Concentrated liquid pharmaceutical formulations of furosemide and methods of administering the same

Abstract

To provide concentrated liquid pharmaceutical formulations of furosemide and methods of administering the same.SOLUTION: Disclosed herein, in part, are liquid pharmaceutical formulations comprising furosemide or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and a pharmaceutically acceptable buffer. Methods of treating congestion, edema, fluid overload, or hypertension in a patient in need thereof are also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 799,215, filed January 31, 2019, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Furosemide, a typical loop diuretic, can be used to treat hypertension, edema, and related disorders, including decompensated heart failure. Furosemide is typically used to treat and / or manage edema associated with cardiac, renal, and hepatic dysfunction or failure, such as congestive heart failure. H. Bundgaard, T. Norgaard, N.M. Nielsen, "Photodegradation and hydrolysis of furosemide and furosemide esters in aqueous solutions," International Journal of Pharmaceutics 42, 217 (1988).

[0003] The oral bioavailability and therefore oral efficacy of furosemide are limited. Due to the combined effects of limited solubility and reduced stability at acidic pH, highly variable oral absorption is observed, but furosemide is typically administered both parenterally and orally. B. Devarakonda, DP Otto, A. Judefeind, RA Hill, MM de Villiers, “Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes,” International Journal of Pharmaceutics 345, 142 (Dec. 10, 2007). Therefore, furosemide is typically administered intravenously or intramuscularly to most patients with decompensated heart failure or other forms of more advanced edema.

[0004] Intravenous administration of medications such as furosemide requires a medical professional trained in catheter placement and administration of the drug solution. In contrast, subcutaneous administration of medications can be achieved using an automatic injection device and / or a minipump, or subcutaneous injection or infusion, which allows administration to be performed by the patient or caregiver, for example, at home. Subcutaneous administration of furosemide by the patient or caregiver can also allow for more optimal therapeutic dosing and total dose, providing a more suitable pharmacokinetic and pharmacodynamic profile and patient outcomes.

[0005] Subcutaneous administration should minimize discomfort and pain during administration to avoid poor patient compliance with the treatment regimen. Factors that may contribute to the pain and discomfort experienced by the patient during, during, or after subcutaneous administration include the injection volume, the pH of the formulation, and the osmolarity or isotonicity of the formulation. Furthermore, such a formulation should be stable in solution so that it is readily available for use and / or can be pre-filled into various dispensing devices. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there is a need for improved pharmaceutical formulations containing furosemide that contain sufficient concentrations of furosemide and have a suitable pH and osmolality, allowing for, for example, subcutaneous administration of furosemide. [Means for solving the problem]

[0007] overview In one aspect, the present invention provides a liquid pharmaceutical formulation of furosemide or a pharmaceutically acceptable salt thereof.

[0008] In various embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) one or more pharmaceutically acceptable excipients; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL. In certain embodiments, the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0009] In certain embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof; and (iii) about 25 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0010] In certain embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0011] In certain embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) N-methyl-pyrrolidone (NMP); and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0012] In certain embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; (iii) N-methyl-pyrrolidone (NMP); and (iv) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0013] In certain embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0014] In certain embodiments of the present invention, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone; (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0015] In another aspect, the present invention provides a unit liquid pharmaceutical formulation of furosemide or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments of the present invention, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof; and (iii) about 25 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0017] In certain embodiments of the present invention, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 200 mg / mL.

[0018] In certain embodiments of the present invention, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone; (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 200 mg / mL.

[0019] In certain embodiments, the liquid pharmaceutical formulation or unit liquid pharmaceutical formulation comprises one or more of water; a pH adjuster; and an osmolality adjuster.

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

[0021] Another aspect of the present invention provides a kit for the treatment of congestion, edema, fluid overload, or hypertension comprising a liquid pharmaceutical formulation or unit liquid pharmaceutical formulation described herein. DETAILED DESCRIPTION OF THE INVENTION

[0022] Detailed Description The present invention provides liquid pharmaceutical formulations and unit liquid pharmaceutical formulations containing furosemide, medical kits containing the same, and methods of using the liquid pharmaceutical formulations and unit liquid pharmaceutical formulations for treating medical disorders such as congestion, edema, fluid overload, or hypertension in patients in need thereof. In particular, the present invention can provide pharmaceutical formulations containing increased concentrations of furosemide or a pharmaceutically acceptable salt thereof, using one or more pharmaceutically acceptable excipients together with a pharmaceutically acceptable buffer capable of maintaining a pH appropriate for administration to a patient.

[0023] definition To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Abbreviations used herein have their usual meaning in the chemical and biological fields. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0025] As used herein, the terms "a" and "an" mean "one or more" and include plurals unless the context is inappropriate.

[0026] In this application, when an element or component is said to be included in and / or selected from a list of recited elements or components, it is to be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0027] Furthermore, it should be understood that elements and / or features of the compositions or methods described herein, whether expressly or implicitly stated herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, when a particular compound is referenced, that compound can be used in various embodiments of the compositions of the invention and / or methods of the invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a manner that facilitates writing and drawing a clear and concise application, but it is intended and will be understood that the embodiments can be combined or separated in various ways without departing from the present teachings and the invention. For example, it will be understood that all features described and depicted herein are applicable to all aspects of the invention as described and depicted herein.

[0028] The phrase "at least one" should be understood to include each of the listed items following the phrase individually and various combinations of two or more listed items, unless otherwise understood from context and usage. The phrase "and / or" in the context of more than two listed items should be understood to have the same meaning, unless otherwise understood from context.

[0029] The use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing" (including grammatical equivalents thereof) should generally be understood as open-ended and open-ended and not excluding, for example, additional, unrecited elements or steps unless specifically stated or understood otherwise from the context.

[0030] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or derived from the context.

[0031] At various places herein, values ​​are disclosed in groups or ranges. The description is specifically intended to include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0032] The use of any and all examples or exemplary language herein, such as "such as" or "including," is intended merely to better describe the invention and does not impose limitations on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0033] As used herein, "compound" (including specifically named compounds, e.g., furosemide) refers to the compound itself and its pharmaceutically acceptable salts, unless otherwise understood from the context of the description or unless expressly limited to one particular form of the compound, e.g., the compound itself or a pharmaceutically acceptable salt, hydrate, or ester thereof.

[0034] As used herein, "furosemide" refers to a compound of the formula: [ka] and its pharmaceutically acceptable salts. Such salts may include, but are not limited to, furosemide sodium salt and furosemide quaternary ammonium salt. Furosemide may also be referred to by other names, such as frusemide, 5-(aminosulfonyl)-4-chloro-2-[(2-furanyl-methyl)amino]benzoic acid or its IUPAC name, 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoyl-benzoic acid or its common trade name, Lasix®.

[0035] As used herein, the terms "subject" and "patient" refer to an organism treated by the methods and / or compositions described herein. Such an organism is preferably a mammal (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), more preferably a human.

[0036] As used herein, a "buffer" refers to an aqueous solution that is resistant to changes in pH. A buffer may contain a "buffering agent," such as a weak acid and its salt or a weak base and its salt, which helps maintain pH stability. Examples of buffers used in pharmaceutical formulations include 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 combinations thereof. Certain of these buffers are suitable for pharmaceutical formulations administered subcutaneously.

[0037] Tris(hydroxymethyl)aminomethane or tris(hydroxymethyl)aminomethane buffer can be referred to as "TRIS," "Tris," "Tris buffer," "Trisamine," "THAM," "tromethamine," and other names. Furthermore, many buffers and / or buffer systems can contain Tris or a pharmaceutically acceptable salt thereof and can be used in the present teachings. For example, Tris-buffered saline ("TBS"), Tris-hydrochloride buffer ("Tris-HCl"), Tris base (pH 10.6), Tris / borate / ethylenediaminetetraacetate ("EDTA") buffer ("TBE"), and Tris / acetate / EDTA buffer ("TAE"). Tris base is often used with Tris-HCl to prepare a Tris buffer of a desired pH. Additionally, the present teachings can include Tris-related compounds, e.g., compounds derived from or structurally related to Tris, that can act as buffers.

[0038] As used herein, "isotonicity" refers to the ionic strength or concentration of ions in a solution, such as a pharmaceutical formulation. Isotonicity is often measured in molar concentrations ("M"). As used herein, "isotonic solution," "isotonic formulation," "isotonic pharmaceutical formulation," and pharmaceutical formulations that are "isotonic" refer to solutions or formulations that have the same or similar concentrations of ions found in bodily fluids.

[0039] As used herein, "physiological pH" refers to a pH of about 7.4.

[0040] As used herein, "osmolality" and "osmolality" refer to the osmotic pressure of a solution, such as a pharmaceutical formulation. Osmolality is often measured in osmolality ("Osm / L" or "OsM") or osmolality ("Osm / kg"), which may be used interchangeably herein. When measuring freezing point depression, the value observed is the osmolality of the solution. In contrast to isotonicity, osmolality describes non-ionized solutes in a solution, if present, such that the osmolality or osmolality of the solution is higher than its isotonicity. The osmolality of the liquid pharmaceutical formulations described herein can be measured, for example, using vapor pressure methods.

[0041] As used herein, "iso-osmotic solution," "iso-osmotic formulation," "iso-osmotic pharmaceutical formulation," and pharmaceutical formulations that are "iso-osmotic" refer to a solution or formulation that has the same or similar concentrations of solutes as found in bodily fluids. In one embodiment, a liquid pharmaceutical formulation that is "iso-osmotic" can have an osmolality ranging from about 275 mOsM to about 350 mOsM, or when the osmolality of the formulation ranges from about 275 mOsm / kg to about 350 mOsm / kg.

[0042] As used herein, "osmolality adjusting agent" and "osmotic agent" refer to pharmaceutically acceptable compounds that may be added to the liquid pharmaceutical formulations described herein to adjust the osmolality of the liquid pharmaceutical formulation.

[0043] As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely interact with the active ingredient. Thus, a pharmaceutically acceptable carrier is one that is compatible with the other ingredients in the formulation and is biologically acceptable. In certain embodiments, supplementary active ingredients can also be incorporated into the pharmaceutical composition.

[0044] As used herein, a "pharmaceutically acceptable excipient" refers to a substance that aids in the administration and absorption of an active agent by a subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, phosphate-buffered saline, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, saline solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. For examples of excipients and carriers, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0045] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The compositions may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0046] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that, upon administration to a subject, is capable of providing a compound of the present invention or its active metabolite or residue. As is known to those skilled in the art, "salts" of compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, are not themselves pharmaceutically acceptable but may be used in the preparation of salts useful as intermediates for obtaining compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0047] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of formula NW4 + (where W is C 1~4 alkyl, etc.

[0048] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. + , NH4 +and NW4 + (Where, W is C 1~4 The anions of the compounds of the present invention comprise anions formed with a suitable cation, such as an alkyl group.

[0049] As used herein, the term "effective amount" refers to an amount of a composition (e.g., a liquid pharmaceutical formulation of the present invention) sufficient to produce a beneficial or desired result. 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.

[0050] As used herein, the terms "treat," "treating," and "treatment" include any effect that results in an improvement in or ameliorates the symptoms of a condition, disease, disorder, etc., e.g., alleviates, reduces, modulates, improves, or eliminates.

[0051] As used herein, the phrase "therapeutically effective amount" means an amount of a composition (eg, a liquid pharmaceutical formulation of the present invention) effective to produce some desired therapeutic effect in a subject.

[0052] As used herein, the term "congestion" (in heart failure) refers to the presence of signs and symptoms of extracellular fluid accumulation resulting in increased cardiac filling pressures leading to decreased cardiac output. This decreased cardiac output is further exacerbated by neurohormonal activation, resulting in increased renal sodium and water binding capacity, resulting in increased plasma volume.

[0053] As used herein, "fluid overload," "volume overload," and "hypervolemia" can describe a medical condition in which there is too much fluid in the blood. Excess fluid, primarily salt and water, can accumulate throughout the body, resulting in weight gain.

[0054] Throughout the description, when compositions and kits are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is further contemplated that there are compositions and kits of the invention that consist essentially of or consist of the recited components, and processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0055] Generally, compositions specifying percentages are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, the variable's prior definition takes precedence.

[0056] Liquid pharmaceutical formulation of furosemide As used herein, in one aspect, the present invention provides a liquid pharmaceutical formulation of furosemide or a pharmaceutically acceptable salt thereof.

[0057] In various embodiments, the liquid pharmaceutical formulation generally comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) one or more pharmaceutically acceptable excipients; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0058] In various embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof. In certain embodiments, the PEG has a weight-average molecular weight of about 3000 g / mol to about 3700 g / mol. In certain embodiments, the polysorbate is polysorbate 80. In certain embodiments, the PVP has a weight-average molecular weight of about 4000 g / mol to about 6000 g / mol. In certain embodiments, the cyclodextrin is β-cyclodextrin.

[0059] In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 30% (w / w), from about 0.5% (w / w) to about 30% (w / w), from about 1% (w / w) to about 30% (w / w), from about 1.5% (w / w) to about 30% (w / w), (w / w), from about 2% (w / w) to about 30% (w / w), from about 2.5% (w / w) to about 30% (w / w), from about 3% (w / w) to about 30% (w / w), from about 3.5% (w / w) to about 30% (w / w), from about 4% (w / w) to About 30% (w / w), about 4.5% (w / w) to about 30% (w / w), about 5% (w / w) to about 30% (w / w), about 10% (w / w) to about 30% (w / w), about 15% (w / w) to about 30% (w / w), about 20% (w / w) to about 30% (w / w), about 25% (w / w) to about 30% (w / w), about 0.1% (w / w) to about 25% (w / w), about 0.1% (w / w) to about 20% (w / w), about 0.1% (w / w) to about 15% (w / w), about 0.1% (w / w) to about 10% (w / w), about 0.1% (w / w) to about 5% (w / w), about 0.1% (w / w) to about 4.5% (w / w), about 0.1% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 3.5% (w / w), about 0.1% (w / w) to about 3% (w / w), about 0.1% (w / w) to about 2.5% (w / w), about 0.1% (w / w) to about 2% (w / w), about 0.1% (w / w) to about 1.5% (w / w), about 0.1% (w / w) to about 1% (w / w), about 0.1% (w / w) to about 0.5% (w / w), about 0.5% (w / w) to about 25% (w / w), about 0.5% (w / w) to about 20% (w / w), about 0.5% (w / w) to about 15% (w / w), about 0.5% (w / w) to about 10% (w / w), about 0.5% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 4.5% (w / w), about 0.5% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3.5% (w / w), about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2.5% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w), about 0.5% (w / w) to approximately 1% (w / w), approximately 1% (w / w) to approximately 25% (w / w), approximately 1% (w / w) to approximately 20% (w / w), approximately 1% (w / w) to approximately 15% (w / w), approximately 1% (w / w) to approximately 10% (w / w), approximately 1% (w / w) to approximately 5% (w / w), approximately 1% (w / w) to approximately 4. 5% (w / w), approximately 1% (w / w) to approximately 4% (w / w), approximately 1% (w / w) to approximately 3.5% (w / w), approximately 1% (w / w) to approximately 2.5% (w / w), approximately 1% (w / w) to approximately 2% (w / w), approximately 1% (w / w) to approximately 1.5% (w / w), approximately 1.5% (w / w) to approximately 25% (w / w) , about 1.5% (w / w) to about 20% (w / w), about 1.5% (w / w) to about 15% (w / w), about 1.5% (w / w) to about 10% (w / w), about 1.5% (w / w) to about 5% (w / w), about 1.5% (w / w) to about 4.5% (w / w), about 1.5% (w / w) to about 4% (w / w) ), about 1.5% (w / w) to about 3.5% (w / w), about 1.5% (w / w) to about 3% (w / w), about 1.5% (w / w) to about 2.5% (w / w), about 1.5% (w / w) to about 2% (w / w), about 2% (w / w) to about 25% (w / w), about 2% (w / w) to about 20% (w / w), Approximately 2% (w / w) to approximately 15% (w / w), approximately 2% (w / w) to approximately 10% (w / w), approximately 2% (w / w) to approximately 5% (w / w), approximately 2% (w / w) to approximately 4.5% (w / w), approximately 2% (w / w) to approximately 4% (w / w), approximately 2% (w / w) to approximately 3.5% (w / w), approximately 2% (w / w) to Approximately 3% (w / w), approximately 2% (w / w) to approximately 2.5% (w / w), approximately 2.5% (w / w) to approximately 25% (w / w), approximately 2.5% (w / w) to approximately 20% (w / w), approximately 2.5% (w / w) to approximately 15% (w / w), approximately 2.5% (w / w) to approximately 10% (w / w), approximately 2.5% (w / w) Approximately 5% (w / w), approximately 2.5% (w / w) to approximately 4.5% (w / w), approximately 2.5% (w / w) to approximately 4% (w / w), approximately 2.5% (w / w) to approximately 3.5% (w / w), approximately 2.5% (w / w) to approximately 3% (w / w), approximately 3% (w / w) to approximately 25% (w / w), approximately 3% (w / w) to approximately 20 % (w / w), about 3% (w / w) to about 15% (w / w), about 3% (w / w) to about 10% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4.5% (w / w), about 3% (w / w) to about 4% (w / w), about 3% (w / w) to about 3.5% (w / w), about 3.5% (w / w) to about 25% (w / w), about 3.5% (w / w) to about 20% (w / w), about 3.5% (w / w) to about 15% (w / w), about 3.5% (w / w) to about 10% (w / w), about 3.5% (w / w) to about 5% (w / w), about 3.5% (w / w) to about 4.5% (w / w), about 3.5% (w / w) to about 4% (w / w), about 4% (w / w) to about 25% (w / w), about 4% (w / w) to about 20% (w / w), about 4% (w / w) to about 15% (w / w), about 4% (w / w) to about 10% (w / w), about 4% (w / w) to about 5% (w / w), about 4% (w / w) to about 4.5% (w / w), about 4.5% (w / w) to about 25% (w / w), about 4. 5% (w / w) to about 20% (w / w), about 4.5% (w / w) to about 15% (w / w), about 4.5% (w / w) to about 10% (w / w), about 4.5% (w / w) to about 5% (w / w), about 5% (w / w) to about 25% (w / w), about 5% (w / w) to about 20% (w / w), about 5% (w / w) to about 15% (w / w), about 5% ( The amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation may be about 1.5% (w / w) to about 30% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation may be about 5% (w / w) to about 15% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation may be about 1.5% (w / w) to about 30% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation may be about 5% (w / w) to about 15% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

[0060] In various embodiments, the amount of one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulations described herein is about 0.1% (w / w), about 0.25% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), or about 12% (w / w). (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), or about 30% (w / w).

[0061] In certain embodiments, the one or more pharmaceutically acceptable excipients include benzyl alcohol. In certain embodiments, the one or more pharmaceutically acceptable excipients include NMP. In certain embodiments, the one or more pharmaceutically acceptable excipients include NMP and benzyl alcohol.

[0062] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0063] In certain embodiments, the liquid pharmaceutical formulation further comprises N-methyl-pyrrolidone (NMP).

[0064] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; (iii) N-methyl-pyrrolidone (NMP); and (iv) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0065] In various embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 10% (w / w), from about 1% (w / w) to about 10% (w / w), from about 2% (w / w) to about 10% (w / w), from about 3% (w / w) to about 10% (w / w), or from about 4% (w / w). (w / w) to about 10% (w / w), about 5% (w / w) to about 10% (w / w), about 0.1% (w / w) to about 5% (w / w), about 0.1% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 3% (w / w), about 0.1% (w / w) to about 2% (w / w), about 0.1% (w / w) to about 1% (w / w), about 0.1% (w / w) to about 0.5 % (w / w), about 0.5% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1% (w / w), about 1% (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 5% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4% (w / w), or about 4% (w / w) to about 5% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulation is about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulation is about 0.5% (w / w) to about 5% (w / w).

[0066] In various embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein can be about 0.1% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulation is about 4% (w / w).

[0067] In various embodiments, the amount of NMP in the liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 10% (w / w), from about 1% (w / w) to about 10% (w / w), from about 2% (w / w) to about 10% (w / w), from about 3% (w / w) to about 10% (w / w), from about 4% (w / w) to about 1 0% (w / w), about 5% (w / w) to about 10% (w / w), about 0.1% (w / w) to about 5% (w / w), about 0.1% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 3% (w / w), about 0.1% (w / w) to about 2% (w / w), about 0.1% (w / w) to about 1% (w / w), about 0.1% (w / w) to about 0.5% (w / w), about 0.5% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1% (w / w), about 1% (w / w) to about 5% (w / w), about 1% (w / w) to about 4% (w / w), about 1% (w The amount of NMP in the liquid pharmaceutical formulation may be about 0.1% (w / w) to about 3% (w / w), about 1% (w / w) to about 2% (w / w), about 2% (w / w) to about 5% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4% (w / w), or about 4% (w / w) to about 5% (w / w). In certain embodiments, the amount of NMP in the liquid pharmaceutical formulation is about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of NMP in the liquid pharmaceutical formulation is about 0.1% (w / w) to about 1% (w / w).

[0068] In various embodiments, the amount of NMP in the liquid pharmaceutical formulations described herein can be about 0.1% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 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). In some embodiments, the amount of NMP in the liquid pharmaceutical formulation is about 0.5% (w / w).

[0069] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) N-methyl-pyrrolidone (NMP); and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0070] In various embodiments, the amount of NMP in the liquid pharmaceutical formulations described herein is from about 1% (w / w) to about 25% (w / w), from about 2.5% (w / w) to about 25% (w / w), from about 5% (w / w) to about 25% (w / w), from about 7.5% (w / w) to about 25% (w / w), from about 10% (w / w) to about 25% (w / w), from about 12.5% ​​(w / w) to about 25% (w / w), from about 15% (w / w) to about 25% (w / w), from about 20% (w / w) to about 25% (w / w), or about 1% (w / w). up to about 20% (w / w), about 1% (w / w) to about 15% (w / w), about 1% (w / w) to about 12.5% ​​(w / w), about 1% (w / w) to about 10% (w / w), about 1% (w / w) to about 7.5% (w / w), about 1% (w / w) to about 5% (w / w), about 1% (w / w) to about 2.5% (w / w), about 2.5% (w / w) to about 20% (w / w), about 2.5% (w / w) to about 15% (w / w), about 2.5% (w / w) to about 12.5% ​​(w / w), about 2.5% (w / w) to about 10% (w / w), about 2.5% (w / w) to about 7.5% (w / w), about 2.5% (w / w) to about 5% (w / w), about 5% (w / w) to about 20% (w / w), about 5% (w / w) to about 15% (w / w), about 5% (w / w) to about 12.5% ​​(w / w), about 5% (w / w) to about 10% (w / w), about 5% (w / w) to about 7.5% (w / w), about 7.5% (w / w) to about 20% (w / w), about 7.5% (w / w) to about 15% (w / w), about 7.5% (w / w) to about 12 The amount of NMP in the liquid pharmaceutical formulation may be about 0.5% (w / w), about 7.5% (w / w) to about 10% (w / w), about 10% (w / w) to about 20% (w / w), about 10% (w / w) to about 15% (w / w), about 10% (w / w) to about 12.5% ​​(w / w), about 12.5% ​​(w / w) to about 20% (w / w), about 12.5% ​​(w / w) to about 15% (w / w), about 12.5% ​​(w / w) to about 20% (w / w), about 12.5% ​​(w / w) to about 15% (w / w), or about 15% (w / w) to about 20% (w / w). In certain embodiments, the amount of NMP in the liquid pharmaceutical formulation is about 1% (w / w) to about 25% (w / w). In certain embodiments, the amount of NMP in the liquid pharmaceutical formulation is from about 5% (w / w) to about 10% (w / w).

[0071] In various embodiments, the amount of NMP in the liquid pharmaceutical formulations described herein is about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about It may be 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), about 10% (w / w), about 12.5% ​​(w / w), about 15% (w / w), about 20% (w / w), or about 25% (w / w).

[0072] In certain embodiments, the liquid pharmaceutical formulation further comprises benzyl alcohol.

[0073] In various embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein is from about 0.5% (w / w) to about 5% (w / w), from about 1% (w / w) to about 5% (w / w), from about 2% (w / w) to about 5% (w / w), from about 3% (w / w) to about 5% (w / w), from about 4% (w / w) to about 5% (w / w), from about 0.5% (w / w) to about 4% (w / w), or about 0.5% (w / w). The amount of benzyl alcohol in the liquid pharmaceutical formulation may be about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1% (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). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulation is about 0.5% (w / w) to about 5% (w / w). In certain embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulation is about 1% (w / w) to about 3% (w / w).

[0074] In various embodiments, the amount of benzyl alcohol in the liquid pharmaceutical formulations described herein can be about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), or about 5% (w / w).

[0075] In various embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulations described herein is from about 25 mM to about 500 mM, from about 30 mM to about 500 mM, from about 40 mM to about 500 mM, from about 50 mM to about 500 mM, from about 75 mM to about 500 mM, from about 100 mM to about 500 mM, from about 150 mM to about 500 mM, from about 200 mM to about 500 mM, from about 200 mM to about 500 mM, from about 250 mM to about 500 mM, from about 300 mM to about 500 mM, from about 350 mM to about 500 mM, from about 400 mM to about 500 mM, from about 450 mM to about 500 mM, from about 25 mM to about 450 mM M, about 25mM to about 400mM, about 25mM to about 350mM, about 25mM to about 300mM, about 25mM to about 250mM, about 25mM to about 200mM, approximately 25mM to approximately 150mM, approximately 25mM to approximately 100mM, approximately 25mM to approximately 75mM, approximately 25mM to approximately 50mM, approximately 25mM to Approximately 40mM, approximately 25mM to approximately 30mM, approximately 30mM to approximately 450mM, approximately 30mM to approximately 400mM, approximately 30mM to approximately 350mM, approximately 30mM ~300mM, about 30mM to about 250mM, about 30mM to about 200mM, about 30mM to about 150mM, about 30mM to about 100mM, about 3 0 mM to about 75 mM, about 30 mM to about 50 mM, about 30 mM to about 40 mM, about 40 mM to about 450 mM, about 40 mM to about 400 mM, about 40 mM to about 350 mM, about 40 mM to about 300 mM, about 40 mM to about 250 mM, about 40 mM to about 200 mM, about 40 mM to about 150 mM M, about 40mM to about 100mM, about 40mM to about 75mM, about 40mM to about 50mM, about 50mM to about 450mM, about 50mM to about 400 mM, about 50mM to about 350mM, about 50mM to about 300mM, about 50mM to about 250mM, about 50mM to about 200mM, about 50mM to about 150mM, about 50mM to about 100mM, about 50mM to about 75mM, about 75mM to about 450mM, about 75mM to about 400mM, about 75m M ~ about 350mM, about 75mM - about 300mM, about 75mM - about 250mM, about 75mM - about 200mM, about 75mM - about 150mM, about 75 mM to about 100 mM, about 100 mM to about 450 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, about 100 mM to about 200 mM, about 100 mM to about 150 mM, about 150 mM to about 450 mM,Approximately 150mM to approximately 400mM, approximately 150mM to approximately 350mM, approximately 150mM to approximately 300mM, approximately 150mM to approximately 250mM, approximately 150mM to approximately 200mM, approximately 200mM to about 450mM, about 200mM to about 400mM, about 200mM to about 350mM, about 200mM to about 300mM, about 200mM to about 250mM, about 25 The concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation may be about 0 mM to about 450 mM, about 250 mM to about 400 mM, about 250 mM to about 350 mM, about 250 mM to about 300 mM, about 300 mM to about 450 mM, about 300 mM to about 400 mM, about 300 mM to about 350 mM, about 350 mM to about 450 mM, about 350 mM to about 400 mM, or about 400 mM to about 450 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation may be about 25 mM to about 250 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the liquid pharmaceutical formulation may be about 25 mM to about 100 mM.

[0076] In various embodiments, the pharmaceutically acceptable buffer comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof.

[0077] In certain embodiments, the buffering agent is tromethamine or a pharmaceutically acceptable salt thereof, hi some embodiments, the pharmaceutically acceptable salt of tromethamine is tromethamine hydrochloride.

[0078] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0079] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; (iii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone (NMP); (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0080] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 1% (w / w) to about 25% (w / w) N-methyl-pyrrolidone (NMP); (iii) about 0.5% (w / w) to about 5% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0081] In various embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulations described herein is about 25 mM to about 250 mM, about 50 mM to about 250 mM, about 75 mM to about 250 mM, about 100 mM to about 250 mM, about 125 mM to about 250 mM, about 150 mM to about 250 mM, about 175 mM to about 250 mM, about 200 mM to about 250 mM, about 225 mM to about 250 mM, or about 265 mM to about 265 mM. Approximately 250mM, approximately 25mM to approximately 225mM, approximately 25mM to approximately 200mM, approximately 25mM to approximately 175mM, approximately 25mM to approximately 150mM, approximately 25mM to approximately 125mM, approximately 25mM to approximately 100mM , about 25mM to about 75mM, about 25mM to about 50mM, about 50mM to about 225mM, about 50mM to about 200mM, about 50mM to about 175mM, about 50mM to about 150mM, about 50mM to about 1 25mM, about 50mM to about 100mM, about 50mM to about 75mM, about 75mM to about 225mM, about 75mM to about 200mM, about 75mM to about 175mM, about 75mM to about 150mM, about 7 5mM to about 125mM, about 75mM to about 100mM, about 100mM to about 225mM, about 100mM to about 200mM, about 100mM to about 175mM, about 100mM to about 150mM, about 100m The concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation may be about 25 mM to about 125 mM, about 125 mM to about 225 mM, about 125 mM to about 200 mM, about 125 mM to about 175 mM, about 125 mM to about 150 mM, about 150 mM to about 225 mM, about 150 mM to about 200 mM, about 150 mM to about 175 mM, about 150 mM to about 250 mM, about 175 mM to about 225 mM, about 175 mM to about 200 mM, or about 200 mM to about 225 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation may be about 25 mM to about 250 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation may be about 25 mM to about 100 mM.

[0082] In various embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulations described herein can be about 25 mM, about 50 mM, about 75 mM, about 100 mM, about 125 mM, about 150 mM, about 175 mM, about 200 mM, about 225 mM, or about 250 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation is about 50 mM.

[0083] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein is from about 50 mg / mL to about 250 mg / mL, from about 60 mg / mL to about 250 mg / mL, from about 70 mg / mL to about 250 mg / mL, from about 80 mg / mL to about 250 mg / mL, from about 90 mg / mL to about 250 mg / mL, from about 100 mg / mL to about 250 mg / mL, from about 120 mg / mL to about 250 mg / mL, from about 140 mg / mL to about 250 mg / mL, from about 160 mg / mL to about 250 mg / mL, from about 180 mg / mL to about 250 mg / mL, from about 200 mg / mL to about 250mg / mL, approximately 50mg / mL to approximately 200mg / mL, approximately 50mg / mL to approximately 180mg / mL, approximately 50mg / mL to approximately 160mg / mL, approximately 50mg / mL to approximately 140mg / mL, approximately 50mg / mL to approximately 120mg / mL, approximately 50mg / mL to approximately 100mg / mL, Approximately 50 mg / mL to approximately 90 mg / mL, approximately 50 mg / mL to approximately 80 mg / mL, approximately 50 mg / mL to approximately 70 mg / mL, approximately 50 mg / mL to approximately 60 mg / mL, approximately 60 mg / mL to approximately 200 mg / mL, approximately 60 mg / mL to approximately 180 mg / mL, approximately 60 mg / mL to approximately 160 m g / mL, about 60 mg / mL to about 140 mg / mL, about 60 mg / mL to about 120 mg / mL, about 60 mg / mL to about 100 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / m L ~ about 200mg / mL, about 70mg / mL - about 180mg / mL, about 70mg / mL - about 160mg / mL, about 70mg / mL - about 140mg / mL, about 70mg / mL - about 120mg / mL, about 70mg / mL - about 100mg / mL, about 70mg / mL - about 90mg / m L, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 200 mg / mL, about 80 mg / mL to about 180 mg / mL, about 80 mg / mL to about 160 mg / mL, about 80 mg / mL to about 140 mg / mL, about 80 mg / mL to about 120 mg / mL, about 80 mg / mL ~100mg / mL, 80mg / mL~90mg / mL, 90mg / mL~200mg / mL, 90mg / mL~180mg / mL, 90mg / mL~160mg / mL, 90mg / mL~140mg / mL, 90mg / mL~120mg / mL,Approximately 90mg / mL to approximately 100mg / mL, approximately 100mg / mL to approximately 200mg / mL, approximately 100mg / mL to approximately 180mg / mL, approximately 100mg / mL to approximately 160mg / mL, approximately 1 00mg / mL to approx. 140mg / mL, approx. 100mg / mL to approx. 120mg / mL, approx. 120mg / mL to approx. 200mg / mL, approx. 120mg / mL to approx. 180mg / mL, approx. 12 The concentration of furosemide in the liquid pharmaceutical formulation may be about 0 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 formulation may be 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, or about 80 mg / mL to about 250 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation may be about 80 mg / mL to about 250 mg / mL.

[0084] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, greater than about 100 mg / mL, greater than about 120 mg / mL, greater than about 140 mg / mL, greater than about 160 mg / mL, greater than about 180 mg / mL, greater than about 200 mg / mL, greater than about 220 mg / mL, or greater than about 250 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 40 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 50 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 60 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 70 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 80 mg / mL.

[0085] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be 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 concentration of furosemide in the liquid pharmaceutical formulation is about 100 mg / mL.

[0086] In various embodiments, the liquid pharmaceutical formulation comprises: (i) 100 mg / mL furosemide or a pharmaceutically acceptable salt thereof; (ii) about 4% (w / w) benzyl alcohol; and (iii) about 50 mM tromethamine or a pharmaceutically acceptable salt thereof Includes.

[0087] In various embodiments, the liquid pharmaceutical formulation comprises: (i) 100 mg / mL furosemide or a pharmaceutically acceptable salt thereof; (ii) about 4% (w / w) benzyl alcohol; (iii) about 0.5% (w / w) N-methyl-pyrrolidone; and (iv) about 50 mM tromethamine or a pharmaceutically acceptable salt thereof Includes.

[0088] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof; and (iii) about 25 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0089] In various embodiments, the pH of the liquid pharmaceutical formulations described herein can be about 5.5 to about 8.5, about 6 to about 8.5, about 6.5 to about 8.5, about 7 to about 8.5, about 7.5 to about 8.5, about 8 to about 8.5, about 5.5 to about 8, about 5.5 to about 7.5, about 5.5 to about 7, about 5.5 to about 6.5, about 5.5 to about 6, about 6 to about 8, about 6 to about 7.5, about 6 to about 7, about 6 to about 6.5, about 6.5 to about 8, about 6.5 to about 7.5, about 6.5 to about 7, about 7 to about 8, about 7 to about 7.5, or about 7.5 to about 8. In certain embodiments, the pH of the liquid pharmaceutical formulation is about 6.5 to about 8.5. In certain embodiments, the pH of the liquid pharmaceutical formulation is about 7 to about 8. In certain embodiments, the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0090] In various embodiments, the pH of the liquid pharmaceutical formulations described herein can be about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, or about 8.5. In certain embodiments, the pH of the liquid pharmaceutical formulation is about 7.4.

[0091] In various embodiments, the pH of the liquid pharmaceutical formulations described herein can be 5.5±0.1, 6±0.1, 6.5±0.1, 7±0.1, 7.5±0.1, 8±0.1, or 8.5±0.1. In certain embodiments, the pH of the liquid pharmaceutical formulation is about 7.4±0.1.

[0092] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0093] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) N-methyl-pyrrolidone (NMP); and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0094] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; (iii) N-methyl-pyrrolidone (NMP); and (iv) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0095] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0096] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone; (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0097] In various embodiments, the liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 1% (w / w) to about 25% (w / w) N-methyl-pyrrolidone; (iii) about 0.5% (w / w) to about 5% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0098] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL The concentration of furosemide in the liquid pharmaceutical formulation may be about 20 mg / mL to about 100 mg / mL, about 10 mg / mL to about 20 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 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 50 mg / mL, about 30 mg / mL to about 40 mg / mL, or about 40 mg / mL to about 50 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation may be about 20 mg / mL to about 100 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation may be about 5 mg / mL to about 20 mg / mL.

[0099] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be greater than about 5 mg / mL, greater than about 10 mg / mL, greater than about 20 mg / mL, greater than about 30 mg / mL, greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, or greater than about 100 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 5 mg / mL. In certain embodiments, the concentration of furosemide in the liquid pharmaceutical formulation is greater than about 20 mg / mL.

[0100] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulations described herein can be about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, 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.

[0101] In various embodiments, the liquid pharmaceutical formulations described herein further comprise a pharmaceutically acceptable pH adjusting agent. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia solution, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine, or any combination thereof. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is sodium hydroxide or hydrochloric acid.

[0102] In various embodiments, the liquid pharmaceutical formulations described herein further comprise an osmolality adjuster. In some embodiments, the osmolality adjuster is selected from the group including sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, or any combination thereof. In certain embodiments, the osmolality adjuster is sodium chloride.

[0103] In various embodiments, the liquid pharmaceutical formulations described herein may further comprise one or more additional pharmaceutically acceptable carriers, excipients, or diluents. Examples of liquid carriers for parenteral administration include water, alcohols (including monohydric and polyhydric alcohols, e.g., glycerol) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). In some embodiments, the carrier is an oily ester such as ethyl oleate and isopropyl myristate. Examples of such carriers are well known to those skilled in the art and can be prepared according to accepted pharmaceutical procedures, such as those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed. Alfonso R. Gennaro (Lippincott Williams & Wilkins, Baltimore, Md. (2000)). For example, liquid vehicles or liquid carriers (used interchangeably herein) can be used to prepare the liquid pharmaceutical formulations described herein, such as solutions, suspensions, and emulsions. In certain embodiments, the pharmaceutically acceptable carrier is a sterile carrier.

[0104] In certain embodiments, the liquid pharmaceutical formulation comprises one or more of water; a pH adjuster; and an osmolality adjuster. In certain embodiments, the pH adjuster is selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and combinations thereof. In some embodiments, the osmolality adjuster is selected from the group consisting of sodium chloride, potassium chloride, and combinations thereof.

[0105] In various embodiments, the liquid pharmaceutical formulations described herein may further comprise other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity adjusting agents, stabilizers, and osmolality adjusting agents.

[0106] In various embodiments, the liquid pharmaceutical formulations described herein further comprise a second therapeutic agent. In certain embodiments, furosemide is the only therapeutic agent present in the liquid pharmaceutical formulations described herein.

[0107] In various embodiments, the liquid pharmaceutical formulations described herein provide a blood glucose concentration of about 100 mOsm / kg to about 1600 mOsm / kg, about 200 mOsm / kg to about 1600 mOsm / kg, about 400 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 1200 mOsm / kg, about 100 mOsm / kg to about 800 mOsm / kg, about 100 mOsm / kg to about 16 ... In some embodiments, the liquid pharmaceutical formulations described herein have an osmolality in the range of about 200 mOsm / kg to about 400 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 400 mOsm / kg, about 400 mOsm / kg to about 1200 mOsm / kg, about 400 mOsm / kg to about 800 mOsm / kg, or about 800 mOsm / kg to about 1200 mOsm / kg.

[0108] In certain embodiments, the liquid pharmaceutical formulations described herein have an osmolality ranging from about 275 mOsm / kg to about 350 mOsm / kg. In certain embodiments, the liquid pharmaceutical formulations described herein are isotonic.

[0109] Furosemide unit liquid pharmaceutical dosage form As described herein, in one aspect, the invention provides a unit liquid pharmaceutical formulation of furosemide or a pharmaceutically acceptable salt thereof.

[0110] In various embodiments, the unit liquid pharmaceutical formulation generally comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) one or more pharmaceutically acceptable excipients; and (iii) a pharmaceutically acceptable buffer solution Includes.

[0111] In various embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof. In certain embodiments, the PEG has a weight-average molecular weight of about 3000 g / mol to about 3700 g / mol. In certain embodiments, the polysorbate is polysorbate 80. In certain embodiments, the PVP has a weight-average molecular weight of about 4000 g / mol to about 6000 g / mol. In certain embodiments, the cyclodextrin is β-cyclodextrin.

[0112] In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 30% (w / w), from about 0.5% (w / w) to about 30% (w / w), from about 1% (w / w) to about 30% (w / w), from about 1.5% (w / w) to about 30% (w / w), (w / w), from about 2% (w / w) to about 30% (w / w), from about 2.5% (w / w) to about 30% (w / w), from about 3% (w / w) to about 30% (w / w), from about 3.5% (w / w) to about 30% (w / w), or about 4% (w / w). ) to about 30% (w / w), about 4.5% (w / w) to about 30% (w / w), about 5% (w / w) to about 30% (w / w), about 10% (w / w) to about 30% (w / w), about 15% (w / w) to about 30% (w / w), about 20% (w / w) to about 30% (w / w), about 25% (w / w) to about 30% (w / w), about 0.1% (w / w) to about 25% (w / w), about 0.1% (w / w) to about 20% (w / w), about 0.1% (w / w) to about 15% (w / w), about 0.1% (w / w) to about 10% (w / w), about 0.1% (w / w) About 5% (w / w), about 0.1% (w / w) to about 4.5% (w / w), about 0.1% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 3.5% (w / w), about 0.1% (w / w) to about 3% (w / w), about 0.1% (w / w) to about 2.5% (w / w), about 0.1% (w / w) to about 2% (w / w), about 0.1% (w / w) to about 1.5% (w / w), about 0.1% (w / w) to about 1% (w / w), about 0.1% (w / w) to about 0.5% (w / w), about 0.5% (w / w) to about 25% (w / w), about 0.5% (w / w) to about 20% (w / w), about 0.5% (w / w) to about 15% (w / w), about 0.5% (w / w) to about 10% (w / w), about 0.5% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 4.5% (w / w), about 0.5% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3.5% (w / w), about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2.5% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1.5% (w / w), about 0.5% (w / w) to approximately 1% (w / w), approximately 1% (w / w) to approximately 25% (w / w), approximately 1% (w / w) to approximately 20% (w / w), approximately 1% (w / w) to approximately 15% (w / w), approximately 1% (w / w) to approximately 10% (w / w), approximately 1% (w / w) to approximately 5% (w / w), approximately 1% (w / w) to approximately 4. 5% (w / w), approximately 1% (w / w) to approximately 4% (w / w), approximately 1% (w / w) to approximately 3.5% (w / w), approximately 1% (w / w) to approximately 2.5% (w / w), approximately 1% (w / w) to approximately 2% (w / w), approximately 1% (w / w) to approximately 1.5% (w / w), approximately 1.5% (w / w) to approximately 25% (w / w) , about 1.5% (w / w) to about 20% (w / w), about 1.5% (w / w) to about 15% (w / w), about 1.5% (w / w) to about 10% (w / w), about 1.5% (w / w) to about 5% (w / w), about 1.5% (w / w) to about 4.5% (w / w), about 1.5% (w / w) to about 4% (w / w) ), about 1.5% (w / w) to about 3.5% (w / w), about 1.5% (w / w) to about 3% (w / w), about 1.5% (w / w) to about 2.5% (w / w), about 1.5% (w / w) to about 2% (w / w), about 2% (w / w) to about 25% (w / w), about 2% (w / w) to about 20% (w / w), Approximately 2% (w / w) to approximately 15% (w / w), approximately 2% (w / w) to approximately 10% (w / w), approximately 2% (w / w) to approximately 5% (w / w), approximately 2% (w / w) to approximately 4.5% (w / w), approximately 2% (w / w) to approximately 4% (w / w), approximately 2% (w / w) to approximately 3.5% (w / w), approximately 2% (w / w) to Approximately 3% (w / w), approximately 2% (w / w) to approximately 2.5% (w / w), approximately 2.5% (w / w) to approximately 25% (w / w), approximately 2.5% (w / w) to approximately 20% (w / w), approximately 2.5% (w / w) to approximately 15% (w / w), approximately 2.5% (w / w) to approximately 10% (w / w), approximately 2.5% (w / w) Approximately 5% (w / w), approximately 2.5% (w / w) to approximately 4.5% (w / w), approximately 2.5% (w / w) to approximately 4% (w / w), approximately 2.5% (w / w) to approximately 3.5% (w / w), approximately 2.5% (w / w) to approximately 3% (w / w), approximately 3% (w / w) to approximately 25% (w / w), approximately 3% (w / w) to approximately 20 % (w / w), about 3% (w / w) to about 15% (w / w), about 3% (w / w) to about 10% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4.5% (w / w), about 3% (w / w) to about 4% (w / w), about 3% (w / w) to about 3.5% (w / w), about 3.5% (w / w) to about 25% (w / w), about 3.5% (w / w) to about 20% (w / w), about 3.5% (w / w) to about 15% (w / w), about 3.5% (w / w) to about 10% (w / w), about 3.5% (w / w) to about 5% (w / w), about 3.5% (w / w) to about 4.5% (w / w), about 3.5% (w / w) to about 4% (w / w), about 4% (w / w) to about 25% (w / w), about 4% (w / w) to about 20% (w / w), about 4% (w / w) to about 15% (w / w), about 4% (w / w) to about 10% (w / w), about 4% (w / w) to about 5% (w / w), about 4% (w / w) to about 4.5% (w / w), about 4.5% (w / w) to about 25% (w / w), about 4. 5% (w / w) to about 20% (w / w), about 4.5% (w / w) to about 15% (w / w), about 4.5% (w / w) to about 10% (w / w), about 4.5% (w / w) to about 5% (w / w), about 5% (w / w) to about 25% (w / w), about 5% (w / w) to about 20% (w / w), about 5% (w / w) to about 15% (w / w), about 5% ( The amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulation may be about 1.5% (w / w) to about 10% (w / w), about 10% (w / w) to about 25% (w / w), about 10% (w / w) to about 20% (w / w), about 10% (w / w) to about 15% (w / w), about 15% (w / w) to about 25% (w / w), about 15% (w / w) to about 20% (w / w), or about 20% (w / w) to about 25% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulation is about 1.5% (w / w) to about 30% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulation is about 5% (w / w) to about 15% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

[0113] In various embodiments, the amount of one or more pharmaceutically acceptable excipients in the unit liquid pharmaceutical formulations described herein is about 0.1% (w / w), about 0.25% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 12% (w / w), about 14% (w / w), about 16% (w / w), about 18% (w / w), about 19% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% ( % (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), or about 30% (w / w).

[0114] In certain embodiments, the one or more pharmaceutically acceptable excipients include benzyl alcohol. In certain embodiments, the one or more pharmaceutically acceptable excipients include NMP. In certain embodiments, the one or more pharmaceutically acceptable excipients include NMP and benzyl alcohol.

[0115] In various embodiments, the concentration of the pharmaceutically acceptable buffer in the unit liquid pharmaceutical formulation described herein is from about 25 mM to about 500 mM, from about 30 mM to about 500 mM, from about 40 mM to about 500 mM, from about 50 mM to about 500 mM, from about 75 mM to about 500 mM, from about 100 mM to about 500 mM, from about 150 mM to about 500 mM, from about 200 mM to about 500 mM, from about 200 mM to about 500 mM, from about 250 mM to about 500 mM, from about 300 mM to about 500 mM, from about 350 mM to about 500 mM, from about 400 mM to about 500 mM, from about 450 mM to about 500 mM, from about 25 mM to about 45 0mM, approximately 25mM to approximately 400mM, approximately 25mM to approximately 350mM, approximately 25mM to approximately 300mM, approximately 25mM to approximately 250mM, approximately 25mM to About 200mM, about 25mM to about 150mM, about 25mM to about 100mM, about 25mM to about 75mM, about 25mM to about 50mM, about 25mM ~about 40mM, about 25mM to about 30mM, about 30mM to about 450mM, about 30mM to about 400mM, about 30mM to about 350mM, about 30m M ~ about 300mM, about 30mM - about 250mM, about 30mM - about 200mM, about 30mM - about 150mM, about 30mM - about 100mM, about 30 mM to about 75 mM, about 30 mM to about 50 mM, about 30 mM to about 40 mM, about 40 mM to about 450 mM, about 40 mM to about 400 mM, about 40 mM to about 350 mM, about 40 mM to about 300 mM, about 40 mM to about 250 mM, about 40 mM to about 200 mM, about 40 mM to about 150 mM, about 40mM to about 100mM, about 40mM to about 75mM, about 40mM to about 50mM, about 50mM to about 450mM, about 50mM to about 40 0mM, approximately 50mM to approximately 350mM, approximately 50mM to approximately 300mM, approximately 50mM to approximately 250mM, approximately 50mM to approximately 200mM, approximately 50mM to Approximately 150mM, approximately 50mM to approximately 100mM, approximately 50mM to approximately 75mM, approximately 75mM to approximately 450mM, approximately 75mM to approximately 400mM, approximately 75m M ~ about 350mM, about 75mM - about 300mM, about 75mM - about 250mM, about 75mM - about 200mM, about 75mM - about 150mM, about 75 mM to about 100 mM, about 100 mM to about 450 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, about 100 mM to about 200 mM, about 100 mM to about 150 mM, about 150 mM to about 450 mM,Approximately 150mM to approximately 400mM, approximately 150mM to approximately 350mM, approximately 150mM to approximately 300mM, approximately 150mM to approximately 250mM, approximately 150mM to approximately 200mM, approximately 200mM to about 450mM, about 200mM to about 400mM, about 200mM to about 350mM, about 200mM to about 300mM, about 200mM to about 250mM, about 25 The concentration of the pharmaceutically acceptable buffer in the unit liquid pharmaceutical formulation may be about 0 mM to about 450 mM, about 250 mM to about 400 mM, about 250 mM to about 350 mM, about 250 mM to about 300 mM, about 300 mM to about 450 mM, about 300 mM to about 400 mM, about 300 mM to about 350 mM, about 350 mM to about 450 mM, about 350 mM to about 400 mM, or about 400 mM to about 450 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the unit liquid pharmaceutical formulation may be about 25 mM to about 250 mM. In certain embodiments, the concentration of the pharmaceutically acceptable buffer in the unit liquid pharmaceutical formulation may be about 25 mM to about 100 mM.

[0116] In various embodiments, the pharmaceutically acceptable buffer comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof.

[0117] In certain embodiments, the buffering agent is tromethamine or a pharmaceutically acceptable salt thereof.

[0118] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; and (iii) tromethamine or a pharmaceutically acceptable salt thereof Includes.

[0119] In certain embodiments, the unit liquid pharmaceutical formulation further comprises N-methyl-pyrrolidone (NMP).

[0120] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) N-methyl-pyrrolidone (NMP); (iii) benzyl alcohol; and (iv) tromethamine or a pharmaceutically acceptable salt thereof Includes.

[0121] In various embodiments, the amount of furosemide or a pharmaceutically acceptable salt thereof in the unit liquid pharmaceutical formulations described herein is from about 20 mg to about 200 mg, from about 40 mg to about 200 mg, from about 60 mg to about 200 mg, from about 80 mg to about 200 mg, from about 100 mg to about 200 mg, from about 120 mg to about 200 mg, from about 140 mg to about 200 mg, from about 160 mg to about 200 mg, from about 1 80mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20mg to about 100mg, about 20m g ~ about 80mg, about 20mg - about 60mg, about 20mg - about 40mg, about 40mg - about 180mg, about 40mg - about 160mg, about 40mg - about 140mg, about 40mg - about 120m g, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg ~ about 120mg, about 60mg - about 100mg, about 60mg - about 80mg, about 80mg - about 180mg, about 80mg - about 160mg, about 80mg - about 140mg, about 80mg - about 1 The amount of furosemide or a pharmaceutically acceptable salt thereof in a unit liquid pharmaceutical formulation may be about 20 mg, about 80 mg to about 100 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, or about 160 mg to about 180 mg. In certain embodiments, the amount of furosemide or a pharmaceutically acceptable salt thereof in a unit liquid pharmaceutical formulation may be about 20 mg to about 200 mg, about 40 mg to about 200 mg, about 60 mg to about 200 mg, or about 80 mg to about 200 mg. In some embodiments, the amount of furosemide or a pharmaceutically acceptable salt thereof in a unit liquid pharmaceutical formulation may be about 80 mg to about 200 mg.

[0122] In various embodiments, the unit liquid pharmaceutical formulations described herein contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of furosemide or a pharmaceutically acceptable salt thereof.

[0123] In various embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 10% (w / w), from about 1% (w / w) to about 10% (w / w), from about 2% (w / w) to about 10% (w / w), from about 3% (w / w) to about 10% (w / w), or from about 4% (w / w). / w) to about 10% (w / w), about 5% (w / w) to about 10% (w / w), about 0.1% (w / w) to about 5% (w / w), about 0.1% (w / w) to about 4% (w / w), about 0.1% (w / w) to about 3% (w / w), about 0.1% (w / w) to about 2% (w / w), about 0.1% (w / w) to about 1% (w / w), about 0.1% (w / w) to about 0. 5% (w / w), about 0.5% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1% (w / w), about 1% (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 5% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4% (w / w), or about 4% (w / w) to about 5% (w / w). In certain embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulation is about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulation is about 0.5% (w / w) to about 5% (w / w).

[0124] In various embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulation described herein can be about 0.1% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w). In certain embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulation is about 4% (w / w).

[0125] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0126] In certain embodiments, the unit liquid pharmaceutical formulation further comprises N-methyl-pyrrolidone (NMP).

[0127] In various embodiments, the amount of NMP in the unit liquid pharmaceutical formulations described herein is from about 0.1% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 10% (w / w), from about 1% (w / w) to about 10% (w / w), from about 2% (w / w) to about 10% (w / w), from about 3% (w / w) to about 10% (w / w), from about 4% (w / w) to about 10% (w / w), Approximately 10% (w / w), approximately 5% (w / w) to approximately 10% (w / w), approximately 0.1% (w / w) to approximately 5% (w / w), approximately 0.1% (w / w) to approximately 4% (w / w), approximately 0.1% (w / w) to approximately 3% (w / w), approximately 0.1% (w / w) to approximately 2% (w / w), approximately 0.1% (w / w) to approximately 1% (w / w), approximately 0.1% (w / w) to approximately 0.5% ( w / w), about 0.5% (w / w) to about 5% (w / w), about 0.5% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1% (w / w), about 1% (w / w) to about 5% (w / w), about 1% (w / w) to about 4% (w / w), about 1% ( The amount of NMP in the unit liquid pharmaceutical formulation may be about 0.1% (w / w) to about 3% (w / w), about 1% (w / w) to about 2% (w / w), about 2% (w / w) to about 5% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3% (w / w), about 3% (w / w) to about 5% (w / w), about 3% (w / w) to about 4% (w / w), or about 4% (w / w) to about 5% (w / w). In certain embodiments, the amount of NMP in the unit liquid pharmaceutical formulation is about 0.1% (w / w) to about 10% (w / w). In certain embodiments, the amount of NMP in the unit liquid pharmaceutical formulation is about 0.1% (w / w) to about 1% (w / w).

[0128] In various embodiments, the amount of NMP in the unit liquid pharmaceutical formulations described herein can be about 0.1% (w / w), about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 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). In some embodiments, the amount of NMP in the unit liquid pharmaceutical formulation is about 0.5% (w / w).

[0129] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; (iii) about 0.1% (w / w) to about 10% (w / w) of N-methyl-pyrrolidone (NMP); and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0130] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) N-methyl-pyrrolidone (NMP); and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0131] In various embodiments, the amount of NMP in the unit liquid pharmaceutical formulations described herein is from about 1% (w / w) to about 25% (w / w), from about 2.5% (w / w) to about 25% (w / w), from about 5% (w / w) to about 25% (w / w), from about 7.5% (w / w) to about 25% (w / w), from about 10% (w / w) to about 25% (w / w), from about 12.5% ​​(w / w) to about 25% (w / w), from about 15% (w / w) to about 25% (w / w), from about 20% (w / w) to about 25% (w / w), or about 1% (w / w). (w / w) to about 20% (w / w), about 1% (w / w) to about 15% (w / w), about 1% (w / w) to about 12.5% ​​(w / w), about 1% (w / w) to about 10% (w / w), about 1% (w / w) to about 7.5% (w / w), about 1% (w / w) to about 5% (w / w), about 1% (w / w) to about 2.5% (w / w), about 2.5% (w / w) to about 20% (w / w), about 2.5% (w / w) to about 15% (w / w), about 2.5% (w / w) to about 12.5% ​​(w / w), about 2.5% (w / w) About 10% (w / w), about 2.5% (w / w) to about 7.5% (w / w), about 2.5% (w / w) to about 5% (w / w), about 5% (w / w) to about 20% (w / w), about 5% (w / w) to about 15% (w / w), about 5% (w / w) to about 12.5% ​​(w / w), about 5% (w / w) to about 10% (w / w), about 5% (w / w) to about 7.5% (w / w), about 7.5% (w / w) to about 20% (w / w), about 7.5% (w / w) to about 15% (w / w), about 7.5% (w / w) to about 12 The amount of NMP in the unit liquid pharmaceutical formulation may be about 0.5% (w / w), about 7.5% (w / w) to about 10% (w / w), about 10% (w / w) to about 20% (w / w), about 10% (w / w) to about 15% (w / w), about 10% (w / w) to about 12.5% ​​(w / w), about 12.5% ​​(w / w) to about 20% (w / w), about 12.5% ​​(w / w) to about 15% (w / w), about 12.5% ​​(w / w) to about 20% (w / w), about 12.5% ​​(w / w) to about 15% (w / w), or about 15% (w / w) to about 20% (w / w). In certain embodiments, the amount of NMP in the unit liquid pharmaceutical formulation is about 1% (w / w) to about 25% (w / w). In certain embodiments, the amount of NMP in the unit liquid pharmaceutical formulation is from about 5% (w / w) to about 10% (w / w).

[0132] In various embodiments, the amount of NMP in the unit liquid pharmaceutical formulations described herein is about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), It can be 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), about 10% (w / w), about 12.5% ​​(w / w), about 15% (w / w), about 20% (w / w), or about 25% (w / w).

[0133] In certain embodiments, the unit liquid pharmaceutical formulation further comprises benzyl alcohol.

[0134] In various embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulations described herein is from about 0.5% (w / w) to about 5% (w / w), from about 1% (w / w) to about 5% (w / w), from about 2% (w / w) to about 5% (w / w), from about 3% (w / w) to about 5% (w / w), from about 4% (w / w) to about 5% (w / w), from about 0.5% (w / w) to about 4% (w / w), or from about 0.5% (w / w). ) to about 3% (w / w), about 0.5% (w / w) to about 2% (w / w), about 0.5% (w / w) to about 1% (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). In certain embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulation is about 0.5% (w / w) to about 5% (w / w). In certain embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulation is about 1% (w / w) to about 3% (w / w).

[0135] In various embodiments, the amount of benzyl alcohol in the unit liquid pharmaceutical formulations described herein can be about 0.5% (w / w), about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), or about 5% (w / w).

[0136] In some embodiments, the pharmaceutically acceptable salt of tromethamine is tromethamine hydrochloride.

[0137] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof; and (iii) about 25 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL, and the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0138] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0139] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; (iii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone (NMP); (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0140] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 1% (w / w) to about 25% (w / w) N-methyl-pyrrolidone (NMP); (iii) about 0.5% (w / w) to about 5% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

[0141] In various embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the unit liquid pharmaceutical formulations described herein is about 25 mM to about 250 mM, about 50 mM to about 250 mM, about 75 mM to about 250 mM, about 100 mM to about 250 mM, about 125 mM to about 250 mM, about 150 mM to about 250 mM, about 175 mM to about 250 mM, about 200 mM to about 250 mM, about 225 mM to about 250 mM, about 250 mM to about 250 mM, about 265 mM to about 250 mM, about 275 mM to about 250 mM, about 285 mM to about 250 mM, about 295 mM to about 250 mM, about 300 mM to about 300 mM, about 315 mM to about 315 mM, about 325 mM to about 325 mM, about 330 mM to about 335 mM, about 345 mM to about 345 mM, about 350 mM to about 350 mM, about 365 mM to about 365 mM, about 375 mM to about 375 mM, about 385 mM to about 385 mM, about 395 mM to about 395 mM, about 400 mM to about 400 mM, about 415 mM to about 415 mM, about 425 mM to about 425 mM, about 435 mM to about 435 mM, about 445 mM to about 445 mM, about 450 mM to about 450 mM, about 465 mM to about 465 mM, about 475 mM to about 475 mM, about 485 mM to about 485 mM, about 495 mM to about 495 mM, about 500 mM to about 5 M ~ about 250mM, about 25mM - about 225mM, about 25mM - about 200mM, about 25mM - about 175mM, about 25mM - about 150mM, about 25mM - about 125mM, about 25mM - about 100m M, about 25mM to about 75mM, about 25mM to about 50mM, about 50mM to about 225mM, about 50mM to about 200mM, about 50mM to about 175mM, about 50mM to about 150mM, about 50mM to about 125mM, approximately 50mM to approximately 100mM, approximately 50mM to approximately 75mM, approximately 75mM to approximately 225mM, approximately 75mM to approximately 200mM, approximately 75mM to approximately 175mM, approximately 75mM to approximately 150mM, approximately 75mM to about 125mM, about 75mM to about 100mM, about 100mM to about 225mM, about 100mM to about 200mM, about 100mM to about 175mM, about 100mM to about 150mM, about 100 The concentration of tromethamine or a pharmaceutically acceptable salt thereof in the unit liquid pharmaceutical formulation may be about 25 mM to about 250 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the unit liquid pharmaceutical formulation may be about 25 mM to about 100 mM.

[0142] In various embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the unit liquid pharmaceutical formulations described herein can be about 25 mM, about 50 mM, about 75 mM, about 100 mM, about 125 mM, about 150 mM, about 175 mM, about 200 mM, about 225 mM, or about 250 mM. In certain embodiments, the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the unit liquid pharmaceutical formulation is about 50 mM.

[0143] In various embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulations described herein is from about 50 mg / mL to about 250 mg / mL, from about 60 mg / mL to about 250 mg / mL, from about 70 mg / mL to about 250 mg / mL, from about 80 mg / mL to about 250 mg / mL, from about 90 mg / mL to about 250 mg / mL, from about 100 mg / mL to about 250 mg / mL, from about 120 mg / mL to about 250 mg / mL, from about 140 mg / mL to about 250 mg / mL, from about 160 mg / mL to about 250 mg / mL, from about 180 mg / mL to about 250 mg / mL, from about 200 mg / mL to about 250 mg / mL, Approximately 250mg / mL, approximately 50mg / mL to approximately 200mg / mL, approximately 50mg / mL to approximately 180mg / mL, approximately 50mg / mL to approximately 160mg / mL, approximately 50mg / mL to approximately 140mg / mL, approximately 50mg / mL to approximately 120mg / mL, approximately 50mg / mL to approximately 100mg / mL , 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 mL~about 200mg / mL, about 70mg / mL~about 180mg / mL, about 70mg / mL~about 160mg / mL, about 70mg / mL~about 140mg / mL, about 70mg / mL~about 120mg / mL, about 70mg / mL~about 100mg / mL, about 70mg / mL~about 90mg / m L, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 200 mg / mL, about 80 mg / mL to about 180 mg / mL, about 80 mg / mL to about 160 mg / mL, about 80 mg / mL to about 140 mg / mL, about 80 mg / mL to about 120 mg / mL, about 80 mg / mL ~100mg / mL, 80mg / mL~90mg / mL, 90mg / mL~200mg / mL, 90mg / mL~180mg / mL, 90mg / mL~160mg / mL, 90mg / mL~140mg / mL, 90mg / mL~120mg / mL,Approximately 90mg / mL to approximately 100mg / mL, approximately 100mg / mL to approximately 200mg / mL, approximately 100mg / mL to approximately 180mg / mL, approximately 100mg / mL to approximately 160mg / mL, approximately 1 00mg / mL to approx. 140mg / mL, approx. 100mg / mL to approx. 120mg / mL, approx. 120mg / mL to approx. 200mg / mL, approx. 120mg / mL to approx. 180mg / mL, approx. 12 The concentration of furosemide in the unit liquid pharmaceutical formulation may be about 0 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 unit liquid pharmaceutical formulation may be 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, or about 80 mg / mL to about 250 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation may be about 80 mg / mL to about 250 mg / mL.

[0144] In various embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulations described herein can be greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, greater than about 100 mg / mL, greater than about 120 mg / mL, greater than about 140 mg / mL, greater than about 160 mg / mL, greater than about 180 mg / mL, greater than about 200 mg / mL, greater than about 220 mg / mL, or greater than about 250 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 40 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 50 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 60 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 70 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 80 mg / mL.

[0145] In various embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulations described herein can be 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 concentration of furosemide in the unit liquid pharmaceutical formulation is about 100 mg / mL.

[0146] In various embodiments, the pH of the unit liquid pharmaceutical formulation described herein can be about 5.5 to about 8.5, about 6 to about 8.5, about 6.5 to about 8.5, about 7 to about 8.5, about 7.5 to about 8.5, about 8 to about 8.5, about 5.5 to about 8, about 5.5 to about 7.5, about 5.5 to about 7, about 5.5 to about 6.5, about 5.5 to about 6, about 6 to about 8, about 6 to about 7.5, about 6 to about 7, about 6 to about 6.5, about 6.5 to about 8, about 6.5 to about 7.5, about 6.5 to about 7, about 7 to about 8, about 7 to about 7.5, or about 7.5 to about 8. In certain embodiments, the pH of the unit liquid pharmaceutical formulation is about 6.5 to about 8.5. In certain embodiments, the pH of the unit liquid pharmaceutical formulation is about 7 to about 8. In certain embodiments, the pH of the unit liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0147] In various embodiments, the pH of the unit liquid pharmaceutical formulations described herein can be about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, or about 8.5. In certain embodiments, the pH of the unit liquid pharmaceutical formulation is about 7.4.

[0148] In various embodiments, the pH of the unit liquid pharmaceutical formulations described herein can be 5.5±0.1, 6±0.1, 6.5±0.1, 7±0.1, 7.5±0.1, 8±0.1, or 8.5±0.1. In certain embodiments, the pH of the unit liquid pharmaceutical formulation is about 7.4±0.1.

[0149] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the unit liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0150] In various embodiments, the unit liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone; (iii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the unit liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0151] In various embodiments, the liquid pharmaceutical formulation comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 1% (w / w) to about 25% (w / w) N-methyl-pyrrolidone; (iii) about 0.5% (w / w) to about 5% (w / w) benzyl alcohol; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of the unit liquid pharmaceutical formulation is from about 5.5 to about 6.5.

[0152] In various embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulations described herein is from about 5 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL. The concentration of furosemide in the unit liquid pharmaceutical formulation may be about 20 mg / mL to about 100 mg / mL, about 10 mg / mL to about 20 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 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 50 mg / mL, about 30 mg / mL to about 40 mg / mL, or about 40 mg / mL to about 50 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation may be about 20 mg / mL to about 100 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation may be about 5 mg / mL to about 20 mg / mL.

[0153] In various embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulations described herein can be greater than about 5 mg / mL, greater than about 10 mg / mL, greater than about 20 mg / mL, greater than about 30 mg / mL, greater than about 40 mg / mL, greater than about 50 mg / mL, greater than about 60 mg / mL, greater than about 70 mg / mL, greater than about 80 mg / mL, greater than about 90 mg / mL, or greater than about 100 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 5 mg / mL. In certain embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulation is greater than about 20 mg / mL.

[0154] In various embodiments, the concentration of furosemide in the unit liquid pharmaceutical formulations described herein can be about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, 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.

[0155] In various embodiments, the unit liquid pharmaceutical formulations described herein further comprise a pharmaceutically acceptable pH adjusting agent. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is selected from the group consisting of acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammonia solution, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, or trolamine. In certain embodiments, the pharmaceutically acceptable pH adjusting agent is sodium hydroxide or hydrochloric acid.

[0156] In various embodiments, the unit liquid pharmaceutical formulations described herein further comprise an osmolality adjuster. In certain embodiments, the osmolality adjuster is selected from the group comprising sodium chloride, potassium chloride, isosorbide, mannitol, xylitol, or any combination thereof. In certain embodiments, the osmolality adjuster is sodium chloride.

[0157] In various embodiments, the unit liquid pharmaceutical formulations described herein may further comprise one or more additional pharmaceutically acceptable carriers, excipients, or diluents. Examples of liquid carriers for parenteral administration include water, alcohols (including monohydric and polyhydric alcohols, e.g., glycerol) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). Examples of such carriers are well known to those skilled in the art and can be prepared according to accepted pharmaceutical procedures, such as those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed. Alfonso R. Gennaro (Lippincott Williams & Wilkins, Baltimore, Md. (2000)). For example, liquid vehicles or liquid carriers (used interchangeably herein) can be used to prepare the liquid pharmaceutical formulations described herein, such as solutions, suspensions, and emulsions.

[0158] In certain embodiments, the unit liquid pharmaceutical formulation comprises one or more of water; a pH adjuster; and an osmolality adjuster. In certain embodiments, the pH adjuster is selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and combinations thereof. In some embodiments, the osmolality adjuster is selected from the group consisting of sodium chloride, potassium chloride, and combinations thereof.

[0159] In various embodiments, the unit liquid pharmaceutical formulations described herein may further comprise other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity adjusting agents, stabilizers, and osmolality adjusting agents.

[0160] In various embodiments, the unit liquid pharmaceutical formulations described herein further comprise a second therapeutic agent. In certain embodiments, furosemide is the only therapeutic agent present in the unit liquid pharmaceutical formulations described herein.

[0161] In various embodiments, the unit liquid pharmaceutical formulations described herein contain a saturation level of about 100 mOsm / kg to about 1600 mOsm / kg, about 200 mOsm / kg to about 1600 mOsm / kg, about 400 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 1200 mOsm / kg, about 100 mOsm / kg to about 800 mOsm / kg, about 100 mOsm / kg to about 16 ... In some embodiments, the unit liquid pharmaceutical formulations described herein have an osmolality in the range of about 200 mOsm / kg to about 400 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 400 mOsm / kg, about 400 mOsm / kg to about 1200 mOsm / kg, about 400 mOsm / kg to about 800 mOsm / kg, or about 800 mOsm / kg to about 1200 mOsm / kg.

[0162] In various embodiments, the unit liquid pharmaceutical formulations described herein may have an osmolality ranging from about 275 mOsm / kg to about 350 mOsm / kg. In certain embodiments, the unit liquid pharmaceutical formulations described herein are isotonic.

[0163] In various embodiments, the unit liquid pharmaceutical formulations described herein may be from about 0.05 mL to about 40 mL, from about 0.1 mL to about 40 mL, from about 0.5 mL to about 40 mL, from about 1 mL to about 40 mL, from about 2 mL to about 40 mL, from about 5 mL to about 40 mL, from about 10 mL to about 40 mL, from about 20 mL to about 40 mL, from about 0.05 mL to about 20 mL, from about 0.05 mL to about 10 mL, from about 0.05 mL to about 5 mL, from about 0.05 mL to about 2 mL, from about 0.05 mL to about 1 mL, from about 0.05 mL to about 0.5 mL, from about 0.05 mL to about 0.1 mL, from about 0.1 mL to about 20 mL, or from about 0.05 mL to about 1 mL. The unit liquid pharmaceutical formulations described herein have a volume of about 0.1 mL to about 10 mL, about 0.1 mL to about 5 mL, about 0.1 mL to about 2 mL, about 0.1 mL to about 1 mL, about 0.1 mL to about 0.5 mL, about 0.5 mL to about 20 mL, about 0.5 mL to about 10 mL, about 0.5 mL to about 5 mL, about 0.5 mL to about 2 mL, about 0.5 mL to about 1 mL, about 1 mL to about 20 mL, about 1 mL to about 10 mL, about 1 mL to about 5 mL, about 1 mL to about 2 mL, about 2 mL to about 20 mL, about 2 mL to about 10 mL, about 2 mL to about 5 mL, about 5 mL to about 20 mL, about 5 mL to about 10 mL, or about 10 mL to about 20 mL. In certain embodiments, the unit liquid pharmaceutical formulations described herein have a volume of about 0.5 mL to about 20 mL. In certain embodiments, the unit liquid pharmaceutical formulations described herein have a volume of about 0.5 mL to about 10 mL.

[0164] In various embodiments, the unit liquid pharmaceutical formulations described herein have a volume of about 0.05 mL, about 0.1 mL, about 0.5 mL, about 1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 4.5 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 20 mL, or about 40 mL. In certain embodiments, the unit liquid pharmaceutical formulations described herein have a volume of about 3.5 mL or about 10 mL.

[0165] Treatment method In one aspect, the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein may be used for the treatment or prevention of various diseases and disorders, such as, but not limited to, congestion, edema, fluid overload, or high blood pressure, in patients in need thereof.

[0166] In various embodiments, the method comprises administering to the patient a liquid pharmaceutical formulation described herein, wherein the liquid pharmaceutical formulation generally comprises: (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) one or more pharmaceutically acceptable excipients; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL. In certain embodiments, the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0167] In various embodiments, the method comprises administering to the patient a unit liquid pharmaceutical formulation described herein, wherein the unit liquid pharmaceutical formulation generally comprises: (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) one or more pharmaceutically acceptable excipients; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in the unit liquid pharmaceutical formulation is from about 40 mg / mL to about 200 mg / mL. In certain embodiments, the pH of the unit liquid pharmaceutical formulation is from about 6.5 to about 8.5.

[0168] In certain embodiments, the liquid pharmaceutical formulation further comprises a second therapeutic agent. In some embodiments, the liquid pharmaceutical formulation and the second therapeutic agent are administered simultaneously, together, or separately at separate or different times as part of a regimen.

[0169] In certain embodiments, the liquid pharmaceutical formulation can be administered parenterally, including by infusion, injection, or implantation, suitably including subcutaneous administration. For example, the liquid pharmaceutical formulation can be administered, for example, by subcutaneous injection or delivery or intravenous injection or delivery. In some embodiments, the liquid pharmaceutical formulation is administered intravenously to a patient. In some embodiments, the liquid pharmaceutical formulation is administered to a patient by subcutaneous injection or infusion. In some embodiments, the liquid pharmaceutical formulation is administered to a patient by subcutaneous infusion using an on-body subcutaneous delivery system. In some embodiments, the liquid pharmaceutical formulation is administered to a patient by subcutaneous infusion using a wearable subcutaneous delivery system. In some embodiments, the liquid pharmaceutical formulation is administered to a patient by subcutaneous infusion using a pump device. In some embodiments, the pump device is a micropump device or a patch device. In some embodiments, the pump device is a patch device.

[0170] In certain embodiments, the liquid pharmaceutical formulation is administered to the patient by subcutaneous infusion over about 0.5 hours, about 1.0 hour, about 1.5 hours, about 2.0 hours, about 4.0 hours, or about 8.0 hours.

[0171] In certain embodiments, the unit liquid pharmaceutical formulation further comprises a second therapeutic agent, hi some embodiments, the unit liquid pharmaceutical formulation and the second therapeutic agent are administered simultaneously, together, or separately at separate or different times as part of a regimen.

[0172] In certain embodiments, the unit liquid pharmaceutical formulation can be administered parenterally, including by infusion, injection, or implantation, suitably including subcutaneous administration. For example, the unit liquid pharmaceutical formulation can be administered, for example, by subcutaneous injection or delivery or intravenous injection or delivery. In some embodiments, the unit liquid pharmaceutical formulation is administered intravenously to the patient. In some embodiments, the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous injection or infusion. In some embodiments, the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous infusion using an on-body subcutaneous delivery system. In some embodiments, the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous infusion using a wearable subcutaneous delivery system. In certain embodiments, the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous infusion using a pump device. In some embodiments, the pump device is a micropump device or a patch device. In some embodiments, the pump device is a patch device.

[0173] In certain embodiments, the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous infusion over a period of about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 4 hours, or about 8 hours.

[0174] When administered for the treatment or prevention of a disease or disorder disclosed herein, it will be understood that the effective dose can vary depending on many factors, such as the particular compound or therapeutic combination utilized, the mode of administration, the severity of the disease being treated, and various physical factors associated with the individual being treated. In therapeutic applications, the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein can be provided to a patient already suffering from said disease or disorder in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease or disorder and its complications. The dose used in treating a specific individual must typically be subjectively determined by the attending physician. Relevant variables include the specific disease and condition, as well as the size, age, and response pattern of the patient. In some embodiments, an effective amount is an amount sufficient to cure or at least partially ameliorate the symptoms of a disease or disorder and its complications. In some embodiments, a therapeutically effective amount is an amount sufficient to cure or at least partially ameliorate the symptoms of a disease or disorder and its complications.

[0175] kit In one aspect, the present invention provides kits for the treatment or prevention of various diseases and disorders, such as, but not limited to, congestion, edema, fluid overload, or hypertension, in a patient in need thereof.

[0176] In various embodiments, the kit comprises a liquid pharmaceutical formulation described herein. In certain embodiments, the kit comprises one or more unit doses of the liquid pharmaceutical formulation. In certain embodiments, the kit further comprises a medical device. In certain embodiments, the kit further comprises instructions for treating a disease or disorder of the invention.

[0177] In various embodiments, the kit comprises a unit liquid pharmaceutical formulation described herein. In certain embodiments, the kit comprises one or more units of the liquid pharmaceutical formulation. In some embodiments, the kit comprises one unit, two units, three units, or more units of the liquid pharmaceutical formulation. In certain embodiments, the kit further comprises a medical device. In certain embodiments, the kit further comprises instructions for treating a disease or disorder of the invention.

[0178] Several medical devices have been proposed to facilitate self-administration of pharmaceutical formulations. The device may include a reservoir containing, e.g., pre-filled with, the liquid pharmaceutical formulation described herein to be administered. For example, a micropump can provide precise subcutaneous administration of small amounts of the liquid pharmaceutical formulation. Such micropumps can be compact and portable. Another type of device useful for subcutaneous delivery or administration of pharmaceutical formulations is often referred to as a patch device, on-body subcutaneous delivery system, or wearable subcutaneous delivery system (e.g., a pump patch device). Patch devices are typically adhered directly to the patient's skin.

[0179] Thus, in various embodiments, a medical device such as a micropump or patch device can include a reservoir containing a pharmaceutical formulation, a hypodermic needle configured for removably insertion into a patient's skin, a micropump having an inlet in fluid communication with the reservoir and an outlet in fluid communication with the hypodermic needle, a control system configured to control the micropump to deliver the pharmaceutical formulation from the reservoir to the hypodermic needle, thereby subcutaneously administering the pharmaceutical formulation to the patient, and a housing for supporting the reservoir, hypodermic needle, micropump, and control system, wherein the housing is portable and adapted for contact with the patient's skin. The liquid pharmaceutical formulation contained within the reservoir can be any of the liquid pharmaceutical formulations or unit liquid pharmaceutical formulations described herein.

[0180] In certain embodiments, the medical device can be of unitary construction. Such medical devices can be for single or single use. In certain embodiments, the medical device can be of multi-piece construction. In such medical devices, there can be disposable or reusable portions or components. For example, a housing defining or containing a reservoir can be a disposable or reusable component of the medical device. In some embodiments, a disposable or reusable housing defining or containing a reservoir can contain a pharmaceutical formulation of the present teachings. In various embodiments, a hypodermic needle can be a disposable component of the medical device.

[0181] In certain embodiments, the medical device is a pump device. In some embodiments, the pump device is a micropump device or a patch device. In some embodiments, the pump device is a patch device. In certain embodiments, the medical device is selected from the group comprising a needle and syringe set, an autoinjector, a single-use fixed-dose injection pen, a multiple-use fixed-dose injection pen, a single-use variable-dose injection pen, or a multiple-use variable-dose injection pen. [Example]

[0182] Example The invention having now been generally described will be more readily understood by reference to the following examples, which are intended only to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0183] Example 1. Effect of pH on the solubility of furosemide in liquid pharmaceutical formulations The solubility of furosemide was measured in six buffers over a pH range of 6.0 to 8.5 at two buffer strengths (50 and 200 mM). The buffers tested are found in Table 1.

[0184] [Table 1]

[0185] Experimental setup: Solid furosemide (approximately 100 mg) was added to the buffer solution (2 mL) until the mixture was saturated (approximately 50 mg / mL).

[0186] Screen I: pH was adjusted using base (NaOH, 1 M) during preparation and at each time point.

[0187] Screen II: Solubility was aided by sonication (20 min) during initial preparation, followed by pH adjustment using base (NaOH, 1 M or 12 M) (only after sonication).

[0188] The samples were tumbled under ambient conditions for 48 hours and protected from light.

[0189] Solids were removed from the samples by centrifugation at t=2 hours, t=24 hours, and t=48 hours, and the supernatants were tested for appearance, pH, osmolality, and recovery (HPLC assay).

[0190] result: The results of the experiment are shown in Tables 2 and 3.

[0191] [Table 2]

[0192] [Table 3]

[0193] [Table 4]

[0194] The solubility was determined to be dependent on the type of buffer (at higher buffer strengths) and was observed to increase with increasing pH values.

[0195] pH Screening Round I The solubility of furosemide was first measured at a concentration of 50 mM in sodium phosphate, potassium phosphate, and tromethamine / HCl buffers.

[0196] A significant pH shift was observed in test samples with a pH of 7.4 or greater over 48 hours by the API. This shift was observed at each time point, indicating a slow dissolution rate of furosemide in the buffered medium.

[0197] At pH 7.4 and 8.5, the maximum equilibrium solubility could not be measured (API shift) due to a pH shift to approximately pH = 7. At pH = 6.0, no pH shift was observed.

[0198] In general, solubility was observed to increase at higher pH values. Furosemide exhibited the highest solubility at approximately 40 mg / mL. All types of buffers appeared to produce similar solubilities.

[0199] All samples were observed to be hypotonic, with increased osmolality at higher pH due to increased solubility of furosemide.

[0200] pH Screening Round II The pH solubility of furosemide was measured in the above buffers with histidine / HCl, citrate, and tromethamine over the pH range of 6.0 to 8.5 at increasing buffer strengths of 200 mM. Additionally, test samples were sonicated prior to pH adjustment to facilitate API dissolution and minimize pH shifts throughout the study.

[0201] Only a small pH shift (0.4 pH units) was observed throughout the study, likely due to the increased buffer strength and initial sonication, which increased the rate of dissolution.

[0202] Supersaturation, likely induced by sonication, was observed at t=2 h and t=24 h in certain buffers.

[0203] All test buffers were shown to produce low solubility at pH=6.0 and support solubility of 8 mg / mL at higher pHs.

[0204] Potassium phosphate appeared to produce higher solubility (2x) than sodium phosphate at higher pH.

[0205] Tromethamine-based buffers yielded maximum solubility at higher pH (approximately 40 mg / mL).

[0206] In general, increasing API concentration correlated with increasing osmolality. Some deviations from this trend were reported for the sodium phosphate test solutions.

[0207] Example 2. Effect of excipients on the solubility of furosemide in liquid pharmaceutical formulations The solubility of furosemide was measured in vehicles designed to cover the formulation space of excipients (single or in mixtures) that are GRAS / regarded as safe and compatible with subcutaneous administration. From the pH-solubility studies, tromethamine was selected as the lead buffer component. A summary of the screening performed is shown in Table 4.

[0208] [Table 5]

[0209] Experimental setup: Solid furosemide was added to the buffer (2 mL) until the mixture was saturated. Solubility was aided by sonication (20 min) during initial preparation, and then the pH was adjusted using base (NaOH, 12 M) (only after sonication).

[0210] The samples were tumbled at ambient conditions for 48 hours and protected from light.

[0211] Solids were removed from the samples by centrifugation at t=2 hours, t=24 hours, and t=48 hours, and the supernatants were tested for appearance, pH, osmolality, and recovery (HPLC assay).

[0212] result: The results of the experiment are shown in Tables 5, 6, 7 and 8.

[0213] The solubility of Studies I and II could not be measured due to the low pH values ​​and large pH shifts.

[0214] [Table 6]

[0215] [Table 7]

[0216] [Table 8]

[0217] [Table 9]

[0218] Excipient solubility studies (Studies 1 and 2) An attempt was made to measure the solubility of furosemide in unbuffered excipient solutions adjusted to pH 7.4 using a strong base (NaOH). The pH was not stable during sample preparation, so solubility could not be measured (Study 1).

[0219] Attempts were made to measure furosemide solubility in excipient solutions without pH adjustment. All test samples showed very low solubility (below the limit of quantitation), which was likely due to the low pH driven by the pKa of the API.

[0220] Solubility Study of Excipients (Study 3) The solubility of furosemide was measured in excipient buffer (tromethamine) at pH 7.4. N-methyl-pyrrolidone (NMP, 20%) reported the highest solubility (approximately 87 mg / mL) that was maintained over 48 hours. Maximum solubility could not be measured because saturation was not achieved.

[0221] Throughout the study, pH fluctuations (up to 0.7 pH units) were observed in certain conditions.

[0222] Benzyl alcohol (BA, 2%), glycerin (20%), and polyethylene glycol (4%) resulted in the highest furosemide solubility (approximately 60-75 mg / mL) that was maintained over 48 hours.

[0223] For some formulations, the osmolality could not be accurately determined due to the organic content.

[0224] Solubility Study of Excipients (Study 4) A thorough factorial DOE study was conducted to determine the optimal amounts of NMP, benzyl alcohol, and buffer (tromethamine) required to yield the highest solubility. Potential synergistic effects resulting from various excipient combinations were also investigated.

[0225] Small pH fluctuations (up to 0.3 pH units) were observed throughout the study.

[0226] The highest solubility (>120 mg / mL) was always achieved at higher NMP concentrations (20%).

[0227] A minimum concentration of 5% NMP in combination with 2% benzyl alcohol was reported to result in a solubility of over 100 mg / mL.

[0228] Furosemide solubility was highest in large amounts of NMP and BA and was relatively unaffected by buffer strength.

[0229] At low NMP levels, higher buffer concentrations appeared to result in slightly higher solubility.

[0230] The effect of NMP was stronger at low BA levels, and the effect of BA was stronger at low NMP levels. Both are cosolvents and likely dissolve furosemide by the same mechanism.

[0231] Due to the organic content of the test vehicle, osmolality could not be properly determined.

[0232] Solubility Study of Excipients (Study 5) The solubility of furosemide was measured in excipient buffer (tromethamine) at pH 6.0.

[0233] Small pH fluctuations (up to 0.4 pH units) were observed throughout the study.

[0234] The solubility ranged from approximately 3 to 10 mg / mL. N-methyl-pyrrolidone (20%) yielded the highest solubility (approximately 10 mg / mL) that was maintained over 48 hours.

[0235] All solutions appeared cloudy, indicating saturation of each solution.

[0236] Due to the organic content of the test vehicle, osmolality could not be properly determined.

[0237] Solubility Study of Excipients (Study 6) The solubility of furosemide was measured in excipient buffers (N-methyl-pyrrolidone, benzyl alcohol, tromethamine) at pH 4.0, 5.0, 6.0 and 7.4.

[0238] In the test sample at pH 4.0, a pH shift of 0.7 units was observed.

[0239] Solubility increased significantly between pH 6 and 7.4. The maximum observed solubility of furosemide was approximately 210 mg / mL at pH 7.4.

[0240] All solutions appeared cloudy, indicating saturation of the solution. Test samples appeared to increase in viscosity at high concentrations (approximately 200 mg / mL).

[0241] Due to the organic content of the test vehicle, osmolality could not be properly determined.

[0242] Example 3. Manufacturing process for a furosemide liquid formulation (107 mg / mL furosemide, 50 mM tromethamine, 10% (w / v) N-methyl-pyrrolidone, 2% (w / v) benzyl alcohol) In the following example, a manufacturing process for preparing a 107 mg / mL furosemide liquid formulation is described.

[0243] 30.5 g of tromethamine (USP), 500.5 g of N-methyl-pyrrolidone (USP), and 100.0 g of benzyl alcohol (USP) were weighed and added to a 5 L volumetric flask. Approximately 2.5 L of ultrapure water was added and then stirred using a magnetic stir bar. Once the solid material had dissolved, 537.5 g of furosemide (USP) was added to form a suspension. After approximately 30 minutes of additional stirring, the pH of the suspension / solution was adjusted to 7.4 using 10 N sodium hydroxide solution (requiring approximately 181.0 mL of 10 N sodium hydroxide solution). Stirring was continued for another 30 minutes, after which the volume of the solution was adjusted to the volume using ultrapure water. Finally, the pH of the solution was verified and found to be 7.5.

[0244] Incorporation by Reference The entire disclosure of each patent document and scientific article referenced herein is incorporated by reference for all purposes.

[0245] equivalent The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments are considered in all respects to be 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 variations that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) one or more pharmaceutically acceptable excipients; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

2. 2. The liquid pharmaceutical formulation of claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof.

3. 3. The liquid pharmaceutical formulation according to claim 1, wherein the amount of the one or more pharmaceutically acceptable excipients in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 30% (w / w).

4. The liquid pharmaceutical formulation according to any one of claims 1 to 3, wherein the one or more pharmaceutically acceptable excipients comprise benzyl alcohol.

5. The liquid pharmaceutical formulation according to any one of claims 1 to 4, wherein the one or more pharmaceutically acceptable excipients comprise NMP.

6. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

7. 7. The liquid pharmaceutical formulation of claim 6, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w).

8. The liquid pharmaceutical formulation according to claim 6 or 7, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

9. The liquid pharmaceutical formulation according to any one of claims 6 to 8, further comprising N-methyl-pyrrolidone (NMP).

10. 10. The liquid pharmaceutical formulation of claim 9, wherein the amount of NMP in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w).

11. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; (iii) N-methyl-pyrrolidone (NMP); and (iv) a pharmaceutically acceptable buffer wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

12. 12. The liquid pharmaceutical formulation of claim 11, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w).

13. The liquid pharmaceutical formulation according to claim 11 or 12, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

14. The liquid pharmaceutical formulation according to any one of claims 11 to 13, wherein the amount of NMP in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w).

15. The liquid pharmaceutical formulation according to any one of claims 1 to 14, wherein the concentration of said pharmaceutically acceptable buffer in said liquid pharmaceutical formulation is from about 25 mM to about 500 mM.

16. 16. The liquid pharmaceutical formulation of any one of claims 1 to 15, wherein the pharmaceutically acceptable buffer comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof.

17. 17. The liquid pharmaceutical formulation of claim 16, wherein the buffering agent is tromethamine or a pharmaceutically acceptable salt thereof.

18. 18. The liquid pharmaceutical formulation according to claim 17, wherein the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation is from about 25 mM to about 250 mM.

19. The liquid pharmaceutical formulation according to claim 17 or 18, wherein the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation is from about 25 mM to about 100 mM.

20. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof; and (iii) about 25 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL, and the pH of said liquid pharmaceutical formulation is from about 6.5 to about 8.

5.

21. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

22. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; (iii) about 0.1% (w / w) to about 10% (w / w) N-methyl-pyrrolidone; and (iv) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL.

23. 23. The liquid pharmaceutical formulation according to claim 21 or 22, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

24. The liquid pharmaceutical formulation according to any one of claims 21 to 23, wherein the amount of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation is from about 25 mM to about 100 mM.

25. The liquid pharmaceutical formulation according to any one of claims 1 to 24, wherein the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.

5.

26. The liquid pharmaceutical formulation according to any one of claims 1 to 25, wherein the pH of the liquid pharmaceutical formulation is from about 7.0 to about 8.

0.

27. (i) furosemide or a pharmaceutically acceptable salt thereof; (ii) benzyl alcohol; and (iii) a pharmaceutically acceptable buffer solution wherein the concentration of furosemide in said liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of said liquid pharmaceutical formulation is from about 5.5 to about 6.

5.

28. 28. The liquid pharmaceutical formulation of claim 27, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w).

29. 29. The liquid pharmaceutical formulation according to claim 27 or 28, wherein the amount of benzyl alcohol in the liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

30. 30. The liquid pharmaceutical formulation according to any one of claims 27 to 29, further comprising N-methyl-pyrrolidone (NMP).

31. 31. The liquid pharmaceutical formulation of claim 30, wherein the amount of NMP in the liquid pharmaceutical formulation is from about 0.1% (w / w) to about 10% (w / w).

32. 32. The liquid pharmaceutical formulation of any one of claims 27 to 31, wherein the pharmaceutically acceptable buffer comprises a buffering agent selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof.

33. 33. The liquid pharmaceutical formulation of claim 32, wherein the buffering agent is tromethamine or a pharmaceutically acceptable salt thereof.

34. 34. The liquid pharmaceutical formulation according to claim 33, wherein the concentration of tromethamine or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation is from about 25 mM to about 250 mM.

35. (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 30% (w / w) of one or more pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and any combination thereof; and (iii) about 25 mM to about 500 mM of a pharmaceutically acceptable buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine or a pharmaceutically acceptable salt thereof, and any combination thereof. wherein a concentration of furosemide in said liquid pharmaceutical formulation is from about 40 mg / mL to about 250 mg / mL, and a pH of said liquid pharmaceutical formulation is from about 6.5 to about 8.

5.

36. (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in said unit liquid pharmaceutical formulation is from about 40 mg / mL to about 200 mg / mL.

37. 37. The unit liquid pharmaceutical formulation of claim 36, wherein the pH of the liquid pharmaceutical formulation is from about 6.5 to about 8.

5.

38. (i) about 10 mg to about 200 mg of furosemide or a pharmaceutically acceptable salt thereof; (ii) about 0.1% (w / w) to about 10% (w / w) benzyl alcohol; and (iii) about 25 mM to about 250 mM tromethamine or a pharmaceutically acceptable salt thereof wherein the concentration of furosemide in said unit liquid pharmaceutical formulation is from about 5 mg / mL to about 100 mg / mL, and the pH of said liquid pharmaceutical formulation is from about 5.5 to about 6.

5.

39. 39. The unit liquid pharmaceutical formulation according to any one of claims 36 to 38, wherein the amount of benzyl alcohol in said unit liquid pharmaceutical formulation is from about 0.5% (w / w) to about 5% (w / w).

40. 40. The unit liquid pharmaceutical formulation of any one of claims 36 to 39, further comprising about 0.1% (w / w) to about 10% (w / w) of N-methyl-pyrrolidone.

41. The liquid pharmaceutical formulation of any one of claims 1 to 34 or the unit liquid pharmaceutical formulation of any one of claims 35 to 40, further comprising one or more of water; a pH adjuster; and an osmolality adjuster.

42. 42. The liquid pharmaceutical formulation or unit liquid pharmaceutical formulation of claim 41, wherein the pH adjuster is selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and combinations thereof; and the osmolality adjuster is selected from the group consisting of sodium chloride, potassium chloride, and combinations thereof.

43. 42. A method of treating congestion, edema, fluid overload or hypertension in a patient in need thereof, comprising administering to said patient a liquid pharmaceutical formulation according to any one of claims 1 to 34, 41 or 42 or a unit liquid pharmaceutical formulation according to any one of claims 35 to 42.

44. 44. The method of claim 43, wherein the liquid pharmaceutical formulation is administered to the patient by subcutaneous injection or subcutaneous infusion.

45. 45. The method of claim 44, wherein the liquid pharmaceutical formulation is administered to the patient by subcutaneous injection using an on-body subcutaneous delivery system.

46. 46. ​​The method of claim 45, wherein the on-body subcutaneous delivery system is a pump device.

47. 44. The method of claim 43, wherein the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous injection or subcutaneous infusion.

48. 48. The method of claim 47, wherein the unit liquid pharmaceutical formulation is administered to the patient by subcutaneous infusion using an on-body subcutaneous delivery system.

49. 49. The method of claim 48, wherein the on-body subcutaneous delivery system is a pump device.

50. A kit for treating congestion, edema, fluid overload or hypertension, comprising the liquid pharmaceutical formulation of any one of claims 1 to 34, 41 or 42 or the unit liquid pharmaceutical formulation of any one of claims 35 to 42.

51. 51. The kit of claim 50, comprising 1 unit, 2 units, 3 units or more units.

52. 52. The kit of claim 50 or 51, further comprising an on-body subcutaneous delivery system.

53. 53. The kit of claim 52, wherein the on-body subcutaneous delivery system is a pump device.

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