Terlipressin preparations

Abstract

The present disclosure provides pharmaceutical compositions comprising terlipressin having increased concentration and long-term storage stability.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 851,366 filed on May 22, 2019, the contents of which are incorporated herein by reference in their entirety.

[0003] background Technical Field

[0004] The present disclosure relates to stable pharmaceutical compositions having increased concentrations of terlipressin at room or ambient temperature or under refrigeration. Background Art

[0005] Terlipressin is a synthetic vasopressin approved for the treatment of life-threatening complications of cirrhosis in many countries outside the United States, including hepatorenal syndrome (HRS) and esophageal bleeding (EVB). Due to its short half-life, its application is limited to hospital settings (Nilsson, et al., (1990) Drugs Explt Clin. Res., XVI (6): 307-314), and it is usually required to be administered as an intravenous (IV) bolus every 4-6 hours. In addition, terlipressin can cause side effects in up to 40% of patients. Severe side effects (including myocardial infarction, arrhythmia and intestinal obstruction) may require up to 10% of patients to discontinue treatment (Angeli, (2011) Ascites, Hyponatremia and Hepatorenal Syndrome: Progress in Treatment, 28: 189-197). Indeed, due to its rapid vasoconstrictor properties, intravenous bolus administration of terlipressin must be used with caution in patients with severe asthma, severe hypertension, advanced atherosclerosis, cardiac arrhythmias, and coronary insufficiency.

[0006] Patients with cirrhosis presenting with type 1 hepatorenal syndrome (HRS-1) have been safely treated with continuous terlipressin outside the United States. The dose range is 2.0-12.0 mg / 24 hours (Angeli, et al., (2009) Journal of Hepatology, 50: S73: 2.0-12.0 mg / 24h; Gerbes, (2009) Gastroenterology, 137: 1179-1189: starting dose 3.0 mg / day; Robertson, et al., (2014) Hepatology, 60(6): 2125-2126: 3.0 mg / day; Ding, et al., (2013), Gastroenterology and Hepatology, 28: 1242-1246: 4.0 mg / day; Cavallin, et al., (2015), Hepatology, 62(2): 567-574: 3-12 mg / day). In the approximately 40 countries where terlipressin is approved, it is usually provided as a lyophilized powder (Glypressin SmPC) or, in some countries, as a liquid in a vial (EVERject label). Both of these forms need to be prepared by a medical professional before they can be administered in a hospital setting.

[0007] There are currently two forms of terlipressin: a lyophilized powder for reconstitution or as a liquid in a vial (0.2 mg / mL). The lyophilized form is usually provided in a vial containing 1 mg of terlipressin powder, reconstituted using an ampoule of 5 mL of saline solution provided (e.g., Glypressin, Ferring Pharmaceuticals is provided in a vial containing 1 mg of terlipressin acetate for reconstitution in 5 mL of solution) to deliver a 0.17 mg / mL terlipressin (0.2 mg / mL terlipressin acetate) solution for injection. Two or three pre-steps are required to administer the product: reconstitute the powder with a diluent, draw the solution, and possibly dilute it further, and then inject it directly into the patient's body or into the patient's intravenous line or IV bag via a slow bolus dose. Glypressin needs to be stored refrigerated at a temperature of 2°C to 8°C.

[0008] Liquid terlipressin acetate 0.2 mg / mL solution for injection (terlipressin acetate, Ever Pharma) is also unstable at room temperature (RT) and requires refrigerated storage at a temperature of 2°C to 8°C. It is provided in vials containing 5 mL or 10 mL of solution. The solution is drawn into a syringe and administered by bolus injection. The current formulation uses acetic acid to adjust the pH of the terlipressin acetate solution.

[0009] Therefore, there is a need for a prefilled syringe product form to simplify the administration of terlipressin by administering the product directly into the patient or through an intravenous line or IV bag placed in the patient. There is also a need for a terlipressin formulation that is stable at room temperature for a period of time, which allows use at home or in rapid access environments (such as ICUs or ambulances), or other environments where terlipressin can be used without the need for refrigerated space and with minimal medical staff handling. Summary of the invention

[0010] One aspect of the present disclosure provides an aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the composition comprises about 0.2 to about 10.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is about 3.4 to about 5.0.

[0011] In some embodiments of the present disclosure, the composition has a total amount of impurities that is less than 4.5% of the total weight of the impurities and terlipressin in the composition.

[0012] In some embodiments of the present disclosure, the pH of the composition is in the range of 4.0 to 5.0.

[0013] In some embodiments of the present disclosure, the composition is stable for at least 24 months at about 25°C and at least 6 months at 30°C and about 75% relative humidity, or for up to 26 weeks at about 30°C to about 40°C and about 75% relative humidity, or for up to 2 years at about 25°C and about 60% relative humidity.

[0014] In some embodiments of the present disclosure, the composition is stored at 2°C to 8°C.

[0015] In some embodiments of the present disclosure, the composition comprises a stabilizer. In some embodiments of the present disclosure, the stabilizer is aspartic acid.

[0016] In some embodiments of the present disclosure, the composition comprises an isotonic agent. In some embodiments of the present disclosure, the isotonic agent is dextrose or sodium chloride.

[0017] In some embodiments of the present disclosure, the composition comprises a pH adjuster. In some embodiments of the present disclosure, the pH adjuster is hydrochloric acid, potassium hydroxide, acetic acid, sodium hydroxide or potassium hydroxide.

[0018] Another aspect of the present disclosure provides a prefilled syringe comprising an aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the composition comprises about 0.2 to about 10.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is about 3.4 to about 5.0.

[0019] In some embodiments of the present disclosure, the head space within the syringe comprises nitrogen.

[0020] Another aspect of the present disclosure provides a kit comprising an aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the composition comprises about 0.2 mg / mL to about 10.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is about 3.4 to about 5.0, wherein the kit comprises a container for the composition, wherein the container optionally has a means for injecting the composition into a subject.

[0021] In some embodiments of the present disclosure, the container is a syringe pre-filled with the composition. In other embodiments of the present disclosure, the pre-filled syringe is made of glass or plastic.

[0022] In some embodiments of the present disclosure, the kit further comprises a needle and / or a syringe rod.

[0023] In some embodiments of the present disclosure, the kit further comprises instructions for administering the composition. In other embodiments of the present disclosure, the instructions provide for administering the composition by continuous infusion or as a bolus intravenous dose.

[0024] In some embodiments of the present disclosure, continuous infusion is administered using an ambulatory pump or other controlled delivery device.

[0025] In some embodiments of the present disclosure, the instructions provide the option of administering the composition by injecting the composition into a diluent container, which can then be connected to or inserted into an ambulatory pump for continuous infusion.

[0026] Yet another aspect of the present disclosure provides an aqueous composition consisting of terlipressin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvent, a stabilizer, an isotonic agent, and a pH adjuster, wherein the composition comprises 0.2 mg / mL to 10.0 mg / mL terlipressin or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is from about 3.4 to about 5.0, wherein after the composition is stored at about 40° C. and about 75% relative humidity for 12 weeks, and wherein the composition has a total amount of impurities of less than about 4.5% of the total weight of the impurities and terlipressin in the composition.

[0027] In some embodiments of the present disclosure, the composition consists of: terlipressin or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg / mL to about 10.0 mg / mL, aspartic acid in an amount of about 0.1 mg / mL to about 2 mg / mL, dextrose, succinic acid, sodium hydroxide, and water.

[0028] In other embodiments of the present disclosure, the composition consists of terlipressin or a pharmaceutically acceptable salt thereof in an amount of about 0.2 mg / mL to about 1.0 mg / mL, sodium acetate, sodium hydroxide, and water.

[0029] In other embodiments of the present disclosure, the composition consists of: terlipressin or a pharmaceutically acceptable salt thereof in an amount of 0.2 mg / mL, methionine in an amount of about 1.0 mg / mL, dextrose in an amount of about 50.0 mg / mL, succinic acid in an amount of about 1.2 mg / mL, sodium hydroxide and water.

[0030] In some embodiments of the present disclosure, the pharmaceutically acceptable solvent is water.

[0031] In some embodiments of the present disclosure, the stabilizer is aspartic acid, acetic acid, adipic acid, citric acid, maleic acid, succinic acid, or phosphate.

[0032] In some embodiments of the present disclosure, the isotonic agent is dextrose or sodium chloride.

[0033] In some embodiments of the present disclosure, the pH adjuster is acetic acid, hydrochloric acid, or sodium hydroxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The foregoing aspects and other features of the present disclosure are explained in the following description in conjunction with the accompanying drawings, in which:

[0035] Figure 1 Overlaid HPLC chromatograms of terlipressin acetate and aspartate formulations (without nitrogen protection) at pH 4.5, 2°C-8°C for 3 months.

[0036] Figure 2 Overlapping HPLC chromatograms of terlipressin acetate and aspartate formulations (without nitrogen protection) at pH 4.5, 25°C for 3 months. Peaks U1 and U2 are impurities.

[0037] Figure 3 Overlapping HPLC chromatograms of terlipressin acetate and aspartate formulations (without nitrogen protection) at pH 4.5, 40°C for 3 months. Peaks U1 and U2 are impurities.

[0038] Figure 4Overlay of HPLC chromatograms showing the effect of temperature on terlipressin aspartate formulations at 2°C-8°C, 25°C and 40°C at pH 4.5 (without nitrogen blanket) for 3 months.

[0039] Figure 5 Overlay of HPLC chromatograms showing the effect of temperature on terlipressin acetate formulations at 2°C-8°C, 25°C and 40°C at pH 4.5 (without nitrogen blanket) for 3 months. DETAILED DESCRIPTION

[0040] The present disclosure relates to a liquid formulation of terlipressin, which has been optimized for pre-filled syringe product form and simplifies drug delivery, particularly for rapid use and outpatient settings. In one aspect, the formulation can be injected into a diluent container, which is connected to or inserted into a mobile pump to controllably infuse the diluent / terlipressin into the patient. Alternatively, the formulation can be directly infused without dilution or administered as an IV bolus.

[0041] definition

[0042] The articles "a" and "an" are used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an element" means at least one element and may include more than one element.

[0043] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. It should also be understood that the terms "including," "comprising," or "having," and variations thereof, used herein, are meant to include the elements listed thereafter and their equivalents as well as additional elements. Embodiments listed as "including," "comprising," or "having" certain elements are also contemplated as "consisting essentially of" and "consisting of" certain elements.

[0044] Unless otherwise indicated herein, the recitation of numerical ranges herein is intended merely to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is recited as 1% to 50%, it is intended that values ​​such as 2% to 40%, 10% to 30%, or 1% to 3% are expressly recited in this specification. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​between and including the lowest and highest values ​​recited are considered to be expressly stated in this disclosure.

[0045] The term "about" in connection with a numerical value means that the numerical value may vary by plus or minus 5% or less of the numerical value.

[0046] The term "excipient" includes non-therapeutic agents added to pharmaceutical compositions to provide the desired consistency or stabilization. Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc.

[0047] The term "patient" refers to non-human animals. The term "non-human animal" of the present disclosure includes all vertebrates, for example, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The patient can be a human patient at risk of or suffering from a complication of cirrhosis (e.g., ascites).

[0048] The term "pharmaceutical composition" or "pharmaceutical formulation" refers to a preparation which is in such a form that the biological activity of the active ingredient is clearly effective and which does not contain additional components which are significantly toxic to the subject to which the preparation is to be administered. "Pharmaceutically acceptable" excipients (vehicles, additives) are those which can reasonably be administered to a patient to provide an effective dose of the active ingredient employed.

[0049] The term "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions or vehicles suitable for administration to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, which are involved in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.

[0050] Terlipressin (also referred to herein as terlipressin acetate) is a synthetic triglycyllysine derivative of vasopressin with vasoconstrictor, antihemorrhagic and antidiuretic properties. Terlipressin is an inactive peptide prodrug having the amino acid sequence GGGCYFQNCPKG, which is bioconverted to its more active form, lysine vasopressin, after administration. Suitable salts of terlipressin include, but are not limited to, terlipressin acetate.

[0051] Stable aqueous formulation of terlipressin

[0052] The aqueous pharmaceutical composition of the present disclosure comprising terlipressin acetate or a pharmaceutically active salt thereof and having a pH within the range of about 3.4 to about 5.0 can be stored at room temperature (e.g., at about 25° C. and about 60% relative humidity) for a sustained period of time (e.g., up to about 2 years). The aqueous composition of the present disclosure comprising terlipressin acetate or other pharmaceutically active salts thereof exhibits improved stability at higher concentrations (e.g., at or above about 0.2 mg / mL) because the formulation can prevent peptide aggregation and stability loss common to peptides when stored in a concentrated liquid form.

[0053] A "stable" composition is one in which the active ingredient (eg, terlipressin) substantially retains its physical stability and / or chemical stability and / or biological activity upon storage.

[0054] A composition "maintains its physical stability" in a pharmaceutical formulation if the composition shows substantially no signs of aggregation and / or precipitation when measured by visual inspection of color and / or clarity or by UV light scattering or by size exclusion chromatography. A composition "maintains its chemical stability" in a pharmaceutical formulation if the chemical stability at a given time is such that the active ingredient (e.g., terlipressin) undergoes minimal change when analyzed by a stability-indicating chromatographic method.

[0055] One aspect of the present disclosure provides an aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the composition comprises about 0.2 to about 10.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is about 3.4 to about 5.0.

[0056] As used herein, the term "aqueous" refers to a solution in which the solvent is water. The solvent may be sterile water suitable for injection. In one embodiment, the solvent may be bacteriostatic water. In other embodiments, the solvent may be a mixture of water and other pharmaceutically acceptable solvents or pharmaceutically acceptable alcohols or other bacteriostatic agents (e.g., benzyl alcohol).

[0057] The concentration of terlipressin in a liquid (e.g., an aqueous composition) can be, for example, 0.2 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 2.0 mg / mL, 5.0 mg / mL or 10.0 mg / mL, etc. In some embodiments, the composition comprises about 0.2 mg / mL to about 10.0 mg / mL, about 0.5 mg / mL to about 10.0 mg / mL, about 1.0 mg / mL to about 9.0 mg / mL, about 1.5 mg / mL to about 8.5 mg / mL, about 2.0 mg / mL to about 8.0 mg / mL, about 2.5 mg / mL to about 7.5 mg / mL, about 3.0 mg / mL to about 7.0 mg / mL, about 3.5 mg / mL to about 6.5 mg / mL, about 0.5 mg / mL to about 2.0 mg / mL, or about 0.5 mg / mL to about 1.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the pH of the composition can be about 3.4 to about 5.0, about 3.5 to about 5.0, about 3.6 to about 5.0, about 3.7 to about 5.0, about 3.8 to about 5.0, about 3.9 to about 5.0, about 4.0 to about 5.0, about 4.1 to about 5.0, about 4.2 to about 5.0, about 4.3 to about 5.0, about 4.4 to about 5.0, about 4.5 to about 5.0, about 4.6 to about 5.0, about 4.7 to about 5.0, about 4.8 to about 5.0, or about 4.9 to about 5.0. In other embodiments, the pH of the composition can be about 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 or 5.1.

[0059] One advantage of the compositions of the present disclosure is their improved stability at room temperature (or ambient temperature). As used herein, the term room temperature stability or stable at room temperature means that the composition can be stored at room temperature without degradation or failure compared to a similar composition stored under refrigerated conditions (e.g., at about 2°C to about 8°C). Examples of room temperature stability include compositions that are stable at about 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C or 45°C for a period of time and at a relative humidity of about 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 78%, 79% or 80%.

[0060] Relative humidity is the ratio of the partial pressure of water vapor to the equilibrium vapor pressure of water at a given temperature. Relative humidity depends on the temperature and pressure of the environment of interest (e.g., a patient's home or other outpatient setting, or an ambulance). Relative humidity can be expressed as a percentage, with higher percentages meaning the air-water mixture is more humid. For example, 100% relative humidity means the air is saturated and at its dew point.

[0061] The amount of time continued can be at least three weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, at least 24 months, at least 28 months, at least 32 months, at least 36 months, at least 40 months, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 29 weeks, at least 30 weeks, at least 1 year, at least 2 years, at least 3 years or at least 4 years.

[0062] The compositions of the present disclosure may be stable at any combination of any of the described temperatures, relative humidity percentages, and time ranges. For example, in some embodiments, the compositions are stable for at least 24 months at about 25°C, or for at least 6 months at about 30°C and about 75% relative humidity. In other embodiments, the compositions are stable for up to 26 weeks at about 30°C to about 40°C and about 75% relative humidity. In other embodiments, the compositions are stable for up to 2 years at about 25°C and about 60% relative humidity. In other embodiments, the compositions are stable for about 12 weeks at about 40°C and about 75% relative humidity.

[0063] In some embodiments of the present disclosure, the composition does not need to be stored under refrigeration and is stable at room temperature for a period of time. In other embodiments, the composition is stored under refrigeration at about 2°C to about 8°C, about 1°C to about 4°C, or about 4°C. The composition can be stored under refrigeration before being administered to a patient or before being stored at room temperature for a period of time and before being administered to a patient.

[0064] The compositions described herein exhibit extended stability against the formation of impurities. Impurities may be hydrolysis products, degradation products, and / or enantiomers of terlipressin. Examples of impurities include, but are not limited to, [6-D-phenylalanine] terlipressin, des-(1-3)-terlipressin, des-1,2-glycine-terlipressin, des-1-glycine-terlipressin, [8-L-β-aspartic acid] terlipressin, [8-L-α-aspartic acid] terlipressin, [12-glycine] terlipressin, and [7-L-glutamate] terlipressin, [8-L-aspartic acid, 12-glycine] terlipressin, N 1 Acetyl terlipressin, [7-L-glutamic acid, 12-glycine] terlipressin and / or [12-glycine] terlipressin ethyl ester or a combination thereof. Impurities in the composition can be identified by HPLC analysis.

[0065] In some embodiments, the total amount of impurities in the composition is less than about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5.0% of the total weight of the impurities and terlipressin in the composition. In other embodiments, the total amount of impurities in the composition is less than about 5.0% of the total weight of the impurities and terlipressin in the composition. Non-limiting examples of total amounts of impurities include 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8% of the total weight of the impurities and terlipressin in the composition.

[0066] The total amount of impurities can be determined by analyzing the composition using chromatography under the conditions described in the examples below. Formulation studies can be performed to reduce the level of impurities that form during the shelf life of the composition.

[0067] In some embodiments, the stability of the composition can have reduced impurity formation compared to commercial formulations of Glypressin, and can reflect reduced impurity formation compared to Glypressin levels stored under the same conditions.

[0068] The composition may include a stabilizer (or buffer), such as a pharmaceutically acceptable stabilizer. As used herein, the term "stabilizer" refers to an agent that is capable of driving an acidic or alkaline solution to a specific pH state and then preventing changes from that state; in other words, a stabilizer is an agent that is added to an already acidic or alkaline solution to change the pH and then maintain the pH at the changed level.

[0069] Stabilizer can be a weak acid or weak base contained in a buffer solution, and is responsible for the buffering effect seen in these solutions. Stabilizer can be, for example, acetic acid, adipic acid, aspartic acid, citric acid, maleic acid, succinic acid or phosphate (for example, sodium phosphate or disodium hydrogen phosphate dihydrate). In some embodiments, stabilizer is aspartic acid. Composition can include a single stabilizer (that is, not including two or more stabilizers). Composition can also include two or more stabilizers (for example, citric acid and sodium phosphate).

[0070] Composition can also include stabilizing solution (or buffer solution).As used herein, the term stabilizing solution refers to a solution comprising a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid, and it has the following properties: when a small amount of strong acid or strong base is added, the pH of the solution changes very little, thereby maintaining the pH of a buffer or buffer solution.Stabilizing solution can be, for example, a citrate stabilizing solution comprising citric acid and citrate (e.g., sodium citrate), a succinate stabilizing solution comprising succinic acid and succinate (e.g., sodium succinate), an aspartate stabilizing solution comprising aspartic acid and aspartate (e.g., monosodium aspartate), an acetate stabilizing solution comprising acetic acid and acetate (e.g., sodium acetate), a citrate / phosphate stabilizing solution comprising citric acid and phosphate, or a phosphate stabilizing solution comprising phosphate (e.g., monosodium phosphate) and its conjugate base (e.g., disodium phosphate).In some embodiments, stabilizing solution is an aspartate stabilizing solution.Composition can include a single stabilizing solution (i.e., not including two or more stabilizing solutions). The composition can also include two or more stabilizing solutions (eg, a succinate stabilizing solution and an acetate stabilizing solution).

[0071] The inventors have found that the inclusion of an aspartic acid stabilizer (or the use of an aspartic acid stabilizing solution) can provide effective room temperature stability. The use of an aspartic acid stabilizer (or an aspartic acid stabilizing solution) can also confer other advantages over other stabilizers, including, for example, reducing injection site reactions and associated pain occurring after administration of a terlipressin formulation. In some embodiments, an aspartic acid stabilizer can be used at a concentration of about 0.05 mg / mL to about 10 mg / ml, such as 0.1 mg / mL to about 10 mg / ml, 0.05 mg / mL to about 9 mg / ml, 1 mg / mL to about 8 mg / ml, 0.5 mg / mL to about 6 mg / mL. Examples of specific concentrations include 0.05 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / mL or 10 mg / mL. Similarly, an acetic acid stabilizer can be used, and in some embodiments, the concentration of acetic acid is about 0.02 mg / mL to about 4.2 mg / ml, such as about 0.02 mg / mL to about 4 mg / ml, about 0.02 mg / mL to about 3 mg / ml, about 0.03 mg / mL to about 2 mg / ml, or about 0.5 mg / mL to about 1 mg / mL. For example, the acetic acid stabilizer can be used at a concentration of about 0.02 mg / ml, 0.03 mg / ml, 0.05 mg / ml, 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / mL or 4.2 mg / mL.

[0072] The composition may further comprise a pH adjuster. The pH adjuster may include, but is not limited to, acetic acid, hydrochloric acid or sodium hydroxide.

[0073] The composition may include an antioxidant. The antioxidant may be any antioxidant commonly used in the art, such as any antioxidant approved for use as a pharmaceutical excipient. For example, the antioxidant may be methionine, EDTA, butylated hydroxytoluene, sodium pyrosulfite, ascorbic acid or L-cysteine. The amount of the antioxidant may be 0.01% to 10% (w / v), such as 0.05% to 5% (w / v) or 0.08% to 1% (w / v). The antioxidant may be methionine, EDTA or a combination of methionine and EDTA. For example, the antioxidant may be methionine in an amount of 0.5% w / v. In another example, the antioxidant may be EDTA in an amount of 0.1% w / v.

[0074] In some embodiments, the composition does not include an antioxidant. Oxygen can be excluded during the manufacturing process, and the container or closed system only contains low levels of oxygen, thereby eliminating the need for an antioxidant in the composition. The liquid preparation can be stored in an oxygen-deficient environment. An oxygen-deficient environment can be produced by storing the preparation under an inert gas (e.g., nitrogen or argon). In some embodiments, the headspace in the container for the composition includes nitrogen to protect the composition from the influence of oxygen.

[0075] The composition may also include an isotonic agent. "Isotonic" is a term recognized in the art. Isotonicity may refer, for example, to a composition of interest having an osmotic pressure substantially the same as human blood. Isotonic compositions typically have an osmotic pressure of about 250-350 mOsm. Isotonicity may be measured using, for example, a vapor pressure or ice-type osmometer. An "isotonic agent" is a compound that makes a composition isotonic.

[0076] Isotonic agents (such as mannitol or sodium chloride (NaCl)) are well known in the art. Isotonic agents can be an amount sufficient to provide an isotonic composition (solution), for example, an amount of 0.01% to 10% (w / v). Isotonic agents can be dextrose. If the isotonic agent is dextrose, its amount can be 0.5% to 7.5% (w / v), or 4.0% to 5.5% (w / v), for example, 5.0% (w / v). If the isotonic agent is mannitol, its amount can be 0.05% to 7.5% (w / v). If the isotonic agent is NaCl, its amount can be 0.05% to 1.2% (w / v), more preferably 0.08% to 1% (w / v), for example, 0.9% (w / v). The amount of the isotonic agent can be from about 0.1 mg / mL to about 100.0 mg / mL, such as from about 0.5 mg / mL to 7.0 mg / mL or from about 1.0 mg / mL to about 5.0 mg / mL. For example, if the isotonic agent is dextrose, the amount can be from 5.0 mg / mL to 75.0 mg / mL, such as from 40.0 mg / mL to 55 mg / mL. If the isotonic agent is NaCl, the amount can be from 0.5 mg / mL to 12 mg / mL, such as from 8.0 mg / mL to 10.0 mg / mL.

[0077] In some embodiments, the aqueous composition consists of terlipressin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvent, a stabilizer, an isotonic agent, and a pH adjuster, wherein the composition comprises 0.2 mg / mL to 10.0 mg / mL terlipressin or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is about 3.4 to about 5.0, wherein after storing the composition at about 40°C and about 75% relative humidity for 12 weeks, and wherein the total amount of impurities of the composition is less than about 4.5% of the total weight of impurities and terlipressin in the composition. In other embodiments, the composition is shelf-stable, reflecting the ability to remain within label specifications for at least 6 months, at least 12 months, at least 18 months, or at least 24 months when stored at room temperature. The stabilizer can be aspartic acid in an amount of about 0.05-10 mg / mL or acetic acid in an amount of about 0.02 mg / mL-4.2 mg / mL.

[0078] In some embodiments, the compositions are free of quaternary ammonium or disinfectant compounds (eg, benzalkonium chloride, didecyldimethylammonium chloride).

[0079] In some embodiments, the composition contains a bacteriostatic / fungiostatic agent as an antimicrobial preservative (e.g., including but not limited to parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal).

[0080] In some embodiments, the composition consists of: terlipressin or a pharmaceutically acceptable salt thereof in an amount of about 0.2 mg / mL to about 10.0 mg / mL, aspartic acid in an amount of about 0.1 mg / mL to about 2 mg / mL, dextrose, succinic acid, sodium hydroxide, and water. In other embodiments, the composition consists of: terlipressin or a pharmaceutically acceptable salt thereof in an amount of about 0.2 mg / mL to about 10 mg / mL, sodium acetate, sodium hydroxide, and water. In other embodiments, the composition consists of: terlipressin or a pharmaceutically acceptable salt thereof in an amount of 0.2 to 10 mg / mL, methionine in an amount of about 1.0 mg / mL, dextrose in an amount of about 50.0 mg / mL, succinic acid in an amount of about 1.2 mg / mL, sodium hydroxide, and water.

[0081] In some embodiments, the present disclosure relates to an aqueous formulation consisting essentially of terlipressin acetate or a pharmaceutically acceptable salt thereof and a stabilizer, the concentration of the stabilizer enabling stability during long-term storage at room temperature. In this regard, the concentration of terlipressin is about 0.2 to about 10.0 mg / mL, and the stabilizer is about 0.05-10 mg / mL aspartic acid or about 0.02 mg / mL-4.2 mg / mL acetic acid. In addition, the composition may include an isotonic agent and an optional pH adjusting agent. The total amount of impurities in the formulation is less than 4.5% of the total weight of impurities and terlipressin in the composition. The pH of the composition is about 3.4 to about 5.0.

[0082] In various aspects of the present disclosure, the terlipressin formulation is stable for storage for several months or longer at room temperature or under accelerated storage conditions when the amount of terlipressin in the formulation is at least 90% of the terlipressin in the formulation at the time of initial production or packaging (label strength ("LS")). For example, the stable formulation of the present disclosure has a LS of at least 90% after storage for 6 months at room temperature or under accelerated conditions. More specifically, the stable terlipressin formulation of the present disclosure has a LS of at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% after storage for at least 6 months, at least 12 months, at least 18 months or at least 24 months at room temperature or under accelerated storage conditions. In addition, after the formulation is stored, the amount of impurities present in the formulation can be less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 1%, less than 8% or less than 9%.

[0083] The composition can be used for any route of administration, such as oral, buccal, nasal, transdermal (e.g., patch technology), parenteral, intravenous, intramuscular or subcutaneous injection, intracisternal, intraperitoneal. In some embodiments, the composition is used for intravenous administration, such as by continuous infusion or by bolus IV dose. As described above, the composition suitable for intravenous administration can remain stable in solution at room temperature for a period of time.

[0084] The compositions of the present disclosure can be used to treat or prevent complications of liver cirrhosis in patients in need (or for the preparation of a medicament for treating or preventing complications of liver cirrhosis in patients in need). Complications of liver cirrhosis can include ascites, HRS, jaundice, hepatic encephalopathy, and esophageal or gastric varicose bleeding. For example, the compositions can be used to treat or prevent ascites caused by liver cirrhosis.

[0085] Another aspect of the present disclosure provides a kit comprising a composition of the present disclosure, wherein the kit comprises a container for the composition, wherein the container optionally has a means for injecting the composition into a subject.

[0086] The container can be, for example, a syringe, vial, bottle, ampoule or cartridge. The container can be made of any material suitable for continuous storage at room temperature, including, but not limited to, glass, plastic or metal. The container can be sterile before filling the aqueous composition. The container can also block natural and / or artificial UV light so that the composition is protected from photodegradation or other chemical reactions that may affect the stability of the composition (e.g., the container is made of amber glass or plastic, or contains foil packaging as an outer packaging).

[0087] In some embodiments, the container (e.g., a prefilled syringe) can contain a volume of 1 mL to 10 mL (e.g., 10 mL, 5 mL, 3.5 mL, 3.0 mL, 2.5 mL, 2.0 mL, 1.5 mL, or 1.0 mL) of the aqueous composition.

[0088] In some embodiments, a container (eg, a prefilled syringe) may comprise a fluoropolymer film coating and a stopper having a closure (eg, cap, stopper) which may have a fluoropolymer-coated coating on any product contacting surface.

[0089] In some embodiments, the kit further comprises a needle and / or a syringe shaft that can be connected to the container.

[0090] The kit can also include instructions for administering the composition. In some embodiments, the instructions provide for administering the composition by continuous infusion or as a bolus intravenous dose. Administering the composition by continuous infusion can be achieved, for example, by using a mobile infusion pump, a programmable syringe pump, a mini infusion pump, a micro infusion pump, a melt contact pump, an osmotic pump, an injection contact pump, a syringe pump or other controlled delivery device.

[0091] In some embodiments, the kit instructions provide the option of administering the composition by injecting the composition into a bag of diluent (eg, saline or dextrose), which can then be connected to or inserted into an infusion pump for continuous infusion.

[0092] The stability of the compositions can be determined at designated time points in a variety of ways, including determination of pH, visual inspection of color and appearance, determination of total peptide content by methods known in the art (e.g., UV spectroscopy), and determination of purity by, for example, SDS-PAGE, size exclusion, and UV HPLC.

[0093] The following examples are offered by way of illustration and not limitation.

[0094] Example

[0095] Analytical methods

[0096] The analytical method described herein is specified in the European Pharmacopoeia for the analysis of terlipressin acetate API. It consists of a gradient system with two mobile phases. The following parameters are used for the analysis of terlipressin acetate solution: Column: X-Terra MS C18 4.6x250mm 3.5μm; Wavelength: 210nm; Flow rate: 0.6 mL / min; Column oven: 30°C; Autosampler temperature: 5°C; Injection volume: 50 μL; Run time: 75 min; Mobile phase: Gradient; Buffer: 5 L aqueous chromatographic solution of 3.30 g ammonium sulfate; 1.0 mL sulfuric acid; Eluent A: Methanol: Buffer (18.5:81.5 v / v); Eluent B: Methanol: Buffer (35:65 v / v). The gradient conditions are shown in Table 1.

[0097] Table 1. Gradient conditions

[0098] Gradient: Time (min) % Eluent A % Eluent B 0 80 20 45 80 20 55 0 100 65 0 100 65.01 80 20 75 80 20

[0099] Example 1: Aspartic acid preparation

[0100] Prepare a terlipressin acetate preparation containing aspartic acid (with nitrogen, without nitrogen), pH 4.5.

[0101] Use nitrogen protection : Perform all procedures using N2 protection. Spray water for injection (WFI) before adding materials. Cover with N2 during mixing operations and stop only when adding solid materials. Keep the solution at 20 - 25°C.

[0102] Add WFI to the preparation container, equivalent to 80% of the final QS volume.

[0103] Add aspartic acid to the WFI; rinse the aspartic acid weighing container with WFI (rinse volume ≤ 3% of the final volume). Mix to dissolve.

[0104] Adjust the pH to 4.0 with 0.1N sodium hydroxide solution.

[0105] Add terlipressin acetate and rinse with WFI (rinse volume ≤ 5% of the QS volume). Mix to dissolve.

[0106] Adjust the pH to 4.5 with 0.1N NaOH or 0.1N acetic acid solution (the pH is expected to be 4.6 after adding terlipressin acetate to the pH 4.0 solution).

[0107] Use low-O2 WFI to reach the final volume. Readjust the pH if necessary.

[0108] No nitrogen protection : Keep the solution at 20 - 25°C.

[0109] Add WFI to the preparation container, equivalent to 80% of the final QS volume.

[0110] Add aspartic acid to the WFI; rinse the aspartic acid weighing container with WFI (rinse volume ≤ 3% of the final volume). Mix to dissolve.

[0111] Adjust the pH to 4.0 with 0.1N sodium hydroxide solution.

[0112] Add terlipressin acetate, and rinse with WFI (rinse volume ≤ 5% of the QS volume). Mix to dissolve.

[0113] Adjust the pH to 4.5 with 0.1N NaOH or 0.1N acetic acid solution (the pH is expected to be 4.6 after adding terlipressin acetate to the pH 4.0 solution).

[0114] Use WFI to reach the final volume. Readjust the pH if necessary.

[0115] The terlipressin aspartic acid preparation is shown in Tables 2 and 3.

[0116] Table 2. Aspartic acid preparation at pH 4.5

[0117] Components Amount per mL Function Terlipressin acetate 1.0mg / mL Active ingredients Aspartic acid 0.46mg / mL Stabilizer 0.1N NaOH To adjust pH pH Adjustment 0.1N acetic acid To adjust pH pH Adjustment Water for injection QS Solvents

[0118] Table 3. Aspartic acid preparation at pH 4.5 with nitrogen

[0119] Components Amount per mL Function Terlipressin acetate 1.0mg / mL Active ingredients Aspartic acid 0.46mg / mL Stabilizer 0.1N NaOH To adjust pH pH Adjustment 0.1N acetic acid To adjust pH pH Adjustment Nitrogen N / A Anti-oxidation Water for injection QS Solvents

[0120] Example 2: Acetic acid preparation

[0121] Prepare a terlipressin acetate preparation containing acetic acid (with nitrogen, without nitrogen), pH 4.5.

[0122] Use nitrogen protection : Perform all procedures using N2 protection. Spray WFI before adding materials. Cover with N2 during mixing operations and stop only when adding solid materials. Keep the solution at 20 - 25 °C.

[0123] Add WFI to the preparation container, equivalent to 80% of the final QS volume.

[0124] Add acetic acid to the WFI; rinse the acetic acid weighing container with WFI (rinse volume ≤ 3% of the final volume). Mix to dissolve

[0125] Adjust the pH to 4.0 with 0.1N NaOH solution.

[0126] Add terlipressin acetate and rinse with WFI (rinse volume ≤ 5% of QS volume). Mix to dissolve.

[0127] Adjust the pH to 4.5 with 0.1N NaOH or 0.1N acetic acid solution (the expected pH after adding terlipressin acetate to a pH 4.0 solution is 4.6).

[0128] Use low O2 WFI to reach the final volume. Readjust the pH if necessary.

[0129] No nitrogen protection : Maintain the solution at 20 - 25 °C.

[0130] Add WFI to the formulation container, equivalent to 80% of the final QS volume.

[0131] Add acetic acid to the WFI; rinse the aspartic acid weighing container with WFI (rinse volume ≤ 3% of the final volume). Mix to dissolve

[0132] Adjust the pH to 4.0 with 0.1N NaOH solution.

[0133] Add terlipressin acetate and rinse with WFI (rinse volume ≤ 5% of QS volume). Mix to dissolve.

[0134] Adjust the pH to 4.5 with 0.1N NaOH or 0.1N acetic acid solution (the expected pH after adding terlipressin acetate to a pH 4.0 solution is 4.6).

[0135] Use WFI to reach the final volume. Readjust the pH if necessary.

[0136] The terlipressin acetate formulation is shown in Tables 4 and 5.

[0137] Table 4. Acetic acid formulation at pH 4.5

[0138] Components Amount per mL Function Terlipressin acetate 1.0mg / mL Active ingredients Acetic acid 0.21mg / mL Stabilizer 0.1N NaOH To adjust pH pH Adjustment 0.1N acetic acid To adjust pH pH Adjustment Water for injection QS Solvents

[0139] Table 5. Acetic acid formulation at pH 4.5 with nitrogen

[0140] Components Amount per mL Function Terlipressin acetate 1.0mg / mL Active ingredients Acetic acid 0.21mg / mL Stabilizer 0.1N NaOH To adjust pH pH Adjustment 0.1N acetic acid To adjust pH pH Adjustment Nitrogen N / A Anti-oxidation Water for injection QS Solvents

[0141] Example 3: Stability of terlipressin formulation

[0142] At 3 and 4 months, the effects of aspartic acid formulations at pH 4.5 with and without nitrogen and acetic acid formulations at pH 4.5 with and without nitrogen were evaluated at 2°C-8°C, 25°C and 40°C. The aspartic acid and acetic acid formulations were prepared by methods similar to those described in Examples 1 and 2. The results shown in Tables 6-9 below are expressed as % label strength (LS) of the active ingredient (terlipressin acetate) and % change compared to the Day 0 (initial) time point. Table 10 shows a comparison of the % LS data shown in Tables 6-9. The label strength percentage was calculated using the following formula: (mg / mL found) / (1.0 mg / mL label strength) x 100%.

[0143] Table 6. Stability of aspartic acid formulations at pH 4.5

[0144]

[0145] Table 7. Stability of Aspartic Acid Formulations at pH 4.5 with Nitrogen

[0146]

[0147]

[0148] Table 8. Stability of acetic acid formulations at pH 4.5

[0149]

[0150] Table 9. Stability of pH 4.5 acetic acid formulations with nitrogen

[0151]

[0152] Table 10. Stability data of combined terlipressin formulations

[0153]

[0154]

[0155] Throughout the study, even at the 40°C, 4 month time point, there was a clear trend indicating acceptable assay values ​​(stability specification 90.0-110.0% tag strength).

[0156] Example 4: Purity of Terlipressin Preparation

[0157] Terlipressin and aspartic acid formulations at pH 4.5 (stored with and without nitrogen) and terlipressin and acetic acid formulations at pH 4.5 (stored with and without nitrogen) were tested for overall purity by HPLC after storage for 3 and 4 months at 2°C-8°C, 25°C and 40°C. The aspartic acid and acetic acid formulations were prepared by methods similar to those described in Examples 1 and 2. The overall purity results at 3 months are shown in Table 11, while the overall purity results at 4 months are shown in Table 12, and the % change values ​​relative to the initial time point are shown. The purity / impurity data further demonstrates the stability of the product at room temperature (i.e., 25°C) and accelerated temperature (i.e., 40°C).

[0158] Table 11. Overall purity of terlipressin preparations at 3 months

[0159]

[0160]

[0161] Table 12. Overall purity of terlipressin preparations at 4 months

[0162]

[0163] also, Figure 1-5 Chromatograms showing the effect of nitrogen-free acetic acid and aspartate terlipressin formulations at pH 4.5 at three months of temperature (2°C-8°C, 25°C and 40°C). Figure 1 Overlaid HPLC chromatograms of terlipressin acetate and aspartate preparations (without nitrogen protection) at pH 4.5, 2°C-8°C, for 3 months. Figure 2 Overlapping HPLC chromatograms of terlipressin acetate and aspartate preparations (without nitrogen protection) at pH 4.5, 25°C, for 3 months. Peaks U1 and U2 are impurities. Figure 3 Overlapping HPLC chromatograms of terlipressin acetate and aspartate preparations at pH 4.5, 40°C, for 3 months (without nitrogen protection). Peaks U1 and U2 are impurities. Figure 4 Overlay of HPLC chromatograms showing the effect of temperature on terlipressin aspartate formulations at 2°C-8°C, 25°C and 40°C, at pH 4.5 (without nitrogen protection), over 3 months. Figure 5 Overlay of HPLC chromatograms showing the effect of temperature on terlipressin acetate formulations at 2°C-8°C, 25°C and 40°C, at pH 4.5 (without nitrogen protection), over 3 months.

[0164] The API batches used for the preparation were identical under all conditions. At the time of preparation, the batch containing aspartic acid showed higher purity than the batch containing acetic acid. Impurity U1 appears to be a hydrolysis product of terlipressin. The purity of the preparation containing aspartic acid was similar to that of the preparation containing acetic acid after three months at both 2°C-8°C and 25°C, as the increase of impurity U2 was higher.

[0165] The acetic acid formulation exhibited a higher impurity profile for the peak that is likely des-1,2-glycine terlipressin, while the aspartic acid formulation produced higher levels of two impurities that are likely enantiomers of terlipressin. Formulations containing a higher enantiomer of terlipressin would preferably have a higher hydrolysis product, as the hydrolysis product is likely to have a much higher potency than terlipressin. In practice, enantiomeric impurities are acceptable and can be found in U.S. vasopressin drug products at 6-7%. The results also indicated that the acetic acid formulation appeared to degrade faster during compounding and then more slowly over time. Using the degradation rates observed in this study, a stable situation of approximately 1.2% impurities per year at 25°C and no impurities (or very small increases) at 2°C-8°C could be expected.

[0166] Example 5: Long-term stability and purity of terlipressin

[0167] The stability and purity of a terlipressin aspartate formulation (with nitrogen, pH 4.4) contained in a 3 mL long glass syringe with a fluorine-coated plunger was evaluated in a 6-month study. The formulation was prepared essentially as described in Example 1, with nitrogen blanketing during the filling process and no nitrogen during the formulation process). The storage stability of the formulation was analyzed at four time points (initial [0 month], 1 month, 3 months, and 6 months) at four temperatures (5°C, 25°C, 30°C, and 40°C). The results shown in Table 13 include the % label strength (% LS) of the active ingredient (terlipressin acetate), the total amount of impurities (% total impurities) of the total weight of impurities and terlipressin in the composition, and the physical appearance ("PA") of the formulation. At 0, 1, and 3 months, the pH of the formulation was 4.4 (results were not available at 6 months).

[0168] Table 13. Long-term stability and purity of terlipressin aspartate formulations at pH 4.4

[0169]

[0170] PA = Physical Appearance

[0171] CCS = clear colorless solution

[0172] As shown in Table 13, the terlipressin formulation maintained acceptable label strength after 6 months at all temperatures except the accelerated condition of 40°C. The formulation met specifications at the intermediate storage temperature (30°C), reflecting the expectation that the formulation will remain stable at room temperature for 12-24 months or longer. After 6 months at all temperatures, the physical appearance of the formulation remained a clear, colorless solution, indicating stability and purity.

[0173] Analytical methods

[0174] The analytical method used in this Example 5 is from the European Pharmacopeia and is used to analyze terlipressin acetate API. It consists of a gradient system with two mobile phases. Therefore, the following parameters were used: column: Waters Symmetry C18 3.0x 150mm 5.0μm; wavelength: 210nm; flow rate: 0.6mL / min; column oven: 30°C; autosampler temperature: 5°C; injection volume: 100μL; run time: 75min; mobile phase: gradient; buffer: 5mM ammonium sulfate in water with 0.02% sulfuric acid; 1.0mL sulfuric acid; eluent A: methanol: buffer (18.5:81.5v / v); eluent B: methanol: buffer (30:70v / v). The gradient conditions are shown in Table 1.

[0175] Table 1. Gradient conditions

[0176]

[0177] Any patents or publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0178] The use of specific embodiments and specific language herein to describe various aspects of the invention is not intended to limit the scope of the invention.Variations and modifications of the disclosure as shown herein are believed to normally occur to those skilled in the art to which the disclosure relates.

[0179] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. It should also be understood that terms (such as those defined in commonly used dictionaries) should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless explicitly defined as such herein.

[0180] It should also be understood that multiple aspects and embodiments are disclosed. Each of these has a separate benefit, and each may also be used in combination with one or more of the other disclosed aspects and embodiments, or in some cases with all other disclosed aspects and embodiments, whether specifically described or not. Therefore, for the sake of clarity, this specification avoids repeating each possible combination of single aspects and embodiments in an unnecessary manner. However, the specification and claims should be understood as such combinations being implicitly disclosed, and unless otherwise stated, are fully within the scope of this disclosure and claims.

[0181] Those skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the objects and advantages, as well as those inherent therein. The examples, together with the methods described herein, are representative of preferred embodiments, are exemplary, and are not intended to limit the scope of the present disclosure. Those skilled in the art will envision changes therein and other uses, which are encompassed within the spirit of the present invention as defined by the scope of the claims.

Claims

1. An aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof, wherein the composition comprises 0.5 to 1.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof and aspartic acid in an amount of 0.1 to 1 mg / mL, wherein the pH of the composition is 3.4 to 5.

0.

2. The composition according to claim 1, wherein the total amount of impurities in the composition is less than 4.5% of the total weight of the impurities and terlipressin in the composition.

3. The composition according to claim 1, wherein the pH of the composition is in the range of 4.0-5.

0.

4. The composition of claim 3, wherein the pH of the composition is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.

0.

5. The composition of claim 1, wherein the composition is stable for at least 24 months at 25°C and for at least 6 months at 30°C and 75% relative humidity.

6. The composition of claim 1, wherein the composition is stable at 30°C to 40°C and 75% relative humidity for up to 26 weeks.

7. The composition of claim 1, wherein the composition is stable at 25°C and 60% relative humidity for up to 2 years.

8. The composition according to claim 1, wherein the composition is stored at 2°C to 8°C.

9. The composition of claim 1, wherein the composition comprises an isotonic agent.

10. The composition according to claim 9, wherein the isotonic agent is dextrose or sodium chloride.

11. The composition of claim 1, wherein the composition comprises a pH adjuster.

12. The composition according to claim 1, wherein the pH adjuster is hydrochloric acid, potassium hydroxide, acetic acid or sodium hydroxide.

13. A prefilled syringe comprising the composition according to any one of claims 1-12.

14. The prefilled syringe of claim 13, wherein the head space within the syringe comprises nitrogen.

15. A kit comprising the composition of any one of claims 1-12, wherein the kit comprises a container for the composition, wherein the container optionally has means for injecting the composition into a subject.

16. The kit of claim 15, wherein the container is a syringe prefilled with the composition.

17. The kit of claim 15, wherein the prefilled syringe is made of glass or plastic.

18. The kit according to claim 15, wherein the kit further comprises a needle and / or a syringe rod.

19. The kit of claim 15, wherein the kit further comprises instructions for administering the composition.

20. The kit of claim 19, wherein the instructions provide for administering the composition by continuous infusion or as a bolus intravenous dose.

21. The kit of claim 20, wherein the continuous infusion is administered using an ambulatory pump or other controlled delivery device.

22. The kit of claim 19, wherein the instructions provide the option of administering the composition by injecting the composition into a diluent container, which can then be connected to or inserted into an ambulatory pump for continuous infusion.

23. An aqueous composition consisting of terlipressin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvent, an isotonic agent, and a pH adjuster, wherein the composition comprises 0.5 mg / mL to 1.0 mg / mL of terlipressin or a pharmaceutically acceptable salt thereof and aspartic acid in an amount of 0.1 to 1 mg / mL, wherein the pH of the composition is 4.0 to 5.0, wherein after storing the composition at 40° C. and 75% relative humidity for 12 weeks, and wherein the total amount of impurities in the composition is less than 4.5% of the total weight of impurities and terlipressin in the composition.

24. The composition according to claim 23, wherein the composition consists of: Terlipressin or a pharmaceutically acceptable salt thereof in an amount of 0.5 mg / mL to 1.0 mg / mL, aspartic acid in an amount of 0.1 mg / mL to 1 mg / mL, dextrose, succinic acid, sodium hydroxide and water.

25. The composition of claim 23, wherein the pharmaceutically acceptable solvent is water.

26. The composition of claim 23, wherein the isotonic agent is dextrose or sodium chloride.

27. The composition of claim 23, wherein the pH adjuster is acetic acid, hydrochloric acid or sodium hydroxide.

28. An aqueous composition comprising 0.5 to 1.0 mg / mL of terlipressin acetate or a pharmaceutically acceptable salt thereof and 0.1 to 1 mg / mL of aspartic acid, and optionally an isotonicity agent and optionally a pH adjuster, and the sum of impurities accounting for less than 4.5% of the total weight of impurities and terlipressin in the composition, wherein the pH of the composition is 3.4 to 5.

0.

29. The composition of claim 28, wherein the isotonic agent is dextrose or sodium chloride.

30. The composition of claim 28, wherein the pH adjuster is hydrochloric acid, potassium hydroxide, acetic acid or sodium hydroxide.

31. The composition of any one of claims 1-12 and 23-30, wherein the composition does not comprise at least one of a quaternary ammonium or disinfectant compound.

32. A composition according to claim 31, wherein the disinfectant compound is selected from benzalkonium chloride or didecyldimethylammonium chloride.

33. The composition of any one of claims 1-12, 23-30 and 32, wherein the composition has a label strength of at least 90% after storage at between room temperature and 40°C for 6 to 24 months.

34. The composition of claim 31, wherein the composition has a label strength of at least 90% after storage at between room temperature and 40°C for 6 to 24 months.

35. The composition of claim 33, wherein the storage is 12 months and the temperature is room temperature.

36. The composition of claim 34, wherein the storage is 12 months and the temperature is room temperature.

37. The composition of claim 33, wherein the storage is 24 months and the temperature is room temperature.

38. The composition of claim 34, wherein the storage is 24 months and the temperature is room temperature.

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