Vasopressin preparations

Abstract

The present disclosure relates to ready-to-use vasopressin formulations, processes for making the formulations, and uses of the formulations for treating patients in need thereof.

Description

[Technical Field]

[0001] The present disclosure is directed to ready-to-administer vasopressin formulations, their preparation and uses. In particular, the present disclosure is directed to ready-to-administer vasopressin formulations that are stable for storage. [Background technology]

[0002] Vasopressin is a polypeptide hormone. Its chemical name is cyclo(1-6)L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-L-arginyl-L-glycinamide. Vasopressin can be in the form of synthetic arginine-vasopressin.

[0003] The structural formula of arginine-vasopressin is shown below.

[0004] [ka]

[0005] Vasopressin has been shown to increase blood pressure in adults in vasodilatory shock who are hypotensive despite the use of fluids and catecholamines. Typically, injectable vasopressin formulations are aqueous solutions of synthetic arginine-vasopressin administered intravenously.

[0006] What is needed is a ready-to-dose aqueous vasopressin formulation that is stable for a predetermined period of time and that can be delivered to a patient without the need for dilution. Summary of the Invention

[0007] The present disclosure relates to ready-to-administer formulations of vasopressin or a pharmaceutically acceptable salt thereof. The formulations described in this disclosure may improve the stability of vasopressin and extend the shelf-life of the formulations.

[0008] In one embodiment, the pH of the vasopressin formulation is 3.4 to 5.5. In one embodiment, the vasopressin formulation is in unit dosage form.

[0009] In one embodiment, the concentration of vasopressin is 0.1 U / mL to 20 U / mL. In one embodiment, the presently disclosed pharmaceutical formulations are in aqueous form.

[0010] The disclosure also provides processes for producing the disclosed pharmaceutical formulations. Pharmaceutical formulations according to the present disclosure may be used to increase blood pressure in a subject in need thereof.

[0011] It is to be understood that both the foregoing and subsequent further description are exemplary and explanatory only and are not intended to be limiting on the scope of the claims. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure relates to ready-to-administer vasopressin formulations. Unless otherwise stated, vasopressin is in the form of synthetic arginine vasopressin. In one embodiment, vasopressin is synthetically produced as known in the art.

[0013] In one embodiment, the aqueous formulation has a pH of 3.4 to 5.5. In one embodiment, the aqueous formulation has a pH of 3.5 to 5.0. In one embodiment, the pH of the aqueous formulation is 3.6 to 5.0.

[0014] In one embodiment, the pH of the aqueous formulation is 3.8 to 5.0. In one embodiment, the aqueous formulation has a pH of 3.8 to 4.4. In one embodiment, the pH of the formulation is 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5.

[0015] "pH" is the conventional unit of measure for hydrogen ion activity in a solution at controlled room temperature unless another temperature is specified. In one embodiment, the pharmaceutical preparation is in unit dosage form, ie, administered to a patient in a single dose.

[0016] It has been found that when vasopressin is formulated into a formulation according to the present disclosure, degradation of vasopressin is slowed, and therefore such formulations exhibit long-lasting chemical and physical stability when stored under controlled room temperature conditions, providing more flexible storage conditions and handling.

[0017] As used herein, the term "controlled room temperature" means a controlled room temperature between 20°C and 25°C. Additionally, pharmaceutical formulations according to the present disclosure have improved stability at 30 degrees Celsius.

[0018] Additionally, pharmaceutical formulations according to the present disclosure have improved 40 degrees Celsius stability. As used herein, the term "stable" means that the pharmaceutical formulation meets one or more of the following criteria: (i) the pharmaceutical preparation exhibits an acceptable assay reduction in vasopressin after a period of time; and / or (ii) the pharmaceutical formulation demonstrates, after a period of time, the formation of an acceptable amount of an impurity compared to the amount of the impurity present at the beginning of that period; and / or (iii) The pharmaceutical formulation retains a pharmaceutically desirable appearance, such as clarity, consistency, and / or improved color, and the absence of visible particles (i.e., a formulation without precipitates or particles). Visual inspection for visible particles may be performed as follows: During inspection, the container is gently swirled and inverted to ensure no air bubbles are introduced and inspected with the naked eye and / or with a magnifying glass for a period of time (approximately 5-20 seconds). Visual inspection for visible particles in a bag may be performed as follows: The solution in the bag is viewed against a light on a white surface, then against a light on a black surface. Visual inspection for color change may be performed as follows: The container is inspected with the naked eye, and a color is assigned to the formulation. The color may also be determined by UV / VIS spectroscopy, and the color difference between two samples may be expressed as ΔE.

[0019] As used herein, an acceptable vasopressin assay loss (i.e., loss in the vasopressin assay) after a certain period of time is calculated as the difference between the vasopressin assay determined immediately after preparation of the formulation (i.e., at time 0) and the vasopressin assay determined at a particular stability test point (e.g., after 1 month, 2 months, 3 months, etc.). The vasopressin assay may be analyzed, for example, by liquid chromatography (e.g., HPLC, UHPLC, LC / MS).

[0020] In one embodiment, the assay for vasopressin may be analyzed by UHPLC. In one embodiment, the assay for vasopressin may be analyzed by UHPLC-FLD, UHPLC-DAD, or UHPLC-MS methods.

[0021] In one aspect, the ready-to-administer aqueous formulations according to the present disclosure are stable under controlled room temperature conditions for a period of time. In one embodiment, the aqueous formulation is stable for at least 14 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months when stored under controlled room temperature conditions.

[0022] In one embodiment, the aqueous formulation is stable for at least one month when stored under controlled room temperature conditions. In one embodiment, the aqueous formulation is stable for at least 3 months when stored under controlled room temperature conditions.

[0023] Formulations according to the present disclosure have demonstrated unexpected stability over reasonable periods of time when stored at a temperature of 30°C. In one embodiment, the formulation is stable when stored at a temperature of 30° C. for at least 14 days, at least 1 month, at least 2 months, at least 3 months, or longer.

[0024] In one embodiment, the formulation is stable when stored at a temperature of 40° C. for at least 14 days, at least 1 month, at least 2 months, at least 3 months, or longer. In one aspect, "stability" can be defined by the amount of total impurities or individual impurities in a formulation after a certain period of time. Stability can also be defined by the increase in the amount of total impurities or individual impurities produced after a set period of time.

[0025] Stability may be determined by measuring the amount of individual impurities in a formulation according to the present disclosure after a predetermined period of time, preferably expressed as a percentage or area percentage when analyzed by HPLC or UHPLC. In one embodiment, the amount of individual impurities in the formulation was analyzed by UHPLC. In one embodiment, the amount of individual impurities in the formulation is expressed as a percentage or area percentage when analyzed by a UHPLC-FLD or UHPLC-DAD method. In one embodiment, the amount of individual impurities in the formulation is expressed as a percentage or area percentage when analyzed by a UHPLC-MS method.

[0026] As used herein, the term "impurity" means a degradation product of an active pharmaceutical ingredient in a pharmaceutical formulation. Some vasopressin-related individual impurities are vasopressin trisulfide and monodeamidated vasopressin.

[0027] The structure of vasopressin trisulfide is shown below as Structure 1.

[0028] [ka]

[0029] The disclosed formulations also minimize the degradation of the active pharmaceutical ingredient into impurities. In one aspect, the disclosed formulations maintain a pharmaceutically desirable appearance, such as avoiding the formation of visible particles, such that no visible particles are present in the disclosed formulations after storage for a set period of time.

[0030] The term "stable" may be defined as an assay decrease of no more than 10% of vasopressin in a pharmaceutical formulation analyzed by liquid chromatography (e.g., HPLC, UHPLC, LC / MS) after a predetermined period of time.

[0031] For example, a stable formulation can be one that exhibits no more than a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% assay decrease in vasopressin after a given period of time. In one embodiment, a stable formulation can be one in which the assay loss of vasopressin does not exceed 8% after a given period of time.

[0032] In one embodiment, a stable or stabilised formulation can be one in which the assay of vasopressin does not decrease by more than 10% after a period of time. In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 3% of vasopressin after one month at controlled room temperature by UHPLC analysis.

[0033] In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 3% of vasopressin after 2 months at controlled room temperature by UHPLC analysis. In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 2% of vasopressin after 2 months at controlled room temperature by UHPLC analysis.

[0034] In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 1% of vasopressin after 2 months at controlled room temperature by UHPLC analysis. In one aspect, a stable or stabilized formulation can be a formulation that exhibits no more than a 5% assay loss of vasopressin after 3 months at controlled room temperature by UHPLC analysis.

[0035] In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 3% of vasopressin after 3 months at controlled room temperature by UHPLC analysis. In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 2% of vasopressin after 3 months at controlled room temperature by UHPLC analysis.

[0036] In one aspect, a stable or stabilized formulation can be a formulation that exhibits an assay loss of no more than 5% of vasopressin after 5 months at controlled room temperature by UHPLC analysis. In one aspect, a stable or stabilized formulation can be a formulation that assays for no more than a 5% decrease in vasopressin after 6 months at controlled room temperature by UHPLC analysis.

[0037] In one embodiment, the term "stable" may be defined as the total amount of impurities in the formulation not increasing by more than 10% after a given period of time. In one embodiment, the term "stable" may be defined as the total amount of impurities in the formulation not increasing by more than 8% after a given period of time.

[0038] In one aspect, a stable formulation can be one that does not increase total impurity formation by more than 5% after 6 months under controlled room temperature conditions by UHPLC analysis. In one aspect, a stable formulation can be one that does not increase total impurity formation by more than 5% after 5 months under controlled room temperature conditions by UHPLC analysis.

[0039] In one aspect, a stable formulation can be one that does not increase total impurity formation by more than 5% after 3 months under controlled room temperature conditions by UHPLC analysis. In one aspect, a stable formulation can be one that does not increase total impurity formation by more than 3% after 3 months under controlled room temperature conditions by UHPLC analysis.

[0040] In one aspect, a stable formulation can be one that does not increase total impurity formation by more than 2% after 3 months under controlled room temperature conditions by UHPLC analysis. In one aspect, a stable formulation can be one in which total impurity formation does not increase by more than 1% after 2 months under controlled room temperature conditions by UHPLC analysis. In one aspect, a stable formulation can be one in which total impurity formation does not increase by more than 2% after 2 months under controlled room temperature conditions by UHPLC analysis.

[0041] In one aspect, a stable formulation can be one that does not increase total impurity formation by more than 3% after 2 months under controlled room temperature conditions by UHPLC analysis. In one embodiment, a stable formulation does not contain more than a 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% increase in total impurities after a given period of time under controlled room temperature conditions.

[0042] In one aspect, where multiple impurities of an individual active pharmaceutical ingredient can form over time, "stable" is defined as no more than a 5% increase in the formation of each individual impurity after a given period of time.

[0043] In one embodiment, a stable formulation does not contain an increase of more than 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% of any individual impurity after a specified period of time.

[0044] In one aspect, multiple impurities of the individual active pharmaceutical ingredients may form over time, and a stable formulation does not contain more than a 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5% increase in any individual impurity after a given period of time.

[0045] In one aspect, multiple impurities of the individual active pharmaceutical ingredients can form over time, and stable formulations do not contain more than a 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% increase in vasopressin trisulfide after a specified period of time.

[0046] In one aspect, a stable formulation can be one in which the formation of any individual impurity does not increase by more than 2% after 3 months under controlled room temperature conditions by UHPLC analysis. In one aspect, a stable formulation can be one that does not increase vasopressin trisulfide by more than 2% after 2 months at controlled room temperature by UHPLC analysis.

[0047] In one aspect, a stable formulation can be one that does not increase vasopressin trisulfide by more than 2% after 3 months at controlled room temperature by UHPLC analysis. In one aspect, a stable formulation can be one that does not increase vasopressin trisulfide by more than 1% after 3 months at controlled room temperature by UHPLC analysis.

[0048] As used herein, "stable" also refers to the absence of visible particles in the pharmaceutical formulation after a given period of time ("particle-free" or "particle / precipitation-free"). In one embodiment, the formulation is particle free at 30° C. for at least 1 month.

[0049] In one embodiment, the formulation is particle free for at least 1 month, at least 2 months, or at least 3 months at controlled room temperature. As used herein, the term "pharmaceutical formulation" or "pharmaceutically acceptable formulation" refers to any formulation suitable for or intended for in vivo use, e.g., any formulation suitable for administration to a patient or subject. As used herein, the terms "patient" and "subject" are interchangeable and refer to any human or any animal individual to whom a formulation as described herein is administered.

[0050] As used herein, "pharmaceutical composition," "pharmaceutically acceptable composition," "pharmaceutical formulation," "composition," and "formulation" are used interchangeably. In one embodiment, the concentration of vasopressin is 0.1 U / mL to 20 U / mL.

[0051] In one embodiment, the concentration of vasopressin is between 0.2 U / mL and 1 U / mL. In one embodiment, the concentration of vasopressin is 0.1 U / mL, 0.2 U / mL, 0.3 U / mL, 0.4 U / mL, 0.5 U / mL, 0.6 U / mL, 0.7 U / mL, 0.8 U / mL, 0.9 U / mL, or 1 U / mL.

[0052] In one embodiment, the concentration of vasopressin is 0.2 U / mL, 0.4 U / mL, 0.6 U / mL, or 1 U / mL. In one embodiment, the vasopressin can be in the form of synthetic lysine vasopressin.

[0053] In one embodiment, the vasopressin is in the form of a salt. The vasopressin salt can be a salt of a lower aliphatic carboxylic acid. In one embodiment, the vasopressin salt can be an acid addition salt such as succinate, maleate, citrate, tartrate, aspartate, gluconate, or acetate. In one embodiment, the vasopressin is in the form of an acetate salt.

[0054] In one embodiment, the vasopressin is in the form of synthetic arginine vasopressin acetate. According to this disclosure, vasopressin arginine acetate means vasopressin arginine containing 15% or less acetic acid according to the USP monograph for vasopressin.

[0055] In one embodiment, the vasopressin is in the form of vasopressin acetate hydrate. In one embodiment, the pharmaceutical formulation is aqueous. The terms "aqueous formulation," "aqueous solution," or "aqueous" are understood to refer to any formulation in which water is present at 50% v / v or more, such as a formulation containing 50% v / v to 99.5% v / v water, 50% v / v to 90% v / v water, 60% v / v to 85% v / v water, or 70% v / v to 80% v / v water. Thus, aqueous formulations include formulations containing 50% v / v or more water, 60% v / v or more water, 70% v / v or more water, 75% v / v or more water, 80% v / v or more water, 85% v / v or more water, 90% v / v or more water, 95% v / v or more water, or 99% v / v or more water.

[0056] In one embodiment, the aqueous vasopressin formulation comprises 90% or more water. In one embodiment, the ready-to-administer pharmaceutical formulation comprises one or more osmotic agents. Exemplary osmotic agents for use in this ready-to-administer pharmaceutical formulation include, but are not limited to, sodium chloride, dextrose 5%, or other osmotic agents.

[0057] In one embodiment, the formulation comprises sodium chloride. In one embodiment, the formulation comprises 0.3-0.9% w / v sodium chloride for injection. In one embodiment, the formulation comprises 0.3-0.5% w / v sodium chloride for injection.

[0058] In one embodiment, the formulation contains 0.9% w / v sodium chloride, ie, 9 g NaCl per 1 L of water. In one embodiment, the formulation consists essentially of vasopressin at a concentration of 0.1 U / mL to 20 U / mL, an osmotic agent, water, and optionally a pH adjuster, and the formulation has a pH of 3.4 to 5.5. The pH may be adjusted with a pH adjuster such as sodium hydroxide or hydrochloric acid.

[0059] In one embodiment, the formulation comprises vasopressin at a concentration of 0.1 U / mL to 20 U / mL, an osmotic agent, water, and optionally a pH adjuster, the formulation having a pH of 3.5 to 5.0. The pH may be adjusted with a pH adjuster such as hydrochloric acid or sodium hydroxide.

[0060] In one embodiment, the formulation consists essentially of vasopressin at a concentration of 0.1 U / mL to 20 U / mL, sodium chloride, e.g., 0.9% w / v sodium chloride, water, and optionally a pH adjuster, the formulation having a pH of 3.4 to 5.5. The pH may be adjusted with a pH adjuster such as sodium hydroxide or hydrochloric acid.

[0061] In one embodiment, the formulation comprises vasopressin at a concentration of 0.1 U / mL to 20 U / mL, sodium chloride, e.g., 0.9% w / v sodium chloride, water, and optionally a pH adjuster, the formulation having a pH of 3.5 to 5.0. The pH may be adjusted with a pH adjuster such as sodium hydroxide or hydrochloric acid.

[0062] In one embodiment, the formulation consists essentially of vasopressin at a concentration of 0.1 U / mL to 20 U / mL, an osmotic agent, water, and a pH adjuster and / or buffer to provide a pH of 3.5 to 5.0.

[0063] In one embodiment, the formulation comprises vasopressin at a concentration of 0.1 U / mL to 1 U / mL, an osmotic agent, water, and optionally a pH adjuster, the formulation having a pH of 3.5 to 5.0. The pH may be adjusted with hydrochloric acid or sodium hydroxide.

[0064] In one embodiment, the formulation consists essentially of vasopressin at a concentration of 0.1 U / mL to 1 U / mL, sodium chloride, water, and optionally a pH adjuster, the formulation having a pH of 3.5 to 5.0. The pH may be adjusted with hydrochloric acid or sodium hydroxide.

[0065] In one embodiment, the formulation comprises vasopressin at a concentration of 0.1 U / mL to 1 U / mL, sodium chloride, water, and optionally a pH adjuster, the formulation having a pH of 3.5 to 5.0. The pH may be adjusted with hydrochloric acid or sodium hydroxide.

[0066] In one embodiment, the formulation consists essentially of vasopressin at a concentration of 0.1 U / mL to 1 U / mL, an osmotic agent, water, and a pH adjuster and / or buffer to provide a pH of 3.5 to 5.0.

[0067] In one embodiment, the vasopressin formulation comprises at least one cyclodextrin. In one embodiment, the vasopressin liquid formulation comprises at least one beta-cyclodextrin. In one embodiment, the cyclodextrins are 2-hydroxypropyl-β-cyclodextrin (HPBCD) and sulfobutylether-β-cyclodextrin (SBECD).

[0068] In one embodiment, the beta cyclodextrin is SBECD. Sulfobutylether-β-cyclodextrin (SBECD) is an anionic β-cyclodextrin derivative sulfonate sodium salt separated from the hydrophobic cavity by butyl ether spacer groups. The sulfobutyl ether substituents are introduced into the 2-, 3-, and 6-positions of one or more glucopyranose units in the cyclodextrin structure.

[0069] "Degree of substitution" may be expressed as the average degree of substitution, which is understood as the number of substitutions per cyclodextrin ring. Degree of substitution may be expressed as molar substitution, which refers to the number of substitutions per glucose unit of the cyclodextrin.

[0070] In one embodiment, the average degree of substitution of SBECD is 5.9 to 7.1. In one embodiment, the average degree of substitution of the SBECD is 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, and 7.1.

[0071] In one embodiment, the beta cyclodextrin is HPBCD. Hydroxypropyl-β-cyclodextrin (HPBCD) is a β-cyclodextrin partially substituted with poly(2-hydroxypropyl) ether. In one embodiment, the molar substitution of the HPBCD is 0.4 to 1.5.

[0072] In one embodiment, the molar substitution of HPBCD is between 0.5 and 1.1. In another embodiment, the molar substitution of HPBCD is between 0.6 and 1.0. In another embodiment, the molar substitution of HPBCD is between 0.6 and 0.9.

[0073] In another embodiment, the molar substitution of HPBCD is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or 1.1. In other embodiments, the at least one cyclodextrin is at a concentration of 0.01 mg / mL to 10 mg / mL.

[0074] In other embodiments, the at least one cyclodextrin is at a concentration of 0.1 mg / mL to 1.4 mg / mL. In other embodiments, the at least one cyclodextrin is at a concentration of 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or 10 mg / mL.

[0075] In some embodiments, the formulation comprises at least one amino acid. The term "amino acid" refers to any amino acid, including but not limited to the 20 amino acids naturally occurring in peptides, and is intended to encompass any salts thereof, particularly pharmaceutically acceptable salts thereof, and derivatives thereof. For example, the term "amino acid" includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, and pharmaceutically acceptable salts thereof and derivatives thereof.

[0076] In one embodiment, the amino acid is glutamic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the amino acid is aspartic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the amino acid is in the form of an N-acetylated amino acid.

[0077] In one embodiment, the formulation comprises at least two amino acids. In one embodiment, the amino acid is alanine, a pharmaceutical salt thereof, or a derivative thereof. In one embodiment, the alanine derivative is N-acetyl-D-alanine (hereinafter "NADA").

[0078] In some embodiments, this amino acid may be in the L-configuration, while in some other embodiments it may be in the D-configuration. In one embodiment, the glutamic acid is L-glutamic acid.

[0079] In one embodiment, the formulation comprises SBECD and N-acetyl-D-alanine. In one embodiment, the formulation comprises SBECD and L-glutamic acid. In one embodiment, the formulation comprises L-glutamic acid and N-acetyl-D-alanine.

[0080] In one embodiment, the concentration of the at least one amino acid is between 0.5 mM and 50 mM. In one embodiment, the concentration of the at least one amino acid is between 5.5 mM and 25 mM. In one embodiment, the concentration of the at least one amino acid is between 5.5 mM and 15 mM.

[0081] In one embodiment, the concentration of at least one amino acid is 0.5 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 5.5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM or 25 mM.

[0082] In one embodiment, the concentration of N-acetyl-D-alanine does not exceed 8 mg / mL. In one embodiment, the concentration of N-acetyl-D-alanine does not exceed 3 mg / mL. In one embodiment, the formulation comprises gluconic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the gluconate may be selected from calcium, sodium, potassium, magnesium, zinc, or iron.

[0083] In one embodiment, the formulation comprises gluconic acid sodium salt. In one embodiment, the formulation comprises SBECD and gluconic acid sodium salt. In one embodiment, the formulation comprises sodium gluconic acid and L-glutamic acid.

[0084] In one embodiment, the formulation comprises gluconic acid sodium salt and N-acetyl-D-alanine. In one embodiment, the concentration of gluconic acid is 0.5 mM to 50 mM.

[0085] In one embodiment, the concentration of sodium gluconate is 5.5 mM to 25 mM. In one embodiment, the concentration of sodium gluconate is 5.5 mM to 15 mM. In one embodiment, the concentration of gluconic acid sodium salt is 0.5 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 5.5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM or 25 mM.

[0086] In one embodiment, the formulation comprises betaine (N,N,N-trimethylglycine) or a pharmaceutically acceptable salt thereof. In one embodiment, the betaine is in the form of betaine hydrochloride. In one embodiment, the formulation comprises SBECD and betaine.

[0087] In one embodiment, the formulation comprises betaine and L-glutamic acid. In one embodiment, the formulation comprises betaine and N-acetyl-D-alanine. In one embodiment, the formulation comprises betaine and gluconic acid sodium salt.

[0088] In one embodiment, the concentration of betaine hydrochloride is 0.01 mg / mL to 2 mg / mL. In one embodiment, the concentration of betaine hydrochloride is 0.1 mg / mL to 1 mg / mL. In one embodiment, the concentration of betaine hydrochloride is 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL or 1 mg / mL.

[0089] In one embodiment, the pharmaceutical formulation comprises a buffer. Exemplary buffers for use in the formulations described herein include, but are not limited to, buffers capable of maintaining the pH range of the formulation. In one embodiment, a buffer having a buffering capacity of approximately pH 3.5 to 5.0 may be used.

[0090] In one embodiment, the buffer may be selected from organic compounds having functional groups susceptible to protonation / deprotonation, such as carboxylic acids and amines. In one embodiment, the pharmaceutical formulation does not include an acetate buffer.

[0091] In one embodiment, the pharmaceutical formulation does not include a citrate or lactate buffer. In one embodiment, the pharmaceutical formulation does not contain aspartic acid. In one embodiment, the pharmaceutical formulation does not include a chelating agent such as EDTA.

[0092] In one embodiment, the pharmaceutical formulation does not include chlorobutanol. The pH of the solution can be adjusted by any suitable method. The pH can be adjusted with one or more pH adjusters, which can be selected from inorganic acids, organic acids, weak bases, and strong bases, as well as their salts and derivatives. Examples of pH adjusters include hydrochloric acid, phosphoric acid, sulfuric acid, succinic acid, phenolic acids, sodium hydroxide, ammonium hydroxide salts, sodium bicarbonate salts, or similar agents, and combinations thereof.

[0093] In one embodiment, the pH is adjusted with sodium hydroxide and hydrochloric acid. In one embodiment, the formulation is in the form of a ready-to-administer formulation. A "ready-to-dose" formulation is used herein synonymously with "ready-to-inject" or "ready-to-inject." A "ready-to-dose" formulation is suitable for direct administration to a patient and does not require any dilution step.

[0094] A ready-to-administer formulation according to the present disclosure may be used to increase blood pressure in a human subject by administering said vasopressin formulation to the human subject in need thereof. In one embodiment, the ready-to-administer formulation may be used to increase blood pressure in a human patient in vasodilatory shock.

[0095] This disclosure also provides a process for producing the pharmaceutical formulations disclosed herein. In various embodiments, this process can include dissolving at least one selected excipient and vasopressin in water or a selected standard diluent for parenteral use and filling a selected container with the resulting formulation. If necessary, the pH is adjusted to reach a desired pH range.

[0096] In one embodiment, this ready-to-administer vasopressin formulation can be prepared by dissolving at least one excipient in water for injection (WFI) or a predetermined standard diluent for parenteral use under predetermined conditions until a clear solution is obtained. Vasopressin is added to this solution containing the dissolved excipient(s), and the solution is mixed until the vasopressin is dissolved. If necessary, the pH is adjusted to a predetermined pH value, and then WFI or an appropriate diluent is added to bring the solution to a predetermined volume. The prepared formulation is then mixed to ensure homogeneity, after which it is filtered through a 0.2 μm filter and dispensed into predetermined packaging containers.

[0097] In another embodiment, the pharmaceutical formulation may be manufactured by any process known to those skilled in the art. In one embodiment, the vasopressin liquid formulation is packaged in a container. The container may be a vial or a bag. In one embodiment, the container is a single unit dose container. In one embodiment, the container is a single unit dose container for IV administration.

[0098] In one embodiment, the volume of the container is 50 mL to 3000 mL. In one embodiment, the volume of the container is 100 mL to 1000 mL. In one embodiment, the volume of the container is 50 mL, 100 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, 600 mL, 700 mL, 800 mL, 900 mL, or 1000 mL.

[0099] In one embodiment, the volume of the container is 100 mL. In one embodiment, the formulation is stored in a container for intravenous formulations, preferably a plastic-based container. In one embodiment, the formulation is packed in a flexible plastic bag. In one embodiment, the formulation is packed in a container manufactured by form-and-seal technology. In one embodiment, the material of the container does not contain PVC. In one embodiment, the formulation does not come into contact with the PVC material of the container.

[0100] As used herein, the term "flexible plastic container" refers to a flexible polymeric infusion bag or other polymeric container. In one aspect, the flexible plastic container is formed from a polyolefin, such as polyethylene, polypropylene, copolymers thereof, and derivatives thereof, which may or may not contain other additives.

[0101] In one embodiment, the flexible plastic container may be formed from a cycloolefin polymer, a cycloolefin copolymer, a polycarbonate; ethylene vinyl acetate (EVA), ethylene vinyl alcohol (EVOH), a modified polyolefin-polyethylene polymer, or a styrene-polyolefin-based polymer, or a block copolymer thereof.

[0102] In one embodiment, the plastic material of the container comprises polyethylene (PE). In one embodiment, the plastic material of the container comprises ethylene vinyl alcohol (EVOH).

[0103] In one embodiment, the container is a single layer container or a multi-layer container. In one embodiment, the inner layer of the container that comes into contact with the formulation comprises polyethylene. In one embodiment, the inner layer of the plastic material that contacts the formulation is polyethylene.

[0104] In one embodiment, the barrier layer of the plastic material is EVOH. In one embodiment, the container may further include packaging. In one embodiment, the packaging may be formed from a gas barrier material and / or a light-blocking material. The packaging material may be a material with low oxygen permeability.

[0105] In one embodiment, the packaging is an aluminum pouch. In one embodiment, the space between the container and the packaging is filled with an inert gas or any other suitable gas, hi one embodiment, the space between the container and the packaging is filled with N2, argon, or any combination thereof.

[0106] In one embodiment, the space between the container and the packaging is evacuated. In one embodiment, the space between the container and the packaging contains an oxygen absorber. In one embodiment, the formulation is sterilized by methods known in the art. Such methods known in the art include sterile filtration, heat treatment, and / or irradiation sterilization. Heat treatment can be performed at a temperature of 100°C or above for a time appropriate for sterilization. In one embodiment, heat treatment can be heat sterilization at 121°C for 15 minutes.

[0107] In one aspect, the present disclosure provides a method of treating a human subject in need thereof by administering, via an IV route, a formulation disclosed herein comprising an effective dose of vasopressin. In one aspect, the present disclosure provides a method of treating a human subject by administering by IV injection a ready-to-administer formulation disclosed herein comprising an effective dose of a vasopressin formulation.

[0108] In one aspect, the disclosure provides a method of increasing blood pressure in a human subject in need thereof, the method comprising intravenously administering to the human subject a pharmaceutical formulation disclosed herein, wherein the pharmaceutical formulation, in unit dosage form, comprises: i) 0.2 U / mL to 1 U / mL of vasopressin or a pharmaceutically acceptable salt thereof; which administration provides the human subject with 0.01 units to 0.1 units of vasopressin or a pharmaceutically acceptable salt thereof per minute; and the human subject is hypotensive.

[0109] In one aspect, the disclosure provides a method of increasing blood pressure in a human subject in need thereof, the method comprising intravenously administering to the human subject a pharmaceutical formulation disclosed herein, wherein the pharmaceutical formulation, in unit dosage form, comprises: i) 1 U / mL of vasopressin or a pharmaceutically acceptable salt thereof; which administration provides the human with between 0.01 units and 0.1 units of vasopressin or a pharmaceutically acceptable salt thereof per minute; and the human is hypotensive.

[0110] In one aspect, the formulations described herein are intended to be administered by, for example, intravenous injection or infusion. In one embodiment, the formulation is an isotonic formulation. The term "isotonic" according to the present disclosure should be understood to mean having an osmotic pressure that approximates the physiological osmotic pressure of blood.

[0111] Typically, the ready-to-administer pharmaceutical formulation has an osmolality of 240-340 mOsm / kg. In one embodiment, the formulation has an osmolality of 240 to 600 mOsm / kg.

[0112] In one aspect, any of the ready-to-administer formulations contained in the ready-to-administer product are isotonic, having an osmotic pressure that approximates the physiological osmotic pressure of blood, as described above. Unless otherwise stated, calculations of vasopressin concentrations in this disclosure are based on vasopressin free base.

[0113] Unless otherwise stated, calculations of excipient concentrations in this disclosure are made based on the free base of that excipient. In addition, the compositions described herein may further comprise one or more pharmaceutical excipients, such as antioxidants, surfactants, complexing agents, preservatives, vehicles, solubilizing agents, and combinations thereof.

[0114] Other objects, features, and advantages will become apparent from the following detailed description and examples. It should be understood, however, that the detailed description and examples, while indicating particular embodiments, are given by way of example only and are not intended to limit the breadth or scope of the concepts in any way.

[0115] The stabilizing effect of various factors on the ready-to-administer formulation was evaluated. Technology overview All formulations shown in the following examples were prepared by providing a solution of vasopressin. Comparative vasopressin liquid formulations were prepared in water only. If necessary, the pH was adjusted to reach the desired pH range.

[0116] The prepared formulation was transferred into containers such as vials or bags so that each container contained the desired amount of active composition. Analysis method After preparation, the amount of active pharmaceutical ingredient and the amount of impurities at early time points were determined by ultra-high performance liquid chromatography (UHPLC), and then the containers were placed in stability chambers at various storage conditions (40°C, 30°C, and 25°C).

[0117] To determine the stability of the active pharmaceutical ingredient of the formulation according to the present disclosure, containers were removed from the stability chamber at various time points (e.g., 14 days, 1 month, 2 months, 3 months, 4 months, 6 months, etc.) and analyzed by UHPLC.

[0118] The assay and impurities of vasopressin were analyzed by UHPLC. For the assay analysis, a UV detector (diode array detector, DAD) was used. For the impurity analysis, a mass spectrometer (MS) was employed.

[0119] Assay Procedure (UV) Chromatography System: Detector: UV detector, detection wavelength 205 nm, column: 2.1 mm, 15 cm; 1.7 μm L1 packing, stationary phase: octadecylsilyl silica gel for chromatography R Column temperature: 50.0℃ Flow rate: 0.4mL / min Injection volume: 10 μL Diluent: 0.3% acetic acid containing 0.9% NaCl solution Solution A: 10 mM sodium dihydrogen phosphate, adjusted to pH 3.0 with phosphoric acid Solution B: Acetonitrile Mobile phase: See table below. JPEG2025535575000003.jpg53170

[0120] Downtime: 30 minutes Sample solution: Inject directly Standard solution: Vasopressin reference standard dissolved in diluent Impurity analysis procedure (MS) Chromatography System Detector: Electrospray ionization-quadrupole mass spectrometer, capillary voltage 3500V, The analysis was carried out in positive ion mode with a gas temperature of 300°C, a gas flow rate of 7 L / min, a nebulizer of 40 psi, a sheath gas temperature of 300°C, and a sheath gas flow rate of 9 L / min.

[0121] Data Acquisition: Selected ion monitoring measurements - performed for the m / z values ​​listed in the table below. JPEG2025535575000004.jpg91170

[0122] Column: 2.1-mm, 15-cm, 1.7 μm L1 packing, Stationary phase: Octadecylsilyl silica gel for chromatography R Column temperature: 50℃ Flow rate: 0.4mL / min Injection volume: 10 μL Solution A: Water containing 0.1% (V / V) formic acid Solution B: acetonitrile containing 0.1% (V / V) formic acid Mobile phase: See table below. JPEG2025535575000005.jpg50170

[0123] Downtime: 23 minutes Sample solution: Inject as is. Calculation of the assay of active compounds The assay of active compound is calculated using the following equation: Assay (%) = (Amps / Ampstd) x (cstd / cs) x 100% where: Amps = peak area of ​​vasopressin peak in sample solution Ampsd = peak area of ​​the vasopressin peak in the standard solution cs = concentration of vasopressin in the sample solution (IU / mL) cstd = concentration of vasopressin in the standard solution (IU / mL) Assay reduction calculation Assay (tp) (%) - Assay value of the main peak analyzed by UHPLC at different time points (tp) (e.g., 7 days, 1 month, 2 months, etc.) and various storage conditions (25°C, 40°C, etc.). Assay (st) (%) - Assay value of the main peak at the initial time point Δ Assay - Calculated assay reduction (%) for the lead compound Δ Assay (%) = Assay (st) (%) - Assay (tp) (%) Individual impurity calculations The content of each impurity (expressed as area %) was calculated as the peak area of ​​the impurity in each extracted ion chromatogram divided by the sum of the peak areas of each extracted ion chromatogram (extraction chromatograms of each impurity and vasopressin). Each component (either an individual impurity or vasopressin) was monitored only in the one extracted chromatogram where its peak area was largest (the extracted chromatogram corresponding to the doubly protonated form).

[0124] Calculation of total impurity and total impurity increase The total impurity content is calculated as the sum of the area % of each individual impurity found. Total impurity content (tp) (%) - Values ​​of total impurity content analyzed by UHPLC at different time points (tp) from the initial stage (e.g., 7 days, 1 month, 2 months, etc.) and various storage conditions (25°C, 40°C, etc.) Total impurities (st) (%) - Total impurity content at the initial time point ΔTotal impurities - calculated increase in total impurities (%) ΔTotal impurity amount (%) = Total impurity amount (tp) (%) - Total impurity amount (st) (%) Example In the examples below, vasopressin is added in the form of arginine vasopressin acetate.

[0125] Example 1 A ready-to-administer vasopressin formulation was prepared by dissolving vasopressin and sodium chloride in water under specified conditions. The solution was stirred using a magnetic stirrer. If necessary, the pH was adjusted to the specified pH using diluted hydrochloric acid and / or sodium hydroxide. The solution was mixed to ensure homogeneity, filtered through a 0.2 μm filter, transferred to a container, and finally, WFI was optionally added to bring the solution to the specified volume.

[0126] The resulting formulation was then stored at controlled room temperature and stability determined at multiple time points, such as at 2 months, 3 months and beyond. Table 1 shows the chemical stability of ready-to-use formulations containing vasopressin and sodium chloride in bags and vials. Unless otherwise stated, the formulations were stored in plastic bags containing PE and EVOH and covered with aluminum packaging. The assay was analyzed using the UHPLC-DAD method, and the assay loss was then calculated according to the calculations described above. Total impurities were analyzed by the UHPLC-MS method. JPEG2025535575000006.jpg52170

[0127] The predicted shelf life was calculated according to the total impurity content determined in the first month, the second month, and the third month. Predictions were made using zero-order degradation prediction. A linear graph of Δtotal impurities (%) (dependent variable) against time (independent variable) was plotted. The predicted shelf life was calculated from the slope and intercept of the obtained linear graph by using Δtotal impurities 8% as the shelf life limit in the following formula: Predicted shelf life = (Δ total impurities - intercept) / slope The stability of the formulation containing vasopressin and 0.9% NaCl was predicted to be greater than 20 months at controlled room temperature. According to the results in Table 1, the predicted stability of the formulation containing vasopressin and 0.9% NaCl packaged in vials at controlled room temperature is 21 months, and the predicted stability of the same formulation packaged in bags is 26 months.

[0128] Example 2 Ready-to-administer vasopressin formulations were prepared by dissolving excipients and vasopressin in 0.9% aqueous sodium chloride solution under specified conditions. The solution was stirred using a magnetic stirrer. If necessary, the pH was adjusted to the specified pH. The solution was mixed to ensure homogeneity, filtered through a 0.2 μm filter, transferred to a container, and finally, 0.9% aqueous sodium chloride solution was optionally added to bring the solution to the specified volume. The resulting formulation was then stored at controlled room temperature, and its stability was determined at time points, such as 2 months, 3 months, and beyond.

[0129] Table 2 shows the chemical stability of various ready-to-use vasopressin formulations in bags and vials. Unless otherwise stated, formulations were stored in plastic bags containing PE and EVOH and covered with aluminum packaging. The assay was analyzed using the UHPLC-DAD method, and the assay loss was then calculated according to the calculation above. The total impurities were analyzed by the UHPLC-MS method. JPEG2025535575000007.jpg229170

[0130] item Item 1. A ready-to-administer vasopressin preparation, vasopressin or a pharmaceutically acceptable salt thereof at a concentration of 0.1 U / mL to 20 U / mL; an osmotic agent; A ready-to-administer vasopressin preparation with a pH of 3.5 to 5.5.

[0131] Item 2. A ready-to-administer vasopressin preparation, vasopressin or a pharmaceutically acceptable salt thereof at a concentration of 0.1 U / mL to 20 U / mL; an osmotic agent; Water and and optionally a pH adjuster; A ready-to-administer vasopressin preparation with a pH of 3.5 to 5.5.

[0132] Item 3. A ready-to-administer vasopressin preparation, Vasopressin in a concentration of 0.1 U / mL to 20 U / mL of a pharmaceutically acceptable salt thereof; an osmotic agent; Water and and optionally a pH adjuster; A ready-to-administer vasopressin preparation with a pH of 3.5 to 5.5.

[0133] Item 4. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the formulation comprises at least one excipient selected from sodium gluconate, sulfobutylether-β-cyclodextrin (SBECD), N-acetyl-D-alanine, glutamic acid, and betaine.

[0134] Item 5. The ready-to-administer vasopressin formulation of Item 4, wherein the excipient is sodium gluconate. Item 6. The ready-to-administer vasopressin formulation of Item 4, wherein the excipient is sulfobutylether-β-cyclodextrin (SBECD).

[0135] Item 7. The ready-to-administer vasopressin formulation of Item 4, wherein the excipient is N-acetyl-D-alanine. Item 8. The ready-to-administer vasopressin formulation of Item 4, wherein the excipient is glutamic acid.

[0136] Item 9. The ready-to-administer vasopressin formulation of Item 4, wherein the excipient is betaine. Item 10. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the osmotic agent is sodium chloride.

[0137] Item 11. The ready-to-administer vasopressin formulation of Item 10, wherein the osmotic agent is at a concentration of 0.9% (w / v). Item 12. The ready-to-administer vasopressin formulation according to Item 11, wherein the sodium chloride is 0.9% (w / v) sodium chloride.

[0138] Item 13. The ready-to-administer vasopressin preparation according to Items 1 to 12, wherein the concentration of the vasopressin is 0.1 U / mL to 1 U / mL. Item 14. The ready-to-administer vasopressin preparation according to Items 1 to 12, wherein the concentration of the vasopressin is 0.2 U / mL to 1 U / mL.

[0139] Item 15. The ready-to-administer vasopressin formulation according to Items 1 to 14, wherein the vasopressin is arginine vasopressin acetate. Item 16. The ready-to-administer vasopressin formulation according to items 1 to 15, wherein the formulation is contained in a single-unit-dose container.

[0140] Item 17. The ready-to-administer vasopressin preparation according to Items 1 to 16, having a pH of 3.5 to 5.0. Item 18. The ready-to-administer vasopressin preparation according to Items 1 to 16, having a pH of 3.8 to 5.0.

[0141] Item 19. The ready-to-administer vasopressin preparation according to Items 1 to 16, having a pH of 3.8 to 4.4. Item 20. The ready-to-administer vasopressin formulation of any of the preceding items, wherein the formulation comprises a buffer.

[0142] Item 21. The ready-to-dose vasopressin formulation of any preceding item, wherein the formulation is stable under controlled room temperature conditions for at least 3 months, and a stable formulation has an assay loss of vasopressin of no more than 5% by UHPLC analysis.

[0143] Item 22. The ready-to-dose vasopressin formulation of any preceding item, wherein the formulation is stable under controlled room temperature conditions for at least 3 months, and a stable formulation has an assay loss of vasopressin of no more than 3% by UHPLC analysis.

[0144] Item 23. The ready-to-dose vasopressin formulation of any preceding item, wherein the formulation is stable under controlled room temperature conditions for at least 3 months, and a stable formulation has an assay loss of vasopressin of no more than 2% by UHPLC analysis.

[0145] Item 24. The ready-to-administer vasopressin formulation of any preceding item, wherein the formulation exhibits no more than a 3% increase in total impurities after 2 months under controlled room temperature conditions by UHPLC analysis. Item 25. The ready-to-administer vasopressin formulation of Item 24, wherein the formulation has no more than 2% total impurities.

[0146] Item 26. The ready-to-administer vasopressin formulation of Item 24, wherein the formulation has no more than 1% total impurities. Item 27. The ready-to-administer vasopressin formulation of any preceding item, wherein the formulation exhibits no more than a 5% increase in total impurities after 3 months under controlled room temperature conditions by UHPLC analysis.

[0147] Item 28. The ready-to-administer vasopressin formulation of Item 27, wherein the formulation has no more than 3% total impurities. Item 29. The ready-to-administer vasopressin formulation of Item 27, wherein the formulation has no more than 2% total impurities.

[0148] Item 30. The ready-to-administer vasopressin formulation of any preceding item, wherein the formulation exhibits no more than a 2% increase in individual impurity formation after 3 months under controlled room temperature conditions by UHPLC analysis.

[0149] Item 31. The ready-to-administer vasopressin formulation of any preceding item, wherein the formulation has no more than a 2% increase in vasopressin trisulfide after 2 months under controlled room temperature conditions by UHPLC analysis.

[0150] Item 32. The ready-to-administer vasopressin formulation of any preceding item, wherein the formulation has no more than a 2% increase in vasopressin trisulfide after 3 months under controlled room temperature conditions by UHPLC analysis.

[0151] Item 33. The ready-to-administer vasopressin formulation of any preceding item, wherein the formulation has no more than a 1% increase in vasopressin trisulfide after 3 months under controlled room temperature conditions by UHPLC analysis.

[0152] Item 34. The ready-to-administer vasopressin formulation of Item 16, wherein the single-unit-dose container is a plastic container. Item 35. The ready-to-administer vasopressin formulation of Item 34, wherein the single-unit-dose container is a plastic bag.

[0153] Item 36. The ready-to-administer vasopressin formulation according to Item 35, wherein the plastic bag does not contain PVC. Item 37. The ready-to-administer vasopressin formulation of item 35, wherein the plastic bag comprises an EVOH barrier material.

[0154] Item 38. The ready-to-administer vasopressin formulation according to Item 35, wherein the plastic bag comprises polyethylene. Item 39. The ready-to-administer vasopressin formulation according to Item 16, wherein the single unit dose container is packaged.

[0155] Item 40. The ready-to-administer vasopressin formulation according to Item 39, wherein the space between the single unit dose container and the packaging is filled with an inert gas or another gas. Item 41. The ready-to-administer vasopressin formulation of Item 40, wherein the space between the single unit dose container and the packaging is filled with N2, argon, or a combination thereof.

[0156] Item 42. The ready-to-administer vasopressin formulation of Item 40, wherein the space between the single unit dose container and the packaging is evacuated. Item 43. The ready-to-administer vasopressin preparation according to Items 1 to 16, having a pH of 3.6 to 5.0.

[0157] Item 44. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the pH is adjusted with hydrochloric acid, sodium hydroxide, or a combination thereof. Item 45. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the formulation does not contain a buffer.

[0158] Item 46. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the formulation does not contain an acetate buffer. Item 47. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the predicted stability of the formulation stored under controlled room temperature conditions is greater than 6 months.

[0159] Item 48. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the predicted stability of the formulation stored under controlled room temperature conditions is greater than 10 months. Item 49. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the predicted stability of the formulation stored under controlled room temperature conditions is greater than 12 months.

[0160] Item 50. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the predicted stability of the formulation stored under controlled room temperature conditions is greater than 20 months. Item 51. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the formulation, packaged in a vial and stored under controlled room temperature conditions, has a predicted stability of 21 months.

[0161] Item 52. The ready-to-administer vasopressin formulation according to Items 1 to 3, wherein the formulation packed in a plastic bag and stored under controlled room temperature conditions has a predicted stability of 26 months.

[0162] Item 53. The ready-to-administer vasopressin formulation according to items 47 to 52, wherein the prediction is performed using zero-order degradation prediction. Item 54. A ready-to-administer vasopressin formulation according to Items 47 to 53, the expected shelf life of which is calculated according to the total impurity amount determined in the first month, the second month, and the third month.

[0163] Item 55. A method of treating a human subject in need of treatment by administering a ready-to-administer vasopressin formulation according to any of the preceding items via an IV route. Item 56. The method of item 55, wherein the method comprises drawing a ready-to-administer formulation from a single unit container and administering the formulation to the human subject via an IV route.

[0164] Item 57. A method for increasing blood pressure in a human subject by administering to the human subject via an IV route the ready-to-administer formulation according to any one of Items 1 to 54.

Claims

1. Vasopressin at a concentration of 0.1 U / mL to 20 U / mL; and at least one osmolality adjusting agent; pH is 3.4 to 5.5; A ready-to-administer formulation of vasopressin or a pharmaceutically acceptable salt thereof.

2. 2. The ready-to-administer formulation of claim 1, wherein at least one osmotic agent is sodium chloride.

3. 2. The ready-to-administer formulation of vasopressin of claim 1, wherein at least one excipient is sulfobutylether-β-cyclodextrin (SBECD).

4. 2. The ready-to-administer formulation of claim 1, wherein at least one excipient is glutamic acid.

5. 2. The ready-to-administer formulation of vasopressin of claim 1, wherein at least one excipient is N-acetyl-D-alanine.

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