Methods of treatment using loop diuretics

Abstract

Disclosed herein, in part, is a method of administering a liquid pharmaceutical formulation containing a loop diuretic to a patient by subcutaneous injection. Methods of treating conditions (e.g., hyperemia, edema, and hypertension caused by liquid overload) in a patient in need thereof are also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 479,093, filed January 9, 2023, the contents of which are incorporated herein in their entirety. Background Art

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

[0004] The oral bioavailability, and hence oral efficacy, of loop diuretics such as furosemide is generally limited. Furosemide is commonly administered both parenterally and orally, but wide variations in oral absorption are observed due to the combined effects of limited solubility and reduced stability at acidic pH. B. Devarakonda, DP Otto, A. Judefeind, RA Hill, MM deVilliers, “ 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, for most patients with congestive heart failure or other forms of more severe edema, furosemide is usually administered intravenously or intramuscularly.

[0005] Intravenous administration of drugs such as loop diuretics requires a trained healthcare professional to place a catheter and administer the drug solution. In contrast, patients or caregivers can administer the drug at home via subcutaneous injection or infusion with the aid of an automatic injection device and / or a wearable, on-body delivery infusion device. Subcutaneous administration of loop diuretics by patients or caregivers can also achieve more optimized therapeutic administration and total dose to provide more appropriate pharmacokinetic and pharmacodynamic profiles and patient outcomes.

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

[0007] Therefore, there is a need for improved pharmaceutical formulations containing loop diuretics (e.g., bumetanide, furosemide, or torsemide) that are chemically and physically stable over shelf life, contain a sufficient concentration of the loop diuretic (e.g., an effective amount in an appropriate volume), and have an appropriate pH and osmolality, e.g., to allow subcutaneous administration (e.g., subcutaneous injection) of the loop diuretic. Summary of the Invention

[0008] In one aspect, the present invention provides a method for treating a condition in a person in need thereof, the condition being selected from the group consisting of congestion, edema, and hypertension due to fluid overload, wherein the method generally comprises administering a liquid pharmaceutical formulation comprising a loop diuretic. In certain embodiments, the effective amount of the loop diuretic is administered by subcutaneous injection. That is, it has been found that the liquid pharmaceutical formulations of the present invention (e.g., a total volume of about 0.5 mL to about 1 mL, comprising an effective amount of a loop diuretic, e.g., about 1 mg to about 100 mg) can be delivered subcutaneously in a shortened time (e.g., equal to or less than 30 seconds). Delivering 80 mg of furosemide in a volume of about 1 mL or less in a shortened time without significantly increasing pain at the injection site allows patients to use a subcutaneous injection device (e.g., an autoinjector) in a shorter time, which will increase compliance with treatment.

[0009] In various embodiments of the invention, the method comprises 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.

[0010] 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 concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL to about 100 mg / mL.

[0011] In certain embodiments, the total urine volume of a human being about 6 hours after administration is completed is about 600 mL to about 5000 mL. In certain embodiments, the total urine volume of a human being about 8 hours after administration is completed is about 600 mL to about 5300 mL. In certain embodiments, the total urine volume of a human being about 12 hours after administration is completed is about 600 mL to about 5500 mL.

[0012] In certain embodiments, the loop diuretic is bumetanide, furosemide, or torsemide.

[0013] In various embodiments of the invention, the method comprises administering to a human an effective amount of furosemide in a liquid pharmaceutical formulation in a total volume of about 1 mL or less by subcutaneous injection.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] In certain embodiments, the method provides furosemide C in human plasma at about 1500 ng / mL to about 9800 ng / mL. max In certain embodiments, the method provides about 4400 h in human plasma ng / mL to about 31700 h Furosemide AUC in ng / mL last In certain embodiments, the method provides about 4000 h in human plasma ng / mL to about 24000 h Furosemide AUC in ng / mL inf In certain embodiments, the total urine volume of the human being about 6 hours after administration is completed is about 600 mL to about 5000 mL. In certain embodiments, the total urine volume of the human being about 8 hours after administration is completed is about 600 mL to about 5300 mL. In certain embodiments, the total urine volume of the human being about 12 hours after administration is completed is about 600 mL to about 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, wherein one or more of the following is true: This method provides furosemide C in human plasma at concentrations ranging from approximately 3000 ng / mL to approximately 9800 ng / mL. max ; This method provides approximately 8800 h in human plasma. ng / mL to about 31700 h Furosemide AUC in ng / mL last ; This method provides approximately 8900 h in human plasma. ng / mL to about 33400 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0019] 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, wherein: This method provides furosemide C in human plasma at concentrations ranging from approximately 3000 ng / mL to approximately 9800 ng / mL. max ; This method provides approximately 8800 h in human plasma. ng / mL to about 31700 h Furosemide AUC in ng / mL last ; This method provides approximately 8900 h in human plasma. ng / mL to about 33400 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 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, wherein one or more of the following is true: This method provides furosemide C in human plasma at concentrations ranging from approximately 1500 ng / mL to approximately 4900 ng / mL. max ; This method provides approximately 4400 h in human plasma. ng / mL to about 15850 h Furosemide AUC in ng / mL last ; This method provides approximately 4450 h in human plasma. ng / mL to about 16700 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0021] 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, wherein: This method provides furosemide C in human plasma at concentrations ranging from approximately 1500 ng / mL to approximately 4900 ng / mL. max ; This method provides approximately 4400 h in human plasma. ng / mL to about 15850 h Furosemide AUC in ng / mL last ; This method provides approximately 4450 h in human plasma. ng / mL to about 16700 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0022] In certain embodiments, administering comprises administering the total volume in a time equal to or less than 30 seconds. In certain embodiments, administering comprises administering the total volume from an automatic injector.

[0023] 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 pH of the liquid pharmaceutical formulation is from 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.

[0024] In various embodiments, the human is an adult, optionally wherein the adult is 45 to 80 years old. In certain embodiments, the adult suffers from New York Heart Association (NYHA) Class II, Class III or Class IV chronic heart failure, liver disease or liver damage, or kidney disease or kidney damage. In certain embodiments, the adult exhibits reduced responsiveness to oral diuretics prior to starting subcutaneous administration according to the method. In certain embodiments, the edema is associated with congestive heart failure, cirrhosis of the liver or kidney disease, optionally wherein the kidney disease is nephrotic syndrome. DETAILED DESCRIPTION

[0025] It has now been discovered that an effective amount of a loop diuretic (in a volume of about 1 mL or less) can be delivered subcutaneously in a shortened period of time without significantly increasing pain at the injection site. Such methods allow patients to use subcutaneous injection devices (e.g., autoinjectors), etc., in a shorter period of time, which will increase compliance with treatment. As generally described herein, the present invention provides methods for treating various conditions, diseases, and disorders (e.g., congestion, edema, and hypertension due to fluid overload) in patients (humans) in need thereof. The method can generally include administering a liquid pharmaceutical formulation of furosemide (e.g., 80 mg in 1 mL) subcutaneously to the patient in a period of 30 seconds or less. The liquid pharmaceutical formulations of furosemide and the delivery characteristics described herein can produce optimized pharmacokinetic and pharmacodynamic properties of furosemide, thereby maximizing the therapeutic effect (e.g., total urine output) of the patient.

[0026] definition

[0027] To facilitate understanding of the present invention, a number of terms and phrases are defined below.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Abbreviations used herein have their conventional meanings in chemistry and biology. The chemical structures and formulae shown herein are constructed according to standard rules of chemical valence known in the chemical art.

[0029] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0030] In this application, when an element or component is referred to as being included in and / or selected from a list of enumerated elements or components, it should be understood that the element or component may be any one of the enumerated elements or components, or the element or component may be selected from a group consisting of two or more enumerated elements or components.

[0031] In addition, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of the present invention, whether explicitly or implicitly herein. For example, when referring to a particular compound, the compound can be used for various embodiments of the compositions of the present invention and / or the methods of the present invention, unless otherwise understood in context. In other words, in this application, embodiments have been described and depicted in a manner that allows for clear and concise writing and drawing of the application, but it is intended and will be appreciated that the embodiments can be combined or separated in various ways without departing from the present teachings and inventions. For example, it should be understood that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0032] It should be understood that the expression "at least one" includes each of the items listed after the expression individually as well as various combinations of two or more of the items listed, unless otherwise understood from the context and usage. The expression "and / or" in relation to three or more of the items mentioned should be understood to have the same meaning, unless otherwise understood from the context.

[0033] The use of the terms "include / includes / including," "have / has / having," "contain / contains / containing" (including grammatical equivalents thereof) should generally be understood as open-ended and non-limiting, e.g., not excluding additional elements or steps that are not listed, unless expressly stated otherwise or understood from the context.

[0034] When the term "about" is used before a numerical value, the present invention also includes the specific numerical value itself, unless otherwise expressly stated. As used herein, the term "about" refers to a variation of ±10%, ±5%, ±3%, ±2%, or ±1% from the nominal value, unless otherwise stated or inferred from the context.

[0035] In various places throughout this specification, values ​​are disclosed as groups or ranges. This description is expressly intended to include each and every individual subcombination of such group members and range members. For example, values ​​in the range of 0 to 40 are specifically intended to 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 individually, and values ​​in the range of 1 to 20 are specifically intended to disclose the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 individually.

[0036] Any and all examples or exemplary language used herein, such as "such as" or "including", are intended merely to better illustrate the invention and do not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0037] As used herein, "compound" (including specifically named compounds, such as furosemide, bumetanide, ethacrynic acid, torsemide) refers to the compound itself and its pharmaceutically acceptable salts, unless otherwise understood from the context of the specification or expressly limited to a specific form of the compound, such as the compound itself or a pharmaceutically acceptable salt thereof.

[0038] As used herein, "furosemide" refers to the compound having the formula: , and pharmaceutically acceptable salts thereof. Such salts may include, but are not limited to, furosemide sodium salt and furosemide quaternary ammonium salt. Furosemide may be known by other names, such as frusemide, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid, or its IUPAC name 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid, or its common trade name Lasix. ® .

[0039] As used herein, "bumetanide" refers to the compound having the formula: , and pharmaceutically acceptable salts thereof. Such salts may include, but are not limited to, furosemide potassium salt and furosemide sodium salt. Bumetanide may be known by other names, such as bumedyl, bumethanide, or its IUPAC name 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid, or its common trade name Bumex ® and Burinex ® .

[0040] As used herein, "ethacrynic acid" refers to a compound having the formula: , and pharmaceutically acceptable salts thereof. Such salts may include, but are not limited to, ethacrynic acid sodium salt (also known as sodium ethacrynate). Ethacrynic acid may be known by other names, such as etacrynic acid, or its IUPAC name, 2-[2,3-dichloro-4-(2-methylenebutanoyl)phenoxy]acetic acid, or its common trade name, Sodium Edecrin. ® and Edecrin ® .

[0041] As used herein, "torsemide" refers to the compound having the formula: , and pharmaceutically acceptable salts thereof. Such salts may include, but are not limited to, torasemide sodium salt. Torsemide may be known by other names, such as torasemide, 1-isopropyl-3-((4-(3-methylphenylamino)pyridinyl)-3-sulfonyl)urea, 1-isopropyl-3-((4-m-tolyl-3-pyridinyl)sulfonyl)urea, or by its IUPAC name 1-[4-(3-methylanilino)pyridin-3-yl]sulfonyl-3-propan-2-ylurea, or by its common trade name Demadex ® .

[0042] As used herein, the terms "subject" and "patient" refer to an organism to be treated by the methods and / or compositions described herein. Such organisms are preferably mammals (e.g., rodents, apes, horses, cattle, porcines, dogs, cats, etc.), more preferably humans.

[0043] " buffer " used herein refers to the aqueous solution that resists pH change. Buffer can include " buffer agent ", such as weak acid and its salt, or weak base and its salt, which helps to maintain the stability of pH. The example of the buffer used in the pharmaceutical preparation includes bicarbonate buffer, carbonate buffer, citrate buffer, histidine buffer, phosphate buffer, tartrate buffer, tris (hydroxymethyl) aminomethane (or 2-amino-2-hydroxymethyl-propane-1,3-diol [(HOCH2)3CNH2]) buffer, and their combination. Some of these buffers are applicable to the pharmaceutical preparation of subcutaneous administration.

[0044] Tris(hydroxymethyl)aminomethane or tris(hydroxymethyl)aminomethane buffer may be referred to as "TRIS," "Tris," "Tris buffer," "trisolamine," "THAM," "tromethamine," and other names. In addition, many buffers and / or buffer systems may include Tris, or a pharmaceutically acceptable salt thereof, and may be used in the present teachings. For example, Tris buffered saline ("TBS"), Tris hydrochloride buffer ("Tris-HCl"), Tris base (pH 10.6), Tris / borate / ethylenediaminetetraacetate ("EDTA") buffer ("TBE"), and Tris / acetate / EDTA buffer ("TAE"). Tris base is typically used with Tris-HCl to prepare a Tris buffer of the desired pH. In addition, the present teachings may include Tris-related compounds that can act as buffers, such as compounds derived from Tris or structurally related to Tris.

[0045] As used herein, "tonicity" refers to the ionic strength or concentration of ions in a solution, such as a pharmaceutical formulation. Tonicity is typically measured in terms of molarity ("M"). As used herein, "isotonic solution," "isotonic formulation," "isotonic pharmaceutical formulation," and "isotonic" pharmaceutical formulation refer to solutions or formulations that have the same or similar concentrations of ions as found in body fluids.

[0046] As used herein, "physiological pH" refers to a pH of about 7.4.

[0047] As used herein, "osmolarity," "osmolality," and "osmolality" refer to the osmotic pressure of a solution, such as a pharmaceutical formulation. Osmolarity is typically measured as osmolality ("Osm / L" or "OsM") or osmolality ("Osm / kg"). When freezing point depression is measured, the observed value is the osmolality of the solution. In contrast to tonicity, osmolality takes into account non-ionized solutes in a solution, so when non-ionized solutes are present, the osmolality or osmolality of a solution will be higher than its tonicity. The osmolality of the liquid pharmaceutical formulations described herein can be measured, for example, using vapor pressure methods.

[0048] As used herein, "osmolarity modifier," "osmolarity adjuster," and "osmotic agent" refer to pharmaceutically acceptable compounds that can be added to the liquid drug formulations described herein to adjust the osmolarity of the liquid drug formulation.

[0049] As used herein, "pharmaceutically acceptable" refers to substances that are suitable for pharmaceutical use from a toxicological standpoint and do not adversely interact with the active ingredient. Thus, pharmaceutically acceptable carriers are those that are compatible with the other ingredients of the formulation and are biologically acceptable. In certain embodiments, supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0050] As used herein, "pharmaceutically acceptable excipients" refer to substances that facilitate the administration of an active agent to a subject and its absorption by the subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, phosphate-buffered saline solutions, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and colorants, etc. The preparations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, surfactants (e.g., polysorbate 20 or polysorbate 80), wetting agents, emulsifiers, salts that influence osmotic pressure, buffers, coloring substances, and / or aromatic substances, which do not adversely react with the compounds of the present invention. For examples of excipients and carriers, see Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA (1975).

[0051] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA (1975).

[0052] The term "pharmaceutically acceptable salt" as used herein refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that can provide a compound of the present invention or its active metabolite or residue after being administered to a subject. As known to those skilled in the art, the "salt" of a compound of the present invention can be derived from an inorganic or organic acid and base. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Other acids, such as oxalic acid, although not pharmaceutically acceptable in themselves, can be used to prepare salts that can be used as intermediates to obtain compounds of the present invention and pharmaceutically acceptable acid addition salts thereof.

[0053] Examples of bases include, but are not limited to, alkali metal (eg, sodium) hydroxides, alkaline earth metal (eg, magnesium) hydroxides, ammonia, and compounds of formula NW4 + Compounds (wherein W is C 1-4 Alkyl) etc.

[0054] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, and undecanoate salts. Other examples of salts include the reaction of anions of the compounds of the present invention with appropriate cations such as Na + NH4 + 、NW4 + (W is C 1-4 alkyl) and other complex salts.

[0055] The term "effective amount" as used herein refers to an amount of a composition (e.g., a liquid pharmaceutical formulation of the present invention) sufficient to achieve 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.

[0056] As used herein, the terms "treat," "treating," and "treatment" include any effect that results in improvement of a disorder, disease, condition, or the like, or ameliorates its symptoms, such as alleviating, reducing, modulating, improving, or eliminating.

[0057] As used herein, the term "congestion" (heart failure) refers to the signs and symptoms of extracellular fluid accumulation, which leads to increased cardiac filling pressures and thus reduced cardiac output. Neurohormonal activation further exacerbates the reduction in cardiac output, leading to an increase in the kidney's affinity for sodium and water, resulting in an increase in plasma volume.

[0058] As used herein, "fluid overload," "volume overload," and "hypervolemia" may describe a medical condition in which there is too much fluid in the blood. Excess fluid (primarily salt and water) may accumulate throughout the body, leading to weight gain.

[0059] Throughout the specification, 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 process steps.

[0060] Generally, percentages of compositions specified are by weight unless otherwise specified.

[0061] Liquid pharmaceutical preparations of loop diuretics

[0062] As described herein, in one aspect, the present invention provides a liquid pharmaceutical formulation comprising an effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof for treating a condition described herein. In certain embodiments, the condition is selected from the group consisting of congestion due to fluid overload, edema, and hypertension, and combinations thereof. In certain embodiments, the condition is congestion due to fluid overload. In certain embodiments, the condition is edema. In certain embodiments, the condition is hypertension.

[0063] (A) Loop diuretics

[0064] In certain embodiments, the effective amount of a 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, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 5 mg to about 90 mg, from about 5 mg to about 80 mg, from about 5 mg to about 70 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg 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 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 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 In some embodiments, the effective amount of the loop diuretic in the liquid pharmaceutical formulations described herein is from about 1 mg to about 100 mg.In certain embodiments, the effective amount of a 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.

[0065] In certain embodiments, the concentration of the loop diuretic in the liquid pharmaceutical formulations described herein can be from 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 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, or about 2 mg / mL to about 50 mg / mL. mg / mL to about 30 mg / mL, about 2 mg / mL to about 20 mg / mL, 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 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 to about 10 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 20 mg / mL, about 20 mg / mL to about 90 mg / mL, about 20 mg / mL to about 80 mg / mL, about 20 mg / mL to about 70 mg / mL, about 20 mg / mL to about 60 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 30 mg / mL, about 30 mg / mL to about 90 mg / mL, about 30 mg / mL to about 80 mg / mL, about 30 mg / mL to about 70 mg / mL, about 20 mg / mL to about 60 mg / mL, about 30From about 100 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, 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 may be from about 2 mg / mL to about 100 mg / mL.

[0066] In various embodiments, the liquid pharmaceutical formulations described herein may include a pharmaceutically acceptable salt of a loop diuretic.

[0067] The liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of a loop diuretic in an amount providing 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, 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 from about 50 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 90 mg, or 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 comprise a pharmaceutically acceptable salt of a loop diuretic in an amount providing from about 1 mg to about 100 mg of the loop diuretic in free acid / free base form.

[0068] In certain embodiments, the liquid pharmaceutical formulations described herein contain a pharmaceutically acceptable salt of a loop diuretic in an amount providing 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 free acid / free base form of the loop diuretic.

[0069] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of a loop diuretic in an amount that provides the following concentrations of the free acid / free base form of the loop diuretic: 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 80 mg / mL, about 2 mg / mL to about 60 mg / mL, about 2 mg / mL to about 8 ... 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 to about 20 mg / mL, 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 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 to about 10 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 20 mg / mL, about 20 mg / mL to about 90 mg / mL, about 20 mg / mL to about 80 mg / mL, about 20 mg / mL to about 70 mg / mL, about 20 mg / mL to about 60 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 30 mg / mL, about 30 mg / mL to about 90 mg / mL, about 30 mg / mL to about 80 mg / mL, about 30 mg / mL to about 70In some embodiments, the present invention provides a method for determining the amount of a nucleic acid sequence of the present invention. The method comprises the following steps: In certain embodiments, the liquid pharmaceutical formulations described herein comprise 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 to about 100 mg.

[0070] In certain embodiments, the loop diuretic is bumetanide, furosemide, or torsemide.

[0071] (i) Furosemide

[0072] In various embodiments, the present invention provides a liquid pharmaceutical formulation comprising an effective amount of furosemide or a pharmaceutically acceptable salt thereof for treating the conditions described herein.

[0073] 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 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg. mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 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 75In some embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is from about 40 mg to about 100 mg. In some embodiments, the effective amount of furosemide in the liquid pharmaceutical formulations described herein is from about 40 mg to about 80 mg.

[0074] 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.

[0075] In various embodiments, the liquid pharmaceutical formulations described herein comprise about 5% (w / w) to about 10% (w / w), about 6% (w / w) to about 10% (w / w), about 7% (w / w) to about 10% (w / w), about 8% (w / w) to about 10% (w / w), about 9% (w / w) to about 10% (w / w), about 5% (w / w) to about 9% (w / w), about 5% (w / w) to about 8% (w / w), about 5% (w / w) to about 7% (w / w), about 5% (w / w) to about 6% (w / w), about 6% (w / w) to about 9% (w / w), about 6% (w / w) to about 8% (w / w), about 6% (w / w) to about 7% (w / w). (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.

[0076] 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.

[0077] In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 5% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 6% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 7% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 8% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 9% (w / w) furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 10% (w / w) furosemide.

[0078] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be from about 50 mg / mL to about 250 mg / mL, from about 60 mg / mL to about 250 mg / mL, from about 70 mg / mL to about 250 mg / mL, from about 80 mg / mL to about 250 mg / mL, from about 90 mg / mL to about 250 mg / mL, from about 100 mg / mL to about 250 mg / mL, from about 120 mg / mL to about 250 mg / mL, from about 140 mg / mL to about 250 mg / mL, from about 160 mg / mL to about 250 mg / mL, from about 180 mg / mL to about 250 mg / mL, from about 200 mg / mL to about 250 mg / mL, from about 50 mg / mL to about 200 mg / mL, from about 50 mg / mL to about 180 mg / mL, from about 50 mg / mL to about 160 mg / mL, from about 50 mg / mL to about 140 mg / mL, from about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 100 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 200 mg / mL, about 60 mg / mL to about 180 mg / mL, about 60 mg / mL to about 160 mg / 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 / mL to about 200 mg / mL, about 70 mg / mL to about 180 mg / mL, about 70 mg / mL to about 160 mg / mL, about 70 mg / mL to about 140 mg / mL, about 70 mg / mL to about 120 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 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 / mL to about 90 mg / mL, about 90 mg / mL to about 200 mg / mL, about 90mg / mL to about 180 mg / mL, about 90 mg / mL to about 160 mg / mL, about 90 mg / mL to about 140 mg / mL, about 90 mg / mL to about 120 mg / mL, about 90 mg / mL to about 100 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 180 mg / mL, about 100 mg / mL to about 160 mg / mL, about 100 mg / mL to about 140 mg / mL, about 100 mg / mL to about 120 mg / mL, about 120 mg / mL to about 200 mg / mL, about 120 mg / mL to about 180 mg / mL, about 120 mg / mL to about 160 mg / mL, about 120 mg / mL to about 140 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 concentration of furosemide in the liquid pharmaceutical formulations described herein may be 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 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 about 80 mg / mL to about 120 mg / mL.

[0079] In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein may 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.

[0080] In various embodiments, the liquid pharmaceutical formulations described herein may comprise a pharmaceutically acceptable salt of furosemide.

[0081] In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing 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 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 45 mg to about 95 mg, about 45 mg to about mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 95 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 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.In some embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing about 40 mg to about 100 mg of the free acid form of furosemide.

[0082] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing 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 furosemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing about 40 mg of furosemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing about 80 mg of furosemide in free acid form.

[0083] In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing about 5% (w / w) to about 10% (w / w), about 6% (w / w) to about 10% (w / w), about 7% (w / w) to about 10% (w / w), about 8% (w / w) to about 10% (w / w), about 9% (w / w) to about 10% (w / w), about 5% (w / w) to about 9% (w / w), about 5% (w / w) to about 8% (w / w), about 5% (w / w) to about 7% (w / w), about 5% (w / w) to about 6% (w / w), about 6% (w / w) to about 9% (w / w), about 6% (w / w) to about 8% (w / w), about 6% (w / w) to about 7% (w / w), or about 7% (w / w) to about 10% (w / w). In some embodiments, the liquid pharmaceutical formulations described herein comprise about 5% (w / w) to about 10% (w / w) of the free acid form of furosemide. In some embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing about 5% (w / w) to about 10% (w / w) of the free acid form of furosemide.

[0084] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount providing 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.

[0085] 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) of furosemide. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide about 6% (w / w) of furosemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide about 7% (w / w) of furosemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide about 8% (w / w) of furosemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide about 9% (w / w) of furosemide in free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide about 10% (w / w) of furosemide in free acid form.

[0086] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount that provides the following concentration of furosemide as the free acid: 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 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 140 mg / mL. mg / mL, about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 100 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 200 mg / mL, about 60 mg / mL to about 180 mg / mL, about 60 mg / mL to about 160 mg / 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 / mL to about 200 mg / mL, about 70 mg / mL to about 180 mg / mL, about 70 mg / mL to about 160 mg / mL, about 70 mg / mL to about 140 mg / mL, about 70 mg / mL to about 120 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 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 / mL to about 90 mg / mL, about 90mg / mL to about 200 mg / mL, about 90 mg / mL to about 180 mg / mL, about 90 mg / mL to about 160 mg / mL, about 90 mg / mL to about 140 mg / mL, about 90 mg / mL to about 120 mg / mL, about 90 mg / mL to about 100 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 180 mg / mL, about 100 mg / mL to about 160 mg / mL, about 100 mg / mL to about 140 mg / mL, about 100 mg / mL to about 120 mg / mL, about 120 mg / mL to about 200 mg / mL, about 120 mg / mL to about 180 mg / mL, about 120 mg / mL to about 160 mg / mL, about 120 mg / mL to about 140 mg / mL, about 140 mg / mL to about 200 mg / mL, about 140 mg / mL to about 180 In some embodiments, the liquid pharmaceutical formulations described herein comprise 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 some embodiments, the liquid pharmaceutical formulations described herein comprise 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 some embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 80 mg / mL to about 120 mg / mL.

[0087] In certain embodiments, the liquid pharmaceutical formulations described herein comprise 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 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 liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 80 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 100 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of furosemide in an amount to provide a concentration of the free acid form of furosemide of about 120 mg / mL.

[0088] (ii) Torsemide

[0089] In various embodiments, the present invention provides liquid pharmaceutical formulations comprising an effective amount of torsemide or a pharmaceutically acceptable salt thereof for treating the conditions described herein.

[0090] In certain embodiments, the effective amount of torasemide in the liquid pharmaceutical formulations described herein is 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 20 mg to about 45 mg, from about 20 mg to about 40 mg, from about 20 mg to about 35 mg, from about 20 mg to about 30 mg, from about 20 mg to about 25 mg, from about 25 mg to about 45 mg, from about 25 mg to about 40 mg, from about 25 mg to about 35 mg, from about 25 mg to about 30 mg, from about 30 mg to about 45 mg, from about 30 mg to about 40 mg, from about 30 mg to about 35 mg, from about 35 mg to about 45 mg, from about 35 mg to about 40 mg, or from about 40 mg to about 45 mg. In certain embodiments, the effective amount of torasemide in the liquid pharmaceutical formulations described herein is from about 20 mg to about 50 mg. In certain embodiments, the effective amount of torsemide in the liquid pharmaceutical formulations described herein is from about 20 mg to about 40 mg.

[0091] 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.

[0092] In certain embodiments, the concentration of torasemide in the liquid pharmaceutical formulations described herein can be 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, from about 100 mg / mL to about 125 mg / mL, from about 25 mg / mL to about 100 mg / mL, from about 25 mg / mL to about 90 mg / mL, from about 25 mg / mL to about 80 mg / mL, from about 25 mg / mL to about 70 mg / mL, from about 25 mg / mL to about 60 mg / mL, from about 25 mg / mL to about 50 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 100 mg / mL, about 30 mg / mL to about 90 mg / 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 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, about 35 mg / mL to about 80 mg / mL, about 35 mg / mL to about 70 mg / mL, about 35 mg / mL to about 60 mg / mL, about 35 mg / mL to about 50 mg / mL, about 35 mg / mL to about 45 mg / mL, about 35 mg / mL to about 40 mg / mL, about 40 mg / mL to about 100 mg / mL, about 40 mg / mL to about 90 mg / mL, about 40 mg / mL to about 80 mg / mL, 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 40 mg / mL to about 45 mg / mL, about 45 mg / mL to about 100 mg / mL, about 45 mg / mL to about 90 mg / mL, about 45 mg / mL to about 80In some embodiments, the present invention provides an amount of the present invention that is preferably from about 45 mg / mL to about 70 mg / mL, about 45 mg / mL to about 60 mg / mL, about 45 mg / mL to about 50 mg / mL, about 50 mg / mL to about 100 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 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 torasemide in the liquid pharmaceutical formulations described herein may be from about 25 mg / mL to about 125 mg / mL.

[0093] In certain embodiments, the concentration of torasemide in the liquid pharmaceutical formulations described herein may 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 torasemide in the liquid pharmaceutical formulations described herein is about 40 mg / mL.

[0094] In various embodiments, the liquid pharmaceutical formulations described herein may comprise a pharmaceutically acceptable salt of torsemide.

[0095] In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount providing 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 its free acid form. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount providing from about 20 mg to about 50 mg of torsemide in free acid form.

[0096] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount providing 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 providing 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 providing about 40 mg of torsemide in free acid form.

[0097] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount that provides the following concentration of torsemide as the free acid: 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, 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 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 100 mg / mL, about 30 mg / mL to about 90 mg / 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 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, about 35 mg / mL to about 80 mg / mL, about 35 mg / mL to about 70 mg / mL, about 35 mg / mL to about 60 mg / mL, about 35 mg / mL to about 50 mg / mL, about 35 mg / mL to about 45 mg / mL, about 35 mg / mL to about 40 mg / mL, about 40 mg / mL to about 100 mg / mL, about 40 mg / mL to about 90 mg / mL, about 40 mg / mL to about 80 mg / mL, 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 40 mg / mL to about 45 mg / mL, about 45 mg / mL to about 100 mg / mL, about 45mg / mL to about 90 mg / mL, about 45 mg / mL to about 80 mg / mL, about 45 mg / mL to about 70 mg / mL, about 45 mg / mL to about 60 mg / mL, about 45 mg / mL to about 50 mg / mL, about 50 mg / mL to about 100 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 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 In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount that provides a concentration of torsemide in the free acid form of from about 25 mg / mL to about 125 mg / mL.

[0098] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of torsemide in an amount that provides a concentration of torsemide in 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 comprise a pharmaceutically acceptable salt of torsemide in an amount that provides a concentration of torsemide in free acid form of about 40 mg / mL.

[0099] (iii) Bumetanide

[0100] In various embodiments, the present invention provides liquid pharmaceutical formulations comprising an effective amount of bumetanide, or a pharmaceutically acceptable salt thereof, for treating the conditions described herein.

[0101] 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, about 1.25 mg to about 2.5 mg, about 1.5 mg to about 2.5 mg, about 1.75 mg to about 2.5 mg, about 2 mg to about 2.5 mg, about 2.25 mg to about 50 mg, about 1 mg to about 2.25 mg, about 1 mg to about 2 mg, about 1 mg to about 1.75 mg, 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 from about 1 mg to about 2.5 mg. In certain embodiments, the effective amount of bumetanide in the liquid pharmaceutical formulations described herein is from about 1 mg to about 2 mg.

[0102] 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.

[0103] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein may be from 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, about 1.25 mg / mL to about 5 mg / mL, about 1.25 mg / mL to about 4.5 mg / mL, about 1.25 mg / mL to about 3.5 mg / mL. mg / mL, about 1.25 mg / mL to about 3 mg / mL, about 1.25 mg / mL to about 2.5 mg / mL, about 1.25 mg / mL to about 2.25 mg / mL, about 1.25 mg / mL to about 2 mg / mL, about 1.25 mg / mL to about 1.75 mg / mL, about 1.25 mg / mL to about 1.5 mg / mL, about 1.5 mg / mL to about 5 mg / mL, about 1.5 mg / mL to about 4.5 mg / mL, about 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 1.75 mg / mL, about 1.75 mg / mL to about 5 mg / mL, about 1.75 mg / mL to about 4.5 mg / mL, about 1.75 mg / mL to about 4 mg / mL, about 1.75 mg / mL to about 3.5 mg / mL, about 1.75 mg / mL to about 3 mg / mL, about 1.75 mg / mL to about 2.5 mg / mL, about 1.75 mg / mL to about 2.25 mg / mL, about 1.75 mg / mL to about 2 mg / mL, about 2 mg / mL to about 5 mg / mL, about 2 mg / mL to about 4.5 mg / mL, about 2 mg / mL to about 4 mg / mL, about 2 mg / mL to about 3.5 mg / mL, about 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.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 3.5 mg / mL, about 2.25 mg / mL to about 3 mg / mL, about 2.25 mg / mL to about 2.5 mg / mL, about 2.5 mg / mL to about 5 mg / mL, about 2.5 mg / mL to about 4.5 mg / 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 to about 4.5 mg / mL, about 3 mg / mL to about 4 mg / mL, about 3 mg / mL to about 3.5 mg / mL, about 3.5 mg / mL to about 5 mg / mL, about 3.5 mg / mL to about 4.5 mg / mL, about 3.5 mg / mL to about 4 mg / mL, about 4 mg / mL to about 5 mg / mL, about 4 mg / mL to about 4.5 mg / mL, or about 4.5 mg / mL to about 5 mg / mL. In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein may be from about 1.25 mg / mL to about 6.25 mg / mL.

[0104] In certain embodiments, the concentration of bumetanide in the liquid pharmaceutical formulations described herein may 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.

[0105] In various embodiments, the liquid pharmaceutical formulations described herein may comprise a pharmaceutically acceptable salt of bumetanide.

[0106] In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount providing about 1 mg to about 2.5 mg, about 1.25 mg to about 2.5 mg, about 1.5 mg to about 2.5 mg, about 1.75 mg to about 2.5 mg, about 2 mg to about 2.5 mg, about 2.25 mg to about 50 mg, about 1 mg to about 2.25 mg, about 1 mg to about 2 mg, about 1 mg to about 1.75 mg, 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, or about 2 mg to about 2.5 mg. In various embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount providing from about 1 mg to about 2.5 mg of bumetanide in free acid form.

[0107] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount providing 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 as the free acid. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount providing about 1 mg of bumetanide as the free acid. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount providing about 2 mg of bumetanide as the free acid.

[0108] In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount that provides the following concentrations of bumetanide as the free acid: 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, about 1.25 mg / mL to about 6.25 mg / mL, about 1.5 mg / mL to about 6.25 mg / mL, about 2.25 mg / mL to about 6.25 mg / mL, about 3.5 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, about 1.25 mg / mL to about 6.25 mg / mL, about 1.5 mg / mL to about 6.25 mg / mL. mg / mL to about 4 mg / mL, about 1.25 mg / mL to about 3.5 mg / mL, about 1.25 mg / mL to about 3 mg / mL, about 1.25 mg / mL to about 2.5 mg / mL, about 1.25 mg / mL to about 2.25 mg / mL, about 1.25 mg / mL to about 2 mg / mL, about 1.25 mg / mL to about 1.75 mg / mL, about 1.25 mg / mL to about 1.5 mg / mL, about 1.5 mg / mL to about 5 mg / mL, about 1.5 mg / mL to about 4.5 mg / mL, about 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 1.25 mg / mL to about 2.25 mg / mL, about 1.25 mg / mL to about 2 mg / mL, about 1.75 mg / mL mg / mL, about 1.75 mg / mL to about 5 mg / mL, about 1.75 mg / mL to about 4.5 mg / mL, about 1.75 mg / mL to about 4 mg / mL, about 1.75 mg / mL to about 3.5 mg / mL, about 1.75 mg / mL to about 3 mg / mL, about 1.75 mg / mL to about 2.5 mg / mL, about 1.75 mg / mL to about 2.25 mg / mL, about 1.75 mg / mL to about 2 mg / mL, about 2 mg / mL to about 5 mg / mL, about 2 mg / mL to about 4.5 mg / mL, about 2 mg / mL to about 4 mg / mL, about 2 mg / mL to about 3.5 mg / mL, about 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 3.5 mg / mL, about 2.25 mg / mL to about 3 mg / mL, about 2.25 mg / mL to about 2.5 mg / mL, about 2.5 mg / mL to about 5 mg / mL, about 2.5 mg / mL to about 4.5 mg / 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 5 mg / mL, about 3 mg / mL to about 4.5 mg / mL, about 3 mg / mL to about 4 mg / mL, about 3 mg / mL to about 3.5 mg / mL, about 3.5 mg / mL to about 5 mg / mL, about 3.5 mg / mL to about 4.5 mg / mL, about 3.5 mg / mL to about 4 mg / mL, about 4 mg / mL to about 5 mg / mL, about 4 mg / mL to about 4.5 mg / mL, or about 4.5 mg / mL to about 5 mg / mL. In certain embodiments, the liquid pharmaceutical formulations described herein comprise a pharmaceutically acceptable salt of bumetanide in an amount that provides a concentration of the free acid form of bumetanide of about 1.25 mg / mL to about 6.25 mg / mL.

[0109] In certain embodiments, the liquid pharmaceutical formulations described herein comprise 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 comprise 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.

[0110] (B) pH, pharmaceutically acceptable buffers, and pH adjusters

[0111] (1) Pharmaceutically acceptable buffer

[0112] In certain embodiments, the liquid pharmaceutical formulations described herein further comprise a pharmaceutically acceptable buffer.

[0113] In various embodiments, the liquid drug formulations described herein can comprise from 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 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 6 mg to about 14 mg. In some embodiments, the liquid pharmaceutical formulations described herein may comprise from about 4 mg to about 16 mg of a pharmaceutically acceptable buffer.

[0114] In various embodiments, the liquid drug formulations described herein can comprise 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, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, 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, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, 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 In some 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.

[0115] In various embodiments, the liquid pharmaceutical formulations described herein comprise 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) 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). (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 / 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). In some embodiments, the liquid pharmaceutical formulations described herein comprise about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer.

[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) 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.

[0117] 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 130 mM, from about 50 mM to about 120 mM, from about 50 mM to about 110 mM, from about 50 mM to about 100 mM, from about 50 mM to about 90 mM, from about 50 mM to about 80 mM, from about 50 mM to about 70 mM, from about 50 mM to about 60 mM. 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.

[0118] 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.

[0119] 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 13 mg / mL, from about 5 mg / mL to about 12 mg / mL, from about 5 mg / mL to about 11 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 9 mg / mL, from about 5 mg / mL to about 15 mg / mL, from about 5 mg / mL to about 15 mg / mL, mg / mL, about 6 mg / mL to about 14 mg / mL, about 6 mg / mL to about 13 mg / mL, about 6 mg / mL to about 12 mg / mL, about 6 mg / mL to about 11 mg / mL, about 6 mg / mL to about 10 mg / mL, about 6 mg / mL to about 9 mg / mL, about 6 mg / mL to about 8 mg / mL, about 6 mg / mL to about 7 mg / 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 6 mg / mL to about 8 mg / mL, about 8 mg / mL to about 14 mg / mL, about 8 mg / mL to about 13 mg / mL, about 8 mg / mL to about 12 mg / mL, about 8 mg / mL to about 11 mg / mL, about 8 mg / mL to about 10 mg / mL, about 8 mg / mL to about 9 mg / mL, about 9 mg / mL to about 14 mg / mL, about 9 mg / mL 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 13In some 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.

[0120] 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 mg / mL, about 7 mg / mL, about 7.1 mg / mL, about 7.2 mg / mL, about 7.3 mg / mL, about 7.4 mg / mL, about 7.5 mg / mL, about 7.6 mg / mL, about 7.7 mg / 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 8.8 mg / mL, about 8.9 mg / mL, about 9 mg / mL, about 9.1 mg / mL, about 9.2 mg / mL, about 9.3 mg / mL, about 9.4 mg / mL, about 9.5 mg / mL, about 9.6 mg / mL, about 9.7 mg / mL, about 9.8 mg / mL, about 9.9 mg / mL, about 10 mg / mL, about 10.1 mg / mL, about 10.2 mg / mL, about 10.3 mg / mL, about 10.3 mg / mL, about 10.4 mg / mL, about 10.5 mg / mL, about 10.6 mg / mL, about 10.7 In some embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 6 mg / mL. In some embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 7 mg / mL.In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 8 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 9 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 10 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 11 mg / mL. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is about 12 mg / mL.

[0121] In certain embodiments, the pharmaceutically acceptable buffer comprises a buffer selected from the group consisting of: histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and combinations thereof. In certain embodiments, the buffer is tromethamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the buffer is tromethamine.

[0122] In various embodiments, the liquid drug formulations described herein can comprise from 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 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 6 mg to about 14 mg. In some embodiments, the liquid pharmaceutical formulations described herein may comprise from about 4 mg to about 16 mg of tromethamine.

[0123] In various embodiments, the liquid drug formulations described herein can comprise 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, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, 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, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, 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 In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 4.5 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 4.6 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 4.7 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 4.8 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 4.9 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 5 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise 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 comprise about 9.7 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 9.8 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 9.9 mg of tromethamine. In certain embodiments, the liquid pharmaceutical formulations described herein comprise about 10 mg of tromethamine.

[0124] In various embodiments, the liquid pharmaceutical formulations described herein comprise 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) 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). (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 / 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). In some embodiments, the liquid pharmaceutical formulations described herein comprise about 0.1% (w / w) to about 1.5% (w / w) tromethamine.

[0125] 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.

[0126] 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 130 mM, from about 50 mM to about 120 mM, from about 50 mM to about 110 mM, from about 50 mM to about 100 mM, from about 50 mM to about 90 mM, from about 50 mM to about 80 mM, from about 50 mM to about 70 mM, from about 50 mM to about 60 mM, 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 In some embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is from about 50 mM to about 150 mM.

[0127] 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.

[0128] 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, from about 5 mg / mL to about 12 mg / mL, from about 5 mg / mL to about 11 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 9 mg / mL, from about 5 mg / mL to about 8 mg / mL, from about 5 mg / mL to about 6 mg / mL. mg / mL, about 6 mg / mL to about 14 mg / mL, about 6 mg / mL to about 13 mg / mL, about 6 mg / mL to about 12 mg / mL, about 6 mg / mL to about 11 mg / mL, about 6 mg / mL to about 10 mg / mL, about 6 mg / mL to about 9 mg / mL, about 6 mg / mL to about 8 mg / mL, about 6 mg / mL to about 7 mg / 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 6 mg / mL to about 8 mg / mL, about 8 mg / mL to about 14 mg / mL, about 8 mg / mL to about 13 mg / mL, about 8 mg / mL to about 12 mg / mL, about 8 mg / mL to about 11 mg / mL, about 8 mg / mL to about 10 mg / mL, about 8 mg / mL to about 9 mg / mL, about 9 mg / mL to about 14 mg / mL, about 9 mg / mL 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 11In various embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 15 mg / mL.

[0129] 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 6.7 mg / mL, about 6.8 mg / mL, about 6.9 mg / mL, about 7 mg / mL, about 7.1 mg / mL, about 7.2 mg / mL, about 7.3 mg / mL, about 7.4 mg / mL, about 7.5 mg / mL, about 7.6 mg / mL, about 7.7 mg / 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 8.8 mg / mL, about 8.9 mg / mL, about 9 mg / mL, about 9.1 mg / mL, about 9.2 mg / mL, about 9.3 mg / mL, about 9.4 mg / mL, about 9.5 mg / mL, about 9.6 mg / mL, about 9.7 mg / mL, about 9.8 mg / mL, about 9.9 mg / mL, about 10 mg / mL, about 10.1 mg / mL, about 10.2 mg / mL, about 10.3 mg / mL, about 10.3 mg / mL, about 10.4 mg / mL, about 10.5 mg / mL, about 10.6 mg / mL, about 10.7 In some embodiments, the concentration of tromethamine in the liquid pharmaceutical formulations described herein is about 6 mg / mL. In some 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.

[0130] In various embodiments, the molar ratio of tromethamine to furosemide, or a pharmaceutically acceptable salt thereof, in the liquid pharmaceutical formulations described herein is from about 1:1 to about 1:3.5, from about 1:1.5 to about 1:3.5, from about 1:2 to about 1:3.5, from about 1:2.5 to about 1:3.5, from about 1:3 to about 1:3.5, from about 1:1 to about 1:3, from about 1:1 to about 1:2.5, from about 1:1 to about 1:2, from about 1:1 to about 1:1.5, from about 1:1.5 to about 1:3, from about 1:1.5 to about 1:2.5, from about 1:1.5 to about 1:2, from about 1:2 to about 1:3, from about 1:2 to about 1:2.5, or from 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 from 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 from about 1:1.5 to about 1:3.5.

[0131] 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. 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.

[0132] (2) pH adjuster

[0133] In various embodiments, the liquid pharmaceutical formulations described herein further comprise a pharmaceutically acceptable pH adjusting agent.

[0134] Exemplary pharmaceutically acceptable pH adjusters include, but are not limited to, one or more of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, aqueous ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, and triethanolamine.

[0135] 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.

[0136] (3) pH of liquid pharmaceutical preparations

[0137] In various embodiments, the pH of the liquid pharmaceutical formulations described herein can be from about 5.5 to about 8.5, from about 6 to about 8.5, from about 6.5 to about 8.5, from about 7 to about 8.5, from about 7.5 to about 8.5, from about 8 to about 8.5, from about 5.5 to about 8, from about 5.5 to about 7.5, from about 5.5 to about 7, from about 5.5 to about 6.5, from about 5.5 to about 6, from about 6 to about 8, from about 6 to about 7.5, from about 6 to about 7, from about 6 to about 6.5, from about 6.5 to about 8, from about 6.5 to about 7.5, from about 6.5 to about 7, from about 7 to about 8, from about 7 to about 7.5, or from about 7.5 to about 8. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is from about 6.5 to about 8.5. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein is from 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.

[0138] In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be from about 7 to about 8.5, from about 7.1 to about 8.5, from about 7.3 to about 8.5, from about 7.5 to about 8.5, from about 7.7 to about 8.5, from about 7.9 to about 8.5, from about 8.1 to about 8.5, from about 8.3 to about 8.5, from about 7 to about 8.3, from about 7 to about 8.1, from about 7 to about 7.9, from about 7 to about 7.7, from about 7 to about 7.5, from about 7 to about 7.3, from about 7 to about 7.1, from about 7.1 to about 8.3, from about 7.1 to about 8.1, from about 7.1 to about 8.3. 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.

[0139] In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may 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 may be about 7.4. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be about 7.5. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be about 7.6. In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may 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.

[0140] In certain embodiments, the pH of the liquid pharmaceutical formulations described herein may be 5.5 ± 0.3, 5.6 ± 0.3, 5.7 ± 0.3, 5.8 ± 0.3, 5.9 ± 0.3, 6 ± 0.3, 6.1 ± 0.3, 6.2 ± 0.3, 6.3 ± 0.3, 6.4 ± 0.3, 6.5 ± 0.3, 6.6 ± 0.3, 6.7 ± 0.3, 6.8 ± 0.3, 6.9 ± 0.3, 7 ± 0.3, 7.1 ± 0.3, 7.2 ± 0.3, 7.3 ± 0.3, 7.4 ± 0.3, 7.5 ± 0.3, 7.6 ± 0.3, 7.7 ± 0.3, 7.8 ± 0.3, 7.9 ± 0.3, 8 ± 0.3, 8.1 ± 0.3, 8.2 ± 0.3, 8.3 ± 0.3, 8.4 ± 0.3, 8.5 ± 0.3, 8.6 ± 0.3, 8.7 ± 0.3, 8.8 ± 0.3, 8.9 ± 0.3, 8.1 ± 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.

[0141] (C) Solubilizer

[0142] In various embodiments, the liquid pharmaceutical formulations described herein further comprise a solubilizer.

[0143] In various embodiments, the liquid pharmaceutical formulations described herein can comprise 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, from about 1 mg to about 25 mg, from about 1 mg to about 20 mg, from about 15 mg to about 25 mg, from about 20 mg to about 15 mg. from about 10 mg to about 20 mg, from about 5 mg to about 5 mg, from about 5 mg to about 45 mg, from about 5 mg to about 40 mg, from about 5 mg to about 35 mg, from about 5 mg to about 30 mg, from about 5 mg to about 25 mg, from about 5 mg to about 20 mg, from about 5 mg to about 15 mg, from about 5 mg to about 10 mg, from about 10 mg to about 45 mg, from about 10 mg to about 40 mg, from about 10 mg to about 35 mg, from about 10 mg to about 30 mg, from about 10 mg to about 25 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 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 45 mg, from about 20 mg to about 40 mg, from about 20 mg to about 35 mg, from about 20 mg to about 30 mg, from about 20 mg to about 25 mg, In some embodiments, the liquid pharmaceutical formulations described herein may comprise about 1 mg to about 50 mg of solubilizing agent. In some embodiments, the liquid pharmaceutical formulations described herein may comprise about 15 mg to about 50 mg of solubilizing agent.

[0144] In certain embodiments, the liquid drug formulations described herein may comprise 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, 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. mg or about 50 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 1 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 2 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 5 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 10 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 15 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 20 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 25 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 30 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 35 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 40 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 45 mg of solubilizer. In certain embodiments, the liquid pharmaceutical formulations described herein may include about 50 mg of solubilizer.

[0145] In various embodiments, the liquid pharmaceutical formulations described herein may comprise 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 a solubilizing agent. In various embodiments, the liquid pharmaceutical formulations described herein may comprise about 1% (w / w) to about 5% (w / w) of a solubilizing agent.

[0146] 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 a solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 1% (w / w) of a solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 2% (w / w) of a solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 3% (w / w) of a solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 4% (w / w) of a solubilizing agent. In certain embodiments, the liquid pharmaceutical formulations described herein may comprise about 5% (w / w) of a solubilizing agent.

[0147] 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, from about 20 mg / mL to about 45 mg / mL, from about 20 mg / mL to about 35 mg / mL, from about 20 mg / mL to about 30 mg / mL, from 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.

[0148] 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 In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 15 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 15 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 20 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 25 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 30 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 35 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 40 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 45 mg / mL. In certain embodiments, the concentration of the solubilizing agent in the liquid pharmaceutical formulations described herein is about 50 mg / mL.

[0149] Examples of solubilizers suitable for use in the liquid pharmaceutical formulations described herein include, but are not limited to, 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 (sodium dioctyl sulfosuccinate), alkyl ether phosphates, sodium lauryl sulfate, polyethylene glycol ethers, polyoxyethylene 15 hydroxystearate (e.g., Macrogol 15 hydroxystearate, Solutol HS15 ® ), polyoxyethylene castor oil derivatives (such as Cremophor ® EL, ELP, RH 40), polyoxyethylene stearate (such as Myrj® ), sorbitan fatty acid esters (such as Span ® ), polyoxyethylene alkyl ether (such as Brij ® ) and polyoxyethylene nonylphenol ethers (such as Nonoxynol ® ).

[0150] 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.

[0151] In various embodiments, the liquid pharmaceutical formulations described herein may comprise 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 45 mg, from about 20 mg to about 40 mg, from about 20 mg to about 35 mg, from about 20 mg to about 30 mg, from about 20 mg to about 25 mg, from about 25 mg to about 45 mg, from about 25 mg to about 40 mg, from about 25 mg to about 35 mg, from about 25 mg to about 30 mg, from about 30 mg to about 45 mg, from about 30 mg to about 40 mg, In various embodiments, the liquid pharmaceutical formulations described herein may comprise from about 15 mg to about 50 mg of benzyl alcohol.

[0152] 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.

[0153] In various embodiments, the liquid pharmaceutical formulations described herein may comprise 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.

[0154] 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) 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.

[0155] 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, from about 20 mg / mL to about 45 mg / mL, from about 20 mg / mL to about 35 mg / mL, from about 20 mg / mL to about 30 mg / mL, from 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.

[0156] 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, 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 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.

[0157] 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 1:5.5, from about 2:1 to about 1:5. 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 about 1:1, about 1: 1 to about 1:65, about 1:1 to about 1:6, about 1:1 to about 1:5.5, about 1:1 to about 1:5, about 1:1 to about 1:4.5, about 1:1 to about 1:4, about 1:1 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 1:65, 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 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 to about 1:6, about 1:2.5 to about 1:5.5, about 1:2.5 to about 1:5, about 1:2.5 to about 1:4.5, about 1:2.5 to about 1:4, about 1:2.5 to about 1:3.5, about 1:2.5 to about 1:3, about 1:3 to about 1:6, about 1:3 to about 1:5.5, about 1:3 to about 1:5, about 1:3 to about 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 From about 1:5 to about 1:65, from about 1:4.5 to about 1:6, from about 1:4.5 to about 1:5.5, from about 1:4.5 to about 1:5, from about 1:5 to about 1:65, from about 1:5 to about 1:6, from about 1:5 to about 1:5.5, from about 1:5.5 to about 1:65, from about 1:5.5 to about 1:6, or from about 1:6 to about 1:65. In certain embodiments, the molar ratio of tromethamine to benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 1.5:1 to about 1:6.5.

[0158] 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, 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.

[0159] (D) Additional pharmaceutically acceptable excipients

[0160] (1) Osmolality and osmolality

[0161] In various embodiments, the liquid pharmaceutical formulations described herein may further comprise an osmolality or osmolality adjusting agent.

[0162] In various embodiments, the osmolarity or osmotic concentration adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, and combinations thereof. In certain embodiments, the osmolarity or osmotic concentration adjusting agent is sodium chloride, potassium chloride, or a combination thereof. In certain embodiments, the osmolarity or osmotic concentration adjusting agent is sodium chloride. In certain embodiments, the osmolarity or osmotic concentration adjusting agent is potassium chloride.

[0163] In various embodiments, the osmolarity of the liquid pharmaceutical formulations described herein ranges from 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 100 mOsm / kg to about 1200 mOsm / kg, about 100 mOsm / kg to about 800 mOsm / kg, about 100 mOsm / kg to about 600 mOsm / kg, about 100 mOsm / kg to about 400 mOsm / kg, about 100 mOsm / kg to about 300 mOsm / kg, about 100 mOsm / kg to about 200 mOsm / kg, about 200 mOsm / kg to about 1200 mOsm / kg, about 200 mOsm / kg to about 800 mOsm / kg, about 200 mOsm / kg to about 600 mOsm / kg, about 200 mOsm / kg to about 400 mOsm / kg, about 200 mOsm / kg to about 300 mOsm / kg, about 300 mOsm / kg to about 1200 mOsm / kg, about 300 mOsm / kg to about 800 mOsm / kg, about 300 mOsm / kg to about 600 mOsm / kg, about 300 mOsm / kg to about 400 mOsm / kg In some embodiments, the osmolality of the liquid pharmaceutical formulations described herein is in the range of about 200 mOsm / kg to about 400 mOsm / kg. In some embodiments, the osmolality of the liquid pharmaceutical formulations described herein is in the range of about 300 mOsm / kg to about 600 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolarity range of about 300 mOsm / kg to about 450 mOsm / kg.

[0164] In certain embodiments, the osmolality of the liquid pharmaceutical formulations described herein ranges from about 100 mOsm / kg to about 1600 mOsm / kg. In certain embodiments, the osmolality of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 800 mOsm / kg. In certain embodiments, the osmolality of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 600 mOsm / kg. In certain embodiments, the osmolality of the liquid pharmaceutical formulations described herein ranges from about 200 mOsm / kg to about 400 mOsm / kg. In certain embodiments, the osmolality of the liquid pharmaceutical formulations described herein ranges from about 275 mOsm / kg to about 400 mOsm / kg.

[0165] It should be understood that the above ranges and descriptions of osmolality apply equally to osmolality, but in the unit of "Osm / kg."

[0166] (2) Water

[0167] In various embodiments, the liquid pharmaceutical formulations described herein further comprise water. In certain embodiments, the water is water for injection.

[0168] In various embodiments, the liquid drug formulations described herein can comprise 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, or from about 0.9 mL to about 2 mL. mL, about 0.2 mL to about 0.8 mL, about 0.2 mL to about 0.7 mL, about 0.2 mL to about 0.6 mL, about 0.2 mL to about 0.5 mL, about 0.2 mL to about 0.4 mL, about 0.2 mL to about 0.3 mL, about 0.3 mL to about 1.5 mL, about 0.3 mL to about 1 mL, about 0.3 mL to about 0.9 mL, about 0.3 mL to about 0.8 mL, about 0.3 mL to about 0.7 mL, about 0.3 mL to about 0.6 mL, about 0.3 mL to about 0.5 mL, about 0.3 mL to about 0.4 mL, about 0.4 mL to about 1.5 mL, about 0.4 mL to about 1 mL, about 0.4 mL to about 0.9 mL, about 0.4 mL to about 0.8 mL, about 0.4 mL to about 0.7 mL, about 0.4 mL to about 0.6 mL, about 0.4 mL to about 0.5 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 1 mL, about 0.5 mL to about 0.9 mL, about 0.5 mL to about 0.8 mL, about 0.5 mL to about 0.7 mL, about 0.5 mL to about 0.6 mL, about 0.6 mL to about 1.5 mL, about 0.6 mL to about 1 mL, about 0.6 mL to about 0.9 mL, about 0.6 mL to about 0.8 mL, about 0.6 mL to about 0.7 mL, about 0.7 mL to about 1.5 mL, about 0.7 mL to about 1 mL, about 0.7 mL to about 0.9 mL, about 0.7 mL to about 0.8 mL, about 0.8 mL to about 1.5 mL, about 0.8 mL to about 1 mL, about 0.8 mL to about 0.9 mL, about 0.9 mL to about 1.5 mL, about 0.9 mL to about 1 mL, or about 1 mL to about 1.5 mL of water.

[0169] In various embodiments, the liquid pharmaceutical compositions described herein may comprise 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 comprise about 0.3 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.4 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.5 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise about 0.6 mL of water. In certain embodiments, the liquid pharmaceutical compositions described herein may comprise 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.

[0170] It will be 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, 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.

[0171] In various embodiments, the liquid pharmaceutical compositions described herein can comprise from about 0.1 g to about 2 g, from about 0.2 g to about 2 g, from about 0.3 g to about 2 g, from about 0.4 g to about 2 g, from about 0.5 g to about 2 g, from about 0.6 g to about 2 g, from about 0.7 g to about 2 g, from about 0.8 g to about 2 g, from about 0.9 g to about 2 g, from about 1 g to about 2 g, from about 1.5 g to about 2 g, from about 0.1 g to about 1.5 g, from about 0.1 g to about 1 g, from about 0.1 g to about 0.9 g, from about 0.1 g to about 0.8 g, from about 0.1 g to about 0.7 g, from about 0.1 g to about 0.6 g, from about 0.1 g to about 0.5 g, from about 0.1 g to about 0.4 g, from about 0.1 g to about 0.3 g, from about 0.1 g to about 0.2 g, from about 0.2 g to about 1.5 g, from about 0.2 g to about 0.9 g. 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 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 of water.

[0172] 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.

[0173] (3) Other excipients

[0174] In various embodiments, the liquid pharmaceutical formulations described herein may comprise one or more additional pharmaceutically acceptable excipients.

[0175] In various embodiments, the one or more additional pharmaceutically acceptable excipients are selected from the group consisting of ethanol, glycerol, N-methylpyrrolidone (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.

[0176] In certain embodiments, one or more additional pharmaceutically acceptable excipients include ethanol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include glycerol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include N-methyl pyrrolidone (NMP). In certain embodiments, one or more additional pharmaceutically acceptable excipients include sodium carbonate. In certain embodiments, one or more additional pharmaceutically acceptable excipients include mannitol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include lactose. In certain embodiments, one or more additional pharmaceutically acceptable excipients include dextrose. In certain embodiments, one or more additional pharmaceutically acceptable excipients include polyethylene glycol (PEG). In certain embodiments, one or more additional pharmaceutically acceptable excipients include propylene glycol. In certain embodiments, one or more additional pharmaceutically acceptable excipients include polysorbates (e.g., polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate). In certain embodiments, one or more additional pharmaceutically acceptable excipients include polyvinylpyrrolidone (PVP). In certain embodiments, one or more additional pharmaceutically acceptable excipients include cyclodextrins (e.g., α(α)-cyclodextrin, β(β)-cyclodextrin, and γ(γ)-cyclodextrin). In certain embodiments, one or more additional pharmaceutically acceptable excipients include cyclodextrin derivatives (e.g., sulfobutyl ether-β-cyclodextrin (e.g., captisol), hydroxypropyl-β-cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin), and methylated β-cyclodextrin (e.g., randomly methylated β-cyclodextrin)). In certain embodiments, the one or more additional pharmaceutically acceptable excipients include vitamin E. In certain embodiments, the one or more additional pharmaceutically acceptable excipients include one or more naturally occurring forms of vitamin E (e.g., α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol). In certain embodiments, the one or more additional pharmaceutically acceptable excipients include vitamin E derivatives (e.g., tocopheryl acetate, tocopheryl glucoside, tocopheryl phosphate).

[0177] (E) Preparation volume

[0178] In various embodiments, the total volume of the liquid drug formulations 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 mL to about 0.9 mL, about 0.2 mL to about 0.8 mL, about 0.2 mL to about 0.7 mL, about 0.2 mL to about 0.6 mL, about 0.2 mL to about 0.5 mL, about 0.2 mL to about 0.4 mL, about 0.2 mL to about 0.3 mL, about 0.3 mL to about 1.5 mL, about 0.3 mL to about 1 mL, about 0.3 mL to about 0.9 mL, about 0.3 mL to about 0.8 mL, about 0.3 mL to about 0.7 mL, about 0.3 mL to about 0.6 mL, about 0.3 mL to about 0.5 mL, about 0.3 mL to about 0.4 mL, about 0.4 mL to about 1.5 mL, about 0.4 mL to about 1 mL, about 0.4 mL to about 0.9 mL, about 0.4 mL to about 0.8 mL, about 0.4 mL to about 0.7 mL, about 0.4 mL to about 0.6 mL, about 0.4 mL to about 0.5 mL, about 0.5 mL to about 1.5 mL. mL, about 0.5 mL to about 1 mL, about 0.5 mL to about 0.9 mL, about 0.5 mL to about 0.8 mL, about 0.5 mL to about 0.7 mL, about 0.5 mL to about 0.6 mL, about 0.6 mL to about 1.5 mL, about 0.6 mL to about 1 mL, about 0.6 mL to about 0.9 mL, about 0.6 mL to about 0.8 mL, about 0.6 mL to about 0.7 mL, about 0.7 mL to about 1.5 mL, about 0.7 mL to about 1 mL, about 0.7 mL to about 0.9 mL, about 0.7 mL to about 0.8 mL, about 0.8 mL to about 1.5 mL, about 0.8 mL to about 1 mL, about 0.8 mL to about 0.9 mL, about 0.9 mL to about 1.5 mL, about 0.9 mL to about 1 mL, or about 1 mL to about 1.5 mL.

[0179] In various embodiments, the total volume of the liquid pharmaceutical formulations described herein may 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 formulations described herein is about 0.8 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 0.9 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 1 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 1.1 mL. In certain embodiments, the total volume of the liquid pharmaceutical formulations described herein is about 1.2 mL.

[0180] (F) Exemplary Liquid Pharmaceutical Formulations

[0181] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable buffer.

[0182] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) Solubilizers.

[0183] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizing agents; and (iv) pH adjuster.

[0184] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of a loop diuretic or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizers; (iv) pH adjusting agent; and (v) Water.

[0185] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 1 mg to about 100 mg of a loop diuretic or a pharmaceutically acceptable salt thereof; and (ii) from about 4 mg to about 16 mg of a pharmaceutically acceptable buffer.

[0186] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 1 mg to about 100 mg of a loop diuretic or a pharmaceutically acceptable salt thereof; (ii) from about 4 mg to about 16 mg of a pharmaceutically acceptable buffer; and (iii) about 15 mg to about 50 mg of a solubilizing agent.

[0187] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) pH adjuster.

[0188] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) pH adjusting agent; and (v) Water.

[0189] 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, a pH of from about 7 to about 8, and a total volume of from about 0.5 mL to about 1 mL.

[0190] (1) Exemplary Furosemide Formulations

[0191] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable buffer.

[0192] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) Solubilizers.

[0193] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizing agents; and (iv) pH adjuster.

[0194] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizers; (iv) pH adjusting agent; and (v) Water.

[0195] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; and (ii) Tromethamine.

[0196] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; (ii) tromethamine; and (iii) Benzyl alcohol.

[0197] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of furosemide or a pharmaceutically acceptable salt thereof; (ii) tromethamine; (iii) benzyl alcohol; (iv) hydrochloric acid; and (v) Sodium hydroxide.

[0198] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) Water.

[0199] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of furosemide or a pharmaceutically acceptable salt thereof; and (ii) about 0.1% (w / w) to about 1.5% (w / w) of a pharmaceutically acceptable buffer.

[0200] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of 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) about 1% (w / w) to about 5% (w / w) of a solubilizing agent.

[0201] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of 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) pH adjuster.

[0202] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of 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) pH adjusting agent; and (v) Water.

[0203] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 40 mg to about 100 mg of furosemide or a pharmaceutically acceptable salt thereof; and (ii) from about 4 mg to about 16 mg of a pharmaceutically acceptable buffer.

[0204] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 40 mg to about 100 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) from about 4 mg to about 16 mg of a pharmaceutically acceptable buffer; and (iii) about 15 mg to about 50 mg of a solubilizing agent.

[0205] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) pH adjuster.

[0206] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) pH adjusting agent; and (v) Water.

[0207] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of furosemide or a pharmaceutically acceptable salt thereof; and (ii) about 0.1% (w / w) to about 1.5% (w / w) tromethamine.

[0208] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 1.5% (w / w) tromethamine; and (iii) about 1% (w / w) to about 5% (w / w) benzyl alcohol.

[0209] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of 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) pH adjuster.

[0210] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 5% (w / w) to about 10% (w / w) of 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; (iv) pH adjusting agent; and (v) Water.

[0211] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 40 mg to about 100 mg of furosemide or a pharmaceutically acceptable salt thereof; and (ii) from about 4 mg to about 16 mg of tromethamine.

[0212] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 40 mg to about 100 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) from about 4 mg to about 16 mg of tromethamine; and (iii) from about 15 mg to about 50 mg of benzyl alcohol.

[0213] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) from about 15 mg to about 50 mg of benzyl alcohol; (iv) hydrochloric acid; and (v) Sodium hydroxide.

[0214] In various embodiments, the liquid pharmaceutical formulation may comprise: (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) from about 15 mg to about 50 mg of benzyl alcohol; (iv) hydrochloric acid; (v) sodium hydroxide; and (v) Water.

[0215] In various embodiments, the liquid pharmaceutical formulation comprises about 40 mg to about 100 mg of furosemide, a pH of about 7 to about 8, and a total volume of about 0.5 mL to about 1 mL.

[0216] (2) Exemplary Torsemide Formulations

[0217] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of torsemide or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable buffer.

[0218] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of torasemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) Solubilizers.

[0219] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of torasemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizing agents; and (iv) pH adjuster.

[0220] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of torasemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizers; (iv) pH adjusting agent; and (v) Water.

[0221] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 20 mg to about 40 mg of torsemide or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable buffer.

[0222] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 20 mg to about 40 mg of torsemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) Solubilizers.

[0223] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 20 mg to about 40 mg of torsemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizing agents; and (iv) pH adjuster.

[0224] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 20 mg to about 40 mg of torsemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizers; (iv) pH adjusting agent; and (v) Water.

[0225] In various embodiments, the liquid pharmaceutical formulation comprises about 20 mg to about 40 mg of torsemide, a pH of about 7 to about 8, and a total volume of about 0.5 mL to about 1 mL.

[0226] (3) Exemplary Bumetanide Formulations

[0227] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of bumetanide or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable buffer.

[0228] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of bumetanide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) Solubilizers.

[0229] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of bumetanide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizing agents; and (iv) pH adjuster.

[0230] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) an effective amount of bumetanide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizers; (iv) pH adjusting agent; and (v) Water.

[0231] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 1 mg to about 2 mg of bumetanide or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable buffer.

[0232] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 1 mg to about 2 mg of bumetanide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) Solubilizers.

[0233] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 1 mg to about 2 mg of bumetanide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizing agents; and (iv) pH adjuster.

[0234] In various embodiments, the liquid pharmaceutical formulation may comprise: (i) about 1 mg to about 2 mg of bumetanide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; (iii) solubilizers; (iv) pH adjusting agent; and (v) Water.

[0235] In various embodiments, the liquid pharmaceutical formulation comprises about 1 mg to about 2 mg of bumetanide, a pH of about 7 to about 8, and a total volume of about 0.5 mL to about 1 mL.

[0236] Treatment

[0237] In one aspect, the liquid pharmaceutical formulations described herein can be used to treat or prevent various disorders in patients in need thereof, such as, but not limited to, congestion, edema, and hypertension caused by fluid overload. In various embodiments, the disorder is selected from the group consisting of: congestion, edema, and hypertension caused by fluid overload, and combinations thereof. In certain embodiments, the disorder is congestion caused by fluid overload. In certain embodiments, the disorder is edema. In certain embodiments, the disorder is hypertension. In certain embodiments, the edema is associated with congestive heart failure, cirrhosis, or nephropathy. In certain embodiments, the nephropathy is nephrotic syndrome.

[0238] In certain embodiments, the patient is a human.

[0239] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, wherein about 1 mL or less of a liquid pharmaceutical formulation described herein is administered to the human by subcutaneous injection.

[0240] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, wherein an effective amount of a loop diuretic in a liquid pharmaceutical formulation having a total volume of about 1 mL or less is administered to the human by subcutaneous injection.

[0241] (A) Effective dose / concentration of loop diuretics

[0242] In various embodiments, 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, from about 2 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 1 mg to about 80 mg, from about 1 mg to about 70 mg, from about 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 50 mg, from about 1 mg to about 2 mg, from about 2 mg to about 80 mg, from about 2 mg to about 70 mg, from about 2 mg to about 60 mg, from about 2 mg to about 50 mg, from about 2 mg to about 40 mg, from about 2 mg to about from about 2 mg to about 30 mg, from about 2 mg to about 20 mg, from about 2 mg to about 10 mg, from about 2 mg to about 5 mg, from about 5 mg to about 80 mg, from about 5 mg to about 70 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 or about 70 mg to about 80 mg.In certain embodiments, 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. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 1 mg to about 80 mg. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 2 mg to about 80 mg. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 40 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 from about 1 mg to about 40 mg. In certain embodiments, the effective amount of the loop diuretic in the total volume of the liquid pharmaceutical formulation is from about 40 mg to about 80 mg.

[0243] 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 the loop diuretic is about 20 mg per total volume of the liquid pharmaceutical formulation. In certain embodiments, the effective amount of the loop diuretic is about 40 mg per total volume of the liquid pharmaceutical formulation. In certain embodiments, the effective amount of the loop diuretic is about 80 mg per total volume of the liquid pharmaceutical formulation. In certain embodiments, the effective amount of the loop diuretic is about 100 mg per total volume of the liquid pharmaceutical formulation.

[0244] 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 70 mg / mL, from about 2 mg / mL to about 60 mg / mL, from about 2 mg / mL to about 50 mg / mL, from about 2 mg / mL to about 40 mg / mL, from about 2 mg / mL to about 30 mg / mL, from about 2 mg / mL to about 20 mg / mL, mg / mL to about 10 mg / mL, about 2 mg / mL to about 5 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 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 to about 10 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 20 mg / mL mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 30 mg / 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 80 mg / mL, 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 50In some 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.

[0245] 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 In some embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 2 mg / mL. In some embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 40 mg / mL. In some embodiments, the concentration of the loop diuretic in the total volume of the liquid pharmaceutical formulation is about 80 mg / mL.

[0246] 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.

[0247] In various embodiments, the total volume of the liquid drug 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.

[0248] 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.

[0249] (1) Furosemide

[0250] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, the method 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.

[0251] In various embodiments, the effective amount of furosemide in the total volume of the liquid pharmaceutical formulation is from about 40 mg to about 80 mg, from about 50 mg to about 80 mg, from about 60 mg to about 80 mg, from about 70 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 70 mg, from about 50 mg to about 60 mg, or from 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 from about 40 mg to about 80 mg.

[0252] 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.

[0253] 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.

[0254] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload 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 liquid pharmaceutical formulation.

[0255] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload 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.

[0256] (2) Bumetanide

[0257] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, the method comprising administering to the human by subcutaneous injection an effective amount of bumetanide in a liquid pharmaceutical formulation in a total volume of about 1 mL or less.

[0258] In various embodiments, the effective amount of bumetanide in the total volume of the liquid pharmaceutical formulation is from about 1 mg to about 2 mg, from about 1.2 mg to about 2 mg, from about 1.4 mg to about 2 mg, from about 1.6 mg to about 2 mg, from about 1.8 mg to about 2 mg, from about 1 mg to about 1.8 mg, from about 1 mg to about 1.6 mg, from about 1 mg to about 1.4 mg, from about 1 mg to about 1.2 mg, from about 1.2 mg to about 1.8 mg, from about 1.2 mg to about 1.6 mg, from about 1.2 mg to about 1.4 mg, from about 1.4 mg to about 1.8 mg, from about 1.4 mg to about 1.6 mg, or from 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 from about 1 mg to about 2 mg.

[0259] 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.

[0260] 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.

[0261] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion caused by fluid overload, 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.

[0262] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 1 mg of bumetanide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation.

[0263] (3) Torsemide

[0264] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, the method comprising administering to the human by subcutaneous injection an effective amount of torsemide in a liquid pharmaceutical formulation having a total volume of about 1 mL or less.

[0265] In various embodiments, the effective amount of torasemide in the total volume of the liquid pharmaceutical formulation is from about 20 mg to about 40 mg, from about 24 mg to about 40 mg, from about 28 mg to about 40 mg, from about 32 mg to about 40 mg, from about 36 mg to about 40 mg, from about 20 mg to about 36 mg, from about 20 mg to about 32 mg, from about 20 mg to about 28 mg, from about 20 mg to about 24 mg, from about 24 mg to about 36 mg, from about 24 mg to about 32 mg, from about 24 mg to about 28 mg, from about 28 mg to about 36 mg, from about 28 mg to about 32 mg, or from about 32 mg to about 36 mg. In certain embodiments, the effective amount of torasemide in the total volume of the liquid pharmaceutical formulation is from about 20 mg to about 40 mg.

[0266] 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.

[0267] In various embodiments, the concentration of torasemide 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 torasemide in the total volume of the liquid pharmaceutical formulation is about 40 mg / mL.

[0268] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload 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 liquid pharmaceutical formulation.

[0269] In various embodiments, provided herein is a method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload 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.

[0270] (B) Pharmacokinetics / pharmacodynamics

[0271] (1) Urine volume

[0272] In various embodiments, the methods described herein result in a total urine volume in a human 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 4000 mL, about 500 mL to about 3500 mL, about 500 mL to about 3000 mL, about 500 mL to about 2500 mL, about 500 mL to about 5000 mL, or about 500 mL to about 5000 mL. mL to about 2000 mL, about 500 mL to about 1500 mL, about 500 mL to about 1000 mL, about 500 mL to about 900 mL, about 500 mL to about 800 mL, about 500 mL to about 700 mL, about 500 mL to about 600 mL, about 600 mL to about 4500 mL, about 600 mL to about 4000 mL, about 600 mL to about 3500 mL, about 600 mL to about 3000 mL, about 600 mL to about 2500 mL, about 600 mL to about 2000 mL, about 600 mL to about 1500 mL, about 600 mL to about 1000 mL, about 600 mL to about 900 mL, about 600 mL to about 800 mL, about 600 mL to about 700 mL, about 700 mL to about 4500 mL, about 700 mL to about 4000 mL, about 700 mL to about 3500 mL, about 700 mL to about mL to about 3000 mL, about 700 mL to about 2500 mL, about 700 mL to about 2000 mL, about 700 mL to about 1500 mL, about 700 mL to about 1000 mL, about 700 mL to about 800 mL, about 800 mL to about 4500 mL, about 800 mL to about 4000 mL, about 800 mL to about 3500 mL, about 800 mL to about 3000 mL, about 800 mL to about 2500 mL, about 800 mL to about 2000 mL, about 800 mL to about 1500 mL, about 800 mL to about 1000 mL, about 800 mL to about 900 mL, about 900 mL to about 4500 mL, about 900 mL to about 4000 mL, about 900 mL to about 3500 mLmL, about 900 mL to about 3000 mL, about 900 mL to about 2500 mL, about 900 mL to about 2000 mL, about 900 mL to about 1500 mL, about 900 mL to about 1000 mL, about 1000 mL to about 4500 mL, about 1000 mL to about 4000 mL, about 1000 mL to about 3500 mL, about 1000 mL to about 3000 mL, about 1000 mL to about 2500 mL, about 1000 mL to about 2000 mL, about 1000 mL to about 1500 mL, about 1500 mL to about 4500 mL, about 1500 mL to about 4000 mL, about 1500 mL to about 3500 mL, about 1500 mL to about 3000 mL, about 1500 mL to about 2500 mL, about 1500 mL to about 2000 mL, about 2000 mL to about 4500 In some embodiments, the methods described herein result in a total urine volume of about 600 mL to about 5000 mL in a human being about 6 hours after administration. In some embodiments, the methods described herein result in a total urine volume of about 1200 mL to about 5000 mL in a human being about 6 hours after administration. In certain embodiments, the methods described herein result in a total urine volume in a human of about 600 mL to about 2500 mL about 6 hours after administration is complete.

[0273] In various embodiments, the methods described herein result in a total urine volume in a human 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 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about 5000 mL to about 5500 mL, about mL to about 3000 mL, about 500 mL to about 2500 mL, about 500 mL to about 2000 mL, about 500 mL to about 1500 mL, about 500 mL to about 1000 mL, about 500 mL to about 900 mL, about 500 mL to about 800 mL, about 500 mL to about 700 mL, about 500 mL to about 600 mL, about 600 mL to about 5000 mL, about 600 mL to about 4500 mL, about 600 mL to about 4000 mL, about 600 mL to about 3500 mL, about 600 mL to about 3000 mL, about 600 mL to about 2500 mL, about 600 mL to about 2000 mL, about 600 mL to about 1500 mL, about 600 mL to about 1000 mL, about 600 mL to about 900 mL, about 600 mL to about 800 mL, about 600 mL to about 700 mL, about 700 mL to about 5000 mL, about 700 mL to about 4500 mL, about 700 mL to about 4000 mL, about 700 mL to about 3500 mL, about 700 mL to about 3000 mL, about 700 mL to about 2500 mL, about 700 mL to about 2000 mL, about 700 mL to about 1500 mL, about 700 mL to about 1000 mL, about 700 mL to about 800 mL, about 800 mL to about 5000 mL, about 800 mL to about 4500 mL, about 800 mL to about 4000 mL, about 800 mL to about 3500 mL, about 800 mL to about 3000 mL, about 800 mL to about 2500 mL, about 800 mL to about 2000 mL, about 800 mL to about 1500 mLmL, about 800 mL to about 1000 mL, about 800 mL to about 900 mL, about 900 mL to about 5000 mL, about 900 mL to about 4500 mL, about 900 mL to about 4000 mL, about 900 mL to about 3500 mL, about 900 mL to about 3000 mL, about 900 mL to about 2500 mL, about 900 mL to about 2000 mL, about 900 mL to about 1500 mL, about 900 mL to about 1000 mL, about 1000 mL to about 5000 mL, about 1000 mL to about 4500 mL, about 1000 mL to about 4000 mL, about 1000 mL to about 3500 mL, about 1000 mL to about 3000 mL, about 1000 mL to about 2500 mL, about 1000 mL to about 2000 mL, about 1000 mL to about 1500 mL, about 1500 mL mL to about 5000 mL, about 1500 mL to about 4500 mL, about 1500 mL to about 4000 mL, about 1500 mL to about 3500 mL, about 1500 mL to about 3000 mL, about 1500 mL to about 2500 mL, about 1500 mL to about 2000 mL, about 2000 mL to about 5000 mL, about 2000 mL to about 4500 mL, about 2000 mL to about 4000 mL, about 2000 mL to about 3500 mL, about 2000 mL to about 3000 mL, about 2000 mL to about 2500 mL, about 2500 mL to about 5000 mL, about 2500 mL to about 4500 mL, about 2500 mL to about 4000 mL, about 2500 mL to about 3500 mL, about 2500 mL to about 3000 mL, about 3000 mL to about 5000 mL. mL, about 3000 mL to about 4500 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 total urine volume of about 600 mL to about 5300 mL in a human being about 8 hours after administration. In certain embodiments, the methods described herein result in a total urine volume of about 1200 mL to about 5300 mL in a human being about 8 hours after administration. In certain embodiments, the methods described herein result in a total urine volume of about 600 mL to about 2650 mL in a human being about 8 hours after administration.

[0274] In various embodiments, the methods described herein result in a total urine volume in a human 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 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about 500 mL to about 5500 mL, about mL, about 500 mL to about 3000 mL, about 500 mL to about 2500 mL, about 500 mL to about 2000 mL, about 500 mL to about 1500 mL, about 500 mL to about 1000 mL, about 500 mL to about 900 mL, about 500 mL to about 800 mL, about 500 mL to about 700 mL, about 500 mL to about 600 mL, about 600 mL to about 5000 mL, about 600 mL to about 4500 mL, about 600 mL to about 4000 mL, about 600 mL to about 3500 mL, about 600 mL to about 3000 mL, about 600 mL to about 2500 mL, about 600 mL to about 2000 mL, about 600 mL to about 1500 mL, about 600 mL to about 1000 mL, about 600 mL to about 900 mL, about 600 mL to about 800 mL, about 600 mL to about 700 mL, about 700 mL to about 5000 mL, about 700 mL to about 4500 mL, about 700 mL to about 4000 mL, about 700 mL to about 3500 mL, about 700 mL to about 3000 mL, about 700 mL to about 2500 mL, about 700 mL to about 2000 mL, about 700 mL to about 1500 mL, about 700 mL to about 1000 mL, about 700 mL to about 800 mL, about 800 mL to about 5000 mL, about 800 mL to about 4500 mL, about 800 mL to about 4000 mL, about 800 mL to about 3500 mL, about 800 mL to about 3000 mL, about 800 mL to about 2500 mL, about 800 mL to about 2000 mL, about 800 mL to about 1500 mLmL, about 800 mL to about 1000 mL, about 800 mL to about 900 mL, about 900 mL to about 5000 mL, about 900 mL to about 4500 mL, about 900 mL to about 4000 mL, about 900 mL to about 3500 mL, about 900 mL to about 3000 mL, about 900 mL to about 2500 mL, about 900 mL to about 2000 mL, about 900 mL to about 1500 mL, about 900 mL to about 1000 mL, about 1000 mL to about 5000 mL, about 1000 mL to about 4500 mL, about 1000 mL to about 4000 mL, about 1000 mL to about 3500 mL, about 1000 mL to about 3000 mL, about 1000 mL to about 2500 mL, about 1000 mL to about 2000 mL, about 1000 mL to about 1500 mL, about 1500 mL mL to about 5000 mL, about 1500 mL to about 4500 mL, about 1500 mL to about 4000 mL, about 1500 mL to about 3500 mL, about 1500 mL to about 3000 mL, about 1500 mL to about 2500 mL, about 1500 mL to about 2000 mL, about 2000 mL to about 5000 mL, about 2000 mL to about 4500 mL, about 2000 mL to about 4000 mL, about 2000 mL to about 3500 mL, about 2000 mL to about 3000 mL, about 2000 mL to about 2500 mL, about 2500 mL to about 5000 mL, about 2500 mL to about 4500 mL, about 2500 mL to about 4000 mL, about 2500 mL to about 3500 mL, about 2500 mL to about 3000 mL, about 3000 mL to about 5000 mL. mL, about 3000 mL to about 4500 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 total urine volume of about 600 mL to about 5500 mL in a human being about 8 hours after administration is complete. In certain embodiments, the methods described herein result in a total urine volume of about 1200 mL to about 5500 mL in a human being about 8 hours after administration is complete. In certain embodiments, the methods described herein result in a total urine volume of about 600 mL to about 2750 mL in a human being about 8 hours after administration is complete.

[0275] (2) Furosemide pharmacokinetics

[0276] In various embodiments, the methods described herein provide a maximum plasma concentration (C max) is 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, about 1500 ng / mL to about 8000 ng / mL, about 1500 ng / mL to about 7000 ng / mL, about 1500 ng / mL to about 6000 ng / mL, about 1500 ng / mL to about 5000 ng / mL, about 1500 ng / mL to about 4000 ng / mL, about 1500 ng / mL to about 3000 ng / mL, about 1500 ng / mL to about 2000 ng / mL, about 2000 ng / mL to about 9000 ng / mL, about 2000 ng / mL to about 8000 ng / mL, about 2000 ng / mL to about 7000 ng / mL, about 2000 ng / mL to about 6000 ng / mL, about 2000 ng / mL to about 5000 ng / mL, about 2000 ng / mL to about 4000 ng / mL, about 2000 ng / mL to about 3000 ng / mL, about 3000 ng / mL to about 9000 ng / mL, about 3000 ng / mL to about ng / mL to about 8000 ng / mL, about 3000 ng / mL to about 7000 ng / mL, about 3000 ng / mL to about 6000 ng / mL, about 3000 ng / mL to about 5000 ng / mL, about 3000 ng / mL to about 4000 ng / mL, about 4000 ng / mL to about 9000 ng / mL, about 4000 ng / mL to about 8000 ng / mL, about 4000 ng / mL to about 7000 ng / mL, about 4000 ng / mL to about 6000 ng / mL, about 4000 ng / mL to about 5000 ng / mL, about 5000 ng / mL to about 9000 ng / mL, about 5000 ng / mL to about 8000 ng / mL, about 5000 ng / mL to about 7000 ng / mL, about 5000 ng / mL to about ng / mL to about 6000 ng / mL, about 6000 ng / mL to about 9000 ng / mL, about 6000 ng / mL to about 8000 ng / mL, about 6000In some embodiments, the methods described herein provide furosemide C in human plasma at a concentration of about 1500 ng / mL to about 9800 ng / mL. max In certain embodiments, the methods described herein provide furosemide C in human plasma at a concentration of about 3000 ng / mL to about 9800 ng / mL. max In certain embodiments, the methods described herein provide furosemide C in human plasma at about 1500 ng / mL to about 4900 ng / mL. max .

[0277] In various embodiments, the methods described herein provide furosemide AUC in human plasma. last The area under the curve (i.e., from the time of administration to the last measurable concentration) was approximately 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 20,000 h ng / mL to about 32000 h ng / mL, about 24000h ng / mL to about 32000 h ng / mL, about 28000 h ng / mL to about 32000 h ng / mL, about 4400 h ng / mL to about 28000 h ng / mL, about 4400 h ng / mL to about 24000 h ng / mL, about 4400 h ng / mL to about 20,000 h ng / mL, about 4400 h ng / mL to about 16000 h ng / mL, about 4400 h ng / mL to about 12000 h ng / mL, about 4400 h ng / mL to about 8000 h ng / mL, about 4400 h ng / mL to about 7000 h ng / mL, about 4400 h ng / mL to about 6000h ng / mL, about 4400 h ng / mL to about 5000 h ng / mL, about 5000 h ng / mL to about 28000 h ng / mL, about 5000 h ng / mL to about 24000 h ng / mL, about 5000 h ng / mL to about 20,000 h ng / mL, about 5000 h ng / mL to about 16000 h ng / mL, about 5000 h ng / mL to about 12000 h ng / mL, about 5000 h ng / mL to about 8000 h ng / mL, about 5000 h ng / mL to about 7000 h ng / mL, about 5000 h ng / mL to about 6000 h ng / mL, about 6000 h ng / mL to about 28000 h ng / mL, about 6000 h ng / mL to about 24000 h ng / mL, about 6000 h ng / mL to about 20,000 h ng / mL, about 6000 h ng / mL to about 16000 h ng / mL, about 6000 h ng / mL to about 12000 h ng / mL, about 6000 h ng / mL to about 8000 h ng / mL, about 6000 h ng / mL to about 7000 h ng / mL, about 7000 h ng / mL to about 28000 h ng / mL, about 7000 h ng / mL to about 24000 h ng / mL, about 7000 h ng / mL to about 20,000 h ng / mL, about 7000 h ng / mL to about 16000 h ng / mL, about 7000 h ng / mL to about 12000 h ng / mL, about 7000 h ng / mL to about 8000 h ng / mL, about 8000 h ng / mL to about 28000 h ng / mL, about 8000 h ng / mL to about 24000 h ng / mL, about 8000 h ng / mL to about 20,000 h ng / mL, about 8000 h ng / mL to about 16000 h ng / mL, about 8000 h ng / mL to about 12000 h ng / mL, about 12000 h ng / mL to about 28000 h ng / mL, about 12000 h ng / mL to about 24000 h ng / mL, about 12000 h ng / mL to about 20,000 h ng / mL, about 12000h 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 20,000 h ng / mL, about 20,000 h ng / mL to about 28000 h ng / mL, about 20,000 h ng / mL to about 24000 h ng / mL or about 24,000 h ng / mL to about 28000 h ng / mL. In various embodiments, the methods described herein provide approximately 4400 h ng / mL to about 31700 h Furosemide AUC in ng / mL last In various embodiments, the methods described herein provide approximately 8800 h ng / mL to about 31700h Furosemide AUC in ng / mL last In various embodiments, the methods described herein provide approximately 4400 h ng / mL to about 15850 h Furosemide AUC in ng / mL last .

[0278] In various embodiments, the methods described herein provide furosemide AUC in human plasma. inf (e.g., the area under the curve extrapolated to infinity) is approximately 4500 h ng / mL to about 36000 h ng / mL, about 6000 h ng / mL to about 36000h 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 20,000 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 32000 h ng / mL to about 36000 h ng / mL, about 4500 h ng / mL to about 32000 h ng / mL, about 4500 h ng / mL to about 28000 h ng / mL, about 4500 h ng / mL to about 24000 h ng / mL, about 4500 h ng / mL to about 20,000 h ng / mL, about 4500 h ng / mL to about 16000 h ng / mL, about 4500 h ng / mL to about 12000 h ng / mL, about 4500 h ng / mL to about 8000 h ng / mL, about 4500 h ng / mL to about 6000 h ng / mL, about 6000 h ng / mL to about 32000 h ng / mL, about 6000 h ng / mL to about 28000 h ng / mL, about 6000 h ng / mL to about 24000 h ng / mL, about 6000 h ng / mL to about 20,000 h ng / mL, about 6000 h ng / mL to about 16000 h ng / mL, about 6000 h ng / mL to about 12000h ng / mL, about 6000 h ng / mL to about 8000 h ng / mL, about 8000 h ng / mL to about 32000 h ng / mL, about 8000 h ng / mL to about 28000 h ng / mL, about 8000 h ng / mL to about 24000 h ng / mL, about 8000 h ng / mL to about 20,000 h ng / mL, about 8000 h ng / mL to about 16000 h ng / mL, about 8000 h ng / mL to about 12000 h ng / mL, about 12000 h ng / mL to about 32000 h ng / mL, about 12000 h ng / mL to about 28000 h ng / mL, about 12000 h ng / mL to about 24000 h ng / mL, about 12000 h ng / mL to about 20,000 h ng / mL, about 12000 h ng / mL to about 16000 h ng / mL, about 16000 h ng / mL to about 32000 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 20,000 h ng / mL, about 20,000 h ng / mL to about 32000 h ng / mL, about 20,000 h ng / mL to about 28000 h ng / mL, about 20,000 h ng / mL to about 24000 h ng / mL, about 24000 h ng / mL to about 32000 h ng / mL, about 24000 h ng / mL to about 28000 h ng / mL or about 28,000 h ng / mL to about 32000 h ng / mL. In certain embodiments, the methods described herein provide about 4500 h ng / mL to about 33400 h Furosemide AUC in ng / mL inf In certain embodiments, the methods described herein provide about 8900 h ng / mL to about 33400 h Furosemide AUC in ng / mL inf In certain embodiments, the methods described herein provide approximately 4500 h ng / mL to about 16700 h Furosemide AUC in ng / mL inf .

[0279] (3) Exemplary Pharmacokinetic / Pharmacodynamic Results

[0280] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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 one or more of the following is true: This method provides furosemide C in human plasma at concentrations ranging from approximately 3000 ng / mL to approximately 9800 ng / mL. max ; This method provides approximately 8800 h in human plasma. ng / mL to about 31700 h Furosemide AUC in ng / mL last ; This method provides approximately 8900 h in human plasma. ng / mL to about 33400 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0281] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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: This method provides furosemide C in human plasma at concentrations ranging from approximately 3000 ng / mL to approximately 9800 ng / mL. max ; This method provides approximately 8800 h in human plasma. ng / mL to about 31700 h Furosemide AUC in ng / mL last ; This method provides approximately 8900 h in human plasma. ng / mL to about 33400 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0282] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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 one or more of the following is true: This method provides furosemide C in human plasma at concentrations ranging from approximately 1500 ng / mL to approximately 4900 ng / mL. max ; This method provides approximately 4400 h in human plasma. ng / mL to about 15850 h Furosemide AUC in ng / mL last ; This method provides approximately 4450 h in human plasma. ng / mL to about 16700 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0283] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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: This method provides furosemide C in human plasma at concentrations ranging from approximately 1500 ng / mL to approximately 4900 ng / mL. max ; This method provides approximately 4400 h in human plasma. ng / mL to about 15850 h Furosemide AUC in ng / mL last ; This method provides approximately 4450 h in human plasma. ng / mL to about 16700 h Furosemide AUC in ng / mL inf ; Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0284] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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 one or more of the following is true: Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0285] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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: Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0286] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 1 mg of bumetanide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation, wherein one or more of the following is true: Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0287] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) in a human in need thereof, the method comprising administering to the human by subcutaneous injection about 1 mg of bumetanide in a total volume of about 0.5 mL of a liquid pharmaceutical formulation, wherein: Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0288] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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 one or more of the following is true: Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0289] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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: Total urine volume in humans about 6 hours after administration is complete is about 1200 mL to about 5000 mL; A total urine volume in a human of about 1200 mL to about 5300 mL about 8 hours after administration is completed; and Total urine volume in humans about 12 hours after administration is complete is about 1200 mL to about 5500 mL.

[0290] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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 one or more of the following is true: Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0291] In various embodiments, provided herein is a method of treating a condition (selected from the group consisting of congestion, edema, and hypertension caused by fluid overload) 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: Total urine volume in humans about 6 hours after administration is complete is about 600 mL to about 2500 mL; The human's total urine volume is from about 600 mL to about 2650 mL about 8 hours after administration is complete; and Total urine volume in humans is about 600 mL to about 2750 mL about 12 hours after administration is complete.

[0292] (C) Delivery device

[0293] In certain embodiments, the liquid drug formulation is administered from a needle and syringe kit, an autoinjector, a disposable fixed-dose pen, a multiple-use fixed-dose pen, a disposable variable-dose pen, or a multiple-use variable-dose pen. In certain embodiments, the liquid drug formulation is administered via a needle and syringe kit. In certain embodiments, the liquid drug formulation is administered via an autoinjector set. In some embodiments, the autoinjector is a disposable autoinjector. In certain embodiments, the liquid drug formulation is administered via a disposable fixed-dose pen. In certain embodiments, the liquid drug formulation is administered via a multiple-use fixed-dose pen. In certain embodiments, the liquid drug formulation is administered via a disposable variable-dose pen. In certain embodiments, the liquid drug formulation is administered via a multiple-use variable-dose pen.

[0294] (D) Application time

[0295] In certain embodiments, a liquid drug formulation described herein is administered to a patient by subcutaneous injection in 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).

[0296] (E) Patients

[0297] In certain embodiments, the human is an adult. In certain embodiments, the adult has New York Heart Association (NYHA) Class II, III, or IV chronic heart failure, liver disease or liver impairment, or kidney disease or kidney impairment. In certain embodiments, the adult exhibits a decreased responsiveness to oral diuretics prior to initiating subcutaneous administration of a loop diuretic according to the methods described herein.

[0298] In certain embodiments, the age of the adult is 30 to 80 years, 35 to 80 years, 40 to 80 years, 45 to 80 years, 50 to 80 years, 55 to 80 years, 60 to 80 years, 65 to 80 years, 70 to 80 years, 75 to 80 years, 30 to 75 years, 30 to 70 years, 30 to 65 years, 30 to 60 years, 30 to 55 years, 30 to 50 years, 30 to 45 years, 30 to 40 years, 30 to 35 years, 35 to 75 years, 35 to 70 years, 35 to 65 years, 35 to 60 years, 35 to 55 years, 35 to 50 years, 35 to 45 years, 35 to 35 years, In some embodiments, the adult is between 30 and 80 years of age. In some embodiments, the adult is between 45 and 80 years of age. In some embodiments, the adult is between 45 and 80 years of age.

[0299] In certain embodiments, the adult 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 of age.

[0300] When used for the treatment or prevention of a disease or condition disclosed herein, it will be understood that the effective dose can vary according to many factors, such as the specific compound or therapeutic combination used, the mode of administration and the severity of the condition being treated, and various physical factors associated with the treated individual. In therapeutic applications, a liquid pharmaceutical preparation as described herein can be provided to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially improve the symptoms of the disease or condition and its complications. The dosage for treating a specific individual must usually be determined subjectively by the attending physician. The variables involved include specific conditions and states and the patient's size, age, and reaction pattern. In some embodiments, the amount sufficient to cure or at least partially improve the symptoms of a disease or condition and its complications is an effective amount. In some embodiments, the amount sufficient to cure or at least partially improve the symptoms of a disease or condition and its complications is an effective amount.

[0301] medicine box

[0302] In one aspect, the present invention provides kits for treating or preventing various conditions (such as, but not limited to, congestion, edema, and hypertension caused by fluid overload) in patients in need thereof. In certain embodiments, the condition, disease, or disorder is selected from the group consisting of congestion, edema, and hypertension caused by fluid overload. In certain embodiments, the condition is congestion caused by fluid overload. 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 kidney disease. In certain embodiments, the kidney disease is nephrotic syndrome.

[0303] In various embodiments, the kit includes a liquid pharmaceutical formulation as described herein. In certain embodiments, the kit includes one or more unit doses of a liquid pharmaceutical formulation as described herein. In certain embodiments, the kit also includes a medical device. In certain embodiments, the kit also includes instructions for treating a disease or condition of the present invention.

[0304] Many medical devices have been proposed to facilitate self-administration of liquid drug formulations. The device can include a reservoir containing, for example, a preloaded liquid drug formulation to be administered as described herein. One device for intramuscular or subcutaneous delivery of a drug formulation is an autoinjector. In various embodiments, the kit includes an autoinjector.

[0305] Thus, in various embodiments, a medical device such as a micropump or patch device may include: a reservoir containing a drug formulation; a hypodermic needle configured to be removably inserted 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 drug formulation from the reservoir to the hypodermic needle, thereby administering the drug formulation subcutaneously to the patient; and a housing for supporting the reservoir, hypodermic needle, micropump, and control system, the housing being portable and suitable for contact with the patient's skin. The liquid drug formulation contained in the reservoir may be any liquid drug formulation or unit liquid drug formulation described herein.

[0306] In certain embodiments, the medical device can be a one-piece structure. Such medical devices can be disposable. In specific embodiments, the medical device can be a multi-piece structure. In such a medical device, there can be disposable or reusable parts or components. For example, the housing that defines or includes a reservoir can be a disposable or reusable component of the medical device. In some embodiments, the disposable or reusable housing that defines or includes a reservoir can include a pharmaceutical formulation of the present teachings. In various embodiments, a hypodermic needle can be a disposable component of the medical device.

[0307] In certain embodiments, the medical device is selected from the group consisting of a needle and syringe set, an autoinjector, a disposable fixed dose injection pen, a multiple use fixed dose injection pen, a disposable variable dose injection pen, or a multiple use variable dose injection pen.

[0308] Example

[0309] Having now generally described the invention, the invention will be more readily understood by reference to the following examples, which are provided merely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0310] Example 1. Method for manufacturing a furosemide liquid pharmaceutical preparation

[0311] In the following examples, the manufacturing methods used to prepare all exemplary furosemide liquid pharmaceutical formulations are described.

[0312] The corresponding amounts of each ingredient are provided in the formulation disclosed in Table 1.

[0313] Add tromethamine to an appropriate amount of water for injection (WFI) and mix until dissolved. Add sodium hydroxide (NaOH). Add approximately 1 / 3 of the total amount of the drug substance furosemide and mix until dissolved. Add benzyl alcohol and mix until homogeneous. Add NaOH. Add approximately 1 / 3 of the total amount of the drug substance furosemide and mix until dissolved. Add NaOH. Add the remaining drug substance furosemide and mix until dissolved. Take a pH sample and adjust the solution to a pH of 7.20 to 7.60 with additional NaOH or HCl. After pH adjustment, add WFI to the resulting solution to the final weight and mix. Filter the solution through a 0.22 µm PVDF filter and inject into a glass syringe.

[0314] Table 1. Formula of furosemide liquid pharmaceutical preparation

[0315] Example 2. Comparison of the Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection of a High-Concentration / Low-Volume Furosemide Liquid Pharmaceutical Formulation with Intravenous Furosemide in Healthy Volunteers

[0316] (1) Research objectives

[0317] Primary Objective: To evaluate the bioavailability of a high concentration / low volume furosemide liquid pharmaceutical formulation (80 mg furosemide in 1 mL) (referred to in this example as SCP-111) administered subcutaneously via autoinjector, compared to two equal doses of 40 mg furosemide administered intravenously over two minutes two hours apart.

[0318] Secondary Objectives: (1) Describe the pharmacokinetics and pharmacodynamics of SCP-111 administered subcutaneously via autoinjector; and (2) Describe the safety and tolerability of SCP-111 administered subcutaneously via autoinjector.

[0319] (2) End point

[0320] Primary endpoint: Log-transformed geometric mean ratios of subcutaneous SCP-111 and 80 mg intravenous furosemide: (1) AUC from time 0 (predose) to the last quantifiable time point (AUC last ); and (2) AUC extrapolated from time 0 (before dosing) to infinity (AUC inf ).

[0321] Secondary endpoints: The following pharmacokinetic (PK) parameters of subcutaneous and intravenous furosemide will be evaluated: (1) maximum observed plasma concentration (C max ); (2) reach C max Time (T max ); (3) terminal elimination rate constant (λz), estimated by linear regression of log-transformed concentration versus time data; (4) terminal elimination half-life (t½), estimated using the equation [ln(2) / λz]; (5) apparent systemic clearance (CL / F); (6) systemic clearance (CL); (7) apparent systemic volume of distribution (Vz / F); and (8) systemic volume of distribution (V).

[0322] For subcutaneous and intravenous furosemide administration, the following pharmacodynamic (PD) parameters were assessed: (1) urine output (0-6, 0-8 hours, and 0-12 hours); (2) urinary sodium excretion (0-6, 0-8 hours, and 0-12 hours); and (3) urinary potassium excretion (0-6, 0-8 hours, and 0-12 hours).

[0323] Adverse events (AEs) and serious adverse events (SAEs) were grouped and summarized by body system. The incidence of AEs and SAEs (number and percentage of subjects) was presented generally by MedDRA system organ class and preferred term.

[0324] (3) Study period

[0325] 3 months

[0326] (4) Research design and methods

[0327] This was an open-label, single-center, single-dose, randomized, two-way (two-period) crossover study in healthy volunteers. Each subject completed screening, baseline, treatment, and follow-up phases.

[0328] The screening phase was conducted in the outpatient clinic 14 to 3 days before the baseline visit. Subjects were instructed to maintain a diet containing < 2 grams of sodium for 2 days before admission to the clinical research unit (CRU). Upon arrival at the CRU (Day 0), baseline and final eligibility assessments were performed.

[0329] The treatment phase consisted of two crossover periods separated by a 2-4 day washout period. After each CRU admission, subjects continued a sodium diet of < 2 grams until discharge. Subjects were randomized in a 1:1 ratio to one of two treatment sequences, receiving either intravenous (IV) furosemide or subcutaneous (SC) SCP-111 during the crossover period (i.e., IV first, then SC or vice versa). Plasma was collected to measure furosemide concentrations pre-dose and 12 hours post-dose. Before dosing each treatment phase, subjects completely emptied their bladders, and urine was collected starting after the injection until 12 hours post-dose. Subjects remained in the CRU for 12 hours after administration of the study drug during each treatment phase. After the final assessment, subjects were discharged from the CRU if safety parameters were acceptable to the investigator.

[0330] The follow-up phase occurred 24–48 hours after discharge from the CRU following crossover period 2 (Day 5 ± 1 day) and completed the subject's study participation.

[0331] (5) Study treatment

[0332] Intravenous furosemide (IV furosemide): Hospira, furosemide injection, solution 10 mg / mL (NDA018667) (total dose = 80 mg) administered intravenously as a 40 mg injection over 2 minutes, followed by a second 40 mg injection over 2 minutes 2 hours later (reference treatment).

[0333] SCP-111 (Furosemide Injection): Total dose = 80 mg; administered subcutaneously via autoinjector (test treatment).

[0334] Study Drug: SCP-111, (Furosemide Injection), 80 mg / 1 mL, is a liquid pharmaceutical formulation of furosemide buffered to neutral pH for subcutaneous administration.

[0335] Study Device: The BD Intevia™ Delivery System is a disposable autoinjector consisting of two subassemblies, equipped with a BD Neopak™ 1 mL long prefilled syringe with a ½-inch push-on needle and a BD FluroTec® 1 mL stopper. The needle is enclosed by a rigid needle shield (RNS).

[0336] 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).

[0337] (6) Study population

[0338] Number of subjects: 18.

[0339] Subjects were included in the study only if they met all inclusion criteria and did not meet any exclusion criteria.

[0340] Inclusion criteria: Female and male subjects were eligible for inclusion only if all of the following criteria were met: (1) signed and dated Institutional Review Board (IRB)-approved informed consent prior to any study-related activities; (2) male and female subjects were 18 years of age or older; (3) subjects were capable of understanding the requirements of the study and were willing to comply with all study procedures; and (4) the investigators determined that the subjects were able to participate in the study.

[0341] Exclusion criteria: Subjects were ineligible for inclusion if they met any of the following criteria: (1) pregnant or breastfeeding women, or women of childbearing age who were unwilling to use adequate 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 serious cardiac abnormalities that could interfere with study participation or study assessments; (7) receiving or planning to receive any intravenous therapy during the study, including inotropes, vasopressors, levosimendan, nesiritide, or analogs; (8) implantation of a ventricular assist device, cardiac defibrillator, or pacemaker; (9) severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2 at screening admission. 2, calculated using the simplified Modification of Diet in Renal Disease (sMDRD) formula; (10) urinary retention due to impaired bladder emptying and / or urethral stricture; (11) presence or need for catheterization; (12) history of liver disease, cirrhosis, or ascites; (13) moderate to severe hepatic dysfunction determined by the investigator; (14) receipt of intravenous radiographic contrast agent within 72 hours before screening; (15) concomitant use of medications known to interact with furosemide (aminoglycoside antibiotics, uric acid, high-dose salicylates, cisplatin, tubocurarine, succinylcholine, chloral hydrate, phenytoin, methotrexate, indomethacin, or lithium); (16) administration of study medication or implantation of study device within 30 days before screening, or participation in another interventional clinical trial; (17) any surgery or medical condition that the investigator believes may interfere with participation in the study or may affect the study results; (18) a positive urine drug screen at screening or baseline; (19) a blood alcohol concentration >2 at screening mg / dL (0.02%); (20) alcohol breath test > 2 mg / dL (0.02%) upon admission to the CRU; and (21) a history of severe allergic or hypersensitivity reaction to furosemide.

[0342] (7) Pharmacokinetic and statistical analysis

[0343] Pharmacokinetic parameters were estimated using noncompartmental methods using Phoenix® WinNonlin® V8.1 or higher. Individual pharmacokinetic parameters for furosemide were calculated using noncompartmental analysis and summarized using descriptive statistics. The bioavailability of SCP-111 was determined by comparing the AUC of SCP-111 with that of IV furosemide. last and AUC inf The 90% confidence interval for the geometric mean ratio was determined to be between 80% and 125% to establish bioequivalence.

[0344] Incorporated by reference

[0345] The entire disclosure of each patent document and scientific article mentioned herein is incorporated by reference for all purposes.

[0346] Equivalent solutions

[0347] The present invention may be embodied in other specific forms without departing from the spirit or essential characteristics of the present invention. The above-described embodiments are therefore to be considered in all respects as illustrative rather than limiting of the present 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 equivalence of the claims are intended to be encompassed therein.

Claims

1. A method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, the method comprising administering to the 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. The method of claim 1, wherein the effective amount of the loop diuretic is from about 1 mg to about 100 mg in the total volume of the liquid pharmaceutical formulation.

3. The method of claim 1 or 2, 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. The method of any one of claims 1 to 3, wherein the human has a total urine volume of about 600 mL to about 5000 mL about 6 hours after administration is complete.

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

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

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

8. A method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, 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. The method of claim 8, wherein the effective amount of furosemide is from about 40 mg to about 80 mg in the total volume of the liquid pharmaceutical formulation.

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 to 10, wherein the total volume of the liquid drug formulation is about 0.5 mL or about 1 mL.

12. A method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, 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.

13. A method of treating a condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload in a human in need thereof, 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.

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

15. The method of any one of claims 8 to 14, wherein the method provides about 4400 h of ng / mL to about 31700 h Furosemide AUC in ng / mL last .

16. The method of any one of claims 8 to 15, wherein the method provides about 4500 h of ng / mL to about 33400 h Furosemide AUC in ng / mL inf .

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

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

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

20. A method of treating a condition in a human in need thereof, the condition selected from the group consisting of congestion, edema, and hypertension caused by fluid overload, 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 one or more of the following is true: The method provides furosemide C in the plasma of the human at about 3000 ng / mL to about 9800 ng / mL. max ; The method provides about 8800 h in the plasma of the human ng / mL to about 31700 h Furosemide AUC in ng / mL last ; The method provides about 8900 h in the plasma of the human ng / mL to about 33400 h Furosemide AUC in ng / mL inf ; the human's total urine volume is from about 1200 mL to about 5000 mL about 6 hours after the administration is completed; the human has a total urine volume of about 1200 mL to about 5300 mL about 8 hours after the administration is completed; and The human's total urine volume about 1200 mL to about 5500 mL about 12 hours after administration is complete.

21. A method of treating a condition in a human in need thereof, said condition being selected from the group consisting of congestion, edema, and hypertension caused by fluid overload, said method 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, wherein: The method provides furosemide C in the plasma of the human at about 3000 ng / mL to about 9800 ng / mL. max ; The method provides about 8800 h in the plasma of the human ng / mL to about 31700 h Furosemide AUC in ng / mL last ; The method provides about 8900 h in the plasma of the human ng / mL to about 33400 h Furosemide AUC in ng / mL inf ; the human's total urine volume is from about 1200 mL to about 5000 mL about 6 hours after the administration is completed; the human has a total urine volume of about 1200 mL to about 5300 mL about 8 hours after the administration is completed; and The human's total urine volume about 1200 mL to about 5500 mL about 12 hours after administration is complete.

22. A method of treating a condition in a human in need thereof, said condition being selected from the group consisting of congestion, edema, and hypertension caused by fluid overload, said method 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, wherein one or more of the following is true: The method provides about 1500 ng / mL to about 4900 ng / mL of furosemide C in the plasma of the human. max ; The method provides about 4400 h of ng / mL to about 15850 h Furosemide AUC in ng / mL last ; The method provides about 4500 h of ng / mL to about 16700 h Furosemide AUC in ng / mL inf ; the human's total urine volume is from about 600 mL to about 2500 mL about 6 hours after the administration is completed; the human's total urine volume about 600 mL to about 2650 mL about 8 hours after the administration is completed; and The human's total urine volume about 12 hours after administration is complete is about 600 mL to about 2750 mL.

23. A method of treating a condition in a human in need thereof, said condition being selected from the group consisting of congestion, edema, and hypertension caused by fluid overload, said method 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, wherein: The method provides about 1500 ng / mL to about 4900 ng / mL of furosemide C in the plasma of the human. max ; The method provides about 4400 h of ng / mL to about 15850 h Furosemide AUC in ng / mL last ; The method provides about 4450 h in the human plasma ng / mL to about 16700 h Furosemide AUC in ng / mL inf ; the human's total urine volume is from about 600 mL to about 2500 mL about 6 hours after the administration is completed; the human's total urine volume about 600 mL to about 2650 mL about 8 hours after the administration is completed; and The human's total urine volume about 12 hours after administration is complete is about 600 mL to about 2750 mL.

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

25. The method of any one of claims 1 to 24, wherein administering comprises administering the total volume from an automatic injector.

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

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

28. The method of any one of claims 1 to 27, wherein the liquid drug 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. The method of any one of claims 1 to 28, wherein the human is an adult, optionally wherein the adult is 45 to 80 years old.

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

31. The method of claim 29 or 30, wherein the adult exhibits a reduced responsiveness to an oral diuretic prior to initiation of subcutaneous administration according to the method.

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

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