal to about 175 mM, less than or equal to about 200 mM, less than or equal to about 225 mM, or less than or equal to about 250 mM.

[0100] (ii) pH regulator

[0101] In certain embodiments, the liquid pharmaceutical formulations described herein further comprise a pharmaceutically acceptable pH adjuster.

[0102] Exemplary pharmaceutically acceptable pH adjusters include, but are not limited to, one or more of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, and triethanolamine.

[0103] In certain embodiments, the pharmaceutically acceptable pH adjuster is selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and combinations thereof. In certain embodiments, the pharmaceutically acceptable pH adjuster is hydrochloric acid and sodium hydroxide. In certain embodiments, the pharmaceutically acceptable pH adjuster is sodium hydroxide. In certain embodiments, the pharmaceutically acceptable pH adjuster is potassium hydroxide. In certain embodiments, the pharmaceutically acceptable pH adjuster is hydrochloric acid.

[0104] Antioxidant

[0105] In certain embodiments, the liquid pharmaceutical formulations described herein may further comprise an antioxidant.

[0106] In certain embodiments, the amount of antioxidant in the liquid pharmaceutical formulations described herein can be from about 0.01% (w / w) to about 2% (w / w), from about 0.05% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.2% (w / w) to about 2% (w / w), from about 0.3% (w / w) to about 2% (w / w), from about 0.4% (w / w) to about 2% (w / w), from about 0.5% (w / w) to about 2% (w / w), from about 0.6% (w / w) to about 2% (w / w), from about 0.7% (w / w) to about 2% (w / w), from about 0.8% (w / w) to about 2% (w / w), from about 0.9% (w / w) to about 2% (w / w), from about 1% (w / w) to about 2% (w / w), from about 1.1% (w / w) to about 2% (w / w), from about 1.2% (w / w) to about 2% (w / w), from about 1.3% (w / w) to about 2% (w / w), from about 1.4% (w / w) to about 2% (w / w), from about 1.5% (w / w) to about 2% (w / w), from about 1.6% (w / w) to about 2% (w / w), from about 1.7% (w / w) to about 2% (w / w), from about 1.8% (w / w) to about 2% (w / w), from about 1.9% (w / w) to about 2% (w / w), from about 0.01% (w / w) to about 1.9% (w / w), from about 0.01% (w / w) to about 1.8% (w / w), from about 0.01% (w / w) to about 1.7% (w / w), from about 0.01% (w / w) to about 1.6% (w / w), from about 0.01% (w / w) to about 1.5% (w / w), from about 0.01% (w / w) to about 1.4% (w / w), from about 0.01% (w / w) to about 1.3% (w / w), from about 0.01% (w / w) to about 1.2% (w / w), from about 0.01% (w / w) to about 1.1% (w / w), from about 0.01% (w / w) to about 1% (w / w), from about 0.01% (w / w) to about 0.9% (w / w), from about 0.01% (w / w) to about 0.8% (w / w), from about 0.01% (w / w) to about 0.7% (w / w), from about 0.01% (w / w) to about 0.6% (w / w), from about 0.01% (w / w) to about 0.5% (w / w), from about 0.01% (w / w) to about 0.4% (w / w), from about 0.01% (w / w) to about 0.3% (w / w), from about 0.01% (w / w) to about 0.2% (w / w), from about 0.01% (w / w) to about 0.1% (w / w), from about 0.01% (w / w) to about 0.05% (w / w), from about 0.05% (w / w) to about 1.9% (w / w), from about 0.05% (w / w) to about 1.8% (w / w), from about 0.05% (w / w) to about 1.7% (w / w), from about 0.05% (w / w) to about 1.6% (w / w), from about 0.05% (w / w) to about 1.5% (w / w), from about 0.05% (w / w) to about 1.4% (w / w), from about 0.05% (w / w) to about 1.3% (w / w), from about 0.05% (w / w) to about 1.2% (w / w), from about 0.05% (w / w) to about 1.1% (w / w), from about 0.05% (w / w) to about 1% (w / w), from about 0.05% (w / w) to about 0.9% (w / w), from about 0.05% (w / w) to about 0.8% (w / w), from about 0.05% (w / w) to about 0.7% (w / w), from about 0.05% (w / w) to about 0.6% (w / w), from about 0.05% (w / w) to about 0.5% (w / w), from about 0.05% (w / w) to about 0.4% (w / w), from about 0.05% (w / w) to about 0.3% (w / w), from about 0.05% (w / w) to about 0.2% (w / w), from about 0.05% (w / w) to about 0.1% (w / w), from about 0.1% (w / w) to about 1.9% (w / w), from about 0.1% (w / w) to about 1.8% (w / w), from about 0.1% (w / w) to about 1.7% (w / w), from about 0.1% (w / w) to about 1.6% (w / w), from about 0.1% (w / w) to about 1.5% (w / w), from about 0.1% (w / w) to about 1.4% (w / w), from about 0.1% (w / w) to about 1.3% (w / w), from about 0.1% (w / w) to about 1.2% (w / w), from about 0.1% (w / w) to about 1.1% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.9% (w / w), from about 0.1% (w / w) to about 0.8% (w / w), from about 0.1% (w / w) to about 0.7% (w / w), from about 0.1% (w / w) to about 0.6% (w / w), from about 0.1% (w / w) to about 0.5% (w / w), from about 0.1% (w / w) to about 0.4% (w / w), from about 0.1% (w / w) to about 0.3% (w / w), from about 0.1% (w / w) to about 0.2% (w / w), from about 0.2% (w / w) to about 1.9% (w / w), from about 0.2% (w / w) to about 1.8% (w / w), from about 0.2% (w / w) to about 1.7% (w / w), from about 0.2% (w / w) to about 1.6% (w / w), from about 0.2% (w / w) to about 1.5% (w / w), from about 0.2% (w / w) to about 1.4% (w / w), from about 0.2% (w / w) to about 1.3% (w / w), from about 0.2% (w / w) to about 1.2% (w / w), from about 0.2% (w / w) to about 1.1% (w / w), from about 0.2% (w / w) to about 1% (w / w), from about 0.2% (w / w) to about 0.9% (w / w), from about 0.2% (w / w) to about 0.8% (w / w), from about 0.2% (w / w) to about 0.7% (w / w), from about 0.2% (w / w) to about 0.6% (w / w), from about 0.2% (w / w) to about 0.5% (w / w), from about 0.2% (w / w) to about 0.4% (w / w), from about 0.2% (w / w) to about 0.3% (w / w), from about 0.3% (w / w) to about 1.9% (w / w), from about 0.3% (w / w) to about 1.8% (w / w), from about 0.3% (w / w) to about 1.7% (w / w), from about 0.3% (w / w) to about 1.6% (w / w), from about 0.3% (w / w) to about 1.5% (w / w), from about 0.3% (w / w) to about 1.4% (w / w), from about 0.3% (w / w) to about 1.3% (w / w), from about 0.3% (w / w) to about 1.2% (w / w), from about 0.3% (w / w) to about 1.1% (w / w), from about 0.3% (w / w) to about 1% (w / w), from about 0.3% (w / w) to about 0.9% (w / w), from about 0.3% (w / w) to about 0.8% (w / w), from about 0.3% (w / w) to about 0.7% (w / w), from about 0.3% (w / w) to about 0.6% (w / w), from about 0.3% (w / w) to about 0.5% (w / w), from about 0.3% (w / w) to about 0.4% (w / w), from about 0.4% (w / w) to about 1.9% (w / w), from about 0.4% (w / w) to about 1.8% (w / w), from about 0.4% (w / w) to about 1.7% (w / w), from about 0.4% (w / w) to about 1.6% (w / w), from about 0.4% (w / w) to about 1.5% (w / w), from about 0.4% (w / w) to about 1.4% (w / w), from about 0.4% (w / w) to about 1.3% (w / w), from about 0.4% (w / w) to about 1.2% (w / w), from about 0.4% (w / w) to about 1.1% (w / w), from about 0.4% (w / w) to about 1% (w / w), from about 0.4% (w / w) to about 0.9% (w / w), from about 0.4% (w / w) to about 0.8% (w / w), from about 0.4% (w / w) to about 0.7% (w / w), from about 0.4% (w / w) to about 0.6% (w / w), from about 0.4% (w / w) to about 0.5% (w / w), from about 0.5% (w / w) to about 1.9% (w / w), from about 0.5% (w / w) to about 1.8% (w / w), from about 0.5% (w / w) to about 1.7% (w / w), from about 0.5% (w / w) to about 1.6% (w / w), from about 0.5% (w / w) to about 1.5% (w / w), from about 0.5% (w / w) to about 1.4% (w / w), from about 0.5% (w / w) to about 1.3% (w / w), from about 0.5% (w / w) to about 1.2% (w / w), from about 0.5% (w / w) to about 1.1% (w / w), from about 0.5% (w / w) to about 1% (w / w), about 0.5% (w / w) to about 0.9% (w / w), about 0.5% (w / w) to about 0.8% (w / w), about 0.5% (w / w) to about 0.7% (w / w), about 0.5% (w / w) to about 0.6% (w / w), about 0.6% (w / w) to about 1.9% (w / w), about 0.6% (w / w) to about 1.8% (w / w), about 0.6% (w / w) to about 1.7% (w / w), about 0.6% (w / w) to about 1.6% (w / w), about 0.6% (w / w) to about 1.5% (w / w), about 0.6% (w / w) to about 1.4% (w / w), about 0.6% (w / w) to about 1.3% (w / w), about 0.6% (w / w) to about 1.2% (w / w), about 0.6% (w / w) to about 1.1% (w / w), about 0.6% (w / w) to about 1% (w / w), about 0.6% (w / w) to about 0.9% (w / w), about 0.6% (w / w) to about 0.8% (w / w), about 0.6% (w / w) to about 0.7% (w / w), about 0.7% (w / w) to about 1.9% (w / w), about 0.7% (w / w) to about 1.8% (w / w), about 0.7% (w / w) to about 1.7% (w / w), about 0.7% (w / w) to about 1.6% (w / w), about 0.7% (w / w) to about 1.5% (w / w), about 0.7% (w / w) to about 1.4% (w / w), about 0.7% (w / w) to about 1.3% (w / w), about 0.7% (w / w) to about 1.2% (w / w), about 0.7% (w / w) to about 1.1% (w / w), about 0.7% (w / w) to about 1% (w / w), about 0.7% (w / w) to about 0.9% (w / w), about 0.7% (w / w) to about 0.8% (w / w), about 0.8% (w / w) to about 1.9% (w / w), about 0.8% (w / w) to about 1.8% (w / w), about 0.8% (w / w) to about 1.7% (w / w), about 0.8% (w / w) to about 1.6% (w / w), about 0.8% (w / w) to about 1.5% (w / w), about 0.8% (w / w) to about 1.4% (w / w), about 0.8% (w / w) to about 1.3% (w / w), about 0.8% (w / w) to about 1.2% (w / w), about 0.8% (w / w) to about 1.1% (w / w), about 0.8% (w / w) to about 1% (w / w), about 0.8% (w / w) to about 0.9% (w / w), about 0.9% (w / w) to about 1.9% (w / w), about 0.9% (w / w) to about 1.8% (w / w), about 0.9% (w / w) to about 1.7% (w / w), about 0.9% (w / w) to about 1.6% (w / w), about 0.9% (w / w) to about 1.5% (w / w), from about 0.9% (w / w) to about 1.4% (w / w), from about 0.9% (w / w) to about 1.3% (w / w), from about 0.9% (w / w) to about 1.2% (w / w), from about 0.9% (w / w) to about 1.1% (w / w), from about 0.9% (w / w) to about 1% (w / w), from about 1% (w / w) to about 1.9% (w / w), from about 1% (w / w) to about 1.8% (w / w), from about 1% (w / w) to about 1.7% (w / w), from about 1% (w / w) to about 1.6% (w / w), from about 1% (w / w) to about 1.5% (w / w), from about 1% (w / w) to about 1.4% (w / w), from about 1% (w / w) to about 1.3% (w / w), from about 1% (w / w) to about 1.2% (w / w), from about 1% (w / w) to about 1.1% (w / w), from about 1.1% (w / w) to about 1.9% (w / w), from about 1.1% (w / w) to about 1.8% (w / w), from about 1.1% (w / w) to about 1.7% (w / w), from about 1.1% (w / w) to about 1.6% (w / w), from about 1.1% (w / w) to about 1.5% (w / w), from about 1.1% (w / w) to about 1.4% (w / w), from about 1.1% (w / w) to about 1.3% (w / w), from about 1.1% (w / w) to about 1.2% (w / w), from about 1.2% (w / w) to about 1.9% (w / w), from about 1.2% (w / w) to about 1.8% (w / w), from about 1.2% (w / w) to about 1.7% (w / w), from about 1.2% (w / w) to about 1.6% (w / w), from about 1.2% (w / w) to about 1.5% (w / w), from about 1.2% (w / w) to about 1.4% (w / w), from about 1.2% (w / w) to about 1.3% (w / w), from about 1.3% (w / w) to about 1.9% (w / w), from about 1.3% (w / w) to about 1.8% (w / w), from about 1.3% (w / w) to about 1.7% (w / w), from about 1.3% (w / w) to about 1.6% (w / w), from about 1.3% (w / w) to about 1.5% (w / w), from about 1.3% (w / w) to about 1.4% (w / w), from about 1.4% (w / w) to about 1.9% (w / w), from about 1.4% (w / w) to about 1.8% (w / w), from about 1.4% (w / w) to about 1.7% (w / w), from about 1.4% (w / w) to about 1.6% (w / w), from about 1.4% (w / w) to about 1.5% (w / w), from about 1.5% (w / w) to about 1.9% (w / w), from about 1.5% (w / w) to about 1.8% (w / w), from about 1.5% (w / w) to about 1.7% (w / w), from about 1.5% (w / w) to about 1.6% (w / w), from about 1.6% (w / w) to about 1.9% (w / w), from about 1.6% (w / w) to about 1.8% (w / w), from about 1.6% (w / w) to about 1.7% (w / w), from about 1.7% (w / w) to about 1.9% (w / w), from about 1.7% (w / w) to about 1.8% (w / w), or from about 1.8% (w / w) to about 1.9% (w / w). In certain embodiments, the amount of antioxidant in the liquid pharmaceutical formulation described herein can be from about 0.01% (w / w) to about 0.3% (w / w). In certain embodiments, the amount of antioxidant in the liquid pharmaceutical formulation described herein can be from about 0.05% (w / w) to about 2% (w / w).

[0107] In certain embodiments, the amount of antioxidant in the liquid pharmaceutical formulation described herein can be about 0.05% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1.0% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w), about 1.5% (w / w), about 1.6% (w / w), about 1.7% (w / w), about 1.8% (w / w), about 1.9% (w / w), or about 2.0% (w / w). In certain embodiments, the amount of antioxidant in the liquid pharmaceutical formulation described herein can be about 0.3% (w / w).

[0108] In certain embodiments, the antioxidant is selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof. In certain embodiments, the antioxidant is sodium metabisulfite. In certain embodiments, the antioxidant is sodium bisulfite. In certain embodiments, the antioxidant is monothioglycerol. In certain embodiments, the antioxidant is methionine. In certain embodiments, the antioxidant is EDTA.

[0109] In certain embodiments, the amount of sodium metabisulfite in the liquid pharmaceutical formulations described herein can be from about 0.01% (w / w) to about 2% (w / w), from about 0.05% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.2% (w / w) to about 2% (w / w), from about 0.3% (w / w) to about 2% (w / w), from about 0.4% (w / w) to about 2% (w / w), from about 0.5% (w / w) to about 2% (w / w), from about 0.6% (w / w) to about 2% (w / w), from about 0.7% (w / w) to about 2% (w / w), from about 0.8% (w / w) to about 2% (w / w), from about 0.9% (w / w) to about 2% (w / w), from about 1% (w / w) to about 2% (w / w), from about 1.1% (w / w) to about 2% (w / w), from about 1.2% (w / w) to about 2% (w / w), from about 1.3% (w / w) to about 2% (w / w), from about 1.4% (w / w) to about 2% (w / w), from about 1.5% (w / w) to about 2% (w / w), from about 1.6% (w / w) to about 2% (w / w), from about 1.7% (w / w) to about 2% (w / w), from about 1.8% (w / w) to about 2% (w / w), from about 1.9% (w / w) to about 2% (w / w), from about 0.01% (w / w) to about 1.9% (w / w), from about 0.01% (w / w) to about 1.8% (w / w), from about 0.01% (w / w) to about 1.7% (w / w), from about 0.01% (w / w) to about 1.6% (w / w), from about 0.01% (w / w) to about 1.5% (w / w), from about 0.01% (w / w) to about 1.4% (w / w), from about 0.01% (w / w) to about 1.3% (w / w), from about 0.01% (w / w) to about 1.2% (w / w), from about 0.01% (w / w) to about 1.1% (w / w), from about 0.01% (w / w) to about 1% (w / w), from about 0.01% (w / w) to about 0.9% (w / w), from about 0.01% (w / w) to about 0.8% (w / w), from about 0.01% (w / w) to about 0.7% (w / w), from about 0.01% (w / w) to about 0.6% (w / w), from about 0.01% (w / w) to about 0.5% (w / w), from about 0.01% (w / w) to about 0.4% (w / w), from about 0.01% (w / w) to about 0.3% (w / w), from about 0.01% (w / w) to about 0.2% (w / w), from about 0.01% (w / w) to about 0.1% (w / w), from about 0.01% (w / w) to about 0.05% (w / w), from about 0.05% (w / w) to about 1.9% (w / w), from about 0.05% (w / w) to about 1.8% (w / w), from about 0.05% (w / w) to about 1.7% (w / w), from about 0.05% (w / w) to about 1.6% (w / w), from about 0.05% (w / w) to about 1.5% (w / w), from about 0.05% (w / w) to about 1.4% (w / w), from about 0.05% (w / w) to about 1.3% (w / w), from about 0.05% (w / w) to about 1.2% (w / w), from about 0.05% (w / w) to about 1.1% (w / w), from about 0.05% (w / w) to about 1% (w / w), from about 0.05% (w / w) to about 0.9% (w / w), from about 0.05% (w / w) to about 0.8% (w / w), from about 0.05% (w / w) to about 0.7% (w / w), from about 0.05% (w / w) to about 0.6% (w / w), from about 0.05% (w / w) to about 0.5% (w / w), from about 0.05% (w / w) to about 0.4% (w / w), from about 0.05% (w / w) to about 0.3% (w / w), from about 0.05% (w / w) to about 0.2% (w / w), from about 0.05% (w / w) to about 0.1% (w / w), from about 0.1% (w / w) to about 1.9% (w / w), from about 0.1% (w / w) to about 1.8% (w / w), from about 0.1% (w / w) to about 1.7% (w / w), from about 0.1% (w / w) to about 1.6% (w / w), from about 0.1% (w / w) to about 1.5% (w / w), from about 0.1% (w / w) to about 1.4% (w / w), from about 0.1% (w / w) to about 1.3% (w / w), from about 0.1% (w / w) to about 1.2% (w / w), from about 0.1% (w / w) to about 1.1% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.9% (w / w), from about 0.1% (w / w) to about 0.8% (w / w), from about 0.1% (w / w) to about 0.7% (w / w), from about 0.1% (w / w) to about 0.6% (w / w), from about 0.1% (w / w) to about 0.5% (w / w), from about 0.1% (w / w) to about 0.4% (w / w), from about 0.1% (w / w) to about 0.3% (w / w), from about 0.1% (w / w) to about 0.2% (w / w), from about 0.2% (w / w) to about 1.9% (w / w), from about 0.2% (w / w) to about 1.8% (w / w), from about 0.2% (w / w) to about 1.7% (w / w), from about 0.2% (w / w) to about 1.6% (w / w), from about 0.2% (w / w) to about 1.5% (w / w), from about 0.2% (w / w) to about 1.4% (w / w), from about 0.2% (w / w) to about 1.3% (w / w), from about 0.2% (w / w) to about 1.2% (w / w), from about 0.2% (w / w) to about 1.1% (w / w), from about 0.2% (w / w) to about 1% (w / w), from about 0.2% (w / w) to about 0.9% (w / w), from about 0.2% (w / w) to about 0.8% (w / w), from about 0.2% (w / w) to about 0.7% (w / w), from about 0.2% (w / w) to about 0.6% (w / w), from about 0.2% (w / w) to about 0.5% (w / w), from about 0.2% (w / w) to about 0.4% (w / w), from about 0.2% (w / w) to about 0.3% (w / w), from about 0.3% (w / w) to about 1.9% (w / w), from about 0.3% (w / w) to about 1.8% (w / w), from about 0.3% (w / w) to about 1.7% (w / w), from about 0.3% (w / w) to about 1.6% (w / w), from about 0.3% (w / w) to about 1.5% (w / w), from about 0.3% (w / w) to about 1.4% (w / w), from about 0.3% (w / w) to about 1.3% (w / w), from about 0.3% (w / w) to about 1.2% (w / w), from about 0.3% (w / w) to about 1.1% (w / w), from about 0.3% (w / w) to about 1% (w / w), from about 0.3% (w / w) to about 0.9% (w / w), from about 0.3% (w / w) to about 0.8% (w / w), from about 0.3% (w / w) to about 0.7% (w / w), from about 0.3% (w / w) to about 0.6% (w / w), from about 0.3% (w / w) to about 0.5% (w / w), from about 0.3% (w / w) to about 0.4% (w / w), from about 0.4% (w / w) to about 1.9% (w / w), from about 0.4% (w / w) to about 1.8% (w / w), from about 0.4% (w / w) to about 1.7% (w / w), from about 0.4% (w / w) to about 1.6% (w / w), from about 0.4% (w / w) to about 1.5% (w / w), from about 0.4% (w / w) to about 1.4% (w / w), from about 0.4% (w / w) to about 1.3% (w / w), from about 0.4% (w / w) to about 1.2% (w / w), from about 0.4% (w / w) to about 1.1% (w / w), from about 0.4% (w / w) to about 1% (w / w), from about 0.4% (w / w) to about 0.9% (w / w), from about 0.4% (w / w) to about 0.8% (w / w), from about 0.4% (w / w) to about 0.7% (w / w), from about 0.4% (w / w) to about 0.6% (w / w), from about 0.4% (w / w) to about 0.5% (w / w), from about 0.5% (w / w) to about 1.9% (w / w), from about 0.5% (w / w) to about 1.8% (w / w), from about 0.5% (w / w) to about 1.7% (w / w), from about 0.5% (w / w) to about 1.6% (w / w), from about 0.5% (w / w) to about 1.5% (w / w), from about 0.5% (w / w) to about 1.4% (w / w), from about 0.5% (w / w) to about 1.3% (w / w), from about 0.5% (w / w) to about 1.2% (w / w), from about 0.5% (w / w) to about 1.1% (w / w), from about 0.5% (w / w) to about 1% (w / w), about 0.5% (w / w) to about 0.9% (w / w), about 0.5% (w / w) to about 0.8% (w / w), about 0.5% (w / w) to about 0.7% (w / w), about 0.5% (w / w) to about 0.6% (w / w), about 0.6% (w / w) to about 1.9% (w / w), about 0.6% (w / w) to about 1.8% (w / w), about 0.6% (w / w) to about 1.7% (w / w), about 0.6% (w / w) to about 1.6% (w / w), about 0.6% (w / w) to about 1.5% (w / w), about 0.6% (w / w) to about 1.4% (w / w), about 0.6% (w / w) to about 1.3% (w / w), about 0.6% (w / w) to about 1.2% (w / w), about 0.6% (w / w) to about 1.1% (w / w), about 0.6% (w / w) to about 1% (w / w), about 0.6% (w / w) to about 0.9% (w / w), about 0.6% (w / w) to about 0.8% (w / w), about 0.6% (w / w) to about 0.7% (w / w), about 0.7% (w / w) to about 1.9% (w / w), about 0.7% (w / w) to about 1.8% (w / w), about 0.7% (w / w) to about 1.7% (w / w), about 0.7% (w / w) to about 1.6% (w / w), about 0.7% (w / w) to about 1.5% (w / w), about 0.7% (w / w) to about 1.4% (w / w), about 0.7% (w / w) to about 1.3% (w / w), about 0.7% (w / w) to about 1.2% (w / w), about 0.7% (w / w) to about 1.1% (w / w), about 0.7% (w / w) to about 1% (w / w), about 0.7% (w / w) to about 0.9% (w / w), about 0.7% (w / w) to about 0.8% (w / w), about 0.8% (w / w) to about 1.9% (w / w), about 0.8% (w / w) to about 1.8% (w / w), about 0.8% (w / w) to about 1.7% (w / w), about 0.8% (w / w) to about 1.6% (w / w), about 0.8% (w / w) to about 1.5% (w / w), about 0.8% (w / w) to about 1.4% (w / w), about 0.8% (w / w) to about 1.3% (w / w), about 0.8% (w / w) to about 1.2% (w / w), about 0.8% (w / w) to about 1.1% (w / w), about 0.8% (w / w) to about 1% (w / w), about 0.8% (w / w) to about 0.9% (w / w), about 0.9% (w / w) to about 1.9% (w / w), about 0.9% (w / w) to about 1.8% (w / w), about 0.9% (w / w) to about 1.7% (w / w), about 0.9% (w / w) to about 1.6% (w / w), about 0.9% (w / w) to about 1.5% (w / w), from about 0.9% (w / w) to about 1.4% (w / w), from about 0.9% (w / w) to about 1.3% (w / w), from about 0.9% (w / w) to about 1.2% (w / w), from about 0.9% (w / w) to about 1.1% (w / w), from about 0.9% (w / w) to about 1% (w / w), from about 1% (w / w) to about 1.9% (w / w), from about 1% (w / w) to about 1.8% (w / w), from about 1% (w / w) to about 1.7% (w / w), from about 1% (w / w) to about 1.6% (w / w), from about 1% (w / w) to about 1.5% (w / w), from about 1% (w / w) to about 1.4% (w / w), from about 1% (w / w) to about 1.3% (w / w), from about 1% (w / w) to about 1.2% (w / w), from about 1% (w / w) to about 1.1% (w / w), from about 1.1% (w / w) to about 1.9% (w / w), from about 1.1% (w / w) to about 1.8% (w / w), from about 1.1% (w / w) to about 1.7% (w / w), from about 1.1% (w / w) to about 1.6% (w / w), from about 1.1% (w / w) to about 1.5% (w / w), from about 1.1% (w / w) to about 1.4% (w / w), from about 1.1% (w / w) to about 1.3% (w / w), from about 1.1% (w / w) to about 1.2% (w / w), from about 1.2% (w / w) to about 1.9% (w / w), from about 1.2% (w / w) to about 1.8% (w / w), from about 1.2% (w / w) to about 1.7% (w / w), from about 1.2% (w / w) to about 1.6% (w / w), from about 1.2% (w / w) to about 1.5% (w / w), from about 1.2% (w / w) to about 1.4% (w / w), from about 1.2% (w / w) to about 1.3% (w / w), from about 1.3% (w / w) to about 1.9% (w / w), from about 1.3% (w / w) to about 1.8% (w / w), from about 1.3% (w / w) to about 1.7% (w / w), from about 1.3% (w / w) to about 1.6% (w / w), from about 1.3% (w / w) to about 1.5% (w / w), from about 1.3% (w / w) to about 1.4% (w / w), from about 1.4% (w / w) to about 1.9% (w / w), from about 1.4% (w / w) to about 1.8% (w / w), from about 1.4% (w / w) to about 1.7% (w / w), from about 1.4% (w / w) to about 1.6% (w / w), from about 1.4% (w / w) to about 1.5% (w / w), from about 1.5% (w / w) to about 1.9% (w / w), from about 1.5% (w / w) to about 1.8% (w / w), from about 1.5% (w / w) to about 1.7% (w / w), from about 1.5% (w / w) to about 1.6% (w / w), from about 1.6% (w / w) to about 1.9% (w / w), from about 1.6% (w / w) to about 1.8% (w / w), from about 1.6% (w / w) to about 1.7% (w / w), from about 1.7% (w / w) to about 1.9% (w / w), from about 1.7% (w / w) to about 1.8% (w / w), or from about 1.8% (w / w) to about 1.9% (w / w). In certain embodiments, the amount of sodium metabisulfite in the liquid pharmaceutical formulation described herein can be from about 0.01% (w / w) to about 0.3% (w / w). In certain embodiments, the amount of sodium metabisulfite in the liquid pharmaceutical formulation described herein can be from about 0.05% (w / w) to about 2% (w / w).

[0110] In certain embodiments, the amount of sodium metabisulfite in the liquid pharmaceutical formulation described herein can be about 0.05% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1.0% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w), about 1.5% (w / w), about 1.6% (w / w), about 1.7% (w / w), about 1.8% (w / w), about 1.9% (w / w), or about 2.0% (w / w). In certain embodiments, the amount of antioxidant in the liquid pharmaceutical formulation described herein can be about 0.3% (w / w).

[0111] Osmolarity and Osmolality

[0112] In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 100 mOsm / kg to about 1600 mOsm / kg, from about 200 mOsm / kg to about 1600 mOsm / kg, from about 300 mOsm / kg to about 1600 mOsm / kg, from about 400 mOsm / kg to about 1600 mOsm / kg, from about 600 mOsm / kg to about 1600 mOsm / kg, from about 800 mOsm / kg to about 1600 mOsm / kg, from about 1200 mOsm / kg to about 1600 mOsm / kg, from about 100 mOsm / kg to about 1200 mOsm / kg, from about 100 mOsm / kg to about 800 mOsm / kg, from about 100 mOsm / kg to about 600 mOsm / kg, from about 100 mOsm / kg to about 400 mOsm / kg, from about 100 mOsm / kg to about 300 mOsm / kg, from about 100 mOsm / kg to about 200 mOsm / kg, from about 200 mOsm / kg to about 1200 mOsm / kg, from about 200 mOsm / kg to about 800 mOsm / kg, from about 200 mOsm / kg to about 600 mOsm / kg, from about 200 mOsm / kg to about 400 mOsm / kg, from about 200 mOsm / kg to about 300 mOsm / kg, from about 300 mOsm / kg to about 1200 mOsm / kg, from about 300 mOsm / kg to about 800 mOsm / kg, from about 300 mOsm / kg to about 600 mOsm / kg, from about 300 mOsm / kg to about 400 mOsm / kg, from about 400 mOsm / kg to about 1200 mOsm / kg, from about 400 mOsm / kg to about 800 mOsm / kg, from about 400 mOsm / kg to about 600 mOsm / kg, from about 600 mOsm / kg to about 1200 mOsm / kg, from about 600 mOsm / kg to about 800 mOsm / kg, or from about 800 mOsm / kg to about 1200 mOsm / kg. In some embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 400 mOsm / kg. In some embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 300 mOsm / kg to about 600 mOsm / kg. In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 300 mOsm / kg to about 450 mOsm / kg.

[0113] In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 100 mOsm / kg to about 1600 mOsm / kg. In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 800 mOsm / kg. In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 600 mOsm / kg. In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 400 mOsm / kg. In certain embodiments, the volumetric osmolarity of the liquid pharmaceutical formulations described herein ranges from about 275 mOsm / kg to about 400 mOsm / kg.

[0114] It should be understood that the above ranges and descriptions of volumetric osmolarity apply equally to weight osmolarity, but with the unit "Osm / kg".

[0115] In certain embodiments, the liquid pharmaceutical formulations described herein may further comprise a volumetric osmolarity or weight osmolarity regulator.

[0116] In certain embodiments, the volumetric osmolarity or weight osmolarity regulator is selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof. In certain embodiments, the volumetric osmolarity or weight osmolarity regulator is sodium chloride, potassium chloride, or a combination thereof. In certain embodiments, the volumetric osmolarity or weight osmolarity regulator is sodium chloride. In certain embodiments, the volumetric osmolarity or weight osmolarity regulator is potassium chloride.

[0117] Other pharmaceutically acceptable excipients

[0118] In certain embodiments, the liquid pharmaceutical formulations described herein may further comprise one or more additional pharmaceutically acceptable excipients (e.g., solubilizers, pharmaceutically acceptable carriers, etc.).

[0119] In certain embodiments, the amount of one or more additional pharmaceutically acceptable excipients in the liquid pharmaceutical formulations described herein can be from about 0.1% (w / w) to about 30% (w / w), from about 0.5% (w / w) to about 30% (w / w), from about 1% (w / w) to about 30% (w / w), from about 1.5% (w / w) to about 30% (w / w), (w / w), from about 2% (w / w) to about 30% (w / w), from about 2.5% (w / w) to about 30% (w / w), from about 3% (w / w) to about 30% (w / w), from about 3.5% (w / w) to about 30% (w / w), from about 4% (w / w) to about 30% (w / w), from about 4.5% (w / w) to about 30% (w / w), from about 5% (w / w) to about 30% (w / w), from about 10% (w / w) to about 30% (w / w), from about 15% (w / w) to about 30% (w / w), from about 20% (w / w) to about 30% (w / w), from about 25% (w / w) to about 30% (w / w), from about 0.1% (w / w) to about 25% (w / w), from about 0.1% (w / w) to about 20% (w / w), from about 0.1% (w / w) to about 15% (w / w), from about 0.1% (w / w) to about 10% (w / w), from about 0.1% (w / w) to about 5% (w / w), from about 0.1% (w / w) to about 4.5% (w / w), from about 0.1% (w / w) to about 4% (w / w), from about 0.1% (w / w) to about 3.5% (w / w), from about 0.1% (w / w) to about 3% (w / w), from about 0.1% (w / w) to about 2.5% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 1.5% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.5% (w / w), from about 0.5% (w / w) to about 25% (w / w), from about 0.5% (w / w) to about 20% (w / w), from about 0.5% (w / w) to about 15% (w / w), from about 0.5% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 5% (w / w), from about 0.5% (w / w) to about 4.5% (w / w), from about 0.5% (w / w) to about 4% (w / w), from about 0.5% (w / w) to about 3.5% (w / w), from about 0.5% (w / w) to about 3% (w / w), from about 0.5% (w / w) to about 2.5% (w / w), from about 0.5% (w / w) to about 2% (w / w), from about 0.5% (w / w) to about 1.5% (w / w), from about 0.5% (w / w) to about 1% (w / w), about 1% (w / w) to about 25% (w / w), about 1% (w / w) to about 20% (w / w), about 1% (w / w) to about 15% (w / w), about 1% (w / w) to about 10% (w / w), about 1% (w / w) to about 5% (w / w), about 1% (w / w) to about 4.5% (w / w), about 1% (w / w) to about 4% (w / w), about 1% (w / w) to about 3.5% (w / w), about 1% (w / w) to about 2.5% (w / w), about 1% (w / w) to about 2% (w / w), about 1% (w / w) to about 1.5% (w / w), about 1.5% (w / w) to about 25% (w / w), about 1.5% (w / w) to about 20% (w / w), about 1.5% (w / w) to about 15% (w / w), about 1.5% (w / w) to about 10% (w / w), about 1.5% (w / w) to about 5% (w / w), about 1.5% (w / w) to about 4.5% (w / w), about 1.5% (w / w) to about 4% (w / w), about 1.5% (w / w) to about 3.5% (w / w), about 1.5% (w / w) to about 3% (w / w), about 1.5% (w / w) to about 2.5% (w / w), about 1.5% (w / w) to about 2% (w / w), about 2% (w / w) to about 25% (w / w), about 2% (w / w) to about 20% (w / w), about 2% (w / w) to about 15% (w / w), about 2% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w), about 2% (w / w) to about 4.5% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3.5% (w / w), about 2% (w / w) to about 3% (w / w), about 2% (w / w) to about 2.5% (w / w), about 2.5% (w / w) to about 25% (w / w), about 2.5% (w / w) to about 20% (w / w), about 2.5% (w / w) to about 15% (w / w), about 2.5% (w / w) to about 10% (w / w), about 2.5% (w / w) to about 5% (w / w), about 2.5% (w / w) to about 4.5% (w / w), about 2.5% (w / w) to about 4% (w / w), about 2.5% (w / w) to about 3.5% (w / w), about 2.5% (w / w) to about 3% (w / w), about 3% (w / w) to about 25% (w / w), about 3% (w / w) to about 20% (w / w), about 3% (w / w) to about 15% (w / w), about 3% (w / w) to about 10% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4.5% (w / w), about 3% (w / w) to about 4% (w / w), about 3% (w / w) to about 3.5% (w / w), about 3.5% (w / w) to about 25% (w / w), about 3.5% (w / w) to about 20% (w / w), about 3.5% (w / w) to about 15% (w / w), about 3.5% (w / w) to about 10% (w / w), about 3.5% (w / w) to about 5% (w / w), about 3.5% (w / w) to about 4.5% (w / w), about 3.5% (w / w) to about 4% (w / w), about 4% (w / w) to about 25% (w / w), about 4% (w / w) to about 20% (w / w), about 4% (w / w) to about 15% (w / w), about 4% (w / w) to about 10% (w / w), about 4% (w / w) to about 5% (w / w), about 4% (w / w) to about 4.5% (w / w), about 4.5% (w / w) to about 25% (w / w), about 4.5% (w / w) to about 20% (w / w), about 4.5% (w / w) to about 15% (w / w), about 4.5% (w / w) to about 10% (w / w), about 4.5% (w / w) to about 5% (w / w), about 5% (w / w) to about 25% (w / w), about 5% (w / w) to about 20% (w / w), about 5% (w / w) to about 15% (w / w), about 5% (w / w) to about 10% (w / w), about 10% (w / w) to about 25% (w / w), about 10% (w / w) to about 20% (w / w), about 10% (w / w) to about 15% (w / w), about 15% (w / w) to about 25% (w / w), about 15% (w / w) to about 20% (w / w) or about 20% (w / w) to about 25% (w / w).

[0120] In certain embodiments, the amount of one or more additional pharmaceutically acceptable excipients in the liquid pharmaceutical formulations described herein can be about 0.1% (w / w), about 0.25% (w / w), about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), or about 30% (w / w). In certain embodiments, the amount of one or more additional pharmaceutically acceptable excipients in the liquid pharmaceutical formulations described herein can be about 1% (w / w). In certain embodiments, the amount of one or more additional pharmaceutically acceptable excipients in the liquid pharmaceutical formulations described herein can be about 3.5% (w / w).

[0121] In certain embodiments, one or more additional pharmaceutically acceptable excipients are selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0122] In certain embodiments, one or more additional pharmaceutically acceptable excipients include ethanol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include benzyl alcohol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include glycerol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include N-methylpyrrolidone (NMP). In certain embodiments, one or more additional pharmaceutically acceptable excipients include sodium chloride. In certain embodiments, one or more additional pharmaceutically acceptable excipients include sodium carbonate. In certain embodiments, one or more additional pharmaceutically acceptable excipients include mannitol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include lactose. In certain embodiments, one or more additional pharmaceutically acceptable excipients include dextrose. In certain embodiments, one or more additional pharmaceutically acceptable excipients include polyethylene glycol (PEG). In certain embodiments, one or more additional pharmaceutically acceptable excipients include propylene glycol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include polysorbates (e.g., polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate). In certain embodiments, one or more additional pharmaceutically acceptable excipients include polyvinylpyrrolidone (PVP). In certain embodiments, one or more additional pharmaceutically acceptable excipients include cyclodextrins. In certain embodiments, one or more additional pharmaceutically acceptable excipients include cyclodextrin derivatives. In certain embodiments, one or more additional pharmaceutically acceptable excipients include vitamin E. In certain embodiments, one or more additional pharmaceutically acceptable excipients include one or more naturally occurring forms of vitamin E (e.g., α-, β-, γ-, and δ-tocopherols and α-, β-, γ-, and δ-tocotrienols). In certain embodiments, one or more additional pharmaceutically acceptable excipients include vitamin E derivatives (e.g., tocopheryl acetate, tocopheryl glucoside, tocopheryl phosphate).

[0123] (1) Benzyl alcohol

[0124] In certain embodiments, the liquid pharmaceutical formulations described herein may further comprise benzyl alcohol. In certain embodiments, benzyl alcohol in the liquid pharmaceutical formulations described herein can act as a solubilizer.

[0125] In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein can be from about 0.1% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 10% (w / w), from about 1% (w / w) to about 10% (w / w), from about 1.5% (w / w) to about 10% (w / w), from about 2% (w / w) to about 10% (w / w), from about 2.5% (w / w) to about 10% (w / w), from about 3% (w / w) to about 10% (w / w), from about 3.5% (w / w) to about 10% (w / w), from about 4% (w / w) to about 10% (w / w), from about 4.5% (w / w) to about 10% (w / w), from about 5% (w / w) to about 10% (w / w), from about 6% (w / w) to about 10% (w / w), from about 7% (w / w) to about 10% (w / w), from about 8% (w / w) to about 10% (w / w), from about 9% (w / w) to about 10% (w / w), from about 0.1% (w / w) to about 9% (w / w), from about 0.1% (w / w) to about 8% (w / w), from about 0.1% (w / w) to about 7% (w / w), from about 0.1% (w / w) to about 6% (w / w), from about 0.1% (w / w) to about 4.5% (w / w), from about 0.1% (w / w) to about 4% (w / w), from about 0.1% (w / w) to about 3.5% (w / w), from about 0.1% (w / w) to about 3% (w / w), from about 0.1% (w / w) to about 2.5% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 1.5% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.5% (w / w), from about 0.5% (w / w) to about 9% (w / w), from about 0.5% (w / w) to about 8% (w / w), from about 0.5% (w / w) to about 7% (w / w), from about 0.5% (w / w) to about 6% (w / w), from about 0.5% (w / w) to about 5% (w / w), from about 0.5% (w / w) to about 4.5% (w / w), from about 0.5% (w / w) to about 4% (w / w), from about 0.5% (w / w) to about 3.5% (w / w), from about 0.5% (w / w) to about 3% (w / w), from about 0.5% (w / w) to about 2.5% (w / w), from about 0.5% (w / w) to about 2% (w / w), from about 0.5% (w / w) to about 1.5% (w / w), from about 0.5% (w / w) to about 1% (w / w), from about 1% (w / w) to about 9% (w / w), from about 1% (w / w) to about 8% (w / w), from about 1% (w / w) to about 7% (w / w), from about 1% (w / w) to about 6% (w / w), from about 1% (w / w) to about 5% (w / w), from about 1% (w / w) to about 4.5% (w / w), from about 1% (w / w) to about 4% (w / w), from about 1% (w / w) to about 3.5% (w / w), from about 1% (w / w) to about 3% (w / w), from about 1% (w / w) to about 2.5% (w / w), from about 1% (w / w) to about 2% (w / w), from about 1% (w / w) to about 1.5% (w / w), from about 1.5% (w / w) to about 9% (w / w), from about 1.5% (w / w) to about 8% (w / w), from about 1.5% (w / w) to about 7% (w / w), from about 1.5% (w / w) to about 6% (w / w), from about 1.5% (w / w) to about 5% (w / w), from about 1.5% (w / w) to about 4.5% (w / w), from about 1.5% (w / w) to about 4% (w / w), from about 1.5% (w / w) to about 3.5% (w / w), from about 1.5% (w / w) to about 3% (w / w), from about 1.5% (w / w) to about 2.5% (w / w), from about 1.5% (w / w) to about 2% (w / w), from about 2% (w / w) to about 9% (w / w), from about 2% (w / w) to about 8% (w / w), from about 2% (w / w) to about 7% (w / w), from about 2% (w / w) to about 6% (w / w), from about 2% (w / w) to about 5% (w / w), from about 2% (w / w) to about 4.5% (w / w), from about 2% (w / w) to about 4% (w / w), from about 2% (w / w) to about 3.5% (w / w), from about 2% (w / w) to about 3% (w / w), from about 2% (w / w) to about 2.5% (w / w), from about 2.5% (w / w) to about 9% (w / w), from about 2.5% (w / w) to about 8% (w / w), from about 2.5% (w / w) to about 7% (w / w), from about 2.5% (w / w) to about 6% (w / w), from about 2.5% (w / w) to about 5% (w / w), from about 2.5% (w / w) to about 4.5% (w / w), from about 2.5% (w / w) to about 4% (w / w), from about 2.5% (w / w) to about 3.5% (w / w), from about 2.5% (w / w) to about 3% (w / w), from about 3% (w / w) to about 9% (w / w), from about 3% (w / w) to about 8% (w / w), from about 3% (w / w) to about 7% (w / w), from about 3% (w / w) to about 6% (w / w), from about 3% (w / w) to about 5% (w / w), from about 3% (w / w) to about 4.5% (w / w), from about 3% (w / w) to about 4% (w / w), from about 3% (w / w) to about 3.5% (w / w), from about 3.5% (w / w) to about 9% (w / w), from about 3.5% (w / w) to about 8% (w / w), from about 3.5% (w / w) to about 7% (w / w), from about 3.5% (w / w) to about 6% (w / w), from about 3.5% (w / w) to about 5% (w / w), from about 3.5% (w / w) to about 4.5% (w / w), from about 3.5% (w / w) to about 4% (w / w), about 4% (w / w) to about 9% (w / w), about 4% (w / w) to about 8% (w / w), about 4% (w / w) to about 7% (w / w), about 4% (w / w) to about 6% (w / w), about 4% (w / w) to about 5% (w / w), about 4% (w / w) to about 4.5% (w / w), about 4.5% (w / w) to about 9% (w / w), about 4.5% (w / w) to about 8% (w / w), about 4.5% (w / w) to about 7% (w / w), about 4.5% (w / w) to about 6% (w / w), about 4.5% (w / w) to about 5% (w / w), about 5% (w / w) to about 9% (w / w), about 5% (w / w) to about 8% (w / w), about 5% (w / w) to about 7% (w / w), about 5% (w / w) to about 6% (w / w), about 6% (w / w) to about 9% (w / w), about 6% (w / w) to about 8% (w / w), about 6% (w / w) to about 7% (w / w), about 7% (w / w) to about 9% (w / w), about 7% (w / w) to about 8% (w / w), or about 8% (w / w) to about 9% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 1% (w / w) to about 3.5% (w / w).

[0126] In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein can be about 0.1% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein can be about 1% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein can be about 3.5% (w / w).

[0127] (2) Cyclodextrin and its derivatives

[0128] In certain embodiments, the liquid pharmaceutical formulations described herein can comprise cyclodextrin. In certain embodiments, the liquid pharmaceutical formulations described herein can comprise cyclodextrin derivatives.

[0129] Cyclodextrins contemplated for use as pharmaceutically acceptable excipients include, but are not limited to, α(alpha)-cyclodextrin, β(beta)-cyclodextrin, and γ(gamma)-cyclodextrin. In certain embodiments, the liquid pharmaceutical formulations described herein may contain α-cyclodextrin. In certain embodiments, the liquid pharmaceutical formulations described herein may contain β-cyclodextrin. In certain embodiments, the liquid pharmaceutical formulations described herein may contain γ-cyclodextrin.

[0130] Cyclodextrin derivatives contemplated for use as pharmaceutically acceptable excipients include, but are not limited to, sulfobutylether-β-cyclodextrin (e.g., captisol), hydroxypropyl-β-cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin), and methylated β-cyclodextrin (e.g., randomly methylated β-cyclodextrin). In certain embodiments, the liquid pharmaceutical formulations described herein may contain sulfobutylether-β-cyclodextrin. In certain embodiments, the liquid pharmaceutical formulations described herein may contain In certain embodiments, the liquid pharmaceutical formulations described herein may contain hydroxypropyl-β-cyclodextrin. In certain embodiments, the liquid pharmaceutical formulations described herein may contain methylated β-cyclodextrin.

[0131] In certain embodiments, the amount of cyclodextrin in the liquid pharmaceutical formulation is from about 5% to about 50% (w / w), from about 10% to about 50% (w / w), from about 15% to about 50% (w / w), from about 20% to about 50% (w / w), from about 20% to about 50% (w / w), from about 25% to about 50% (w / w), from about 30% to about 50% (w / w), from about 35% to about 50% (w / w), from about 40% to about 50% (w / w), from about 45% to about 50% (w / w), from about 5% to about 45% (w / w), from about 5% to about 40% (w / w), from about 5% to about 35% (w / w), from about 5% to about 30% (w / w), from about 5% to about 25% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 5% to about 10% (w / w), from about 10% to about 45% (w / w), from about 10% to about 40% (w / w), from about 10% to about 35% (w / w), from about 10% to about 30% (w / w), from about 10% to about 25% (w / w), from about 10% to about 20% (w / w), from about 10% to about 15% (w / w), from about 15% to about 45% (w / w), from about 15% to about 40% (w / w), from about 15% to about 35% (w / w), from about 15% to about 30% (w / w), from about 15% to about 25% (w / w), from about 15% to about 20% (w / w), from about 20% to about 45% (w / w), from about 20% to about 40% (w / w), from about 20% to about 35% (w / w), from about 20% to about 30% (w / w), from about 20% to about 25% (w / w), from about 25% to about 45% (w / w), from about 25% to about 40% (w / w), from about 25% to about 35% (w / w), from about 25% to about 30% (w / w), from about 30% to about 45% (w / w), from about 30% to about 40% (w / w), from about 30% to about 35% (w / w), from about 35% to about 45% (w / w), from about 35% to about 40% (w / w), or from about 40% to about 45% (w / w).

[0132] In certain embodiments, the amount of cyclodextrin derivative in the liquid pharmaceutical formulation is from about 5% to about 50% (w / w), from about 10% to about 50% (w / w), from about 15% to about 50% (w / w), from about 20% to about 50% (w / w), from about 20% to about 50% (w / w), from about 25% to about 50% (w / w), from about 30% to about 50% (w / w), from about 35% to about 50% (w / w), from about 40% to about 50% (w / w), from about 45% to about 50% (w / w), from about 5% to about 45% (w / w), from about 5% to about 40% (w / w), from about 5% to about 35% (w / w), from about 5% to about 30% (w / w), from about 5% to about 25% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 5% to about 10% (w / w), from about 10% to about 45% (w / w), from about 10% to about 40% (w / w), from about 10% to about 35% (w / w), from about 10% to about 30% (w / w), from about 10% to about 25% (w / w), from about 10% to about 20% (w / w), from about 10% to about 15% (w / w), from about 15% to about 45% (w / w), from about 15% to about 40% (w / w), from about 15% to about 35% (w / w), from about 15% to about 30% (w / w), from about 15% to about 25% (w / w), from about 15% to about 20% (w / w), from about 20% to about 45% (w / w), from about 20% to about 40% (w / w), from about 20% to about 35% (w / w), from about 20% to about 30% (w / w), from about 20% to about 25% (w / w), from about 25% to about 45% (w / w), from about 25% to about 40% (w / w), from about 25% to about 35% (w / w), from about 25% to about 30% (w / w), from about 30% to about 45% (w / w), from about 30% to about 40% (w / w), from about 30% to about 35% (w / w), from about 35% to about 45% (w / w), from about 35% to about 40% (w / w), or from about 40% to about 45% (w / w).

[0133] In certain embodiments, the amount of cyclodextrin in the liquid pharmaceutical formulation is less than or equal to 5% (w / w), less than or equal to 10% (w / w), less than or equal to 15% (w / w), less than or equal to 20% (w / w), less than or equal to 25% (w / w), less than or equal to 30% (w / w), less than or equal to 35% (w / w), less than or equal to 40% (w / w), less than or equal to 45% (w / w), or less than or equal to 50% (w / w).

[0134] In certain embodiments, the amount of cyclodextrin derivative in the liquid pharmaceutical formulation is less than or equal to 5% (w / w), less than or equal to 10% (w / w), less than or equal to 15% (w / w), less than or equal to 20% (w / w), less than or equal to 25% (w / w), less than or equal to 30% (w / w), less than or equal to 35% (w / w), less than or equal to 40% (w / w), less than or equal to 45% (w / w), or less than or equal to 50% (w / w).

[0135] In certain embodiments, the amount of cyclodextrin in the liquid pharmaceutical formulation is about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 25% (w / w), about 30% (w / w), about 35% (w / w), about 40% (w / w), about 45% (w / w), or about 50% (w / w).

[0136] In certain embodiments, the amount of cyclodextrin derivative in the liquid pharmaceutical formulation is about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 25% (w / w), about 30% (w / w), about 35% (w / w), about 40% (w / w), about 45% (w / w), or about 50% (w / w).

[0137] In certain embodiments, the concentration of cyclodextrin in the liquid pharmaceutical formulation is from about 40 mM to about 200 mM, from about 50 mM to about 200 mM, from about 60 mM to about 200 mM, from about 70 mM to about 200 mM, from about 80 mM to about 200 mM, from about 90 mM to about 200 mM, from about 100 mM to about 200 mM, from about 120 mM to about 200 mM, from about 140 mM to about 200 mM, from about 160 mM to about 200 mM, from about 180 mM to about 200 mM, from about 40 mM to about 180 mM, from about 40 mM to about 160 mM, from about 40 mM to about 140 mM, from about 40 mM to about 120 mM, from about 40 mM to about 100 mM, from about 40 mM to about 90 mM, from about 40 mM to about 80 mM, from about 40 mM to about 70 mM, from about 40 mM to about 60 mM, from about 40 mM to about 50 mM, from about 50 mM to about 180 mM, from about 50 mM to about 160 mM, from about 50 mM to about 140 mM, from about 50 mM to about 120 mM, from about 50 mM to about 100 mM, from about 50 mM to about 90 mM, from about 50 mM to about 80 mM, from about 50 mM to about 70 mM, from about 50 mM to about 60 mM, from about 60 mM to about 180 mM, from about 60 mM to about 160 mM, from about 60 mM to about 140 mM, from about 60 mM to about 120 mM, from about 60 mM to about 100 mM, from about 60 mM to about 90 mM, from about 60 mM to about 80 mM, from about 60 mM to about 70 mM, from about 70 mM to about 180 mM, from about 70 mM to about 160 mM, from about 70 mM to about 140 mM, from about 70 mM to about 120 mM, from about 70 mM to about 100 mM, from about 70 mM to about 90 mM, from about 70 mM to about 80 mM, from about 80 mM to about 180 mM, from about 80 mM to about 160 mM, from about 80 mM to about 140 mM, from about 80 mM to about 120 mM, from about 80 mM to about 100 mM, from about 80 mM to about 90 mM, from about 90 mM to about 180 mM, from about 90 mM to about 160 mM, from about 90 mM to about 140 mM, from about 90 mM to about 120 mM, from about 90 mM to about 100 mM, from about 100 mM to about 180 mM, from about 100 mM to about 160 mM, from about 100 mM to about 140 mM, from about 100 mM to about 120 mM, from about 120 mM to about 180 mM, from about 120 mM to about 160 mM, from about 120 mM to about 140 mM, from about 140 mM to about 180 mM, from about 140 mM to about 160 mM, or from about 160 mM to about 180 mM.

[0138] In certain embodiments, the concentration of the cyclodextrin derivative in the liquid pharmaceutical formulation is from about 40 mM to about 200 mM, from about 50 mM to about 200 mM, from about 60 mM to about 200 mM, from about 70 mM to about 200 mM, from about 80 mM to about 200 mM, from about 90 mM to about 200 mM, from about 100 mM to about 200 mM, from about 120 mM to about 200 mM, from about 140 mM to about 200 mM, from about 160 mM to about 200 mM, from about 180 mM to about 200 mM, from about 40 mM to about 180 mM, from about 40 mM to about 160 mM, from about 40 mM to about 140 mM, from about 40 mM to about 120 mM, from about 40 mM to about 100 mM, from about 40 mM to about 90 mM, from about 40 mM to about 80 mM, from about 40 mM to about 70 mM, from about 40 mM to about 60 mM, from about 40 mM to about 50 mM, from about 50 mM to about 180 mM, from about 50 mM to about 160 mM, from about 50 mM to about 140 mM, from about 50 mM to about 120 mM, from about 50 mM to about 100 mM, from about 50 mM to about 90 mM, from about 50 mM to about 80 mM, from about 50 mM to about 70 mM, from about 50 mM to about 60 mM, from about 60 mM to about 180 mM, from about 60 mM to about 160 mM, from about 60 mM to about 140 mM, from about 60 mM to about 120 mM, from about 60 mM to about 100 mM, from about 60 mM to about 90 mM, from about 60 mM to about 80 mM, from about 60 mM to about 70 mM, from about 70 mM to about 180 mM, from about 70 mM to about 160 mM, from about 70 mM to about 140 mM, from about 70 mM to about 120 mM, from about 70 mM to about 100 mM, from about 70 mM to about 90 mM, from about 70 mM to about 80 mM, from about 80 mM to about 180 mM, from about 80 mM to about 160 mM, from about 80 mM to about 140 mM, from about 80 mM to about 120 mM, from about 80 mM to about 100 mM, from about 80 mM to about 90 mM, from about 90 mM to about 180 mM, from about 90 mM to about 160 mM, from about 90 mM to about 140 mM, from about 90 mM to about 120 mM, from about 90 mM to about 100 mM, from about 100 mM to about 180 mM, from about 100 mM to about 160 mM, from about 100 mM to about 140 mM, from about 100 mM to about 120 mM, from about 120 mM to about 180 mM, from about 120 mM to about 160 mM, from about 120 mM to about 140 mM, from about 140 mM to about 180 mM, from about 140 mM to about 160 mM, or from about 160 mM to about 180 mM.

[0139] In certain embodiments, the concentration of cyclodextrin in the liquid pharmaceutical formulation is about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, or about 200 mM.

[0140] In certain embodiments, the concentration of cyclodextrin derivative in the liquid pharmaceutical formulation is about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, or about 200 mM.

[0141] In certain embodiments, the liquid pharmaceutical formulation further comprises water (such as water for injection (WFI)).

[0142] Exemplary furosemide liquid pharmaceutical formulation

[0143] In various embodiments, provided herein are liquid pharmaceutical formulations for treating a disease or disorder described herein (e.g., congestion, edema, fluid overload, or hypertension) in a patient in need thereof, comprising a therapeutically effective amount of furosemide and a pharmaceutically acceptable excipient. Among other things, the liquid pharmaceutical formulation may include a pharmaceutically acceptable pH adjuster, antioxidant, tonicity modifier, and / or pharmaceutically acceptable buffer described herein.

[0144] In various embodiments, the liquid pharmaceutical formulation comprises:

[0145] (i) from about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof; and

[0146] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer.

[0147] In various embodiments, the liquid pharmaceutical formulation comprises:

[0148] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; and

[0149] (ii) tromethamine or a pharmaceutically acceptable salt thereof.

[0150] In various embodiments, the liquid pharmaceutical formulation comprises:

[0151] (i) about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof; and

[0152] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof.

[0153] In various embodiments, the liquid pharmaceutical formulation comprises:

[0154] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0155] (ii) a pharmaceutically acceptable buffer; and

[0156] (iii) a pharmaceutically acceptable pH regulator.

[0157] In various embodiments, the liquid pharmaceutical formulation comprises:

[0158] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0159] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0160] (iii) a pharmaceutically acceptable pH regulator selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0161] In various embodiments, the liquid pharmaceutical formulation comprises:

[0162] (i) about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0163] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0164] (iii) a pharmaceutically acceptable pH regulator.

[0165] In various embodiments, the liquid pharmaceutical formulation comprises:

[0166] (i) about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0167] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0168] (iii) A pharmaceutically acceptable pH regulator.

[0169] In various embodiments, the liquid pharmaceutical formulation comprises:

[0170] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0171] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0172] (iii) A pharmaceutically acceptable pH regulator selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0173] In various embodiments, the liquid pharmaceutical formulation comprises:

[0174] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0175] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0176] (iii) A pharmaceutically acceptable pH regulator comprising sodium hydroxide and hydrochloric acid.

[0177] In various embodiments, the liquid pharmaceutical formulation comprises:

[0178] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0179] (ii) A pharmaceutically acceptable buffer; and

[0180] (iii) An antioxidant.

[0181] In various embodiments, the liquid pharmaceutical formulation comprises:

[0182] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0183] (ii) A pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0184] (iii) An antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0185] In various embodiments, the liquid pharmaceutical formulation comprises:

[0186] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0187] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0188] (iii) About 0.01% (w / w) to about 2% (w / w) of an antioxidant.

[0189] In various embodiments, the liquid pharmaceutical formulation comprises:

[0190] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0191] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0192] (iii) About 0.01% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0193] In various embodiments, the liquid pharmaceutical formulation comprises:

[0194] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0195] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0196] (iii) About 0.01% (w / w) to about 2% (w / w) of sodium metabisulfite.

[0197] In various embodiments, the liquid pharmaceutical formulation comprises:

[0198] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0199] (ii) A pharmaceutically acceptable buffer; and

[0200] (iii) An osmolarity regulator.

[0201] In various embodiments, the liquid pharmaceutical formulation comprises:

[0202] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0203] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0204] (iii) an osmolarity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0205] In various embodiments, the liquid pharmaceutical formulation comprises:

[0206] (i) from about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0207] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0208] (iii) an osmolarity regulator.

[0209] In various embodiments, the liquid pharmaceutical formulation comprises:

[0210] (i) from about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0211] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0212] (iii) an osmolarity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0213] In various embodiments, the liquid pharmaceutical formulation comprises:

[0214] (i) from about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0215] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0216] (iii) sodium chloride.

[0217] In various embodiments, the liquid pharmaceutical formulation comprises:

[0218] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0219] (ii) a pharmaceutically acceptable buffer; and

[0220] (iii) one or more additional pharmaceutically acceptable excipients.

[0221] In various embodiments, the liquid pharmaceutical formulation comprises:

[0222] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0223] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0224] (iii) one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or a derivative thereof, vitamin E or a derivative thereof, and combinations thereof.

[0225] In various embodiments, the liquid pharmaceutical formulation comprises:

[0226] (i) from about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0227] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0228] (iii) from about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0229] In various embodiments, the liquid pharmaceutical formulation comprises:

[0230] (i) from about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0231] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof; and

[0232] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0233] In various embodiments, the liquid pharmaceutical formulation comprises:

[0234] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0235] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0236] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0237] In various embodiments, the liquid pharmaceutical formulation comprises:

[0238] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0239] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0240] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0241] In various embodiments, the liquid pharmaceutical formulation comprises:

[0242] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; and

[0243] (ii) Cyclodextrin or its derivatives.

[0244] In various embodiments, the liquid pharmaceutical formulation comprises:

[0245] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof; and

[0246] (ii) about 5% to about 50% (w / w) of cyclodextrin or its derivative.

[0247] In various embodiments, the liquid pharmaceutical formulation comprises:

[0248] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0249] (ii) a pharmaceutically acceptable buffer; and

[0250] (iii) cyclodextrin or its derivative.

[0251] In various embodiments, the liquid pharmaceutical formulation comprises:

[0252] (i) about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0253] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0254] (iii) about 5% to about 50% (w / w) of cyclodextrin or its derivative.

[0255] In various embodiments, the liquid pharmaceutical formulation comprises:

[0256] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0257] (ii) tromethamine or a pharmaceutically acceptable salt thereof; and

[0258] (iii) cyclodextrin or its derivative.

[0259] In various embodiments, the liquid pharmaceutical formulation comprises:

[0260] (i) about 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0261] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0262] (iii) about 5% to about 50% (w / w) of cyclodextrin or its derivative.

[0263] In various embodiments, the liquid pharmaceutical formulation comprises:

[0264] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; and

[0265] (ii) benzyl alcohol.

[0266] In various embodiments, the liquid pharmaceutical formulation comprises:

[0267] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof; and

[0268] (ii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0269] In various embodiments, the liquid pharmaceutical formulation comprises:

[0270] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0271] (ii) A pharmaceutically acceptable buffer; and

[0272] (iii) Benzyl alcohol

[0273] In various embodiments, the liquid pharmaceutical formulation comprises:

[0274] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0275] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0276] (iii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0277] In various embodiments, the liquid pharmaceutical formulation comprises:

[0278] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0279] (ii) Tromethamine or a pharmaceutically acceptable salt thereof; and

[0280] (iii) Benzyl alcohol.

[0281] In various embodiments, the liquid pharmaceutical formulation comprises:

[0282] (i) About 1 mg / mL to about 250 mg / mL of furosemide or a pharmaceutically acceptable salt thereof;

[0283] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0284] (iii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0285] In various embodiments, the liquid pharmaceutical formulation comprises:

[0286] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0287] (ii) Tromethamine or a pharmaceutically acceptable salt thereof;

[0288] (iii) Benzyl alcohol;

[0289] (iv) Sodium chloride; and

[0290] (v) A pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[0291] In various embodiments, the liquid pharmaceutical formulation comprises:

[0292] (i) About 1 mg / mL to about 250 mg / mL furosemide or a pharmaceutically acceptable salt thereof;

[0293] (ii) About 10 mM to about 250 mM Tromethamine or a pharmaceutically acceptable salt thereof;

[0294] (iii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol;

[0295] (iv) Sodium chloride; and

[0296] (v) A pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[0297] In various embodiments, the liquid pharmaceutical formulation comprises:

[0298] (i) About 1 mg / mL to about 250 mg / mL furosemide or a pharmaceutically acceptable salt thereof;

[0299] (ii) About 10 mM to about 250 mM Tromethamine or a pharmaceutically acceptable salt thereof; and

[0300] (iii) About 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[0301] Exemplary bumetanide liquid pharmaceutical formulation

[0302] In various embodiments, provided herein is a liquid pharmaceutical formulation for treating a disease or disorder (e.g., congestion, edema, fluid overload, or hypertension) described herein in a patient in need thereof, which comprises a therapeutically effective amount of bumetanide and a pharmaceutically acceptable excipient. Among other things, the liquid pharmaceutical formulation may include a pharmaceutically acceptable pH adjuster, antioxidant, tonicity modifier, and / or pharmaceutically acceptable buffer described herein.

[0303] In various embodiments, the liquid pharmaceutical formulation comprises:

[0304] (i) About 0.025 mg / mL to about 65 mg / mL bumetanide or a pharmaceutically acceptable salt thereof; and

[0305] (ii) A pharmaceutically acceptable buffer from about 10 mM to about 500 mM.

[0306] In various embodiments, the liquid pharmaceutical formulation comprises:

[0307] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and

[0308] (ii) Tromethamine or a pharmaceutically acceptable salt thereof.

[0309] In various embodiments, the liquid pharmaceutical formulation comprises:

[0310] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof; and

[0311] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof.

[0312] In various embodiments, the liquid pharmaceutical formulation comprises:

[0313] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0314] (ii) A pharmaceutically acceptable buffer; and

[0315] (iii) A pharmaceutically acceptable pH adjuster.

[0316] In various embodiments, the liquid pharmaceutical formulation comprises:

[0317] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0318] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0319] (iii) A pharmaceutically acceptable pH adjuster selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0320] In various embodiments, the liquid pharmaceutical formulation comprises:

[0321] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0322] (ii) a pharmaceutically acceptable buffer in an amount of about 10 mM to about 500 mM; and

[0323] (iii) a pharmaceutically acceptable pH adjuster.

[0324] In various embodiments, the liquid pharmaceutical formulation comprises:

[0325] (i) bumetanide or a pharmaceutically acceptable salt thereof in an amount of about 0.025 mg / mL to about 65 mg / mL;

[0326] (ii) a pharmaceutically acceptable buffer in an amount of about 10 mM to about 500 mM; and

[0327] (iii) a pharmaceutically acceptable pH adjuster.

[0328] In various embodiments, the liquid pharmaceutical formulation comprises:

[0329] (i) bumetanide or a pharmaceutically acceptable salt thereof in an amount of about 0.025 mg / mL to about 65 mg / mL;

[0330] (ii) a pharmaceutically acceptable buffer in an amount of about 10 mM to about 500 mM, which buffer comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0331] (iii) a pharmaceutically acceptable pH adjuster selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0332] In various embodiments, the liquid pharmaceutical formulation comprises:

[0333] (i) bumetanide or a pharmaceutically acceptable salt thereof in an amount of about 0.025 mg / mL to about 65 mg / mL;

[0334] (ii) tromethamine or a pharmaceutically acceptable salt thereof in an amount of about 10 mM to about 250 mM; and

[0335] (iii) a pharmaceutically acceptable pH adjuster comprising sodium hydroxide and hydrochloric acid.

[0336] In various embodiments, the liquid pharmaceutical formulation comprises:

[0337] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0338] (ii) a pharmaceutically acceptable buffer; and

[0339] (iii) Antioxidant.

[0340] In various embodiments, the liquid pharmaceutical formulation comprises:

[0341] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0342] (ii) A pharmaceutically acceptable buffer comprising a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0343] (iii) An antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0344] In various embodiments, the liquid pharmaceutical formulation comprises:

[0345] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0346] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0347] (iii) From about 0.01% (w / w) to about 2% (w / w) of an antioxidant.

[0348] In various embodiments, the liquid pharmaceutical formulation comprises:

[0349] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0350] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0351] (iii) From about 0.01% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0352] In various embodiments, the liquid pharmaceutical formulation comprises:

[0353] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0354] (ii) About 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof; and

[0355] (iii) About 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[0356] In various embodiments, the liquid pharmaceutical formulation comprises:

[0357] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0358] (ii) A pharmaceutically acceptable buffer; and

[0359] (iii) An isotonicity regulator.

[0360] In various embodiments, the liquid pharmaceutical formulation comprises:

[0361] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0362] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0363] (iii) An isotonicity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0364] In various embodiments, the liquid pharmaceutical formulation comprises:

[0365] (i) About 0.025 mg / mL to about 65 mg / mL bumetanide or a pharmaceutically acceptable salt thereof;

[0366] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0367] (iii) An isotonicity regulator.

[0368] In various embodiments, the liquid pharmaceutical formulation comprises:

[0369] (i) About 0.025 mg / mL to about 65 mg / mL bumetanide or a pharmaceutically acceptable salt thereof;

[0370] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0371] (iii) An osmolarity regulator, selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0372] In various embodiments, the liquid pharmaceutical formulation comprises:

[0373] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0374] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0375] (iii) Sodium chloride.

[0376] In various embodiments, the liquid pharmaceutical formulation comprises:

[0377] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0378] (ii) A pharmaceutically acceptable buffer; and

[0379] (iii) One or more additional pharmaceutically acceptable excipients.

[0380] In various embodiments, the liquid pharmaceutical formulation comprises:

[0381] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0382] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0383] (iii) One or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or derivatives thereof, vitamin E or derivatives thereof, and combinations thereof.

[0384] In various embodiments, the liquid pharmaceutical formulation comprises:

[0385] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0386] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0387] (iii) from about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0388] In various embodiments, the liquid pharmaceutical formulation comprises:

[0389] (i) from about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0390] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffer selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof; and

[0391] (iii) from about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of: ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or a derivative thereof, vitamin E or a derivative thereof, and combinations thereof.

[0392] In various embodiments, the liquid pharmaceutical formulation comprises:

[0393] (i) from about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0394] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0395] (iii) from about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0396] In various embodiments, the liquid pharmaceutical formulation comprises:

[0397] (i) from about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0398] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0399] (iii) From about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0400] In various embodiments, the liquid pharmaceutical formulation comprises:

[0401] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and

[0402] (ii) Cyclodextrin or a derivative thereof.

[0403] In various embodiments, the liquid pharmaceutical formulation comprises:

[0404] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof; and

[0405] (ii) From about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0406] In various embodiments, the liquid pharmaceutical formulation comprises:

[0407] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0408] (ii) A pharmaceutically acceptable buffer; and

[0409] (iii) Cyclodextrin or a derivative thereof.

[0410] In various embodiments, the liquid pharmaceutical formulation comprises:

[0411] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0412] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0413] (iii) From about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0414] In various embodiments, the liquid pharmaceutical formulation comprises:

[0415] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0416] (ii) Tromethamine or a pharmaceutically acceptable salt thereof; and

[0417] (iii) Cyclodextrin or its derivative.

[0418] In various embodiments, the liquid pharmaceutical preparation comprises:

[0419] (i) About 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0420] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0421] (iii) About 5% to about 50% (w / w) of cyclodextrin or its derivative.

[0422] In various embodiments, the liquid pharmaceutical preparation comprises:

[0423] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and

[0424] (ii) Benzyl alcohol.

[0425] In various embodiments, the liquid pharmaceutical preparation comprises:

[0426] (i) About 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof; and

[0427] (ii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0428] In various embodiments, the liquid pharmaceutical preparation comprises:

[0429] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0430] (ii) A pharmaceutically acceptable buffer; and

[0431] (iii) Benzyl alcohol

[0432] In various embodiments, the liquid pharmaceutical preparation comprises:

[0433] (i) About 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0434] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0435] (iii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0436] In various embodiments, the liquid pharmaceutical preparation comprises:

[0437] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0438] (ii) Tromethamine or a pharmaceutically acceptable salt thereof; and

[0439] (iii) Benzyl alcohol.

[0440] In various embodiments, the liquid pharmaceutical formulation comprises:

[0441] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0442] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0443] (iii) From about 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0444] In various embodiments, the liquid pharmaceutical formulation comprises:

[0445] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0446] (ii) Tromethamine or a pharmaceutically acceptable salt thereof;

[0447] (iii) Benzyl alcohol;

[0448] (iv) Sodium chloride; and

[0449] (v) A pH regulator, including sodium hydroxide and / or hydrochloric acid.

[0450] In various embodiments, the liquid pharmaceutical formulation comprises:

[0451] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0452] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof;

[0453] (iii) From about 0.1% (w / w) to about 10% (w / w) of benzyl alcohol;

[0454] (iv) Sodium chloride; and

[0455] (v) A pH regulator, including sodium hydroxide and / or hydrochloric acid.

[0456] In various embodiments, the liquid pharmaceutical formulation comprises:

[0457] (i) From about 0.025 mg / mL to about 65 mg / mL of bumetanide or a pharmaceutically acceptable salt thereof;

[0458] (ii) about 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof; and

[0459] (iii) about 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[0460] Exemplary torasemide liquid pharmaceutical formulations

[0461] In various embodiments, provided herein are liquid pharmaceutical formulations for treating a disease or disorder described herein (e.g., congestion, edema, fluid overload, or hypertension) in a patient in need thereof, comprising a therapeutically effective amount of torasemide and a pharmaceutically acceptable excipient. Among other things, the liquid pharmaceutical formulations can include a pharmaceutically acceptable pH adjuster, antioxidant, tonicity adjuster, and / or pharmaceutically acceptable buffer described herein.

[0462] In various embodiments, the liquid pharmaceutical formulation comprises:

[0463] (i) about 0.5 mg / mL to about 125 mg / mL torasemide or a pharmaceutically acceptable salt thereof; and

[0464] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer.

[0465] In various embodiments, the liquid pharmaceutical formulation comprises:

[0466] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof; and

[0467] (ii) tromethamine or a pharmaceutically acceptable salt thereof.

[0468] In various embodiments, the liquid pharmaceutical formulation comprises:

[0469] (i) about 0.5 mg / mL to about 125 mg / mL torasemide or a pharmaceutically acceptable salt thereof; and

[0470] (ii) about 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof.

[0471] In various embodiments, the liquid pharmaceutical formulation comprises:

[0472] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0473] (ii) a pharmaceutically acceptable buffer; and

[0474] (iii) a pharmaceutically acceptable pH adjuster.

[0475] In various embodiments, the liquid pharmaceutical formulation comprises:

[0476] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0477] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0478] (iii) a pharmaceutically acceptable pH regulator selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0479] In various embodiments, the liquid pharmaceutical formulation comprises:

[0480] (i) from about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0481] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0482] (iii) a pharmaceutically acceptable pH regulator.

[0483] In various embodiments, the liquid pharmaceutical formulation comprises:

[0484] (i) from about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0485] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0486] (iii) a pharmaceutically acceptable pH regulator.

[0487] In various embodiments, the liquid pharmaceutical formulation comprises:

[0488] (i) from about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0489] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0490] (iii) pharmaceutically acceptable pH regulators selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0491] In various embodiments, the liquid pharmaceutical formulation comprises:

[0492] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0493] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0494] (iii) a pharmaceutically acceptable pH regulator comprising sodium hydroxide and hydrochloric acid.

[0495] In various embodiments, the liquid pharmaceutical formulation comprises:

[0496] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0497] (ii) a pharmaceutically acceptable buffer; and

[0498] (iii) an antioxidant.

[0499] In various embodiments, the liquid pharmaceutical formulation comprises:

[0500] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0501] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0502] (iii) an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0503] In various embodiments, the liquid pharmaceutical formulation comprises:

[0504] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0505] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0506] (iii) about 0.01% (w / w) to about 2% (w / w) of an antioxidant.

[0507] In various embodiments, the liquid pharmaceutical formulation comprises:

[0508] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0509] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0510] (iii) about 0.01% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0511] In various embodiments, the liquid pharmaceutical formulation comprises:

[0512] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0513] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0514] (iii) about 0.01% (w / w) to about 2% (w / w) of sodium metabisulfite.

[0515] In various embodiments, the liquid pharmaceutical formulation comprises:

[0516] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0517] (ii) a pharmaceutically acceptable buffer; and

[0518] (iii) an osmolarity regulator.

[0519] In various embodiments, the liquid pharmaceutical formulation comprises:

[0520] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0521] (ii) a pharmaceutically acceptable buffer, which comprises a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0522] (iii) an osmolarity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0523] In various embodiments, the liquid pharmaceutical formulation comprises:

[0524] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0525] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0526] (iii) an osmolarity regulator.

[0527] In various embodiments, the liquid pharmaceutical formulation comprises:

[0528] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0529] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0530] (iii) an osmolarity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0531] In various embodiments, the liquid pharmaceutical formulation comprises:

[0532] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0533] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0534] (iii) sodium chloride.

[0535] In various embodiments, the liquid pharmaceutical formulation comprises:

[0536] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0537] (ii) a pharmaceutically acceptable buffer; and

[0538] (iii) one or more additional pharmaceutically acceptable excipients.

[0539] In various embodiments, the liquid pharmaceutical formulation comprises:

[0540] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0541] (ii) A pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0542] (iii) One or more additional pharmaceutically acceptable excipients, which are selected from the group consisting of: ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0543] In various embodiments, the liquid pharmaceutical formulation comprises:

[0544] (i) About 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0545] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0546] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0547] In various embodiments, the liquid pharmaceutical formulation comprises:

[0548] (i) About 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0549] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof; and

[0550] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients, which are selected from the group consisting of: ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0551] In various embodiments, the liquid pharmaceutical formulation comprises:

[0552] (i) About 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0553] (ii) about 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof; and

[0554] (iii) about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0555] In various embodiments, the liquid pharmaceutical formulation comprises:

[0556] (i) about 0.5 mg / mL to about 125 mg / mL torasemide or a pharmaceutically acceptable salt thereof;

[0557] (ii) about 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof; and

[0558] (iii) about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0559] In various embodiments, the liquid pharmaceutical formulation comprises:

[0560] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof; and

[0561] (ii) cyclodextrin or its derivatives.

[0562] In various embodiments, the liquid pharmaceutical formulation comprises:

[0563] (i) about 0.5 mg / mL to about 125 mg / mL torasemide or a pharmaceutically acceptable salt thereof; and

[0564] (ii) about 5% to about 50% (w / w) of cyclodextrin or its derivatives.

[0565] In various embodiments, the liquid pharmaceutical formulation comprises:

[0566] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0567] (ii) a pharmaceutically acceptable buffer; and

[0568] (iii) cyclodextrin or its derivatives.

[0569] In various embodiments, the liquid pharmaceutical formulation comprises:

[0570] (i) About 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0571] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0572] (iii) About 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0573] In various embodiments, the liquid pharmaceutical formulation comprises:

[0574] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0575] (ii) Tromethamine or a pharmaceutically acceptable salt thereof; and

[0576] (iii) Cyclodextrin or a derivative thereof.

[0577] In various embodiments, the liquid pharmaceutical formulation comprises:

[0578] (i) About 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0579] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0580] (iii) About 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0581] In various embodiments, the liquid pharmaceutical formulation comprises:

[0582] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof; and

[0583] (ii) Benzyl alcohol.

[0584] In various embodiments, the liquid pharmaceutical formulation comprises:

[0585] (i) About 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof; and

[0586] (ii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0587] In various embodiments, the liquid pharmaceutical formulation comprises:

[0588] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0589] (ii) A pharmaceutically acceptable buffer; and

[0590] (iii) Benzyl alcohol

[0591] In various embodiments, the liquid pharmaceutical formulation comprises:

[0592] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0593] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0594] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0595] In various embodiments, the liquid pharmaceutical formulation comprises:

[0596] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0597] (ii) tromethamine or a pharmaceutically acceptable salt thereof; and

[0598] (iii) benzyl alcohol.

[0599] In various embodiments, the liquid pharmaceutical formulation comprises:

[0600] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0601] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0602] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0603] In various embodiments, the liquid pharmaceutical formulation comprises:

[0604] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0605] (ii) tromethamine or a pharmaceutically acceptable salt thereof;

[0606] (iii) benzyl alcohol;

[0607] (iv) sodium chloride; and

[0608] (v) a pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[0609] In various embodiments, the liquid pharmaceutical formulation comprises:

[0610] (i) about 0.5 mg / mL to about 125 mg / mL of torasemide or a pharmaceutically acceptable salt thereof;

[0611] (ii) about 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof;

[0612] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol;

[0613] (iv) sodium chloride; and

[0614] (v) a pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[0615] In various embodiments, the liquid pharmaceutical formulation comprises:

[0616] (i) about 0.5 mg / mL to about 125 mg / mL torasemide or a pharmaceutically acceptable salt thereof;

[0617] (ii) about 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof; and

[0618] (iii) about 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[0619] Unit liquid pharmaceutical preparation of furosemide

[0620] As described herein, in one aspect, the present invention provides a unit liquid pharmaceutical formulation of a loop diuretic (such as bumetanide, furosemide or torasemide).

[0621] In various embodiments, the liquid pharmaceutical formulation generally comprises:

[0622] (i) a therapeutically effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof; and

[0623] (ii) a pharmaceutically acceptable excipient, for example, a pharmaceutically acceptable pH adjuster, antioxidant, tonicity modifier and / or pharmaceutically acceptable buffer as described herein.

[0624] Loop diuretic

[0625] In certain embodiments, the amount of loop diuretic in the unit liquid pharmaceutical preparation described herein can be from about 0.025 mg to about 250 mg, from about 0.1 mg to about 250 mg, from about 1 mg to about 250 mg, from about 5 mg to about 250 mg, from about 10 mg to about 250 mg, from about 20 mg to about 250 mg, from about 30 mg to about 250 mg, from about 40 mg to about 250 mg, from about 50 mg to about 250 mg, from about 60 mg to about 250 mg, from about 70 mg to about 250 mg, from about 80 mg to about 250 mg, from about 90 mg to about 250 mg, from about 100 mg to about 250 mg, from about 120 mg to about 250 mg, from about 140 mg to about 250 mg, from about 160 mg to about 250 mg, from about 180 mg to about 250 mg, from about 200 mg to about 250 mg, from about 225 mg to about 250 mg, from about 0.025 mg to about 225 mg, from about 0.025 mg to about 200 mg, from about 0.025 mg to about 180 mg, from about 0.025 mg to about 160 mg, from about 0.025 mg to about 140 mg, from about 0.025 mg to about 120 mg, from about 0.025 mg to about 100 mg, from about 0.025 mg to about 90 mg, from about 0.025 mg to about 80 mg, from about 0.025 mg to about 70 mg, from about 0.025 mg to about 60 mg, from about 0.025 mg to about 50 mg, from about 0.025 mg to about 40 mg, from about 0.025 mg to about 30 mg, from about 0.025 mg to about 20 mg, from about 0.025 mg to about 10 mg, from about 0.025 mg to about 5 mg, from about 0.025 mg to about 1 mg, from about 0.025 mg to about 0.1 mg, from about 0.1 mg to about 225 mg, from about 0.1 mg to about 200 mg, from about 0.1 mg to about 180 mg, from about 0.1 mg to about 160 mg, from about 0.1 mg to about 140 mg, from about 0.1 mg to about 120 mg, from about 0.1 mg to about 100 mg, from about 0.1 mg to about 90 mg, from about 0.1 mg to about 80 mg, from about 0.1 mg to about 70 mg, from about 0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about 1 mg to about 225 mg, from about 1 mg to about 200 mg, from about 1 mg to about 180 mg, from about 1 mg to about 160 mg, from about 1 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg,from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 5 mg to about 225 mg, from about 5 mg to about 200 mg, from about 5 mg to about 180 mg, from about 5 mg to about 160 mg, from about 5 mg to about 140 mg, from about 5 mg to about 120 mg, from about 5 mg to about 100 mg, from about 5 mg to about 90 mg, from about 5 mg to about 80 mg, from about 5 mg to about 70 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 10 mg to about 225 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 140 mg, from about 10 mg to about 120 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 225 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, from about 20 mg to about 140 mg, from about 20 mg to about 120 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 225 mg, from about 30 mg to about 200 mg, from about 30 mg to about 180 mg, from about 30 mg to about 160 mg, from about 30 mg to about 140 mg, from about 30 mg to about 120 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 225 mg, from about 40 mg to about 200 mg, from about 40 mg to about 180 mg, from about 40 mg to about 160 mg, from about 40 mg to about 140 mg, from about 40 mg to about 120 mg, from about 40 mg to about 100 mg, from about 40 mg to about 90 mg, from about 40 mg to about 80 mg, from about 40 mg to about 70 mg, from about 40 mg to about 60 mg, from about 40 mg to about 50 mg, from about 50 mg to about 225 mg, from about 50 mg to about 200 mg, from about 50 mg to about 180 mg, from about 50 mg to about 160 mg, from about 50 mg to about 140 mg, from about 50 mg to about 120 mg, from about 50 mg to about 100 mg, from about 50 mg to about 90 mgFrom about 50 mg to about 80 mg, from about 50 mg to about 70 mg, from about 50 mg to about 60 mg, from about 60 mg to about 225 mg, from about 60 mg to about 200 mg, from about 60 mg to about 180 mg, from about 60 mg to about 160 mg, from about 60 mg to about 140 mg, from about 60 mg to about 120 mg, from about 60 mg to about 100 mg, from about 60 mg to about 90 mg, from about 60 mg to about 80 mg, from about 60 mg to about 70 mg, from about 70 mg to about 225 mg, from about 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 160 mg, from about 70 mg to about 140 mg, from about 70 mg to about 120 mg, from about 70 mg to about 100 mg, from about 70 mg to about 90 mg, from about 70 mg to about 80 mg, from about 70 mg to about 225 mg, from about 80 mg to about 200 mg, from about 80 mg to about 180 mg, from about 80 mg to about 160 mg, from about 80 mg to about 140 mg, from about 80 mg to about 120 mg, from about 80 mg to about 100 mg, from about 80 mg to about 90 mg, from about 70 mg to about 225 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 160 mg, from about 90 mg to about 140 mg, from about 90 mg to about 120 mg, from about 90 mg to about 100 mg, from about 100 mg to about 225 mg, from about 100 mg to about 200 mg, from about 100 mg to about 180 mg, from about 100 mg to about 160 mg, from about 100 mg to about 140 mg, from about 100 mg to about 120 mg, from about 120 mg to about 225 mg, from about 120 mg to about 200 mg, from about 120 mg to about 180 mg, from about 120 mg to about 160 mg, from about 120 mg to about 140 mg, from about 140 mg to about 225 mg, from about 140 mg to about 200 mg, from about 140 mg to about 180 mg, from about 140 mg to about 160 mg, from about 160 mg to about 225 mg, from about 160 mg to about 200 mg, from about 160 mg to about 180 mg, from about 180 mg to about 225 mg, from about 180 mg to about 200 mg, or from about 200 mg to about 225 mg. In certain embodiments, the amount of loop diuretic in the unit liquid pharmaceutical preparation described herein can be from about 0.025 mg to about 250 mg.

[0626] In certain embodiments, the amount of loop diuretic in the unit liquid pharmaceutical preparation described herein can be greater than about 0.025 mg, greater than about 0.1 mg, greater than about 1 mg, greater than about 5 mg, greater than about 10 mg, greater than about 20 mg, greater than about 30 mg, greater than about 40 mg, greater than about 50 mg, greater than about 60 mg, greater than about 70 mg, greater than about 80 mg, greater than about 90 mg, greater than about 100 mg, greater than about 110 mg, greater than about 120 mg, greater than about 130 mg, greater than about 140 mg, greater than about 150 mg, greater than about 160 mg, greater than about 170 mg, greater than about 180 mg, greater than about 190 mg, greater than about 200 mg, greater than about 210 mg, greater than about 220 mg, greater than about 230 mg, greater than about 240 mg or greater than about 250 mg.

[0627] In certain embodiments, the amount of loop diuretic in the unit liquid pharmaceutical preparation described herein can be about 0.025 mg, about 0.05 mg, about 0.075 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg or about 250 mg.

[0628] In certain embodiments, the loop diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, torasemide or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is furosemide or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is bumetanide or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is ethacrynic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the loop diuretic is torasemide or a pharmaceutically acceptable salt thereof.

[0629] In certain embodiments, the amount of furosemide in the unit liquid pharmaceutical preparation described herein can be from about 1 mg to about 250 mg, from about 5 mg to about 250 mg, from about 10 mg to about 250 mg, from about 20 mg to about 250 mg, from about 30 mg to about 250 mg, from about 40 mg to about 250 mg, from about 50 mg to about 250 mg, from about 60 mg to about 250 mg, from about 70 mg to about 250 mg, from about 80 mg to about 250 mg, from about 90 mg to about 250 mg, from about 100 mg to about 250 mg, from about 120 mg to about 250 mg, from about 140 mg to about 250 mg, from about 160 mg to about 250 mg, from about 180 mg to about 250 mg, from about 200 mg to about 250 mg, from about 225 mg to about 250 mg, from about 1 mg to about 225 mg, from about 1 mg to about 200 mg, from about 1 mg to about 180 mg, from about 1 mg to about 160 mg, from about 1 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 5 mg to about 225 mg, from about 5 mg to about 200 mg, from about 5 mg to about 180 mg, from about 5 mg to about 160 mg, from about 5 mg to about 140 mg, from about 5 mg to about 120 mg, from about 5 mg to about 100 mg, from about 5 mg to about 90 mg, from about 5 mg to about 80 mg, from about 5 mg to about 70 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 10 mg to about 225 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 140 mg, from about 10 mg to about 120 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 225 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, from about 20 mg to about 140 mg, from about 20 mg to about 120 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg,from about 20 mg to about 30 mg, from about 30 mg to about 225 mg, from about 30 mg to about 200 mg, from about 30 mg to about 180 mg, from about 30 mg to about 160 mg, from about 30 mg to about 140 mg, from about 30 mg to about 120 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 225 mg, from about 40 mg to about 200 mg, from about 40 mg to about 180 mg, from about 40 mg to about 160 mg, from about 40 mg to about 140 mg, from about 40 mg to about 120 mg, from about 40 mg to about 100 mg, from about 40 mg to about 90 mg, from about 40 mg to about 80 mg, from about 40 mg to about 70 mg, from about 40 mg to about 60 mg, from about 40 mg to about 50 mg, from about 50 mg to about 225 mg, from about 50 mg to about 200 mg, from about 50 mg to about 180 mg, from about 50 mg to about 160 mg, from about 50 mg to about 140 mg, from about 50 mg to about 120 mg, from about 50 mg to about 100 mg, from about 50 mg to about 90 mg, from about 50 mg to about 80 mg, from about 50 mg to about 70 mg, from about 50 mg to about 60 mg, from about 60 mg to about 225 mg, from about 60 mg to about 200 mg, from about 60 mg to about 180 mg, from about 60 mg to about 160 mg, from about 60 mg to about 140 mg, from about 60 mg to about 120 mg, from about 60 mg to about 100 mg, from about 60 mg to about 90 mg, from about 60 mg to about 80 mg, from about 60 mg to about 70 mg, from about 70 mg to about 225 mg, from about 70 mg to about 200 mg, from about 70 mg to about 180 mg, from about 70 mg to about 160 mg, from about 70 mg to about 140 mg, from about 70 mg to about 120 mg, from about 70 mg to about 100 mg, from about 70 mg to about 90 mg, from about 70 mg to about 80 mg, from about 70 mg to about 225 mg, from about 80 mg to about 200 mg, from about 80 mg to about 180 mg, from about 80 mg to about 160 mg, from about 80 mg to about 140 mg, from about 80 mg to about 120 mg, from about 80 mg to about 100 mg, from about 80 mg to about 90 mg, from about 70 mg to about 225 mg, from about 90 mg to about 200 mg, from about 90 mg to about 180 mg, from about 90 mg to about 160 mg, from about 90 mg to about 140 mg, from about 90 mg to about 120 mg, from about 90 mg to about 100 mg, from about 100 mg to about 225 mg, from about 100 mg to about 200 mg, from about 100 mg to about 180 mg, from about 100 mg to about 160 mg, from about 100 mg to about 140 mg, from about 100 mg to about 120 mg, from about 120 mg to about 225 mgFrom about 120 mg to about 200 mg, from about 120 mg to about 180 mg, from about 120 mg to about 160 mg, from about 120 mg to about 140 mg, from about 140 mg to about 225 mg, from about 140 mg to about 200 mg, from about 140 mg to about 180 mg, from about 140 mg to about 160 mg, from about 160 mg to about 225 mg, from about 160 mg to about 200 mg, from about 160 mg to about 180 mg, from about 180 mg to about 225 mg, from about 180 mg to about 200 mg or from about 200 mg to about 225 mg. In certain embodiments, the amount of furosemide in the unit liquid pharmaceutical preparation described herein can be from about 1 mg to about 250 mg.,

[0630] In certain embodiments, the amount of furosemide in the unit liquid pharmaceutical preparation described herein can be greater than about 1 mg, greater than about 5 mg, greater than about 10 mg, greater than about 20 mg, greater than about 30 mg, greater than about 40 mg, greater than about 50 mg, greater than about 60 mg, greater than about 70 mg, greater than about 80 mg, greater than about 90 mg, greater than about 100 mg, greater than about 110 mg, greater than about 120 mg, greater than about 130 mg, greater than about 140 mg, greater than about 150 mg, greater than about 160 mg, greater than about 170 mg, greater than about 180 mg, greater than about 190 mg, greater than about 200 mg, greater than about 210 mg, greater than about 220 mg, greater than about 230 mg, greater than about 240 mg or greater than about 250 mg.

[0631] In certain embodiments, the amount of furosemide in the unit liquid pharmaceutical preparation described herein can be about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg or about 250 mg. In certain embodiments, the amount of furosemide in the unit liquid pharmaceutical preparation described herein can be about 80 mg.

[0632] In certain embodiments, the amount of bumetanide in the unit liquid pharmaceutical preparation described herein can be from about 0.025 mg to about 65 mg, from about 0.1 mg to about 65 mg, from about 0.5 mg to about 65 mg, from about 1 mg to about 65 mg, from about 5 mg to about 65 mg, from about 10 mg to about 65 mg, from about 20 mg to about 65 mg, from about 30 mg to about 65 mg, from about 40 mg to about 65 mg, from about 50 mg to about 65 mg, from about 60 mg to about 65 mg, from about 0.025 mg to about 60 mg, from about 0.025 mg to about 50 mg, from about 0.025 mg to about 40 mg, from about 0.025 mg to about 30 mg, from about 0.025 mg to about 20 mg, from about 0.025 mg to about 10 mg, from about 0.025 mg to about 5 mg, from about 0.025 mg to about 1 mg, from about 0.025 mg to about 0.5 mg, from about 0.025 mg to about 0.1 mg, from about 0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 1 mg, from about 0.5 mg to about 60 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, from about 0.5 mg to about 30 mg, from about 0.5 mg to about 20 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 60 mg, from about 40 mg to about 50 mg, or from about 50 mg to about 60 mg. In certain embodiments, the amount of bumetanide in the unit liquid pharmaceutical preparation described herein can be from about 0.025 mg to about 65 mg.

[0633] In certain embodiments, the amount of bumetanide in the unit liquid pharmaceutical preparation described herein can be greater than about 0.025 mg, greater than about 1 mg, greater than about 5 mg, greater than about 10 mg, greater than about 20 mg, greater than about 30 mg, greater than about 40 mg, greater than about 50 mg or greater than about 60 mg.

[0634] In certain embodiments, the amount of bumetanide in the unit liquid pharmaceutical preparation described herein can be about 0.025 mg, about 0.05 mg, about 0.075 mg, about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg or about 65 mg.

[0635] In certain embodiments, the amount of torasemide in the unit liquid pharmaceutical preparation described herein can be from about 0.5 mg to about 125 mg, from about 1 mg to about 125 mg, from about 5 mg to about 125 mg, from about 10 mg to about 125 mg, from about 20 mg to about 125 mg, from about 30 mg to about 125 mg, from about 40 mg to about 125 mg, from about 50 mg to about 125 mg, from about 75 mg to about 125 mg, from about 100 mg to about 125 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 75 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, from about 0.5 mg to about 30 mg, from about 0.5 mg to about 20 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 100 mg, from about 1 mg to about 75 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 5 mg to about 100 mg, from about 5 mg to about 75 mg, from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 10 mg to about 100 mg, from about 10 mg to about 75 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 100 mg, from about 20 mg to about 75 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 75 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 100 mg, from about 40 mg to about 75 mg, from about 40 mg to about 50 mg, from about 50 mg to about 100 mg, from about 50 mg to about 75 mg, or from about 75 mg to about 100 mg.

[0636] In certain embodiments, the amount of torasemide in the liquid pharmaceutical preparation described herein can be greater than about 0.5 mg, greater than about 1 mg, greater than about 5 mg, greater than about 10 mg, greater than about 20 mg, greater than about 30 mg, greater than about 40 mg, greater than about 50 mg, greater than about 60 mg, greater than about 70 mg, greater than about 80 mg, greater than about 90 mg, greater than about 100 mg, or greater than about 125 mg.

[0637] In certain embodiments, the amount of torasemide in the unit liquid pharmaceutical preparation described herein can be about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 125 mg.

[0638] Excipients and further components of the unit liquid pharmaceutical preparation

[0639] It should be understood that the excipients, amounts, and concentrations, as well as other conditions and parameters, described herein for the liquid pharmaceutical preparation are equally applicable to the unit liquid pharmaceutical preparation described herein, as if these excipients, amounts, and concentrations, as well as other conditions and parameters, had been written in this section, but are not repeated here for the sake of brevity.

[0640] More specifically, the pH, pharmaceutically acceptable buffers and their concentrations, pharmaceutically acceptable pH regulators and their concentrations, antioxidants and their concentrations, osmolality, and additional pharmaceutically acceptable excipients (such as benzyl alcohol, cyclodextrins, and cyclodextrin derivatives) and their concentrations described herein for the liquid pharmaceutical preparation are equally applicable to the unit liquid pharmaceutical preparation described herein.

[0641] Exemplary furosemide unit liquid pharmaceutical preparations

[0642] In various embodiments, the present disclosure provides unit liquid pharmaceutical preparations for treating the diseases or disorders described herein (e.g., congestion, edema, fluid overload, or hypertension) in a patient in need thereof, comprising a therapeutically effective amount of furosemide and a pharmaceutically acceptable excipient. Among other things, the unit liquid pharmaceutical preparation can include the pharmaceutically acceptable pH regulators, antioxidants, osmolality regulators, and / or pharmaceutically acceptable buffers described herein.

[0643] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0644] (i) about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof; and

[0645] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer.

[0646] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0647] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; and

[0648] (ii) Tromethamine or a pharmaceutically acceptable salt thereof.

[0649] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0650] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof; and

[0651] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof.

[0652] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0653] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0654] (ii) A pharmaceutically acceptable buffer; and

[0655] (iii) A pharmaceutically acceptable pH regulator.

[0656] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0657] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0658] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0659] (iii) A pharmaceutically acceptable pH regulator selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0660] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0661] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0662] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0663] (iii) A pharmaceutically acceptable pH regulator.

[0664] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0665] (i) about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0666] (ii) a pharmaceutically acceptable buffer in an amount of about 10 mM to about 500 mM; and

[0667] (iii) a pharmaceutically acceptable pH adjuster.

[0668] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0669] (i) about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0670] (ii) a pharmaceutically acceptable buffer in an amount of about 10 mM to about 500 mM, which comprises a buffering agent selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0671] (iii) a pharmaceutically acceptable pH adjuster selected from the group consisting of: acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0672] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0673] (i) about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0674] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0675] (iii) a pharmaceutically acceptable pH adjuster comprising sodium hydroxide and hydrochloric acid.

[0676] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0677] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0678] (ii) a pharmaceutically acceptable buffer; and

[0679] (iii) an antioxidant.

[0680] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0681] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0682] (ii) A pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0683] (iii) An antioxidant, which is selected from the group consisting of: sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0684] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0685] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0686] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0687] (iii) About 0.01% (w / w) to about 2% (w / w) of an antioxidant.

[0688] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0689] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0690] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0691] (iii) About 0.01% (w / w) to about 2% (w / w) of an antioxidant, which is selected from the group consisting of: sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0692] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0693] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0694] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0695] (iii) About 0.01% (w / w) to about 2% (w / w) of sodium metabisulfite.

[0696] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0697] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0698] (ii) A pharmaceutically acceptable buffer; and

[0699] (iii) An isotonicity regulator.

[0700] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0701] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0702] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0703] (iii) An isotonicity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0704] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0705] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0706] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0707] (iii) An isotonicity regulator.

[0708] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0709] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0710] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0711] (iii) An isotonicity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0712] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0713] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0714] (ii) About 10 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof; and

[0715] (iii) Sodium chloride.

[0716] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0717] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0718] (ii) A pharmaceutically acceptable buffer; and

[0719] (iii) One or more additional pharmaceutically acceptable excipients.

[0720] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0721] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0722] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0723] (iii) One or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or a derivative thereof, vitamin E or a derivative thereof, and combinations thereof.

[0724] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0725] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0726] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0727] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0728] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0729] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0730] (ii) A pharmaceutically acceptable buffer from about 10 mM to about 500 mM, which comprises a buffer selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof; and

[0731] (iii) One or more additional pharmaceutically acceptable excipients from about 0.1% (w / w) to about 30% (w / w), which are selected from the group consisting of: ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0732] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0733] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0734] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0735] (iii) One or more additional pharmaceutically acceptable excipients from about 0.1% (w / w) to about 30% (w / w).

[0736] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0737] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0738] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0739] (iii) One or more additional pharmaceutically acceptable excipients from about 0.1% (w / w) to about 30% (w / w), which are selected from the group consisting of: ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0740] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0741] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; and

[0742] (ii) Cyclodextrin or its derivatives.

[0743] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0744] (i) from about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof; and

[0745] (ii) from about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0746] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0747] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0748] (ii) a pharmaceutically acceptable buffer; and

[0749] (iii) cyclodextrin or a derivative thereof.

[0750] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0751] (i) from about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0752] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0753] (iii) from about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0754] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0755] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0756] (ii) tromethamine or a pharmaceutically acceptable salt thereof; and

[0757] (iii) cyclodextrin or a derivative thereof.

[0758] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0759] (i) from about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0760] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0761] (iii) from about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0762] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0763] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; and

[0764] (ii) Benzyl alcohol.

[0765] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0766] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof; and

[0767] (ii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0768] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0769] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0770] (ii) A pharmaceutically acceptable buffer; and

[0771] (iii) Benzyl alcohol.

[0772] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0773] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0774] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0775] (iii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0776] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0777] (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0778] (ii) Tromethamine or a pharmaceutically acceptable salt thereof; and

[0779] (iii) Benzyl alcohol.

[0780] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0781] (i) About 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0782] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0783] (iii) About 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[0784] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0785] (i) a therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof;

[0786] (ii) tromethamine or a pharmaceutically acceptable salt thereof;

[0787] (iii) benzyl alcohol;

[0788] (iv) sodium chloride; and

[0789] (v) a pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[0790] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0791] (i) about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0792] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof;

[0793] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol;

[0794] (iv) sodium chloride; and

[0795] (v) a pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[0796] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0797] (i) about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof;

[0798] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0799] (iii) about 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[0800] Exemplary bumetanide unit liquid pharmaceutical preparations

[0801] In various embodiments, provided herein are unit liquid pharmaceutical preparations for treating a disease or disorder described herein (e.g., congestion, edema, fluid overload, or hypertension) in a patient in need thereof, comprising a therapeutically effective amount of bumetanide and a pharmaceutically acceptable excipient. Among other things, the unit liquid pharmaceutical preparation may include a pharmaceutically acceptable pH adjuster, antioxidant, tonicity modifier, and / or pharmaceutically acceptable buffer described herein.

[0802] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0803] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof; and

[0804] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer.

[0805] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0806] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and

[0807] (ii) tromethamine or a pharmaceutically acceptable salt thereof.

[0808] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0809] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof; and

[0810] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof.

[0811] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0812] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0813] (ii) a pharmaceutically acceptable buffer; and

[0814] (iii) a pharmaceutically acceptable pH adjuster.

[0815] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0816] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0817] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0818] (iii) a pharmaceutically acceptable pH adjuster selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0819] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0820] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0821] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0822] (iii) a pharmaceutically acceptable pH adjuster.

[0823] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0824] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0825] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0826] (iii) a pharmaceutically acceptable pH adjuster.

[0827] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0828] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0829] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0830] (iii) a pharmaceutically acceptable pH adjuster selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0831] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0832] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0833] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0834] (iii) a pharmaceutically acceptable pH adjuster comprising sodium hydroxide and hydrochloric acid.

[0835] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0836] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0837] (ii) a pharmaceutically acceptable buffer; and

[0838] (iii) an antioxidant.

[0839] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0840] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0841] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0842] (iii) an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0843] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0844] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0845] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0846] (iii) from about 0.01% (w / w) to about 2% (w / w) of an antioxidant.

[0847] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0848] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0849] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0850] (iii) from about 0.01% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[0851] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0852] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0853] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0854] (iii) from about 0.01% (w / w) to about 2% (w / w) of sodium metabisulfite.

[0855] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0856] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0857] (ii) a pharmaceutically acceptable buffer; and

[0858] (iii) an osmolarity regulator.

[0859] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0860] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0861] (ii) a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0862] (iii) an osmolarity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0863] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0864] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0865] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0866] (iii) an osmolarity regulator.

[0867] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[0868] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0869] (ii) A pharmaceutically acceptable buffer in an amount of about 10 mM to about 500 mM, which comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0870] (iii) An osmolarity regulator selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[0871] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[0872] (i) About 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0873] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0874] (iii) Sodium chloride.

[0875] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[0876] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0877] (ii) A pharmaceutically acceptable buffer; and

[0878] (iii) One or more additional pharmaceutically acceptable excipients.

[0879] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[0880] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0881] (ii) A pharmaceutically acceptable buffer, which comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0882] (iii) One or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or a derivative thereof, vitamin E or a derivative thereof, and combinations thereof.

[0883] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[0884] (i) From about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0885] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0886] (iii) From about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0887] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0888] (i) From about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0889] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof; and

[0890] (iii) From about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients, which are selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0891] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0892] (i) From about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0893] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0894] (iii) From about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[0895] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0896] (i) From about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0897] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0898] (iii) from about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[0899] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0900] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and

[0901] (ii) cyclodextrin or a derivative thereof.

[0902] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0903] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof; and

[0904] (ii) from about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0905] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0906] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0907] (ii) a pharmaceutically acceptable buffer; and

[0908] (iii) cyclodextrin or a derivative thereof.

[0909] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0910] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0911] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0912] (iii) from about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[0913] In various embodiments, a unit liquid pharmaceutical formulation typically comprises:

[0914] (i) a therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0915] (ii) tromethamine or a pharmaceutically acceptable salt thereof; and

[0916] (iii) Cyclodextrin or its derivative.

[0917] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0918] (i) About 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0919] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0920] (iii) About 5% to about 50% (w / w) of cyclodextrin or its derivative.

[0921] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0922] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and

[0923] (ii) Benzyl alcohol.

[0924] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0925] (i) About 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof; and

[0926] (ii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0927] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0928] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0929] (ii) A pharmaceutically acceptable buffer; and

[0930] (iii) Benzyl alcohol.

[0931] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0932] (i) About 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0933] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0934] (iii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0935] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0936] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0937] (ii) Tromethamine or a pharmaceutically acceptable salt thereof; and

[0938] (iii) Benzyl alcohol.

[0939] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0940] (i) About 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0941] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0942] (iii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol.

[0943] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0944] (i) A therapeutically effective amount of bumetanide or a pharmaceutically acceptable salt thereof;

[0945] (ii) Tromethamine or a pharmaceutically acceptable salt thereof;

[0946] (iii) Benzyl alcohol;

[0947] (iv) Sodium chloride; and

[0948] (v) A pH regulator, including sodium hydroxide and / or hydrochloric acid.

[0949] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0950] (i) About 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0951] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof;

[0952] (iii) About 0.1% (w / w) to about 10% (w / w) of benzyl alcohol;

[0953] (iv) Sodium chloride; and

[0954] (v) A pH regulator, including sodium hydroxide and / or hydrochloric acid.

[0955] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0956] (i) from about 0.025 mg to about 65 mg of bumetanide or a pharmaceutically acceptable salt thereof;

[0957] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0958] (iii) from about 0.01% (w / w) to about 2% (w / w) of sodium metabisulfite.

[0959] Exemplary torsemide unit liquid pharmaceutical formulations

[0960] In various embodiments, provided herein are unit liquid pharmaceutical formulations for treating a disease or disorder described herein (e.g., congestion, edema, fluid overload, or hypertension) in a patient in need thereof, comprising a therapeutically effective amount of torsemide and a pharmaceutically acceptable excipient. Among other things, the unit liquid pharmaceutical formulations may include a pharmaceutically acceptable pH adjuster, antioxidant, tonicity adjuster, and / or pharmaceutically acceptable buffer described herein.

[0961] In various embodiments, the unit liquid pharmaceutical formulations generally comprise:

[0962] (i) from about 0.5 mg to about 125 mg of torsemide or a pharmaceutically acceptable salt thereof; and

[0963] (ii) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer.

[0964] In various embodiments, the unit liquid pharmaceutical formulations generally comprise:

[0965] (i) a therapeutically effective amount of torsemide or a pharmaceutically acceptable salt thereof; and

[0966] (ii) tromethamine or a pharmaceutically acceptable salt thereof.

[0967] In various embodiments, the unit liquid pharmaceutical formulations generally comprise:

[0968] (i) from about 0.5 mg to about 125 mg of torsemide or a pharmaceutically acceptable salt thereof; and

[0969] (ii) from about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof.

[0970] In various embodiments, the unit liquid pharmaceutical formulations generally comprise:

[0971] (i) a therapeutically effective amount of torsemide or a pharmaceutically acceptable salt thereof;

[0972] (ii) a pharmaceutically acceptable buffer; and

[0973] (iii) A pharmaceutically acceptable pH regulator.

[0974] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0975] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0976] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0977] (iii) A pharmaceutically acceptable pH regulator selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0978] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0979] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[0980] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0981] (iii) A pharmaceutically acceptable pH regulator.

[0982] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0983] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[0984] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[0985] (iii) A pharmaceutically acceptable pH regulator.

[0986] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[0987] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[0988] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[0989] (iii) A pharmaceutically acceptable pH regulator selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia water, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, and combinations thereof.

[0990] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0991] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[0992] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[0993] (iii) A pharmaceutically acceptable pH regulator comprising sodium hydroxide and hydrochloric acid.

[0994] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0995] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[0996] (ii) A pharmaceutically acceptable buffer; and

[0997] (iii) An antioxidant.

[0998] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[0999] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1000] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[1001] (iii) An antioxidant selected from the group consisting of sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[1002] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1003] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1004] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[1005] (iii) About 0.01% (w / w) to about 2% (w / w) antioxidant.

[1006] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1007] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1008] (ii) About 10 mM to about 500 mM of a pharmaceutically acceptable buffer, which comprises a buffer selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[1009] (iii) About 0.01% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of: sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

[1010] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1011] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1012] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1013] (iii) About 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[1014] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1015] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1016] (ii) A pharmaceutically acceptable buffer; and

[1017] (iii) An osmolarity regulator.

[1018] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1019] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1020] (ii) A pharmaceutically acceptable buffer, which comprises a buffer selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[1021] (iii) An osmolarity regulator, selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[1022] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1023] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1024] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[1025] (iii) An osmolarity regulator.

[1026] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1027] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1028] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[1029] (iii) An osmolarity regulator, selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof.

[1030] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1031] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1032] (ii) From about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1033] (iii) Sodium chloride.

[1034] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1035] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1036] (ii) A pharmaceutically acceptable buffer; and

[1037] (iii) One or more additional pharmaceutically acceptable excipients.

[1038] In various embodiments, the unit liquid pharmaceutical preparation typically comprises:

[1039] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1040] (ii) A pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof, and combinations thereof; and

[1041] (iii) One or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or derivatives thereof, vitamin E or derivatives thereof, and combinations thereof.

[1042] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1043] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1044] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[1045] (iii) From about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[1046] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1047] (i) From about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1048] (ii) From about 10 mM to about 500 mM of a pharmaceutically acceptable buffer comprising a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or a pharmaceutically acceptable salt thereof; and

[1049] (iii) From about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or derivatives thereof, vitamin E or derivatives thereof, and combinations thereof.

[1050] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1051] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1052] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1053] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients.

[1054] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1055] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1056] (ii) About 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1057] (iii) About 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and combinations thereof.

[1058] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1059] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof; and

[1060] (ii) Cyclodextrin or its derivatives.

[1061] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1062] (i) About 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof; and

[1063] (ii) About 5% to about 50% (w / w) of cyclodextrin or its derivatives.

[1064] In various embodiments, the unit liquid pharmaceutical formulation typically comprises:

[1065] (i) A therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1066] (ii) A pharmaceutically acceptable buffer; and

[1067] (iii) Cyclodextrin or its derivatives.

[1068] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[1069] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1070] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[1071] (iii) about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[1072] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[1073] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1074] (ii) tromethamine or a pharmaceutically acceptable salt thereof; and

[1075] (iii) cyclodextrin or a derivative thereof.

[1076] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[1077] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1078] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1079] (iii) about 5% to about 50% (w / w) of cyclodextrin or a derivative thereof.

[1080] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[1081] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof; and

[1082] (ii) benzyl alcohol.

[1083] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[1084] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof; and

[1085] (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[1086] In various embodiments, a unit liquid pharmaceutical preparation typically comprises:

[1087] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1088] (ii) a pharmaceutically acceptable buffer; and

[1089] (iii) benzyl alcohol.

[1090] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1091] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1092] (ii) about 10 mM to about 500 mM of a pharmaceutically acceptable buffer; and

[1093] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[1094] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1095] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1096] (ii) tromethamine or a pharmaceutically acceptable salt thereof; and

[1097] (iii) benzyl alcohol.

[1098] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1099] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1100] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1101] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol.

[1102] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1103] (i) a therapeutically effective amount of torasemide or a pharmaceutically acceptable salt thereof;

[1104] (ii) tromethamine or a pharmaceutically acceptable salt thereof;

[1105] (iii) benzyl alcohol;

[1106] (iv) sodium chloride; and

[1107] (v) a pH adjuster, including sodium hydroxide and / or hydrochloric acid.

[1108] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1109] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1110] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof;

[1111] (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol;

[1112] (iv) sodium chloride; and

[1113] (v) a pH regulator, including sodium hydroxide and / or hydrochloric acid.

[1114] In various embodiments, the unit liquid pharmaceutical preparation generally comprises:

[1115] (i) about 0.5 mg to about 125 mg of torasemide or a pharmaceutically acceptable salt thereof;

[1116] (ii) about 10 mM to about 250 mM of tromethamine or a pharmaceutically acceptable salt thereof; and

[1117] (iii) about 0.01% (w / w) to about 2% (w / w) sodium metabisulfite.

[1118] Therapeutic method

[1119] In one aspect, the liquid pharmaceutical preparation or unit liquid pharmaceutical preparation described herein can be used to treat or prevent various diseases and disorders in a patient in need thereof, such as but not limited to congestion, edema, fluid overload, and / or hypertension.

[1120] In various embodiments, the method comprises administering to a patient the liquid pharmaceutical preparation described herein.

[1121] In various embodiments, the method comprises administering to a patient the unit liquid pharmaceutical preparation described herein.

[1122] In certain embodiments, the liquid pharmaceutical preparation described herein comprises a loop diuretic such as furosemide as the sole therapeutic active ingredient in the liquid pharmaceutical preparation. In some embodiments, the liquid pharmaceutical preparation described herein further comprises a second therapeutic agent. In certain embodiments, the liquid pharmaceutical preparation and the second therapeutic agent are administered simultaneously, together, separately, or at different times as part of a treatment regimen.

[1123] In certain embodiments, the liquid pharmaceutical formulations described herein can be administered parenterally, including by infusion or injection, including subcutaneous administration where appropriate. For example, the liquid pharmaceutical formulations can be administered by, for example, subcutaneous injection or delivery or intravenous injection or delivery. In some embodiments, the liquid pharmaceutical formulations are administered intravenously to a patient. In some embodiments, the liquid pharmaceutical formulations are administered to a patient by intramuscular injection, subcutaneous injection, or subcutaneous infusion. In some embodiments, the liquid pharmaceutical formulations are administered to a patient by subcutaneous infusion using a body-worn subcutaneous delivery system. In some embodiments, the liquid pharmaceutical formulations are administered to a patient by subcutaneous infusion using a wearable subcutaneous delivery system. In some embodiments, the liquid pharmaceutical formulations are administered to a patient by subcutaneous infusion using a pump device. In some embodiments, the pump device is a micro-pump device or a patch device. In some embodiments, the pump device is a patch device. In some embodiments, the liquid pharmaceutical formulations are administered to a patient by intramuscular injection or subcutaneous injection using an autoinjector. In some embodiments, the autoinjector is a disposable autoinjector.

[1124] In certain embodiments, the liquid pharmaceutical formulations described herein are administered to a patient by subcutaneous infusion over a period of about 0.5 hours, about 1.0 hours, about 1.5 hours, about 2.0 hours, about 4.0 hours, or about 8.0 hours. In certain embodiments, the liquid pharmaceutical formulations described herein are administered to a patient by subcutaneous infusion over a period of about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 120 minutes, about 240 minutes, or about 480 minutes. In certain embodiments, the liquid pharmaceutical formulations described herein are administered to a patient by subcutaneous injection in a time equal to or less than 30 seconds (e.g., 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 16 seconds, 17 seconds, 18 seconds, 19 seconds, 20 seconds, 21 seconds, 22 seconds, 23 seconds, 24 seconds, 25 seconds, 26 seconds, 27 seconds, 28 seconds, 29 seconds, or 30 seconds).

[1125] In certain embodiments, the unit liquid pharmaceutical formulations described herein contain a loop diuretic such as furosemide as the sole therapeutic active agent in the unit liquid pharmaceutical formulation. In some embodiments, the unit liquid pharmaceutical formulations described herein further contain a second therapeutic agent. In some embodiments, the unit liquid pharmaceutical formulation and the second therapeutic agent are administered simultaneously, together, or separately or at different times separately as part of a regimen.

[1126] In certain embodiments, the unit liquid pharmaceutical formulations described herein can be administered parenterally, including by infusion, injection, or implantation, including subcutaneous administration where appropriate. For example, the unit liquid pharmaceutical formulations can be administered by, for example, subcutaneous injection or delivery or intravenous injection or delivery. In some embodiments, the unit liquid pharmaceutical formulations are administered intravenously to a patient. In some embodiments, the unit liquid pharmaceutical formulations are administered by subcutaneous injection or subcutaneous infusion to a patient. In some embodiments, the unit liquid pharmaceutical formulations are administered by subcutaneous infusion to a patient using a body-worn subcutaneous delivery system. In some embodiments, the unit liquid pharmaceutical formulations are administered by subcutaneous infusion to a patient using a wearable subcutaneous delivery system. In certain embodiments, the unit liquid pharmaceutical formulations are administered by subcutaneous infusion to a patient using a pump device. In some embodiments, the pump device is a micro-pump device or a patch device. In some embodiments, the pump device is a patch device.

[1127] In certain embodiments, the unit liquid pharmaceutical formulations described herein are administered by subcutaneous infusion to a patient over a period of about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 4 hours, or about 8 hours. In certain embodiments, the unit liquid pharmaceutical formulations described herein are administered by subcutaneous infusion to a patient in a time equal to or less than 30 seconds.

[1128] When administered for the treatment or prevention of the diseases or disorders disclosed herein, it will be understood that the effective dose can vary depending on a number of factors, such as the specific compound or treatment combination used, the mode of administration, and the severity of the disorder being treated, as well as various physical factors related to the individual being treated. In a therapeutic application, the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein can be provided to a patient already suffering from the disease or disorder in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease or disorder and its complications. The dose for treating a particular individual will generally have to be determined subjectively by the attending physician. The variables involved include the specific condition and state as well as the patient's body size, age, and response pattern. In some embodiments, the amount sufficient to cure or at least partially ameliorate the symptoms of the disease or disorder and its complications is an effective amount. In some embodiments, the amount sufficient to cure or at least partially ameliorate the symptoms of the disease or disorder and its complications is a therapeutically effective amount.

[1129] Medicine box

[1130] In one aspect, the present invention provides a kit for treating or preventing various diseases and disorders (such as, but not limited to, congestion, edema, fluid overload, or hypertension) in a patient in need thereof.

[1131] In various embodiments, the cartridge comprises a liquid pharmaceutical formulation as described herein. In certain embodiments, the cartridge comprises one or more unit doses of a liquid pharmaceutical formulation. In certain embodiments, the cartridge further comprises a medical device. In certain embodiments, the cartridge further comprises instructions for treating the diseases or disorders of the present invention.

[1132] In various embodiments, the cartridge comprises a unit liquid pharmaceutical formulation as described herein. In certain embodiments, the cartridge comprises one or more units of a liquid pharmaceutical formulation. In some embodiments, the cartridge comprises one, two, three or more units of a liquid pharmaceutical formulation. In certain embodiments, the cartridge further comprises a medical device. In certain embodiments, the cartridge further comprises instructions for treating the diseases or disorders of the present invention.

[1133] Numerous medical devices have been proposed to facilitate self - administration of pharmaceutical formulations. The device may comprise a reservoir containing, for example, a pre - loaded liquid pharmaceutical formulation to be administered as described herein. For example, a micropump may provide precise subcutaneous administration of a small amount of a liquid pharmaceutical formulation. Such a micropump may be small and portable. Another device for subcutaneous delivery or administration of a pharmaceutical formulation is commonly referred to as a patch device, a transdermal subcutaneous delivery system or a wearable subcutaneous delivery system (e.g., a pump - patch device). The patch device is typically placed directly on the skin of the patient. A device for intramuscular or subcutaneous delivery of a pharmaceutical formulation is an auto - injector.

[1134] Thus, in various embodiments, a medical device such as a micropump or a patch device may comprise: a reservoir containing a pharmaceutical formulation; a subcutaneous injection needle configured to be removably inserted into the skin of a patient; a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the subcutaneous injection needle; a control system configured to control the micropump to deliver the pharmaceutical formulation from the reservoir to the subcutaneous injection needle, thereby subcutaneously administering the pharmaceutical formulation to the patient; and a housing for supporting the reservoir, the subcutaneous injection needle, the micropump and the control system, the housing being portable and adapted to contact the skin of the patient. The liquid pharmaceutical formulation contained in the reservoir may be any liquid pharmaceutical formulation or unit liquid pharmaceutical formulation as described herein.

[1135] In certain embodiments, the medical device may be a one - piece structure. Such a medical device may be disposable. In a particular embodiment, the medical device may be a multi - piece structure. In such a medical device, there may be disposable or reusable parts or components. For example, the housing that defines or includes the reservoir may be a disposable or reusable component of the medical device. In some embodiments, the disposable or reusable housing that defines or includes the reservoir may contain the pharmaceutical formulation of the present teachings. In various embodiments, the subcutaneous injection needle may be a disposable component of the medical device.

[1136] In certain embodiments, the medical device is a pump device. In some embodiments, the pump device is a micropump device or a patch device. In some embodiments, the pump device is a patch device. In certain embodiments, the medical device is selected from the group consisting of: a needle and syringe kit, an autoinjector, a disposable fixed-dose injection pen, a reusable fixed-dose injection pen, a disposable variable-dose injection pen, or a reusable variable-dose injection pen.

[1137] Example

[1138] The present invention will now be described generally, and it will be more readily understood by reference to the following examples, which are merely illustrative of certain aspects and embodiments of the present invention and are not intended to limit the present invention.

[1139] Example 1. Method for manufacturing a furosemide liquid pharmaceutical formulation

[1140] In the following examples, the manufacturing methods of all exemplary furosemide liquid pharmaceutical formulations are outlined.

[1141] The corresponding amounts of the respective ingredients are provided in the formulations disclosed in Table 1.

[1142] Add tromethamine and sodium metabisulfite to an appropriate amount of water for injection (WFI) and mix until dissolved. Add sodium hydroxide (NaOH). Add approximately 1 / 3 of the total amount of the drug substance furosemide and mix until dissolved. Add benzyl alcohol and mix until homogeneous. Add NaOH. Add approximately 1 / 3 of the total amount of the drug substance furosemide and mix until dissolved. Add NaOH. Add the remaining drug substance furosemide and mix until dissolved. Take a pH sample and adjust the solution to pH 7.20 to 7.60 with additional NaOH. After adjusting the pH, add WFI to the resulting solution to reach the final weight and mix. Filter the solution through a 0.22 μm PVDF filter and inject it into a glass syringe.

[1143] Table 1. Formulation of furosemide liquid pharmaceutical formulation

[1144]

[1145] Incorporated by reference

[1146] The entire disclosure of each patent document and scientific article mentioned herein is incorporated herein by reference for all purposes.

[1147] Equivalent solutions

[1148] Without departing from the spirit or essential characteristics of the present invention, the present invention may be embodied in other specific forms. Therefore, the above-described embodiments should be considered illustrative in all respects and not restrictive of the present disclosure described herein. The scope of the present disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes within the meaning and equivalent scope of the claims are intended to be covered by the claims.

Claims

1. A liquid pharmaceutical preparation, comprising: (i) A therapeutically effective amount of furosemide or a pharmaceutically acceptable salt thereof; (ii) An antioxidant; and (iii) A pharmaceutically acceptable buffer.

2. The liquid pharmaceutical preparation according to claim 1, further comprising: (iv) One or more additional pharmaceutically acceptable excipients.

3. The liquid pharmaceutical preparation according to claim 2, wherein the one or more additional pharmaceutically acceptable excipients are selected from the group consisting of ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and any combination thereof.

4. The liquid pharmaceutical preparation according to claim 2 or 3, wherein the one or more additional pharmaceutically acceptable excipients include benzyl alcohol.

5. The liquid pharmaceutical preparation according to claim 4, wherein the amount of benzyl alcohol in the liquid pharmaceutical preparation is from about 0.1% (w / w) to about 10% (w / w).

6. The liquid pharmaceutical preparation according to any one of claims 1-5, wherein the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical preparation is from about 10 mM to about 500 mM.

7. The liquid pharmaceutical preparation according to any one of claims 1-6, wherein the pharmaceutically acceptable buffer comprises a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof.

8. The liquid pharmaceutical preparation according to claim 7, wherein the buffer is tromethamine or a pharmaceutically acceptable salt thereof.

9. The liquid pharmaceutical preparation according to claim 8, wherein the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical preparation is from about 10 mM to about 200 mM.

10. The liquid pharmaceutical preparation according to claim 8 or 9, wherein the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical preparation is from about 25 mM to about 150 mM.

11. The liquid pharmaceutical preparation according to any one of claims 1-10, wherein the amount of the antioxidant in the liquid pharmaceutical preparation is from about 0.05% (w / w) to about 2% (w / w).

12. The liquid pharmaceutical preparation according to any one of claims 1-11, wherein the antioxidant is selected from the group consisting of: sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, EDTA, and combinations thereof.

13. The liquid pharmaceutical preparation according to any one of claims 1-12, wherein the concentration of furosemide in the liquid pharmaceutical preparation is from about 1 mg / mL to about 250 mg / mL.

14. The liquid pharmaceutical preparation according to any one of claims 1-13, wherein the pH of the liquid pharmaceutical preparation is from about 6.5 to about 8.

5.

15. The liquid pharmaceutical preparation according to any one of claims 1-14, wherein the pH of the liquid pharmaceutical preparation is from about 7 to about 8.

3.

16. A unit liquid pharmaceutical preparation comprising: (i) from about 1 mg to about 250 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) from about 0.1% (w / w) to about 30% (w / w) of one or more additional pharmaceutically acceptable excipients selected from the group consisting of: ethanol, benzyl alcohol, glycerol, N-methylpyrrolidone (NMP), sodium chloride, sodium carbonate, mannitol, lactose, dextrose, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin or its derivatives, vitamin E or its derivatives, and any combination thereof; (iii) from about 0.05% (w / w) to about 2% (w / w) of an antioxidant selected from the group consisting of: sodium metabisulfite, sodium bisulfite, monothioglycerol, methionine, EDTA, and combinations thereof; and (iv) from about 10 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof, wherein the pH of the liquid pharmaceutical preparation is from about 6.5 to about 8.

5.

17. The liquid pharmaceutical preparation according to any one of claims 1-15 or the unit liquid pharmaceutical preparation according to claim 16, further comprising one or more of water, a pH adjuster, and an osmolarity adjuster.

18. The liquid pharmaceutical preparation or unit liquid pharmaceutical preparation according to claim 17, wherein the pH adjuster is selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and combinations thereof; and the osmolarity adjuster is selected from the group consisting of sodium chloride, potassium chloride, and combinations thereof.

19. A method for treating congestion, edema, fluid overload or hypertension in a patient in need thereof, the method comprising administering to the patient the liquid pharmaceutical preparation according to any one of claims 1-15, 17 and 18, or the unit liquid pharmaceutical preparation according to any one of claims 16-18.

20. The method according to claim 19, wherein the liquid pharmaceutical preparation is administered to the patient by subcutaneous injection or subcutaneous infusion.

21. The method according to claim 20, wherein the liquid pharmaceutical preparation is administered to the patient by subcutaneous infusion using a body-worn subcutaneous delivery system.

22. The method according to claim 21, wherein the body-worn subcutaneous delivery system is a pump device.

23. The method according to claim 19, wherein the unit liquid pharmaceutical preparation is administered to the patient by subcutaneous injection or subcutaneous infusion.

24. The method according to claim 23, wherein the unit liquid pharmaceutical preparation is administered to the patient by subcutaneous infusion using a body-worn subcutaneous delivery system.

25. The method according to claim 24, wherein the body-worn subcutaneous delivery system is a pump device.

26. A kit for treating congestion, edema, fluid overload or hypertension, comprising the liquid pharmaceutical preparation according to any one of claims 1-15, 17 and 18, or the unit liquid pharmaceutical preparation according to any one of claims 16-18.

27. The kit according to claim 26, comprising one, two, three or more units.

28. The kit according to claim 26 or 27, further comprising a body-worn subcutaneous delivery system.

29. The kit according to claim 28, wherein the body-worn subcutaneous delivery system is a pump device.

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