Treatment methods using loop diuretics

Abstract

Disclosed herein, in part, is a method for administering a liquid pharmaceutical formulation containing a loop diuretic to a patient via subcutaneous injection. Methods for treating conditions such as fluid overload, congestion, edema, and hypertension in a patient in need thereof are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 479,093, filed January 9, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Loop diuretics can be used to treat hypertension, edema, and related conditions, such as congestive heart failure. For example, furosemide is commonly used to treat and / or manage 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).

[0003] The oral bioavailability, and therefore oral efficacy, of loop diuretics such as furosemide is often limited. Furosemide is commonly administered both parenterally and orally; however, significant variability in oral absorption is observed due to the combined effects of limited solubility and reduced stability at acidic pH. B. Devarakonda, DP Otto, A. Judefeind, RA Hill, MM de Villiers, “Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes,” International Journal of Pharmaceutics 345, 142 (Dec. 10, 2007). Therefore, furosemide is typically administered intravenously or intramuscularly for most patients with congestive heart failure or other forms of more advanced edema.

[0004] Intravenous administration of medications such as loop diuretics requires trained medical professionals to place a catheter and administer the medication. In contrast, medications can be administered by subcutaneous injection or infusion, e.g., at home, by the patient or caregiver using an automatic injection device and / or a wearable, body-worn delivery and infusion device. Subcutaneous administration of loop diuretics by the patient or caregiver can also enable more optimal therapeutic dosing and total dose to produce more favorable pharmacokinetic and pharmacodynamic profiles and patient outcomes.

[0005] For subcutaneous administration, discomfort and pain during administration should be minimized to avoid decreased patient compliance with the treatment regimen. Factors that may contribute to the pain and discomfort experienced by patients during, during, or after subcutaneous administration include the injection volume, the pH of the formulation, and the osmolarity or isotonicity of the formulation. Furthermore, such formulations should be stable in solution so that they can be quickly utilized and / or pre-loaded into a wide variety of drug delivery devices.

[0006] Thus, there is a need for improved pharmaceutical formulations containing a loop diuretic (e.g., bumetanide, furosemide, or torsemide) that are chemically and physically stable over their shelf life, contain a sufficient concentration of the loop diuretic (e.g., an effective amount in an appropriate volume), and are at an appropriate pH and osmolality to allow, for example, subcutaneous administration (e.g., subcutaneous injection) of the loop diuretic. Summary of the Invention

[0007] In one aspect, the present invention provides a method for treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method generally comprising administering a liquid pharmaceutical formulation containing a loop diuretic. In certain embodiments, an effective amount of the loop diuretic is administered by subcutaneous injection. That is, it has been discovered that a liquid pharmaceutical formulation of the present invention containing an effective amount of loop diuretic, e.g., about 1 mg to about 100 mg, and having a total volume of, e.g., about 0.5 mL to about 1 mL, can be delivered subcutaneously in a short time, e.g., 30 seconds or less. Delivering 80 mg of furosemide in a volume of about 1 mL or less in a short time without a substantial increase in pain at the injection site may enable patients to use subcutaneous injection devices (e.g., autoinjectors) more quickly, which should increase compliance with treatment.

[0008] In various embodiments of the invention, the methods comprise administering to a human by subcutaneous injection an effective amount of a loop diuretic in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0009] In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 100 mg, and in certain embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL to about 100 mg / mL.

[0010] In certain embodiments, the total urine output of a human is about 600 mL to about 5000 mL about 6 hours after completion of administration. In certain embodiments, the total urine output of a human is about 600 mL to about 5300 mL about 8 hours after completion of administration. In certain embodiments, the total urine output of a human is about 600 mL to about 5500 mL about 12 hours after completion of administration.

[0011] In certain embodiments, the loop diuretic is bumetanide, furosemide, or torsemide.

[0012] In various embodiments of the invention, the methods comprise administering to a human by subcutaneous injection an effective amount of furosemide in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0013] In certain embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is about 40 mg to about 80 mg. In certain embodiments, the concentration of furosemide in the total volume of the liquid pharmaceutical formulation is about 80 mg / mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation is about 0.5 mL or about 1 mL.

[0014] In various embodiments of the invention, the methods comprise administering to a human by subcutaneous injection about 80 mg of furosemide in a liquid pharmaceutical formulation in a total volume of about 1 mL.

[0015] In various embodiments of the invention, the methods comprise administering to a human by subcutaneous injection about 40 mg of furosemide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL.

[0016] In certain embodiments, the method provides a furosemide C in human plasma of about 1500 ng / mL to about 9800 ng / mL. max In certain embodiments, the method provides a furosemide AUC in human plasma of about 4400 h*ng / mL to about 31700 h*ng / mL. last In certain embodiments, the method provides a furosemide AUC in human plasma of about 4000 h*ng / mL to about 24000 h*ng / mL.inf In certain embodiments, the total urine output of a human is about 600 mL to about 5000 mL about 6 hours after completion of administration. In certain embodiments, the total urine output of a human is about 600 mL to about 5300 mL about 8 hours after completion of administration. In certain embodiments, the total urine output of a human is about 600 mL to about 5500 mL about 12 hours after completion of administration.

[0017] In various embodiments of the invention, the method comprises administering to a human by subcutaneous injection about 80 mg of furosemide in a total volume of about 1 mL of a liquid pharmaceutical formulation, which is one or more of the following: The method involves measuring furosemide C in human plasma from about 3000 ng / mL to about 9800 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 8800 h*ng / mL to about 31700 h*ng / mL. last provide; The method involves measuring the AUC of furosemide in human plasma from about 8900 h*ng / mL to about 33400 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0018] In various embodiments of the invention, the method comprises administering to a human by subcutaneous injection about 80 mg of furosemide in a total volume of about 1 mL of a liquid pharmaceutical formulation; The method involves measuring furosemide C in human plasma from about 3000 ng / mL to about 9800 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 8800 h*ng / mL to about 31700 h*ng / mL. last provide; The method involves measuring the AUC of furosemide in human plasma from about 8900 h*ng / mL to about 33400 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0019] In various embodiments of the invention, the method comprises administering to a human by subcutaneous injection about 40 mg of furosemide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation, which is one or more of the following: The method involves measuring furosemide C in human plasma from about 1500 ng / mL to about 4900 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 4400 h*ng / mL to about 15850 h*ng / mL. last provide; The method provides a method for determining the AUC of furosemide in human plasma from about 4450 h*ng / mL to about 16700 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0020] In various embodiments of the invention, the method comprises administering to a human by subcutaneous injection about 40 mg of furosemide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation; The method involves measuring furosemide C in human plasma from about 1500 ng / mL to about 4900 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 4400 h*ng / mL to about 15850 h*ng / mL.last provide; The method provides a method for determining the AUC of furosemide in human plasma from about 4450 h*ng / mL to about 16700 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0021] In certain embodiments, administering comprises administering the total dose in a time period of 30 seconds or less, hi certain embodiments, administering comprises administering the total dose from an autoinjector.

[0022] In certain embodiments, the liquid pharmaceutical formulation further comprises a pharmaceutically acceptable buffer, optionally wherein the pharmaceutically acceptable buffer comprises tromethamine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the liquid pharmaceutical formulation has a pH of about 7.2 to about 8. In certain embodiments, the liquid pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients, optionally wherein the one or more pharmaceutically acceptable excipients are selected from benzyl alcohol, sodium hydroxide, sodium chloride, hydrochloric acid, and combinations thereof.

[0023] In various embodiments, the human is an adult human, and optionally, the adult human is 45 to 80 years of age. In certain embodiments, the adult human has New York Heart Association (NYHA) Class II, Class III, or Class IV chronic heart failure, liver disease or dysfunction, or renal disease or dysfunction. In certain embodiments, the adult human exhibits reduced responsiveness to oral diuretics prior to initiating subcutaneous administration according to the method. In certain embodiments, the edema is associated with congestive heart failure, cirrhosis, or renal disease, and optionally, the renal disease is nephrotic syndrome. DETAILED DESCRIPTION OF THE INVENTION

[0024] It has been discovered that an effective amount of a loop diuretic can be delivered subcutaneously in a volume of about 1 mL or less in a short period of time without a substantial increase in pain at the injection site. Such a method may enable patients to use subcutaneous injection devices (e.g., autoinjectors) and the like in a shorter time, which should increase treatment compliance. As generally described herein, the present invention provides methods for treating various conditions, diseases, and disorders (e.g., fluid overload, congestion, edema, and hypertension) in a human patient in need of such treatment. The methods may generally involve subcutaneously administering a liquid pharmaceutical formulation of furosemide (e.g., 80 mg in 1 mL) to a patient in 30 seconds or less. The liquid pharmaceutical formulations and delivery profiles of furosemide described herein can result in optimized pharmacokinetic and pharmacodynamic profiles of furosemide that can maximize patient outcomes (e.g., total urine output).

[0025] definition To facilitate the understanding of this invention, several terms and phrases are defined below.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0027] As used herein, the terms "a" and "an" mean "one or more" and include the plural forms unless the context requires otherwise.

[0028] In this application, when an element or component is described as being included in and / or selected from a list of described elements or components, it is to be understood that such element or component can be any of the described elements or components, and that such element or component can be selected from a group consisting of two or more of the described elements or components.

[0029] Furthermore, it should be understood that elements and / or features of the compositions or methods described herein, whether expressly or implied herein, can be combined in various manners without departing from the spirit and scope of the invention. For example, when a particular compound is referenced, that compound can be used in various embodiments of the compositions of the invention and / or methods of the invention, unless otherwise understood from the context. In other words, although embodiments are described and illustrated within this application so that the application is written and depicted concisely and clearly, it is intended and understood that the embodiments can be combined or separated in various ways without departing from the present teachings and invention(s). For example, it will be recognized that all features described and illustrated herein are applicable to all aspects of the invention(s) described and illustrated herein.

[0030] The phrase "at least one of" should be understood to include the object(s) described after such phrase and each of the various combinations of two or more of the described object(s) individually, unless otherwise understood from context and usage. The phrase "and / or" in the context of more than two described object(s) should be understood to have the same meaning, unless otherwise understood from context.

[0031] Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including their grammatical equivalents, generally, unless specifically stated or understood otherwise from the context, should be understood as open-ended and non-limiting, i.e., not excluding additional, unrecited elements or steps.

[0032] When the term "about" is used before a quantitative value, the present invention also includes that particular quantitative value itself unless specifically stated otherwise. As used herein, the term "about" refers to a ±10%, ±5%, ±3%, ±2%, or ±1% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0033] At various places herein, values ​​are disclosed in groups or ranges. It is specifically intended that such descriptions include any and all individual subcombinations of the members of such groups and ranges. For example, a number in the range of 0 to 40 is specifically intended to individually disclose the integers 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 a number in the range of 1 to 20 is specifically intended to individually disclose the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0034] Any examples or use of exemplary language herein, such as "such as" or "including," are intended solely to better describe the invention and do not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0035] As used herein, "compound" (including specifically named compounds, e.g., furosemide, bumetanide, ethacrynic acid, torsemide) refers to the compound per se and pharmaceutically acceptable salts thereof, unless otherwise understood from the context of the description or unless expressly limited to a particular form of the compound, e.g., the compound per se or a pharmaceutically acceptable salt thereof.

[0036] As used herein, "furosemide" refers to a compound of the formula: [ka] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, furosemide sodium salt and quaternary ammonium salts of furosemide. Furosemide may also be referred to by other names, such as frusemide, 5-(aminosulfonyl)-4-chloro-2-[(2-furanyl-methyl)amino]benzoic acid, its IUPAC name 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid, or its generic name Lasix®.

[0037] As used herein, "bumetanide" refers to a compound of the formula: [ka] and pharmaceutically acceptable salts thereof. Such salts may include, but are not limited to, furosemide potassium salt and furosemide sodium salt. Bumetanide may also be referred to by other names, such as bumethyi, bumetanide, its IUPAC name 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid, or its generic trade names Bumex® and Burinex®.

[0038] As used herein, "ethacrynic acid" refers to a compound of the formula: [ka] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, ethacrynic acid sodium salt (also called sodium ethacrynate). Ethacrynic acid may also be referred to by other names, such as ethacrynic acid, its IUPAC name 2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid, or its generic trade names Sodium Edecrin® and Edecrin®.

[0039] As used herein, "torsemide" refers to a compound of the formula: [ka] and pharmaceutically acceptable salts thereof. Such salts may include, but are not limited to, torsemide sodium salt. Torsemide may also be referred to by other names, such as torasemide, 1-isopropyl-3-((4-(3-methylphenylamino)pyridine)-3-sulfonyl)urea, 1-isopropyl-3-((4-m-toluidino-3-pyridyl)sulfonyl)urea, its IUPAC name 1-[4-(3-methylanilino)pyridin-3-yl]sulfonyl-3-propan-2-ylurea, or its generic trade name Demadex®.

[0040] As used herein, the terms "subject" and "patient" refer to an organism treated by the methods and / or compositions described herein. Such an organism is preferably a mammal (e.g., mouse, ape, horse, cow, pig, dog, cat, etc.), more preferably a human.

[0041] As used herein, a "buffer" refers to an aqueous solution that is resistant to changes in pH. Buffers may include "buffering agents," such as weak acids and their salts or weak bases and their salts, which help maintain pH stability. Examples of buffers used in pharmaceutical formulations include bicarbonate buffers, carbonate buffers, citrate buffers, histidine buffers, phosphate buffers, tartrate buffers, tris(hydroxymethyl)aminomethane (or 2-amino-2-hydroxymethyl-propane-1,3-diol [(HOCH2)3CNH2]) buffers, and combinations thereof. Some of these buffers are suitable for pharmaceutical formulations administered subcutaneously.

[0042] Tris(hydroxymethyl)aminomethane or tris(hydroxymethyl)aminomethane buffer may also be referred to as "TRIS," "Tris," "Tris buffer," "Trisamine," "THAM," "tromethamine," and other names. Furthermore, many buffers and / or buffering systems can include Tris or its pharmaceutically acceptable salts and can be used in the present teachings. For example, Tris-buffered saline ("TBS"), Tris-hydrochloride buffer ("Tris-HCl"), Tris base (pH 10.6), Tris / borate / ethylenediaminetetraacetate ("EDTA") buffer ("TBE"), and Tris / acetate / EDTA buffer ("TAE"). Tris base is often used with Tris-HCl to prepare Tris buffers at desired pHs. Furthermore, the present teachings can include Tris-related compounds, e.g., compounds derived from or structurally related to Tris, that can act as buffers.

[0043] As used herein, "isotonicity" refers to the ionic strength or concentration of ions in a solution, such as a pharmaceutical formulation. Isotonicity is often measured in molarity ("M"). As used herein, "isotonic solution," "isotonic formulation," "isotonic pharmaceutical formulation," and pharmaceutical formulations that are "isotonic" refer to a solution or formulation that has ion concentrations that are the same as or similar to the concentrations of ions found in bodily fluids.

[0044] As used herein, "physiological pH" refers to a pH of about 7.4.

[0045] As used herein, "osmolality," "osmolality," and "osmolality" refer to the osmotic pressure of a solution, such as a pharmaceutical formulation. Osmolality is often measured in osmolality ("Osm / L" or "OsM") or osmolality ("Osm / kg"). When measuring freezing point depression, the observed value is the osmolality of the solution. In contrast to isotonicity, osmolality takes into account non-ionized solutes in a solution, which, if present, will cause the osmolality or osmolality of a solution to be higher than the isotonicity of that solution. The osmolality of the liquid pharmaceutical formulations described herein can be measured, for example, using vapor pressure methods.

[0046] As used herein, "osmolality adjusting agent," "osmolality adjusting agent," and "osmotic agent" refer to pharmaceutically acceptable compounds that can be added to liquid pharmaceutical formulations described herein to adjust the osmolality of the liquid pharmaceutical formulations.

[0047] As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely interact with the active ingredient. Thus, a pharmaceutically acceptable carrier is one that is compatible with other ingredients in the formulation and is biologically acceptable. In certain embodiments, additional active ingredients can also be incorporated into the pharmaceutical composition.

[0048] As used herein, "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and the absorption of the active agent by the subject, and can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, phosphate buffered saline, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohol, oil, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxypropylmethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, can be mixed with auxiliary substances that do not deleteriously react with the compounds of the invention, such as lubricants, preservatives, stabilizers, surfactants (e.g., polysorbate 20 or polysorbate 80), wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and / or flavoring substances, etc. For examples of excipients and carriers, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0049] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil-in-water or water-in-oil emulsions), and various types of wetting agents. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention, which, upon administration to a subject, can provide a compound of the present invention or its active metabolite or residue. As known to those skilled in the art, "salts" of the compounds of the present 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, toluene-p-sulfonic 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, while not themselves pharmaceutically acceptable, may be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0051] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of formula NW4 + (Wherein W is C 1-4 Examples of suitable compounds include, but are not limited to, compounds of the formula:

[0052] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include those containing a suitable cation, e.g., Na + , NH4 + , and NW4 + (Wherein W is C 1-4 Examples of the anion of the compound of the present invention include an anion having a substituent such as an alkyl group.

[0053] As used herein, the term "effective amount" refers to an amount of a composition (e.g., a liquid pharmaceutical formulation of the present invention) sufficient to produce a beneficial or desired result, including a desired therapeutic effect. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0054] As used herein, the terms "treat," "treating," and "treatment" include any effect that results in improvement of a condition, disease, disorder, etc., or the amelioration of a symptom thereof, e.g., alleviation, reduction, modulation, remission, or elimination.

[0055] As used herein, the term "congestion" (in heart failure) refers to the presence of signs and symptoms of extracellular fluid accumulation resulting in elevated cardiac filling pressures that cause reduced cardiac output, which is further exacerbated by neurohormonal activation, causing increased renal sodium and water binding capacity, resulting in plasma volume expansion.

[0056] As used herein, "fluid overload," "volume overload," and "hypervolemia" can refer to a medical condition in which there is too much fluid in the blood. Excess fluid, primarily salt and water, can accumulate throughout the body and lead to weight gain.

[0057] Throughout the description, when compositions and kits are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is additionally contemplated that there are compositions and kits of the invention that consist essentially of or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0058] As a general matter, compositions in which percentages are specified are by weight unless otherwise specified.

[0059] Liquid pharmaceutical formulation of loop diuretic As described herein, in one aspect, the present invention provides a liquid pharmaceutical formulation for treating a condition described herein, comprising an effective amount of a loop diuretic, or a pharmaceutically acceptable salt thereof. In certain embodiments, the condition is selected from the group consisting of fluid congestion, edema, and hypertension, and combinations thereof. In certain embodiments, the condition is fluid congestion. In certain embodiments, the condition is edema. In certain embodiments, the condition is hypertension.

[0060] (A) Loop diuretics In certain embodiments, the effective amount of the loop diuretic in the liquid pharmaceutical formulations described herein is from about 1 mg to about 100 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 60 mg to about 100 mg, from about 70 mg to about 100 mg, from about 80 mg to about 100 mg, from about 90 mg to about 100 mg, from about 1 mg to about 90 mg, from about 1 mg to about 80 mg, or from about 1 mg to about 100 mg. mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 90 mg, about 5 mg to about 8 0mg, about 5mg to about 70mg, about 5mg to about 60mg, about 5mg to about 50mg, about 5mg to about 40mg, about 5mg to about 30mg, about 5mg to about 20mg, about 5mg to about 10mg, about 10mg to about 90mg, about 10mg to about 80mg , about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about About 70mg, about 20mg to about 60mg, about 20mg to about 50mg, about 20mg to about 40mg, about 20mg to about 30mg, about 30mg to about 90mg, about 30mg to about 80mg, about 30mg to about 70mg, about 30mg to about 60mg, about 3 In certain embodiments, the effective amount of loop diuretic in the liquid pharmaceutical formulations described herein is about 1 mg to about 100 mg.In certain embodiments, the effective amount of the loop diuretic in the liquid pharmaceutical formulations described herein is 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 15 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, or about 100 mg.

[0061] In certain embodiments, the concentration of the loop diuretic in the liquid pharmaceutical formulations described herein is from about 2 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 30 mg / mL to about 100 mg / mL, from about 40 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 60 mg / mL to about 100 mg / mL, from about 70 mg / mL to about 100 mg / mL, from about 80 mg / mL to about 100 mg / mL, or from about 90 mg / mL to about 100 mg / mL. L, about 2 mg / mL to about 90 mg / mL, about 2 mg / mL to about 80 mg / mL, about 2 mg / mL to about 70 mg / mL, about 2 mg / mL to about 60 mg / mL, about 2 mg / mL to about 50 mg / mL, about 2 mg / mL to about 40 mg / mL, about 2 mg / mL to about 30 mg / mL, about 2 mg / mL~about 20mg / mL, about 2mg / mL~about 10mg / mL, about 2mg / mL~about 5mg / mL, about 5mg / mL~about 90mg / mL, about 5mg / mL~about 80mg / mL, about 5mg / mL~about 70mg / mL, about 5mg / mL~about 60mg / mL, about 5mg / mL ~50mg / mL, 5mg / mL~40mg / mL, 5mg / mL~30mg / mL, 5mg / mL~20mg / mL, 5mg / mL~10mg / mL, 10mg / mL~90mg / mL, 10mg / mL~80mg / mL, 10mg / mL~ Approximately 70 mg / mL, approximately 10 mg / mL to approximately 60 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 10 mg / mL to approximately 40 mg / mL, approximately 10 mg / mL to approximately 30 mg / mL, approximately 10 mg / mL to approximately 20 mg / mL, approximately 20 mg / mL to approximately 90 mg / mL, approximately 20 mg / mL mL~about 80mg / mL, about 20mg / mL~about 70mg / mL, about 20mg / mL~about 60mg / mL, about 20mg / mL~about 50mg / mL, about 20mg / mL~about 40mg / mL, about 20mg / mL~about 30mg / mL, about 30mg / mL~about 90mg / mL, about 30 mg / mL to about 80 mg / mL, about 30 mg / mL to about 70 mg / mL, about 30 mg / mL to about 60 mg / mL, about 30 mg / mL to about 50 mg / mL, about 30 mg / mL to about 40 mg / mL, about 40 mg / mL to about 90 mg / mL, about 40 mg / mL to about 80 mg / mL,The concentration of the loop diuretic in the liquid pharmaceutical formulations described herein can be about 40 mg / mL to about 70 mg / mL, about 40 mg / mL to about 60 mg / mL, about 40 mg / mL to about 50 mg / mL, about 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 80 mg / mL, about 50 mg / mL to about 70 mg / mL, about 50 mg / mL to about 60 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / mL to about 90 mg / mL, about 70 mg / mL to about 80 mg / mL, or about 80 mg / mL to about 90 mg / mL. In certain embodiments, the concentration of the loop diuretic in the liquid pharmaceutical formulations described herein can be about 2 mg / mL to about 100 mg / mL.

[0062] In various embodiments, the liquid pharmaceutical formulations described herein may include a pharmaceutically acceptable salt of a loop diuretic.

[0063] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a dose of about 1 mg to about 100 mg, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 60 mg to about 100 mg, about 70 mg to about 100 mg, about 80 mg to about 100 mg, about 90 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, or about 1 mg to about 60 mg , about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 1 0mg to about 50mg, about 10mg to about 40mg, about 10mg to about 30mg, about 10mg to about 20mg, about 20mg to about 90mg, about 20mg to about 80mg, about 20mg to about 70mg, about 20mg to about 60mg, about 20mg to about 50mg, about 20mg to about 40mg, about 20mg to about 30mg, about 30mg to about 90mg, about 30mg to about 80mg, about 30mg to about 70mg, about 30mg to about 60mg, about 30mg to about 50mg, about 30mg to about 40mg, about 40mg to about 90mg, about The liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of a loop diuretic in an amount to provide 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 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 90 mg, from about 60 mg to about 80 mg, from about 60 mg to about 70 mg, from about 70 mg to about 90 mg, from about 70 mg to about 80 mg, or from about 80 mg to about 90 mg of the loop diuretic in its free acid / free base form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of a loop diuretic in an amount to provide from about 1 mg to about 100 mg of the loop diuretic in its free acid / free base form.

[0064] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of a loop diuretic in an amount to provide 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 15 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, or about 100 mg of the loop diuretic in free acid / free base form.

[0065] In certain embodiments, the liquid pharmaceutical formulations described herein may comprise a dilution of about 2 mg / mL to about 100 mg / mL, about 5 mg / mL to about 100 mg / mL, about 10 mg / mL to about 100 mg / mL, about 20 mg / mL to about 100 mg / mL, about 30 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 70 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, about 90 mg / mL to about 100 mg / mL, about 2 mg / mL to about 9 0mg / mL, about 2mg / mL to about 80mg / mL, about 2mg / mL to about 70mg / mL, about 2mg / mL to about 60mg / mL, about 2mg / mL to about 50mg / mL, about 2mg / mL to about 40mg / mL, about 2mg / mL to about 30mg / mL, about 2mg / mL to about 20mg / m L, about 2 mg / mL to about 10 mg / mL, about 2 mg / mL to about 5 mg / mL, about 5 mg / mL to about 90 mg / mL, about 5 mg / mL to about 80 mg / mL, about 5 mg / mL to about 70 mg / mL, about 5 mg / mL to about 60 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL~about 40mg / mL, about 5mg / mL~about 30mg / mL, about 5mg / mL~about 20mg / mL, about 5mg / mL~about 10mg / mL, about 10mg / mL~about 90mg / mL, about 10mg / mL~about 80mg / mL, about 10mg / mL~about 70mg / mL, about 10mg / mL mL~about 60mg / mL, about 10mg / mL~about 50mg / mL, about 10mg / mL~about 40mg / mL, about 10mg / mL~about 30mg / mL, about 10mg / mL~about 20mg / mL, about 20mg / mL~about 90mg / mL, about 20mg / mL~about 80mg / mL, about 20m g / mL~about 70mg / mL, about 20mg / mL~about 60mg / mL, about 20mg / mL~about 50mg / mL, about 20mg / mL~about 40mg / mL, about 20mg / mL~about 30mg / mL, about 30mg / mL~about 90mg / mL, about 30mg / mL~about 80mg / mL, about 3 0mg / mL to about 70mg / mL, about 30mg / mL to about 60mg / mL, about 30mg / mL to about 50mg / mL, about 30mg / mL to about 40mg / mL, about 40mg / mL to about 90mg / mL, about 40mg / mL to about 80mg / mL, about 40mg / mL to about 70mg / mL,The present invention includes a pharmaceutically acceptable salt of a loop diuretic in an amount to provide a concentration of the loop diuretic in its free acid / free base form of about 40 mg / mL to about 60 mg / mL, about 40 mg / mL to about 50 mg / mL, about 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 80 mg / mL, about 50 mg / mL to about 70 mg / mL, about 50 mg / mL to about 60 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / mL to about 90 mg / mL, about 70 mg / mL to about 80 mg / mL, or about 80 mg / mL to about 90 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein include a pharmaceutically acceptable salt of a loop diuretic in an amount to provide a concentration of the loop diuretic in free acid / free base form of about 2 mg / mL to about 100 mg / mL.

[0066] In certain embodiments, the loop diuretic is bumetanide, furosemide, or torsemide.

[0067] (i) Furosemide In various aspects, the present invention provides a liquid pharmaceutical formulation for the treatment of the conditions described herein, comprising an effective amount of furosemide, or a pharmaceutically acceptable salt thereof.

[0068] In certain embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is about 40 mg to about 100 mg, about 45 mg to about 100 mg, about 50 mg to about 100 mg, about 55 mg to about 100 mg, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, about 95 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, About 40mg to about 75mg, about 40mg to about 70mg, about 40mg to about 65mg, about 40mg to about 60mg, about 40mg to about 55mg, about 40mg to about 50mg, about 45mg to about 95mg, about 45mg to about 90mg, about 45mg to about 85mg, about 45mg to about 80mg, about 45 mg ~ about 75mg, about 45mg - about 70mg, about 45mg - about 65mg, about 45mg - about 60mg, about 45mg - about 55mg, about 45mg - about 50mg, about 50mg - about 95mg, about 50mg - about 90mg, about 50mg - about 85mg, about 50mg - about 80mg, about 50mg Approx. 75 mg, approx. 50 mg ~ approx. 70 mg, approx. 50 mg ~ approx. 65 mg, approx. 50 mg ~ approx. 60 mg, approx. 50 mg ~ approx. 55 mg, approx. 55 mg ~ approx. 95 mg, approx. mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, or about 90 mg to about 95 mg.In certain embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is about 40 mg to about 100 mg. In certain embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is about 40 mg to about 80 mg.

[0069] In various embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is about 40 mg, about 45 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, or about 100 mg.In certain embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is about 40 mg.In certain embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is about 80 mg.

[0070] In various embodiments, the liquid pharmaceutical formulations described herein may be 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 5% (w / w) to about 9% (w / w), from 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) of furosemide.

[0071] In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 5% (w / w), about 5.5% (w / w), about 6% (w / w), about 6.5% (w / w), about 7% (w / w), about 7.5% (w / w), about 8% (w / w), about 8.5% (w / w), about 9% (w / w), about 9.5% (w / w), or about 10% (w / w) furosemide.

[0072] In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 6% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 7% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 8% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 10% (w / w) furosemide.

[0073] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein is 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, or from about 200 mg / mL to about 250mg / mL, approximately 50mg / mL to approximately 200mg / mL, approximately 50mg / mL to approximately 180mg / mL, approximately 50mg / mL to approximately 160mg / mL, approximately 50mg / mL to approximately 140mg / mL, approximately 50mg / mL to approximately 120mg / mL, approximately 50mg / mL to approximately 100mg / mL, Approximately 50 mg / mL to approximately 90 mg / mL, approximately 50 mg / mL to approximately 80 mg / mL, approximately 50 mg / mL to approximately 70 mg / mL, approximately 50 mg / mL to approximately 60 mg / mL, approximately 60 mg / mL to approximately 200 mg / mL, approximately 60 mg / mL to approximately 180 mg / mL, approximately 60 mg / mL to approximately 160 m g / mL, about 60 mg / mL to about 140 mg / mL, about 60 mg / mL to about 120 mg / mL, about 60 mg / mL to about 100 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / m L ~ about 200mg / mL, about 70mg / mL - about 180mg / mL, about 70mg / mL - about 160mg / mL, about 70mg / mL - about 140mg / mL, about 70mg / mL - about 120mg / mL, about 70mg / mL - about 100mg / mL, about 70mg / mL - about 90mg / m L, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 200 mg / mL, about 80 mg / mL to about 180 mg / mL, about 80 mg / mL to about 160 mg / mL, about 80 mg / mL to about 140 mg / mL, about 80 mg / mL to about 120 mg / mL, about 80 mg / mL ~100mg / mL, 80mg / mL~90mg / mL, 90mg / mL~200mg / mL, 90mg / mL~180mg / mL, 90mg / mL~160mg / mL, 90mg / mL~140mg / mL, 90mg / mL~120mg / mL,Approximately 90mg / mL to approximately 100mg / mL, approximately 100mg / mL to approximately 200mg / mL, approximately 100mg / mL to approximately 180mg / mL, approximately 100mg / mL to approximately 160mg / mL, approximately 1 00mg / mL~Approx. 140mg / mL, Approx. 100mg / mL~Approx. 120mg / mL, Approx. 120mg / mL~Approx. 200mg / mL, Approx. 120mg / mL~Approx. 180mg / mL, Approx. 120 The concentration of furosemide in the liquid pharmaceutical formulations described herein may be from about 50 mg / mL to about 250 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein may be from about 60 mg / mL to about 140 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein may be from about 80 mg / mL to about 120 mg / mL.

[0074] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, or about 250 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein is about 80 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein is about 100 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein is about 120 mg / mL.

[0075] In various embodiments, the liquid pharmaceutical formulations described herein may include a pharmaceutically acceptable salt of furosemide.

[0076] In various embodiments, the liquid pharmaceutical formulations described herein contain about 40 mg to about 100 mg, about 45 mg to about 100 mg, about 50 mg to about 100 mg, about 55 mg to about 100 mg, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, about 95 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 40 mg Approx. 75 mg, approx. 40 mg ~ approx. 70 mg, approx. 40 mg ~ approx. 65 mg, approx. 40 mg ~ approx. 60 mg, approx. 40 mg ~ approx. 55 mg, approx. 40 mg ~ approx. 50 mg, approx. ~75mg, 45mg~70mg, 45mg~65mg, 45mg~60mg, 45mg~55mg, 45mg~50mg, 50mg~95mg, 50mg~90mg, 50mg~85mg, 50mg~80mg, 50m g ~ about 75 mg, about 50 mg - about 70 mg, about 50 mg - about 65 mg, about 50 mg - about 60 mg, about 50 mg - about 55 mg, about 55 mg - about 95 mg, about 55 mg - about 90 mg, about 55 mg - about 85 mg, about 55 mg - about 80 mg, about 55 mg - about 75 mg, about 55 mg ~ about 70 mg, about 55 mg - about 65 mg, about 55 mg - about 60 mg, about 60 mg - about 95 mg, about 60 mg - about 90 mg, about 60 mg - about 85 mg, about 60 mg - about 80 mg, about 60 mg - about 75 mg, about 60 mg - about 70 mg, about 60 mg - about 65 mg, about 6 5mg to about 95mg, about 65mg to about 90mg, about 65mg to about 85mg, about 65mg to about 80mg, about 65mg to about 75mg, about 65mg to about 70mg, about 70mg to about 95mg, about 70mg to about 90mg, about 70mg to about 85mg, about 70mg to about 80mg, about 70mg to about 75mg, about 75mg to about 95mg, about 75mg to about 90mg, about 75mg to about 85mg, about 75mg to about 80mg, about 80mg to about 95mg, about 80mg to about 90mg, about 80mg to about 85mg, about 85mg to about 95mg, about 85mg to about 90mg,Or a pharmaceutically acceptable salt of furosemide in an amount to provide about 90 mg to about 95 mg of furosemide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 40 mg to about 100 mg of furosemide in the free acid form.

[0077] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 40 mg, about 45 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, or about 100 mg of the free acid form of furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 40 mg of the free acid form of furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 80 mg of the free acid form of furosemide.

[0078] In various embodiments, the liquid pharmaceutical formulations described herein may be 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 5% (w / w) to about 9% (w / w), from about 5% (w / w) to about 8% (w / w), from about 5% (w / w) to about 7% (w / w), In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide about 5% (w / w) to about 10% (w / w) of furosemide in the free acid form.

[0079] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 5% (w / w), about 5.5% (w / w), about 6% (w / w), about 6.5% (w / w), about 7% (w / w), about 7.5% (w / w), about 8% (w / w), about 8.5% (w / w), about 9% (w / w), about 9.5% (w / w), or about 10% (w / w) of the free acid form of furosemide.

[0080] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 5% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 6% (w / w) furosemide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 7% (w / w) furosemide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 8% (w / w) furosemide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 9% (w / w) furosemide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 10% (w / w) of furosemide in the free acid form.

[0081] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a dilution of about 50 mg / mL to about 250 mg / mL, about 60 mg / mL to about 250 mg / mL, about 70 mg / mL to about 250 mg / mL, about 80 mg / mL to about 250 mg / mL, about 90 mg / mL to about 250 mg / mL, about 100 mg / mL to about 250 mg / mL, about 120 mg / mL to about 250 mg / mL, about 140 mg / mL to about 250 mg / mL, about 160 mg / mL to about 250 mg / mL, about 180 mg / mL to about 250 mg / mL, about 200 mg / mL to about 250 mg / mL, about 5 ... mg / mL~about 200mg / mL, about 50mg / mL~about 180mg / mL, about 50mg / mL~about 160mg / mL, about 50mg / mL~about 140mg / mL, about 50mg / mL~about 120mg / mL, about 50mg / mL~about 100mg / mL, about 50mg / mL~about 90m g / mL, approximately 50 mg / mL to approximately 80 mg / mL, approximately 50 mg / mL to approximately 70 mg / mL, approximately 50 mg / mL to approximately 60 mg / mL, approximately 60 mg / mL to approximately 200 mg / mL, approximately 60 mg / mL to approximately 180 mg / mL, approximately 60 mg / mL to approximately 160 mg / mL, approximately 60 mg / mL Approximately 140 mg / mL, approximately 60 mg / mL to approximately 120 mg / mL, approximately 60 mg / mL to approximately 100 mg / mL, approximately 60 mg / mL to approximately 90 mg / mL, approximately 60 mg / mL to approximately 80 mg / mL, approximately 60 mg / mL to approximately 70 mg / mL, approximately 70 mg / mL to approximately 200 mg / mL, approximately 70 mg / mL to approx. 180 mg / mL, approx. 70 mg / mL to approx. 160 mg / mL, approx. 70 mg / mL to approx. 140 mg / mL, approx. 70 mg / mL to approx. 120 mg / mL, approx. 70 mg / mL to approx. mL, about 80 mg / mL to about 200 mg / mL, about 80 mg / mL to about 180 mg / mL, about 80 mg / mL to about 160 mg / mL, about 80 mg / mL to about 140 mg / mL, about 80 mg / mL to about 120 mg / mL, about 80 mg / mL to about 100 mg / mL, about 80 mg / m L ~ about 90mg / mL, about 90mg / mL - about 200mg / mL, about 90mg / mL - about 180mg / mL, about 90mg / mL - about 160mg / mL, about 90mg / mL - about 140mg / mL, about 90mg / mL - about 120mg / mL, about 90mg / mL - about 100mg / mL,Approximately 100mg / mL to approximately 200mg / mL, approximately 100mg / mL to approximately 180mg / mL, approximately 100mg / mL to approximately 160mg / mL, approximately 100mg / mL to approximately 140mg / mL, approximately 100mg / mL ~ approx. 120 mg / mL, approx. 120 mg / mL ~ approx. 200 mg / mL, approx. 120 mg / mL ~ approx. 180 mg / mL, approx. 120 mg / mL ~ approx. 160 mg / mL, approx. 120 mg / mL ~ approx. 1 The liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 40 mg / mL, about 140 mg / mL to about 200 mg / mL, about 140 mg / mL to about 180 mg / mL, about 140 mg / mL to about 160 mg / mL, about 160 mg / mL to about 200 mg / mL, about 160 mg / mL to about 180 mg / mL, or about 180 mg / mL to about 200 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 50 mg / mL to about 250 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 60 mg / mL to about 140 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 80 mg / mL to about 120 mg / mL of the free acid form of furosemide.

[0082] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of about 40 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, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, or about 250 mg / mL of the free acid form of furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 80 mg / mL of the free acid form of furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 100 mg / mL of the free acid form of furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of furosemide in an amount to provide about 120 mg / mL of the free acid form of furosemide.

[0083] (ii) Torsemide In various aspects, the present invention provides a liquid pharmaceutical formulation for the treatment of the conditions described herein, comprising an effective amount of torsemide, or a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is about 20 mg to about 50 mg, about 25 mg to about 50 mg, about 30 mg to about 50 mg, about 35 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 40 mg to about 45 mg. In certain embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is about 20 mg to about 50 mg. In certain embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is about 20 mg to about 40 mg.

[0085] In various embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.In certain embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is about 20 mg.In certain embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is about 40 mg.

[0086] In certain embodiments, the concentration of torsemide in the liquid pharmaceutical formulations described herein is from about 25 mg / mL to about 125 mg / mL, from about 30 mg / mL to about 125 mg / mL, from about 35 mg / mL to about 125 mg / mL, from about 40 mg / mL to about 125 mg / mL, from about 45 mg / mL to about 125 mg / mL, from about 50 mg / mL to about 125 mg / mL, from about 60 mg / mL to about 125 mg / mL, from about 70 mg / mL to about 125 mg / mL, from about 80 mg / mL to about 125 mg / mL, from about 90 mg / mL to about 125 mg / mL, or from about 100 mg / mL to about 125 mg / mL. L, about 25 mg / mL to about 100 mg / mL, about 25 mg / mL to about 90 mg / mL, about 25 mg / mL to about 80 mg / mL, about 25 mg / mL to about 70 mg / mL, about 25 mg / mL to about 60 mg / mL, about 25 mg / mL to about 50 mg / mL, about 25 mg / mL to about 45 m g / mL, approximately 25 mg / mL to approximately 40 mg / mL, approximately 25 mg / mL to approximately 35 mg / mL, approximately 25 mg / mL to approximately 30 mg / mL, approximately 30 mg / mL to approximately 100 mg / mL, approximately 30 mg / mL to approximately 90 mg / mL, approximately 30 mg / mL to approximately 80 mg / mL, approximately 30 mg / mL to approximately 7 0mg / mL, about 30mg / mL to about 60mg / mL, about 30mg / mL to about 50mg / mL, about 30mg / mL to about 45mg / mL, about 30mg / mL to about 40mg / mL, about 30mg / mL to about 35mg / mL, about 35mg / mL to about 100mg / mL, about 35mg / mL ~90mg / mL, 35mg / mL~80mg / mL, 35mg / mL~70mg / mL, 35mg / mL~60mg / mL, 35mg / mL~50mg / mL, 35mg / mL~45mg / mL, 35mg / mL~40mg / mL, 40mg / mL mL~about 100mg / mL, about 40mg / mL~about 90mg / mL, about 40mg / mL~about 80mg / mL, about 40mg / mL~about 70mg / mL, about 40mg / mL~about 60mg / mL, about 40mg / mL~about 50mg / mL, about 40mg / mL~about 45mg / mL, about 45 mg / mL~about 100mg / mL, about 45mg / mL~about 90mg / mL, about 45mg / mL~about 80mg / mL, about 45mg / mL~about 70mg / mL, about 45mg / mL~about 60mg / mL, about 45mg / mL~about 50mg / mL, about 50mg / mL~about 100mg / mL,The concentration of torsemide in the liquid pharmaceutical formulations described herein can be about 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 80 mg / mL, about 50 mg / mL to about 70 mg / mL, about 50 mg / mL to about 60 mg / mL, about 60 mg / mL to about 100 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / mL to about 100 mg / mL, about 70 mg / mL to about 90 mg / mL, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 100 mg / mL, about 80 mg / mL to about 90 mg / mL, or about 90 mg / mL to about 100 mg / mL. In certain embodiments, the concentration of torsemide in the liquid pharmaceutical formulations described herein can be about 25 mg / mL to about 125 mg / mL.

[0087] In certain embodiments, the concentration of torsemide in the liquid pharmaceutical formulations described herein can be 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, about 110 mg / mL, or about 125 mg / mL. In certain embodiments, the concentration of torsemide in the liquid pharmaceutical formulations described herein is about 40 mg / mL.

[0088] In various embodiments, the liquid pharmaceutical formulations described herein may include a pharmaceutically acceptable salt of torsemide.

[0089] In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount to provide about 20 mg to about 50 mg, about 25 mg to about 50 mg, about 30 mg to about 50 mg, about 35 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 40 mg to about 45 mg of torsemide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of torsemide in an amount to provide about 20 mg to about 50 mg of torsemide in the free acid form.

[0090] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount that provides about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of torsemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount that provides about 20 mg of torsemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount that provides about 40 mg of torsemide in free acid form.

[0091] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a dilution of about 25 mg / mL to about 125 mg / mL, about 30 mg / mL to about 125 mg / mL, about 35 mg / mL to about 125 mg / mL, about 40 mg / mL to about 125 mg / mL, about 45 mg / mL to about 125 mg / mL, about 50 mg / mL to about 125 mg / mL, about 60 mg / mL to about 125 mg / mL, about 70 mg / mL to about 125 mg / mL, about 80 mg / mL to about 125 mg / mL, about 90 mg / mL to about 125 mg / mL, about 100 mg / mL to about 125 mg / mL, ...5 mg / mL to about 125 mg / mL, about 45 mg / mL to about 125 mg / mL, about 50 mg / mL to about 125 mg / mL, about 60 mg / mL to about 125 mg / mL, about 70 mg / mL to about 125 mg / mL, about 80 mg / mL to about 125 mg / mL mL~about 100mg / mL, about 25mg / mL~about 90mg / mL, about 25mg / mL~about 80mg / mL, about 25mg / mL~about 70mg / mL, about 25mg / mL~about 60mg / mL, about 25mg / mL~about 50mg / mL, about 25mg / mL~about 45mg / mL, about 2 5mg / mL to about 40mg / mL, about 25mg / mL to about 35mg / mL, about 25mg / mL to about 30mg / mL, about 30mg / mL to about 100mg / mL, about 30mg / mL to about 90mg / mL, about 30mg / mL to about 80mg / mL, about 30mg / mL to about 70mg / m L, about 30 mg / mL to about 60 mg / mL, about 30 mg / mL to about 50 mg / mL, about 30 mg / mL to about 45 mg / mL, about 30 mg / mL to about 40 mg / mL, about 30 mg / mL to about 35 mg / mL, about 35 mg / mL to about 100 mg / mL, about 35 mg / mL to about 90 mg / mL, approximately 35 mg / mL to approximately 80 mg / mL, approximately 35 mg / mL to approximately 70 mg / mL, approximately 35 mg / mL to approximately 60 mg / mL, approximately 35 mg / mL to approximately 50 mg / mL, approximately 35 mg / mL to approximately 45 mg / mL, approximately 35 mg / mL to approximately 40 mg / mL, approximately 40 mg / mL Approx. 100mg / mL, Approx. 40mg / mL to approx. 90mg / mL, Approx. 40mg / mL to approx. 80mg / mL, Approx. 40mg / mL to approx. 70mg / mL, Approx. 40mg / mL to approx. 60mg / mL, Approx. 40mg / mL to approx. 50mg / mL, Approx. 40mg / mL to approx. 45mg / mL, Approx. 45mg / mL~about 100mg / mL, about 45mg / mL~about 90mg / mL, about 45mg / mL~about 80mg / mL, about 45mg / mL~about 70mg / mL, about 45mg / mL~about 60mg / mL, about 45mg / mL~about 50mg / mL, about 50mg / mL~about 100mg / mL,The pharmaceutical composition contains a pharmaceutically acceptable salt of torsemide in an amount to provide a concentration of the free acid form of torsemide of about 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 80 mg / mL, about 50 mg / mL to about 70 mg / mL, about 50 mg / mL to about 60 mg / mL, about 60 mg / mL to about 100 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / mL to about 100 mg / mL, about 70 mg / mL to about 90 mg / mL, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 100 mg / mL, about 80 mg / mL to about 90 mg / mL, or about 90 mg / mL to about 100 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of torsemide in an amount to provide a concentration of torsemide in the free acid form of about 25 mg / mL to about 125 mg / mL.

[0092] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of torsemide in an amount to provide a concentration of torsemide in the free acid form of 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, about 110 mg / mL, or about 125 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of torsemide in an amount to provide a concentration of torsemide in the free acid form of about 40 mg / mL.

[0093] (iii) bumetanide In various aspects, the present invention provides a liquid pharmaceutical formulation for the treatment of a condition described herein, comprising an effective amount of bumetanide, or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is from about 1 mg to about 2.5 mg, from about 1.25 mg to about 2.5 mg, from about 1.5 mg to about 2.5 mg, from about 1.75 mg to about 2.5 mg, from about 2 mg to about 2.5 mg, from about 2.25 mg to about 50 mg, from about 1 mg to about 2.25 mg, from about 1 mg to about 2 mg, from about 1 mg to about 1.75 mg, or from about 1 mg to about 1. 5 mg, about 1 mg to about 1.25 mg, about 1.25 mg to about 2.25 mg, about 1.25 mg to about 2 mg, about 1.25 mg to about 1.75 mg, about 1.25 mg to about 1.5 mg, about 1.5 mg to about 2.25 mg, about 1.5 mg to about 2 mg, about 1.5 mg to about 1.75 mg, about 1.75 mg to about 2.25 mg, about 1.75 mg to about 2 mg, or about 2 mg to about 2.25 mg. In certain embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is about 1 mg to about 2.5 mg. In certain embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is about 1 mg to about 2 mg.

[0095] In various embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg. In certain embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is about 1 mg. In certain embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is about 2 mg.

[0096] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein is from about 1.25 mg / mL to about 6.25 mg / mL, from about 1.5 mg / mL to about 6.25 mg / mL, from about 1.75 mg / mL to about 6.25 mg / mL, from about 2 mg / mL to about 6.25 mg / mL, from about 2.25 mg / mL to about 6.25 mg / mL, from about 2.5 mg / mL to about 6.25 mg / mL, from about 3 mg / mL to about 6.25 mg / mL, from about 3.5 mg / mL to about 6.25 mg / mL, from about 4 mg / mL to about 6.25 mg / mL, from about 4.5 mg / mL to about 6.25 mg / mL, or from about 5 mg / mL to about 6.25 mg / mL. mg / mL~about 6.25mg / mL, about 1.25mg / mL~about 5mg / mL, about 1.25mg / mL~about 4.5mg / mL, about 1.25mg / mL~about 4mg / mL, about 1.25mg / mL~about 3.5mg / mL, about 1.25mg / mL~about 3mg / mL, about 1.25mg / m L~2.5mg / mL, 1.25mg / mL~2.25mg / mL, 1.25mg / mL~2mg / mL, 1.25mg / mL~1.75mg / mL, 1.25mg / mL~1.5mg / mL, 1.5mg / mL~5mg / mL, 1.5mg / mL~1.5mg / mL 4.5mg / mL, approximately 1.5mg / mL to approximately 4mg / mL, approximately 1.5mg / mL to approximately 3.5mg / mL, approximately 1.5mg / mL to approximately 3mg / mL, approximately 1.5mg / mL to approximately 2.5mg / mL, approximately 1.5mg / mL to approximately 2.25mg / mL, approximately 1.5mg / mL to approximately 2mg / mL, approximately 1.5mg / mL~about 1.75mg / mL, about 1.75mg / mL~about 5mg / mL, about 1.75mg / mL~about 4.5mg / mL, about 1.75mg / mL~about 4mg / mL, about 1.75mg / mL~about 3.5mg / mL, about 1.75mg / mL~about 3mg / mL, about 1.75m g / mL ~ approx. 2.5 mg / mL, approx. 1.75 mg / mL ~ approx. 2.25 mg / mL, approx. 1.75 mg / mL ~ approx. 2 mg / mL, approx. 2 mg / mL ~ approx. 5 mg / mL, approx. 2 mg / mL to about 3 mg / mL, about 2 mg / mL to about 2.5 mg / mL, about 2 mg / mL to about 2.25 mg / mL, about 2.25 mg / mL to about 5 mg / mL, about 2.25 mg / mL to about 4.5 mg / mL, about 2.25 mg / mL to about 4 mg / mL, about 2.25 mg / mL to about 3.5mg / mL, about 2.25mg / mL to about 3mg / mL, about 2.25mg / mL to about 2.5mg / mL, about 2.5mg / mL to about 5mg / mL, about 2.5mg / mL to about 4.5mg / mL, about 2.5 mg / mL to about 4 mg / mL, about 2.5 mg / mL to about 3.5 mg / mL, about 2.5 mg / mL to about 3 mg / mL, about 3 mg / mL to about 5 mg / mL, about 3 mg / mL The concentration of bumetanide in the liquid pharmaceutical formulations described herein can be from about 1.25 mg / mL to about 6.25 mg / mL.

[0097] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein can be about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 2.25 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, or about 6.25 mg / mL. In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein is about 2 mg / mL.

[0098] In various embodiments, the liquid pharmaceutical formulations described herein may include a pharmaceutically acceptable salt of bumetanide.

[0099] In various embodiments, the liquid pharmaceutical formulations described herein contain from about 1 mg to about 2.5 mg, from about 1.25 mg to about 2.5 mg, from about 1.5 mg to about 2.5 mg, from about 1.75 mg to about 2.5 mg, from about 2 mg to about 2.5 mg, from about 2.25 mg to about 50 mg, from about 1 mg to about 2.25 mg, from about 1 mg to about 2 mg, from about 1 mg to about 1.75 mg, from about 1 mg to about 1.5 mg, from about 1 mg to about 1.25 mg, or from about 1.25 mg In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount to provide about 1 mg to about 2.5 mg of bumetanide in the free acid form.

[0100] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of bumetanide in an amount that provides about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg of bumetanide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of bumetanide in an amount that provides about 1 mg of bumetanide in the free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of bumetanide in an amount that provides about 2 mg of bumetanide in the free acid form.

[0101] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a dilution of about 1.25 mg / mL to about 6.25 mg / mL, about 1.5 mg / mL to about 6.25 mg / mL, about 1.75 mg / mL to about 6.25 mg / mL, about 2 mg / mL to about 6.25 mg / mL, about 2.25 mg / mL to about 6.25 mg / mL, about 2.5 mg / mL to about 6.25 mg / mL, about 3 mg / mL to about 6.25 mg / mL, about 3.5 mg / mL to about 6.25 mg / mL, about 4 mg / mL to about 6.25 mg / mL, about 4.5 mg / mL to about 6.25 mg / mL, about 5 mg / mL to about 6.25 mg / mL, or about 6.25 mg / mL. 5mg / mL, about 1.25mg / mL to about 5mg / mL, about 1.25mg / mL to about 4.5mg / mL, about 1.25mg / mL to about 4mg / mL, about 1.25mg / mL to about 3.5mg / mL, about 1.25mg / mL to about 3mg / mL, about 1.25mg / mL to about 2.5mg / m L, approximately 1.25 mg / mL to approximately 2.25 mg / mL, approximately 1.25 mg / mL to approximately 2 mg / mL, approximately 1.25 mg / mL to approximately 1.75 mg / mL, approximately 1.25 mg / mL to approximately 1.5 mg / mL, approximately 1.5 mg / mL to approximately 5 mg / mL, approximately 1.5 mg / mL to approximately 4.5 mg / mL, 1.5 mg / mL to about 4 mg / mL, about 1.5 mg / mL to about 3.5 mg / mL, about 1.5 mg / mL to about 3 mg / mL, about 1.5 mg / mL to about 2.5 mg / mL, about 1.5 mg / mL to about 2.25 mg / mL, about 1.5 mg / mL to about 2 mg / mL, about 1.5 mg / mL to about 1.75mg / mL, about 1.75mg / mL to about 5mg / mL, about 1.75mg / mL to about 4.5mg / mL, about 1.75mg / mL to about 4mg / mL, about 1.75mg / mL to about 3.5mg / mL, about 1.75mg / mL to about 3mg / mL, about 1.75mg / mL to about 2.5m g / mL, approximately 1.75 mg / mL to approximately 2.25 mg / mL, approximately 1.75 mg / mL to approximately 2 mg / mL, approximately 2 mg / mL to approximately 5 mg / mL, approximately 2 mg / mL to approximately 4.5 mg / mL, approximately 2 mg / mL to approximately 4 mg / mL, approximately 2 mg / mL to approximately 3.5 mg / mL, approximately 2 mg / mL to approximately 3 m g / mL, approximately 2 mg / mL to approximately 2.5 mg / mL, approximately 2 mg / mL to approximately 2.25 mg / mL, approximately 2.25 mg / mL to approximately 5 mg / mL, approximately 2.25 mg / mL to approximately 4.5 mg / mL, approximately 2.25 mg / mL to approximately 4 mg / mL, approximately 2.25 mg / mL to approximately 3.5 mg / mL, approximately 2.25mg / mL to approx. 3mg / mL, approx. 2.25mg / mL to approx. 2.5mg / mL, approx. 2.5mg / mL to approx. 5mg / mL, approx. 2.5mg / mL to approx. 4.5mg / mL, approx. 2.5mg / mL to approx. 4 mg / mL, about 2.5 mg / mL to about 3.5 mg / mL, about 2.5 mg / mL to about 3 mg / mL, about 3 mg / mL to about 5 mg / mL, about 3 mg / mL to about 4.5 mg / mL, about 3 mg / mL to about 4 In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of bumetanide in an amount to provide a concentration of bumetanide in the free acid form of about 1.25 mg / mL to about 6.25 mg / mL.

[0102] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of bumetanide in an amount to provide a concentration of the free acid form of bumetanide of about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 2.25 mg / mL, about 2.50 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, or about 6.25 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of bumetanide in an amount to provide a concentration of the free acid form of bumetanide of about 2 mg / mL.

[0103] (B) pH, pharmaceutically acceptable buffers, and pH adjusters (1) A pharmaceutically acceptable buffer solution In various embodiments, the liquid pharmaceutical formulations described herein may further comprise a pharmaceutically acceptable buffer.

[0104] In various embodiments, the liquid pharmaceutical formulations described herein contain about 4 mg to about 16 mg, about 5 mg to about 16 mg, about 6 mg to about 16 mg, about 7 mg to about 16 mg, about 8 mg to about 16 mg, about 9 mg to about 16 mg, about 10 mg to about 16 mg, about 12 mg to about 16 mg, about 14 mg to about 16 mg, about 4 mg to about 14 mg, about 4 mg to about 12 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 14 mg, about 5 mg to about 12 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 5 ... In certain embodiments, the liquid pharmaceutical formulations described herein may comprise from about 4 mg to about 16 mg of a pharmaceutically acceptable buffer.

[0105] In various embodiments, the liquid pharmaceutical formulations described herein may contain at least one of the following: about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, Approximately 6.1mg, approximately 6.2mg, approximately 6.3mg, approximately 6.4mg, approximately 6.5mg, approximately 6.6mg, approximately 6.7mg, approximately 6.8mg, approximately 6.9mg, approximately 7mg, approximately 7.1mg, approximately 7.2mg, approximately 7 .3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about 7.8mg, about 7.9mg, about 8mg, about 8.1mg, about 8.2mg, about 8.3mg, about 8.4mg, about 8.5m g, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, Approximately 9.8mg, approximately 9.9mg, approximately 10mg, approximately 10.1mg, approximately 10.2mg, approximately 10.3mg, approximately 10.4mg, approximately 10.5mg, approximately 10.6mg, approximately 10.7mg, approximately 10.8mg, approximately The amount of the pharmaceutically acceptable buffer may include 10.9 mg, about 11 mg, about 11.1 mg, about 11.2 mg, about 11.3 mg, about 11.4 mg, about 11.5 mg, about 11.6 mg, about 11.7 mg, about 11.8 mg, about 11.9 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of a pharmaceutically acceptable buffer. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg of a pharmaceutically acceptable buffer.

[0106] In various embodiments, the liquid pharmaceutical formulations described herein may be from about 0.1% (w / w) to about 1.5% (w / w), 0.3% (w / w) to about 1.5% (w / w), from about 0.5% (w / w) to about 1.5% (w / w), from about 0.7% (w / w) to about 1.5% (w / w), from about 0.9% (w / w) to about 1.5% (w / w), from about 1.1% (w / w) to about 1.5% (w / w), from about 1.3% (w / w), or from about 1.5% (w / w). (w / w) to about 1.5% (w / w), about 0.1% (w / w) to about 1.3% (w / w), about 0.1% (w / w) to about 1.1% (w / w), about 0.1% (w / w) to about 0.9% (w / w), about 0.1% (w / w) to about 0.7% (w / w), about 0.1% (w / w) to about 0.5% (w / w), about 0.1% (w / w) to about 0.3% (w / w), about 0.3% (w / w) to about 1.3% (w / w), about 0.3% (w / w) to about 1.1% (w / w), about 0.3% (w / w) to about 0.9% (w / w), about 0.3% (w / w) to about 0.7% (w / w), about 0.3% (w / w) to about 0.5% (w / w), about 0.5% (w / w) to about 1.3% (w / w), about 0.5% (w / w) to about 1.1% (w / w), about 0.5% (w / w) to about 0.9% (w / w), about 0.5% (w In various embodiments, the liquid pharmaceutical formulations described herein comprise from about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer.

[0107] In various embodiments, the liquid pharmaceutical formulations described herein comprise 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% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w), or about 1.5% (w / w) of a pharmaceutically acceptable buffer. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.5% (w / w) of a pharmaceutically acceptable buffer. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.6% (w / w) of a pharmaceutically acceptable buffer. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.7% (w / w) of a pharmaceutically acceptable buffer. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.8% (w / w) of a pharmaceutically acceptable buffer. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.9% (w / w) of a pharmaceutically acceptable buffer.

[0108] In various embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is from about 50 mM to about 150 mM, from about 60 mM to about 150 mM, from about 70 mM to about 150 mM, from about 80 mM to about 150 mM, from about 90 mM to about 150 mM, from about 100 mM to about 150 mM, from about 110 mM to about 150 mM, from about 120 mM to about 150 mM, from about 130 mM to about 150 mM, from about 140 mM to about 150 mM, from about 50 mM to about 140 mM, from about 50 mM to about 140 mM, from about 50 mM to about 15 ... 0 mM to about 130 mM, about 50 mM to about 120 mM, about 50 mM to about 110 mM, about 50 mM to about 100 mM, about 50 mM to about 90 mM, about 50 mM to about 80 mM, about 50 mM to about 70 mM, about 50 mM to about 60 mM, about 60 mM to about 140 mM, about 60 mM to about 130 mM, about 60 mM to about 120 mM, about 60 mM to about 110 mM, about 60 mM to about 100 mM, about 60 mM to about 90 mM, about 60 mM to about 80 mM, about 60 mM to about 70 mM, about 70 mM to about 140 mM, about 70 mM to about 130 mM, about 70 mM to about 120 mM, about 70 mM to about 110 mM, about 70 mM to about 100 mM, about 70 mM to about 90 mM, about 70 mM to about 80 mM, about 80 mM to about 140 mM, about 80 mM to about 130 mM, about 80 mM to about 120 mM, about 80 mM to about 110 mM, about 80 mM to about 100 mM, about 80 mM to about 90 mM, about 90 mM to about 140 mM, about 90 mM to about 130 mM, about 90 mM to about 120 mM, about 90 mM to about 110 mM, about 90 mM to about 100 mM, about 100 mM to about 140 mM, about 100 mM to about 130 mM, about 100 mM to about 120 mM, about 100 mM to about 110 mM, about 110 mM to about 140 mM, about 110 mM to about 130 mM, about 110 mM to about 120 mM, about 120 mM to about 140 mM, about 130 mM to about 140 mM, or about 130 mM to about 140 mM.

[0109] In various embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, or about 150 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 50 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 60 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 70 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 80 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 90 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 100 mM.

[0110] In various embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 15 mg / mL, from about 6 mg / mL to about 15 mg / mL, from about 7 mg / mL to about 15 mg / mL, from about 8 mg / mL to about 15 mg / mL, from about 9 mg / mL to about 15 mg / mL, from about 10 mg / mL to about 15 mg / mL, from about 11 mg / mL to about 15 mg / mL, from about 12 mg / mL to about 15 mg / mL, from about 13 mg / mL to about 15 mg / mL, from about 14 mg / mL to about 15 mg / mL, from about 5 mg / mL to about 14 mg / mL, from about 5 mg / mL to about 15 mg / mL, 3mg / mL, about 5mg / mL to about 12mg / mL, about 5mg / mL to about 11mg / mL, about 5mg / mL to about 10mg / mL, about 5mg / mL to about 9mg / mL, about 5mg / mL to about 8mg / mL, about 5mg / mL to about 7mg / mL, about 5mg / mL to about 6mg / mL, about 6 mg / mL~about 14mg / mL, about 6mg / mL~about 13mg / mL, about 6mg / mL~about 12mg / mL, about 6mg / mL~about 11mg / mL, about 6mg / mL~about 10mg / mL, about 6mg / mL~about 9mg / mL, about 6mg / mL~about 8mg / mL, about 6mg / mL~about 7mg / mL, about 7mg / mL to about 14mg / mL, about 7mg / mL to about 13mg / mL, about 7mg / mL to about 12mg / mL, about 7mg / mL to about 11mg / mL, about 7mg / mL to about 10mg / mL, about 7mg / mL to about 9mg / mL, about 7mg / mL to about 8mg / mL, Approximately 8 mg / mL to approximately 14 mg / mL, approximately 8 mg / mL to approximately 13 mg / mL, approximately 8 mg / mL to approximately 12 mg / mL, approximately 8 mg / mL to approximately 11 mg / mL, approximately 8 mg / mL to approximately 10 mg / mL, approximately 8 mg / mL to approximately 9 mg / mL, approximately 9 mg / mL to approximately 14 mg / mL, approximately 9 mg / m 1 to about 13 mg / mL, about 9 mg / mL to about 12 mg / mL, about 9 mg / mL to about 11 mg / mL, about 9 mg / mL to about 10 mg / mL, about 10 mg / mL to about 14 mg / mL, about 10 mg / mL to about 13 mg / mL, about 10 mg / mL to about 12 mg / mL, about 10 mg / mL to about 11 mg / mL, about 11 mg / mL to about 14 mg / mL, about 11 mg / mL to about 13 mg / mL, about 11 mg / mL to about 12 mg / mL, about 12 mg / mL to about 14 mg / mL, about 12 mg / mL to about 13 mg / mL, or about 13 mg / mL to about 14 mg / mL.In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 15 mg / mL.

[0111] In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 5.6 mg / mL, about 5.7 mg / mL, about 5.8 mg / mL, about 5.9 mg / mL, about 6 mg / mL, about 6.1 mg / mL, about 6.2 mg / mL, about 6.3 mg / mL, about 6.4 mg / mL, about 6.5 mg / mL, about 6.6 mg / mL, about 6.7 mg / mL, about 6.8 mg / mL, about 6.9 ...1 mg / mL, about 6.2 mg / mL, about 6.3 mg / mL, about 6.4 mg / mL, about 6.5 mg / mL / mL, about 6.7mg / mL, about 6.8mg / mL, about 6.9mg / mL, about 7mg / mL, about 7.1mg / mL, about 7.2mg / mL, about 7.3mg / mL, about 7.4mg / mL, about 7.5mg / mL, about 7.6mg / mL, about 7. 7mg / mL, about 7.8mg / mL, about 7.9mg / mL, about 8mg / mL, about 8.1mg / mL, about 8.2mg / mL, about 8.3mg / mL, about 8.4mg / mL, about 8.5mg / mL, about 8.6mg / mL, about 8.7mg / mL, Approximately 8.8mg / mL, approximately 8.9mg / mL, approximately 9mg / mL, approximately 9.1mg / mL, approximately 9.2mg / mL, approximately 9.3mg / mL, approximately 9.4mg / mL, approximately 9.5mg / mL, approximately 9.6mg / mL, approximately 9.7mg / mL, approximately 9.8mg / mL, approximately 9.9 mg / mL, approximately 10 mg / mL, approximately 10.1 mg / mL, approximately 10.2 mg / mL, approximately 10.3 mg / mL, approximately 10.3 mg / mL, approximately 10.4 mg / mL, approximately 10.5 mg / mL, approximately 10.6 mg / mL, approximately 10.7 m 10.8mg / mL, about 10.9mg / mL, about 11mg / mL, about 11.1mg / mL, about 11.2mg / mL, about 11.3mg / mL, about 11.4mg / mL, about 11.5mg / mL, about 11.6mg / mL, about 11.7mg / mL, about 11.8mg / mL, about 11.9mg / mL, about 12mg / mL, about 12.5mg / mL, about 13mg / mL, about 13.5mg / mL, about 14mg / mL, about 14.5mg / mL, or about 15mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 6mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 7mg / mL.In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 8 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 9 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 10 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 11 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation described herein is about 12 mg / mL.

[0112] 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 combinations thereof. In certain embodiments, the buffering agent is tromethamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the buffering agent is tromethamine.

[0113] In various embodiments, the liquid pharmaceutical formulations described herein contain a 200 mg to 250 mg (200 mg to 250 mg) or 200 mg (250 mg to 250 mg) of 200 mg to 250 mg of 200 mg of ... In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 4 mg to about 16 mg of tromethamine.

[0114] In various embodiments, the liquid pharmaceutical formulations described herein contain about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg g, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7mg, about 7.1mg, about 7.2mg, About 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about 7.8mg, about 7.9mg, about 8mg, about 8.1mg, about 8.2mg, about 8.3mg, about 8.4mg, about 8 0.5mg, approximately 8.6mg, approximately 8.7mg, approximately 8.8mg, approximately 8.9mg, approximately 9mg, approximately 9.1mg, approximately 9.2mg, approximately 9.3mg, approximately 9.4mg, approximately 9.5mg, approximately 9.6mg, approximately 9.7mg, approximately 9.8mg, approximately 9.9mg, approximately 10mg, approximately 10.1mg, approximately 10.2mg, approximately 10.3mg, approximately 10.4mg, approximately 10.5mg, approximately 10.6mg, approximately 10.7mg, approximately 10.8 The liquid pharmaceutical formulations described herein may contain about 10.9 mg, about 11 mg, about 11.1 mg, about 11.2 mg, about 11.3 mg, about 11.4 mg, about 11.5 mg, about 11.6 mg, about 11.7 mg, about 11.8 mg, about 11.9 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 4.5 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 4.6 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 4.7 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 4.8 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 4.9 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5.1 mg of tromethamine.In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5.2 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5.3 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5.4 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 5.5 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.1 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.2 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.3 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.4 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.5 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.6 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.7 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.8 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 9.9 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein contain about 10 mg of tromethamine.

[0115] In various embodiments, the liquid pharmaceutical formulations described herein may be from about 0.1% (w / w) to about 1.5% (w / w), 0.3% (w / w) to about 1.5% (w / w), about 0.5% (w / w) to about 1.5% (w / w), about 0.7% (w / w) to about 1.5% (w / w), about 0.9% (w / w) to about 1.5% (w / w), about 1.1% (w / w) to about 1.5% (w / w), about 1.3% (w / w), or about 1.5% (w / w). (w / w) to about 1.5% (w / w), about 0.1% (w / w) to about 1.3% (w / w), about 0.1% (w / w) to about 1.1% (w / w), about 0.1% (w / w) to about 0.9% (w / w), about 0.1% (w / w) to about 0.7% (w / w), about 0.1% (w / w) to about 0.5% (w / w), about 0.1% (w / w) to about 0.3% (w / w), about 0.3% (w / w) to about 1.3 % (w / w), approximately 0.3% (w / w) to approximately 1.1% (w / w), approximately 0.3% (w / w) to approximately 0.9% (w / w), approximately 0.3% (w / w) to approximately 0.7% (w / w), approximately 0.3% (w / w) to approximately 0.5% (w / w), approximately 0.5% (w / w) to approximately 1.3% (w / w), approximately 0.5% (w / w) to approximately 1.1% (w / w), approximately 0.5% (w / w) to approximately 0.9% (w / w), approximately 0. The liquid pharmaceutical formulations described herein contain 5% (w / w) to about 0.7% (w / w), about 0.7% (w / w) to about 1.3% (w / w), about 0.7% (w / w) to about 1.1% (w / w), about 0.7% (w / w) to about 0.9% (w / w), about 0.9% (w / w) to about 1.3% (w / w), about 0.9% (w / w) to about 1.1% (w / w), or about 1.1% (w / w) to about 1.3% (w / w) of tromethamine. In various embodiments, the liquid pharmaceutical formulations described herein contain about 0.1% (w / w) to about 1.5% (w / w) of tromethamine.

[0116] In various embodiments, the liquid pharmaceutical formulations described herein comprise 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% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w), or about 1.5% (w / w) tromethamine. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.5% (w / w) tromethamine. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.6% (w / w) tromethamine. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.7% (w / w) tromethamine. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.8% (w / w) tromethamine. In various embodiments, the liquid pharmaceutical formulations described herein comprise about 0.9% (w / w) tromethamine.

[0117] In various embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is from about 50 mM to about 150 mM, from about 60 mM to about 150 mM, from about 70 mM to about 150 mM, from about 80 mM to about 150 mM, from about 90 mM to about 150 mM, from about 100 mM to about 150 mM, from about 110 mM to about 150 mM, from about 120 mM to about 150 mM, from about 130 mM to about 150 mM, from about 140 mM to about 150 mM, from about 50 mM to about 140 mM, from about 50 mM to about 150 mM, about 130 mM, about 50 mM to about 120 mM, about 50 mM to about 110 mM, about 50 mM to about 100 mM, about 50 mM to about 90 mM, about 50 mM to about 80 mM, about 50 mM to about 70 mM, about 50 mM to about 60 mM, about 60 mM to about 140 mM, about 60 mM to about 130 mM, about 60 mM to about 120 mM, about 60 mM to about 110 mM, about 60 mM to about 100 mM, about 60 mM to about 90 mM, about 60 mM to about 80 mM, about 60 mM to about 70 mM, about 70 mM to about 140 mM, about 70 mM to about 130 mM, about 70 mM to about 120 mM, about 70 mM to about 110 mM, about 70 mM to about 100 mM, about 70 mM to about 90 mM, about 70 mM to about 80 mM, about 80 mM to about 140 mM, about 80 mM to about 130 mM, about 80 mM to about 120 mM, about 80 mM to about 110 mM, about 80 mM to about 100 mM, about 80 mM to about 90 mM, about 90 mM to about 140 mM, about 90 mM to about In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 50 mM to about 150 mM.

[0118] In various embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, or about 150 mM. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 50 mM. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 60 mM. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 70 mM. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 80 mM. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 90 mM. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 100 mM.

[0119] In various embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 15 mg / mL, from about 6 mg / mL to about 15 mg / mL, from about 7 mg / mL to about 15 mg / mL, from about 8 mg / mL to about 15 mg / mL, from about 9 mg / mL to about 15 mg / mL, from about 10 mg / mL to about 15 mg / mL, from about 11 mg / mL to about 15 mg / mL, from about 12 mg / mL to about 15 mg / mL, from about 13 mg / mL to about 15 mg / mL, from about 14 mg / mL to about 15 mg / mL, from about 5 mg / mL to about 14 mg / mL, from about 5 mg / mL to about 13 mg / mL L, approximately 5 mg / mL to approximately 12 mg / mL, approximately 5 mg / mL to approximately 11 mg / mL, approximately 5 mg / mL to approximately 10 mg / mL, approximately 5 mg / mL to approximately 9 mg / mL, approximately 5 mg / mL to approximately 8 mg / mL, approximately 5 mg / mL to approximately 7 mg / mL, approximately 5 mg / mL to approximately 6 mg / mL, approximately 6 mg / m L~14mg / mL, 6mg / mL~13mg / mL, 6mg / mL~12mg / mL, 6mg / mL~11mg / mL, 6mg / mL~10mg / mL, 6mg / mL~9mg / mL, 6mg / mL~8mg / mL, 6mg / mL~7mg / mL, about 7 mg / mL to about 14 mg / mL, about 7 mg / mL to about 13 mg / mL, about 7 mg / mL to about 12 mg / mL, about 7 mg / mL to about 11 mg / mL, about 7 mg / mL to about 10 mg / mL, about 7 mg / mL to about 9 mg / mL, about 7 mg / mL to about 8 mg / mL, about 8 mg / mL to approx. 14 mg / mL, approx. 8 mg / mL to approx. 13 mg / mL, approx. 8 mg / mL to approx. 12 mg / mL, approx. 8 mg / mL to approx. 11 mg / mL, approx. 8 mg / mL to approx. 10 mg / mL, approx. 8 mg / mL to approx. 9 mg / mL, approx. 9 mg / mL to approx. 14 mg / mL, approx. about 13 mg / mL, about 9 mg / mL to about 12 mg / mL, about 9 mg / mL to about 11 mg / mL, about 9 mg / mL to about 10 mg / mL, about 10 mg / mL to about 14 mg / mL, about 10 mg / mL to about 13 mg / mL, about 10 mg / mL to about 12 mg / mL, about 10 mg / mL to about 11 mg / mL, about 11 mg / mL to about 14 mg / mL, about 11 mg / mL to about 13 mg / mL, about 11 mg / mL to about 12 mg / mL, about 12 mg / mL to about 14 mg / mL, about 12 mg / mL to about 13 mg / mL, or about 13 mg / mL to about 14 mg / mL.In various embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 15 mg / mL.

[0120] In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 5.6 mg / mL, about 5.7 mg / mL, about 5.8 mg / mL, about 5.9 mg / mL, about 6 mg / mL, about 6.1 mg / mL, about 6.2 mg / mL, about 6.3 mg / mL, about 6.4 mg / mL, about 6.5 mg / mL, about 6.6 mg / mL, about 6.7mg / mL, approximately 6.8mg / mL, approximately 6.9mg / mL, approximately 7mg / mL, approximately 7.1mg / mL, approximately 7.2mg / mL, approximately 7.3mg / mL, approximately 7.4mg / mL, approximately 7.5mg / mL, approximately 7.6mg / mL, approximately 7.7mg / mL, about 7.8 mg / mL, about 7.9 mg / mL, about 8 mg / mL, about 8.1 mg / mL, about 8.2 mg / mL, about 8.3 mg / mL, about 8.4 mg / mL, about 8.5 mg / mL, about 8.6 mg / mL, about 8.7 mg / mL, about 8. 8mg / mL, approximately 8.9mg / mL, approximately 9mg / mL, approximately 9.1mg / mL, approximately 9.2mg / mL, approximately 9.3mg / mL, approximately 9.4mg / mL, approximately 9.5mg / mL, approximately 9.6mg / mL, approximately 9.7mg / mL, approximately 9.8mg / mL , about 9.9mg / mL, about 10mg / mL, about 10.1mg / mL, about 10.2mg / mL, about 10.3mg / mL, about 10.3mg / mL, about 10.4mg / mL, about 10.5mg / mL, about 10.6mg / mL, about 10.7mg

[0042] In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 6 mg / mL. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 7 mg / mL. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 8 mg / mL.In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 9 mg / mL. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 10 mg / mL. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 11 mg / mL. In certain embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 12 mg / mL.

[0121] In various embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:1 to about 1:3.5, about 1:1.5 to about 1:3.5, about 1:2 to about 1:3.5, about 1:2.5 to about 1:3.5, about 1:3 to about 1:3.5, about 1:1 to about 1:3, about 1:1 to about 1:2.5, about 1:1 to about 1:2, about 1:1 to about 1:1.5, about 1:1.5 to about 1:3, about 1:1.5 to about 1:2.5, about 1:1.5 to about 1:2, about 1:2 to about 1:3, about 1:2 to about 1:2.5, or about 1:2.5 to about 1:3. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:1 to about 1:3.5. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:1.5 to about 1:3.5.

[0122] In various embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, or about 1:3.5. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:1. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:1.5. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:2. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1:2.5. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1: 3. In certain embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is about 1: 3.5.

[0123] (2) pH adjuster In various embodiments, the liquid pharmaceutical formulations described herein further comprise a pharmaceutically acceptable pH adjusting agent.

[0124] Exemplary pharmaceutically acceptable pH adjusting agents 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, aqueous ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, and trolamine.

[0125] In certain embodiments, the pharmaceutically acceptable pH adjusting agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and combinations thereof. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is hydrochloric acid and sodium hydroxide. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is sodium hydroxide. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is potassium hydroxide. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is hydrochloric acid.

[0126] (3) pH of liquid pharmaceutical preparations In various embodiments, the pH of the liquid pharmaceutical formulations described herein can be about 5.5 to about 8.5, about 6 to about 8.5, about 6.5 to about 8.5, about 7 to about 8.5, about 7.5 to about 8.5, about 8 to about 8.5, about 5.5 to about 8, about 5.5 to about 7.5, about 5.5 to about 7, about 5.5 to about 6.5, about 5.5 to about 6, about 6 to about 8, about 6 to about 7.5, about 6 to about 7, about 6 to about 6.5, about 6.5 to about 8, about 6.5 to about 7.5, about 6.5 to about 7, about 7 to about 8, about 7 to about 7.5, or about 7.5 to about 8. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is about 6.5 to about 8.5. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is about 7 to about 8. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is from about 7.5 to about 8.5.

[0127] In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is about 7 to about 8.5, about 7.1 to about 8.5, about 7.3 to about 8.5, about 7.5 to about 8.5, about 7.7 to about 8.5, about 7.9 to about 8.5, about 8.1 to about 8.5, about 8.3 to about 8.5, about 7 to about 8.3, about 7 to about 8.1, about 7 to about 7.9, about 7 to about 7.7, about 7 to about 7.5, about 7 to about 7.3, about 7 to about 7.1, about 7.1 to about 8.3, about 7.1 to about 8.1, about 7.1 to about 8.1 It can be about 7.9, about 7.1 to about 7.7, about 7.1 to about 7.5, about 7.1 to about 7.3, about 7.3 to about 8.3, about 7.3 to about 8.1, about 7.3 to about 7.9, about 7.3 to about 7.7, about 7.3 to about 7.5, about 7.5 to about 8.3, about 7.5 to about 8.1, about 7.5 to about 7.9, about 7.5 to about 7.7, about 7.7 to about 8.3, about 7.7 to about 8.1, about 7.7 to about 7.9, about 7.9 to about 8.3, about 7.9 to about 8.1, or about 8.1 to about 8.3.

[0128] In certain embodiments, the pH of the liquid pharmaceutical formulations 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 formulations described herein can be about 7.4. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein can be about 7.5. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein can be about 7.6. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein can be about 7.7. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be about 7.8. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be about 7.9. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be about 8.0.

[0129] In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is 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. The pH of the liquid pharmaceutical formulations described herein may be 7.3, 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 formulations described herein may be 7.4±0.3. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 7.5±0.3. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 7.6±0.3. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 7.7±0.3. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 7.8±0.3. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 7.9±0.3. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 8.0±0.3.

[0130] (C) Solubilizer In various embodiments, the liquid pharmaceutical formulations described herein may further comprise a solubilizing agent.

[0131] In various embodiments, the liquid pharmaceutical formulations described herein contain from about 1 mg to about 50 mg, from about 2 mg to about 50 mg, from about 5 mg to about 50 mg, from about 10 mg to about 50 mg, from about 15 mg to about 50 mg, from about 20 mg to about 50 mg, from about 25 mg to about 50 mg, from about 30 mg to about 50 mg, from about 35 mg to about 50 mg, from about 40 mg to about 50 mg, from about 45 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 1 mg to about 35 mg, from about 1 mg to about 30 mg , about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 1 mg to about 2 mg, about 2 mg to about 45 mg, about 2 mg to about 40 mg, about 2 mg to about 35 mg, about 2 mg ~ about 30mg, about 2mg - about 25mg, about 2mg - about 20mg, about 2mg - about 15mg, about 2mg - about 10mg, about 2mg - about 5mg, about 5mg - about 45mg, about 5mg - about 40mg, about 5mg - about 35mg, about 5mg About 30mg, about 5mg to about 25mg, about 5mg to about 20mg, about 5mg to about 15mg, about 5mg to about 10mg, about 10mg to about 45mg, about 10mg to about 40mg, about 10mg to about 35mg, about 10mg to about 30mg, about 1 0mg to about 25mg, about 10mg to about 20mg, about 10mg to about 15mg, about 15mg to about 45mg, about 15mg to about 40mg, about 15mg to about 35mg, about 15mg to about 30mg, about 15mg to about 25mg, about 15mg to The liquid pharmaceutical formulations described herein may contain about 20 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 40 mg to about 45 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 1 mg to about 50 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 15 mg to about 50 mg of solubilizing agent.

[0132] In various embodiments, the liquid pharmaceutical formulations described herein contain 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 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg g, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 1 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 2 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 5 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 10 mg of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 15 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 20 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 25 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 30 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 35 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 40 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 45 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 50 mg of solubilizer.

[0133] In various embodiments, the liquid pharmaceutical formulations described herein may comprise from about 1% (w / w) to about 5% (w / w), from about 2% (w / w) to about 5% (w / w), from about 3% (w / w) to about 5% (w / w), from about 4% (w / w) to about 5% (w / w), from about 1% (w / w) to about 4% (w / w), from about 1% (w / w) to about 3% (w / w), from about 1% (w / w) to about 2% (w / w), from about 2% (w / w) to about 4% (w / w), from about 2% (w / w) to about 3% (w / w), or from about 3% (w / w) to about 4% (w / w) of solubilizing agent. In various embodiments, the liquid pharmaceutical formulations described herein may comprise from about 1% (w / w) to about 5% (w / w) of solubilizing agent.

[0134] In various embodiments, the liquid pharmaceutical formulations described herein may comprise about 1% (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), about 2% (w / w), about 2.2% (w / w), about 2.4% (w / w), about 2.6% (w / w), about 2.8% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), or about 5% (w / w) of solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 1% (w / w) solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 2% (w / w) solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 3% (w / w) solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 4% (w / w) solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 5% (w / w) solubilizer.

[0135] In various embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is from about 15 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 25 mg / mL to about 50 mg / mL, from about 30 mg / mL to about 50 mg / mL, from about 35 mg / mL to about 50 mg / mL, from about 40 mg / mL to about 50 mg / mL, from about 45 mg / mL to about 50 mg / mL, from about 15 mg / mL to about 45 mg / mL, from about 15 mg / mL to about 40 mg / mL, from about 15 mg / mL to about 35 mg / mL, from about 15 mg / mL to about 30 mg / mL, from about 15 mg / mL to about 25 mg / mL, from about 15 mg / mL to about 20 mg / mL, or from about 20 mg / mL to about 35 mg / mL. 0 mg / mL to about 45 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 25 mg / mL, about 25 mg / mL to about 45 mg / mL, about 25 mg / mL to about 40 mg / mL, about 25 mg / mL to about 35 mg / mL, about 25 mg / mL to about 30 mg / mL, about 30 mg / mL to about 45 mg / mL, about 30 mg / mL to about 40 mg / mL, about 30 mg / mL to about 35 mg / mL, about 35 mg / mL to about 45 mg / mL, about 35 mg / mL to about 40 mg / mL, or about 40 mg / mL to about 45 mg / mL.

[0136] In various embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is 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 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL, about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL, about 64 mg / mL, about 65 mg / mL, about 66 mg / mL, about 67 mg / mL, about 68 mg / mL, about 69 mg / mL, about 70 mg / mL, about 71 mg / mL, about 72 mg / mL, about 73 mg / mL, about 74 mg / mL, about 75 mg / mL, about The solubilizing agent concentration in the liquid pharmaceutical formulations described herein is about 1 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL. In certain embodiments, the solubilizing agent concentration in the liquid pharmaceutical formulations described herein is about 15 mg / mL. In certain embodiments, the solubilizing agent concentration in the liquid pharmaceutical formulations described herein is about 20 mg / mL. In certain embodiments, the solubilizing agent concentration in the liquid pharmaceutical formulations described herein is about 25 mg / mL. In certain embodiments, the concentration of the solubilizer in the liquid pharmaceutical formulation described herein is about 30 mg / mL. In certain embodiments, the concentration of the solubilizer in the liquid pharmaceutical formulation described herein is about 35 mg / mL. In certain embodiments, the concentration of the solubilizer in the liquid pharmaceutical formulation described herein is about 40 mg / mL. In certain embodiments, the concentration of the solubilizer in the liquid pharmaceutical formulation described herein is about 45 mg / mL. In certain embodiments, the concentration of the solubilizer in the liquid pharmaceutical formulation described herein is about 50 mg / mL.

[0137] Examples of solubilizing agents suitable for use in the liquid pharmaceutical formulations described herein include benzyl alcohol, polysorbates (e.g., polysorbate 20 (e.g., Tween® 20), or polysorbate 80 (e.g., Tween® 80), sodium stearate, 4-(5-dodecyl)benzenesulfonate, docusate (dioctyl sodium sulfosuccinate), alkyl ether phosphates, sodium lauryl sulfate, polyethylene glycol ethers, polyoxyethylene 15 hydroxystearate (e.g., macrogol 15 hydroxystearate, Solutol HS15®), polyoxyethylene castor oil derivatives (e.g., Cremophor® EL, ELP, RH40), polyoxyethylene stearates (e.g., Myrj®), sorbitan fatty acid esters (e.g., Span®), polyoxyethylene alkyl ethers (e.g., Brij®), and polyoxyethylene nonylphenol ethers (e.g., Nonoxynol®).

[0138] In certain embodiments, the solubilizing agent is benzyl alcohol. In certain embodiments, the solubilizing agent is polysorbate 20. In certain embodiments, the solubilizing agent is polysorbate 80. In some embodiments, the solubilizing agent is a combination thereof.

[0139] In various embodiments, the liquid pharmaceutical formulations described herein contain from about 15 mg to about 50 mg, from about 20 mg to about 50 mg, from about 25 mg to about 50 mg, from about 30 mg to about 50 mg, from about 35 mg to about 50 mg, from about 40 mg to about 50 mg, from about 45 mg to about 50 mg, from about 15 mg to about 45 mg, from about 15 mg to about 40 mg, from about 15 mg to about 35 mg, from about 15 mg to about 30 mg, from about 15 mg to about 25 mg, from about 15 mg to about 20 mg, from about 20 mg to about 4 In various embodiments, the liquid pharmaceutical formulations described herein may contain about 5 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 40 mg to about 45 mg of benzyl alcohol.

[0140] In various embodiments, the liquid pharmaceutical formulations described herein may contain about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 15 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 20 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 25 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 30 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 35 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 40 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 45 mg of benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may contain about 50 mg of benzyl alcohol.

[0141] In various embodiments, the liquid pharmaceutical formulations described herein may contain about 1% (w / w) to about 5% (w / w), about 2% (w / w) to about 5% (w / w), about 3% (w / w) to about 5% (w / w), about 4% (w / w) to about 5% (w / w), about 1% (w / w) to about 4% (w / w), about 1% (w / w) to about 3% (w / w), about 1% (w / w) to about 2% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3% (w / w), or about 3% (w / w) to about 4% (w / w) of benzyl alcohol.

[0142] In various embodiments, the liquid pharmaceutical formulations described herein may contain about 1% (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), about 2% (w / w), about 2.2% (w / w), about 2.4% (w / w), about 2.6% (w / w), about 2.8% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), or about 5% (w / w) benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 1% (w / w) benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 2% (w / w) benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 3% (w / w) benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 4% (w / w) benzyl alcohol. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 5% (w / w) benzyl alcohol.

[0143] In various embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 15 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 25 mg / mL to about 50 mg / mL, from about 30 mg / mL to about 50 mg / mL, from about 35 mg / mL to about 50 mg / mL, from about 40 mg / mL to about 50 mg / mL, from about 45 mg / mL to about 50 mg / mL, from about 15 mg / mL to about 45 mg / mL, from about 15 mg / mL to about 40 mg / mL, from about 15 mg / mL to about 35 mg / mL, from about 15 mg / mL to about 30 mg / mL, from about 15 mg / mL to about 25 mg / mL, from about 15 mg / mL to about 20 mg / mL, about 20 mg / mL to about 45 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 25 mg / mL, about 25 mg / mL to about 45 mg / mL, about 25 mg / mL to about 40 mg / mL, about 25 mg / mL to about 35 mg / mL, about 25 mg / mL to about 30 mg / mL, about 30 mg / mL to about 45 mg / mL, about 30 mg / mL to about 40 mg / mL, about 30 mg / mL to about 35 mg / mL, about 35 mg / mL to about 45 mg / mL, about 35 mg / mL to about 40 mg / mL, or about 40 mg / mL to about 45 mg / mL.

[0144] In various embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is 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 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, The concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 15 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 20 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 25 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 30 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 35 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 40 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 45 mg / mL. In certain embodiments, the concentration of benzyl alcohol in the liquid pharmaceutical formulations described herein is about 50 mg / mL.

[0145] In various embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 2:1 to about 1:7, from about 1.5:1 to about 1:7, from about 1:1.5 to about 1:7, from about 1:2 to about 1:7, from about 1:2.5 to about 1:7, from about 1:3 to about 1:7, from about 1:3.5 to about 1:7, from about 1:4 to about 1:7, from about 1:4.5 to about 1:7, from about 1:5 to about 1:7, from about 1:5.5 to about 1:7, from about 1:6 to about 1:7, from about 1:6.5 to about 1:7, from about 1:2 to about 1:7, from about 2:1 to about 1:6.5, from about 2:1 to about 1:6, from about 2:1 to about 1:5.5, from about 2:1 to about 1:5, from about 2:1 to about 1:4.5, about 2:1 to about 1:4, about 2:1 to about 1:3.5, about 2:1 to about 1:3, about 2:1 to about 1:2.5, about 2:1 to about 1:2, about 2:1 to about 1:1.5, about 2:1 to about 1:1, about 2:1 to about 1.5:1, about 1.5:1 to about 1:65, about 1.5:1 to about 1:6, about 1.5:1 to about 1:5.5, about 1.5:1 to about 1:5, about 1.5:1 to about 1:4.5, about 1.5:1 to about 1:4, about 1.5:1 to about 1:3.5, about 1.5:1 to about 1:3, about 1.5:1 to about 1:2.5, about 1.5:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1.5:1 to Approximately 1:1, approximately 1:1 to approximately 1:65, approximately 1:1 to approximately 1:6, approximately 1:1 to approximately 1:5.5, approximately 1:1 to approximately 1:5, approximately 1:1 to approximately 1:4.5, approximately 1:1 to approximately 1:4, approximately 1:1 to approximately 1:3.5, approximately 1:1 to approximately 1:3, approximately 1:1 to approximately 1:2.5, approximately 1:1 to approximately 1:2, approximately 1:1 to approximately 1:1. 5, about 1:1.5 to about 1:65, about 1:1.5 to about 1:6, about 1:1.5 to about 1:5.5, about 1:1.5 to about 1:5, about 1:1.5 to about 1:4.5, about 1:1.5 to about 1:4, about 1:1.5 to about 1:3.5, about 1:1.5 to about 1:3, about 1:1.5 to about 1:2.5, about 1:1.5 to about 1:2, about 1:2 to about 1:65, about 1:2 to about 1:6, about 1:2 to about 1:5.5, about 1:2 to about 1:5, about 1:2 to about 1:4.5, about 1:2 to about 1:4, about 1:2 to about 1:3.5, about 1:2 to about 1:3, about 1:2 to about 1:2.5, about 1:2.5 to about 1:65, about 1:2.5 Approximately 1:6, approximately 1:2.5 to approximately 1:5.5, approximately 1:2.5 to approximately 1:5, approximately 1:2.5 to approximately 1:4.5, approximately 1:2.5 to approximately 1:4, approximately 1:2.5 to approximately 1:3.5, approximately 1:2.5 to approximately 1:3, approximately 1:3 to approximately 1:6, approximately 1:3 to approximately 1:5.5, approximately 1:3 to approximately 1:5, approximately 1:3 to approximately 1:4.5, about 1:3 to about 1:4, about 1:3 to about 1:3.5, about 1:3.5 to about 1:65, about 1:3.5 to about 1:6, about 1:3.5 to about 1:5.5, about 1:3.5 to about 1:5, about 1:3.5 to about 1:4.5, about 1:3.5 to about 1:4, about 1:4 to about 1:65, about 1:4 to about 1:6, about 1:4 to about 1:5.5, about 1:4 to about The molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 1.5:1 to about 1:6.5. In certain embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 1.5:1 to about 1:6.5.

[0146] In various embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, or about 1:7. In certain embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 1.5:1. In certain embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 1:2. In certain embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 1:4. In certain embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is about 1:6.5.

[0147] (D) Additional pharmaceutically acceptable excipients (1) Osmolality and osmolality In various embodiments, the liquid pharmaceutical formulations described herein may further comprise an osmolality or osmolality adjuster.

[0148] In various embodiments, the osmolality or osmolality adjuster is selected from the group including sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof. In certain embodiments, the osmolality or osmolality adjuster is sodium chloride, potassium chloride, or a combination thereof. In certain embodiments, the osmolality or osmolality adjuster is sodium chloride. In certain embodiments, the osmolality or osmolality adjuster is potassium chloride.

[0149] In various embodiments, the liquid pharmaceutical formulations described herein provide a blood glucose concentration of about 100 mOsm / kg to about 1600 mOsm / kg, about 200 mOsm / kg to about 1600 mOsm / kg, about 300 mOsm / kg to about 1600 mOsm / kg, about 400 mOsm / kg to about 1600 mOsm / kg, about 600 mOsm / kg to about 1600 mOsm / kg, about 800 mOsm / kg to about 1600 mOsm / kg, about 1200 mOsm / kg to about 1600 mOsm / kg, about 1800 mOsm / kg to about 1600 mOsm / kg, about 200 mOsm / kg to about 1600 mOsm / kg, about 250 mOsm / kg to about 1600 mOsm / kg, about 300 mOsm / kg to about 1600 mOsm / kg, about 400 mOsm / kg to about 1600 mOsm / kg, about 500 mOsm / kg to about 1600 mOsm / kg, about 600 mOsm / kg to about 1600 mOsm / kg, about 800 mOsm / kg to about 1600 mOsm / kg, about 1200 mOsm / kg to about 1600 mOsm / kg, about 18 ... mOsm / kg ~ approx. 1600mOsm / kg, approx. 100mOsm / kg ~ approx. 1200mOsm / kg, approx. 100mOsm / kg ~ approx. 800mOsm / kg, approx. 100mOsm / kg ~ approx. 600mOsm / k g, about 100mOsm / kg to about 400mOsm / kg, about 100mOsm / kg to about 300mOsm / kg, about 100mOsm / kg to about 200mOsm / kg, about 200mOsm / kg to about 1200m Osm / kg, about 200mOsm / kg~about 800mOsm / kg, about 200mOsm / kg~about 600mOsm / kg, about 200mOsm / kg~about 400mOsm / kg, about 200mOsm / kg~ Approx. 300mOsm / kg, Approx. 300mOsm / kg~Approx. 1200mOsm / kg, Approx. 300mOsm / kg~Approx. 800mOsm / kg, Approx. 300mOsm / kg~Approx. 600mOsm / kg, Approx. 300mOs mOsm / kg to about 400 mOsm / kg, about 400 mOsm / kg to about 1200 mOsm / kg, about 400 mOsm / kg to about 800 mOsm / kg, about 400 mOsm / kg to about 600 mOsm / kg, about 600 mOsm / kg to about 1200 mOsm / kg, about 600 mOsm / kg to about 800 mOsm / kg, or about 800 mOsm / kg to about 1200 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality in the range of about 200 mOsm / kg to about 400 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality in the range of about 300 mOsm / kg to about 600 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 300 mOsm / kg to about 450 mOsm / kg.

[0150] In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 100 mOsm / kg to about 1600 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 200 mOsm / kg to about 800 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 200 mOsm / kg to about 600 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 200 mOsm / kg to about 400 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 275 mOsm / kg to about 400 mOsm / kg.

[0151] It should be understood that the above ranges and explanations for osmolality are equally applicable to osmolality, but using the units "Osm / kg."

[0152] (2)Water In various embodiments, the liquid pharmaceutical formulations described herein further comprise water. In certain embodiments, the water is water for injection.

[0153] In various embodiments, the liquid pharmaceutical formulations described herein may contain from about 0.1 mL to about 2 mL, from about 0.2 mL to about 2 mL, from about 0.3 mL to about 2 mL, from about 0.4 mL to about 2 mL, from about 0.5 mL to about 2 mL, from about 0.6 mL to about 2 mL, from about 0.7 mL to about 2 mL, from about 0.8 mL to about 2 mL, from about 0.9 mL to about 2 mL, from about 1 mL to about 2 mL, from about 1.5 mL to about 2 mL, from about 0.1 mL to about 1.5 mL, from about 0.1 mL to about 1 mL, from about 0.1 mL to about 0.9 mL, from about 0.1 mL to about 0.8 mL, from about 0.1 mL to about 0.7 mL, from about 0.1 mL to about 0.6 mL, from about 0.1 mL to about 0.5 mL, from about 0.1 mL to about 0.4 mL, from about 0.1 mL to about 0.3 mL, from about 0.1 mL to about 0.2 mL, from about 0.2 mL to about 1.5 mL, from about 0.2 mL to about 1 mL, from about 0.2 mL to about 0.9 mL, from about 0.2 mL to about 0.8 mL, from about 0.2 mL to about 0.7 mL, from about 0.2 mL to about 0.6 mL, from about 0.2 mL to about 0.5 mL, from about 0.2 mL to about 0.4 mL, from about 0.2 mL to about 0.3 mL, from about 0.3 mL to about 1.5 mL, from about 0.3 mL to about 1 mL, from about 0.3 mL to about 0.9 mL, from about 0.3 mL to about 0.8 mL, from about 0.3 mL to about 0.7 mL, from about 0.3 mL to about 0.6 mL, from about 0.3 mL to about 0.5 mL, from about 0.3 mL to about 0.4 mL, from about 0.4 mL to about 1.5 mL, from about 0.4 mL to about 1 mL, from about 0.4 mL to about 0.9 mL, from about 0.4 mL to about 0.8 mL, from about 0.4 mL to about 0.7 mL, from about 0.4 mL to about 0.6 mL, from about 0.4 mL to about 0.5 mL, from about 0.5 mL to about 1.5 mL, from about 0.5 mL to about 1 mL, from about 0.5 mL to about 0.9 mL, from about 0.5 mL to about 0.8 mL, from about 0.5 mL to about 0.7 mL, from about 0.5 mL to about 0.6 mL, from about 0.6 mL to about 1.5 mL, from about 0.6 mL to about 1 mL, from about 0.6 mL to about 0.9 mL, from about 0.6 mL to about 0.8 mL, from about 0.6 mL to about 0.7 mL, from about 0.7 mL to about 1.5 mL, from about 0.7 mL to about 1 mL, from about 0.7 mL to about 0.9 mL, from about 0.7 mL to about 0.8 mL, from about 0.8 mL to about 1.5 mL, from about 0.8 mL to about 1 mL, from about 0.8 mL to about 0.9 mL, from about 0.9 mL to about 1.5 mL, from about 0.9 mL to about 1 mL, or from about 1 mL to about 1.5 mL of water.

[0154] In various embodiments, the liquid pharmaceutical compositions described herein may contain about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, or about 2 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may contain about 0.3 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may contain about 0.4 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may contain about 0.5 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may contain about 0.6 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may contain about 0.7 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.8 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.9 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 1 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 1.1 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 1.2 mL of water.

[0155] It is understood that the volume of water added to the pharmaceutical formulation can be an amount that brings the total volume to one of the volumes of water recited herein, for example, an amount that brings the total volume of the pharmaceutical formulation to about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1.0 mL.

[0156] In various embodiments, the liquid pharmaceutical composition described herein may contain water in amounts of about 0.1 g to about 2 g, about 0.2 g to about 2 g, about 0.3 g to about 2 g, about 0.4 g to about 2 g, about 0.5 g to about 2 g, about 0.6 g to about 2 g, about 0.7 g to about 2 g, about 0.8 g to about 2 g, about 0.9 g to about 2 g, about 1 g to about 2 g, about 1.5 g to about 2 g, about 0.1 g to about 1.5 g, about 0.1 g to about 1 g, about 0.1 g to about 0.9 g, about 0.1 g to about 0.8 g, about 0.1 g to about 0.7 g, about 0.1 g to about 0.6 g, about 0.1 g to about 0.5 g, about 0.1 g to about 0.4 g, about 0.1 g to about 0.3 g, about 0.1 g to about 0.2 g, about 0.2 g to about 1.5 g, about 0.2 g to about 1 g, about 0.2 g to about 0.9 g, about 0.2 g to about 0.8 g, about 0.2 g to about 0.7 g, about 0.2 g to about 0.6 g, about 0.2 g to about 0.5 g, about 0.2 g to about 0.4 g, about 0.2 g to about 0.3 g, about 0.3 g to about 1.5 g, about 0.3 g to about 1 g, about 0.3 g to about 0.9 g, about 0.3 g to about 0.8 g, about 0.3 g to about 0.7 g, about 0.3 g to about 0.6 g, about 0.3 g to about 0.5 g, about 0.3 g to about 0.4 g, about 0.4 g to about 1.5 g, about 0.4 g to about 1 g, about 0.4 g to about 0.9 g, about 0.4 g to about 0.8 g, about 0.4 g to about 0.7 g, about 0.4 g to about 0.6 g, about 0.4 g to about 0.5 g, about 0.5 g to about 1.5 g, about 0.5 g to about 1 g, about 0.5 g to about 0.9 g, about 0.5 g to about 0.8 g, about 0.5 g to about 0.7 g, about 0.5 g to about 0.6 g, about 0.6 g to about 1.5 g, about 0.6 g to about 1 g, about 0.6 g to about 0.9 g, about 0.6 g to about 0.8 g, about 0.6 g to about 0.7 g, about 0.7 g to about 1.5 g, about 0.7 g to about 1 g, about 0.7 g to about 0.9 g, about 0.7 g to about 0.8 g, about 0.8 g to about 1.5 g, about 0.8 g to about 1 g, about 0.8 g to about 0.9 g, about 0.9 g to about 1.5 g, about 0.9 g to about 1 g, or about 1 g to about 1.5 g.

[0157] In various embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.1 g, about 0.2 g, about 0.3 g, about 0.4 g, about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about 1.8 g, about 1.9 g, or about 2 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.3 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.4 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.5 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.6 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.7 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.8 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.9 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 1 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 1.1 g of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 1.2 g of water.

[0158] (3) Other excipients In various embodiments, the liquid pharmaceutical formulations described herein may further comprise one or more additional pharmaceutically acceptable excipients.

[0159] In various embodiments, the one or more additional pharmaceutically acceptable excipients are selected from the group consisting of ethanol, glycerin, N-methyl-pyrrolidone (NMP), 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.

[0160] In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise ethanol. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise glycerin. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise N-methyl-pyrrolidone (NMP). In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise sodium carbonate. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise mannitol. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise lactose. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise dextrose. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise polyethylene glycol (PEG). In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise propylene glycol. In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise a polysorbate (e.g., polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate). In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise polyvinylpyrrolidone (PVP). In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise a cyclodextrin (e.g., α (alpha)-cyclodextrin, β (beta)-cyclodextrin, and γ (gamma)-cyclodextrin). In certain embodiments, the one or more additional pharmaceutically acceptable excipients include a cyclodextrin derivative (e.g., sulfobutyl-ether-β-cyclodextrin (e.g., Captisol), hydroxypropyl-β-cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin), and a methylated β-cyclodextrin (e.g., randomly methylated β-cyclodextrin)). In certain embodiments, the one or more additional pharmaceutically acceptable excipients include vitamin E.In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise one or more naturally occurring forms of vitamin E (e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol, and delta-tocopherol, and alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol). In certain embodiments, the one or more additional pharmaceutically acceptable excipients comprise a vitamin E derivative (e.g., tocopheryl acetate, tocopheryl glucoside, tocopheryl phosphate).

[0161] (E) Volume of formulation In various embodiments, the total volume of the liquid pharmaceutical preparation described herein can be from about 0.1 mL to about 2 mL, from about 0.2 mL to about 2 mL, from about 0.3 mL to about 2 mL, from about 0.4 mL to about 2 mL, from about 0.5 mL to about 2 mL, from about 0.6 mL to about 2 mL, from about 0.7 mL to about 2 mL, from about 0.8 mL to about 2 mL, from about 0.9 mL to about 2 mL, from about 1 mL to about 2 mL, from about 1.5 mL to about 2 mL, from about 0.1 mL to about 1.5 mL, from about 0.1 mL to about 1 mL, from about 0.1 mL to about 0.9 mL, from about 0.1 mL to about 0.8 mL, from about 0.1 mL to about 0.7 mL, from about 0.1 mL to about 0.6 mL, from about 0.1 mL to about 0.5 mL, from about 0.1 mL to about 0.4 mL, from about 0.1 mL to about 0.3 mL, from about 0.1 mL to about 0.2 mL, from about 0.2 mL to about 1.5 mL, from about 0.2 mL to about 1 mL, from about 0.2 mL to about 0.9 mL, from about 0.2 mL to about 0.8 mL, from about 0.2 mL to about 0.7 mL, from about 0.2 mL to about 0.6 mL, from about 0.2 mL to about 0.5 mL, from about 0.2 mL to about 0.4 mL, from about 0.2 mL to about 0.3 mL, from about 0.3 mL to about 1.5 mL, from about 0.3 mL to about 1 mL, from about 0.3 mL to about 0.9 mL, from about 0.3 mL to about 0.8 mL, from about 0.3 mL to about 0.7 mL, from about 0.3 mL to about 0.6 mL, from about 0.3 mL to about 0.5 mL, from about 0.3 mL to about 0.4 mL, from about 0.4 mL to about 1.5 mL, from about 0.4 mL to about 1 mL, from about 0.4 mL to about 0.9 mL, from about 0.4 mL to about 0.8 mL, from about 0.4 mL to about 0.7 mL, from about 0.4 mL to about 0.6 mL, from about 0.4 mL to about 0.5 mL, from about 0.5 mL to about 1.5 mL, from about 0.5 mL to about 1 mL, from about 0.5 mL to about 0.9 mL, from about 0.5 mL to about 0.8 mL, from about 0.5 mL to about 0.7 mL, from about 0.5 mL to about 0.6 mL, from about 0.6 mL to about 1.5 mL, from about 0.6 mL to about 1 mL, from about 0.6 mL to about 0.9 mL, from about 0.6 mL to about 0.8 mL, from about 0.6 mL to about 0.7 mL, from about 0.7 mL to about 1.5 mL, from about 0.7 mL to about 1 mL, from about 0.7 mL to about 0.9 mL, from about 0.7 mL to about 0.8 mL, from about 0.8 mL to about 1.5 mL, from about 0.8 mL to about 1 mL, from about 0.8 mL to about 0.9 mL, from about 0.9 mL to about 1.5 mL, from about 0.9 mL to about 1 mL, or from about 1 mL to about 1.5 mL. <00,00606><000,0607>In various embodiments, the total volume of the liquid pharmaceutical formulations described herein can be about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, or about 2 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 0.3 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 0.4 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 0.5 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 0.6 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 0.7 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation described herein is about 0.8 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation described herein is about 0.9 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation described herein is about 1 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation described herein is about 1.1 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation described herein is about 1.2 mL.

[0163] (F) Exemplary Liquid Pharmaceutical Formulations In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of a loop diuretic, or a pharmaceutically acceptable salt thereof, and (ii) It may contain a pharmaceutically acceptable buffer.

[0164] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of a loop diuretic, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer, and (iii) A solubilizer may be included.

[0165] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of a loop diuretic, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizing agent, and (iv) A pH adjuster may be included.

[0166] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of a loop diuretic, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizer; (iv) a pH adjuster, and (v) It may contain water.

[0167] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 100 mg of a loop diuretic, or a pharmaceutically acceptable salt thereof, and (ii) It may contain about 4 mg to about 16 mg of a pharmaceutically acceptable buffer.

[0168] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 100 mg of a loop diuretic, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of a pharmaceutically acceptable buffer, and (iii) It may contain about 15 mg to about 50 mg of a solubilizer.

[0169] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 100 mg of a loop diuretic, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of a pharmaceutically acceptable buffer; (iii) about 15 mg to about 50 mg of a solubilizing agent, and (iv) A pH adjuster may be included.

[0170] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 100 mg of a loop diuretic, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of a pharmaceutically acceptable buffer; (iii) about 15 mg to about 50 mg of a solubilizing agent; (iv) a pH adjuster, and (v) It may contain water.

[0171] In various embodiments, the liquid pharmaceutical formulation comprises from about 1 mg to about 100 mg of a loop diuretic, or a pharmaceutically acceptable salt thereof, has a pH of from about 7 to about 8, and has a total volume of from about 0.5 mL to about 1 mL.

[0172] (1) Exemplary Furosemide Formulations In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain a pharmaceutically acceptable buffer.

[0173] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer, and (iii) A solubilizer may be included.

[0174] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizing agent, and (iv) A pH adjuster may be included.

[0175] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizer; (iv) a pH adjuster, and (v) It may contain water.

[0176] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain tromethamine.

[0177] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof; (ii) tromethamine, and (iii) It may contain benzyl alcohol.

[0178] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof; (ii) tromethamine, (iii) benzyl alcohol, (iv) hydrochloric acid, and (v) May contain sodium hydroxide.

[0179] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of furosemide, or a pharmaceutically acceptable salt thereof; (ii) tromethamine, (iii) benzyl alcohol, (iv) hydrochloric acid, (v) sodium hydroxide, and (v) It may contain water.

[0180] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer.

[0181] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer, and (iii) It may contain about 1% (w / w) to about 5% (w / w) of a solubilizing agent.

[0182] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer; (iii) about 1% (w / w) to about 5% (w / w) of a solubilizing agent, and (iv) A pH adjuster may be included.

[0183] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer; (iii) about 1% (w / w) to about 5% (w / w) of a solubilizing agent; (iv) a pH adjuster, and (v) It may contain water.

[0184] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain about 4 mg to about 16 mg of a pharmaceutically acceptable buffer.

[0185] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of a pharmaceutically acceptable buffer, and (iii) It may contain about 15 mg to about 50 mg of a solubilizer.

[0186] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of a pharmaceutically acceptable buffer; (iii) about 15 mg to about 50 mg of a solubilizing agent, and (iv) A pH adjuster may be included.

[0187] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of a pharmaceutically acceptable buffer; (iii) about 15 mg to about 50 mg of a solubilizing agent; (iv) a pH adjuster, and (v) It may contain water.

[0188] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain about 0.1% (w / w) to about 1.5% (w / w) tromethamine.

[0189] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) tromethamine, and (iii) It may contain about 1% (w / w) to about 5% (w / w) of benzyl alcohol.

[0190] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) tromethamine; (iii) about 1% (w / w) to about 5% (w / w) benzyl alcohol, and (iv) A pH adjuster may be included.

[0191] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 5% (w / w) to about 10% (w / w) furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) tromethamine; (iii) about 1% (w / w) to about 5% (w / w) of benzyl alcohol; (iv) a pH adjuster, and (v) It may contain water.

[0192] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain about 4 mg to about 16 mg of tromethamine.

[0193] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of tromethamine, and (iii) It may contain about 15 mg to about 50 mg of benzyl alcohol.

[0194] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of tromethamine; (iii) about 15 mg to about 50 mg of benzyl alcohol; (iv) hydrochloric acid, and (v) May contain sodium hydroxide.

[0195] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 40 mg to about 100 mg of furosemide, or a pharmaceutically acceptable salt thereof; (ii) about 4 mg to about 16 mg of tromethamine; (iii) about 15 mg to about 50 mg of benzyl alcohol; (iv) hydrochloric acid, (v) sodium hydroxide, and (v) It may contain water.

[0196] In various embodiments, the liquid pharmaceutical formulation comprises about 40 mg to about 100 mg of furosemide, has a pH of about 7 to about 8, and has a total volume of about 0.5 mL to about 1 mL.

[0197] (2) Exemplary Torsemide Formulations In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of torsemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain a pharmaceutically acceptable buffer.

[0198] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of torsemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer, and (iii) A solubilizer may be included.

[0199] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of torsemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizing agent, and (iv) A pH adjuster may be included.

[0200] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of torsemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizer; (iv) a pH adjuster, and (v) It may contain water.

[0201] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 20 mg to about 40 mg of torsemide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain a pharmaceutically acceptable buffer.

[0202] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 20 mg to about 40 mg of torsemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer, and (iii) A solubilizer may be included.

[0203] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 20 mg to about 40 mg of torsemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizing agent, and (iv) A pH adjuster may be included.

[0204] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 20 mg to about 40 mg of torsemide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizer; (iv) a pH adjuster, and (v) It may contain water.

[0205] In various embodiments, the liquid pharmaceutical formulation comprises about 20 mg to about 40 mg of torsemide, has a pH of about 7 to about 8, and has a total volume of about 0.5 mL to about 1 mL.

[0206] (3) Exemplary Bumetanide Formulations In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of bumetanide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain a pharmaceutically acceptable buffer.

[0207] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of bumetanide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer, and (iii) A solubilizer may be included.

[0208] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of bumetanide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizing agent, and (iv) A pH adjuster may be included.

[0209] In various embodiments, the liquid pharmaceutical formulation comprises: (i) an effective amount of bumetanide, or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) a solubilizer; (iv) a pH adjuster, and (v) It may contain water.

[0210] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 2 mg of bumetanide, or a pharmaceutically acceptable salt thereof, and (ii) It may contain a pharmaceutically acceptable buffer.

[0211] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 2 mg of bumetanide, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable buffer, and (iii) A solubilizer may be included.

[0212] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 2 mg of bumetanide, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable buffer; (iii) a solubilizing agent, and (iv) A pH adjuster may be included.

[0213] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 1 mg to about 2 mg of bumetanide, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable buffer; (iii) a solubilizer; (iv) a pH adjuster, and (v) It may contain water.

[0214] In various embodiments, the liquid pharmaceutical formulation comprises about 1 mg to about 2 mg of bumetanide, has a pH of about 7 to about 8, and has a total volume of about 0.5 mL to about 1 mL.

[0215] Treatment methods In one aspect, the liquid pharmaceutical formulations described herein can be used to treat or prevent various conditions, including, but not limited to, fluid congestion, edema, and hypertension, in patients in need thereof. In various embodiments, the condition is selected from the group consisting of fluid congestion, edema, and hypertension, and combinations thereof. In certain embodiments, the condition is fluid congestion. In certain embodiments, the condition is edema. In certain embodiments, the condition is hypertension. In certain embodiments, the edema is associated with congestive heart failure, cirrhosis, or renal disease. In certain embodiments, the renal disease is nephrotic syndrome.

[0216] In certain embodiments, the patient is a human.

[0217] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to the human by subcutaneous injection no more than about 1 mL of a liquid pharmaceutical formulation described herein.

[0218] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to the human via subcutaneous injection an effective amount of a loop diuretic in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0219] (A) Effective dose / concentration of loop diuretics In various embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 100 mg, about 2 mg to about 100 mg, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 60 mg to about 100 mg, about 70 mg to about 100 mg, about 80 mg to about 100 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about 1 mg to about 70 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about 1 mg to about 70 mg, about 1 mg to about 80 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 5 ... mg, about 1mg to about 40mg, about 1mg to about 30mg, about 1mg to about 20mg, about 1mg to about 10mg, about 1mg to about 5mg, about 1mg to about 2mg, about 2mg to about 80mg, about 2mg to about 70mg, about 2mg to about 60mg, about 2mg to about 50m g, about 2mg to about 40mg, about 2mg to about 30mg, about 2mg to about 20mg, about 2mg to about 10mg, about 2mg to about 5mg, about 5mg to about 80mg, about 5mg to about 70mg, about 5mg to about 60mg, about 5mg to about 50mg, about 5mg to about 40m g, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 1 0mg to about 20mg, about 20mg to about 80mg, about 20mg to about 70mg, about 20mg to about 60mg, about 20mg to about 50mg, about 20mg to about 40mg, about 20mg to about 30mg, about 30mg to about 70mg, about 20mg to about 60mg, about 20 In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 100 mg. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 80 mg.In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg to about 80 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 40 mg to about 100 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 40 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 40 mg to about 80 mg.

[0220] In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is 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 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 35 mg, about 40 mg, about 45 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, or about 100 mg. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 1 mg. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 20 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 40 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 80 mg. In certain embodiments, the effective amount of loop diuretic in the total volume of the liquid pharmaceutical formulation is about 100 mg.

[0221] In various embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 2 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 30 mg / mL to about 100 mg / mL, from about 40 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 60 mg / mL to about 100 mg / mL, from about 70 mg / mL to about 100 mg / mL, from about 80 mg / mL to about 100 mg / mL, from about 2 mg / mL to about 80 mg / mL, from about 2 mg / mL to about 80 mg / mL, 70mg / mL, about 2mg / mL to about 60mg / mL, about 2mg / mL to about 50mg / mL, about 2mg / mL to about 40mg / mL, about 2mg / mL to about 30mg / mL, about 2mg / mL to about 20mg / mL, about 2mg / mL to about 10mg / mL, about 2mg / mL to about 5mg / m L, about 5 mg / mL to about 80 mg / mL, about 5 mg / mL to about 70 mg / mL, about 5 mg / mL to about 60 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL to about 40 mg / mL, about 5 mg / mL to about 30 mg / mL, about 5 mg / mL to about 20 mg / mL, about 5 mg / mL~about 10mg / mL, about 10mg / mL~about 80mg / mL, about 10mg / mL~about 70mg / mL, about 10mg / mL~about 60mg / mL, about 10mg / mL~about 50mg / mL, about 10mg / mL~about 40mg / mL, about 10mg / mL~about 30mg / mL, about 10 mg / mL~about 20mg / mL, about 20mg / mL~about 80mg / mL, about 20mg / mL~about 70mg / mL, about 20mg / mL~about 60mg / mL, about 20mg / mL~about 50mg / mL, about 20mg / mL~about 40mg / mL, about 20mg / mL~about 30mg / mL, about 3 0mg / mL to approx. 80mg / mL, approx. 30mg / mL to approx. 70mg / mL, approx. 30mg / mL to approx. 60mg / mL, approx. 30mg / mL to approx. 50mg / mL, approx. 30mg / mL to approx. 40mg / mL, approx. 40mg / mL to approx. 80mg / mL, approx. 40mg / mL to about 60mg / mL, about 40mg / mL to about 50mg / mL, about 50mg / mL to about 80mg / mL, about 50mg / mL to about 70mg / mL, about 50mg / mL to about 60mg / mL, about 60mg / mL to about 80mg / mL, about 60mg / mL to about 70mg / mL,Or about 70 mg / mL to about 80 mg / mL. In certain embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL to about 100 mg / mL.

[0222] In various embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is 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 35 mg / mL, about 40 mg / mL, about 45 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, or about 100 mg / mL. In certain embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL. In certain embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 40 mg / mL. In certain embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 80 mg / mL.

[0223] In various embodiments, the loop diuretic is bumetanide, furosemide, or torsemide. In certain embodiments, the loop diuretic is bumetanide. In certain embodiments, the loop diuretic is furosemide. In certain embodiments, the loop diuretic is torsemide.

[0224] In various embodiments, the total volume of the liquid pharmaceutical formulation is about 0.3 mL or less, about 0.4 mL or less, about 0.5 mL or less, about 0.6 mL or less, about 0.7 mL or less, about 0.8 mL or less, about 0.9 mL or less, or about 1 mL or less.

[0225] In various embodiments, the total volume of the liquid pharmaceutical formulation is about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation is about 0.5 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulation is about 1 mL.

[0226] (1) Furosemide In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human via subcutaneous injection an effective amount of furosemide in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0227] In various embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is about 40 mg to about 80 mg, about 50 mg to about 80 mg, about 60 mg to about 80 mg, about 70 mg to about 80 mg, about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 50 mg to about 70 mg, about 50 mg to about 60 mg, or about 50 mg to about 60 mg. In certain embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is about 40 mg to about 80 mg.

[0228] In various embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg. In certain embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is about 40 mg. In certain embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is about 80 mg.

[0229] In various embodiments, the concentration of furosemide in the total volume of the liquid pharmaceutical formulation is about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL. In certain embodiments, the concentration of furosemide in the total volume of the liquid pharmaceutical formulation is about 80 mg / mL.

[0230] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 80 mg of furosemide in a liquid pharmaceutical formulation in a total volume of about 1 mL.In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 40 mg of furosemide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL.

[0231] (2) Bumetanide In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human via subcutaneous injection an effective amount of bumetanide in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0232] In various embodiments, the effective amount of bumetanide in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 2 mg, about 1.2 mg to about 2 mg, about 1.4 mg to about 2 mg, about 1.6 mg to about 2 mg, about 1.8 mg to about 2 mg, about 1 mg to about 1.8 mg, about 1 mg to about 1.6 mg, about 1 mg to about 1.4 mg, about 1 mg to about 1.2 mg, about 1.2 mg to about 1.8 mg, about 1.2 mg to about 1.6 mg, about 1.2 mg to about 1.4 mg, about 1.4 mg to about 1.8 mg, about 1.4 mg to about 1.6 mg, or about 1.6 mg to about 1.8 mg. In certain embodiments, the effective amount of bumetanide in the total volume of the liquid pharmaceutical formulation is about 1 mg to about 2 mg.

[0233] In various embodiments, the effective amount of bumetanide in the total volume of the liquid pharmaceutical formulation is about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, or about 2 mg. In certain embodiments, the effective amount of bumetanide in the total volume of the liquid pharmaceutical formulation is about 1 mg. In certain embodiments, the effective amount of bumetanide in the total volume of the liquid pharmaceutical formulation is about 2 mg.

[0234] In various embodiments, the concentration of bumetanide in the total volume of the liquid pharmaceutical formulation is about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL. In certain embodiments, the concentration of bumetanide in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL.

[0235] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to the human by subcutaneous injection about 2 mg of bumetanide in a liquid pharmaceutical formulation in a total volume of about 1 mL.In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to the human by subcutaneous injection about 1 mg of bumetanide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL.

[0236] (3) Torsemide In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human via subcutaneous injection an effective amount of torsemide in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0237] In various embodiments, the effective amount of torsemide in the total volume of the liquid pharmaceutical formulation is about 20 mg to about 40 mg, about 24 mg to about 40 mg, about 28 mg to about 40 mg, about 32 mg to about 40 mg, about 36 mg to about 40 mg, about 20 mg to about 36 mg, about 20 mg to about 32 mg, about 20 mg to about 28 mg, about 20 mg to about 24 mg, about 24 mg to about 36 mg, about 24 mg to about 32 mg, about 24 mg to about 28 mg, about 28 mg to about 36 mg, about 28 mg to about 32 mg, or about 32 mg to about 36 mg. In certain embodiments, the effective amount of torsemide in the total volume of the liquid pharmaceutical formulation is about 20 mg to about 40 mg.

[0238] In various embodiments, the effective amount of torsemide in the total volume of the liquid pharmaceutical formulation is about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg. In certain embodiments, the effective amount of torsemide in the total volume of the liquid pharmaceutical formulation is about 20 mg. In certain embodiments, the effective amount of torsemide in the total volume of the liquid pharmaceutical formulation is about 40 mg.

[0239] In various embodiments, the concentration of torsemide in the total volume of the liquid pharmaceutical formulation is 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, or about 40 mg / mL. In certain embodiments, the concentration of torsemide in the total volume of the liquid pharmaceutical formulation is about 40 mg / mL.

[0240] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 40 mg of torsemide in a liquid pharmaceutical formulation in a total volume of about 1 mL.In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 20 mg of torsemide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL.

[0241] (B) Pharmacokinetics / Pharmacodynamics (1)Urine output In various embodiments, the methods described herein comprise a method for preparing a solution of about 500 mL to about 5000 mL, about 600 mL to about 5000 mL, about 700 mL to about 5000 mL, about 800 mL to about 5000 mL, about 900 mL to about 5000 mL, about 1000 mL to about 5000 mL, about 1500 mL to about 5000 mL, about 2000 mL to about 5000 mL, about 2500 mL to about 5000 mL, about 3000 mL to about 5000 mL, about 3500 mL to about 5000 mL, about 4000 mL to about 5000 mL, about 4500 mL to about 5000 mL, about 500 mL to about 4500 mL, about 500 mL to about 4000mL, about 500mL to about 3500mL, about 500mL to about 3000mL, about 500mL to about 2500mL, about 500mL to about 2000mL, about 500mL to about 1500mL, about 500mL to about 1000mL, about 500mL to about 900mL, about 500mL to about 800mL, Approximately 500mL to approximately 700mL, approximately 500mL to approximately 600mL, approximately 600mL to approximately 4500mL, approximately 600mL to approximately 4000mL, approximately 600mL to approximately 3500mL, approximately 600mL to approximately 3000mL, approximately 600mL to approximately 2500mL, approximately 600mL to approximately 2000mL, approximately 600mL Approximately 1500mL, approximately 600mL to approximately 1000mL, approximately 600mL to approximately 900mL, approximately 600mL to approximately 800mL, approximately 600mL to approximately 700mL, approximately 700mL to approximately 4500mL, approximately 700mL to approximately 4000mL, approximately 700mL to approximately 3500mL, approximately 700mL to approximately 3000mL, Approximately 700mL to approximately 2500mL, approximately 700mL to approximately 2000mL, approximately 700mL to approximately 1500mL, approximately 700mL to approximately 1000mL, approximately 700mL to approximately 800mL, approximately 800mL to approximately 4500mL, approximately 800mL to approximately 4000mL, approximately 800mL to approximately 3500mL, approximately 800mL ~3000mL, 800mL~2500mL, 800mL~2000mL, 800mL~1500mL, 800mL~1000mL, 800mL~900mL, 900mL~4500mL, 900mL~4000mL, 900mL~3500 mL, about 900mL to about 3000mL, about 900mL to about 2500mL, about 900mL to about 2000mL, about 900mL to about 1500mL, about 900mL to about 1000mL, about 1000mL to about 4500mL, about 1000mL to about 4000mL, about 1000mL to about 3500mL,Approximately 1000mL to approximately 3000mL, approximately 1000mL to approximately 2500mL, approximately 1000mL to approximately 2000mL, approximately 1000mL to approximately 1500mL, approximately 1500mL to approximately 4500mL, approximately 1500mL to approximately 4000mL, approximately 1500mL to approximately 35 00mL, about 1500mL to about 3000mL, about 1500mL to about 2500mL, about 1500mL to about 2000mL, about 2000mL to about 4500mL, about 2000mL to about 4000mL, about 2000mL to about 3500mL, about 2000m In certain embodiments, the methods described herein result in a human having a total urine output of about 6 hours after completion of administration of about 600 mL to about 5000 mL. In certain embodiments, the methods described herein result in a human total urine output about 6 hours after completion of administration of about 1200 mL to about 5000 mL. In certain embodiments, the methods described herein result in a human total urine output about 6 hours after completion of administration of about 600 mL to about 2500 mL.

[0242] In various embodiments, the methods described herein involve the use of a solution of about 500 mL to about 5500 mL, about 600 mL to about 5500 mL, about 700 mL to about 5500 mL, about 800 mL to about 5500 mL, about 900 mL to about 5500 mL, about 1000 mL to about 5500 mL, about 1500 mL to about 5500 mL, about 2000 mL to about 5500 mL, about 2500 mL to about 5500 mL, about 3000 mL to about 5500 mL, about 3500 mL to about 5500 mL, about 4000 mL to about 5500 mL, about 4500 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 500 mL ~5000mL, 500mL~4500mL, 500mL~4000mL, 500mL~3500mL, 500mL~3000mL, 500mL~2500mL, 500mL~2000mL, 500mL~1500mL, 500mL~100 0mL, about 500mL to about 900mL, about 500mL to about 800mL, about 500mL to about 700mL, about 500mL to about 600mL, about 600mL to about 5000mL, about 600mL to about 4500mL, about 600mL to about 4000mL, about 600mL to about 3500mL, about 600m L~3000mL, 600mL~2500mL, 600mL~2000mL, 600mL~1500mL, 600mL~1000mL, 600mL~900mL, 600mL~800mL, 600mL~700mL, 700mL~5000m L, about 700mL to about 4500mL, about 700mL to about 4000mL, about 700mL to about 3500mL, about 700mL to about 3000mL, about 700mL to about 2500mL, about 700mL to about 2000mL, about 700mL to about 1500mL, about 700mL to about 1000mL, about 70 0mL to about 800mL, about 800mL to about 5000mL, about 800mL to about 4500mL, about 800mL to about 4000mL, about 800mL to about 3500mL, about 800mL to about 3000mL, about 800mL to about 2500mL, about 800mL to about 2000mL, about 800mL to about 1 500mL, about 800mL to about 1000mL, about 800mL to about 900mL, about 900mL to about 5000mL, about 900mL to about 4500mL, about 900mL to about 4000mL, about 900mL to about 3500mL, about 900mL to about 3000mL, about 900mL to about 2500mL,Approximately 900mL to approximately 2000mL, approximately 900mL to approximately 1500mL, approximately 900mL to approximately 1000mL, approximately 1000mL to approximately 5000mL, approximately 1000mL to approximately 4500mL, approximately 100 0mL to approx. 4000mL, approx. 1000mL to approx. 3500mL, approx. 1000mL to approx. 3000mL, approx. 1000mL to approx. 2500mL, approx. 1000mL to approx. 2000mL, approx. 1000 mL ~ approx. 1500mL, approx. 1500mL ~ approx. 5000mL, approx. 1500mL ~ approx. 4500mL, approx. 1500mL ~ approx. 4000mL, approx. 1500mL ~ approx. 3500mL, approx. 1500m L ~ approx. 3000mL, approx. 1500mL ~ approx. 2500mL, approx. 1500mL ~ approx. 2000mL, approx. 2000mL ~ approx. 5000mL, approx. 2000mL ~ approx. 4500mL, approx. 2000mL ~ Approximately 4000mL, approximately 2000mL to approximately 3500mL, approximately 2000mL to approximately 3000mL, approximately 2000mL to approximately 2500mL, approximately 2500mL to approximately 5000mL, approximately 2500mL to approximately 4500mL, about 2500mL to about 4000mL, about 2500mL to about 3500mL, about 2500mL to about 3000mL, about 3000mL to about 5000mL, about 3000mL to about 4 The methods described herein result in a human total urine output about 8 hours after completion of administration of about 500 mL, about 3000 mL to about 4000 mL, about 3000 mL to about 3500 mL, about 3500 mL to about 5000 mL, about 3500 mL to about 4500 mL, about 3500 mL to about 4000 mL, about 4000 mL to about 5000 mL, about 4000 mL to about 4500 mL, or about 4500 mL to about 5000 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 600 mL to about 5300 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 1200 mL to about 5300 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 600 mL to about 2650 mL.

[0243] In various embodiments, the methods described herein involve the use of a solution of about 500 mL to about 5500 mL, about 600 mL to about 5500 mL, about 700 mL to about 5500 mL, about 800 mL to about 5500 mL, about 900 mL to about 5500 mL, about 1000 mL to about 5500 mL, about 1500 mL to about 5500 mL, about 2000 mL to about 5500 mL, about 2500 mL to about 5500 mL, about 3000 mL to about 5500 mL, about 3500 mL to about 5500 mL, about 4000 mL to about 5500 mL, about 4500 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 500 mL ~5000mL, 500mL~4500mL, 500mL~4000mL, 500mL~3500mL, 500mL~3000mL, 500mL~2500mL, 500mL~2000mL, 500mL~1500mL, 500mL~100 0mL, about 500mL to about 900mL, about 500mL to about 800mL, about 500mL to about 700mL, about 500mL to about 600mL, about 600mL to about 5000mL, about 600mL to about 4500mL, about 600mL to about 4000mL, about 600mL to about 3500mL, about 600m L~3000mL, 600mL~2500mL, 600mL~2000mL, 600mL~1500mL, 600mL~1000mL, 600mL~900mL, 600mL~800mL, 600mL~700mL, 700mL~5000m L, about 700mL to about 4500mL, about 700mL to about 4000mL, about 700mL to about 3500mL, about 700mL to about 3000mL, about 700mL to about 2500mL, about 700mL to about 2000mL, about 700mL to about 1500mL, about 700mL to about 1000mL, about 70 0mL to about 800mL, about 800mL to about 5000mL, about 800mL to about 4500mL, about 800mL to about 4000mL, about 800mL to about 3500mL, about 800mL to about 3000mL, about 800mL to about 2500mL, about 800mL to about 2000mL, about 800mL to about 1 500mL, about 800mL to about 1000mL, about 800mL to about 900mL, about 900mL to about 5000mL, about 900mL to about 4500mL, about 900mL to about 4000mL, about 900mL to about 3500mL, about 900mL to about 3000mL, about 900mL to about 2500mL,Approximately 900mL to approximately 2000mL, approximately 900mL to approximately 1500mL, approximately 900mL to approximately 1000mL, approximately 1000mL to approximately 5000mL, approximately 1000mL to approximately 4500mL, approximately 100 0mL to approx. 4000mL, approx. 1000mL to approx. 3500mL, approx. 1000mL to approx. 3000mL, approx. 1000mL to approx. 2500mL, approx. 1000mL to approx. 2000mL, approx. 1000 mL ~ approx. 1500mL, approx. 1500mL ~ approx. 5000mL, approx. 1500mL ~ approx. 4500mL, approx. 1500mL ~ approx. 4000mL, approx. 1500mL ~ approx. 3500mL, approx. 1500m L ~ approx. 3000mL, approx. 1500mL ~ approx. 2500mL, approx. 1500mL ~ approx. 2000mL, approx. 2000mL ~ approx. 5000mL, approx. 2000mL ~ approx. 4500mL, approx. 2000mL ~ Approximately 4000mL, approximately 2000mL to approximately 3500mL, approximately 2000mL to approximately 3000mL, approximately 2000mL to approximately 2500mL, approximately 2500mL to approximately 5000mL, approximately 2500mL to approximately 4500mL, about 2500mL to about 4000mL, about 2500mL to about 3500mL, about 2500mL to about 3000mL, about 3000mL to about 5000mL, about 3000mL to about 45 The methods described herein result in a human total urine output about 12 hours after completion of administration of about 600 mL to about 5500 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 1200 mL to about 5500 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 600 mL to about 5500 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 1200 mL to about 5500 mL. In certain embodiments, the methods described herein result in a human total urine output about 8 hours after completion of administration of about 600 mL to about 2750 mL.

[0244] (2) Pharmacokinetics of Furosemide In various embodiments, the methods described herein provide for the administration of a serotonin-releasing hormone (SHR) antibody to a subject's blood at a concentration of about 1500 ng / mL to about 10000 ng / mL, about 2000 ng / mL to about 10000 ng / mL, about 3000 ng / mL to about 10000 ng / mL, about 4000 ng / mL to about 10000 ng / mL, about 5000 ng / mL to about 10000 ng / mL, about 6000 ng / mL to about 10000 ng / mL, about 7000 ng / mL to about 10000 ng / mL, about 8000 ng / mL to about 10000 ng / mL, about 9000 ng / mL to about 10000 ng / mL, about 1500 ng / mL to about 9000 ng / mL, or about 1500 ng / mL to about 9000 ng / mL. mL, about 1500ng / mL to about 8000ng / mL, about 1500ng / mL to about 7000ng / mL, about 1500ng / mL to about 6000ng / mL, about 1500ng / mL to about 5000ng / mL, about 1500ng / mL to about 4000ng / mL, about 1500ng / mL to about 3000ng / mL, about 1500ng / mL to about 2000ng / mL, about 2000ng / mL to about 9000ng / mL, about 2000ng / mL to about 8000ng / mL, about 2000ng / mL to about 7000ng / mL, about 2000ng / mL to about 6000ng / mL, about 2000 ng / mL~about 5000ng / mL, about 2000ng / mL~about 4000ng / mL, about 2000ng / mL~about 3000ng / mL, about 3000ng / mL~about 9000ng / mL, about 3000ng / mL~about 8000ng / mL, about 3000ng / mL~about 7000ng / m L, about 3000ng / mL to about 6000ng / mL, about 3000ng / mL to about 5000ng / mL, about 3000ng / mL to about 4000ng / mL, about 4000ng / mL to about 9000ng / mL, about 4000ng / mL to about 8000ng / mL, about 4000ng / mL to about 7 000ng / mL, about 4000ng / mL to about 6000ng / mL, about 4000ng / mL to about 5000ng / mL, about 5000ng / mL to about 9000ng / mL, about 5000ng / mL to about 8000ng / mL, about 5000ng / mL to about 7000ng / mL, about 5000n g / mL~about 6000ng / mL, about 6000ng / mL~about 9000ng / mL, about 6000ng / mL~about 8000ng / mL, about 6000ng / mL~about 7000ng / mL, about 7000ng / mL~about 9000ng / mL, about 7000ng / mL~about 8000ng / mL,or the peak plasma concentration (C ) of furosemide in humans of about 8000 ng / mL to about 9000 ng / mL. max In certain embodiments, the methods described herein provide a method for determining furosemide C in human plasma of about 1500 ng / mL to about 9800 ng / mL. max In certain embodiments, the methods described herein provide a method for determining furosemide C in human plasma of about 3000 ng / mL to about 9800 ng / mL. max In certain embodiments, the methods described herein provide a method for determining furosemide C in human plasma of about 1500 ng / mL to about 4900 ng / mL. max to provide.

[0245] In various embodiments, the methods described herein provide a method for treating a range of conditions including: about 4400 h*ng / mL to about 32000 h*ng / mL, about 5000 h*ng / mL to about 32000 h*ng / mL, about 6000 h*ng / mL to about 32000 h*ng / mL, about 7000 h*ng / mL to about 32000 h*ng / mL, about 8000 h*ng / mL to about 32000 h*ng / mL, about 12000 h*ng / mL to about 32000 h*ng / mL, about 16000 h*ng / mL to about 32000 h*ng / mL, about 20000 h*ng / mL to about 32000 h*ng / mL, about 2400 h*ng / mL to about 32000 h*ng / mL, about 3000 h*ng / mL to about 32000 h*ng / mL, about 4000 h*ng / mL to about 32000 h*ng / mL, about 5000 h*ng / mL to about 32000 h*ng / mL, about 6000 h*ng / mL to about 32000 h*ng / mL, about 7000 h*ng / mL to about 32000 h*ng / mL, about 8000 h*ng / mL to about 32000 h*ng / mL, about 12000 h*ng / mL to about 32000 h*ng / mL, about 16000 h*ng / mL to about 32000 h*ng / mL, about 20000 h*ng / mL to about 32000 h*ng / mL, about 2400 0h*ng / mL ~ approx. 32000h*ng / mL, approx. 28000h*ng / mL ~ approx. 32000h*ng / mL, approx. 4400h*ng / mL ~ approx. 28000h*ng / mL, approx. 4400h*ng / mL ~ approx. 24000h*ng / mL, approx. 4400h*ng / mL ~ approx. 20000 h*ng / mL, approximately 4400h*ng / mL to approximately 16000h*ng / mL, approximately 4400h*ng / mL to approximately 12000h*ng / mL, approximately 4400h*ng / mL to approximately 8000h*ng / mL, approximately 4400h*ng / mL to approximately 7000h*ng / mL, approximately 4400h*ng / mL~about 6000h*ng / mL, about 4400h*ng / mL~about 5000h*ng / mL, about 5000h*ng / mL~about 28000h*ng / mL, about 5000h*ng / mL~about 24000h*ng / mL, about 5000h*ng / mL~about 20000h*ng / mL, about 5000h*ng / mL~about 16000h*ng / mL, about 5000h*ng / mL~about 12000h*ng / mL, about 5000h*ng / mL~about 8000h*ng / mL, about 5000h*ng / mL~about 7000h*ng / mL, about 5000h*ng / mL~about 6000h *ng / mL, about 6000h*ng / mL to about 28000h*ng / mL, about 6000h*ng / mL to about 24000h*ng / mL, about 6000h*ng / mL to about 20000h*ng / mL, about 6000h*ng / mL to about 16000h*ng / mL, about 6000h*ng / mL~about 12000h*ng / mL, about 6000h*ng / mL~about 8000h*ng / mL, about 6000h*ng / mL~about 7000h*ng / mL, about 7000h*ng / mL~about 28000h*ng / mL, about 7000h*ng / mL~about 24000h*ng / mL,Approx. 7000h*ng / mL ~ Approx. 20000h*ng / mL, Approx. 7000h*ng / mL ~ Approx. 16000h*ng / mL, Approx. 7000h*ng / mL ~ Approx. 12000h*ng / mL, about 7000h*ng / mL~about 8000h*ng / mL, about 8000h*ng / mL~about 28000h*ng / mL, about 8 000h*ng / mL ~ approx. 24000h*ng / mL, approx. 8000h*ng / mL ~ approx. 20000h*ng / mL, approx. 8000h*ng / mL ~ approx. 16 000h*ng / mL, about 8000h*ng / mL~about 12000h*ng / mL, about 12000h*ng / mL~about 28000h*ng / mL, about 1 a furosemide AUC in human plasma of 2000 h*ng / mL to about 24000 h*ng / mL, about 12000 h*ng / mL to about 20000 h*ng / mL, about 12000 h*ng / mL to about 16000 h*ng / mL, about 16000 h*ng / mL to about 28000 h*ng / mL, about 16000 h*ng / mL to about 24000 h*ng / mL, about 16000 h*ng / mL to about 20000 h*ng / mL, about 20000 h*ng / mL to about 24000 h*ng / mL, or about 24000 h*ng / mL to about 28000 h*ng / mL; last (e.g., area under the curve from time of administration to last measurable concentration). In various embodiments, the methods described herein provide a furosemide AUC in human plasma of about 4400 h*ng / mL to about 31700 h*ng / mL. last In various embodiments, the methods described herein provide a furosemide AUC in human plasma of about 8800 h*ng / mL to about 31700 h*ng / mL. last In various embodiments, the methods described herein provide a method for increasing the AUC of furosemide in human plasma from about 4400 h*ng / mL to about 15850 h*ng / mL. last to provide.

[0246] In various embodiments, the methods described herein provide a method for treating a range of conditions, including: about 4500 h*ng / mL to about 36000 h*ng / mL, about 6000 h*ng / mL to about 36000 h*ng / mL, about 8000 h*ng / mL to about 36000 h*ng / mL, about 12000 h*ng / mL to about 36000 h*ng / mL, about 16000 h*ng / mL to about 36000 h*ng / mL, about 20000 h*ng / mL to about 36000 h*ng / mL, about 24000 h*ng / mL to about 36000 h*ng / mL, about 28000 h*ng / mL to about 36000 h*ng / mL , about 32000h*ng / mL to about 36000h*ng / mL, about 4500h*ng / mL to about 32000h*ng / mL, about 4500h*ng / mL to about 28000h*ng / mL, about 4500h*ng / mL to about 24000h*ng / mL, about 4500h*ng / mL ~20000h*ng / mL, approximately 4500h*ng / mL~16000h*ng / mL, approximately 4500h*ng / mL~12000h*ng / mL, approximately 4500h*ng / mL~8000h*ng / mL, approximately 4500h*ng / mL~6000h*ng / mL, approx. 6000h*ng / mL ~ approx. 32000h*ng / mL, approx. 6000h*ng / mL ~ approx. 28000h*ng / mL, approx. 6000h*ng / mL ~ approx. 24000h*ng / mL, approx. 6000h*ng / mL ~ approx. 20000h*ng / mL, approx. 6000h*ng / mL ~ approx. 1 6000h*ng / mL, about 6000h*ng / mL to about 12000h*ng / mL, about 6000h*ng / mL to about 8000h*ng / mL, about 8000h*ng / mL to about 32000h*ng / mL, about 8000h*ng / mL to about 28000h*ng / mL, about 80 00h*ng / mL~Approx. 24000h*ng / mL, Approx. 8000h*ng / mL~Approx. 20000h*ng / mL, Approx. 8000h*ng / mL~Approx. 16000h*ng / mL, Approx. 8000h*ng / mL~Approx. 12000h*ng / mL, Approx. 12000h*ng / mL~Approx. 32 000h*ng / mL, about 12000h*ng / mL~about 28000h*ng / mL, about 12000h*ng / mL~about 24000h*ng / mL, about 12000h*ng / mL~about 20000h*ng / mL, about 12000h*ng / mL~about 16000h*ng / mL,Approx. 16000h*ng / mL ~ Approx. 32000h*ng / mL, Approx. 16000h*ng / mL ~ Approx. 28000h*ng / mL, Approx. 16000h*ng / mL ~ Approx. 2400 0h*ng / mL, about 16000h*ng / mL~about 20000h*ng / mL, about 20000h*ng / mL~about 32000h*ng / mL, about 20000h*ng / a furosemide AUC in human plasma of about 28,000 h*ng / mL, about 20,000 h*ng / mL to about 24,000 h*ng / mL, about 24,000 h*ng / mL to about 32,000 h*ng / mL, about 24,000 h*ng / mL to about 28,000 h*ng / mL, or about 28,000 h*ng / mL to about 32,000 h*ng / mL; inf (e.g., area under the curve extrapolated to infinity). In certain embodiments, the methods described herein provide a furosemide AUC in human plasma of about 4500 h*ng / mL to about 33400 h*ng / mL. inf In certain embodiments, the methods described herein provide a furosemide AUC in human plasma of about 8900 h*ng / mL to about 33400 h*ng / mL. inf In certain embodiments, the methods described herein provide a furosemide AUC in human plasma of about 4500 h*ng / mL to about 16700 h*ng / mL. inf to provide.

[0247] (3) Illustrative pharmacokinetic / pharmacodynamic outcomes In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 80 mg of furosemide in a total volume of about 1 mL of a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation is one or more of the following: The method involves measuring furosemide C in human plasma from about 3000 ng / mL to about 9800 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 8800 h*ng / mL to about 31700 h*ng / mL. last provide; The method involves measuring the AUC of furosemide in human plasma from about 8900 h*ng / mL to about 33400 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0248] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 80 mg of furosemide in a liquid pharmaceutical formulation in a total volume of about 1 mL; The method involves measuring furosemide C in human plasma from about 3000 ng / mL to about 9800 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 8800 h*ng / mL to about 31700 h*ng / mL. last provide; The method involves measuring the AUC of furosemide in human plasma from about 8900 h*ng / mL to about 33400 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0249] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 40 mg of furosemide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation is one or more of the following: The method involves measuring furosemide C in human plasma from about 1500 ng / mL to about 4900 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 4400 h*ng / mL to about 15850 h*ng / mL. last provide; The method provides a method for determining the AUC of furosemide in human plasma from about 4450 h*ng / mL to about 16700 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0250] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 40 mg of furosemide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL; The method involves measuring furosemide C in human plasma from about 1500 ng / mL to about 4900 ng / mL. max provide; The method involves measuring the AUC of furosemide in human plasma from about 4400 h*ng / mL to about 15850 h*ng / mL. last provide; The method provides a method for determining the AUC of furosemide in human plasma from about 4450 h*ng / mL to about 16700 h*ng / mL. inf provide; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0251] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 2 mg of bumetanide in a total volume of about 1 mL of a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation is one or more of the following: Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0252] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 2 mg of bumetanide in a liquid pharmaceutical formulation in a total volume of about 1 mL; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0253] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 1 mg of bumetanide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL, wherein the liquid pharmaceutical formulation is one or more of the following: Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0254] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 1 mg of bumetanide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0255] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 40 mg of torsemide in a total volume of about 1 mL of a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation is one or more of the following: Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0256] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 40 mg of torsemide in a liquid pharmaceutical formulation in a total volume of about 1 mL; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 1200 mL to approximately 5000 mL; The total urine output of a human is about 1200 mL to about 5300 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 1200 mL to approximately 5500 mL.

[0257] In various embodiments, provided herein are methods of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 20 mg of torsemide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation, wherein the liquid formulation is one or more of the following: Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0258] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 20 mg of torsemide in a liquid pharmaceutical formulation in a total volume of about 0.5 mL; Approximately 6 hours after the completion of administration, the total urine output in humans is approximately 600 mL to approximately 2500 mL; The total urine output of a human is about 600 mL to about 2650 mL approximately 8 hours after the completion of administration; and Approximately 12 hours after the completion of administration, the total urine output of a human is approximately 600 mL to approximately 2750 mL.

[0259] (C) Delivery device In certain embodiments, the liquid pharmaceutical formulation is administered from a needle and syringe set, an autoinjector, a single-use fixed-dose injection pen, a multi-use fixed-dose injection pen, a single-use variable-dose injection pen, or a multi-use variable-dose injection pen. In certain embodiments, the liquid pharmaceutical formulation is administered from a needle and syringe set. In certain embodiments, the liquid pharmaceutical formulation is administered from an autoinjector. In some embodiments, the autoinjector is a disposable autoinjector. In certain embodiments, the liquid pharmaceutical formulation is administered from a single-use fixed-dose injection pen. In certain embodiments, the liquid pharmaceutical formulation is administered from a multi-use fixed-dose injection pen. In certain embodiments, the liquid pharmaceutical formulation is administered from a single-use variable-dose injection pen. In certain embodiments, the liquid pharmaceutical formulation is administered from a multi-use variable-dose injection pen.

[0260] (D) Time of administration In certain embodiments, the liquid pharmaceutical formulations described herein are administered to a patient by subcutaneous injection in a time period of 30 seconds or less (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).

[0261] (E)Patient In certain embodiments, the human is an adult human. In certain embodiments, the adult human has New York Heart Association (NYHA) Class II, Class III, or Class IV chronic heart failure, liver disease or dysfunction, or renal disease or dysfunction. In certain embodiments, the adult human exhibits reduced responsiveness to oral diuretics prior to initiating subcutaneous administration of a loop diuretic according to the methods described herein.

[0262] In certain embodiments, the adult human is 30-80 years old, 35-80 years old, 40-80 years old, 45-80 years old, 50-80 years old, 55-80 years old, 60-80 years old, 65-80 years old, 70-80 years old, 75-80 years old, 30-75 years old, 30-70 years old, 30-65 years old, 30-60 years old, 30-55 years old, 30-50 years old, 30-45 years old, 30-40 years old, 30-35 years old, 35-75 years old, 35-70 years old, 35-65 years old, 35-60 years old, 35-55 years old, 35-50 years old, 35-45 years old, 35-40 years old, 35-50 years old, 35-60 ...80 years old, 35-80 years old, 35-80 years old, 35-80 years old, 35-80 years old, 35-90 years old, 35-90 years old, 35-90 years old, 35-100 years old, 35-110 years old, 35-120 years old, 35-130 years old, 35-140 years old, 35-150 years old, 35-160 years old, The adult human may be 0 years old, 40-75 years old, 40-70 years old, 40-65 years old, 40-60 years old, 40-55 years old, 40-50 years old, 40-45 years old, 45-75 years old, 45-70 years old, 45-65 years old, 45-60 years old, 45-55 years old, 45-50 years old, 50-75 years old, 50-70 years old, 50-65 years old, 50-60 years old, 50-55 years old, 55-75 years old, 55-70 years old, 55-65 years old, 55-60 years old, 60-75 years old, 60-70 years old, 60-65 years old, 65-75 years old, 65-70 years old, or 70-75 years old. In certain embodiments, the adult human is 30-80 years old. In certain embodiments, the adult human is 45-80 years old.

[0263] In certain embodiments, the adult human is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 years old.

[0264] When administered for the treatment or prevention of a disease or disorder disclosed herein, it will be understood that an effective dosage may vary depending on many factors, such as the particular compound or therapeutic combination used, the method of administration, the severity of the condition being treated, and various physical factors related to the individual being treated. For therapeutic use, the liquid pharmaceutical formulations described herein may 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 dosage used to treat a particular individual must typically be subjectively determined by the attending physician. The variables involved include the patient's particular condition and condition, as well as their size, age, and response pattern. In some embodiments, an effective amount is an amount sufficient to cure or at least partially ameliorate the symptoms of a disease or disorder and its complications. In some embodiments, an effective amount is an amount sufficient to cure or at least partially ameliorate the symptoms of a disease or disorder and its complications.

[0265] kit In one aspect, the present invention provides kits for the treatment or prevention of various conditions, including, but not limited to, fluid overload, edema, and hypertension, in a patient in need thereof. In certain embodiments, the condition, disease, or disorder is selected from the group consisting of fluid overload, edema, and hypertension. In certain embodiments, the condition is fluid overload, edema, or hypertension. In certain embodiments, the condition is fluid overload, edema, or hypertension. In certain embodiments, the condition is hypertension. In certain embodiments, the edema is associated with congestive heart failure, cirrhosis, or renal disease. In certain embodiments, the renal disease is nephrotic syndrome.

[0266] In various embodiments, the kit comprises the liquid pharmaceutical formulation described herein. In certain embodiments, the kit comprises one or more unit doses of the liquid pharmaceutical formulation described herein. In certain embodiments, the kit further comprises a medical device. In certain embodiments, the kit further comprises instructions for treating the disease or disorder of the present invention.

[0267] Several medical devices have been proposed to facilitate self-administration of liquid pharmaceutical formulations. The device may include a reservoir (e.g., pre-filled) containing the liquid pharmaceutical formulation described herein to be administered. One type of device useful for intramuscular or subcutaneous delivery of pharmaceutical formulations is an autoinjector. In various embodiments, the kit includes an autoinjector.

[0268] Thus, in various embodiments, a medical device such as a micropump or patch device may include a reservoir containing a pharmaceutical formulation, a hypodermic needle configured for removable insertion into a patient's skin, a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the hypodermic needle, a control system configured to control the micropump to deliver the pharmaceutical formulation from the reservoir to the hypodermic needle (thereby administering the pharmaceutical formulation subcutaneously to the patient), and a housing for supporting the reservoir, hypodermic needle, micropump, and control system, wherein the housing is portable and adapted for contact with a patient's skin. The liquid pharmaceutical formulation contained within the reservoir may be any of the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein.

[0269] In certain embodiments, the medical device can be of unitary construction. Such medical devices can be single-use or one-time use. In certain embodiments, the medical device can be of multi-part construction. In such medical devices, there can be disposable or reusable parts or components. For example, a housing defining or containing a reservoir can be a disposable or reusable component of the medical device. In some embodiments, a disposable or reusable housing defining or containing a reservoir can contain a pharmaceutical formulation of the present teachings. In various embodiments, a hypodermic needle can be a disposable component of a medical device.

[0270] In certain embodiments, the medical device is selected from the group comprising a needle and syringe set, an autoinjector, a single-use fixed dose injection pen, a multi-use fixed dose injection pen, a single-use variable dose injection pen, or a multi-use variable dose injection pen. [Example]

[0271] The invention generally described herein will be more readily understood by reference to the following examples, which are intended merely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0272] Example 1. Manufacturing process of furosemide liquid pharmaceutical formulation The following examples illustrate the manufacturing processes for preparing all furosemide liquid pharmaceutical formulations.

[0273] The corresponding amounts of ingredients are listed in the formulations disclosed in Table 1.

[0274] Tromethamine was added to the appropriate amount of water for injection (WFI) and mixed until dissolved. Sodium hydroxide (NaOH) was added. Approximately 1 / 3 of the total amount of furosemide bulk drug was added and mixed until dissolved. Benzyl alcohol was added and mixed until uniform. NaOH was added. Approximately 1 / 3 of the total amount of furosemide bulk drug was added and mixed until dissolved. NaOH was added. The remaining furosemide bulk drug was added and mixed until dissolved. pH samples were taken, and the solution was adjusted to a pH of 7.20-7.60 with additional NaOH or HCl. After pH adjustment, WFI was added to the resulting solution to reach the final weight and mixed. The solution was filtered through a 0.22 μm PVDF filter and filled into glass syringes. [Table 1]

[0275] Example 2. Study comparing the pharmacokinetics and pharmacodynamics of a high-concentration / low-volume liquid pharmaceutical formulation of furosemide administered as a subcutaneous injection with furosemide administered as an intravenous injection in healthy volunteers. (1) Purpose of the test Primary Objective: To estimate the bioavailability of a high-concentration / low-volume liquid pharmaceutical formulation of furosemide (80 mg furosemide in 1 mL) (referred to in this example as SCP-111) administered as a subcutaneous injection via autoinjector, compared to an equivalent dose of furosemide administered as two 40 mg intravenous injections over two minutes, two hours apart. Secondary Objectives: (1) To describe the pharmacokinetics and pharmacodynamics of SCP-111 administered as a subcutaneous injection via an autoinjector; and (2) To describe the safety and tolerability of SCP-111 administered as a subcutaneous injection via an autoinjector.

[0276] (2) Evaluation items Primary endpoint: (1) AUC (AUC last and (2) the AUC (AUC inf ) log-transformed geometric mean ratio between subcutaneous SCP-111 and 80 mg intravenous furosemide. Secondary endpoints: Evaluate the following pharmacokinetic (PK) parameters for subcutaneous and intravenous furosemide administration: (1) maximum observed plasma concentration (C max );(2)C max Arrival time (T max (3) the terminal elimination rate constant (λz) estimated by linear regression of log-transformed concentration versus time data; (4) the elimination half-life (t1 / 2) estimated using the equation [ln(2) / λz]; (5) the apparent total body clearance (CL / F); (6) the total body clearance (CL); (7) the apparent total body volume of distribution (Vz / F); and (8) the total body volume of distribution (V).

[0277] The following pharmacodynamic (PD) parameters will be assessed for subcutaneous and intravenous furosemide administration: (1) urinary output (0-6, 0-8, and 0-12 hours); (2) urinary sodium excretion (0-6, 0-8, and 0-12 hours); and (3) urinary potassium excretion (0-6, 0-8, and 0-12 hours).

[0278] Adverse events (AEs) and serious adverse events (SAEs) will be grouped and summarized by body system. The incidence (number and percentage of subjects) of adverse events and serious adverse events will be presented overall and by MedDRA system organ class and preferred term.

[0279] (3) Exam period 3 months

[0280] (4) Study design and methodology This is an open-label, single-center, single-dose, randomized, two-way (two-period) crossover study in healthy volunteers. Each subject will complete a screening phase, a baseline phase, a treatment phase, and a follow-up phase.

[0281] The screening phase will be conducted on an outpatient basis 14 days prior to the baseline visit. Subjects will be instructed to maintain a diet of less than 2 grams of sodium within 2 days prior to admission to the Clinical Research Unit (CRU). Upon arrival at the CRU (Day 0), baseline and final eligibility assessments will be conducted.

[0282] The treatment phases include two crossover periods separated by a 2-4 day washout period. After each CRU admission, subjects will continue a <2 gram sodium diet until discharge. Subjects will be randomly assigned in a 1:1 ratio to one of two treatment sequences (i.e., IV followed by SC or vice versa) to receive intravenous (IV) furosemide or subcutaneous (SC) SCP-111 during the crossover period. Plasma will be collected to measure pre-dose and 12 hours post-dose furosemide concentrations. Prior to each treatment phase, subjects will completely empty their bladders and collect urine starting after injection and continuing until 12 hours post-injection. Subjects will remain in the CRU for each treatment phase until 12 hours post-dose. After final evaluations are performed, subjects will be discharged from the CRU if safety parameters are acceptable to the investigator.

[0283] The follow-up phase will occur 24–48 hours (day 5 ± 1) after discharge from the CRU following crossover period 2, completing the subject's study participation.

[0284] (5) Test procedures Intravenous Furosemide (IV Furosemide): Hospira, Furosemide Injection, Solution 10 mg / mL (NDA018667) (total dose = 80 mg) administered intravenously. 40 mg over 2 minutes by IV infusion, followed by a second dose of 40 mg over 2 minutes 2 hours later (reference treatment). SCP-111 (Furosemide Injection): Total dose = 80 mg; administered as a subcutaneous injection via autoinjector (test treatment). Test Medications: SCP-111, (Furosemide Injection), 80 mg / 1 mL, is a liquid pharmaceutical formulation of furosemide buffered to neutral pH for subcutaneous administration. Test device: The BD Intevia™ delivery system is a disposable autoinjector consisting of two subassemblies: a BD Neopak™ 1 mL long pre-filled syringe with a ½ inch pre-fitted needle, covered with a rigid needle shield (RNS) closure, and a BD FluroTec® 1 mL stopper.

[0285] The SCP-111 autoinjector is an investigational drug-device combination product consisting of SCP-111 and a commercially available two-step disposable autoinjector (BD Intevia™ 1.0 mL disposable autoinjector).

[0286] (6) Target population Number of subjects in the study: 18.

[0287] Subjects are enrolled in the study only if they meet all inclusion criteria and none of the exclusion criteria.

[0288] Selection criteria: Female and male subjects are eligible for inclusion only if all of the following criteria are met: (1) an Institutional Review Board (IRB)-approved informed consent is signed and dated prior to any study-related activity; (2) male and female subjects are 18 years of age or older; (3) the subject is capable of understanding the requirements of the study and willing to comply with all study procedures; and (4) in the opinion of the investigator, the subject is able to participate in the study.

[0289] Exclusion criteria: Subjects were ineligible for inclusion if they met any of the following criteria: (1) pregnant or lactating women, or women of childbearing age who were not willing to use an adequate form of contraception; (2) systolic blood pressure (SBP) <90 mmHg at screening or baseline; (3) heart rate >110 beats per minute (BPM) at screening or baseline; (4) body temperature >38°C (oral or equivalent); (5) serum potassium <3.0 or >5.5 mEq / L at screening; (6) other significant cardiac abnormalities that may interfere with study participation or study assessments; (7) current or planned treatment with any IV therapy, including inotropes, vasopressors, levosimendan, nesiritide, or analogs during the study; (8) presence of an implantable circulatory assist device, cardioverter-defibrillator, or pacemaker; (9) severe renal impairment (<30 mL / min / 1.73 m as calculated using the simplified Modification of Diet in Renal Disease (sMDRD) formula). 2(10) urinary retention due to bladder outlet obstruction and / or urethral stricture; (11) presence of or need for urinary catheterization; (12) history of liver disease, cirrhosis, or ascites; (13) moderate to severe hepatic dysfunction as determined by the investigator; (14) intravenous administration of radiographic contrast material within 72 hours prior to screening; (15) medications known to interact with furosemide (aminoglycoside antibiotics, ethacrynic acid, high-dose salicylates, cisplatin, tubocurarine, succinylcholine, chloral hydrate, phenytoin, methotrexate, indomethacin, or (16) receipt of an investigational drug or implantation of an investigational device within 30 days prior to screening, or participation in another interventional clinical trial; (17) any surgical or medical condition that, in the opinion of the investigator, may preclude participation in the study or affect the outcome of the study; (18) a positive urine drug screen at screening or baseline; (19) a blood alcohol concentration >2 mg / dL (0.02%) at screening; (20) an alcohol breath test >2 mg / dL (0.02%) upon admission to the CRU; and (21) a history of a severe allergic or hypersensitivity reaction to furosemide.

[0290] (7) Pharmacokinetic and statistical analysis Pharmacokinetic parameters are estimated using noncompartmental methods with Phoenix® WinNonlin® V8.1 or higher. Individual pharmacokinetic parameters of furosemide are calculated using noncompartmental analysis and summarized using descriptive statistics. Bioavailability of SCP-111 is measured by IV furosemide AUC last and AUC inf The ratio of the logarithmically transformed geometric mean of SCP-111 to that of SCP-111 is determined, and the 90% confidence interval for the geometric mean ratio is determined and must be within 80%-125% to establish bioequivalence.

[0291] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0292] equivalent The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments should be considered in all respects as illustrative rather than limiting of the disclosure described herein. The scope of the present disclosure is, therefore, indicated by the appended claims, rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A method for treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to said human by subcutaneous injection an effective amount of a loop diuretic in a liquid pharmaceutical formulation having a total volume of about 1 mL or less.

2. 10. The method of claim 1, wherein the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 1 mg to about 100 mg.

3. 3. The method of claim 1, wherein the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 2 mg / mL to about 100 mg / mL.

4. 4. The method of any one of claims 1-3, wherein the human has a total urine output of about 600 mL to about 5000 mL about 6 hours after completion of administration.

5. 5. The method of any one of claims 1-4, wherein the human has a total urine output of about 600 mL to about 5300 mL about 8 hours after completion of administration.

6. 6. The method of any one of claims 1-5, wherein the human has a total urine output of about 600 mL to about 5500 mL about 12 hours after completion of administration.

7. 7. The method of any one of claims 1-6, wherein the loop diuretic is bumetanide, furosemide, or torsemide.

8. A method for treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need of such treatment, comprising administering to the human by subcutaneous injection an effective amount of furosemide in a liquid pharmaceutical formulation having a total volume of about 1 mL or less.

9. 9. The method of claim 8, wherein the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is from about 40 mg to about 80 mg.

10. 10. The method of claim 8 or 9, wherein the concentration of furosemide in the total volume of the liquid pharmaceutical formulation is about 80 mg / mL.

11. The method of any one of claims 8-10, wherein the total volume of the liquid pharmaceutical formulation is about 0.5 mL or about 1 mL.

12. A method for treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need of such treatment, comprising administering to the human by subcutaneous injection approximately 80 mg of furosemide in a liquid pharmaceutical formulation in a total volume of approximately 1 mL.

13. A method for treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need of such treatment, comprising administering to the human by subcutaneous injection approximately 40 mg of furosemide in a liquid pharmaceutical formulation having a total volume of approximately 0.5 mL.

14. The method includes measuring furosemide C in the human's plasma from about 1500 ng / mL to about 9800 ng / mL. ｍａｘ The method of any one of claims 8 to 13, wherein

15. The method includes determining a furosemide AUC in the human's plasma from about 4400 h*ng / mL to about 31700 h*ng / mL. ｌａｓｔ The method of any one of claims 8 to 14, wherein

16. The method includes determining a furosemide AUC in the human's plasma from about 4500 h*ng / mL to about 33400 h*ng / mL. ｉｎｆ The method of any one of claims 8 to 15, wherein

17. 17. The method of any one of claims 8-16, wherein the human has a total urine output of about 600 mL to about 5000 mL about 6 hours after completion of administration.

18. 18. The method of any one of claims 8-17, wherein the human has a total urine output of about 600 mL to about 5300 mL about 8 hours after completion of administration.

19. 19. The method of any one of claims 8-18, wherein the human has a total urine output of about 600 mL to about 5500 mL about 12 hours after completion of administration.

20. 1. A method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to said human by subcutaneous injection about 80 mg of furosemide in a total volume of about 1 mL of a liquid pharmaceutical formulation, comprising: The method includes measuring furosemide C in the human's plasma from about 3000 ng / mL to about 9800 ng / mL. ｍａｘ provide; The method includes determining a furosemide AUC in the human's plasma from about 8800 h*ng / mL to about 31700 h*ng / mL. ｌａｓｔ provide; The method includes determining a furosemide AUC in the human's plasma from about 8900 h*ng / mL to about 33400 h*ng / mL. ｉｎｆ provide; the human has a total urine output of about 1200 mL to about 5000 mL at about 6 hours after completion of administration; the human has a total urine output of about 1200 mL to about 5300 mL at about 8 hours after completion of administration; and wherein the human has a total urine output of about 1200 mL to about 5500 mL about 12 hours after completion of administration.

21. 1. A method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to said human by subcutaneous injection about 80 mg of furosemide in a total volume of about 1 mL of a liquid pharmaceutical formulation; The method includes measuring furosemide C in the human's plasma from about 3000 ng / mL to about 9800 ng / mL. ｍａｘ provide; The method includes determining a furosemide AUC in the human's plasma from about 8800 h*ng / mL to about 31700 h*ng / mL. ｌａｓｔ provide; The method includes determining a furosemide AUC in the human's plasma from about 8900 h*ng / mL to about 33400 h*ng / mL. ｉｎｆ provide; the human has a total urine output of about 1200 mL to about 5000 mL at about 6 hours after completion of administration; the human has a total urine output of about 1200 mL to about 5300 mL at about 8 hours after completion of administration; and The method, wherein the human has a total urine output of about 1200 mL to about 5500 mL about 12 hours after completion of administration.

22. 1. A method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to said human by subcutaneous injection about 40 mg of furosemide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation, comprising: The method includes measuring furosemide C in the human's plasma from about 1500 ng / mL to about 4900 ng / mL. ｍａｘ provide; The method includes determining a furosemide AUC in the human's plasma from about 4400 h*ng / mL to about 15850 h*ng / mL. ｌａｓｔ provide; The method includes determining a furosemide AUC in the human's plasma from about 4500 h*ng / mL to about 16700 h*ng / mL. ｉｎｆ provide; the human has a total urine output of about 600 mL to about 2500 mL at about 6 hours after completion of administration; the human has a total urine output of about 600 mL to about 2650 mL at about 8 hours after completion of administration; and wherein the human has a total urine output of about 600 mL to about 2750 mL about 12 hours after completion of administration.

23. 1. A method of treating a condition selected from the group consisting of fluid overload, congestion, edema, and hypertension in a human in need thereof, comprising administering to said human by subcutaneous injection about 40 mg of furosemide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation; The method includes measuring furosemide C in the human's plasma from about 1500 ng / mL to about 4900 ng / mL. ｍａｘ provide; The method includes determining a furosemide AUC in the human's plasma from about 4400 h*ng / mL to about 15850 h*ng / mL. ｌａｓｔ provide; The method includes determining a furosemide AUC in the human's plasma from about 4450 h*ng / mL to about 16700 h*ng / mL. ｉｎｆ provide; the human has a total urine output of about 600 mL to about 2500 mL at about 6 hours after completion of administration; the human has a total urine output of about 600 mL to about 2650 mL at about 8 hours after completion of administration; and The method, wherein the human has a total urine output of about 600 mL to about 2750 mL about 12 hours after completion of administration.

24. 24. The method of any one of claims 1-23, wherein administering comprises administering the total volume in a time period of 30 seconds or less.

25. 25. The method of any one of claims 1-24, wherein administering comprises administering the total volume from an autoinjector.

26. 26. The method of any one of claims 1-25, wherein the liquid pharmaceutical formulation further comprises a pharmaceutically acceptable buffer, and optionally, the pharmaceutically acceptable buffer comprises tromethamine, or a pharmaceutically acceptable salt thereof.

27. 27. The method of any one of claims 1-26, wherein the liquid pharmaceutical formulation has a pH of about 7.2 to about 8.

28. 28. The method of any one of claims 1-27, wherein the liquid pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients, optionally wherein the one or more pharmaceutically acceptable excipients are selected from benzyl alcohol, sodium hydroxide, sodium chloride, hydrochloric acid, and combinations thereof.

29. 29. The method of any one of claims 1-28, wherein the human is an adult human, and optionally the adult human is between 45 and 80 years old.

30. 30. The method of claim 29, wherein the adult human has New York Heart Association (NYHA) Class II, Class III, or Class IV chronic heart failure, liver disease or dysfunction, or renal disease or dysfunction.

31. 31. The method of claim 29 or 30, wherein the adult human exhibits a reduced responsiveness to oral diuretics prior to initiating subcutaneous administration according to the method.

32. 32. The method of any one of claims 1-31, wherein the edema is associated with congestive heart failure, cirrhosis, or renal disease, optionally wherein the renal disease is nephrotic syndrome.

Images