Terlipressin composition and use thereof

Abstract

Described herein are pharmaceutical compositions comprising terlipressin, and methods of treatment using the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 685,447, filed on June 15, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0003] Described herein are stable pharmaceutical compositions comprising terlipressin, and methods of treatment using the same. Background Art

[0004] Cirrhosis is a chronic disorder of the liver in which scar tissue replaces normal liver. When blood flow to the kidneys is insufficient, people with cirrhosis develop a kidney disease called hepatorenal syndrome. Terlipressin, a drug that increases blood flow to the kidneys by constricting blood vessels, has been shown to help people with hepatorenal syndrome.

[0005] Terlipressin, also known as triglycyllysine vasopressin, is a synthetic peptide. It is an analog of vasopressin, an endogenous vasoactive hormone. In many countries outside the United States, terlipressin has been approved for the treatment of life-threatening complications of cirrhosis, including hepatorenal syndrome (HRS) and esophageal bleeding (EVB). The structural formula of terlipressin is as follows:

[0006]

[0007] It can also be expressed as follows:

[0008]

[0009] Due to the short half-life of terlipressin, its use is limited to the hospital setting. 0.1 mg / mL is an existing Ferring liquid formulation of terlipressin. The product can be used as a solution for injection in a 10 mL glass ampoule type I with a fill volume of 8.5 mL. The product contains 0.1 mg / mL of terlipressin free base (corresponding to about 0.12 mg / mL as acetate), 20 mM acetate buffer and 9 mg / mL of NaCl. The pH of the product is pH 3.5-4.5, wherein the pH is adjusted between 3.6-3.9. The product must be stored in a refrigerator and has a shelf life of 24 months at 2°C-8°C. In order to improve the availability of the product outside of a hospital (e.g., in an ambulance), it is desirable to develop a liquid terlipressin formulation with an improved shelf life that is stable at room temperature (about 25°C or about 30°C) for at least 1 or 2 years. Summary of the invention

[0010] In one aspect, provided herein is a pharmaceutical composition comprising terlipressin or a pharmaceutically acceptable salt thereof, a monovalent organic buffer salt in an amount to provide a total buffer concentration of 5 mM or less in the composition, optionally an isotonic agent, and water. The composition may have a pH from about 4.5 to about 6. In some embodiments, the composition has a pH from about 4.5 to about 5.5.

[0011] In some embodiments, the isotonic agent is or includes mannitol. In some embodiments, the isotonic agent is or includes one or more salts selected from the following: potassium sulfate (K2SO4), ammonium sulfate ((NH4)2SO4), sodium sulfate (Na2SO4), magnesium sulfate (MgSO4), sodium chloride (NaCl), and sodium iodide (NaI). In some embodiments, the isotonic agent includes sodium chloride, for example, in a concentration range from about 1mg / mL to about 10mg / mL. In some embodiments, the isotonic agent includes mannitol, for example, in a concentration range from about 30mg / mL to about 70mg / mL.

[0012] In some embodiments, the buffer salt is selected from one or more of acetate buffer salt and benzoate buffer salt. In some embodiments, the acetate buffer salt is selected from one or more of the following: sodium acetate, ammonium acetate, and potassium acetate. In some embodiments, the acetate buffer salt is sodium acetate. In some embodiments, the buffer salt is present in an amount that provides a total buffer concentration ranging from about 0.1 mM to about 5 mM.

[0013] In some embodiments, the pharmaceutical composition comprises terlipressin or a pharmaceutically acceptable salt thereof in an amount providing from about 0.1 mg / mL to about 5 mg / mL terlipressin free base. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount providing from about 0.1 mg / mL to about 5 mg / mL terlipressin free base.

[0014] In some embodiments, the pharmaceutical composition comprises or consists essentially of terlipressin acetate in an amount to provide from about 0.1 mg / mL to about 5 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration ranging from about 0.1 mM to about 5 mM, optionally sodium chloride in a concentration ranging from about 1 mg / mL to about 10 mg / mL, and water.

[0015] In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 0.1 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, wherein the composition has a pH of about 4.8±0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 1 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, wherein the composition has a pH of about 4.8±0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 2 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, wherein the composition has a pH of about 4.8±0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 3 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, wherein the composition has a pH of about 4.8 ± 0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 4 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, wherein the composition has a pH of about 4.8 ± 0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 5 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, wherein the composition has a pH of about 4.8 ± 0.3.

[0016] In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 0.1 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, wherein the composition has a pH of about 4.8 ± 0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 1 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, wherein the composition has a pH of about 4.8 ± 0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 2 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, wherein the composition has a pH of about 4.8 ± 0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 3 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, wherein the composition has a pH of about 4.8 ± 0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 4 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, wherein the composition has a pH of about 4.8±0.3. In some embodiments, the pharmaceutical composition comprises terlipressin acetate in an amount to provide 5 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, wherein the composition has a pH of about 4.8±0.3.

[0017] According to any embodiment, at room temperature, the pharmaceutical composition can be stable for at least 1 year. In some embodiments, after storage at 25°C and 60% relative humidity for a period of at least one year, the total impurity content in the composition is less than about 1.9% w / w based on the total weight of terlipressin. In some embodiments, the period is selected from one year, 18 months, 24 months, and 36 months. In some embodiments, the period is 12 months.

[0018] On the other hand, a method of treatment is provided herein, comprising administering any of the pharmaceutical terlipressin compositions described herein to a subject in need thereof. In some embodiments, the method is used to treat esophageal bleeding (EVB). In some embodiments, the method is used to treat hepatorenal syndrome (HRS). In some embodiments, the method is used to treat acute kidney injury. In some embodiments, administration is by intravenous injection.

[0019] In another aspect, provided herein is a pharmaceutical terlipressin composition as described herein for use in treating a condition selected from the group consisting of esophageal bleeding (EVB), hepatorenal syndrome, and acute kidney injury.

[0020] In another aspect, provided herein is the use of terlipressin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating esophageal bleeding (EVB), hepatorenal syndrome, or acute kidney injury, wherein the medicament comprises any one of the pharmaceutical terlipressin compositions described herein.

[0021] On the other hand, provided herein is a pharmaceutical composition comprising terlipressin or a pharmaceutically acceptable salt thereof, at least one buffer salt, and at least one salt selected from one or more of the following: potassium sulfate (K2SO4), ammonium sulfate ((NH4)2SO4), sodium sulfate (Na2SO4), magnesium sulfate (MgSO4), sodium chloride (NaCl), and sodium iodide (NaI). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a graphical depiction of the sum of impurities for Formulation A and Comparative Formulation stored at 25°C for 26 weeks.

[0023] Figure 2 is a graphical depiction of the sum of impurities for Formulation 1 and the comparative formulation stored at 25°C / 60%RH.

[0024] Figure 3 is a graphical depiction of the sum of impurities for Formulation 1 and the comparative formulation stored at 30°C / 75%RH.

[0025] Figure 4 Chromatograms of terlipressin and specific terlipressin-related impurities described herein are shown.

[0026] Figure 5 is a graphical depiction of the extrapolation of the sum of the impurity data for Formulation 7A and Formulation 14A (reference formulation) at 25°C / 60%RH.

[0027] Figure 6 is a graphical depiction of the extrapolation of the sum of the impurity data for Formulation 7A and Formulation 14A (reference formulation) at 30°C / 75%RH.

[0028] Figure 7 is a graphical depiction of the extrapolation of the desGly1Gly2 data for Formulation 7A at 25°C / 60%RH and 30°C / 75%RH. DETAILED DESCRIPTION

[0029] The present disclosure provides a pharmaceutically acceptable terlipressin composition comprising terlipressin or a pharmaceutically acceptable salt thereof, a buffer salt (e.g., a monovalent organic buffer salt (e.g., an acetate buffer salt or a benzoate buffer salt), optionally an isotonic agent (e.g., mannitol or a salt selected from one or more of the following: potassium sulfate (K2SO4), ammonium sulfate ((NH4)2SO4), sodium sulfate (Na2SO4), magnesium sulfate (MgSO4), sodium chloride (NaCl), and sodium iodide (NaI)), and water. The composition can have a total buffer concentration of 5 mM or less, for example, from 0.1 mM to about 5 mM.

[0030] The compositions described herein exhibit good stability against impurity formation. In some embodiments, the compositions are stable for at least one year at room temperature. In some embodiments, the compositions are stable to commercial formulations. Compared to , the compositions described herein have improved stability, which can be reflected, for example, in reduced impurity formation. Without being bound by any theory, the improved stability of the compositions described herein is due to the specific combination of ingredients and their amounts, and pH.

[0031] definition

[0032] Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the field of pharmaceutical formulations to which this disclosure belongs. Various methods known to those of ordinary skill in the art are referenced herein. Suitable materials and / or methods known to those of ordinary skill in the art can be used to implement this disclosure. However, specific materials and methods are described. Unless otherwise stated, the materials, reagents, etc. referenced in the following description and examples can be obtained from commercial sources.

[0033] As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless explicitly stated to refer to the singular only.

[0034] As used herein, the term "about" means that as will be understood by one of ordinary skill in the art, depending on the context in which a number or range is used, the number or range is not limited to the exact number or range recited, but encompasses values ​​around the recited number or range. Unless otherwise apparent from the context or custom in the art, "about" means plus or minus 10% of the particular term.

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a reference compound. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, saccharates, formates, benzoates, glutamates, methanesulfonates (methanesulfonate "mesylate"), ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. In some embodiments, the pharmaceutically acceptable salt of terlipressin is acetate.

[0036] As used herein, "subject" means any mammal (including humans). For example, the subject may have or be at risk of developing a condition that can be diagnosed, treated or prevented with terlipressin, or may be taking terlipressin for other purposes.

[0037] As used herein, the terms "administer," "administration," or "administering" refer to providing, giving, dosing, and / or prescribing, for example, by or under the guidance of a health professional or his or her authorized agent; and putting, taking, or consuming, for example, by a health professional or a subject.

[0038] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating a disease or condition or one or more symptoms thereof, whether or not the disease or condition is considered "cured" or "recovered," and whether or not all symptoms have been eliminated. The term also includes reducing or preventing the progression of a disease or condition or one or more symptoms thereof, hindering or preventing the underlying mechanisms of a disease or condition or one or more symptoms thereof, and obtaining any therapeutic and / or preventive benefit.

[0039] As used herein, the phrase "therapeutically effective amount" refers to a dosage that provides a specific pharmacological effect when a drug is administered to a subject in need of such treatment. It should be emphasized that even if such a dosage is considered by those skilled in the art to be a therapeutically effective amount, a therapeutically effective amount is not always effective in treating the conditions described herein. Exemplary dosages and therapeutically effective amounts are provided below with reference to adult subjects only for convenience. Those skilled in the art can adjust such amounts according to standard practices required for treating a particular subject and / or condition / disease.

[0040] The terms "comprising," "including," "containing," and the like are to be interpreted broadly and are non-limiting. In addition, the phrase "consisting essentially of will be understood to include those elements specifically recited and additional elements that do not materially affect the basic and novel characteristics of the claimed invention, for example, ingredients that do not materially affect the stability of the composition or do not promote the formation of impurities. For example, "consisting essentially of excludes citrate or succinate buffers present in amounts that materially affect the stability of the composition. The phrase "consisting essentially of excludes any unspecified elements.

[0041] Terlipressin

[0042] As noted above, the compositions described herein include terlipressin or a pharmaceutically acceptable salt thereof, such as acetate. Terlipressin is also known as N-[N-(N-glycylglycyl)glycyl]-8-L-lysine vasopressin and has a molecular formula C 52 H 74 N 16 O 15 S2 and a molecular weight of 1227.4. It is registered under CAS Registry Number 14636-12-5.

[0043] The composition may include terlipressin or a pharmaceutically acceptable salt thereof in an amount that provides from about 0.01 mg / mL to about 10 mg / mL of terlipressin free base, including from about 0.1 mg / mL to about 5 mg / mL of terlipressin free base, for example, from 0.1 mg / mL to 5 mg / mL, for example, about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 2.0 mg / mL, about 3.0 mg / mL, about 4.0 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL, including 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5mg / mL, 0.6mg / mL, 0.7mg / mL, 0.8mg / mL, 0.9mg / mL, 1.0mg / mL, 2.0mg / mL, 3.0mg / mL, 4.0mg / mL, 5mg / mL, 6mg / mL, 7mg / mL, 8mg / mL, 9mg / mL, or 10mg / mL. The composition may include terlipressin or a pharmaceutically acceptable salt thereof in an amount to provide about 0.1 mg / mL of terlipressin free base, including in an amount to provide 0.1 mg / mL of terlipressin free base,

[0044] In some embodiments, the composition comprises terlipressin acetate in an amount that provides from about 0.01 mg / mL to about 10 mg / mL terlipressin free base, including from about 0.1 mg / mL to about 5 mg / mL terlipressin free base, for example, from 0.1 mg / mL to 5 mg / mL, for example, about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 2.0 mg / mL, about 3.0 mg / mL. In some embodiments, the composition comprises terlipressin acetate in an amount providing about 0.1 mg / mL of terlipressin free base, including an amount providing 0.1 mg / mL of terlipressin free base. In some embodiments, the composition comprises terlipressin acetate in an amount providing about 1 mg / mL of terlipressin free base (including an amount providing 1 mg / mL of terlipressin free base). In some embodiments, the composition comprises terlipressin acetate in an amount providing about 2 mg / mL of terlipressin free base (including an amount providing 2 mg / mL of terlipressin free base). In some embodiments, the composition comprises terlipressin acetate in an amount providing about 3 mg / mL of terlipressin free base (including an amount providing 3 mg / mL of terlipressin free base). In some embodiments, the composition comprises terlipressin acetate in an amount providing about 4 mg / mL of terlipressin free base (including an amount providing 4 mg / mL of terlipressin free base). In some embodiments, the composition comprises terlipressin acetate in an amount providing about 5 mg / mL of terlipressin free base (including an amount providing 5 mg / mL of terlipressin free base).

[0045] pH

[0046] In some embodiments, the pharmaceutically acceptable terlipressin composition has a pH ranging from about 3 to about 6, for example, a pH of about 3, about 3.5, about 3.7, about 4, about 4.3, about 4.5, about 4.7, about 5, about 5.5, or about 6. The compositions described herein may have a pH ranging from about 4.5 to about 6, or from about 4.5 to about 5, including a pH from 4.5 to 6, or from 4.5 to 5, for example, a pH of about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.5, about 5.7, about 5.8, about 5.9, or about 6.0, or any value therebetween. Non-limiting examples also include a pH of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.5, 5.7, 5.8, 5.9, or 6.0. Pharmaceutically acceptable terlipressin compositions can have a pH ranging from about 4.5 to about 5, such as a pH of about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5.0. Non-limiting examples also include a pH of 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.

[0047] Buffer salt

[0048] As noted above, the compositions described herein include buffer salts, such as pharmaceutically acceptable monovalent organic buffer salts (e.g., acetate buffer salts or benzoate buffer salts). The buffer salts may be present in an amount that provides a total buffer concentration ranging from about 0.1 mM to about 5 mM in the composition, including any value therebetween, such as from about 0.1 mM to about 1 mM. In a composition comprising terlipressin acetate, the terlipressin acetate will contribute to the buffer concentration. For example, 0.12 mg / mL terlipressin acetate corresponds to 0.2 mM acetate. Thus, for example, in a composition comprising 0.12 mg / mL terlipressin acetate (corresponding to 0.10 mg / mL terlipressin free base), the terlipressin acetate will provide a 0.2 mM acetate buffer, in a composition comprising 1.2 mg / mL terlipressin acetate (corresponding to 1.0 mg / mL terlipressin free base), the terlipressin acetate will provide a 2 mM acetate buffer, in a composition comprising 2.4 mg / mL terlipressin acetate (corresponding to 2.0 mg / mL terlipressin free base), the terlipressin acetate will provide a 4 mM acetate buffer, etc. Thus, in a composition comprising terlipressin acetate, the amount of buffer salt used can be adjusted to account for the acetate provided by the terlipressin acetate, such that the total buffer concentration (from the buffer salt and the terlipressin acetate) in the composition is any of the amounts described herein.

[0049] In some embodiments, the buffer salt comprises acetate, for example, can be provided by any pharmaceutically acceptable acetate salt. Such a composition can include an acetate buffer salt in an amount that provides a total acetate concentration ranging from about 0.1 mM to about 5 mM in the composition, including any value therebetween, for example, from about 0.1 mM to about 1 mM, including from 0.1 mM to 1 mM. As a non-limiting example, the composition can include an acetate buffer salt at a concentration of about 1 mM, about 3 mM, or about 5 mM, or an acetate buffer salt in an amount that provides a total acetate concentration of about 1 mM, about 3 mM, or about 5 mM in the composition. The composition can include an acetate buffer salt at a concentration in the following range, or an acetate buffer salt in an amount that provides a total acetate concentration in the composition of about 0.1 mM to about 1 mM, including any value therebetween, such as about 0.1 mM, about 0.2 mM, about 0.3 mM, about 0.4 mM, about 0.5 mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, about 0.9 mM, or about 1.0 mM, about 1.1 mM, or about 1.2 mM. Non-limiting examples of suitable acetate concentrations also include 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, or 1.2 mM. As noted above, a composition comprising 0.12 mg / mL terlipressin acetate will have an acetate buffer concentration of 0.2 mM, even without the addition of additional acetate buffer salt (etc.).

[0050] In some embodiments, the acetate buffer salt is sodium acetate, ammonium acetate, or potassium acetate. Thus, the buffer salt can be sodium acetate. Additionally or alternatively, the buffer salt can be ammonium acetate. Additionally or alternatively, the buffer salt can be potassium acetate.

[0051] In some embodiments, at least one buffer salt comprises benzoate, for example, can be provided by any pharmaceutically acceptable benzoate. Such a composition can include a benzoate buffer salt at a concentration in the following range, or a benzoate buffer salt in an amount to provide the following total buffer concentration in the composition: about 0.1 mM to about 5 mM, including any value therebetween, for example, from about 0.1 mM to about 1 mM, including from 0.1 mM to 1 mM. As a non-limiting example, the composition can include a benzoate buffer salt at a concentration of about 1 mM, or a benzoate buffer salt in an amount to provide a total buffer concentration of about 1 mM in the composition. The composition can include a benzoate buffer salt at a concentration in the following range, or a benzoate buffer salt in an amount that provides the following total buffer concentration in the composition: about 0.1 mM to about 1 mM, including any value therebetween, such as about 0.1 mM, about 0.2 mM, about 0.3 mM, about 0.4 mM, about 0.5 mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, about 0.9 mM, or about 1.0 mM, about 1.1 mM, or about 1.2 mM. Non-limiting examples of suitable benzoate buffer salt concentrations or total buffer concentrations in the composition also include 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, or 1.2 mM.

[0052] In some embodiments, at least one buffer salt is sodium benzoate.In some embodiments, the composition comprises sodium benzoate at a concentration of about 1 mM, or in an amount to provide a total buffer concentration of about 1 mM in the composition.

[0053] In compositions comprising terlipressin acetate, the amount of benzoate buffer salt used can be adjusted to account for the acetate provided by terlipressin acetate so that the total buffer concentration (benzoate plus acetate) in the composition is any of the amounts listed above, for example having a total acetate plus benzoate concentration of about 1 mM.

[0054] Isotonicity Agents / Salts

[0055] As noted above, in some embodiments, the compositions described herein include an isotonic agent, such as a salt selected from one or more of potassium sulfate (K2SO4), ammonium sulfate ((NH4)2SO4), sodium sulfate (Na2SO4), magnesium sulfate (MgSO4), sodium chloride (NaCl), and sodium iodide (NaI), or mannitol. The isotonic agent may be present in any amount effective to make the composition isotonic.

[0056] In certain embodiments, isotonic agent is salt sodium chloride.Sodium chloride can be in any amount effectively making composition isotonic.Therefore, composition can comprise the sodium chloride of concentration by following scope: from about 1mg / mL to about 10mL / mL, including any amount therebetween, for example about 1mg / mL, about 1.5mg / mL, about 2.0mg / mL, about 2.5mg / mL, about 3.0mg / mL, about 3.5mg / mL, about 4.0mg / mL, about 4.5mg / mL, about 5.0mg / mL, about 5.5mg / mL, about 6.0mg / mL, about 6.5mg / mL, about 7.0mg / mL, about 7.5mg / mL, about 8.0mg / mL, about 8.5mg / mL, about 9.0mg / mL, about 9.5mg / mL or about 10.0mg / mL. Non-limiting examples of suitable sodium chloride concentrations also include 1 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.5 mg / mL, 6.0 mg / mL, 6.5 mg / mL, 7.0 mg / mL, 7.5 mg / mL, 8.0 mg / mL, 8.5 mg / mL, 9.0 mg / mL, 9.5 mg / mL, or 10.0 mg / mL.

[0057] In certain embodiments, isotonic agent is mannitol.Mannitol can exist by any amount that effectively makes compositions isotonic.Therefore, compositions can comprise the mannitol by the concentration of following scope: from about 30mg / mL to about 70mL / mL, including any amount therebetween, for example, about 30mg / mL, about 35mg / mL, about 40mg / mL, about 45mg / mL, about 50mg / mL, about 55mg / mL, about 60mg / mL, about 65mg / mL or about 70mg / mL.The limiting examples of mannitol concentration that is applicable also comprises 30mg / mL, 35mg / mL, 40mg / mL, 45mg / mL, 50mg / mL, 55mg / mL, 60mg / mL, 65mg / mL or 70mg / mL.In a particular embodiment, compositions comprises the mannitol by following concentration: about 50mg / mL, for example 50mg / mL.

[0058] In some embodiments, the composition comprises the salt sodium sulfate. Further in some embodiments, the composition comprises sodium sulfate at a concentration ranging from about 0.1 mM to about 120 mM. In some embodiments, the composition comprises sodium sulfate at a concentration of about 120 mM. In some embodiments, the composition does not include sodium sulfate.

[0059] Composition

[0060] The present disclosure includes a terlipressin composition, the terlipressin composition includes any amount of terlipressin or its pharmaceutically acceptable salt, any amount of any one or more of the above-described buffer salts and optionally any amount of one or more of the above-described isotonic agents (such as one or more salts and / or mannitol), in any suitable pH described above. The present disclosure also includes a terlipressin composition, the terlipressin composition includes any amount of terlipressin or its pharmaceutically acceptable salt, any amount of any one or more of the above-described pharmaceutically acceptable monovalent organic buffer salts (which provide a total buffer concentration from about 0.1mM to about 5mM in the composition) and optionally any amount of one or more of the above-described isotonic agents, in any suitable pH described above. The following content is disclosed as a specific exemplary embodiment.

[0061] In some embodiments, the composition comprises the following: terlipressin acetate providing from about 0.1 mg / mL to about 5 mg / mL terlipressin free base, acetate buffer salt in an amount providing a total acetate concentration ranging from about 0.1 mM to about 5 mM, optionally sodium chloride at a concentration ranging from about 1 mg / mL to about 10 mg / mL, and water, and has a pH from 4.5 to about 5.5.

[0062] In some embodiments, the composition consists essentially of terlipressin acetate in an amount providing from about 0.1 mg / mL to about 5 mg / mL terlipressin free base, acetate buffer in an amount providing a total acetate concentration ranging from about 0.1 mM to about 5 mM, optionally sodium chloride at a concentration ranging from about 1 mg / mL to about 10 mg / mL, and water. Such a composition does not include any additional ingredients that may substantially affect the stability of the composition or promote the formation of impurities. In some embodiments, such a composition does not include a citrate buffer and does not include a succinate buffer. Additionally or alternatively, in some embodiments, such a composition does not include a sulfate (e.g., sodium sulfate).

[0063] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 0.1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water. Such a composition may have a pH of 4.8±0.3.

[0064] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water. Such a composition may have a pH of 4.8±0.3.

[0065] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 2 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water. Such a composition may have a pH of 4.8±0.3.

[0066] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 3 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water. Such a composition may have a pH of 4.8±0.3.

[0067] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 4 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water. Such a composition may have a pH of 4.8±0.3.

[0068] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 5 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water. Such a composition may have a pH of 4.8±0.3.

[0069] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 0.1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water.Such a composition may have a pH of 4.8±0.3.

[0070] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water.Such a composition may have a pH of 4.8±0.3.

[0071] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 2 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water.Such a composition may have a pH of 4.8±0.3.

[0072] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 3 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water.Such a composition may have a pH of 4.8±0.3.

[0073] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 4 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water.Such a composition may have a pH of 4.8±0.3.

[0074] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 5 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water.Such a composition may have a pH of 4.8±0.3.

[0075] In some embodiments, the pharmaceutically acceptable terlipressin compositions disclosed herein comprise terlipressin or a pharmaceutically acceptable salt thereof, at least one buffer salt selected from sodium acetate and sodium benzoate, and sodium sulfate.

[0076] In some embodiments, a pharmaceutically acceptable terlipressin composition disclosed herein comprises terlipressin or a pharmaceutically acceptable salt thereof, sodium acetate, and sodium sulfate.

[0077] In some embodiments, the pharmaceutically acceptable terlipressin composition disclosed herein comprises about 0.1 mg / mL terlipressin or a pharmaceutically acceptable salt thereof, about 5 mM sodium acetate, and about 120 mM sodium sulfate, and further wherein the pharmaceutically acceptable terlipressin composition has a pH of about 5.

[0078] The present disclosure further provides a pharmaceutically acceptable terlipressin composition consisting essentially of: terlipressin or a pharmaceutically acceptable salt thereof and at least one buffer salt. In some embodiments, the terlipressin composition consists essentially of: terlipressin or a pharmaceutically acceptable salt thereof and sodium acetate. In some embodiments, the terlipressin composition consists essentially of: terlipressin or a pharmaceutically acceptable salt thereof and sodium benzoate. Moreover, further in some embodiments, the terlipressin composition consists essentially of: about 0.1 mg / mL terlipressin or a pharmaceutically acceptable salt thereof and about 1 mM sodium acetate, and further, wherein the pharmaceutically acceptable terlipressin composition has a pH of about 4.6.

[0079] stability

[0080] As noted above, the compositions described herein exhibit good stability against the formation of impurities, including degradation products. As described in more detail in Example 1 below, the studies described herein identified two major degradation pathways for terlipressin: (1) acid-catalyzed hydrolysis (accelerated by low pH) to form [Gly 12 OH]、[Asp 8 ] and [Glu 7] terlipressin and (2) diketopiperazine ring closure (accelerated by high pH) via the positively charged amino group of the terminal glycine residue to form desGly1Gly2-terlipressin. In some embodiments, the composition is stable against the formation of impurities (including one or more or all of these degradation products) when stored at room temperature for one year or longer, including one, two or three years. It should be understood that the room temperature can be 25°C or even 30°C.

[0081] In some embodiments, with commercial The compositions described herein have improved stability, which can be reflected, for example, in reduced impurity formation, compared to the formulations. For example, in some embodiments, when stored at room temperature (e.g., at 25° C.) for 12 months, the amount of any one or more or all of the impurities listed in the table below in the composition is within the acceptance criteria listed below.

[0082] Table A

[0083] Impurities Acceptance Criteria Sum of degradation products ≤3.5％ <![CDATA[desGly 1 ,Gly 2 ,Gly 3 -Terlipressin]]> ≤0.1％ <![CDATA[desGly 1 ,Gly 2 -Terlipressin]]> ≤1.0％ <![CDATA[desGly 1 -Terlipressin]]> ≤1.0％ <![CDATA[[Gly 12 OH]Terlipressin]]> ≤1.0％ <![CDATA[[Asp 8 ]Terlipressin]]> ≤1.0％ <![CDATA[[Glu 7 ]Terlipressin]]> ≤1.0％ <![CDATA[[Ac-Gly 1 ]Terlipressin]]> ≤1.0％ Any individual terlipressin dimer ≤1.0％ Any single unknown impurity ≤0.5％

[0084] In some embodiments, when stored at room temperature (e.g., at 25° C.), the terlipressin compositions disclosed herein are stable for at least one year, e.g., about one year, about 18 months, about 24 months, about 30 months, or about 36 months. In some embodiments, relative to commercial formulations, To assess stability, for example, it can be reflected in the same storage conditions as Reduced impurity formation compared to the levels formed in the formulation.

[0085] In some embodiments, based on the total weight of terlipressin, after storage at room temperature (e.g., at 25° C.) for a period of time (e.g., at least one year), the terlipressin compositions disclosed herein have a total impurity content of less than or equal to about 3.5% w / w, including less than or equal to 3.5% w / w, including the following total impurity contents: about 3.5%, about 3.4%, about 3.3%, about 3.2%, about 3.1%, about 3.0%, about 2.9%, about 2.8%, about 2.7%, about 2.9%, about 2.8 ... 6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%. Non-limiting examples of total impurity levels include 3.5%, 3.4%, 3.3%, 3.2%, 3.1%, 3.0%, 2.9%, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2.0%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0086] In some embodiments, the terlipressin compositions disclosed herein have a total impurity content of less than or equal to about 1.9% w / w, including less than or equal to 1.9 w / w, including a total impurity content of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%, based on the total weight of terlipressin, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year). Non-limiting examples of total impurity content include 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the total impurity content in the composition is less than or equal to about 1.2% w / w, including less than or equal to 1.2% w / w, based on the total weight of terlipressin.

[0087] In some embodiments, the terlipressin compositions disclosed herein have less than or equal to about 0.1% w / w desGly based on the total weight of terlipressin after storage at room temperature (e.g., at 25° C.) for a period of time (e.g., at least one year). 1 ,Gly 2 ,Gly 3 - Terlipressin content, including less than or equal to 0.1% w / w, including the following desGly 1 ,Gly 2 ,Gly 3 -Terlipressin content: about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, or about 0.01%. desGly 1 ,Gly 2 ,Gly 3 - Non-limiting examples of terlipressin levels include 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%.

[0088] In some embodiments, the terlipressin compositions disclosed herein have a desGly content of less than or equal to about 1.0% w / w based on the total weight of terlipressin after storage at room temperature (e.g., at 25° C.) for a period of time (e.g., at least one year). 1 ,Gly 2 - Terlipressin content, including less than or equal to 1.0% w / w, including the following desGly 1 ,Gly 2 -Terlipressin content: about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%. desGly 1 ,Gly 2 -Non-limiting examples of terlipressin content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the desGly in the composition is 1 ,Gly 2 - The terlipressin content is less than or equal to about 0.3% w / w, including less than or equal to 0.3% w / w.

[0089] In some embodiments, the terlipressin compositions disclosed herein have a desGly content of less than or equal to about 1.0% w / w based on the total weight of terlipressin after storage at room temperature (e.g., at 25° C.) for a period of time (e.g., at least one year). 1 - Terlipressin content, including less than or equal to 1.0% w / w, including the following desGly 1 -Terlipressin content: about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%. desGly 1 -Non-limiting examples of terlipressin content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the desGly in the composition is 1 - The terlipressin content is less than or equal to about 0.3% w / w, including less than or equal to 0.3% w / w.

[0090] In some embodiments, the terlipressin compositions disclosed herein have less than or equal to about 1.0% w / w [Gly 12 OH] terlipressin content, including less than or equal to 1.0% w / w, including the following [Gly 12 OH] terlipressin content: about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%. [Gly 12 Non-limiting examples of terlipressin content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the [Gly 12 OH] terlipressin content is less than or equal to about 0.3% w / w, including less than or equal to 0.3% w / w.

[0091] In some embodiments, the terlipressin compositions disclosed herein have less than or equal to about 1.0% w / w [Asp 8 ] terlipressin content, including less than or equal to 1.0% w / w, including the following [Asp 8]Terlipressin content: about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%. [Asp 8 Non-limiting examples of terlipressin content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the [Asp 8 ] The terlipressin content is less than or equal to about 0.05% w / w, including less than or equal to 0.05% w / w.

[0092] In some embodiments, the terlipressin compositions disclosed herein have less than or equal to about 1.0% w / w [Glu] based on the total weight of terlipressin after storage at room temperature (e.g., at 25° C.) for a period of time (e.g., at least one year). 7 ] terlipressin content, including less than or equal to 1.0w / w, including the following [Glu 7 ]Terlipressin content: about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%. [Glu 7 Non-limiting examples of terlipressin content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the [Glu in the composition is 7 ] The terlipressin content is less than or equal to about 0.2% w / w, including less than or equal to 0.2% w / w.

[0093] In some embodiments, the terlipressin compositions disclosed herein have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content, including less than or equal to 1.0% w / w, including the following [Ac-Gly 1 ] Terlipressin content: about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%. [Ac-Gly 1Non-limiting examples of terlipressin content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the [Ac-Gly 1 ] The terlipressin content is less than or equal to about 0.1% w / w, including less than or equal to 0.1% w / w.

[0094] In some embodiments, the terlipressin compositions disclosed herein have a terlipressin dimer content of less than or equal to about 1.0% w / w, including less than or equal to 1.0% w / w, including a terlipressin dimer content of about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, or about 0.01%, based on the total weight of terlipressin, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year). Non-limiting examples of any individual terlipressin dimer content include 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the content of any individual terlipressin dimer in the composition is less than or equal to about 0.01% w / w, including less than or equal to 0.01% w / w.

[0095] In some embodiments, the terlipressin compositions disclosed herein have a content of any other individual impurity (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w, including less than or equal to 0.5 w / w, including any other individual impurity content of about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, or about 0.01%, based on the total weight of terlipressin after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year). Non-limiting examples of any other individual impurity content include 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%. In some embodiments, after storage at room temperature (e.g., at 25°C) for a period of time (e.g., at least one year), the content of any other individual impurity in the composition is less than about 0.05% w / w, including less than 0.05% w / w.

[0096] In some embodiments, the terlipressin compositions disclosed herein have a total impurity content of less than or equal to about 1.9% w / w, including less than or equal to 1.9% w / w, including a total impurity content of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%, based on the total weight of terlipressin, after storage at 25° C. and 60% relative humidity for a period of time (e.g., at least one year). Non-limiting examples of total impurity content include 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, after storage for a period of time (e.g., at least one year) at 25°C and 60% relative humidity, the total impurity content in the composition is less than or equal to about 1.2% w / w, including less than or equal to 1.2% w / w, based on the total weight of terlipressin. In some embodiments, the period is selected from one year, 18 months, 24 months, and 36 months. In some embodiments, the period is 12 months. In some embodiments, the period is 24 months. In some embodiments, the period is 36 months.

[0097] In some embodiments, the terlipressin compositions disclosed herein are stored at room temperature (e.g., at 25° C. or 30° C.) for a period of time (e.g., about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 2 years), and the total impurities formed in the terlipressin compositions are less than about 3.5% by weight relative to the total weight of terlipressin. In some embodiments, the terlipressin compositions disclosed herein are stored at room temperature (e.g., at 25° C. or 30° C.) for a period of time (e.g., about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 2 years), and the total impurities formed in the terlipressin compositions are less than about 1.9% by weight relative to the total weight of terlipressin.

[0098] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 0.1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly 12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0099] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 1.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly 12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0100] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 2.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly 12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0101] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 3.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly 12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year.8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0102] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 4.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly 12Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0103] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 5.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, sodium chloride at a concentration of about 9 mg / mL, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0104] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 0.1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0105] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 1.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0106] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 2.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0107] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 3.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0108] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 4.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0109] In some embodiments, the composition comprises terlipressin acetate in an amount to provide 5.0 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of about 1 mM, and water, and has a total impurity content of less than or equal to about 1.9% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. Additionally or alternatively, such a composition may have a desGly less than or equal to about 0.1% w / w after storage at room temperature (e.g., at 25° C.) for a period of at least one year. 1 ,Gly 2 ,Gly 3 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 ,Gly 2 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w desGly after storage at room temperature (e.g. at 25°C) for a period of at least one year. 1 - terlipressin content. Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Gly12 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Asp OH] after storage at room temperature (e.g., at 25°C) for a period of at least one year. 8 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Glu 7 Additionally or alternatively, such a composition may have less than or equal to about 1.0% w / w [Ac-Gly 1 ] terlipressin content. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have a separate terlipressin dimer content of less than or equal to about 1.0% w / w. Additionally or alternatively, after storage for a period of at least one year at room temperature (e.g., at 25°C), such a composition may have any other separate impurity content (e.g., any impurity other than those disclosed above) of less than or equal to about 0.5% w / w. In any of these embodiments, the composition may have a pH of 4.8±0.3.

[0110] Method / Purpose

[0111] The present disclosure also provides methods of treatment comprising administering a pharmaceutically acceptable terlipressin composition as described herein to a subject in need thereof, for example, for treating a subject with cirrhosis, and / or for treating hepatorenal syndrome (HRS), acute kidney injury, and / or esophageal bleeding (EVB). In some embodiments, the methods are used to treat hepatorenal syndrome (HRS). In some embodiments, the methods are used to treat acute kidney injury. In some embodiments, the methods are used to treat esophageal bleeding (EVB) or esophageal hemorrhagic esophageal varices. In some embodiments, administration is by intravenous injection.

[0112] The present disclosure also provides any composition disclosed herein for treating a condition selected from the group consisting of hepatorenal syndrome (HRS), esophageal bleeding (EVB), and / or acute kidney injury. Such a composition may comprise 1 mg / mL, 2 mg / mL, 3 mg / mL, or 4 mg / mL of terlipressin or a pharmaceutically acceptable salt thereof.

[0113] The present disclosure also provides the use of terlipressin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatorenal syndrome (HRS), esophageal bleeding (EVB), and / or acute kidney injury, wherein the medicament comprises any one of the terlipressin compositions described herein. Such uses include the use of a higher dose of terlipressin or a pharmaceutically acceptable salt thereof, wherein the higher dose may be 1 mg / mL, 2 mg / mL, 3 mg / mL, or 4 mg / mL terlipressin or a pharmaceutically acceptable salt thereof.

[0114] Examples

[0115] The following specific examples are included as illustrations of the compositions described herein. These examples are in no way intended to limit the scope of the present disclosure. Other aspects of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

[0116] Example 1

[0117] According to a factorial design, formulations containing 0.1 mg / mL of terlipressin were prepared as shown below with different pH, buffer amounts, and buffer salts, and stored at 25°C / 60%RH for 6 months. The amounts of terlipressin and impurities were determined using an ultra-performance liquid chromatography (UPLC) method.

[0118] Table 1.

[0119] Low level Center Point High level pH 4.5 5.0 5.5 Amount of acetate buffer (mM) 5 20 35 Buffer salt Acetate Citrate Succinate

[0120] At the end of the study, citrate and succinate were found to react with terlipressin and result in high impurity levels. Based on this study, acetate was demonstrated to be a suitable buffer salt for terlipressin.

[0121] From this study, it is known that there are two main degradation pathways of terlipressin:

[0122] 1. Acid-catalyzed hydrolysis (accelerated by low pH) to form [Gly 12 OH]、[Asp 8 ] and [Glu 7 ]Terlipressin.

[0123] 2. The diketopiperazine ring closure (accelerated by high pH) via the positively charged amino group of the terminal glycine residue forms desGly1Gly2-terlipressin.

[0124] The acid-catalyzed hydrolysis pathway (1) can be controlled by adjusting the pH to about pH 5. The diketopiperazine pathway (2) is more difficult to control because the reaction pathway is "built-in" to the molecule. In addition, increasing the pH to control the degradation pathway (1) will accelerate the degradation pathway (2). Decreasing the buffer concentration will result in lower amounts of desGly 1 Gly 2 -terlipressin. However, at a buffer level of 5 mM, the diketopiperazine reaction is too fast to be controlled. In this pH range, it was found that the stability-limiting degradation pathway was the diketopiperazine ring closure formation of the N-terminal glycine residue (forming the impurity desGly1Gly2-terlipressin). Preliminary studies reported in Examples 2-4 below show that the diketopiperazine pathway can be slowed down by using low buffer strengths, and by adding sodium sulfate as a stabilizer to slow down the diketopiperazine pathway to a certain extent.

[0125] Example 2

[0126] Three 0.1 mg / mL terlipressin formulations were prepared:

[0127] 1. 5 mM acetate buffer, pH 5.0;

[0128] 2. 5 mM acetate buffer, pH 5.0 + 0.12 M sodium sulfate; and

[0129] 3. Zero buffer, and 0.12 M ammonium sulfate, adjusted to pH 5.0.

[0130] The formulations were placed at 50°C and after 0, 1, 2, 4 and 8 days of storage, desGly 1 Gly 2 - The content of terlipressin. The results are as follows:

[0131] -desGly 1 Gly 2 -Amount of terlipressin

[0132] Table 2.

[0133] Preparations initial 1 day 2 days 4 days 8 days Preparation 1 <0.05％ 0.08％ 0.12％ 0.17％ 0.33％ Preparation 2 <0.05％ 0.07％ 0.09％ 0.13％ 0.25％ Preparation 3 <0.05％ 0.06％ 0.08％ 0.11％ 0.22％

[0134] This study showed that the addition of sulfate ions reduced the diketopiperazine reaction (i.e., Formulations 2 and 3 compared to Formulation 1). Although Formulation 3 did not contain any buffer (which could be a problem for pH stability), at the end of 8 days of storage, the desGly 1 Gly 2 - The amount of terlipressin is lower than that in Formulation 1.

[0135] Example 3

[0136] The following two formulations were stored at 25°C / 65%RH for 26 weeks.

[0137] - 0.1 mg / mL terlipressin, 20 mM acetate buffer, pH 3.7, and sodium chloride (control formulation); and

[0138] - 0.1 mg / mL of terlipressin, 0.12 M sodium sulfate, and pH 5.0 (Formulation A)

[0139] Figure 1 The results in show that Formulation A containing sodium sulfate has lower impurities than the comparative formulation. Extrapolation of the data indicates that Formulation A will likely have less than 3.5% impurities when stored at 25°C / 65%RH for 156 weeks (3 years). The slopes of the two curves indicate that the degradation rate is about 7 times higher in the comparative formulation than in Formulation A (0.1077 / 0.0158).

[0140] Example 4

[0141] According to the factorial design, terlipressin formulations were prepared, see the table below:

[0142] Table 3.

[0143] Low level Center Point High level pH 4.6 5.0 5.4 Amount of acetate buffer (mM) 1 5 9 Amount of sulfate (mM) 0 40 80

[0144] A comparative formulation as described in Example 3 was also included in this study for comparison.

[0145] The formulations were stored at 25°C / 60%RH and 30°C / 75%RH for 3 months and the results showed that the most stable formulation was the one with the lowest pH, the lowest amount of acetate buffer, and no sodium sulfate, referred to herein as Formulation 1. Figure 2 and Figure 3 Display, at 25℃ / 60%RH( Figure 2 ) and 30℃ / 75%RH( Figure 3 ) in both conditions. Sum of impurities of Formulation 1 compared to the Control Formulation.

[0146] The slopes of the two curves indicate that the degradation rate in the comparative formulation is about 7 times higher compared to Formulation 1 at both 25°C / 60%RH and 30°C / 75%RH, (0.1398 / 0.0180) and (0.2598 / 0.0348), respectively.

[0147] This study shows that reducing the acetate content can improve the overall stability of terlipressin compositions. At acetate concentrations of 5 mM and 9 mM, the stabilizing effect of sulfate is more pronounced, but at low acetate concentrations of 1 mM, the stabilizing effect of sulfate is almost absent.

[0148] Example 5

[0149] This example describes the stability results obtained in a terlipressin formulation screening study. This example contains results at time points up to 12 months at 25°C and 30°C and will continue for up to 3 years. The purpose of this study was to investigate the stability of terlipressin in 2 formulations with 2 center points (CP). 3 Effects of pH, sodium sulfate, and sodium acetate buffers in a full factorial design of experiments (“DoE”):

[0150] pH: 4.6-5.4

[0151] Sodium sulfate: 0-80mM

[0152] Sodium acetate: 1-9mM

[0153] The reference formulation used in this study corresponds to the commercial terlipressin formulation pH 3.7, 20 mM sodium acetate, 9 mg / mL NaCl. The following table shows the composition of the formulations tested in this example.

[0154] Table 4.

[0155]

[0156]

[0157] 1 The pH was adjusted with 0.2 M NaOH or 0.1 N H2SO4. Formulation 14A was adjusted with 0.2 M NaOH or 0.2 M acetic acid.

[0158] 2 Terlipressin acetate constituted approximately 0.2 mM included in the sodium acetate concentration.

[0159] 3 These formulations showed high interference from leachables and were not evaluated.

[0160] Storage conditions

[0161] Formulation screening samples are stored at:

[0162] 25℃ / 60%RH for 2 years (can be further extended to 3 years); sampling intervals at 0 months, 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months

[0163] Up to 2 years at 30°C / 75%RH (can be further extended to 3 years); 0 months, 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months

[0164] Store the vials upright to avoid contact between the formulation and the rubber stopper.

[0165] The acceptance criteria for determining the stability of the formulations are provided in the following table. The limits for each impurity were initially set at the acceptance limits for impurities in synthetic peptides according to the European Pharmacopeia, Substances for Pharmaceutical Use, Table 2034.-2. The limits for individual unidentified impurities correspond to the identification limits according to the European Pharmacopeia.

[0166] Table 7.

[0167]

[0168] *Limits of impurities according to European Pharmacopoeia, Substances for Pharmaceutical Use, Table 2034.-2

[0169] The following reverse phase UPLC method was used to determine the terlipressin content and impurities in a terlipressin solution (0.1 mg / mL). The terlipressin solution was purified by HPLC at 60°C on a C18 column (henomenex Luna Omega C 18 , 1.6 μm, 2.1 x 150 mm) and UV detection at 210 nm by using a Waters Acquity or equivalent LC system. The following table shows the parameters for the UPLC method.

[0170] Table B

[0171]

[0172] Figure 4 Chromatograms of terlipressin and specific terlipressin related impurities described herein are shown. Terlipressin content was determined against an external one point calibration curve and impurities were assessed as area % of the total peak area. Peaks with a relative peak area of ​​<0.05% were not reported or included in the impurity sum.

[0173] result

[0174] Data from the 12-month time point at 30°C / 75%RH were entered into MINITAB software (Minitab, LLC, State College, PA). The evaluation showed that the two stability limiting parameters were the sum of impurities and the amount of the desGly1Gly2 impurity. These two parameters were selected for further analysis. Figure 4 Statistical evaluation of the data at 25°C / 60%RH was very similar and is not shown here.

[0175] From the statistical analysis, the most stable formulation was predicted to be the one with the lowest pH (4.6), the lowest amount of acetate buffer (1 mM) and the lowest amount of sodium sulfate (0 mM).Sodium sulfate was found to have a positive effect on the formation of the desGly1Gly2- impurity, but a negative effect on the sum of impurities.

[0176] The following table summarizes the sum of impurities obtained at time points up to 12 months for the formulations tested at 25°C / 60%RH and 30°C / 75%RH respectively.

[0177] Table 8.

[0178]

[0179] Table 9.

[0180]

[0181]

[0182] The results after 12 months showed that a large improvement in room temperature stability had been achieved compared to the reference formulation.The stability data shown above show that the most stable formulation of this study is Formulation 7A, which contains no sodium sulfate, 1 mM acetate buffer and has a pH of 4.6.

[0183] The following table summarizes the stability data obtained for Formulation 7A over a period of up to 12 months.

[0184] Table 10.

[0185]

[0186] NA = Not analyzed

[0187] ND = Not Detected

[0188] X = time point not reached

[0189] Table 11.

[0190]

[0191] NA = Not analyzed

[0192] ND = Not Detected

[0193] X = time point not reached

[0194] Extrapolation of stability data

[0195] Figure 5 and 6The extrapolation of the sum of the impurity data for Formulation 7A and Formulation 14A (reference formulation) at 25°C / 60%RH and 30°C / 75%RH is shown. The extrapolation predicts that Formulation 7A will remain within specification (≤3.5% impurities) with a good margin for 36 months at 25°C / 60%RH. It can be noted that the reference formulation (Formulation 14A) has exceeded the specification limit after about 5 months at 25°C / 60%RH.

[0196] Although the difference in temperature is small, the data at 30°C / 75%RH are very different. At 30°C, Formulation 7A is predicted to exceed the specification for the sum of impurities after about 24 months without any margin at all. This indicates that Formulation 7A is most likely not a suitable formulation for climate zones III / IV at the proposed specifications.

[0197] However, at both temperatures, the improvement in stability compared to the existing product was significant. By dividing by the slope of the regression line for the existing product and Formulation 7A, the following improvement factors can be estimated:

[0198] 25℃ / 60%RH:0.5996 / 0.0701=8.6 times improvement

[0199] 30℃ / 75%RH: 1.1015 / 0.1351=8.2 times improvement

[0200] A second potential stability limiting parameter is the amount of desGly1Gly2, which is a result of the diketopiperazine reaction. Figure 7 Extrapolation of the desGly1Gly2 data for Formulation 7A at 25°C / 60%RH and 30°C / 75%RH is shown. The extrapolation predicts that Formulation 7A will remain within specification (≤1.0%) with a good margin for 36 months at 25°C / 60%RH. At 30°C / 75%RH, Formulation 7A is predicted to exceed the specification for the sum of impurities after approximately 23 months.

[0201] Example 6

[0202] This example describes stability results obtained in a terlipressin formulation screening study conducted in a manner similar to that described in Example 5.

[0203] Tested formulations

[0204] The table below shows the composition of the formulations tested in this example, and the corresponding sum of impurities obtained after storage at 40°C for 1 and 3 months.

[0205] Table 12.

[0206]

[0207]

[0208] *Terlipressin supplied as terlipressin acetate

[0209] *Total acetate concentration added as sodium acetate includes the amount contributed by terlipressin acetate

[0210] The results show that lower acetate concentrations correlate with improved stability. For example, formulations 7B and 8B are identical, except that formulation 8B has less acetate and is more stable. The results also show that including NaCl improves stability. For example, formulations 4B and 8B are identical, except that formulation 8B has NaCl and is more stable.

Claims

1. A pharmaceutical composition comprising terlipressin acetate in an amount to provide from 0.1 mg / mL to 5 mg / mL terlipressin free base, a monovalent organic buffer salt in an amount to provide a total buffer concentration of the composition in the range of 0.1 mM to 5 mM, and water, wherein the monovalent organic buffer salt comprises sodium acetate, and the pharmaceutical composition has a pH from 4.5 to 6.

2. The pharmaceutical composition of claim 1, further comprising sodium chloride.

3. A pharmaceutical composition as claimed in any one of the preceding claims, wherein the composition further comprises mannitol.

4. The pharmaceutical composition of claim 1 or 2, wherein the composition has a pH of 4.8±0.

3.

5. The pharmaceutical composition of claim 2, wherein the composition comprises sodium chloride at a concentration ranging from 1 mg / mL to 10 mg / mL.

6. The pharmaceutical composition of claim 3, wherein the composition comprises mannitol at a concentration ranging from 30 mg / mL to 70 mg / mL.

7. The pharmaceutical composition of claim 1 or 2, which consists essentially of: Terlipressin acetate in amounts to provide from 0.1 mg / mL to 5 mg / mL terlipressin free base, sodium acetate and water in amounts to provide a total acetate concentration ranging from 0.1 mM to 5 mM.

8. The pharmaceutical composition of claim 7, comprising sodium chloride at a concentration ranging from 1 mg / mL to 10 mg / mL.

9. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 0.1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, sodium chloride at a concentration of 9 mg / mL, and water, wherein the composition has a pH of 4.8±0.

3.

10. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 1 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, sodium chloride at a concentration of 9 mg / mL, and water, wherein the composition has a pH of 4.8±0.

3.

11. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 2 mg / mL of terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, sodium chloride at a concentration of 9 mg / mL, and water, wherein the composition has a pH of 4.8±0.

3.

12. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 3 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, sodium chloride at a concentration of 9 mg / mL, and water, wherein the composition has a pH of 4.8±0.

3.

13. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 4 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, sodium chloride at a concentration of 9 mg / mL, and water, wherein the composition has a pH of 4.8±0.

3.

14. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 5 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, sodium chloride at a concentration of 9 mg / mL, and water, wherein the composition has a pH of 4.8±0.

3.

15. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 0.1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, and water, wherein the composition has a pH of 4.8 ± 0.

3.

16. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 1 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, and water, wherein the composition has a pH of 4.8 ± 0.

3.

17. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 2 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, and water, wherein the composition has a pH of 4.8 ± 0.

3.

18. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 3 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, and water, wherein the composition has a pH of 4.8 ± 0.

3.

19. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 4 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, and water, wherein the composition has a pH of 4.8 ± 0.

3.

20. The pharmaceutical composition of claim 1 or 2, comprising terlipressin acetate in an amount to provide 5 mg / mL terlipressin free base, sodium acetate in an amount to provide a total acetate concentration of 1 mM, and water, wherein the composition has a pH of 4.8 ± 0.

3.

21. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is stable at room temperature for at least 1 year.

22. The pharmaceutical composition of claim 1 or 2, wherein the total impurity content in the composition is less than 1.9% w / w based on the total weight of terlipressin after storage at 25°C and 60% relative humidity for a period of at least one year.

23. The pharmaceutical composition of claim 22, wherein the period is selected from one year, 18 months, 24 months, and 36 months.

24. The pharmaceutical composition of claim 22, wherein the period is 12 months.

25. Use of terlipressin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating esophageal bleeding, hepatorenal syndrome, or acute kidney injury, wherein the medicament comprises the composition according to any one of claims 1 to 24.

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