Treatment methods using furosemide

Abstract

Disclosed herein, in part, is a method for subcutaneously administering a liquid pharmaceutical formulation of furosemide to an adult patient from a prefilled cartridge using a 5-hour biphasic delivery profile. Also provided is a method for treating congestion, edema, fluid overload, or hypertension in a patient in need thereof.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 061,518, filed on August 5, 2020, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background Furosemide, a typical loop diuretic, can be used in the treatment of hypertension, edema, and related diseases, including decompensated heart failure. Furosemide is commonly used in the treatment and / or management of edema associated with cardiac, renal, and hepatic dysfunction or insufficiency, 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 effect of limited solubility and reduced stability at acidic pH, highly variable oral absorption is observed, yet furosemide is usually 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 medical professionals trained in catheter placement and drug solution administration. In contrast, subcutaneous administration of medications can be achieved using autoinjectors and / or minipumps, or subcutaneous injections or infusions, which allows administration to be carried out by the patient or caregiver, for example, at home.

[0005] In subcutaneous administration, discomfort and pain during administration should be minimized to avoid poor patient adherence to the treatment plan. Factors that may contribute to pain and discomfort perceived by the patient during, during, or after subcutaneous administration include the injection volume, the pH of the formulation, and the osmotic or isotonic properties of the formulation. Furthermore, such formulations should be stable in solution so that they are readily available for use and / or can be pre-filled into various dispensing devices. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, in this field, there is a need for new alternative formulations, delivery vehicles, and profiles for subcutaneous administration of furosemide in therapeutically effective doses. [Means for solving the problem]

[0007] overview In one embodiment, the present invention provides a method for treating congestion due to fluid overload in an adult in need thereof, the method generally comprising administering a liquid pharmaceutical formulation comprising furosemide. In some embodiments, a therapeutically effective dose of furosemide is administered subcutaneously, for example, over a period of 5 hours, to produce one or more of the results or outcomes described herein, for example, the furosemide concentration in the adult plasma is 1000 ng / mL or higher from the first hour after administration until about 1 hour after administration is completed. In some embodiments, the method comprises administering a liquid pharmaceutical formulation comprising furosemide, the liquid pharmaceutical formulation being contained in a prefilled cartridge, for example, a prefilled polymer cartridge.

[0008] In various embodiments of the present invention, the method comprises subcutaneously administering a liquid pharmaceutical formulation to an adult from a prefilled polymer cartridge over a period of about 5 hours, The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; and The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete.

[0009] In various embodiments of the present invention, the method comprises subcutaneously administering a liquid pharmaceutical formulation to an adult from a prefilled polymer cartridge over a period of about 5 hours, The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours, and The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0010] In various embodiments of the present invention, the method comprises subcutaneously administering a liquid pharmaceutical formulation to an adult from a prefilled polymer cartridge over a period of about 5 hours, The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0011] In various embodiments of the present invention, the method comprises subcutaneously administering a liquid pharmaceutical formulation to an adult from a pre-filled polymer cartridge using a 5-hour biphasic delivery profile, The liquid pharmaceutical preparation contains approximately 80 mg of furosemide, approximately 79 mg of tromethamine hydrochloride, and water, with a pH of approximately 7 to 7.8 and a total volume of 10 mL; The 5-hour biphasic delivery profile involves administering approximately 30 mg of furosemide over the first hour, and approximately 12.5 mg of furosemide over each of the following four hours, with a total volume of approximately 10 mL of liquid pharmaceutical formulation being administered over approximately 5 hours. The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0012] In various embodiments of the present invention, the method comprises subcutaneous administration of a liquid pharmaceutical formulation to an adult from a pre-filled polymer cartridge using a 5-hour biphasic delivery profile, The liquid pharmaceutical formulation comprises about 80 mg of furosemide, about 79 mg of tromethamine hydrochloride and water, has a pH of about 7 to about 7.8 and a total volume of 10 mL; The 5-hour biphasic delivery profile administers about 30 mg of furosemide over the first hour and about 12.5 mg of furosemide over each of the subsequent 4 hours, and the total volume of about 10 mL of the liquid pharmaceutical formulation is administered over about 5 hours; The furosemide concentration in the plasma of an adult is about 1200 ng / mL to about 1850 ng / mL after the first hour of administration and about 1000 ng / mL to about 1800 ng / mL about 1 hour after administration is completed; The total urine volume of an adult during the first hour of administration is about 150 mL to about 450 mL, and the average urine volume per hour of an adult about 1 hour after administration is completed is about 250 mL to about 550 mL; The total urine volume of an adult about 1 hour after administration is completed is about 1500 mL to about 4000 mL; The total urinary sodium excretion about 1 hour after administration is completed is about 375 mmol to about 500 mmol; The maximum total urine volume of an adult about 1 hour after administration is completed is about 2800 mL to about 4000 mL; and The maximum total urinary sodium excretion about 1 hour after administration is completed is about 450 mmol to about 550 mmol.

[0013] In another aspect, the present invention provides a disposable polymer pre-filled cartridge that can be associated with an on-body wearable delivery device that uses a 5-hour biphasic delivery profile for subcutaneous administration of a liquid pharmaceutical formulation to an adult.

[0014] In various embodiments, the disposable polymer prefilled cartridge contains a liquid pharmaceutical formulation, and the liquid pharmaceutical formulation is isotonic and has a pH of about 7 to about 7.8. Approximately 80 mg of furosemide; Approximately 79 mg of tromethamine hydrochloride; Optionally, one or more other pharmaceutically acceptable excipients; and A quantity of water that makes a total volume of 10 mL It consists of. [Brief explanation of the drawing]

[0015] Brief explanation of the drawing [Figure 1] This is a plot, further described in Example 2, showing the effect of plasma furosemide concentration (ng / mL) on the mean urine volume per hour (mL). [Figure 2] This plot, further described in Example 2, shows the effect of plasma furosemide concentration (ng / mL) on the mean urinary sodium excretion per hour (mL). [Modes for carrying out the invention]

[0016] Detailed explanation As generally described herein, the present invention provides a method for treating various conditions, diseases, and disorders (e.g., fluid-overload congestion) in adult patients (humans) in need. This method may generally involve subcutaneous administration of a liquid pharmaceutical formulation of furosemide to an adult patient from a pre-filled polymer cartridge using a 5-hour delivery profile. The liquid pharmaceutical formulation of furosemide and the delivery profile described herein can result in an optimized furosemide pharmacokinetic and pharmacodynamic profile that maximizes patient outcomes (e.g., total urine volume and urinary sodium excretion).

[0017] definition To facilitate understanding of the present invention, several terms and phrases are defined below.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. Abbreviations used herein have their usual meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the field of chemistry.

[0019] As used herein, the terms “a” and “an” mean “one or more” and include the plural form unless the context is appropriate.

[0020] In this application, when it is said that an element or component is included in and / or selected from a list of cited elements or components, it should be understood that the element or component may be any one of the cited elements or components, or may be selected from a group consisting of two or more cited elements or components.

[0021] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether express or implied herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, where a particular compound is referred to, that compound can be used in various embodiments of the compositions of the invention and / or in the methods of the invention unless otherwise understood from the context. In other words, while embodiments within this application have been described and depicted in a manner that enables the description and depiction of a clear and concise application, it is intended and understood that embodiments can be combined or separated in various ways without departing from the teachings and the invention. For example, it should be understood that all features described and expressed herein are applicable to all embodiments of the invention described and expressed herein.

[0022] The expression "at least one" should be understood to include each of the items listed after the expression, as well as various combinations of two or more listed items, unless otherwise understood from the context and usage. The expression "and / or" relating to three or more listed items should be understood to have the same meaning unless otherwise understood from the context.

[0023] The use of the terms “include,” “includes,” “has,” “have,” “contain,” “contains,” or “contains” (including their grammatical equivalents) should generally be understood as open-ended and unrestricted, and not to exclude any additional unquoted elements or steps unless specifically stated or understood otherwise from the context.

[0024] Where the term “about” is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term “about” means a variation of ±10% from the nominal value, unless otherwise indicated or derived from the context.

[0025] In various places in this specification, values ​​are disclosed in groups or ranges. The descriptions are specifically intended to include each and every individual partial combination of members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to disclose, individually, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range of 1 to 20 are specifically intended to disclose, individually, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0026] Any use of any examples or exemplary language herein, such as “etc.” or “including,” is intended solely to better illustrate the invention and, unless otherwise claimed, does not impose any limitation on the scope of the invention. Nothing in this specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0027] As used herein, “compound” (including compounds specifically named, such as furosemide) means the compound itself and its pharmaceutically acceptable salts, unless it is understood from the context of the description that this is not the case, or unless it is explicitly limited to a particular form of the compound, such as the compound itself or a pharmaceutically acceptable salt, hydrate, or ester thereof.

[0028] As used herein, "furosemide" means formula: [ka] This refers to compounds containing and their 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 furosemide, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid or its IUPAC name, 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid or its common trade name, Lasix®.

[0029] As used herein, the terms “subject” and “patient” refer to an organism treated by the methods and / or compositions described herein. Such organisms are preferably mammals (e.g., mice, monkeys, horses, cattle, pigs, dogs, cats, etc.), more preferably humans.

[0030] As used herein, “buffer” refers to an aqueous solution that is resistant to changes in pH. A buffer may contain “buffering agents,” such as weak acids and their salts or weak bases and their salts, which help maintain pH stability. Examples of buffers used in pharmaceutical formulations include bicarbonate buffers, carbonate buffers, citrate buffers, histidine buffers, phosphate buffers, tartrate buffers, tris(hydroxymethyl)aminomethane (or 2-amino-2-hydroxymethyl-propane-1,3-diol [(HOCH2)3CNH2]) buffers, and combinations thereof. Certain buffers are suitable for pharmaceutical formulations administered subcutaneously.

[0031] Tris(hydroxymethyl)aminomethane or Tris(hydroxymethyl)aminomethane buffer may be referred to as "TRIS," "Tris," "Tris buffer," "Trisamine," "THAM," "tromethamine," and other names. Furthermore, many buffers and / or buffer systems may contain Tris or its pharmaceutically acceptable salts and may be used in this teaching. For example, Tris-buffered saline ("TBS"), Tris-hydrochloride buffer ("Tris-HCl"), Tris base (pH 10.6), Tris / borate / ethylenediaminetetraacetate ("EDTA") buffer ("TBE"), and Tris / acetate / EDTA buffer ("TAE"). Tris base is often used with Tris-HCl to prepare Tris buffers at a desired pH. In addition, this teaching may include Tris-related compounds, such as compounds derived from or structurally related to Tris that can act as buffers.

[0032] As used herein, “isotonic” refers to the ionic strength or concentration of ions in a solution, such as a pharmaceutical preparation. Isotonicity is often measured in molar concentration ("M"). As used herein, “isotonic solution,” “isotonic preparation,” “isotonic pharmaceutical preparation,” and “isotonic pharmaceutical preparation” refer to a solution or preparation having the same or similar concentrations of ions found in body fluids.

[0033] As used herein, “physiological pH” refers to a pH of approximately 7.4.

[0034] As used herein, “osmoticity” and “osmolality” refer to the osmotic pressure of a solution, such as a pharmaceutical formulation. Osmoticity is often measured in terms of volumetric osmolality ("Osm / L" or "OsM") or gravimetric osmolality ("Osm / kg"), which are interchangeable as used herein. When measuring freezing point depression, the value observed is the gravimetric osmolality of the solution. In contrast to isotonicity, osmoticity describes non-ionized solutes in a solution where, if present, the volumetric osmolality or gravimetric osmolality of the solution is higher than its isotonicity. The volumetric osmolality of liquid pharmaceutical formulations described herein can be measured, for example, using the vapor pressure method.

[0035] As used herein, “isotromic solution,” “isotromic formulation,” “isotromic pharmaceutical formulation,” and “isotromic” pharmaceutical formulation refer to a solution or formulation having the same or similar solute concentration as found in body fluids. In some embodiments, an “isotromic” liquid pharmaceutical formulation may have a volume osmolality in the range of about 275 mOsM to about 350 mOsM, or the weight osmolality of the formulation may be in the range of about 275 mOsm / kg to about 350 mOsm / kg.

[0036] As used herein, “volume osmolality adjuster” and “osmotic agent” refer to pharmaceutically acceptable compounds that may be added to liquid pharmaceutical formulations described herein to adjust the volume osmolality of the liquid pharmaceutical formulation.

[0037] 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. Therefore, a pharmaceutically acceptable carrier is compatible with the other components in the formulation and is bioacceptable. In certain embodiments, supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0038] As used herein, “pharmaceutically acceptable excipients” refers to substances that assist in the administration of activators to a subject and their absorption by the subject, and can be included in the compositions of the present invention without causing any toxicological effects of serious harm to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, ordinary saline, phosphate-buffered saline, emulsions (e.g., oil / water or water / oil emulsions), Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, saline solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose or starch), fatty acid esters, hydroxypropyl methylcellulose, polyvinylpyrrolidine, and colorants. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatic substances that do not react harmfully 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).

[0039] 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 composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0040] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt (e.g., an acid or a base) of the compounds of the present invention that, when administered to a subject, can provide the compounds of the present invention or their active metabolites or residues. As is known to those skilled in the art, “salts” of the compounds of the present invention may 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, and benzenesulfonic acid. Other acids, such as oxalic acid, are not pharmaceutically acceptable in themselves, but may be used in the preparation of salts that are useful as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0041] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and formula NW4. + The compound (where W is C 1~4 This includes, but is not limited to, alkyl groups.

[0042] Examples of salts include, but are not limited to, acetate, adipine, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, 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, and undecanoate. Other examples of salts include Na + NH4 +and NW4 + (Here, W is C 1~4 The present invention includes anions of compounds configured with appropriate cations (such as alkyl groups).

[0043] As used herein, the term “effective amount” refers to an amount of the composition (e.g., the liquid pharmaceutical formulation of the present invention) sufficient to produce a beneficial or desired result. An effective amount may be administered in one or more doses, applications, or dosages and is not intended to be limited to a specific formulation or route of administration.

[0044] As used herein, the terms “to treat,” “to treat,” and “treatment” include any effect that results in improvement of a condition, disease, disorder, etc., or improves its symptoms, such as reducing, decreasing, regulating, improving, or eliminating them.

[0045] As used herein, the phrase “therapeutic dose” means the amount of a composition (e.g., the liquid pharmaceutical formulation of the present invention) that is effective in producing some desired therapeutic effect in a subject.

[0046] 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 pressure, which in turn leads to decreased cardiac output. This decrease in cardiac output is further exacerbated by the activation of neurohormones, which leads to increased sodium-water binding in the kidneys, resulting in increased plasma volume.

[0047] As used herein, “fluid excess,” “volume overload,” and “excessive circulating blood volume” may describe a medical condition in which there is an excess of fluid in the blood. The excess fluid, mainly salt and water, accumulates throughout the body, which can result in weight gain.

[0048] Throughout the description, where compositions and kits are described as having, encompassing, or including certain components, or where processes and methods are described as having, encompassing, or including certain steps, it is further intended that there are compositions and kits of the present invention that are essentially composed of or comprise the described components, and processes and methods of the present invention that are essentially composed of or comprise the described processing steps.

[0049] Generally, compositions that specify percentages are expressed by weight unless otherwise specified. Furthermore, if a variable is not defined, the previous definition of the variable takes precedence.

[0050] Furosemide liquid pharmaceutical formulation As used herein, in one embodiment, the present invention provides a liquid pharmaceutical formulation comprising furosemide or a pharmaceutically acceptable salt thereof for the treatment of a condition, disease, or disorder described herein. In various embodiments, the condition, disease, or disorder is selected from the group consisting of congestion, edema, fluid overload, hypertension, and combinations thereof. In a particular embodiment, the condition, disease, or disorder is congestion due to fluid overload.

[0051] In various embodiments, the liquid pharmaceutical formulations described herein are available in doses of approximately 60 mg to 100 mg, approximately 65 mg to 100 mg, approximately 70 mg to 100 mg, approximately 75 mg to 100 mg, approximately 80 mg to 100 mg, approximately 85 mg to 100 mg, approximately 90 mg to 100 mg, approximately 95 mg to 100 mg, approximately 60 mg to 95 mg, approximately 60 mg to 90 mg, approximately 60 mg to 85 mg, approximately 60 mg to 80 mg, approximately 60 mg to 75 mg, approximately 60 mg to 70 mg, approximately 60 mg to 65 mg, approximately 65 mg to 95 mg, approximately 65 mg to 90 mg, It may contain approximately 65mg to 85mg, 65mg to 80mg, 65mg to 75mg, 65mg to 70mg, 70mg to 95mg, 70mg to 90mg, 70mg to 85mg, 70mg to 80mg, 70mg to 75mg, 75mg to 95mg, 75mg to 90mg, 75mg to 85mg, 75mg to 80mg, 80mg to 95mg, 80mg to 90mg, 80mg to 85mg, 85mg to 95mg, 85mg to 90mg, or 90mg to 95mg of furosemide.

[0052] In various embodiments, the liquid pharmaceutical formulations described herein may contain about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of furosemide. In a particular embodiment, the liquid pharmaceutical formulation contains about 80 mg of furosemide.

[0053] In various embodiments, the liquid pharmaceutical formulations described herein may further comprise a pharmaceutically acceptable salt of furosemide.

[0054] In various embodiments, the pharmaceutically acceptable salts of furosemide described herein are approximately 60 mg to 100 mg, approximately 65 mg to 100 mg, approximately 70 mg to 100 mg, approximately 75 mg to 100 mg, approximately 80 mg to 100 mg, approximately 85 mg to 100 mg, approximately 90 mg to 100 mg, approximately 95 mg to 100 mg, approximately 60 mg to 95 mg, approximately 60 mg to 90 mg, approximately 60 mg to 85 mg, approximately 60 mg to 80 mg, approximately 60 mg to 75 mg, approximately 60 mg to 70 mg, approximately 60 mg to 65 mg, approximately 65 mg to 95 mg, approximately 65 mg to 90 mg, approximately 65 mg to 90 mg. Furosemide may be present in liquid pharmaceutical preparations in amounts of approximately 85 mg, approximately 65 mg to approximately 80 mg, approximately 65 mg to approximately 75 mg, approximately 65 mg to approximately 70 mg, approximately 70 mg to approximately 95 mg, approximately 70 mg to approximately 90 mg, approximately 70 mg to approximately 85 mg, approximately 70 mg to approximately 80 mg, approximately 70 mg to approximately 75 mg, approximately 75 mg to approximately 95 mg, approximately 75 mg to approximately 90 mg, approximately 75 mg to approximately 85 mg, approximately 75 mg to approximately 80 mg, approximately 80 mg to approximately 95 mg, approximately 80 mg to approximately 90 mg, approximately 80 mg to approximately 85 mg, approximately 85 mg to approximately 95 mg, or approximately 90 mg to approximately 95 mg in free base form.

[0055] In various embodiments, the pharmaceutically acceptable salts of furosemide described herein may be present in a liquid pharmaceutical formulation in an amount that provides about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of furosemide in free base form. In a particular embodiment, the pharmaceutically acceptable salt of furosemide is present in a liquid pharmaceutical formulation in an amount that provides about 80 mg of furosemide in free base form.

[0056] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulation described herein is approximately 5 mg / mL to approximately 15 mg / mL, approximately 6 mg / mL to approximately 15 mg / mL, approximately 7 mg / mL to approximately 15 mg / mL, approximately 8 mg / mL to approximately 15 mg / mL, approximately 9 mg / mL to approximately 15 mg / mL, approximately 10 mg / mL to approximately 15 mg / mL, approximately 11 mg / mL to approximately 15 mg / mL, approximately 12 mg / mL to approximately 15 mg / mL, approximately 13 mg / mL to approximately 15 mg / mL, approximately 14 mg / mL to approximately 15 mg / mL, approximately 5 mg / mL to approximately 14 mg / mL, and approximately 5 mg / mL to approximately 13 mg / mL. , about 5 mg / mL to about 12 mg / mL, about 5 mg / mL to about 11 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 9 mg / mL, about 5 mg / mL to about 8 mg / mL, about 5 mg / mL to about 7 mg / mL, about 5 mg / mL to about 6 mg / mL, about 6 mg / mL ~14mg / mL, 6mg / mL~13mg / mL, 6mg / mL~12mg / mL, 6mg / mL~11mg / mL, 6mg / mL~10mg / mL, 6mg / mL~9mg / mL, 6mg / mL~8mg / mL, 6mg / mL~7mg / mL mL, about 7 mg / mL to about 14 mg / mL, about 7 mg / mL to about 13 mg / mL, about 7 mg / mL to about 12 mg / mL, about 7 mg / mL to about 11 mg / mL, about 7 mg / mL to about 10 mg / mL, about 7 mg / mL to about 9 mg / mL, about 7 mg / mL to about 8 mg / mL, about 8 m g / mL~about 14mg / mL, about 8mg / mL~about 13mg / mL, about 8mg / mL~about 12mg / mL, about 8mg / mL~about 11mg / mL, about 8mg / mL~about 10mg / mL, about 8mg / mL~about 9mg / mL, about 9mg / mL~about 14mg / mL, about 9mg / mL~ It may be approximately 13 mg / mL, approximately 9 mg / mL to approximately 12 mg / mL, approximately 9 mg / mL to approximately 11 mg / mL, approximately 9 mg / mL to approximately 10 mg / mL, approximately 10 mg / mL to approximately 14 mg / mL, approximately 10 mg / mL to approximately 13 mg / mL, approximately 10 mg / mL to approximately 12 mg / mL, approximately 10 mg / mL to approximately 11 mg / mL, approximately 11 mg / mL to approximately 14 mg / mL, approximately 11 mg / mL to approximately 13 mg / mL, approximately 11 mg / mL to approximately 12 mg / mL, approximately 12 mg / mL to approximately 14 mg / mL, approximately 12 mg / mL to approximately 13 mg / mL, or approximately 13 mg / mL to approximately 14 mg / mL.

[0057] In various embodiments, the concentration of furosemide in the liquid pharmaceutical formulation described herein may be about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, or about 15 mg / mL. In a particular embodiment, the concentration of furosemide in the liquid pharmaceutical formulation is about 8 mg / mL.

[0058] In various embodiments, the liquid pharmaceutical formulations described herein may further comprise a pharmaceutically acceptable buffer.

[0059] In various embodiments, the liquid pharmaceutical composition is (i) furosemide or a pharmaceutically acceptable salt thereof; and (ii) A pharmaceutically acceptable buffer Includes.

[0060] In certain embodiments, the pharmaceutically acceptable buffer comprises a buffer selected from the group consisting of histidine, citrate, sodium phosphate, potassium phosphate, tromethamine, or pharmaceutically acceptable salts thereof, and combinations thereof. In certain embodiments, the buffer is tromethamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutically acceptable salt of tromethamine is tromethamine hydrochloride.

[0061] In various embodiments, the liquid pharmaceutical formulations described herein may further contain water.

[0062] In various embodiments, the liquid pharmaceutical formulation is (i) Furosemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) water Includes.

[0063] In various embodiments, the liquid pharmaceutical formulations described herein include approximately 75 mg to approximately 85 mg, approximately 76 mg to approximately 85 mg, approximately 77 mg to approximately 85 mg, approximately 78 mg to approximately 85 mg, approximately 79 mg to approximately 85 mg, approximately 80 mg to approximately 85 mg, approximately 81 mg to approximately 85 mg, approximately 82 mg to approximately 85 mg, approximately 83 mg to approximately 85 mg, approximately 84 mg to approximately 85 mg, approximately 75 mg to approximately 84 mg, approximately 75 mg to approximately 83 mg, and approximately 75 mg. g ~ about 82mg, about 75mg - about 81mg, about 75mg - about 80mg, about 75mg - about 79mg, about 75mg - about 78mg, about 75mg - about 77mg, about 75mg - about 76mg, about 76mg - about 8 4mg, about 76mg to about 83mg, about 76mg to about 82mg, about 76mg to about 81mg, about 76mg to about 80mg, about 76mg to about 79mg, about 76mg to about 78mg, about 76mg to about 77mg, Approximately 77mg to approximately 84mg, approximately 77mg to approximately 83mg, approximately 77mg to approximately 82mg, approximately 77mg to approximately 81mg, approximately 77mg to approximately 80mg, approximately 77mg to approximately 79mg, approximately 77mg to approximately 78mg, approximately 78m g ~ about 84mg, about 78mg - about 83mg, about 78mg - about 82mg, about 78mg - about 81mg, about 78mg - about 80mg, about 78mg - about 79mg, about 79mg - about 84mg, about 79mg - about 8 It may contain 3 mg, approximately 79 mg to 82 mg, approximately 79 mg to 81 mg, approximately 79 mg to 80 mg, approximately 80 mg to 84 mg, approximately 80 mg to 83 mg, approximately 80 mg to 82 mg, approximately 80 mg to 81 mg, approximately 81 mg to 84 mg, approximately 81 mg to 83 mg, approximately 81 mg to 82 mg, approximately 82 mg to 84 mg, approximately 82 mg to 83 mg, or approximately 83 mg to 84 mg of tromethamine hydrochloride.

[0064] In various embodiments, the liquid pharmaceutical formulation described herein may contain about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, or about 85 mg of tromethamine hydrochloride. In a particular embodiment, the liquid pharmaceutical formulation described herein may contain about 79 mg of tromethamine hydrochloride.

[0065] In various embodiments, the concentration of tromethamine hydrochloride in the liquid pharmaceutical formulation is approximately 25 mmol to 500 mmol, approximately 50 mmol to 500 mmol, approximately 100 mmol to 500 mmol, approximately 150 mmol to 500 mmol, approximately 200 mmol to 500 mmol, approximately 250 mmol to 500 mmol, approximately 300 mmol to 500 mmol, approximately 400 mmol to 500 mmol. Approximately 500mmol, approximately 25mmol to approximately 400mmol, approximately 25mmol to approximately 300mmol, approximately 25mmol to approximately 250mmol, approximately 25mmol to approximately 200mmol, approximately 25mmol ~about 150mmol, about 25mmol to about 100mmol, about 25mmol to about 50mmol, about 50mmol to about 400mmol, about 50mmol to about 300mmol, about 50mmol ~250mmol, 50mmol~200mmol, 50mmol~150mmol, 50mmol~100mmol, 100mmol~400mmol, 100mmol~300mmol, 100mmol~250mmol, 100mmol~200mmol, 100mmol~150mmol, 150mmol~400mmol l, approximately 150 mmol to approximately 300 mmol, approximately 150 mmol to approximately 250 mmol, approximately 150 mmol to approximately 200 mmol, approximately 200 mmol to approximately 400 mmol, approximately 200 mmol to approximately 300 mmol, approximately 200 mmol to approximately 250 mmol, approximately 250 mmol to approximately 400 mmol, approximately 250 mmol to approximately 300 mmol, or approximately 300 mmol to approximately 400 mmol.

[0066] In various embodiments, the concentration of tromethamine hydrochloride in the liquid pharmaceutical formulation is about 25 mmol, about 50 mmol, about 100 mmol, about 150 mmol, about 200 mmol, about 250 mmol, about 300 mmol, about 400 mmol, or about 500 mmol.

[0067] In various embodiments, the molar ratio of tromethamine hydrochloride to furosemide or a pharmaceutically acceptable salt thereof in a liquid pharmaceutical formulation is about 1 to about 3.5, about 1.5 to about 3.5, about 2 to about 3.5, about 2.5 to about 3.5, about 3 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 3, about 2 to about 2.5, or about 2.5 to about 3.

[0068] In various embodiments, the molar ratio of tromethamine hydrochloride to furosemide or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical formulation is about 1, about 1.5, about 2, about 2.5, about 3, or about 3.5.

[0069] In various embodiments, the molar ratio of tromethamine hydrochloride to furosemide in the liquid pharmaceutical formulation is about 1 to about 3.5, about 1.5 to about 3.5, about 2 to about 3.5, about 2.5 to about 3.5, about 3 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 3, about 2 to about 2.5, or about 2.5 to about 3.

[0070] In various embodiments, the molar ratio of tromethamine hydrochloride to furosemide in the liquid pharmaceutical formulation is about 1, about 1.5, about 2, about 2.5, about 3, or about 3.5.

[0071] In various embodiments, the liquid pharmaceutical compositions described herein are in concentrations of approximately 8 mL to 12 mL, approximately 8.5 mL to 12 mL, approximately 9 mL to 12 mL, approximately 9.5 mL to 12 mL, approximately 10 mL to 12 mL, approximately 10.5 mL to 12 mL, approximately 11 mL to 12 mL, approximately 11.5 mL to 12 mL, approximately 8 mL to 11.5 mL, approximately 8 mL to 11 mL, approximately 8 mL to 10.5 mL, approximately 8 mL to 10 mL, approximately 8 mL to 9.5 mL, approximately 8 mL to 9 mL, approximately 8 mL to 8.5 mL, approximately 8.5 mL to 11.5 mL, approximately 8.5 mL to 11 mL, and approximately 8.5 mL to 10 mL. It can be contained in 5 mL, approximately 8.5 mL to 10 mL, approximately 8.5 mL to 9.5 mL, approximately 8.5 mL to 9 mL, approximately 9 mL to 11.5 mL, approximately 9 mL to 11 mL, approximately 9 mL to 10.5 mL, approximately 9 mL to 10 mL, approximately 9 mL to 9.5 mL, approximately 9.5 mL to 11.5 mL, approximately 9.5 mL to 11 mL, approximately 9.5 mL to 10.5 mL, approximately 9.5 mL to 10 mL, approximately 10 mL to 11.5 mL, approximately 10 mL to 10.5 mL, approximately 10.5 mL to 11.5 mL, approximately 10.5 mL to 11 mL, or approximately 11 mL to 11.5 mL of water.

[0072] In various embodiments, the liquid pharmaceutical compositions described herein may contain about 8 mL, about 8.5 mL, about 9 mL, about 9.5 mL, about 10 mL, about 10.5 mL, about 11 mL, about 11.5 mL, or about 12 mL of water. In a particular embodiment, the liquid pharmaceutical compositions described herein may contain about 10 mL of water.

[0073] The volume of water added to a pharmaceutical preparation should be understood to be an amount that brings the total volume to one of the volumes of water listed herein, for example, an amount that brings the total volume of the pharmaceutical preparation to 10 mL.

[0074] In various embodiments, the liquid pharmaceutical compositions described herein include approximately 8g to 12g, approximately 8.5g to 12g, approximately 9g to 12g, approximately 9.5g to 12g, approximately 10g to 12g, approximately 10.5g to 12g, approximately 11g to 12g, approximately 11.5g to 12g, approximately 8g to 11.5g, approximately 8g to 11g, approximately 8g to 10.5g, approximately 8g to 10g, approximately 8g to 9.5g, approximately 8g to 9g, approximately 8g to 8.5g, approximately 8.5g to 11.5g, approximately 8.5g to 11g, and approximately 8.5g to 10g. .5g, about 8.5g to about 10g, about 8.5g to about 9.5g, about 8.5g to about 9g, about 9g to about 11.5g, about 9g to about 11g, about 9g to about 10.5g, about 9g to about 10g, about 9g to about 9.5g, about 9.5g to about 11.5g, about 9.5g to about 11 g, about 9.5 g to about 10.5 g, about 9.5 g to about 10 g, about 10 g to about 11.5 g, about 10 g to about 11 g, about 10 g to about 10.5 g, about 10.5 g to about 11.5 g, about 10.5 g to about 11 g, or about 11 g to about 11.5 g.

[0075] In various embodiments, the liquid pharmaceutical compositions described herein may contain about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, or about 12 g of water. In a particular embodiment, the liquid pharmaceutical compositions described herein may contain about 10 g of water.

[0076] In various embodiments, the liquid pharmaceutical formulations described herein may further comprise one or more pharmaceutically acceptable excipients.

[0077] In various embodiments, the liquid pharmaceutical formulation is (i) Furosemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) One or more pharmaceutically acceptable excipients Includes.

[0078] In various embodiments, the liquid pharmaceutical formulation is (i) Furosemide or a pharmaceutically acceptable salt thereof; (ii) A pharmaceutically acceptable buffer; (iii) one or more pharmaceutically acceptable excipients; and (iv) water Includes.

[0079] In various embodiments, one or more pharmaceutically acceptable excipients are selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methylpyrrolidone (NMP), sodium chloride, sodium hydroxide, hydrochloric acid, polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin, and combinations thereof. In specific embodiments, one or more pharmaceutically acceptable excipients are selected from the group consisting of sodium chloride, sodium hydroxide, hydrochloric acid, or combinations thereof. In specific embodiments, the liquid pharmaceutical formulation described herein further comprises sodium chloride, sodium hydroxide, hydrochloric acid, or combinations thereof.

[0080] In various embodiments, the liquid pharmaceutical formulations described herein have a pH of 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 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 particular embodiments, the liquid pharmaceutical formulations described herein have a pH of about 7 to about 8.

[0081] In various embodiments, the liquid pharmaceutical formulations described herein have a pH of about 7 to about 8, about 7.2 to about 8, about 7.4 to about 8, about 7.6 to about 8, about 7.8 to about 8, about 7 to about 7.8, about 7 to about 7.6, about 7 to about 7.4, about 7 to about 7.2, about 7.2 to about 7.8, about 7.2 to about 7.6, about 7.2 to about 7.4, about 7.4 to about 7.8, about 7.4 to about 7.6, or about 7.6 to about 7.8. In particular embodiments, the liquid pharmaceutical formulations described herein have a pH of about 7 to about 7.8.

[0082] In various embodiments, the liquid pharmaceutical formulations described herein have a pH of about 6.5, about 7, about 7.5, about 8, or about 8.5.

[0083] In various embodiments, the liquid pharmaceutical formulations described herein have a pH of about 7, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.

[0084] In various embodiments, the liquid pharmaceutical formulation is (i) furosemide or a pharmaceutically acceptable salt thereof; and (ii) A pharmaceutically acceptable buffer The liquid pharmaceutical formulation contains [ingredients] and has a pH of approximately 7 to 7.8.

[0085] In various embodiments, the liquid pharmaceutical formulation is (i) Furosemide or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable buffer; and (iii) One or more pharmaceutically acceptable excipients The liquid pharmaceutical formulation contains [ingredients] and has a pH of approximately 7 to 7.8.

[0086] In various embodiments, the total volume of the liquid pharmaceutical formulations described herein is approximately 8 mL to approximately 12 mL, approximately 8.5 mL to approximately 12 mL, approximately 9 mL to approximately 12 mL, approximately 9.5 mL to approximately 12 mL, approximately 10 mL to approximately 12 mL, approximately 10.5 mL to approximately 12 mL, approximately 11 mL to approximately 12 mL, approximately 11.5 mL to approximately 12 mL, approximately 8 mL to approximately 11.5 mL, approximately 8 mL to approximately 11 mL, approximately 8 mL to approximately 10.5 mL, approximately 8 mL to approximately 10 mL, approximately 8 mL to approximately 9.5 mL, approximately 8 mL to approximately 9 mL, approximately 8 mL to approximately 8.5 mL, approximately 8.5 mL to approximately 11.5 mL, approximately 8.5 mL to approximately 11 mL, approximately 8.5 mL to approximately 1 0.5 mL, approximately 8.5 mL to 10 mL, approximately 8.5 mL to 9.5 mL, approximately 8.5 mL to 9 mL, approximately 9 mL to 11.5 mL, approximately 9 mL to 11 mL, approximately 9 mL to 10.5 mL, approximately 9 mL to 10 mL, approximately 9 mL to 9.5 mL, approximately 9.5 mL to 11.5 mL, approximately 9.5 mL to 11 mL, approximately 9.5 mL to 10.5 mL, approximately 9.5 mL to 10 mL, approximately 10 mL to 11.5 mL, approximately 10 mL to 11 mL, approximately 10 mL to 10.5 mL, approximately 10.5 mL to 11.5 mL, approximately 10.5 mL to 11 mL, or approximately 11 mL to 11.5 mL.

[0087] In various embodiments, the total volume of the liquid pharmaceutical formulation described herein may be about 8 mL, about 8.5 mL, about 9 mL, about 9.5 mL, about 10 mL, about 10.5 mL, about 11 mL, about 11.5 mL, or about 12 mL. In a particular embodiment, the total volume of the liquid pharmaceutical formulation is about 10 mL.

[0088] In various embodiments, the liquid pharmaceutical formulation contains about 80 mg of furosemide. In specific embodiments, the liquid pharmaceutical formulation contains about 80 mg of furosemide and a total volume of about 10 mL.

[0089] In various embodiments, the liquid pharmaceutical formulation is (i) about 80 mg of furosemide; and (ii) Approximately 79 mg of tromethamine hydrochloride; and (iii) water Includes.

[0090] In various embodiments, the liquid pharmaceutical formulation is (i) about 80 mg of furosemide; and (ii) Approximately 79 mg of tromethamine hydrochloride; and (iii) water The liquid pharmaceutical preparation contains [the specified ingredient] and has a total volume of approximately 10 mL.

[0091] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients Includes.

[0092] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients The liquid pharmaceutical preparation contains [the specified ingredient] and has a total volume of approximately 10 mL.

[0093] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients The liquid pharmaceutical formulation contains [ingredients] and has a pH of approximately 7 to 7.8.

[0094] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients The liquid pharmaceutical preparation contains [ingredients] and has a pH of approximately 7 to approximately 7.8 and a total volume of approximately 10 mL.

[0095] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients selected from the group consisting of sodium chloride, sodium hydroxide, hydrochloric acid, and combinations thereof. Includes.

[0096] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients selected from the group consisting of sodium chloride, sodium hydroxide, hydrochloric acid, and combinations thereof. The liquid pharmaceutical preparation contains [the specified ingredient] and has a total volume of approximately 10 mL.

[0097] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients selected from the group consisting of sodium chloride, sodium hydroxide, hydrochloric acid, and combinations thereof. The liquid pharmaceutical formulation contains [ingredients] and has a pH of approximately 7 to 7.8.

[0098] In various embodiments, the liquid pharmaceutical formulation is (i) Approximately 80 mg of furosemide; (ii) Approximately 79 mg of tromethamine hydrochloride; (iii) water; and (iv) One or more pharmaceutically acceptable excipients selected from the group consisting of sodium chloride, sodium hydroxide, hydrochloric acid, and combinations thereof. The liquid pharmaceutical preparation contains [ingredients] and has a pH of approximately 7 to approximately 7.8 and a total volume of approximately 10 mL.

[0099] In various embodiments, the liquid pharmaceutical formulations described herein range from approximately 250 mOsM (or 250 mOsm / kg) to approximately 350 mOsM (or 350 mOsm / kg), approximately 275 mOsM (or 275 mOsm / kg) to approximately 350 mOsM (or 350 mOsm / kg), approximately 300 mOsM (or 300 mOsm / kg) to approximately 350 mOsM (or 350 mOsm / kg), approximately 325 mOsM (or 325 mOsm / kg) to approximately 350 mOsM (or 350 mOsm / kg), and approximately 250 mOsM (or 250 mOsm / kg) to approximately 325 mOsM (or 325 mOsm / kg). It has a gravimetric osmolality in the range of m / kg, approximately 250 mOsM (or 250 mOsm / kg) to approximately 300 mOsM (or 300 mOsm / kg), approximately 250 mOsM (or 250 mOsm / kg) to approximately 275 mOsM (or 275 mOsm / kg), approximately 275 mOsM (or 275 mOsm / kg) to approximately 325 mOsM (or 325 mOsm / kg), approximately 275 mOsM (or 275 mOsm / kg) to approximately 300 mOsM (or 300 mOsm / kg), or approximately 300 mOsM (or 300 mOsm / kg) to approximately 325 mOsM (or 325 mOsm / kg).

[0100] In various embodiments, the liquid pharmaceutical formulations described herein are isotonic.

[0101] In various embodiments, the liquid pharmaceutical formulation described herein further comprises a second therapeutic agent. In certain embodiments, furosemide is the only therapeutic agent present in the liquid pharmaceutical formulation described herein.

[0102] In various embodiments, a liquid pharmaceutical formulation useful for treating a condition, disease, or disorder described herein is the liquid pharmaceutical formulation described in whole by reference of U.S. Patent No. 9,884,039.

[0103] Treatment method In one embodiment, the liquid pharmaceutical formulation described herein may be used to treat or prevent a variety of conditions, diseases, and disorders in patients requiring it, including but not limited to congestion, edema, fluid overload, or hypertension. In various embodiments, the condition, disease, or disorder is selected from the group consisting of congestion, edema, fluid overload, hypertension, and combinations thereof. In a particular embodiment, the condition, disease, or disorder is congestion due to fluid overload.

[0104] In various embodiments, the patient is an adult.

[0105] In various embodiments, a method for treating a condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein to an adult from a prefilled polymer cartridge over a period of approximately 5 hours, wherein the furosemide concentration in the adult's plasma is approximately 1200 ng / mL to approximately 1850 ng / mL one hour after the first hour of administration and approximately 1000 ng / mL to approximately 1800 ng / mL one hour after the completion of administration.

[0106] In various embodiments, a method for treating congestion due to fluid overload in an adult in need thereof includes subcutaneous administration of the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours, wherein the furosemide concentration in the adult's plasma is approximately 1200 ng / mL to approximately 1850 ng / mL one hour after the first hour of administration and approximately 1000 ng / mL to approximately 1800 ng / mL one hour after the completion of administration.

[0107] In various embodiments, approximately 8 mL to 12 mL, approximately 8.5 mL to 12 mL, approximately 9 mL to 12 mL, approximately 9.5 mL to 12 mL, approximately 10 mL to 12 mL, approximately 10.5 mL to 12 mL, approximately 11 mL to 12 mL, approximately 11.5 mL to 12 mL, approximately 8 mL to 11.5 mL, approximately 8 mL to 11 mL, approximately 8 mL to 10.5 mL, approximately 8 mL to 10 mL, approximately 8 mL to 9.5 mL, approximately 8 mL to 9 mL, approximately 8 mL to 8.5 mL, approximately 8.5 mL to 11.5 mL, approximately 8.5 mL to 11 mL, approximately 8.5 mL to 10.5 mL, approximately 8.5 mL to 10 mL, approximately 8 Liquid pharmaceutical preparations with a total volume of 0.5 mL to approximately 9.5 mL, approximately 8.5 mL to approximately 9 mL, approximately 9 mL to approximately 11.5 mL, approximately 9 mL to approximately 11 mL, approximately 9 mL to approximately 10.5 mL, approximately 9 mL to approximately 10 mL, approximately 9 mL to approximately 9.5 mL, approximately 9.5 mL to approximately 11.5 mL, approximately 9.5 mL to approximately 11 mL, approximately 9.5 mL to approximately 10.5 mL, approximately 9.5 mL to approximately 10 mL, approximately 10 mL to approximately 11.5 mL, approximately 10 mL to approximately 10.5 mL, approximately 10.5 mL to approximately 11.5 mL, approximately 10.5 mL to approximately 11 mL, or approximately 11 mL to approximately 11.5 mL are administered over a period of approximately 5 hours.

[0108] In various embodiments, a liquid pharmaceutical formulation with a total volume of approximately 8 mL, 8.5 mL, 9 mL, 9.5 mL, 10 mL, 10.5 mL, 11 mL, 11.5 mL, or 12 mL is administered over approximately 5 hours. In a specific embodiment, a liquid pharmaceutical formulation with a total volume of approximately 10 mL is administered over approximately 5 hours.

[0109] In various embodiments, a method for treating a condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours. A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; and The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete.

[0110] In various embodiments, a method for treating the condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering a liquid pharmaceutical formulation from a prefilled polymer cartridge to an adult over a period of approximately 5 hours. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; and The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete.

[0111] In various embodiments, a method for treating congestion due to fluid overload in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours, A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; and The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete.

[0112] In various embodiments, this method involves subcutaneously administering a liquid pharmaceutical formulation from a prefilled polymer cartridge to an adult over a period of approximately 5 hours to treat congestion due to fluid overload in an adult in need of such treatment. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; and The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete.

[0113] In various embodiments, a method for treating a condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours. A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours, and The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0114] In various embodiments, a method for treating the condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering a liquid pharmaceutical formulation from a prefilled polymer cartridge to an adult over a period of approximately 5 hours. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours, and The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0115] In various embodiments, a method for treating a condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours. A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0116] In various embodiments, a method for treating the condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering a liquid pharmaceutical formulation from a prefilled polymer cartridge to an adult over a period of approximately 5 hours. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0117] In various embodiments, a method for treating congestion due to fluid overload in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours, A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours, and The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0118] In various embodiments, this method involves subcutaneously administering a liquid pharmaceutical formulation from a prefilled polymer cartridge to an adult over a period of approximately 5 hours to treat congestion due to fluid overload in an adult in need of such treatment. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours, and The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0119] In various embodiments, a method for treating congestion due to fluid overload in an adult in need thereof, comprising subcutaneously administering the liquid pharmaceutical formulation described herein from a prefilled polymer cartridge to an adult over a period of approximately 5 hours, A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0120] In various embodiments, this method involves subcutaneously administering a liquid pharmaceutical formulation from a prefilled polymer cartridge to an adult over a period of approximately 5 hours to treat congestion due to fluid overload in an adult in need of such treatment. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide; A liquid pharmaceutical preparation with a total volume of approximately 10 mL is administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0121] In various embodiments, the liquid pharmaceutical formulation is administered to adults from a pre-filled polymer cartridge using a 5-hour biphasic delivery profile.

[0122] In various embodiments, the 5-hour biphasic delivery profile involves administering approximately 30 mg of furosemide over the first hour, and approximately 12.5 mg of furosemide over each hour of the following 4 hours.

[0123] In various embodiments, a method for treating the condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering a liquid pharmaceutical formulation from a pre-filled polymer cartridge to an adult using a 5-hour biphasic delivery profile, The liquid pharmaceutical preparation contains approximately 80 mg of furosemide, approximately 79 mg of tromethamine hydrochloride, and water, with a pH of approximately 7 to 7.8 and a total volume of 10 mL; The 5-hour biphasic delivery profile involves administering approximately 30 mg of furosemide over the first hour, and approximately 12.5 mg of furosemide over each of the following four hours, with a total volume of approximately 10 mL of liquid pharmaceutical formulation being administered over approximately 5 hours. The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is complete should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0124] In various embodiments, a method for treating the condition, disease, or disorder described herein in an adult in need thereof, comprising subcutaneously administering a liquid pharmaceutical formulation from a pre-filled polymer cartridge to an adult using a 5-hour biphasic delivery profile, The liquid pharmaceutical preparation contains approximately 80 mg of furosemide, approximately 79 mg of tromethamine hydrochloride, and water, with a pH of approximately 7 to 7.8 and a total volume of 10 mL; The 5-hour biphasic delivery profile involves administering approximately 30 mg of furosemide over the first hour, and approximately 12.5 mg of furosemide over each of the following four hours, with a total volume of approximately 10 mL of the liquid pharmaceutical formulation being administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0125] In various embodiments, a method for treating congestion due to fluid overload in adults in need thereof involves subcutaneously administering a liquid pharmaceutical formulation to an adult from a pre-filled polymer cartridge using a 5-hour biphasic delivery profile. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide, approximately 79 mg of tromethamine hydrochloride, and water, with a pH of approximately 7 to 7.8 and a total volume of 10 mL; The 5-hour biphasic delivery profile involves administering approximately 30 mg of furosemide over the first hour, and approximately 12.5 mg of furosemide over each of the following four hours, with a total volume of approximately 10 mL of liquid pharmaceutical formulation being administered over approximately 5 hours. The plasma concentration of furosemide in adults should be approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete. The total urine volume of an adult during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of an adult one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration should be between approximately 1500 mL and 4000 mL. The total urinary sodium excretion approximately one hour after administration is complete should be approximately 375 mmol to 500 mmol. The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete should be approximately 450 mmol to 550 mmol. It is one or more of the following.

[0126] In various embodiments, a method for treating congestion due to fluid overload in adults in need thereof involves subcutaneously administering a liquid pharmaceutical formulation to an adult from a pre-filled polymer cartridge using a 5-hour biphasic delivery profile. The liquid pharmaceutical preparation contains approximately 80 mg of furosemide, approximately 79 mg of tromethamine hydrochloride, and water, with a pH of approximately 7 to 7.8 and a total volume of 10 mL; The 5-hour biphasic delivery profile involves administering approximately 30 mg of furosemide over the first hour, and approximately 12.5 mg of furosemide over each of the following four hours, with a total volume of approximately 10 mL of the liquid pharmaceutical formulation being administered over approximately 5 hours; The plasma concentration of furosemide in adults is approximately 1200 ng / mL to 1850 ng / mL one hour after administration, and approximately 1000 ng / mL to 1800 ng / mL one hour after administration is complete; The total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, and the average hourly urine volume of adults one hour after administration is completed is approximately 250 mL to 550 mL; The total urine volume of an adult approximately one hour after administration is about 1500 mL to 4000 mL; The total urinary sodium excretion approximately one hour after administration is complete is about 375 mmol to about 500 mmol; The maximum total urine volume in adults approximately one hour after administration is complete is approximately 2800 mL to 4000 mL; and The maximum total urinary sodium excretion approximately one hour after administration is complete is about 450 mmol to 550 mmol.

[0127] In various embodiments, the furosemide concentration in adult plasma was approximately 1200 ng / mL to 1850 ng / mL, 1250 ng / mL to 1850 ng / mL, 1300 ng / mL to 1850 ng / mL, 1350 ng / mL to 1850 ng / mL, 1400 ng / mL to 1850 ng / mL, 1450 ng / mL to 1850 ng / mL, 1500 ng / mL to 1850 ng / mL, 1550 ng / mL to 1850 ng / mL, 1600 ng / mL to 1850 ng / mL, and 1650 ng / mL after the first hour of administration. L ~ about 1850ng / mL, about 1700ng / mL - about 1850ng / mL, about 1750ng / mL - about 1850ng / mL, about 1800ng / mL - about 1850ng / mL, about 1200ng / mL - about 1800ng / mL, about 1200ng / mL - about 1750ng / mL, Approximately 1200ng / mL to approximately 1700ng / mL, approximately 1200ng / mL to approximately 1650ng / mL, approximately 1200ng / mL to approximately 1600ng / mL, approximately 1200ng / mL to approximately 1550ng / mL, approximately 1200ng / mL to approximately 1500ng / mL, approximately 1200ng / mL to approximately 1 450ng / mL, about 1200ng / mL to about 1400ng / mL, about 1200ng / mL to about 1350ng / mL, about 1200ng / mL to about 1300ng / mL, about 1200ng / mL to about 1250ng / mL, about 1250ng / mL to about 1800ng / mL, about 125 0ng / mL~about 1750ng / mL, about 1250ng / mL~about 1700ng / mL, about 1250ng / mL~about 1650ng / mL, about 1250ng / mL~about 1600ng / mL, about 1250ng / mL~about 1550ng / mL, about 1250ng / mL~about 1500n g / mL, about 1250ng / mL to about 1450ng / mL, about 1250ng / mL to about 1400ng / mL, about 1250ng / mL to about 1350ng / mL, about 1250ng / mL to about 1300ng / mL, about 1300ng / mL to about 1800ng / mL, about 1300ng / mL mL~about 1750ng / mL, about 1300ng / mL~about 1700ng / mL, about 1300ng / mL~about 1650ng / mL, about 1300ng / mL~about 1600ng / mL, about 1300ng / mL~about 1550ng / mL, about 1300ng / mL~about 1500ng / mL,Approximately 1300 ng / mL to approximately 1450 ng / mL, approximately 1300 ng / mL to approximately 1400 ng / mL, approximately 1300 ng / mL to approximately 1350 ng / mL, approximately 1350 ng / mL to approximately 1800 ng / mL, approximately 1350 ng / mL to approximately 1750 ng / mL, approximately 1350 ng / mL to approximately 1700 ng / mL, approximately 1350 ng / mL to approximately 1650 ng / mL, approximately 1350 ng / mL to approximately 1600 ng / mL, approximately 1350 ng / mL to approximately 1550 ng / mL, approximately 1350 ng / mL to approximately 1500 ng / mL, approximately 1350 ng / mL to approximately 1450 ng / mL, approximately 1350 ng / mL ~ approx. 1400 ng / mL, approx. 1400 ng / mL ~ approx. 1800 ng / mL, approx. 1400 ng / mL ~ approx. 1750 ng / mL, approx. 1400 ng / mL ~ approx. 1700 ng / mL, approx. 1400 ng / mL ~ approx. 1650 ng / mL, approx. 1400 ng / mL ~ approx. 1600 ng / mL, approx. 1400 ng / mL ~ approx. 1550 ng / mL, approx. 1400 ng / mL ~ approx. 1500 ng / mL, approx. 1400 ng / mL ~ approx. 1450 ng / mL, approx. 1450 ng / mL ~ approx. 1800 ng / mL, approx. 1450 ng / mL ~ approx. 1750 ng / mL, approx. 1450 ng / mL ~ Approximately 1700 ng / mL, approximately 1450 ng / mL to approximately 1650 ng / mL, approximately 1450 ng / mL to approximately 1600 ng / mL, approximately 1450 ng / mL to approximately 1550 ng / mL, approximately 1450 ng / mL to approximately 1500 ng / mL, approximately 1500 ng / mL to approximately 1800 ng / mL, approximately 1500 ng / mL to approximately 1750 ng / mL, approximately 1500 ng / mL to approximately 1700 ng / mL, approximately 1500 ng / mL to approximately 1650 ng / mL, approximately 1500 ng / mL to approximately 1600 ng / mL, approximately 1500 ng / mL to approximately 1550 ng / mL, approximately 1550 ng / mL to approximately 1800 ng / mL ng / mL, approximately 1550 ng / mL to approximately 1750 ng / mL, approximately 1550 ng / mL to approximately 1700 ng / mL, approximately 1550 ng / mL to approximately 1650 ng / mL, approximately 1550 ng / mL to approximately 1600 ng / mL, approximately 1600 ng / mL to approximately 1800 ng / mL, approximately 1600 ng / mL to approximately 1750 ng / mL, approximately 1600 ng / mL to approximately 1700 ng / mL, approximately 1600 ng / mL to approximately 1650 ng / mL, approximately 1650 ng / mL to approximately 1800 ng / mL, approximately 1650 ng / mL to approximately 1750 ng / mL, approximately 1650 ng / mL to approximately 1700 ng / mLThe range is approximately 1700 ng / mL to 1800 ng / mL, approximately 1700 ng / mL to 1750 ng / mL, or approximately 1750 ng / mL to 1800 ng / mL.

[0128] In certain embodiments, the furosemide concentration in adult plasma is approximately 1200 ng / mL, 1250 ng / mL, 1300 ng / mL, 1350 ng / mL, 1400 ng / mL, 1450 ng / mL, 1500 ng / mL, 1550 ng / mL, 1600 ng / mL, 1650 ng / mL, 1700 ng / mL, 1750 ng / mL, 1800 ng / mL, or 1850 ng / mL one hour after administration.

[0129] In various embodiments, the furosemide concentration in adult plasma approximately 1 hour after administration is about 1000 ng / mL to 1800 ng / mL, about 1100 ng / mL to 1800 ng / mL, about 1200 ng / mL to 1800 ng / mL, about 1300 ng / mL to 1800 ng / mL, about 1400 ng / mL to 1800 ng / mL, about 1500 ng / mL to 1800 ng / mL, about 1600 ng / mL to 1800 ng / mL, about 1700 ng / mL to 1800 ng / mL, and about 1000 ng / mL to 17 00ng / mL, about 1000ng / mL to about 1600ng / mL, about 1000ng / mL to about 1500ng / mL, about 1000ng / mL to about 1400ng / mL, about 1000ng / mL to about 1300ng / mL, about 1000ng / mL to about 1200ng / mL mL, about 1000ng / mL to about 1100ng / mL, about 1100ng / mL to about 1700ng / mL, about 1100ng / mL to about 1600ng / mL, about 1100ng / mL to about 1500ng / mL, about 1100ng / mL to about 1400ng / mL, about 11 00ng / mL~about 1300ng / mL, about 1100ng / mL~about 1200ng / mL, about 1200ng / mL~about 1700ng / mL, about 1200ng / mL~about 1600ng / mL, about 1200ng / mL~about 1500ng / mL, about 1200ng / mL mL~about 1400ng / mL, about 1200ng / mL~about 1300ng / mL, about 1300ng / mL~about 1700ng / mL, about 1300ng / mL~about 1600ng / mL, about 1300ng / mL~about 1500ng / mL, about 1300ng / mL~about 14 The ranges are 00 ng / mL, approximately 1400 ng / mL to approximately 1700 ng / mL, approximately 1300 ng / mL to approximately 1600 ng / mL, approximately 1300 ng / mL to approximately 1500 ng / mL, approximately 1300 ng / mL to approximately 1400 ng / mL, approximately 1400 ng / mL to approximately 1700 ng / mL, approximately 1400 ng / mL to approximately 1600 ng / mL, approximately 1400 ng / mL to approximately 1500 ng / mL, approximately 1500 ng / mL to approximately 1700 ng / mL, approximately 1500 ng / mL to approximately 1600 ng / mL, or approximately 1600 ng / mL to approximately 1700 ng / mL.

[0130] In various embodiments, the furosemide concentration in adult plasma is approximately 1000 ng / mL, 1100 ng / mL, 1200 ng / mL, 1300 ng / mL, 1400 ng / mL, 1500 ng / mL, 1600 ng / mL, 1700 ng / mL, or 1800 ng / mL about one hour after administration is complete.

[0131] In various embodiments, the furosemide concentration in adult plasma is 500 ng / mL or higher, 600 ng / mL or higher, 700 ng / mL or higher, 800 ng / mL or higher, 900 ng / mL or higher, 1000 ng / mL or higher, 1100 ng / mL or higher, 1200 ng / mL or higher, 1300 ng / mL or higher, 1400 ng / mL or higher, 1500 ng / mL or higher, 1600 ng / mL or higher, 1700 ng / mL or higher, or 1800 ng / mL or higher, from 1 hour after the first hour of administration until approximately 1 hour after the completion of administration. In a specific embodiment, the furosemide concentration in adult plasma is 1000 ng / mL or higher from 1 hour after the first hour of administration until approximately 1 hour after the completion of administration.

[0132] In various embodiments, the furosemide concentration in adult plasma is 500 ng / mL or higher, 600 ng / mL or higher, 700 ng / mL or higher, 800 ng / mL or higher, 900 ng / mL or higher, 1000 ng / mL or higher, 1100 ng / mL or higher, 1200 ng / mL or higher, 1300 ng / mL or higher, 1400 ng / mL or higher, or 1500 ng / mL or higher from the first hour after administration to about 3 hours after the completion of administration.

[0133] In various embodiments, the total urine volume of adults during the first hour after administration is approximately 150 mL to 450 mL, 200 mL to 450 mL, 250 mL to 450 mL, 300 mL to 450 mL, 350 mL to 450 mL, 400 mL to 450 mL, 150 mL to 400 mL, 150 mL to 350 mL, 150 mL to 300 mL, and 150 mL to 450 mL. The sizes are approximately 250 mL, approximately 150 mL to 200 mL, approximately 200 mL to 400 mL, approximately 200 mL to 350 mL, approximately 200 mL to 300 mL, approximately 200 mL to 250 mL, approximately 250 mL to 400 mL, approximately 250 mL to 350 mL, approximately 250 mL to 300 mL, approximately 300 mL to 400 mL, approximately 350 mL to 400 mL, or approximately 350 mL to 400 mL.

[0134] In various embodiments, the total urine volume of an adult during the first hour after administration is approximately 150 mL, 200 mL, 250 mL, 300 mL, 350 mL, 400 mL, or 450 mL.

[0135] In various embodiments, the total urine volume of an adult during the first hour after administration is 50 mL or more, 75 mL or more, 100 mL or more, 125 mL or more, 150 mL or more, 175 mL or more, 200 mL or more, 225 mL or more, 250 mL or more, 275 mL or more, 300 mL or more, 325 mL or more, 350 mL or more, 375 mL or more, 400 mL or more, or 425 mL or more.

[0136] In various embodiments, the average hourly urine volume of adults one hour after administration is approximately 250 mL to 500 mL, 300 mL to 500 mL, 350 mL to 500 mL, 400 mL to 500 mL, 450 mL to 500 mL, 250 mL to 450 mL, 250 mL to 400 mL, 250 mL to 350 mL, 250 mL to 300 mL, 300 mL to 450 mL, 300 mL to 400 mL, 300 mL to 350 mL, 350 mL to 450 mL, 350 mL to 400 mL, or 400 mL to 450 mL.

[0137] In various embodiments, the average hourly urine volume of adults one hour after administration is approximately 250 mL, 300 mL, 350 mL, 400 mL, 450 mL, or 500 mL.

[0138] In various embodiments, the average hourly urine volume of adults one hour after administration is 200 mL or more, 225 mL or more, 250 mL or more, 275 mL or more, 300 mL or more, 325 mL or more, 350 mL or more, 375 mL or more, 400 mL or more, 425 mL or more, or 450 mL or more.

[0139] In various embodiments, the total urine volume of an adult approximately one hour after payment is approximately 1500 mL to 4000 mL, 2000 mL to 4000 mL, 2500 mL to 4000 mL, 3000 mL to 4000 mL, 3500 mL to 4000 mL, 1500 mL to 3500 mL, 1500 mL to 3000 mL, 1500 mL to 2500 mL, 1500 mL to 2000 mL, 2000 mL to 3500 mL, 2000 mL to 3000 mL, 2000 mL to 2500 mL, 2500 mL to 3500 mL, or 3000 mL to 3500 mL.

[0140] In various embodiments, the total urine volume of an adult approximately one hour after administration is approximately 1500 mL, 2000 mL, 2500 mL, 3000 mL, 3500 mL, or 4000 mL.

[0141] In various embodiments, the total urine volume of an adult approximately one hour after administration is 1000 mL or more, 1100 mL or more, 1200 mL or more, 1300 mL or more, 1400 mL or more, 1500 mL or more, 1600 mL or more, 1700 mL or more, 1800 mL or more, 1900 mL or more, 2000 mL or more, 2100 mL or more, 2200 mL or more, 2300 mL or more, 2400 mL or more, 2500 mL or more, 2600 mL or more, 2700 mL or more, 2800 mL or more, 2900 mL or more, 3000 mL or more, 3100 mL or more, 3200 mL or more, 3300 mL or more, 3400 mL or more, 3500 mL or more, 3600 mL or more, 3700 mL or more, 3800 mL or more, or 3900 mL or more.

[0142] In various embodiments, the total urinary sodium excretion approximately one hour after administration is approximately 375 mmol to 500 mmol, approximately 400 mmol to 500 mmol, approximately 425 mmol to 500 mmol, approximately 450 mmol to 500 mmol, approximately 475 mmol to 500 mmol, approximately 375 mmol to 475 mmol, approximately 375 mmol to 450 mmol, approximately 375 mmol to 425 mmol, approximately 425 mmol to 475 mmol, approximately 425 mmol to 450 mmol, or approximately 450 mmol to 475 mmol.

[0143] In various embodiments, the total urinary sodium excretion approximately one hour after administration is approximately 375 mmol, approximately 400 mmol, approximately 425 mmol, approximately 450 mmol, approximately 475 mmol, or approximately 500 mmol.

[0144] In various embodiments, the total urinary sodium excretion in adults approximately one hour after administration is 300 mmol or more, 325 mmol or more, 350 mmol or more, 375 mmol or more, 400 mmol or more, 425 mmol or more, 450 mmol or more, or 475 mmol or more.

[0145] In various embodiments, the maximum total urine volume of adults approximately one hour after administration is approximately 2800 mL to 4000 mL, 2900 mL to 4000 mL, 3000 mL to 4000 mL, 3100 mL to 4000 mL, 3200 mL to 4000 mL, 3300 mL to 4000 mL, 3400 mL to 4000 mL, 3500 mL to 4000 mL, 3600 mL to 4000 mL, 3700 mL to 4000 mL, 3800 mL to 4000 mL, 3900 mL to 4000 mL, 2800 mL to 3900 mL, and 2800 mL. mL ~ approx. 3800 mL, approx. 2800 mL ~ approx. 3700 mL, approx. 2800 mL ~ approx. 3600 mL, approx. 2800 mL ~ approx. 3500 mL, approx. 2800mL to 3000mL, 2800mL to 2900mL, 2900mL to 3900mL, 2900mL to 3800mL, 2900mL to 3700mL, 2900mL to 3600mL, 2900mL to 3500mL, 2900mL to 3400m L, about 2900mL to about 3300mL, about 2900mL to about 3200mL, about 2900mL to about 3100mL, about 2900mL to about 3000mL, about 3000mL to about 3900mL, about 3000mL to about 3800mL, about 3000mL to about 3700mL, about 3000mL to about 3 600mL, about 3000mL to about 3500mL, about 3000mL to about 3400mL, about 3000mL to about 3300mL, about 3000mL to about 3200mL, about 3000mL to about 3100mL, about 3100mL to about 3900mL, about 3100mL to about 3800mL, about 3100mL ~3700mL, 3100mL~3600mL, 3100mL~3500mL, 3100mL~3400mL, 3100mL~3300mL, 3100mL~3200mL, 3200mL~3900mL, 3200mL~3800mL, 32 00mL~3700mL, 3200mL~3600mL, 3200mL~3500mL, 3200mL~3400mL, 3200mL~3300mL, 3300mL~3900mL, 3300mL~3800mL, 3300mL~3700mL,Approximately 3300mL to approximately 3600mL, approximately 3300mL to approximately 3500mL, approximately 3300mL to approximately 3400mL, approximately 3400mL to approximately 3900mL, approximately 3400mL to approximately 3800mL, about 3400mL to about 3700mL, about 3400mL to about 3600mL, about 3400mL to about 3500mL, about 3500mL to about 3900mL, about 3 The available sizes are approximately 500mL to 3800mL, 3500mL to 3700mL, 3500mL to 3600mL, 3600mL to 3900mL, 3600mL to 3800mL, 3600mL to 3700mL, 3700mL to 3900mL, 3700mL to 3800mL, or 3800mL to 3900mL.

[0146] In various embodiments, the maximum total urine volume of an adult approximately one hour after administration is approximately 2800 mL, 2900 mL, 3000 mL, 3100 mL, 3200 mL, 3300 mL, 3400 mL, 3500 mL, 3600 mL, 3700 mL, 3800 mL, 3900 mL, or 4000 mL.

[0147] In various embodiments, the maximum total urine volume of an adult approximately one hour after administration is 2000 mL or more, 2100 mL or more, 2200 mL or more, 2300 mL or more, 2400 mL or more, 2500 mL or more, 2600 mL or more, 2700 mL or more, 2800 mL or more, 2900 mL or more, 3000 mL or more, 3100 mL or more, 3200 mL or more, 3300 mL or more, 3400 mL or more, 3500 mL or more, 3600 mL or more, 3700 mL or more, 3800 mL or more, 3900 mL or more, or 4000 mL or more.

[0148] In various embodiments, the maximum total urinary sodium excretion approximately one hour after administration is approximately 450 mmol to 550 mmol, approximately 475 mmol to 550 mmol, approximately 500 mmol to 550 mmol, approximately 525 mmol to 550 mmol, approximately 450 mmol to 525 mmol, approximately 450 mmol to 500 mmol, approximately 450 mmol to 475 mmol, approximately 475 mmol to 525 mmol, approximately 475 mmol to 500 mmol, or approximately 500 mmol to 525 mmol.

[0149] In various embodiments, the maximum total urinary sodium excretion approximately one hour after administration is approximately 450 mmol, 475 mmol, 500 mmol, 525 mmol, or 550 mmol.

[0150] In various embodiments, the maximum total urinary sodium excretion approximately one hour after administration is 400 mmol or more, 425 mmol or more, 450 mmol or more, 475 mmol or more, 500 mmol or more, or 525 mmol or more.

[0151] In various embodiments, the method further includes warning an adult if the total volume of 10 mL of the liquid pharmaceutical formulation has not been administered within a 5-hour delivery profile. In certain embodiments, the warning includes visualizing to the adult that the entire 10 mL total volume of the liquid pharmaceutical formulation has not been delivered from the polymer prefilled cartridge.

[0152] In various embodiments, adults have worsening New York Heart Association (NYHA) class II and class III heart failure.

[0153] In various embodiments, adults exhibit a reduced response to oral diuretics.

[0154] kit In one embodiment, the present invention provides a kit for treating or preventing various conditions, diseases, and disorders, including but not limited to congestion, edema, fluid overload, or hypertension, in patients who require such treatment or prevention. In a particular embodiment, the condition, disease, or disorder is selected from the group consisting of congestion, edema, fluid overload, hypertension, and combinations thereof. In a particular embodiment, the condition, disease, or disorder is congestion due to fluid overload.

[0155] In various embodiments, the present invention provides polymer prefilled cartridges containing the liquid pharmaceutical formulations described herein.

[0156] In various embodiments, polymer prefilled cartridges are associated with body-worn delivery devices.

[0157] In various embodiments, the polymer prefilled cartridge is a disposable cartridge.

[0158] In various embodiments, a disposable polymer prefilled cartridge may be associated with a body-worn delivery device that uses a 5-hour biphasic delivery profile for subcutaneous administration of a liquid pharmaceutical formulation to an adult, wherein the disposable polymer prefilled cartridge contains the liquid pharmaceutical formulation, and the liquid pharmaceutical formulation is isotonic and has a pH of about 7 to about 7.8. Approximately 80 mg of furosemide; Approximately 79 mg of tromethamine hydrochloride; Optionally, one or more other pharmaceutically acceptable excipients; and A quantity of water that makes a total volume of 10 mL It consists of.

[0159] In various embodiments, one or more other pharmaceutically acceptable excipients include sodium chloride, sodium hydroxide, hydrochloric acid, or a combination thereof.

[0160] In various embodiments, the kit includes, for example, a pre-filled polymer cartridge and instructions for use of a body-worn delivery device. [Examples]

[0161] Examples The present invention, as generally described herein, will be more readily understood by referring to the following examples. This is intended solely to illustrate specific aspects and embodiments of the invention and is not intended to limit the invention.

[0162] Example 1. Manufacturing process of furosemide preparation (8 mg / mL) The following example describes the manufacturing process for preparing an 8 mg / mL furosemide liquid formulation.

[0163] The excipients (sodium chloride and tromethamine hydrochloride) and the active pharmaceutical ingredient furosemide USP / EP were dispensed into individual containers in the amounts necessary to achieve final concentrations of 8 mg / mL, 5.84 mg / mL, and 7.88 mg / mL of furosemide, sodium chloride, and tromethamine hydrochloride, respectively.

[0164] The specified amount of water for injection (WFI) and the excipients, tromethamine hydrochloride and sodium chloride, were added to a mixing container of appropriate size. The container was closed and the excipients were mixed. Sodium hydroxide (NaOH) solution was added to the container and mixed.

[0165] pH samples were collected, and the solutions were adjusted to pH 8.50 ± 0.10 with hydrochloric acid (HCl) or additional NaOH as needed. If adjustment was necessary, the solutions were mixed after each addition and then sampled again.

[0166] Next, furosemide USP / NF / EP was added to the excipient solution, and then the dispensing container was rinsed with water-based filtration (WFI). The container was closed, the lid was placed over the container to protect the active pharmaceutical ingredient from light, and the solution was mixed. If the API was not dissolved after mixing, NaOH solution was added to the solution to promote dissolution.

[0167] pH samples were collected, and the solutions were adjusted to pH 7.40 ± 0.10 with HCl or additional NaOH solution.

[0168] After pH adjustment, WFI was added to the resulting solution to achieve the final weight. Before continuing filtration, samples were collected after final mixing for assay, pH, gravimetric osmolality, and visual inspection.

[0169] The furosemide liquid formulation was first filtered through a 0.45 μm bioburden reduction filter, and then sterilized by filtration through a double 0.22 μm filter. The furosemide liquid formulation was then filled into 10 mL polymer cartridges and sealed using a sterile process.

[0170] Example 2. Pharmacokinetic and pharmacodynamic properties of subcutaneous administration of furosemide liquid formulation. Research purpose The objectives of this study were to characterize the pharmacokinetics of furosemide administered by continuous subcutaneous infusion using a biphasic delivery profile, and to estimate the absolute bioavailability of furosemide administered by continuous subcutaneous infusion compared to an equivalent dose of furosemide administered by intravenous bolus.

[0171] Research design and duration This study was an open-label, single-center, single-dose, randomized, two-way (2-period) crossover study involving 16 adults previously diagnosed with mild to moderate heart failure (NYHA class II / III) and concurrently receiving oral furosemide therapy at doses of 40 mg / day or higher.

[0172] Each participant completed the screening, baseline, treatment, and follow-up phases. The screening phase was conducted on an outpatient basis 14–3 days prior to baseline. Participants were instructed to maintain a sodium diet of <2 gm within 3 days prior to baseline. Baseline (Day 0) consisted of admission to the Clinical Research Unit (CRU) and final qualification assessment. The treatment phase included two crossover periods separated by a 7-day outpatient fluid reequilibrium washout. After CRU admission, participants discontinued oral furosemide at least 24 hours prior to administration of the study drug in each crossover period. Participants were randomly assigned in a 1:1 ratio to one of two treatment sequences and received both intravenous (IV) and subcutaneous (SC) furosemide during the crossover period (i.e., IV followed by SC or vice versa). Participants remained in the CRU throughout each crossover period during the treatment phase up to 24 hours after administration of the study drug, and were subsequently discharged if safety parameters were acceptable to the investigator. Oral furosemide therapy was resumed after crossover period 1 (i.e., during the 7-day fluid reequilibrium washout) and at discharge after crossover period 2. The follow-up period occurred 7(±1) days after discharge from the CRU following crossover period 2, at which point participation in the study was completed.

[0173] Research drug Intravenous furosemide (IV furosemide): Hospira, furosemide injection, solution 10 mg / mL (NDA018667) (total dose = 80 mg) is administered intravenously as a bolus injection of 40 mg over 2 minutes, followed by a second dose of 40 mg over 2 minutes 120 minutes later (reference treatment).

[0174] Subcutaneous furosemide (SC furosemide): Furosemide injection solution, 8 mg / mL (total dose = 80 mg), administered subcutaneously at a rate of 30 mg over the first hour, followed by 12.5 mg per hour over the next 4 hours (experimental treatment).

[0175] The study drug was administered at time zero (0) for the purpose of recording drug administration, PK plasma sampling, urine collection, and AE monitoring. Following the procedural schedule, continuous venous blood samples were collected over 24 hours for the quantification of furosemide in plasma. Urine was collected from spontaneous urination every hour for the first 2 hours, every 2 hours until 12 hours post-administration, and then every 6 hours until 24 hours post-administration, for the purpose of measuring total urine volume and sodium concentration over time. Plasma samples were processed and stored according to the protocol instructions and analyzed using valid bioanalytical methods.

[0176] Number of subjects The number of subjects in this crossover study (i.e., n=16) was intended to provide a reasonably accurate estimate of systemic exposure to furosemide after IV and SC furosemide treatment. In one study, the mean coefficient of variation of furosemide AUCinf after 20 mg administration via intravenous, oral, and sublingual routes was 50%, 25%, and 33%, respectively (Haegeli, L., et al., Sublingual administration of furosemide: new application of an old drug. Br J Clin Pharmacol., 2007. 64(6): p. 804-9. Epub 2007 Sep 13). Assuming a relative bioavailability equal to 1 and within-subject variability of AUC within the range of 25–50%, an estimated 90% CI for the ratio of AUC between the study treatment and the reference treatment was obtained using a sample size of 12–16 subjects. A minimum of 12 subjects were expected to complete the study. When the number of participants who completed the study approached the minimum number, the sponsor and the principal investigator had the discretion to enroll additional participants.

[0177] Target group Patients enrolled were those with a history of treatment for heart failure (NYHA class II / III) for at least three months and requiring continuous treatment with oral furosemide at a dose of 40 mg or more per day for at least 30 days. Open to men and women aged 18 and over. Symptoms of chronic dose overload requiring oral furosemide at a dose of 40 mg or more for at least 30 days. There have been no hospitalizations due to acute decompensated heart failure (ADHF) in the past four weeks. The subjects discontinued oral furosemide more than 24 hours before administration of the study drug.

[0178] Pharmacokinetic analysis Individual pharmacokinetic parameters of furosemide were summarized using descriptive statistics. For both SC furosemide (test) and IV furosemide (reference), pharmacokinetic parameters such as observed maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve (AUClast) from time 0 (pre-administration) to the last quantifiable time point (AUCinf), AUC from time 0 (pre-administration) to infinity (AUCinf), elimination rate constant (λz), final elimination half-life (t1 / 2), and apparent systematic clearance (CL / F) for SC furosemide and IV furosemide, apparent systematic volume of distribution (Vz / F) for SC furosemide and IV furosemide (V) were calculated using non-compartmental analysis. The absolute bioavailability of SC furosemide was calculated based on the AUCinf of IV furosemide (reference) and SC furosemide (test). Compartment modeling of pharmacokinetic data was performed where necessary.

[0179] result Table 1 summarizes the individual efficacy response data (urine volume (mL) at 1, 6, and 8 hours post-administration; cumulative urine volume (mL) at 6 and 8 hours post-administration; cumulative sodium excretion (mmol) at 6 and 8 hours post-administration; plasma furosemide concentration (ng / mL) at 1, 5, 6, and 8 hours post-administration) for patients who received SC furosemide (80 mg intravenous injection). Table 2 summarizes the individual efficacy response data (urine volume (mL) at 1, 6, and 8 hours post-administration; cumulative urine volume (mL) at 6 and 8 hours post-administration; cumulative sodium excretion (mmol) at 6 and 8 hours post-administration; plasma furosemide concentration (ng / mL) at 1, 5, 6, and 8 hours post-administration) for patients who received IV furosemide (2-40 mg intravenous injection).

[0180] [Table 1]

[0181] [Table 2]

[0182] [Table 3]

[0183] [Table 4]

[0184] Further analysis of individual efficacy response data for SC furosemide revealed, surprisingly, that both the maximum hourly urine output and hourly sodium excretion were achieved in patients with a furosemide plasma concentration of approximately 1000 ng / mL (Figures 1 and 2). Further increases in furosemide plasma concentration did not result in a corresponding increase in hourly urine output or hourly sodium excretion.

[0185] Embedding by reference The entirety of each patent and scientific paper disclosure referenced herein is incorporated by reference for all purposes.

[0186] Equal portions This disclosure can be embodied in other specific forms without departing from its intent or essential features. Therefore, the prior embodiments are considered in all respects to the disclosure described herein as illustrative rather than restrictive. Accordingly, the scope of this disclosure is indicated by the appended claims rather than by the prior description, and all variations falling within the meaning and scope of the claims are intended to be included therein.

Claims

1. A disposable polymer prefilled cartridge, which can be associated with a body-worn delivery device, uses a 5-hour biphasic delivery profile for subcutaneous administration of a liquid pharmaceutical formulation to an adult, wherein the disposable polymer prefilled cartridge contains the liquid pharmaceutical formulation, and the liquid pharmaceutical formulation is isotonic and has a pH of about 7 to about 7.

8. Approximately 80 mg of furosemide; Approximately 79 mg of tromethamine hydrochloride; One or more other pharmaceutically acceptable excipients selected from the group consisting of ethanol, benzyl alcohol, glycerin, N-methylpyrrolidone (NMP), polyethylene glycol (PEG), propylene glycol, polysorbate, polyvinylpyrrolidone (PVP), cyclodextrin and combinations thereof; and A disposable polymer prefilled cartridge containing enough water to form a total volume of 10 mL.

2. The polymer prefilled cartridge according to claim 1, wherein the liquid pharmaceutical preparation further comprises sodium chloride, sodium hydroxide, hydrochloric acid, or a combination thereof.

3. The polymer prefilled cartridge according to claim 1, wherein the one or more pharmaceutically acceptable excipients are benzyl alcohol, N-methylpyrrolidone (NMP), and combinations thereof.

4. A kit comprising a disposable polymer prefilled cartridge and instructions for use according to any one of claims 1 to 3.

5. The kit according to claim 4, further comprising a body-worn delivery device.

6. A kit according to claim 4 or 5 for the treatment or prevention of congestion, edema, fluid overload, hypertension, and combinations thereof.

7. A kit according to any one of claims 4 to 6 for the treatment or prevention of congestion due to excess body fluid.

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