WO2022029497A1 - Ularitide for use in methods of treating refractory ascites - Google Patents

Abstract

Disclosed is ularitide for use in methods for treating refractory ascites, comprising subcutaneously administering ularitide to a patient in need thereof via an implantable drug depot composition or via an infusion pump system, wherein the implantable drug depot composition or the infusion pump system releases continuously a therapeutically effective amount of ularitide to treat refractory ascites over a time period ranging from about 24 hours to about 6 months.

Description

ULARITIDE FOR USE IN METHODS OF TREATING REFRACTORY ASCITES

CROSS REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Application No. 63/061,893 filed on August 6, 2020, the entire contents of which are incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The instant disclosure is directed to methods of treating refractory ascites, preventing deterioration of refractory ascites, preventing or minimizing reoccurrence of refractory ascites, as well as medicaments, compositions, and systems that may be used in these methods.

BACKGROUND OF THE INVENTION

[0003] A family of related peptides has been discovered that works in concert to achieve salt and water homeostasis in the body. These peptides, termed natriuretic peptides for their role in moderating natriuresis, diuresis and vasodilation, have varying amino acid sequences and originate from different tissues within the body. This family of natriuretic peptides consists of atrial natriuretic peptide (“ANP”), brain natriuretic peptide (“BNP”), C-type natriuretic peptide (“CNP”), Dendroaspis natriuretic peptide (“DNP”), urodilatin (“URO”, or ularitide), hybrid natriuretic peptides such as centeritide (a fusion between CNP and DNP). The tissuespecific distribution of these peptides is as follows: heart (ANP, BNP, and DNP); brain (ANP, BNP, and CNP); endothelial cells (CNP); plasma (DNP); and kidney (CNP, URO). These peptides are constituents of a hormonal system that plays a critical role in maintaining an intricate balance of blood volume/pressure in the human body. For instance, urodilatin, a close analog of ANP secreted by kidney tubular cells, promotes excretion of sodium and water by acting directly on kidney cells in the collecting duct to inhibit sodium and water reabsorption. [0004] Like other natriuretic peptides, such as ANP and BNP, urodilatin has been studied for use in treating various conditions, including renal failure, cardiovascular conditions such as congestive heart failure, bronchoconstrictive conditions and cirrhosis (see, e.g., U.S. Pat. Nos. 5,571,789 and 6,831,064; Kentsch et al., Eur. J. Clin. Invest. 1992, 22(10):662-669; Kentsch et al., Eur. J. Clin. Invest. 1995, 25(4):281-283; Elsner et al., Am. Heart J. 1995, 129(4):766- 773; Forssmann et al., Clin. Pharmacol. Therap. 1998, 64(3):322-330; Fluge et al., Eur. J. Clin. Invest. 1995, 25:728-736; Carstens et al., BMC Gastroenterology 2007, 7(1): 1-9, and Carstens et al., J. Am. Soc. Nephrol. 1998, 9: 1489-1498).

[0005] Cirrhosis is associated with serious clinical problems such as sodium retention and ascites. Cirrhotic ascites accounts for about 75% of ascites patients with the remaining about 25% ascites occurrences being due to malignancies (10%), cardiac failure (3%), tuberculosis (2%), pancreatitis (1%) and other rarer causes (Moore et al., Hepatology 2003, 38:258-266 and Reynolds TB, Clin Liver Dis 2000, 4: 151-168). The prevalence of refractory ascites in patients with cirrhosis is 5-10% (Ring-Larsen H, Therapy of Ascites and Renal Dysfunction in Cirrhosis. Malden, Massachusetts: Blackwell Co. 1999, 480-491). Patients who suffer from cirrhosis and refractory ascites exhibit diuretic resistance (European Association for the Study of the Liver, J. Hepatol. 2010, 53:397-417).

[0006] Patients with refractory ascites have a survival rate as low as 50% at six to twelve months post-diagnosis (Cardenas and Arroyo, .Dig. Dis. 2005, 23:30-38 and Guardiola et al., Am. J. Gastroenterol. 2002; 97:2374-2378).

[0007] Currently, management of refractory ascites includes repeated large volume paracentesis, diuretics (Moore et al., Hepatology 2003, 38:258-266), transjugular intrahepatic portosystemic shunts (TIPS), peritoneovenous shunt, or liver transplantation (European Association for the Study of the Liver, J. Hepatol. 2010, 53:397-417 and Carstens et al., BMC Gastroenterology 2007, 7(1): 1-9).

[0008] There continues to be a need for new and more effective methods for treating refractory ascites.

[0009] All documents referenced herein are hereby incorporated by reference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

[0010] It is an object of the present invention to provide methods for the treatment of refractory ascites.

[0011] It is an object of the present invention to provide methods for preventing deterioration of refractory ascites.

[0012] It is an object of the present invention to provide methods for preventing or minimizing reoccurrence of refractory ascites (e.g., after the refractory ascites has been treated via paracentesis or transjugular intrahepatic portosystemic shunt (TIPS)).

[0013] The above objects and others are met by the present invention which in certain embodiments is directed to a method of treating refractory ascites comprising intravenously administering ularitide to a patient in need thereof continuously for a first time period of from about 2 hours to about 48 hours followed by subcutaneously administering ularitide to a patient in need thereof continuously for a second time period of from about 24 hours to about 6 months. The subcutaneous administration may be done through an infusion pump system or through an implantable drug depot composition. Continuous infusion is meant to include intervals where the infusion is temporarily stopped (e.g., due to lack of tolerability caused e.g. by ahypotensive state, to provide a bolus dose, change bags/devices, provide maintenance to the delivery system, etc.) as long as the interval does not result in a sub-therapeutic condition [0014] In certain embodiments, the present invention is directed to a method of treating refractory ascites or preventing deterioration of refractory ascites or preventing or minimizing reoccurrence of refractory ascites comprising subcutaneously administering ularitide via an infusion pump system to a patient in need thereof, wherein the infusion pump system releases a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of from about 24 hours to about 6 months.

[0015] In certain embodiments, the present invention is directed to a method of treating refractory ascites comprising intravenously administering ularitide to a patient in need thereof continuously for a first time period of from about 2 hours to about 168 hours (or from about 8 hours to about 84 hours, or from about 12 hours to about 48 hours, or any single duration value or sub-range of durations therein) followed by administering an implantable drug depot, wherein the implantable drug depot continuously releases a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of from about 24 hours to about 6 months.

[0016] In certain embodiments, the present invention is directed to a method of treating refractory ascites or preventing deterioration of refractory ascites or preventing or minimizing reoccurrence of refractory ascites comprising administering an implantable drug depot to a patient in need thereof, wherein the implantable drug depot releases a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of from about 24 hours to about 6 months.

[0017] In one embodiment, the methods of the present invention may result in the increase of the urine sodium excretion rate. In one embodiment, the methods of the present invention may result in the increase of urine flow. In another embodiment, the methods of the present invention may result in the increase of serum cGMP. [0018] In certain embodiments, the present invention is directed to a use of an implantable drug depot composition for the treatment of refractory ascites in a patient in need thereof. The implantable drug depot composition may comprise at least one biodegradable polymer and ularitide and may be capable of continuously releasing a therapeutically effective amount of ularitide to treat refractory ascites over a second time period ranging from about 24 hours to about 6 months.

[0019] In certain embodiments, the present invention is directed to a use of an infusion pump system for the treatment of refractory ascites on a patient in need thereof. The infusion pump system may comprise a wearable pump housing that receives ularitide to dispense to a patient in need thereof. The pump housing may at least partially contain a pump drive system to dispense ularitide to the patient. The infusion pump system may further comprise a controller that activates the pump drive system to dispense ularitide from the wearable pump housing. The infusion pump system may be capable of continuously releasing a therapeutically effective amount of ularitide to treat refractory ascites over a second time period ranging from about 24 hours to about 6 months.

BRIEF DESCRIPTION OF THE FIGURES

[0020] The above and other features of the present disclosure, their nature, and various advantages will become more apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which:

[0021] FIG. 1 depicts a standard method of treatment currently provided to patients hospitalized with refractory ascites.

[0022] FIG. 2 depicts a method of treating refractory ascites according to embodiments described herein. DEFINITIONS

[0023] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "an active agent" includes a single active agent as well as a mixture of two or more different active agents; and reference to an “excipient” includes a single excipient as well as a mixture of two or more different excipients, and the like.

[0024] As used herein, the term “about” in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment. In certain embodiments, the term “about” includes the recited number ±10%, such that “about 10” would include from 9 to 11.

[0025] As used herein, the terms "active agent" refer to any material that is intended to produce a therapeutic, prophylactic, pharmacologic, immunologic, metabolic, physical or other intended effect, whether or not approved by a government agency for that purpose. These terms with respect to specific agents include all pharmaceutically active agents, all pharmaceutically acceptable salts thereof, stereoisomers, crystalline forms, co-crystals, ether, esters, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.

[0026] The term "administrate" or "administration," as used herein (unless the mode of administration is explicitly specified), encompasses various methods of delivering a composition containing ularitide to a patient. Modes of administration may include, but are not limited to, methods that involve delivering the composition intravenously, intraperitoneally, intranasally, transdermally, topically, subcutaneously, parentally, intramuscularly, orally, or systemically, and via injection, ingestion, implantation, intraarterial, intracictemal, intradermal, nasal (aerosol or inhalation), buccal, intralesional, intracranial, intraprostatic, intrapleural, intratracheal, intravitreal, intravaginal, intrarectal, intratumoral, intraocular, subconjunctival, intravesicular, mucosal, intrapericardial, intrumbilical, local, by infusion, by continuous infusion, by bolus infusion, by absorption, by immersion, be localized perfusion, via catheter, via a lavage, by adsorption by any other means. One means of administering a composition comprising a ularitide is intravenous injection, where the composition is formulated as a sterile solution. Another route of administration is oral ingestion, where the ularitide can be formulated as a pharmaceutical composition in the form of a syrup, an elixir, a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an ointment, a lotion, a gel or an emulsion. In some embodiments, the pharmaceutical composition for oral ingestion is formulated for sustained release over a period of at least 24 hours, for immediate release, or for immediate release followed by a sustained release. Furthermore, administration of ularitide can be achieved by subcutaneous injection of a ularitide-containing composition, where the composition is formulated as a sterile solution and which is prepared as a sustained release system comprising microspheres or biodegradable polymers, such that the ularitide can be released into a patient's body at a controlled rate over a period of time.

[0027] An "effective amount" or a “therapeutically effective amount” or a “pharmacologically effective amount” refers to the amount of an active ingredient, e.g., ularitide, in a pharmaceutical composition that is sufficient to produce a beneficial or desired effect at a level that is readily detectable by a method commonly used for detection of such an effect. In some embodiments, such an effect results in a change of at least 10% from the value of a basal level where the active ingredient is not administered. In other embodiments, the change is at least 20%, 50%, 80%, or an even higher percentage from the basal level. As will be described below, the effective amount of an active ingredient may vary from subject to subject, depending on age, general condition of the subject, pre-existing or concomitant diseases of the subject, medical history of the subject, the severity of the condition being treated, and the particular biologically active agent administered and the like. An appropriate

"effective" amount in any individual case may be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation.

[0028] The term "natriuretic peptide" refers to a peptide that has the biological activity of promoting natriuresis, diuresis and vasodilation. Assays for testing such activity are known in the art, e.g., as described in U.S. Pat. Nos. 4,751,284 and 5,449,751. Examples of natriuretic peptides include, but are not limited to, atrial natriuretic peptide (ANP(99-126)), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), Dendroaspis natriuretic peptide (DNP), hybrid natriuretic peptides such as centeritide (a fusion between CNP and DNP), urodilatin (URO, or ularitide), and any fragments of the prohormone ANP(1-126) or BNP precursor polypeptide that retains the vasodilating, natriuretic or diuretic activity, long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), vessel dilator (VD), and combinations thereof. For further description of exemplary natriuretic peptides and their use or preparation, see, e.g., U.S. Pat. Nos. 4,751,284, 4,782,044, 4,895,932, 5,449,751, 5,461,142, 5,571,789, and 5,767,239. See also, Ha et al., Regul. Pept. 2006, 133(1-3): 13-19. The invention can also be practiced with peptides and proteins which may cause a diuresis or vasodilation effect such as relaxin.

[0029] As used in this application, the term "urodilatin" refers to a 32-amino acid peptide hormone that is described by U.S. Pat. No. 5,449,751 and has the amino acid sequence set forth in GenBank Accession No. 1506430A. Urodilatin, the 95-126 fragment of atrial natriuretic peptide (ANP), is also referred to as ANP(95-126). The term "atrial natriuretic peptide" or "ANP(99-126)" refers to a 28-amino acid peptide hormone, which is transcribed from the same gene and derived from the same polypeptide precursor, ANP(1-126), as urodilatin but without the first four amino acids at the N-terminus of urodilatin. For a detailed description of the prohormone, see, e.g., Oikawa et al., Nature 1984, 309:724-726 ; Nakayama et al., Nature 1984, 310:699-701 ; Greenberg et al., Nature 1984, 312:656-658 ; Seidman et al., Hypertension

1985, 7:31-34; and GenBank Accession Nos. 1007205A, 1009248A, 1101403A and AAA35529.

[0030] Conventionally, the term urodilatin (URO) is more often used to refer to the naturally occurring peptide, whereas the term ularitide is often used to refer to the recombinantly produced or chemically synthesized identical peptide. In this application, the term "urodilatin" and "ularitide" are used interchangeably to broadly encompass both a naturally occurring peptide and a recombinant or synthetic identical peptide. The terms also encompass any peptide of the above-cited amino acid sequence containing chemical modification (e.g., linearization, deamination, phosphorylation, PEGylation, etc.) at one or more residues or substitution by the corresponding D-isomer(s), so long as the peptide retains the biological activity as a natriuretic peptide. Furthermore, a chemically modified ularitide may contain one or two amino acid substitutions for the purpose of facilitating the desired chemical modification (e.g., to provide a reactive group for conjugation). "Urodilatin" or "ularitide" of this application, regardless of whether it contains chemical modifications, retains a substantial portion, i.e., at least 50%, preferably at least 80%, and more preferably at least 90%, of the biological activity of the naturally-occurring wild-type urodilatin or ANP(95-126). [0031] Any reference to ularitide should not be construed as limiting and should be understood as also being applicable to other natriuretic peptides, such as, without limitations, atrial natriuretic peptide (ANP(99-126)), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), Dendroaspis natriuretic peptide (DNP), hybrid natriuretic peptides such as centeritide (a fusion between CNP and DNP), urodilatin (URO, or ularitide), and any fragments of the prohormone ANP(1-126) or BNP precursor polypeptide that retains the vasodilating, natriuretic or diuretic activity, long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), vessel dilator (VD), and combinations thereof. [0032] The term "pharmaceutically acceptable excipient or carrier" refers to any pharmaceutically inert ingredient in a composition that may act, for example, to stabilize the active ingredient. A pharmaceutically acceptable excipient can include, but is not limited to, carbohydrates (such as glucose, sucrose, or dextrans), antioxidants (such as ascorbic acid or glutathione), chelating agents, low-molecular weight proteins, high-molecular weight polymers, gel-forming agents or other stabilizers and additives. Other examples of a pharmaceutically acceptable carrier include wetting agents, emulsifying agents, dispersing agents or preservatives, which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. Examples of carriers, stabilizers or adjuvants can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 18th ed. (1990).

[0033] As used herein, a "patient" refers to a subject, particularly a human (but could also encompass a non-human), who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated prophylactically for a condition, or who has been diagnosed with a condition to be treated.

[0034] The term “subject” encompasses the definition of the term “patient” and does not exclude individuals who are otherwise healthy.

[0035] The terms “treatment of’ and “treating” include the administration of an active agent(s) with the intent to lessen the severity of or prevent a condition, e.g., refractory ascites. [0036] The terms “prevention of’ and “preventing” include the avoidance of the onset of a condition, e.g., refractory ascites.

[0037] The term “condition” or “conditions” refers to those medical conditions, such as refractory ascites, that can be treated, mitigated or prevented by administration to a subject of an effective amount of an active agent (such as ularitide or pharmaceutically acceptable salt thereof). [0038] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to illuminate certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

DETAILED DESCRIPTION

[0039] FIG. 1 depicts the standard method of treatment 100 for patients with refractory ascites. According to block 110, patients with refractory ascites may get hospitalized. At the hospital, the patients may be treated for refractory ascites, in accordance with block 120. The patients may undergo paracentesis or transjugular intrahepatic portosystemic shunt (TIPS) to drain fluid from the abdominal cavity, in accordance with block 130. This therapy is conventionally combined with oral treatment administration of diuretics, such as, spironolactone and furosemide, in accordance with block 140. Thereafter, patients may get discharged from the hospital with a continuous oral treatment of spironolactone and furosemide, in accordance with block 150. However, it has been observed that after a time period of about four to about eight weeks at home, the refractory ascites reoccurs, in accordance with block 160. As a result, patients need to be again hospitalized to undergo paracentesis or TIPS to drain fluid from the abdominal cavity, in accordance with blocks 110, 120, and 130.

[0040] It would be beneficial to provide a treatment for patients experiencing refractory ascites that would allow drainage of fluid from the abdominal cavity of a patient without employing paracentesis or TIPS, and/or prevent or reduce reoccurrence of the ascites so as to minimize the patient’s need for hospitalization and for invasive procedures such as paracentesis or TIPS.

[0041] In certain embodiments, the present invention is directed to a method of treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites.

[0042] In certain embodiments, the method comprises administering an implantable drug depot that continuously releases a therapeutically effective amount of ularitide to treat refractory ascites and/or prevent deterioration of refractory ascites and/or prevent reoccurrence of refractory ascites over a time period of about 24 hours to about 6 months.

[0043] In certain embodiments, the method comprises administering subcutaneously ularitide via an infusion pump system to a patient in need thereof, wherein the infusion pump system continuously releases a therapeutically effective amount of ularitide to treat refractory ascites and/or prevent deterioration of refractory ascites and/or prevent reoccurrence of refractory ascites over a time period of about 24 hours to about 6 months.

[0044] In certain embodiments, any of the above methods may further comprise intravenously administering ularitide to a patient in need thereof continuously for a first time period of from about 2 hours to about 168 hours (or about 8 hours to about 84 hours, or about 12 hours to about 48 hours, or any single value or sub-range therein), prior to subcutaneous administration of an implantable drug depot or of an infusion pump system capable of releasing ularitide for a second time period of from about 24 hours to about 6 months.

[0045] In certain embodiments, any of the above methods may further comprise intravenously administering ularitide to a patient in need thereof as a bolus dose, prior to subcutaneous administration of an implantable drug depot or of an infusion pump system capable of releasing ularitide for a second time period of from about 24 hours to about 6 months.

[0046] The methods of the present invention can be utilized to treat refractory ascites. The refractory ascites may originate from one or more of cirrhosis, malignancy, cardiac failure, tuberculosis, pancreatitis, or other rare causes.

[0047] In certain embodiments, the present invention is directed to an implantable drug depot composition for treating refractory ascites and/or preventing deterioration of refractory ascites and/or reoccurrence of refractory ascites. The implantable drug depot may comprise at least one biodegradable polymer and ularitide and may be capable of releasing a therapeutically effective amount of ularitide to treat refractory ascites and/or prevent deterioration of refractory ascites and/or prevent reoccurrence of refractory ascites over a time period ranging from about 24 hours to about 6 months.

[0048] In certain embodiments, the present invention is directed to an infusion pump system for treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites. The infusion pump system may comprise a wearable pump housing that receives ularitide for dispensing to a patient in need thereof. The pump housing may at least partially contain a pump drive system to dispense ularitide to the patient. The infusion pump system may further comprise a controller that activates the pump drive system to dispense ularitide from the wearable pump housing.

[0049] By virtue of the present invention, the continuous administration of ularitide over a time period ranging from about 24 hours to about 6 months may result in improved outcomes (e.g., increasing urine sodium excretion rate, increasing urine flow, or increasing serum cGMP) compared to short treatment, outside of the time frame of the continuous administration. The continuous administration of ularitide may also maintain the patient’s improved state upon discharge from hospitalization over an extended duration and may minimize the patient’s need and/or frequency of re-hospitalization for repeated treatment of refractory ascites (e.g., for invasive procedures such as paracentesis or TIPS).

Method of Treatment

[0050] FIG. 2 depicts a method 200 of treating refractory ascites according to embodiments described herein. The method may comprise hospitalizing a patient with refractory ascites, in accordance with block 210. Upon hospitalization, the patient may be provided initial refractory ascites treatment, in accordance with block 220. The initial refractory ascites treatment may comprise treating the patient with paracentesis or TIPS to drain fluid from a patient’s abdominal cavity, pursuant to block 230. The initial treatment may also comprise orally administering a diuretic (e.g., spironolactone and/or furosemide) to the patient, pursuant to block 240. The initial treatment may also comprise intravenously administering ularitide to the patient, pursuant to block 250, and as described in further detail below.

[0051] Upon initiation of therapy (e.g., when a patient in need thereof is hospitalized with refractory ascites), the ularitide administration may be an immediate administration (e.g. by a parenteral bolus) or continuous over a time period of at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, at least about 18 hours, up to about 20 hours, up to about 22 hours, up to about 24 hours, up to about 30 hours, up to about 32 hours, up to about 36 hours, up to about 40 hours, up to about 44 hours or up to about 48 hours. In certain embodiments, the duration is from about 2 hours to about 168 hours, from about 2 hours to about 120 hours, from about 2 hours to about 48 hours, from about 2 hours to about 24 hours, from about 12 hours to about 120 hours, and in other embodiments, from about 12 hours to about 96 hours, from about 24 hours to about 96 hours, or from about 24 hours to about 72 hours, from about 24 hours to about 36 hours, or from about 36 hours to about 60 hours, or from about 40 hours to about 56 hours, from about 44 hours to about 52 hours, from about 46 hours to about 50 hours, about 48 hours, from about 4 hours to about 144 hours, from about 8 hours to about 120 hours, from about 16 hours to about 72 hours, from about 20 hours to about 48 hours, or for about 30 hours, or any sub-range or single duration value therein. A preferred means for administering the ularitide initially (as a bolus or continuously) is by parenteral (e.g., intravenous) administration.

[0052] In some embodiments, the initial administration at the hospital may further comprise a bolus dose of ularitide (e.g. by a parenteral bolus). The bolus dose may occur over a duration of about 5 minutes to about 90 minutes, about 15 minutes to about 75 minutes, about 30 minutes to about 60 minutes, or about 45 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or any range in between.

[0053] The rate of bolus administration may range from about 300 ng/kg/minute to about 5000 ng/kg/minute, from about 1000 ng/kg/minute to about 4000 ng/kg/minutes, from about 2000 ng/kg/minute to about 3000 ng/kg/minute, or about 300 ng/kg/minute, about 500 ng/kg/minute, about 1000 ng/kg/minute, about 2000 ng/kg/minute, about 3000 ng/kg/minute, about 4000 ng/kg/minute, or any range in between.

[0054] In some embodiments, the bolus administration may precede the continuous administration of ularitide. In other embodiments, the bolus administration may come after the completion of an initial continuous intravenous administration of ularitide. In yet other embodiments, the bolus administration may intervene the initial continuous intravenous administration of ularitide. For instance, if an initial total amount of ularitide (ULAtotaic) is to be administered continuously at the hospital, 50% of ULAtotaic may be administered continuously, followed by a break in continuous administration to allow for a bolus administration of ularitide, which may then be followed by completion of the remaining 50% of ULAtotaic to be administered continuously. Similar breaks to allow for bolus administration in the middle of the continuous administration may occur, e.g., after about 10% of ULAtotaic is administered, after about 20% of ULAtotaic is administered, after about 30% of ULAtotaic is administered, after about 40% of ULAtotaic is administered, after about 50% of ULAtotaic is administered, after about 60% of ULAtotaic is administered, after about 70% of ULAtotaic is administered, after about 80% of ULAtotaic is administered, after about 90% of ULAtotaic is administered, or any range in between.

[0055] In some embodiments, the initial continuous intravenous administration of ularitide may be stopped once to allow for bolus administration of ularitide. In other embodiments, the initial continuous intravenous administration of ularitide may be stopped a plurality of times, e.g., twice, three times, four times, five times, six times, 7 times, 8 times, 9 times, 10 times, etc. to allow for a plurality of bolus administrations of ularitide.

[0056] When the peptide (e.g., ularitide) is administered parenterally at the hospital, the administration can be, e.g., by injection or infusion. When the parenteral administration is by injection, the route can be intravenous (into a vein), subcutaneous (under the skin), intradermal (into the skin), intramuscular (into muscle), intraperitoneal (into the abdominal cavity), intravitreal (intraocular), intracerebral or intraspinal. When the parenteral administration is by infusion, it is typically by an intravenous or subcutaneous route. The parenteral administration can be by a sterile dosage form that is a sterile solution, suspension or emulsion.

[0057] For the present invention, the ularitide that is administered in the hospital, can be formulated for administration by a variety of techniques, including, for example, intravenous, intra-arterial, subcutaneous, intramuscular, intracictemal, intraperitoneal, intradermal, transdermal, nasal (inhalation or aerosol), buccal, topical, intralesional, intracranial, intraprostatic, intrapleural, intratracheal, intranasal, intravitreal, intrathecal, intravaginal, intrarectal, intratumoral, intraocular, subconjunctival, intravesicular, transmucosal, intramedullary, intestinal, parenteral, intrapericardial, intrumbilical, direct intraventricular, intraperitoneal, oral, local, by injection, by infusion, by continuous infusion, by absorption, by adsorption, by immersion, by localized perfusion, via a catheter, or via a lavage, among others. [0058] In another embodiment, one or more different active agents (e.g., diuretics and aldosterone antagonists) are administered to the patient. These one or more different active agents may be administered in combination with the ularitide, for example, by the same route (e.g., intravenously), with the option of being in one single pharmaceutical composition or two or more separate compositions; or these one or more different active agents may be administered separately by a different means (e.g., by oral ingestion). In some embodiments, the ularitide may be administered with other diuretics, such as, without limitations, spironolactone, furosemide, or a combination thereof.

[0059] Returning to FIG. 2, after providing initial refractory ascites treatment to the patient at the hospital, pursuant to block 220, the patient may be discharged from the hospital while being continuously subcutaneously administered ularitide for a second time period of from about 24 hours to about 6 months, pursuant to block 260.

[0060] In some embodiments, e.g., upon discharge from hospitalization, a patient may be administered an implantable drug depot composition for treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites. The implantable drug depot composition may comprise at least one biodegradable polymer and ularitide and may continuously release a therapeutically effective amount of ularitide to treat refractory ascites over a second time period ranging from about 24 hours to about 6 months. In some embodiments, the implantable drug depot composition may be administered subcutaneously to a patient in need thereof.

[0061] The at least one biodegradable polymer in the implantable drug depot composition may comprise one or more of poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-e- caprolactone, D,L-lactide-co-glycolide-co-e-caprolactone polyhydroxybutyrate, poly(glycolide-co-trimethylenecarbonate), poly(lactic acid-co-lysine), poly(lactide-co- urethane), poly(ester-co-amide), PEG conjugates of poly (alpha-hydroxy acids), poly(orthoester)s, polyaspirins, polyphosphazenes, polyanhydrides, polyketals, collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs (such as alpha tocopheryl acetate, d-alpha tocopheryl succinate), e- caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT- PBT copolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate) or a combination thereof.

[0062] In some embodiments, e.g., upon discharge from hospitalization, a patient may be administered ularitide via an infusion pump system to treat refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites. The infusion pump system may comprise a wearable pump housing that receives ularitide for dispensing to a patient in need thereof. The pump housing may at least partially contain a pump drive system to dispense ularitide to the patient. The infusion pump system may further comprise a controller that activates the pump drive system to dispense ularitide from the wearable pump housing.

[0063] Suitable infusion pump systems may comprise a wearable pump housing that receives ularitide to dispense to a patient in need thereof. The pump housing may at least partially contain a pump drive system to dispense ularitide to the patient. The infusion pump system may further comprise a controller that activates the pump drive system to dispense ularitide from the wearable pump housing. In some embodiments, the infusion pump system may comprise a user interface coupled to a controller to allow a user to control the rate and/or dose of administration of ularitide. In other embodiments, the infusion pump system may be pre-programmed to continuously subcutaneously administer a therapeutically effective amount of ularitide to treat refractory ascites. It should be understood by the skilled artisan that other suitable external infusion pumps may also be used to continuously release a therapeutically effective amount of ularitide over a second time period ranging from about 24 hours to about 6 months.

[0064] In some embodiments, the implantable drug depot composition or the infusion pump system may continuously release a therapeutically effective amount of ularitide to treat refractory ascites and/or prevent deterioration of refractory ascites and/or prevent reoccurrence of refractory ascites over a second time period of from any of about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 108 hours, about 120 hours, about 132 hours, about 144 hours, about 156 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 week to any of about 30 days, about 5 week, about 6 week, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks.

[0065] The ularitide compositions used in the method of this invention (for an initial bolus and/or continuous intravenous administration and/or for continuous subcutaneous administration) optionally further comprises a pharmaceutically acceptable excipient or carrier. For example, mannitol may be used in such a pharmaceutical composition. In an exemplary embodiment, the concentration of mannitol is two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times the concentration of the ularitide (or any range within these values). In another exemplary embodiment, the composition is an aqueous solution of 0.9% NaCl in which the ularitide is dissolved. In one particular embodiment of the method, the composition is an aqueous solution of 0.9% NaCl in which ularitide and mannitol are dissolved.

[0066] In the methods described herein, the continuous intravenous administration of ularitide in the hospital may occur over a first period of time and the continuous subcutaneous release of ularitide may occur over a second period of time.

[0067] The first period of time may range from about 2 hours to about 168 hours, from about 2 hours to about 120 hours, from about 2 hours to about 48 hours, from about 2 hours to about 24 hours, from about 12 hours to about 120 hours, and in other embodiments, from about 12 hours to about 96 hours, from about 24 hours to about 96 hours, or from about 24 hours to about 72 hours, from about 24 hours to about 36 hours, from about 36 hours to about 60 hours, from about 40 hours to about 56 hours, from about 44 hours to about 52 hours, from about 46 hours to about 50 hours, about 48 hours, from about 4 hours to about 144 hours, from about 8 hours to about 120 hours, from about 16 hours to about 72 hours, from about 20 hours to about 48 hours, or for about 30 hours, or any sub-range or single value therein. In other embodiments, the ularitide is administered to a patient in need thereof continuously for a time period between about 12 hours and about 72 hours, or between about 24 hours and about 60 hours, or between about 36 hours and about 54 hours or about 46 hours. Continuous infusion is meant to include intervals where the infusion is stopped (e.g., to provide a bolus dose, change bags, provide a bolus dose etc.) as long as the interval does not result in a subtherapeutic condition.

[0068] The second period of time may range any of about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 108 hours, about 120 hours, about 132 hours, about 144 hours, about 156 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 week to any of about 30 days, about 5 week, about 6 week, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks, or any sub-range or single value therein.

Implantable Drug Depot Composition

[0069] In another aspect, the present invention is directed to an implantable drug depot composition for treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites. The implantable drug depot composition may comprise at least one biodegradable polymer and ularitide. The implantable drug depot composition may be capable of releasing a therapeutically effective amount of ularitide to treat refractory ascites over a second time period ranging from about 24 hours to about 6 months.

[0070] In certain embodiments, the implantable drug depot composition may be capable of continuously releasing a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of from any of about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 108 hours, about 120 hours, about 132 hours, about 144 hours, about 156 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 week to any of about 30 days, about 5 week, about 6 week, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks, or any sub-range or single value therein.

[0071] The at least one biodegradable polymer that may be used in the implantable drug depot composition may comprise one or more of poly(alpha-hydroxy acids), poly(lactide-co- glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-e-caprolactone, D,L-lactide-co-glycolide-co-e-caprolactone polyhydroxybutyrate, poly(glycolide-co-trimethylenecarbonate), poly(lactic acid-co-lysine), poly(lactide-co-urethane), poly(ester-co-amide), PEG conjugates of poly (alpha-hydroxy acids), poly(orthoester)s, polyaspirins, polyphosphazenes, polyanhydrides, polyketals, collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs (such as alpha tocopheryl acetate, d-alpha tocopheryl succinate), e- caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT- PBT copolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate) or a combination thereof.

Infusion Pump System

[0072] In another aspect, the present invention is directed to an infusion pump system for treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites. The infusion pump system may comprise a wearable pump housing that receives ularitide for dispensing to the patient in need thereof. The pump housing may at least partially contain a pump drive system to dispense ularitide to the patient. The infusion pump system may further comprise a controller that activates the pump drive system to dispense ularitide from the wearable pump housing.

[0073] In some embodiments, the infusion pump system may comprise a user interface coupled to a controller to allow a user to control the rate and/or dose of administration of ularitide. In other embodiments, the infusion pump system may be pre-programmed to continuously subcutaneously administer a therapeutically effective amount of ularitide to treat refractory ascites. It should be understood by the skilled artisan that other external infusion pumps may also be used to continuously release a therapeutically effective amount of ularitide over a time period ranging from about 24 hours to about 6 months. [0074] In certain embodiments, the infusion pump system may be capable of continuously releasing a therapeutically effective amount of ularitide to treat refractory ascites over a time period of from any of about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 108 hours, about 120 hours, about 132 hours, about 144 hours, about 156 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 week to any of about 30 days, about 5 week, about 6 week, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks, or any sub-range or single value therein.

Ularitide Medicament Composition

[0075] In yet another aspect, the present invention provides the use of ularitide for the manufacture of a medicament for the treatment of refractory ascites. The medicament may contain, in addition to an effective amount of the active agent (e.g., ularitide), a pharmaceutically acceptable excipient or carrier. In one embodiment, the medicament is formulated for continuous intravenous administration over a first time period of at least about 2 hours. In other embodiments, the medicament is formulated for continuous intravenous administration over a time period between about 2 hours and about 168 hours, or any sub-range therein. In some cases, the medicament is formulated for continuous intravenous administration of the active agent over a period of at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, at least about 18 hours, up to about 20 hours, up to about 22 hours, up to about 24 hours, up to about 30 hours, up to about 32 hours, up to about 36 hours, up to about 40 hours, up to about 44 hours or up to about 48 hours. In certain embodiments, the duration is from about 2 hours to about 168 hours, from about 2 hours to about 120 hours, from about 2 hours to about 48 hours, from about 2 hours to about 24 hours, from about 12 hours to about 120 hours, and in other embodiments, from about 12 hours to about 96 hours, from about 24 hours to about 96 hours, or from about 24 hours to about 72 hours, from about 24 hours to about 36 hours, or from about 36 hours to about 60 hours, or from about 40 hours to about 56 hours, from about 44 hours to about 52 hours, from about 46 hours to about 50 hours, about 48 hours, from about 4 hours to about 144 hours, from about 8 hours to about 120 hours, from about 16 hours to about 72 hours, from about 20 hours to about 48 hours, or for about 30 hours, or any sub-range or single value therein. For example, the administration of the ularitide-containing medicament via continuous intravenous administration for a first time period may last about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 96 hours, about 120 hours or any desirable time duration within this range.

[0076] In some embodiments, the medicament formulated for continuous intravenous administration and/or for continuous subcutaneous administration is administered in a manner such that the patient is receiving the active agent (e.g., ularitide) at a rate of at least about 1 ng/kg/minute, of at least about 2 ng/kg/minute, of at least about 5 ng/kg/minute, of at least about 7.5 ng/kg/minute, of at least about 10 ng/kg/minute, of at least about 15 ng/kg/minute, of at least about 20 ng/kg/minute, of at least about 30 ng/kg/minute, of at least about 45 ng/kg/minute, of at least about 60 ng/kg/minute, of at least about 75 ng/kg/minute, of at least about 100 ng/kg/minute, or of at least about 200 ng/kg/minute, or any desirable administration rate within this range such as for instance from about 1 ng/kg/minute to about 250 ng/kg/minute. In other embodiments, the administration rate is about 7.5 ng/kg/ minute, about 15 ng/kg/minute, about 20 ng/kg/minute, about 30 ng/kg/minute, about 45 ng/kg/minute, about 60 ng/kg/minute, about 100 ng/kg/minute, or about 200 ng/kg/minute. In one preferred example, ularitide is administered at the rate of about 15 ng/kg/minute.

[0077] In one embodiment, the medicament is formulated for continuous subcutaneous administration over a time period of at least about 24 hours. In other embodiments, the medicament is formulated for continuous subcutaneous administration over a time period between about 24 hours and about 6 months. In some cases, the medicament is formulated for continuous subcutaneous administration of the active agent (e.g., as an implantable drug depot or in a cartridge form for an infusion pump system) over a period of any of at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60 hours, at least about 72 hours, at least about 84 hours, at least about 96 hours, at least about 108 hours, at least about 120 hours, at least about 132 hours, at least about 144 hours, at least about 156 hours, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, to any of about 30 days, about 5 week, about 6 week, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks, or any sub-range or single value therein.

[0078] The ularitide injectable compositions described herein (for intravenous or subcutaneous administration) may be formulated with an aqueous diluent, suitably mixed with other optional additives such as a surfactant and/or a preservative for proper fluidity, stability and sterility of the composition, necessary for easy storage and injection. The injectable solution containing the ularitide may be prepared using a solvent or dispersion medium including water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and/or vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating material, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the proliferation of microorganisms can be facilitated by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. The injectable solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. Lastly, the injectable solution, once prepared by incorporating the active agents in the required amount in the appropriate solvent with optional excipients, is sterilized using a method that does not inactivate the active ingredient(s) of the composition, e.g., by filtered sterilization.

[0079] As disclosed herein, the ularitide can be formulated with mannitol. Non-limiting examples of other sugars that may be used in embodiments of the present invention include abequose, allose, allulose, altrose, apiose, arabinose, beet oligosaccharides, bifurcose, deoxyribose, dextrose(D-glucose), erlose, erythrose, erythrulose, fructose (levulose), fucose, fuculose, galactose, gentiobiose, gentiotriose, gentiotetraose, gulose, hamamelose, inulobiose, inulotriose, inulotetraose, isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose, isomaltulose (palatinose), kestose, kojibiose, lactose, lactulose, laminaribiose, lyxose, mannose, maltose, maltotriose, maltotetraose, maltulose, meletzitose, melibiose, methose, nigerose, nystose, panose, paratose, primeverose, psicose, raffinose, rhamnose, ribose, ribulose, rutinose, sorbinose, sorbose, soybean oligosaccharides, stachyose, sucrose, tagatose, talose, theanderose, threose, trehalose, turanose, xylobiose, xylotriose, xylose or xylulose. The carbohydrates used in embodiments of the present invention may be of their respective D- or

L-configurations. In certain embodiments, non-limiting examples of sugar alcohols that may be used include allitol, arabitol, erythritol, galactitol, glycerol, glycol, iditol, inositol, isomalt, lactitol, maltotetraol, maltotriol, ribitol, sorbitol, talitol, threitol and xylitol. The sugar alcohols used in embodiments according to the present invention may be of their respective the D- or L- configurations. These sugar alcohols have the benefits of having low glycemic indices.

[0080] In the foregoing description, numerous specific details are set forth, such as specific materials, dimensions, processes parameters, etc., to provide a thorough understanding of the present invention. The particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words “example” or “exemplary” are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “example” or “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects or designs. Rather, use of the words “example” or “exemplary” is simply intended to present concepts in a concrete fashion. As used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or”. That is, unless specified otherwise, or clear from context, “X includes A or B” is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied under any of the foregoing instances. Reference throughout this specification to “an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.

[0081] The present invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0082] Prophetic Example

[0083] A patient is admitted to the hospital fur to refractory ascites. The patient is intravenously administered ularitide for a first time period of about 48 hours. After treatment the patient is discharged with a subcutaneous pump to provide ularitide continuously for a second time period of about 1 month.

Claims

We claim: A method of treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites comprising intravenously administering ularitide to a patient in need thereof continuously for a first time period of about 2 hours to about 168 hours followed by subcutaneously administering ularitide to the patient continuously for a second time period of about 24 hours to about 6 months. The method of claim 1, wherein subcutaneously administering is done via an infusion pump system or via an implantable drug depot composition. A method of treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites comprising subcutaneously administering ularitide via an infusion pump system to a patient in need thereof, wherein the infusion pump system continuously releases a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of about 24 hours to about 6 months. The method of any one of claims 2-3, wherein the infusion pump system comprises a wearable pump housing that receives ularitide to dispense to the patient, the pump housing at least partially containing a pump drive system to dispense ularitide to the patient, and a controller that activates the pump drive system to dispense ularitide from the wearable pump housing. A method of treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites comprising intravenously administering

29 ularitide to a patient in need thereof continuously for a first time period of about 2 hours to about 168 hours followed by administering an implantable drug depot composition, wherein the implantable drug depot composition continuously releases a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of about 24 hours to about 6 months. A method of treating refractory ascites and/or preventing deterioration of refractory ascites and/or preventing reoccurrence of refractory ascites comprising administering an implantable drug depot composition to a patient in need thereof, wherein the implantable drug depot composition continuously releases a therapeutically effective amount of ularitide to treat refractory ascites over a second time period of about 24 hours to about 6 months. The method of any one of claims 2 or 5-6, wherein the implantable drug depot composition comprises at least one biodegradable polymer and ularitide. The method of claim 7, wherein the at least one biodegradable polymer comprises one or more of poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-e-caprolactone, D,L- lactide-co-glycolide-co-e-caprolactone polyhydroxybutyrate, poly(glycolide-co- trimethylenecarbonate), poly(lactic acid-co-lysine), poly(lactide-co-urethane), poly(ester-co- amide), PEG conjugates of poly (alpha-hydroxy acids), poly(orthoester)s, poly aspirins, polyphosphazenes, polyanhydrides, polyketals, collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs (such as alpha tocopheryl acetate, d-alpha tocopheryl succinate), e-caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (poly active), PEO-PPO-PAA

30 copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate) or a combination thereof. The method of any one of the preceding claims, wherein the refractory ascites originates from one or more of cirrhosis, malignancy, cardiac failure, tuberculosis, pancreatitis, or other rare causes. The method of any one of the preceding claims, wherein the second time period ranges from any of about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, about 108 hours, about 120 hours, about 132 hours, about 144 hours, about 156 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 week to any of about 30 days, about 5 week, about 6 week, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks. The method of any one of the preceding claims, wherein the ularitide is intravenously or subcutaneously administered at a rate of about 1 ng/kg/min to about 250 ng/kg/minute, about 7.5 ng/kg/minute, about 15 ng/kg/minute, about 20 ng/kg/minute, about 30 ng/kg/minute, about 45 ng/kg/minute, about 60 ng/kg/minute, about 100 ng/kg/minute, or about 200 ng/kg/minute. The method of any one of the preceding claims, wherein the first time period for the intravenous administration is from about 4 hours to about 144 hours, from about 8 hours to about 120 hours, from about 12 hours to about 96 hours, from about 16 hours to about 72 hours, from about 20 hours to about 48 hours, or from about 24 hours to about 36 hours. An infusion pump system for treating refractory ascites, comprising: a wearable pump housing that receives ularitide to dispense to a patient in need thereof; a pump housing partially containing a pump drive system to dispense ularitide to the patient; and a controller that activates the pump drive system to dispense ularitide from the wearble pump housing, wherein the infusion pump system is capable of continuously releasing a therapeutically effective amount of ularitide to treat refractory ascites over a second time period ranging from about 24 hours to about 6 months. An implantable drug depot composition for treating refractory ascites, the implantable drug depot composition comprising at least one biodegradable polymer and ularitide, wherein the implantable drug depot composition is capable of continuously releasing a therapeutically effective amount of ularitide to treat refractory ascites over a second time period ranging from about 24 hours to about 6 months. The implantable drug depot composition of claim 14, wherein the at least one biodegradable polymer comprises one or more of poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L- lactide-co-e-caprolactone, D,L-lactide-co-glycolide-co-e-caprolactone polyhydroxybutyrate, poly(glycolide-co-trimethylenecarbonate), poly(lactic acid-co-lysine), poly(lactide-co- urethane), poly(ester-co-amide), PEG conjugates of poly (alpha-hydroxy acids), poly(orthoester)s, polyaspirins, polyphosphazenes, polyanhydrides, polyketals, collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs (such as alpha tocopheryl acetate, d-alpha tocopheryl succinate), e- caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT- PBT copolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate) or a combination thereof.

33