Furosemide pharmaceutical composition and use thereof

Abstract

Disclosed are a pharmaceutical composition and a method of administering the pharmaceutical composition to a patient suffering from edema, heart failure, kidney disease or liver disease or having symptoms thereof. The pharmaceutical composition comprises furosemide or a pharmaceutically acceptable salt, hydrate or ester thereof and cyclodextrin.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 62 / 788,244, filed on January 4, 2019, the contents of which are incorporated herein by reference in their entirety. Field of the Invention

[0003] The present disclosure relates to a pharmaceutical composition comprising furosemide and cyclodextrin and a method of administering the pharmaceutical composition to a patient. More specifically, the present disclosure relates to a pharmaceutical composition comprising furosemide and cyclodextrin and uses thereof,

[0004] background

[0005] Furosemide is a benzylsulfonamide-furan that is used as a potent loop diuretic with a rapid onset of action and a short duration of action for the treatment of hypertension, edema, and edema-related conditions, such as congestive heart failure, cirrhosis or liver failure, and other renal diseases. Furosemide is typically administered orally for chronic treatment. In some cases, it is administered parenterally to patients with decompensated heart failure or other forms of advanced edema. Parenteral administration is typically performed in the form of a bolus administration by intravenous infusion.

[0006] Furosemide is poorly soluble. Typical injections are alkaline and contain 8-10 mg furosemide / mL, requiring 8-10 mL to administer a typical clinical dose of 80 mg. Increasing furosemide concentration to reduce administration volume may result in precipitation, affecting drug formulation stability and presenting additional challenges. Lowering pH may also result in precipitation.

[0007] Furthermore, high pH in pharmaceutical formulations precludes or limits certain clinical uses, including subcutaneous administration and use in certain infusion fluids or infusion systems where precipitation may occur.

[0008] Therefore, in order to provide a therapeutic dose of furosemide to a patient by subcutaneous injection or small volume infusion, a pharmaceutical composition of furosemide is required to have a higher solubility at physiological pH to reduce drug irritation and effective drug delivery with minimal or negligible adverse toxicological effects.

[0009] Additionally, furosemide formulations that are stable and suitable for administration at neutral pH can be combined with other drugs for intravenous administration. This may facilitate the use of furosemide in certain situations, such as in intensive care settings or in neonatal or pediatric applications.

[0010] Therefore, there is a need for pharmaceutical compositions comprising furosemide with improved therapeutic effectiveness at physiological pH.

[0011] Overview

[0012] The present disclosure provides a pharmaceutical composition comprising furosemide or a pharmaceutically acceptable form of furosemide and cyclodextrin or a cyclodextrin derivative. The present disclosure also provides a method for treating a patient suffering from edema, heart failure, kidney disease or liver disease or symptoms thereof by administering a pharmaceutical composition comprising furosemide or any such pharmaceutical form of furosemide and cyclodextrin or a cyclodextrin derivative.

[0013] In one aspect, the present disclosure provides a pharmaceutical composition comprising furosemide or a pharmaceutically acceptable salt, hydrate or ester of furosemide and cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. The β-cyclodextrin present in the pharmaceutical composition is a sulfobutyl ether derivative of β-cyclodextrin. In another embodiment of the present disclosure, the pharmaceutical composition comprises furosemide and a sulfobutyl ether derivative of β-cyclodextrin. In certain embodiments, the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl cyclodextrin (captisol).

[0014] The present disclosure also provides a pharmaceutical composition comprising furosemide or a derivative thereof and cyclodextrin or a cyclodextrin derivative for administration at a pH of about 7.0 to about 8.5. In one embodiment, the present disclosure provides a pharmaceutical composition comprising furosemide or a pharmaceutically acceptable salt, hydrate or ester thereof and cyclodextrin, the amount of the cyclodextrin being less than or equal to 50% of the pharmaceutical composition. The pharmaceutical composition comprises about 8 mg / mL to 30 mg / mL of furosemide. The pH value of the pharmaceutical composition is about 7.0 to about 8.7. In certain embodiments, the pH value of the pharmaceutical composition is about 7.2 to about 7.6.

[0015] In another aspect, the present disclosure provides a method for treating a patient suffering from edema, heart failure, kidney disease or liver disease or having symptoms thereof. The method comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising furosemide or a pharmaceutically acceptable salt, hydrate or ester thereof and cyclodextrin. In some embodiments, the method comprises administering 20-200 mg of furosemide. In certain embodiments, the amount of cyclodextrin is less than or equal to 50% of the pharmaceutical composition. In various embodiments, the method comprises administering a pharmaceutical composition at a pH of about 7.0 to about 8.5. In some embodiments, the method comprises administering a pharmaceutical composition at a pH of about 7.2 to about 7.6.

[0016] In some embodiments, the present disclosure provides a pharmaceutical composition for subcutaneous administration and intravenous administration. The method also includes administering a therapeutically effective dose of the pharmaceutical composition to the patient using a pump device. The pump device is a patch device for parenteral administration of the composition. In another embodiment, an injection device is used to administer the pharmaceutical composition to the patient. The injection device is an automatic injector device. In different embodiments, a patch device or an automatic injector device is used to administer the pharmaceutical composition to the patient subcutaneously or intravenously.

[0017] The foregoing and other features and advantages of the present disclosure will be more fully understood from the following description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The drawings described below are for illustration purposes only and are not intended to limit the scope of the present disclosure in any way.

[0020] Figure 1 Overlay of HPLC chromatograms of HPLC standards, selected furosemide formulation stability samples, and diluents.

[0021] Detailed Description

[0022] The disclosure shown in this application only includes examples of the present invention. It will be appreciated by those skilled in the art that various alternative embodiments and forms can be prepared. Therefore, the examples provided are only for illustrative purposes and are not intended to limit the embodiments to a given set of embodiments. Specific functional aspects are provided only to enable technicians to implement the present invention and should not be interpreted as limitations of the present invention.

[0023] Use of the terms "including," "having," "comprising," "containing," etc. should be generally construed as open ended and non-limiting unless otherwise specifically stated.

[0024] The present disclosure includes a pharmaceutical composition of furosemide and cyclodextrin and a method of administering the pharmaceutical composition to treat a patient suffering from edema, heart failure, kidney disease or liver disease or having symptoms of such diseases. More specifically, the present disclosure provides a pharmaceutical composition having furosemide and β-cyclodextrin or a derivative of β-cyclodextrin such as a sulfobutyl ether derivative. In certain embodiments, the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl cyclodextrin. At a pH value of about 7.0 to about 8.7, the amount of cyclodextrin can be less than or equal to 50% of the pharmaceutical composition. The pharmaceutical composition is suitable for parenteral administration, more specifically, for subcutaneous and intravenous administration. The pharmaceutical composition can be used to treat edema, hypertension or heart failure in patients suffering from or showing symptoms of these conditions.

[0025] As used herein, "furosemide" refers to a compound having the formula C 12 H10 ClN2O5S or C 12 H 11 ClN2O5S compounds and pharmaceutically acceptable salts, hydrates and esters thereof, for example, furosemide sodium salt (C 12 H 10 ClN2NaO5S) and furosemide quaternary ammonium salt or any amino acid salt, the amino acid includes basic amino acids of natural origin, such as ornithine, lysine and arginine, which should include L-arginine, DL-arginine, L-lysine, DL-lysine, L-ornithine, DL-ornithine or histidine and any variants thereof. Furosemide may be referred to by other names, such as furosemide, 5-(aminosulfonyl)-4-chloro-2-[(2-furanyl-methyl)amino]benzoic acid, or its IUPAC name, 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid, or its common trade names, such as Lasix, Furosmid and Furanthril. It should be understood that "furosemide" also refers to any precursor or metabolite required for administration, such as 4-chloro-N-furanyl-5-sulfamoyl-anthranilic acid.

[0026] As used herein, "cyclodextrin" refers to a cyclic compound of 5 or more α-D-pyranoglucoside units connected by 1,4 glycosidic bonds, or a compound containing 6 to 8 units of glucose monomers in one ring, which are designated as 6 glucose subunits, called α-cyclodextrin, 7 glucose subunits, called β-cyclodextrin, and 8 glucose subunits, called γ-cyclodextrin. In addition, the present disclosure includes cyclodextrin-related compounds, for example, compounds derived from cyclodextrin or compounds structurally related to cyclodextrin.

[0027] As used herein, A trade name for a proprietary mixture of modified cyclodextrin formulations that have been structurally modified to optimize drug solubility and stability. It is a mixture of polyanionic β-cyclodextrin derivatives of sodium sulfonate salts attached to the lipophilic cavity of butyl ether groups or sulfobutyl ethers. It is commercially available from Ligand Pharmaceuticals Inc. in San Diego, California.

[0028] As used herein, the term "sulfobutylcyclodextrin" is a mixture of polyanionic β-cyclodextrin derivatives of sodium sulfonate salt separated from the hydrophobic cavity of β-cyclodextrin with butyl ether spacer groups. Chemically, sulfobutylcyclodextrin is also known as sodium sulfobutyl ether β-cyclodextrin.

[0029] As used herein, "derivatives" refers to modified forms of compounds produced by various methods or processes, including but not limited to methylation, acetylation, substitution such as alkylation, amidation, quaternization, thiolation, sulfation and oxidation, chain extension such as cross-linking and grafting, and depolymerization by chemical, physical or biological (including enzymatic) means. These methods and processes can be used alone or in any combination, without any particular order.

[0030] As used herein, "prevention or treatment" refers to partial or complete relief and / or improvement of a condition and / or its symptoms, and / or preventing its recurrence or stopping its progression. The present disclosure therefore includes methods of providing a combination product to a patient, the combination product comprising a combination or association of a compound or therapeutic composition of the present disclosure with a pharmaceutically acceptable carrier, solubilizer, or suitable buffer.

[0031] As used herein, "pharmaceutically acceptable" refers to a substance that is toxicologically acceptable for pharmaceutical use and does not adversely interact with the active ingredient. Thus, a pharmaceutically acceptable carrier is a carrier that is compatible with the other ingredients in the formulation and is biologically acceptable. Supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0032] As used herein, "therapeutically effective" refers to a substance or amount that causes a desired biological activity or effect to reduce or prevent a disease process. For example, a "therapeutically effective amount" of a composition can deliver a dose sufficient to induce a desired biological response (also referred to as a "therapeutic dose"). In the present invention, the desired biological response is "treating" edema, heart failure, kidney disease or liver disease or symptoms thereof. As used herein, "treating" refers to partial or complete relief and / or improvement of a condition and / or its symptoms.

[0033] As used herein, "administration" refers to parenteral, including intravenous, subcutaneous, topical, transdermal, intradermal, transmucosal, intraperitoneal, intramuscular, intracapsular, intraorbital, intracardiac, transtracheal, intracuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, except for special mention. Specifically, the pharmaceutical composition of the present disclosure can be administered parenterally, including infusion, injection or implantation, including subcutaneous and intravenous administration. When administered to treat a disease state or condition, it should be understood that the effective dose can vary according to many factors, such as the compound or therapeutic composition used, the mode of administration and the severity of the condition being treated, and various physical factors associated with the individual being treated. In therapeutic applications, the compound or therapeutic composition of the present disclosure can be provided to a patient already suffering from a disease, such as an edema-related condition, in an amount sufficient to at least partially improve the symptoms of the disease and its complications and to prevent or slow the progression of the disease. If administered to a patient suffering from the condition before clinical manifestation, the administration of the therapeutic composition can prevent the first clinical manifestation or delay its onset.

[0034] As used herein, "patient" refers to a mammal, such as a human or a domestic animal, such as a pet or livestock.

[0035] As used herein, the term "about" refers to a ±10% variation from a nominal value, unless otherwise indicated or inferred. For example, in certain applications, such as pH measurements, the term "about" may refer to a ±5% or ±2.5% or ±1% variation from a nominal value or a fixed variation from a nominal value, e.g., ±0.1 pH unit or ±0.2 pH unit.

[0036] The present disclosure provides a pharmaceutical composition comprising furosemide or a therapeutic combination including furosemide, and one or more pharmaceutically acceptable carriers, excipients or diluents, such as a buffer. Excipients may include sodium chloride, sodium hydroxide, water, glycerol, mannitol, sodium phosphate, sodium carbonate, lactose, glucose and other electrolytes.

[0037] Examples of such carriers are well known to those skilled in the art and can be prepared according to acceptable pharmaceutical methods, for example, those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed.Alfonso R.Gennaro (Lippincott Williams & Wilkins, Baltimore, MD (2000)). For example, liquid media or liquid carriers (used interchangeably herein) can be used to prepare pharmaceutical compositions of the present disclosure, such as solutions, suspensions, and emulsions. The compounds described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as a buffer, an organic solvent, and / or a pharmaceutically acceptable oil and / or fat.

[0038] The pharmaceutical compositions of the present disclosure may include other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers, adsorbents, binders, antioxidants, fillers, pH modifiers, preservatives, solvents, fluidizers and osmotic regulators. Since the present disclosure provides pharmaceutical compositions and their intended use is for patients, each ingredient or compound of the pharmaceutical compositions described herein may be a pharmaceutically acceptable ingredient or compound.

[0039] Unless specifically stated otherwise, the use of the singular herein includes the plural (and vice versa).

[0040] It should be understood that the order of steps or the order in which certain actions are performed can be changed as long as the expected results are obtained. In addition, two or more steps or behaviors can be performed simultaneously.

[0041] Throughout this specification, when compositions are described as having, including, or comprising particular components, or processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additional compositions of the invention that consist essentially of, or consist of, the ingredients, and that there are processes and methods of the invention that consist essentially of, or consist of, the processing steps.

[0042] Pharmaceutical compositions and methods of treatment comprising furosemide

[0043] The present disclosure provides pharmaceutical compositions and treatment methods using the same, which include furosemide and cyclodextrin or a cyclodextrin derivative for administration to a patient, which have significantly higher water solubility at lower pH, enhanced drug stability, reduced drug irritation, and reduced drug incompatibility when used with other infusion agents.

[0044] Cyclodextrin

[0045] Cyclodextrins are cyclic carbohydrates, the number of pyranose glucose units in their structures differs from each other. The cyclodextrin structure provides a molecular shape similar to a truncated cone, which has a hydrophilic outer surface and a hydrophobic inner cavity. These properties make cyclodextrins very valuable for drug administration. The hydrophilic surface provides good water solubility for cyclodextrins, while the hydrophobic cavity creates a suitable position to accommodate drug molecules. A variety of non-covalent forces, such as van der Waals forces, hydrophobic interactions and other forces are responsible for the formation of stable complexes of cyclodextrins and drug molecules. A variety of methods are used to form cyclodextrin-drug complexes, such as coprecipitation, heating, extrusion, dry mixing, wet mixing, slurry compounding, and paste compounding. The oral application of naturally occurring cyclodextrins is well known, but parenteral use and application are limited. Therefore, modified forms of cyclodextrins are often used for parenteral and other routes of administration to obtain higher stability and bioavailability.

[0046] One such modified cyclodextrin is sulfobutylcyclodextrin, which is an anionic β-cyclodextrin derivative in which the sodium sulfate salt is separated from the hydrophobic cavity with a butyl ether spacer group. Parenteral studies using sulfobutylcyclodextrin have shown a significantly greater safety profile, with complexing properties and water stability substantially 35 times greater than the parent cyclodextrin.

[0047] Exemplary cyclodextrins for use in the pharmaceutical compositions of the present invention include, for example, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-ether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and randomly methylated β-cyclodextrin.

[0048] Pharmaceutical composition comprising furosemide

[0049] The present disclosure relates to a pharmaceutical composition of furosemide and cyclodextrin or a derivative thereof, such as a β-cyclodextrin derivative (e.g., sulfobutyl cyclodextrin). The route of administration of the pharmaceutical composition may be parenteral, more specifically subcutaneous and intravenous. The specific amount of cyclodextrin is less than or equal to about 50% of the pharmaceutical composition, and the pH reaches about 7.0 to about 8.5. As such, one advantage of the present disclosure is that furosemide can be administered to patients in need by subcutaneous infusion or injection. Another advantage of the present disclosure is that a therapeutic dose of furosemide can be administered to a patient using an infusion device such as a patch pump, such as 80 mg in a standard volume of a commonly used cartridge for drug delivery, i.e., 3-5 mL. Another advantage of the present disclosure is that a therapeutic dose of furosemide, such as 50 mg, can be administered by an injection device such as an automatic syringe. Another advantage of the present disclosure is its use in intravenous infusion when other infusion fluids are used simultaneously or sequentially, without the need for line flushing before and after the administration of furosemide. Yet another advantage of the present disclosure is that the pharmaceutical composition remains stable at a pH of about 7.0 to about 8.3 and is compatible with subcutaneous or intravenous administration of furosemide with effective delivery and minimal or negligible adverse toxicological effects.

[0050] In one embodiment of the present disclosure, the pharmaceutical composition is stable at a pH value of about 7.0 to about 8.5. In certain embodiments of the present disclosure, the pharmaceutical composition is stable at a pH value of 7.2 to 7.6 for subcutaneous or intravenous administration of furosemide.

[0051] Furosemide may be present in the pharmaceutical composition as any variation of furosemide or an analog, such as a pharmaceutically acceptable salt, hydrate, or ester. In certain embodiments, the amount of furosemide in the pharmaceutical composition is from about 8 mg / mL to about 40 mg / mL. In some embodiments, the amount of furosemide is from about 15 mg / mL to about 26 mg / mL. The pharmaceutical composition also contains less than or equal to 50% of a cyclodextrin or a derivative thereof, and the pH of the pharmaceutical composition is maintained at about 7.0 to about 8.5. In certain embodiments, the pH of the pharmaceutical composition is maintained at about 7.2 to about 7.6.

[0052] In certain embodiments, the amount of furosemide in the pharmaceutical composition is about 8 mg / mL to about 40 mg / mL, and the cyclodextrin is included in the pharmaceutical composition in an amount less than or equal to 50%. The pH of the pharmaceutical composition is maintained at about 7.2 to about 7.6. One advantage of combining the ingredients in the disclosed amounts and under the disclosed conditions is that a therapeutic dose of furosemide, such as 80 mg, can be contained in a standard size cartridge (e.g., 3-5 mL) of a patch pump and administered to a patient, or self-administered by a patient using, for example, a patch pump.

[0053] In some embodiments, the amount of furosemide in the pharmaceutical composition is about 8 mg / mL to 40 mg / mL. In certain embodiments, the amount of the sulfobutyl ether derivative of β-cyclodextrin (e.g., sulfobutyl cyclodextrin) in the pharmaceutical composition is less than or equal to 50%. In certain embodiments, the pH value of the pharmaceutical composition is about 7.0 to about 8.5. In another embodiment, the above-mentioned pharmaceutical composition is administered to the patient subcutaneously or intravenously as needed.

[0054] In another embodiment, the present disclosure provides a pharmaceutical composition comprising:

[0055] about 40 mM to about 160 mM of a diuretic selected from the group consisting of 4-chloro-2-((furan-2-ylmethyl)amino)-5-sulfamoylbenzoic acid, pharmaceutically acceptable salts thereof, and mixtures of the foregoing;

[0056] From about 45 mM to about 190 mM of a sulfobutyl ether derivative of beta-cyclodextrin; and

[0057] water;

[0058] wherein the pharmaceutical composition has a pH of about 7.0 to about 8.5.

[0059] The pharmaceutical composition can also be characterized according to the amount of the sulfobutyl ether derivative of β-cyclodextrin. For example, in certain embodiments, the pharmaceutical composition comprises about 120 mM to about 160 mM of the sulfobutyl ether derivative of β-cyclodextrin. In certain embodiments, the pharmaceutical composition comprises about 135 mM to about 145 mM of the sulfobutyl ether derivative of β-cyclodextrin. In certain embodiments, the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl ether β-cyclodextrin sodium.

[0060] The pharmaceutical composition can also be characterized according to the amount of the diuretic. For example, in certain embodiments, the pharmaceutical composition comprises about 80 mM to about 100 mM of a diuretic. In certain embodiments, the pharmaceutical composition comprises about 91 mM of a diuretic.

[0061] In certain embodiments, the pharmaceutical composition further comprises a buffer. In certain embodiments, the buffer comprises tris(hydroxymethyl)aminomethane. In certain embodiments, the buffer is present in an amount of about 1 mM to about 50 mM. In certain embodiments, the buffer is present in an amount of about 25 mM.

[0062] In certain embodiments, the pharmaceutical composition has a pH of about 7.0 to about 8.0. In certain embodiments, the pharmaceutical composition has a pH of about 7.4.

[0063] In certain embodiments, the pharmaceutical composition comprises at least 50% (w / w) water.

[0064] The pharmaceutical composition of the present disclosure comprises furosemide with high solubility and enhanced stability, which advantageously enables administration of higher doses of furosemide with lower volumes of the pharmaceutical composition. The pharmaceutical composition of the present disclosure achieves administration of higher concentrations of furosemide at pH values ​​compatible with subcutaneous administration to patients. More specifically, the pharmaceutical composition is stable and suitable for subcutaneous or intravenous administration.

[0065] In some embodiments, the present disclosure includes a pharmaceutical composition of a higher concentration of furosemide in a drug volume of 2-20 mL. In another embodiment, the amount of cyclodextrin in the pharmaceutical composition is less than or equal to 50%. In yet another embodiment, the pharmaceutical composition has a pH value of about 7.0 to about 8.5 compatible with subcutaneous and intravenous administration.

[0066] In some embodiments, the present disclosure includes a pharmaceutical composition of furosemide and a cyclodextrin or a cyclodextrin derivative such as sulfobutylcyclodextrin in an amount of about 40% to about 50%.

[0067] Treatment

[0068] In another embodiment, the present disclosure includes a method of treating a patient suffering from or exhibiting symptoms of edema, heart failure, kidney disease or liver disease by administering to the patient a pharmaceutical composition comprising furosemide or a pharmaceutically acceptable salt, hydrate or ester thereof. More specifically, the pharmaceutical composition comprises furosemide or a pharmaceutically acceptable salt, hydrate or ester thereof in an amount of about 30 mg / mL. The pharmaceutical composition further comprises a cyclodextrin in an amount less than or equal to 50% of the pharmaceutical composition.

[0069] In one embodiment, the pharmaceutical composition is administered subcutaneously to the patient. Specifically, the pharmaceutical composition is administered subcutaneously to the patient using a pump device or an injection device. The pump device may include, for example, a patch device. The injection device may include, for example, an automatic injector device. In another embodiment, the pharmaceutical composition is administered intravenously to the patient. Specifically, the pharmaceutical composition is administered intravenously to the patient using the pump device or injection device. In various embodiments, the pharmaceutical composition is administered subcutaneously or intravenously to the patient using a patch device or an automatic injector device. In some embodiments, the present disclosure includes a method for treating a patient suffering from edema, heart failure, kidney disease or liver disease or showing symptoms thereof, the method being performed by administering to the patient a pharmaceutical composition of furosemide or a pharmaceutically acceptable salt, hydrate or furosemide ester, wherein the amount of furosemide in the pharmaceutical composition is about 40 mg / mL. At a pH value of about 7.2 to about 7.6 of the pharmaceutical composition, the pharmaceutical composition further comprises a cyclodextrin or a derivative thereof in an amount less than or equal to 50%. In one embodiment, the cyclodextrin is β-cyclodextrin. In another embodiment, the cyclodextrin is a sulfobutyl ether derivative of β-cyclodextrin. In yet another embodiment, the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl cyclodextrin. In one embodiment, the pH of the pharmaceutical composition is about 7.0 to about 7.8. In certain embodiments, the pH is maintained at about 7.0 to about 8.3.

[0070] In one embodiment, a pharmaceutical composition having an amount of furosemide of about 8 mg / mL to about 40 mg / mL is administered to a patient suffering from edema, heart failure, kidney disease, or liver disease, or exhibiting symptoms thereof. In another embodiment, the amount of sulfobutylcyclodextrin in the pharmaceutical composition is less than or equal to 50%. In another embodiment, the pH of the pharmaceutical composition is about 7.0 to about 8.5.

[0071] In another embodiment, the disclosure provides a method for treating a patient suffering from a condition selected from edema, heart failure, kidney disease or liver disease or having any of the symptoms thereof, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein to treat the condition. In certain embodiments, the condition is edema. In certain embodiments, the condition is heart failure. In certain embodiments, the condition is kidney disease or liver disease.

[0072] In some embodiments, the pharmaceutical composition is administered to the patient parenterally, including subcutaneous or intravenous administration. In the present disclosure, several devices can be used to promote the self-administration of the pharmaceutical composition. The device typically includes a reservoir or a cartridge, for example, pre-loaded with the pharmaceutical composition to be administered, or inserted into the device before its use. For example, a micropump can provide the precise parenteral administration of the liquid pharmaceutical composition of the desired amount. Another type of device that can be used for parenteral delivery or administration of a pharmaceutical composition is generally referred to as a pump device or an injection device.

[0073] In some embodiments, the present disclosure includes a medical device of an integral structure. Such a medical device can be disposable. In certain embodiments, the medical device can have a multi-piece structure. In such medical devices, there can be disposable or reusable parts or components. For example, a housing defining or including a reservoir can be a disposable or reusable component of a medical device.

[0074] The patch pump or patch device of the present disclosure may include a pump device with a drug reservoir and an electrolytic, manual, mechanical, automatic or electronically driven piston. The drug pump device may be equipped with a pre-loaded cartridge. If a glass cartridge or other suitable pharmaceutical grade composite material cartridge is used, the drug may be stored in the pump device for a long-term storage period or inserted into the device before use. The drug pump device may be implantable, including an adhesive patch for adhering to the patient's skin, or may be worn on a belt or attached to the body by a belt or by other means.

[0075] Other features of the pharmaceutical composition and methods of treatment

[0076] The pharmaceutical dosage form suitable for injection of the present disclosure can include a sterile aqueous solution or dispersion for the temporary preparation of a sterile injection solution or dispersion. In certain embodiments, the pharmaceutical dosage form is sterile, and its viscosity allows it to flow through an infusion tube or a needle. If necessary, the drug form should remain stable under manufacturing and storage conditions, for example, to prevent the contamination of microorganisms. The carrier can be a solvent or a dispersion medium containing a liquid, such as water, ethanol, a polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), their appropriate mixture and vegetable oil.

[0077] In the present disclosure, the pharmaceutical composition can achieve higher levels of furosemide suitable for administration. For example, the amount of furosemide in the pharmaceutical composition can be about 8 mg / mL or more, about 10 mg / mL or more, or about 15 mg / mL or more. In different embodiments, the amount of furosemide can be about 15 mg / mL or more, about 20 mg / mL or more, about 26 mg / mL or more, or about 30 mg / mL or about 40 mg / mL.

[0078] Furosemide concentration

[0079] In some embodiments, furosemide may be present in an amount from about 8 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 26 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 15 mg / mL, from about 15 mg / mL to about 40 mg / mL, from about 16 mg / mL to about 24 mg / mL, from about 20 mg / mL to about 40 mg / mL.

[0080] Barriers to treatment

[0081] In the present disclosure, furosemide, therapeutic combinations and pharmaceutical compositions can be used to treat a pathological condition or disorder or symptom in a patient. The present disclosure provides for the parenteral administration of higher concentrations of furosemide to alleviate conditions such as edema, heart failure, kidney disease or liver disease or such symptoms therewith. The present disclosure therefore includes methods of providing a pharmaceutical composition to a patient, the pharmaceutical composition comprising a compound or therapeutic combination of the present disclosure in combination or in conjunction with a pharmaceutically acceptable carrier or solubilizer or a suitable buffer. The compounds and therapeutic combinations of the present disclosure can be administered alone or in combination with other therapeutically effective compounds or therapies to treat pathological conditions or disorders.

[0082] The present disclosure also includes methods of administering a pharmaceutical composition comprising furosemide or one or more analogs or variants or precursors thereof to a patient suffering from an edema-related disease or disorder. The edema-related disease or disorder may also include heart failure, chronic kidney disease.

[0083] pH of the pharmaceutical composition

[0084] In certain embodiments, the pharmaceutical composition may have a pH of about 7.0 to about 8.7. In certain embodiments, the pharmaceutical formulation may have a pH of about 7.0 to about 8.5, or about 7.2 to about 7.6, or about 7.3 to about 7.8. In some embodiments, the pharmaceutical composition may have a pH of about 7.4 to about 8.0, or about 7.4 to about 9.0.

[0085] Amount of cyclodextrin

[0086] In addition, in different embodiments, the cyclodextrin in the pharmaceutical composition can be less than or equal to about 50%. In some embodiments, the cyclodextrin in the pharmaceutical composition can be less than or equal to about 50%. In some embodiments, the amount of cyclodextrin can be less than or equal to about 35%, less than or equal to about 30%, or less than or equal to about 25%. In certain embodiments, the amount of cyclodextrin can be about 5% to about 50%, about 40% to about 50%, about 20% to about 40%, or about 20% to about 30%. In certain embodiments, the amount of cyclodextrin can be about 10% or about 40%.

[0087] In addition, in certain embodiments, the cyclodextrin in the pharmaceutical composition can be less than or equal to about 45% (w / w). In some embodiments, the cyclodextrin in the pharmaceutical composition can be less than or equal to about 40% (w / w). In some embodiments, the amount of cyclodextrin can be less than or equal to about 35%, less than or equal to about 20% (w / w) or less than or equal to about 15% (w / w). In certain embodiments, the amount of cyclodextrin can be about 10% (w / w) to about 50% (w / w), about 35% (w / w) to about 50% (w / w), about 25% (w / w) to about 40% (w / w) or about 25% (w / w) to about 30% (w / w). In certain embodiments, the amount of cyclodextrin can be about 20% (w / w) to about 30% (w / w). In certain embodiments, the amount of cyclodextrin can be about 15% (w / w) or about 45% (w / w).

[0088] The amount of cyclodextrin in the pharmaceutical composition can be characterized according to the molar ratio of cyclodextrin to furosemide in the pharmaceutical composition. For example, in certain embodiments, the molar ratio of cyclodextrin (e.g., sulfobutyl cyclodextrin) to furosemide is greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In certain embodiments, the molar ratio of cyclodextrin to furosemide is greater than about 2. In certain embodiments, the molar ratio of cyclodextrin to furosemide is greater than about 3. In certain other embodiments, the molar ratio of cyclodextrin to furosemide is 2: 1 to about 15: 1. In certain other embodiments, the molar ratio of cyclodextrin to furosemide is 2: 1 to about 3: 1. In certain other embodiments, the molar ratio of cyclodextrin to furosemide is 2: 1 to about 5: 1. In certain other embodiments, the molar ratio of cyclodextrin to furosemide is 5: 1 to about 10: 1.

[0089] Therapeutic benefits

[0090] In the present disclosure, the pharmaceutical composition can reduce disease conditions and symptoms by at least about 5% to at least about 99% compared to untreated patients. The compound can be administered to patients in various forms, including injections, transdermal patches, and sustained-release injections. The composition can be administered by enteral or parenteral routes, including intravenous, subcutaneous, topical, transdermal, intradermal, transmucosal, intraperitoneal, intramuscular, intracapsular, intraorbital, intracardiac, transtracheal, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0091] Typical dosages of the compounds and compositions of the present disclosure may vary widely depending on many factors including, but not limited to, route of administration, stage of treatment, pre-treatment use of oral medications, body weight, age, and general condition of the patient.

[0092] Water content of the pharmaceutical composition

[0093] Pharmaceutical composition can also be characterized according to the amount of water in the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises at least 40% (w / w), 45% (w / w), 50% (w / w), 55% (w / w), 60% (w / w), 65% (w / w), 70% (w / w), 75% (w / w), 80% (w / w) or 85% (w / w) water. In certain embodiments, the pharmaceutical composition comprises at least 90% (w / w), 91% (w / w), 92% (w / w), 93% (w / w), 94% (w / w), 95% (w / w), 96% (w / w), 97% (w / w), 98% (w / w) and 99% (w / w) water. In certain embodiments, the pharmaceutical composition comprises at least 50% (w / w). In certain embodiments, the pharmaceutical composition comprises at least 55% (w / w). In certain embodiments, the pharmaceutical composition comprises at least 60% (w / w). In certain embodiments, the pharmaceutical composition comprises at least 65% (w / w). In certain embodiments, the pharmaceutical composition comprises at least 95% (w / w) water. In certain embodiments, the pharmaceutical composition comprises at least 96% (w / w) water. In certain embodiments, the pharmaceutical composition comprises at least 97% (w / w) water. In certain embodiments, the pharmaceutical composition comprises at least 98% (w / w) water. In certain embodiments, the pharmaceutical composition comprises at least 99% (w / w) water. In certain embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 70% (w / w) water. In certain embodiments, the pharmaceutical composition comprises about 60% (w / w) to about 70% (w / w) water.

[0094] Buffer

[0095] In certain embodiments, the pharmaceutical composition comprises a buffer. In certain embodiments, the buffer is present in the pharmaceutical composition in an amount of less than about 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w) or 10% (w / w). In certain embodiments, the buffer may include phosphoric acid, citric acid, acetic acid, histidine, lactic acid, tromethamine, gluconic acid, aspartic acid, glutamic acid, tartaric acid, succinic acid, malic acid, fumaric acid or alpha-ketoglutaric acid.

[0096] Additional ingredients of the pharmaceutical composition

[0097] The pharmaceutical compositions of the present disclosure may also contain adjuvants, diluents, excipients and / or carriers known in the art which are compatible with the compounds and other ingredients of the pharmaceutical compositions and not deleterious to the recipients thereof.

[0098] Stability of pharmaceutical compositions

[0099] The characteristics of the pharmaceutical composition can also be characterized according to the stability of the pharmaceutical composition on storage. This can be achieved by storing the pharmaceutical composition at a specified temperature for a period of time, then removing an aliquot of the pharmaceutical composition and analyzing the aliquot to determine whether any ingredients in the original pharmaceutical composition have degraded. For example, the aliquot can be visually analyzed to determine whether there are any undissolved solids and / or changes in the color or transparency of the solution. In addition, the aliquot can be analyzed to determine the amount of diuretic (e.g., furosemide or a pharmaceutically acceptable salt thereof) present relative to the original amount of diuretic in the pharmaceutical composition.

[0100] Thus, in certain embodiments, when the pharmaceutical composition is stored at 40°C for 29 days, less than 4% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 40°C for 29 days, less than 1% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 40°C for 29 days, less than 0.5% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 40°C for 29 days, less than 0.1% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 70°C for 29 days, less than 10% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 70°C for 29 days, less than 7% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 70°C for 29 days, less than 5% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 70°C for 29 days, less than 3% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 70°C for 29 days, less than 1% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 25°C for 24 months, less than 3% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 25°C for 24 months, less than 2% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 25°C for 24 months, less than 1% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 25°C for 24 months, less than 0.5% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 25°C for 24 months, less than 0.1% of the diuretic degrades. In certain embodiments, when the pharmaceutical composition is stored at 25°C for 24 months, less than 0.05% of the diuretic degrades.

[0101] In addition, in certain embodiments, the pharmaceutical composition is characterized by the purity of the diuretic in the pharmaceutical composition when stored. For example, in certain embodiments, after the pharmaceutical composition is stored at 40°C for 29 days, the diuretic has a purity of at least 97%. In certain embodiments, after the pharmaceutical composition is stored at 40°C for 29 days, the diuretic has a purity of at least 98%. In certain embodiments, after the pharmaceutical composition is stored at 40°C for 29 days, the diuretic has a purity of at least 99%. In certain embodiments, after the pharmaceutical composition is stored at 40°C for 29 days, the diuretic has a purity of at least 99.5%. In certain embodiments, after the pharmaceutical composition is stored at 40°C for 29 days, the diuretic has a purity of at least 99.9%. In certain embodiments, after the pharmaceutical composition is stored at 70°C for 29 days, the diuretic has a purity of at least 95%. In certain embodiments, after the pharmaceutical composition is stored at 70°C for 29 days, the diuretic has a purity of at least 97%. In certain embodiments, after the pharmaceutical composition is stored at 70°C for 29 days, the diuretic has a purity of at least 98%. In certain embodiments, the diuretic has a purity of at least 99%. In certain embodiments, after the pharmaceutical composition is stored at 70°C for 29 days, the diuretic has a purity of at least 99.5%. In certain embodiments, after the pharmaceutical composition is stored at 25°C for 24 months, the diuretic has a purity of at least 97%. In certain embodiments, after the pharmaceutical composition is stored at 25°C for 24 months, the diuretic has a purity of at least 98%. In certain embodiments, after the pharmaceutical composition is stored at 25°C for 24 months, the diuretic has a purity of at least 99%. In certain embodiments, after the pharmaceutical composition is stored at 25°C for 24 months, the diuretic has a purity of at least 99.5%. In certain embodiments, after the pharmaceutical composition is stored at 25°C for 24 months, the diuretic has a purity of at least 99.9%.

[0102] Exemplary Benefits of Pharmaceutical Compositions

[0103] Various embodiments of the present disclosure enable administration of higher concentrations of furosemide to a patient. In addition, the pharmaceutical compositions of various embodiments of the present disclosure have a pH suitable for subcutaneous or intravenous administration of the composition to a patient.

[0104] Another advantage of the presently disclosed embodiments is that pharmaceutical compositions having higher concentrations of furosemide and lower amounts of sulfobutylcyclodextrin can be administered via a pump device or an injection device.

[0105] Yet another advantage of the pharmaceutical compositions of the present disclosure is that the solubility at the desired pH is very high, which can facilitate intravenous infusion by allowing co-administration with other infusion fluids or pharmaceutical formulations.

[0106] It has been observed that in pharmaceutical compositions combined with cyclodextrin or cyclodextrin derivatives (e.g., sulfobutyl ether derivatives of β-cyclodextrin), furosemide exhibits higher solubility and enhanced stability compared to other excipients of furosemide for the treatment of renal diseases such as edema and hypertension.

[0107] Unit container

[0108] Another aspect of the present disclosure provides a unit container, which includes a pharmaceutical composition as described herein. In certain embodiments, the container includes about 1mL to about 10mL, about 1mL to about 5mL, about 1mL to about 4mL, about 1mL to about 3mL, about 1mL to about 2mL, about 1mL to about 1.5mL, about 2mL to about 5mL, or about 2mL to about 3mL of a pharmaceutical composition. In certain embodiments, the container includes about 1mL to about 3mL of a pharmaceutical composition. In certain embodiments, the container includes about 2mL to about 3mL of a pharmaceutical composition. In certain embodiments, the container includes about 5mL to about 10mL of a pharmaceutical composition. In certain embodiments, the container includes about 8mL to about 10mL of a pharmaceutical composition.

[0109] Medical test kit

[0110] Another aspect of the invention provides a medical kit comprising, for example, (i) a pharmaceutical composition as described herein, and (ii) instructions for use, for example, in the methods described herein.

[0111] It should be understood that the examples, embodiments and teachings presented in this application are described for exemplary purposes only. Any changes or modifications thereof will be included within the scope of the application under discussion. Example

[0112] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0113] Example 1 - Preparation of an exemplary aqueous furosemide formulation

[0114] An exemplary furosemide aqueous solution formulation was prepared according to the method set forth below. The furosemide aqueous solution formulation contained furosemide at a concentration of 30 mg / mL, sulfobutylcyclodextrin at a concentration of about 300 mg / mL, and tris(hydroxymethyl)aminomethane buffer at a concentration of 25 mM. The formulation had a pH of 7.4.

[0115] Sulfobutyl cyclodextrin (157.65 g, 5.1% water, USP grade, Hovione) was slowly added (to promote dissolution and avoid agglomeration) to approximately 350 mL of water for injection (Rocky Mountain Biologics, product number WIFI-USP-1X6) in a 1-L beaker over about 6.5 minutes while stirring with a magnetic stir bar. Tris(hydroxymethyl)aminomethane free base (1.514 g, Sigma, product number 101974108) was added over about 3 minutes, followed by 3.6 mL of 10N NaOH solution (Fisher, product number S71993-1) over about 2.5 minutes. Furosemide (15.0 g, USP grade, Spectrum, product number F1133) was slowly added and dissolved over approximately 1 hour, while approximately 5 μL of 10N NaOH was added (to maintain the pH in the range of 7.4-7.5) and sonicated (26-28 minutes, 31-36 minutes, 38-43 minutes, and 50-55 minutes during the one-hour dissolution period). The solution was poured from the beaker into a 500-mL volumetric flask. The beaker was rinsed with approximately 20 mL of water for injection, which was then added to the volumetric flask. The solution was diluted to nearly 500 mL with water for injection, and the pH was measured to ensure it was in the range of 7.4-7.5. The solution was diluted to 500 mL with water for injection, and the pH was measured to be 7.408. Finally, the solution was filtered through an Argos bottle top filter system (product number BPV2250) in a laminar flow hood.

[0116] Example 2 - Stability Analysis of Exemplary Furosemide Formulations

[0117] Stability analysis was performed on an exemplary furosemide formulation prepared using methods similar to those described in Example 1. The experimental methods and results are provided below.

[0118] Part I - Experimental Methods

[0119] The furosemide aqueous solution formulations AH described in Table 1 below were prepared according to the following general method. The required amount of sulfobutyldextrin (50, 100 or 150 grams) and tris(hydroxymethyl)aminomethane free base (1.5 g, in the formulations including it) were added to a 500-mL volumetric flask. Water for injection (about 350 mL) was added and the solids were dissolved by shaking and / or rotating the flask. Sodium hydroxide (10N) was added in an amount sufficient to deprotonate the carboxylic acid group of furosemide (3.6 mL for formulations containing tris(hydroxymethyl)aminomethane free base, and 4.5 mL for formulations without tris(hydroxymethyl)aminomethane free base). Furosemide (15 g) was added and the mixture was mixed by rotation, shaking and / or sonication for about 10 minutes. Sodium hydroxide (1N or 10N) was added dropwise to adjust the pH to the desired value (7.4 or 8.4). The solution was diluted to 500 mL with water for injection and then filtered through a Millex-GV 33 mm hydrophilic PVDF membrane syringe filter (0.22 μm pore size) into a vial or bottle. The entire 500-mL solution was filtered using more than one filter and the first few drops that passed through each filter were discarded.

[0120] Aliquots of the furosemide formulation (10 mL) were added to 12-mL glass vials (Fisherbrand Type 1 Class A Clear Borosilicate Glass Sample Vials) and the vials were sealed with black phenolic caps and white PTFE-faced white rubber cap liners. The vials were then stored in an oven at 25°C, 40°C, and 60°C for a specified duration (e.g., 1 week). After storage for 1 week, 2 weeks, 1 month, 2 months, 3 months, or 6 months, the vials were removed from the oven and the furosemide formulation was analyzed for appearance, pH, and the amount of furosemide and / or impurities in the formulation was determined. The impurity analysis included determining the amounts of the impurities 2-chloro-4-furfurylamino-5-sulfamoylbenzoic acid and 4-chloro-5-sulfamoylanthranilic acid, which are shown in the following table and Figure 1 Designated as Peak A and Peak B in the HPLC chromatogram.

[0121] HPLC analysis was performed after dilution of the formulation according to the method described in Table 2 below. Samples for HPLC analysis were diluted 1,000-fold (serial dilutions 100 and 10-fold to a concentration of ˜30 μg / mL furosemide) or 60-fold (to a concentration of ˜500 μg / mL furosemide) as specified in the description and table below. The diluent was 1:1 methanol: pH 5.7 buffer (prepared with 1,000 mL MQ water, 750 μL triethylamine, 250 μL formic acid and adjusted to pH 5.7 with triethylamine).

[0122] Part II - Results

[0123] The results of the stability analysis are provided in Tables 3-24 below. Figure 1 Depicted are representative HPLC chromatograms of analytical samples for selected furosemide formulation samples (analyte detection analysis was performed at 270 nm). All values ​​determined by HPLC (ie, in Tables 3-6, 11-13 and 18-20) are the average of three HPLC chromatogram results obtained for a given sample.

[0124] The data of furosemide concentration (i.e., 30 mg / mL) as a percentage of theoretical value in Tables 3, 11, and 18 were calculated based on the standard calibration curve and obtained from HPLC samples that had been diluted 1,000 times. The data of the area percentage of furosemide peak, Peak A, or Peak B in Tables 4-6, 12, 13, 19, and 20 (relative to the total area of ​​all peaks integrated in the chromatogram) were obtained from HPLC samples that were diluted 1,000 times (storage period of 0 days, 1 week, 2 weeks, and 1 month) or 60 times (storage period of 2, 3, or 6 months).

[0125] Table 1. Aqueous furosemide formulations subjected to stability studies

[0126]

[0127] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0128] Table 2. HPLC method used for analytical analysis of stored furosemide formulations

[0129]

[0130]

[0131] Table 3. Furosemide concentration as a percentage of theoretical value for formulations stored at 60°C (30 mg / mL)

[0132]

[0133] Table 4. Furosemide area percentage of the total chromatogram of the formulations stored at 60°C

[0134]

[0135] *Samples for HPLC analysis were diluted 1000-fold (for storage periods of 0 days, 1 week, 2 weeks, and 1 month) or 60-fold (for storage periods of 2 months and 3 months).

[0136] **Only one of the three samples analyzed contained a non-furosemide peak.

[0137] Table 5. Peak B area percentage of the total chromatogram of the formulations stored at 60°C

[0138]

[0139] *Samples for HPLC analysis were diluted 1000-fold (for storage periods of 0 days, 1 week, 2 weeks, and 1 month) or 60-fold (for storage periods of 2 months and 3 months).

[0140] Table 6. Peak A area percentage of the total chromatogram of the formulations stored at 60°C

[0141]

[0142] *Samples for HPLC analysis were diluted 1000-fold (for storage periods of 0 days, 1 week, 2 weeks, and 1 month) or 60-fold (for storage periods of 2 months and 3 months).

[0143] **Only one of the three samples analyzed contained this peak.

[0144] Table 7. pH of formulations stored at 60°C

[0145]

[0146] *Different pH meters were used to measure samples stored for 1 month.

[0147] Table 8. Osmolality of formulations stored at 60°C (in mOsm / kg)

[0148]

[0149] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0150] Table 9. Viscosity of formulations stored at 60°C (in cP)

[0151]

[0152] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0153] **"ND" indicates that the viscosity was not determined for the sample.

[0154] Table 10. Color of formulations stored at 60°C

[0155]

[0156] *All samples were clear solutions with no visible precipitation.

[0157] Table 11. Furosemide concentration as a percentage of theoretical value for formulations stored at 40°C (30 mg / mL)

[0158]

[0159] Table 12. Furosemide area percentage of the total chromatogram of the formulations stored at 40°C

[0160]

[0161] Table 13. Peak B area percentage of the total chromatogram of the formulations stored at 40°C

[0162]

[0163]

[0164] Table 14. pH of formulations stored at 40°C

[0165]

[0166] Table 15. Osmolality of formulations stored at 40°C (in mOsm / kg)

[0167]

[0168] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0169] Table 16. Viscosity of formulations stored at 40°C (in cP)

[0170]

[0171] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0172] **"ND" indicates that the viscosity was not determined for the sample.

[0173] Table 17. Color of formulations stored at 40°C

[0174]

[0175] *All samples were clear solutions with no visible precipitation.

[0176] Table 18. Furosemide concentration as a percentage of theoretical value for formulations stored at 25°C (30 mg / mL)

[0177]

[0178] Table 19. Furosemide area percentage of the total chromatogram for formulations stored at 25°C

[0179]

[0180] Table 20. Peak B area percentage of the total chromatogram of formulations stored at 25°C

[0181]

[0182]

[0183] Table 21. pH of formulations stored at 25°C

[0184]

[0185] Table 22. Osmolality of formulations stored at 25°C (in mOsm / kg)

[0186]

[0187] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0188] Table 23. Viscosity of formulations stored at 25°C (in cP)

[0189]

[0190] *Formulation H prepared using sulfobutylcyclodextrin buffered with sodium phosphate.

[0191] **"ND" indicates that the viscosity was not determined for the sample.

[0192] Table 24. Color of formulations stored at 25°C

[0193]

[0194] *All samples were clear solutions with no visible precipitation.

[0195] Equivalent solutions

[0196] The present invention may be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the foregoing embodiments are considered to be exemplary in all respects, rather than limiting the invention described herein. Therefore, the scope of the present invention is indicated by the appended claims rather than by the foregoing description, and all changes within the equivalent meaning and scope of the claims are intended to be included therein.

Claims

1. A pharmaceutical composition comprising: Furosemide or a pharmaceutically acceptable salt thereof, wherein the furosemide is present in the pharmaceutical composition in an amount of 30 mg / mL; 10% to 40% by weight of cyclodextrin, wherein the cyclodextrin is β-cyclodextrin; 25 mM buffer comprising tris(hydroxymethyl)aminomethane; and water; The pharmaceutical composition has a pH value of 7.0 to 8.

0.

2. The pharmaceutical composition of claim 1, wherein the β-cyclodextrin is a sulfobutyl ether derivative of β-cyclodextrin.

3. The pharmaceutical composition of claim 2, wherein the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl cyclodextrin.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pH value of the pharmaceutical composition is 7.2 to 7.

6.

5. The pharmaceutical composition of claim 3, wherein the cyclodextrin is present in an amount of 20% to 30% by weight.

6. The pharmaceutical composition of claim 1, wherein the cyclodextrin is present in an amount of 20% to 30% by weight.

7. The pharmaceutical composition of any one of claims 1-3, wherein the cyclodextrin is present in an amount of 30% by weight.

8. A pharmaceutical composition comprising: 80 mM to 100 mM of a diuretic selected from 4-chloro-2-((furan-2-ylmethyl)amino)-5-sulfamoylbenzoic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof; 45 mM to 190 mM sulfobutyl ether derivative of β-cyclodextrin; 25 mM buffer comprising tris(hydroxymethyl)aminomethane; and water; The pharmaceutical composition has a pH value of 7.0 to 8.

0.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 120 mM to 160 mM of the sulfobutyl ether derivative of β-cyclodextrin.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 135 mM to 145 mM of the sulfobutyl ether derivative of β-cyclodextrin.

11. The pharmaceutical composition of claim 8, wherein the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl ether β-cyclodextrin sodium.

12. The pharmaceutical composition of claim 9, wherein the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl ether β-cyclodextrin sodium.

13. The pharmaceutical composition of claim 10, wherein the sulfobutyl ether derivative of β-cyclodextrin is sulfobutyl ether β-cyclodextrin sodium.

14. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 91 mM of a diuretic.

15. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises 91 mM of a diuretic.

16. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises 91 mM of a diuretic.

17. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition has a pH of 7.

4.

18. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition has a pH of 7.

4.

19. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises at least 50% (w / w) water.

20. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises at least 50% (w / w) water.

21. The pharmaceutical composition of claim 8, wherein less than 1% of the diuretic is degraded when the pharmaceutical composition is stored at 40°C for 29 days.

22. The pharmaceutical composition of claim 8, wherein less than 1% of the diuretic is degraded when the pharmaceutical composition is stored at 25°C for 24 months.

23. Use of a pharmaceutical composition according to any one of claims 1 to 22 for the preparation of a medicament for treating a condition selected from edema, heart failure, kidney disease or liver disease.

24. The use according to claim 23, wherein the condition is edema.

25. The use according to claim 23, wherein the disorder is heart failure.

26. The use of claim 23, wherein the disorder is kidney disease or liver disease.

27. The use of claim 23, wherein the pharmaceutical composition is administered using a pump device.

28. The use of claim 27, wherein the pump device is a patch device.

29. The use of claim 23, wherein the pharmaceutical composition is administered using an injection device.

30. The use according to claim 29, wherein the injection device is an autoinjector device.

31. The use of claim 23, wherein the pharmaceutical composition is administered to the patient subcutaneously.

32. The use of claim 23, wherein the pharmaceutical composition is administered to the patient intravenously.

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