DESC:TECHNICAL FIELD:
The present subject matter relates to a stable pharmaceutical composition, comprising vasopressin or pharmaceutically acceptable salts thereof as an active ingredient and suitable buffer, wherein the composition is for intravenous use. Further the stable pharmaceutical composition may be ready to use or ready to dilute for intravenous administration. Further provided is a process for preparing the stable pharmaceutical composition of vasopressin for intravenous administration.

BACKGROUND:
Vasopressin is a polypeptide hormone. Vasopressin is a nonapeptide, having a disulfide bridge between cysteine residues. Vasopressin is also known by the chemical name: cyclo(1-6)-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutarninyl-L-asparaginyl-L-cysteinyl-L-propyl-L-arginyl-L-glycinamide and is reported to have the following chemical structure:

Vasopressin is synthesized and stored in the hypothalamus and excreted by the pituitary gland. Vasopressin having role in both as osmolality regulator as well as a neurotransmitter, but vasopressin's role in increasing blood pressure by reduction of renal restriction at low concentrations and higher concentrations has been clinically significant. Vasopressin is currently marketed under the tradename VASOSTRICT® for increasing blood pressure in adults with vasodilatory shock (e.g. post-cardiotomy or sepsis who remain hypotensive despite fluids and catecholamines).
Vasopressin is known in the pharmaceutical art for increasing blood pressure in adults with vasodilatory shock and formulations containing vasopressin are commercially available, e.g., VASOSTRICT® single and multiple dose vials and their corresponding generic products. As per product label it is available as two types of formulations, one is VASOSTRICT ® Solution for Dilution, 20 units/mL single dose vials and 200 units/10 mL (20 units/mL ) multiple dose. Both the VASOSTRICT® single and multiple dose vials contain an aqueous sodium acetate buffer adjusted to pH 3.8. The 10 mL solution additionally contains chlorobutanol (0.5%) as a preservative. The product label instructed for dilution in normal saline (0.9% Sodium chloride) or 5% dextrose in water (D5W) prior to administration. Another type of formulation is Vasostrict® Premixed Solutions are, 20 units/100 mL (0.2 units/mL), 40 units/100 mL (0.4 units/mL), 60 units/100 mL (0.6 units/mL) and 50 units/50 mL (1 unit/mL). This product does not require further dilution prior to administration. VASOSTRICT ® Premixed Vials contain dextrose anhydrous, an aqueous solution containing acetic acid and sodium acetate and Sodium hydroxide and hydrochloric acid adjusted to pH 3.8. According to the product label, vials are to be stored between 2° C and 8° C. Once removed from refrigeration, unopened vials can be stored at room temperature (20° C. to 25° C.) for up to 12 months with in the labeled shelf life. The label further instructs that vials should not be stored above 25° C.

U.S. Pat. No. 9,375,478 discloses a pharmaceutical composition comprising vasopressin and a buffer having acidic pH. It also discloses pharmaceutical composition comprising about 0.01 mg/mL to about 0.07 mg/mL vasopressin and 10 mM acetate buffer having pH of 3.8.

U.S. Pat. No. 9,744,239 discloses a method of increasing blood pressure with a unit dosage form of vasopressin, wherein the unit dosage form is diluted in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 unit/mL to about 1 unit/mL of vasopressin and administering the diluted unit dosage form to the human by intravenous administration.

U.S. Pat. No. 11,684,573 discloses a stable liquid formulation containing vasopressin and a lactate buffer or buffer comprising lactic acid, a lactate salt, or a combination thereof having pH of from about 3.0 to about 4.1.

U.S. Pat. No. 11,318,183 discloses a pharmaceutical composition of vasopressin having 0.025% w/v to 1.25% w/v of a buffering agent for parenteral administration and has a pH in the range of 2.8 to 3.2. It also discloses buffering agents: citrate, phosphate, tris HCl, acetic acid, sodium acetate, glycine, aspartic acid, histidine, cysteine, tyrosine, phenylalanine, praline, arginine, threonine, serine, valine, isoleucine, lysine, glutamine, or combinations thereof.
Aqueous formulations of therapeutic peptides are prone to degradation. Peptides can undergo deamidation during which an amide group is removed from an amino acid, and can be associated with protein degradation.
In view of the above, it is therefore desirable to provide a stable pharmaceutical composition of vasopressin which is more resistant to deamidation and the stress conditions encountered during their distribution and storage. The inventors of the present subject matter developed a composition of vasopressin which is stable during the stress conditions.
SUMMARY OF THE SUBJECT MATTER:
The present subject matter aims to provide a stable pharmaceutical composition comprising vasopressin or pharmaceutically acceptable salts thereof and buffer, wherein the pharmaceutical composition is for intravenous use.
In the first aspect, the stable pharmaceutical composition comprises vasopressin in an amount of about 0.01 mg/mL to about 0.07 mg/mL and buffer, wherein the pharmaceutical composition is for intravenous use.
In an embodiment of the first aspect, the stable pharmaceutical composition is in liquid form.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition comprises vasopressin in an amount of about 10 units/mL to about 30 units/mL. More specifically the stable liquid pharmaceutical composition comprises vasopressin in an amount of about 20 units/mL.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition comprises buffer selected from Tris, phosphate buffer (Sodium dihydrogen phosphate dehydrate), acetic acid, citric acid, Sodium citrate (Tri-sodium citrate dihydrate), histidine, sodium carbonate, sodium bicarbonate, tartarate, benzoate, sodium acetate, aspartic acid, ascorbic acid, succinic acid, lactic acid, Sodium lactate, glutaric acid, malic acid, boric acid, orthophosphoric acid, citrate, sodium acetate, glycine, Tartaric acid, cysteine, tyrosine, phenylalanine, praline, arginine, threonine, serine, valine, isoleucine, lysine, glutamine, and carbonic acid, alkali or alkaline earth salt of one of these acids.
In a preferred embodiment of the first aspect, the stable liquid pharmaceutical composition comprises buffer selected from acetic acid, citric acid and histidine or combinations thereof.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition comprises buffer in an amount of between about 0.010 %w/v to about 0.040 % w/v, specifically the stable liquid pharmaceutical composition comprises buffer in an amount of between about 0.020 %w/v to about 0.030% w/v, more specifically the stable liquid pharmaceutical composition comprises buffer in an amount of about 0.020%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about 0.028%, about 0.029% or about 0.030% w/v.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition has adjusted pH from about 2.5 to about 4.5, specifically the stable liquid pharmaceutical composition has adjusted pH from about 2.8 to about 3.6 or about 3.0 to about 3.6, and more specifically the stable liquid pharmaceutical composition has adjusted pH about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9 or about 4.0.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition further comprises pharmaceutically acceptable ingredients.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition further comprises pharmaceutically acceptable ingredients as buffers, pH adjusting agents, vehicles, preservatives etc.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition further comprises as pH adjusting agents selected from sodium hydroxide, hydrochloric acid, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, potassium hydroxide, sodium bicarbonate, sodium carbonate, trolamine or combinations thereof.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition further comprises sodium hydroxide and hydrochloric acid as pH adjusting agents.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition comprises, suitable preservative is selected from benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, and thiomersal or combination thereof.
In preferred embodiment of the first aspect, the stable liquid pharmaceutical composition, comprises chlorobutanol as preservative.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition comprises suitable vehicles are selected from the group comprising water for injection, ethanol, glycerin, propylene glycol, corn oil, peanut oil, and cotton seed oil or combination thereof.
In a preferred embodiment of the first aspect, the stable liquid pharmaceutical composition comprises water for injection as a vehicle.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition can be stored in or supplied in single dose vial or multiple dose vial comprising preservatives.
In preferred embodiment of the first aspect, the stable liquid pharmaceutical composition can be stored in or supplied in single dose vial is free of preservatives.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition can be stored in or supplied in multiple dose vials, comprising preservatives.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition further requires to dilute prior to administration.
In an embodiment of the first aspect, the stable liquid pharmaceutical composition is for intravenous administration.
In another embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied or stored in any suitable volume for intravenous administration or for ready to dilute prior to intravenous administration. In one or more embodiments, the composition volume is between about 0.1 mL and about 1000 mL. For example, the formulation volume can be about 0.1 mL to about 10 mL, about 0.5 mL to about 5 mL, or about 1 mL. In some embodiments, the formulation volume is about 1 mL, about 2 mL, about 3 mL, about 5 mL, about 8 mL, about 10 mL or about 15 mL.
In preferred embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied or stored in volume of 1 mL or 10 mL for intravenous administration or for ready to dilute prior to intravenous administration.
In one embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied or stored in any suitable container. For example, the composition can be in a container that includes, but is not limited to, a vial, ampoule, bag (IV bag), bottle, or syringe (e.g., pre-filled syringe or component of an auto-injector).
In one embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied or stored in vial.
In another embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied as single dose vial or multiple dose vial.
In preferred embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied as single dose vial in volume of 1mL having vasopressin in amount of 20 units/mL.
In preferred embodiment of the first aspect, the stable liquid pharmaceutical composition can be supplied as multiple dose vial in volume of 10 mL having vasopressin in amount of 200 units/10 mL.
In an preferred embodiment of the first aspect, the stable liquid pharmaceutical composition comprising vasopressin in an amount of 0.01 mg/mL to about 0.07 mg/mL, acetic acid as a preferred buffer, pH is adjusted from about 3.0 to 3.6 using sodium hydroxide and hydrochloric acid as pH adjustment agent and supplied as single dose vial.
In an preferred embodiment of the first aspect, the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.01 mg/mL to about 0.07 mg/mL, acetic acid as a buffer, chlorobutanol as preservative, pH is adjusted about 3.0 to 3.6 using sodium hydroxide and hydrochloric acid as pH adjustment agent and supplied as multiple dose vial.
In a second aspect, the present subject matter relates to a stable pharmaceutical composition comprising a therapeutically effective amount of vasopressin or a pharmaceutically acceptable salt(s) thereof and a buffer.
In an embodiment of the second aspect, the stable pharmaceutical composition comprises vasopressin in an amount of about 0.1 µg/mL to about 2 µg/mL, specifically the stable liquid pharmaceutical composition comprises vasopressin in an amount of about 0.2 µg/mL to about 1.5µg/mL, more specifically the stable liquid pharmaceutical composition comprises vasopressin in an amount of about 0.37µg/mL, 0.38µg/mL, 0.75 µg/mL, 1.13 µg/mL and 1.09 µg/mL.
In an embodiment of the second aspect, the stable pharmaceutical composition comprises vasopressin in an amount of about 0.1 units/mL to about 2 units/mL, specifically the stable liquid pharmaceutical composition comprises vasopressin in an amount of about 0.1 units/mL to about 1.5 unit/mL, more specifically the stable liquid pharmaceutical composition comprises vasopressin in an amount of about 0.1 units/mL to about 1 unit/mL.
In a preferred embodiment of the second aspect, the stable pharmaceutical composition comprises vasopressin in an amount of about 0.2 units/mL, about 0.4 units/mL, about 0.6 units/mL and about 1 unit/mL.
In an embodiment of the second aspect, the stable pharmaceutical composition is in liquid form.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition comprises buffer selected from Tris, phosphate buffer (Sodium dihydrogen phosphate dehydrate), acetic acid, citric acid, Sodium citrate (Tri-sodium citrate dihydrate), histidine, sodium carbonate, sodium bicarbonate, tartarate, benzoate, aspartic acid, sodium acetate, ascorbic acid, succinic acid, lactic acid, Sodium lactate, glutaric acid, malic acid, boric acid, orthophosphoric acid, citrate, sodium acetate, glycine, cysteine, Tartaric acid, tyrosine, phenylalanine, praline, arginine, threonine, serine, valine, isoleucine, lysine, glutamine, and carbonic acid, alkali or alkaline earth salt of one of these acids.
In a preferred embodiment of the second aspect, the stable liquid pharmaceutical composition comprises buffer selected from acetic acid, citric acid and histidine or combinations thereof.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition comprises buffer in an amount of between about 0.001% w/v to about 0.1% w/v, specifically the stable liquid pharmaceutical composition comprising buffer in an amount of between about 0.002% w/v to about 0.050% w/v., more specifically the stable liquid pharmaceutical composition comprising buffer in an amount of about 0.001%, about 0.0015%, about 0.0020%, about 0.0025%, about 0.0030%, about 0.0035%, about 0.0040%, about 0.0045%, about 0.0050%, about 0.0060%, about 0.0070%, about 0.0080%, about 0.0090%, about 0.01%, about 0.020%, about 0.030%, about 0.040%, about 0.050%, about 0.060%, about 0.070%, about 0.080%, about 0.090% or about 0.1%w/v.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition has adjusted pH about 2.5 to about 4.5, specifically the stable liquid pharmaceutical composition has adjusted pH from about 3.0 to about 4.0 or about 3.5 to about 4.0 and more specifically the stable liquid pharmaceutical composition has adjusted pH about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9 or about 4.0, about 4.1, about 4.2, about 4.3, about 4.4 or about 4.5.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition further comprises pharmaceutically acceptable ingredients.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition further comprises pharmaceutically acceptable ingredients as buffers, pH adjusting agents, vehicles, preservatives, tonicity agents, etc.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition further comprises as pH adjusting agents selected from sodium hydroxide, hydrochloric acid, acetic acid, citric acid, fumaric acid, hydrochloric acid, phosphoric acid, sulfuric acid, potassium hydroxide, sodium bicarbonate, sodium carbonate, trolamine or combinations thereof.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition further comprises sodium hydroxide and hydrochloric acid as pH adjusting agents.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition comprises, suitable tonicity agents include dextrose, glycerol, sodium chloride, potassium chloride, glycerine and mannitol.
In preferred embodiment of the second aspect, the stable liquid pharmaceutical composition comprises dextrose as tonicity agent.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition comprises preservatives.
In preferred embodiment of the second aspect, the stable liquid pharmaceutical composition is free of preservatives.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition comprising suitable vehicles selected from the group comprising water for injection, ethanol, glycerin, propylene glycol, corn oil, peanut oil, and cotton seed oil or combination thereof.
In a preferred embodiment of the second aspect, the stable liquid pharmaceutical composition comprises water for injection as a vehicle.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition is ready to use and not requires diluting prior to administration.
In an embodiment of the second aspect, the stable liquid pharmaceutical composition is for intravenous administration.
In another embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied or stored in any suitable volume for intravenous administration. In one or more embodiments, the composition volume is between about 0.1 mL and about 1000 mL. For example, the composition volume can be about 1 mL to about 500 mL, about 25 mL to about 200 mL. In preferred embodiments, the composition volume is about 50 mL or about 100 mL.
In preferred embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied or stored in volume of about 50 mL or about 100 mL for intravenous administration.
In one embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied or stored in any suitable container. For example, the composition can be in a container that includes, but is not limited to, a vial, ampoule, bag (IV bag), bottle, or syringe (e.g., pre-filled syringe or component of an auto-injector).
In one embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied or stored in vial.
In another embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied as single dose vial or multiple dose vial.
In preferred embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied as single dose vial.
In more preferred embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied as single dose vial in volume of 100 mL having vasopressin in amount of 0.2 units/mL (20 units/100 mL), 0.4 units/mL (40 units/100 mL) and 0.6 units/mL (60 units/100 mL).
In preferred embodiment of the second aspect, the stable liquid pharmaceutical composition can be supplied as single dose vial in volume of 50 mL having vasopressin in amount of 1 unit/mL (50 units/50mL).
In an preferred embodiment of the second aspect, the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.1 unit/mL to about 1 unit/mL, histidine or citric acid or combinations thereof as a buffer, pH is adjusted about 3.0 to 4.0, specifically 3.5 to 4.0, more specifically 3.8, using sodium hydroxide and hydrochloric acid as pH adjustment agent, dextrose as a tonicity agent and supplied as single dose vial.
In an embodiment of the first and second aspect, the stable liquid pharmaceutical composition of the present subject matter comprises a composition that is stable for about 1 month or more, about 3 months or more, about 6 months or more, about 9 months or more, about 12 months or more, or about 18 months or more when stored at an accelerated temperature of about 25° C / 60% RH or about 30° C /65% RH.
In an embodiment of the first and second aspect, related to a process for preparation of the stable pharmaceutical composition comprising vasopressin or pharmaceutically acceptable salts thereof as an active ingredient and, suitable buffer, wherein the formulations for intravenous use.
In an embodiment of the first and second aspect, related to a process, a process for preparation of the stable liquid pharmaceutical composition comprising
(a) 90% vehicle was collected in a vessel and was cooled down,
(b) Buffer was added to step (a) under continuous stirring until uniform solution was achieved,
(c) Optionally pH was adjusted using pH adjusting agents and stirred well to get the stable pH,
(d) Optionally preservative was added under continuous stirring condition and solution was cooled down,
(e) Vasopressin was added under continuous stirring until it get dissolved,
(f) pH of the solution was measured and adjusted using pH adjusting agents, further it was stirred well to get the stable pH and again pH was measured,
g) Final volume was adjusted with vehicle and stirred well,
(i) The solution was filtered and filled in vial, sealed it with pre and post nitrogen purging.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:
In this specification, the term "a" or "an" means one or more unless otherwise specified.
In this specification, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The terms "composition" and "formulation" can be used interchangeably to represent a composition for pharmaceutical use or a pharmaceutical dosage form.

In this specification, the term “comprising” or “comprise” or “comprises” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In this specification, the term "stable" and "stability" as used herein refers to both the physical form and the chemical purity of the active pharmaceutical ingredient or the pharmaceutical active dosage form.

In this specification, the term “about” means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors.
In this specification, the term “buffer” means a compound or mixture of compounds that by their presence in the solution resist changes in the pH upon the addition of small quantities of acid or base.
In this specification, the term “ready to use” compositions means they can be used without dilution or not require dilution before administer.
In this specification, the term “ready to dilute” compositions means they can be diluted prior to administer or require further dilution before administer.
In this specification, the term “vasopressin” is intended to encompass vasopressin and salts thereof.
An embodiment of the present subject matter is directed to stable pharmaceutical composition for intravenous administration that comprising vasopressin, or a pharmaceutically acceptable salt thereof, in a buffer.
An embodiment of the present subject matter is directed to stable liquid pharmaceutical composition for intravenous administration that comprising vasopressin, or a pharmaceutically acceptable salt thereof, in a buffer.
In an embodiment of the present subject matter the stable pharmaceutical composition may be administered intravenously and contains a therapeutically effective amount of vasopressin. As described herein, a therapeutically effective amount can be present in a composition at a concentration of vasopressin, for example, about 0.1 units/mL, about 0.2 units/mL , about 0.3 units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9 units/mL, about 1.0 units/mL, about 2.0 units/mL, about 3.0 units/mL, about 4.0 units/mL, about 5.0 units/mL, about 6.0 units/mL, about 7.0 units/mL, about 8.0 units/mL, about 9.0 units/mL, about 10 units/mL, about 15 units/mL, about 20 units/mL, about 30 units/mL, about 40 units/mL, about 50 units/mL, about 60 units/mL, about 70 units/mL, about 80 units/mL, about 90 units/mL, about 100 units/mL, about 110 units/mL, about 120 units/mL, about 130 units/mL, about 140 units/mL, about 150 units/mL, about 160 units/mL, about 170 units/mL, about 180 units/mL, about 190 units/mL, or about 200 units/mL.
In an embodiment of the present subject matter a therapeutically effective amount of vasopressin can be present in an amount of, for example, about 0.01 µg, about 0.02 µg, about 0.03 µg, about 0.04 µg, about 0.05 µg, about 0.06 µg, about 0.07 µg, about 0.08 µg, about 0.09 µg, about 0.1 µg, about 0.11 µg, about 0.12 µg, about 0.13 µg, about 0.14 µg, about 0.15 µg, about 0.16 µg, about 0.17 µg, about 0.18 µg, about 0.19 µg, about 0.2 µg, about 0.3 µg, about 0.4 µg, about 0.5 µg, about 0.6 µg, about 0.7 µg, about 0.8 µg, about 0.9 µg, about 1.0 µg, about 1.5 µg, about 2.0 µg, about 2.5 µg, about 3.0 µg, about 3.5 µg, about 4.0 µg, about 4.5 µg, about 5.0 µg, about 5.5 µg, about 6.0 µg, about 6.5 µg, about 7.0 µg, about 7.5 µg, about 8.0 µg, about 8.5 µg, about 9.0 µg, about 9.5 µg, about 10 µg, about 20 µg, about 30 µg, about 40 µg, about 50 µg, about 60 µg, about 70 µg, about 80 µg, about 90 µg, about 100 µg, about 120 µg, about 140 µg, about 160 µg, about 180 µg, about 200 µg, about 220 µg, about 240 µg, about 260 µg, about 280 µg, about 300 µg, about 320 µg, about 340 µg, about 360 µg, about 380 µg, about 400 µg, about 420 µg, about 440 µg, about 460 µg, about 480 µg, about 500 µg, about 520 µg, about 540 µg, about 560 µg, about 580 µg, about 600 µg, about 620 µg, about 640 µg, about 660 µg, about 680 µg, about 700 µg, about 720 µg, about 740 µg, about 760 µg, about 780 µg, about 800 µg, about 820 µg, about 840 µg, about 860 µg, about 880 µg, about 900 µg, about 920 µg, about 940 µg, about 960 µg, about 980 µg, or about 1 mg.
In an embodiment of the present subject matter a therapeutically effective amount of vasopressin can be present in a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.015 mg/mL, about 0.02 mg/mL, about 0.025 mg/mL, about 0.03 mg/mL, about 0.035 mg/mL, about 0.04 mg/mL, about 0.045 mg/mL, about 0.05 mg/mL, about 0.055 mg/mL, about 0.06 mg/mL, about 0.065 mg/mL, about 0.07 mg/mL, about 0.075 mg/mL, about 0.08 mg/mL, about 0.085 mg/mL, about 0.08 mg/mL, about 0.085 mg/mL, about 0.09 mg/mL, about 0.095 mg/mL, about 0.1 mg/mL, about 0.15 mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL, about 0.35 mg/mL, about 0.4 mg/mL, about 0.45 mg/mL, about 0.5 mg/mL, about 0.55 mg/mL, about 0.6 mg/mL, about 0.65 mg/mL, about 0.7 mg/mL, about 0.75 mg/mL, about 0.8 mg/mL, about 0.85 mg/mL, about 0.9 mg/mL, about 0.95 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 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 .
In a preferred embodiment of the present subject matter a therapeutically effective amount of vasopressin can be present in a concentration of about 0.01 mg/mL to about 0.07 mg/mL.
In another preferred embodiment, the stable pharmaceutical composition comprising vasopressin in an amount of about 0.1 units/mL to about 2 units/mL, specifically the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.1 units/mL to about 1.5 unit/mL, more specifically the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.1 units/mL to about 1 unit/mL.
In an preferred embodiment, the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.2 units/mL , about 0.4 units/mL , about 0.6 units/mL and about 1 unit/mL .
In an embodiment of the present subject matter, the stable liquid pharmaceutical composition has adjusted pH about 2.5 to about 4.5, specifically the stable liquid pharmaceutical composition has adjusted pH in the range of about 2.8 to about 3.6, about 3.0 to about 4.0, about 3.0 to about 3.6, about 3.5 to about 4.0 and more specifically the stable liquid pharmaceutical composition has adjusted pH to about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9 or about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5.
In an embodiment of the present subject matter, the stable liquid pharmaceutical composition comprising a buffer or buffering agent. Suitable buffers or buffering agents include Tris, phosphate buffer (Sodium dihydrogen phosphate dehydrate), acetic acid, citric acid, Sodium citrate (Tri-sodium citrate dihydrate), histidine, sodium carbonate, sodium bicarbonate, tartarate, benzoate, aspartic acid, ascorbic acid, succinic acid, lactic acid, sodium acetate, glutaric acid, malic acid, boric acid, orthophosphoric acid, citrate, Tartaric acid, sodium acetate, glycine, cysteine, tyrosine, phenylalanine, praline, arginine, threonine, serine, valine, isoleucine, lysine, glutamine, and carbonic acid, alkali or alkaline earth salt of one of these acids.
In a preferred embodiment of the present subject matter, the stable liquid pharmaceutical composition comprising buffer selected from acetic acid, citric acid, histidine or combinations thereof.
The buffer for use with the formulations disclosed herein can be a premixed buffer or can be made in situ as part of the formulation process.
In an embodiment of the present subject matter, the stable liquid pharmaceutical composition comprising buffer in an amount of between about 0.001% w/v to about 0.1% w/v, specifically the stable liquid pharmaceutical composition comprising buffer in an amount of between about 0.002% w/v to about 0.05% w/v., more specifically the stable liquid pharmaceutical composition comprising buffer in an amount of about 0.001%, about 0.0015%, about 0.0020%, about 0.0023%, about 0.0024%, about 0.0025%, about 0.003%, about 0.0035%, about 0.004%, about 0.0045%, about 0.0050%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.010%, about 0.015%, about 0.018%, about 0.020%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about 0.028%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09% or about 0.1%w/v.
In an embodiment, the stable liquid pharmaceutical composition can further include ingredients, such as diluents, pH adjusting agents, salts, tonicity agents, antioxidants, and preservatives, vehicles etc.
In an embodiment, the stable liquid pharmaceutical composition can further include a pH adjusting agents, for example, an acid or a base. The pH adjusting agents to aid in adjusting the pH of the composition. In one or more embodiments, the pH adjusting agent may be sodium hydroxide, hydrochloric acid, acetic acid, citric acid, fumaric acid, hydrochloric acid, phosphoric acid, sulfuric acid, potassium hydroxide, sodium bicarbonate, sodium carbonate, trolamine or combinations thereof.
In a preferred embodiment, the stable liquid pharmaceutical composition further comprises sodium hydroxide and hydrochloric acid as pH adjusting agents.
In another embodiment, the stable liquid pharmaceutical composition comprising suitable vehicles are selected from the group comprising water for injection, ethanol, glycerin, propylene glycol, corn oil, peanut oil, and cotton seed oil.
In a preferred embodiment of the second aspect, the stable liquid pharmaceutical composition comprising water for injection as a vehicle.
In an embodiment, the stable liquid pharmaceutical composition comprising, suitable tonicity agents include dextrose, glycerol, sodium chloride, potassium chloride, glycerine, and mannitol.
In a preferred embodiment, the stable liquid pharmaceutical composition comprising dextrose as tonicity agent.
In an embodiment, the stable liquid pharmaceutical composition comprising, suitable preservative is selected from benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, and thiomersal.
In a preferred embodiment, the stable liquid pharmaceutical composition comprising chlorobutanol as a preservative,
In another embodiment of the present subject matter, the stable liquid pharmaceutical composition may be formulated for single or multiple dosage administration. Multiple dosage composition may include preservatives or antimicrobial agents. All formulations must be sterile, as known and practiced in the art.
In an embodiment of the present subject matter, the stable liquid pharmaceutical composition of the present subject matter comprising a composition that is stable for about 1 month or more, about 3 months or more, about 6 months or more, about 9 months or more, about 12 months or more, or about 18 months or more when stored at an accelerated condition of temperature about 25°C and Relative Humidity of 60% (i.e. 25°C/60% RH) or about 30° C./65% RH. In one or more embodiments, a stable liquid formulation comprising a composition that is stable for about 1 month, about 3 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months or more when stored at room temperature accelerated conditions (i.e. 25±2° C., 60±5% RH).
In another embodiment of the present subject matter, the stable liquid pharmaceutical composition can be supplied or stored in any suitable volume for intravenous administration or for ready to dilute prior to intravenous administration. In one or more embodiments, the composition volume is between about 0.1 mL and about 1000 mL. For example, the composition volume can be about 1 mL to about 500 mL, about 25 mL to about 200mL. In preferred embodiments, the composition volume is about 1mL, about 10 mL, about 50 mL or about 100 mL.
In preferred embodiment, the stable liquid pharmaceutical composition can be supplied or stored in volume of about 1 mL, about 10 mL, about 50 mL or about 100 mL for intravenous administration or for ready to dilute prior to intravenous administration.
In preferred embodiment, the stable liquid pharmaceutical composition can be supplied or stored in volume of about 1 mL, about 10 mL, about 50 mL or about 100 mL for intravenous administration is ready to use and not requires diluting prior to administration.
In another embodiment of the present subject matter, the stable liquid pharmaceutical composition can be stored in or supplied in any suitable container. For example, the formulation can be in a container that includes, but is not limited to, a vial, ampoule, bag (IV bag), bottle, or syringe (e.g., pre-filled syringe or component of an auto-injector). The container can be made of any suitable material, for instance, glass, plastic, or rubber.
In an embodiment, the stable liquid pharmaceutical composition can be stored in or supplied in single dose vial or multiple dose vial.
In an embodiment, the stable liquid pharmaceutical composition prior to filling the composition in a container, the container is preferably sterile and has been subjected to a sterilization process prior to filing with the sterile formulations of the subject matter. Formulations may also be subject to sterilization after filling of the vials or other containers.
In an embodiment, the stable liquid pharmaceutical composition of the present subject matter contain, vasopressin or any pharmaceutically acceptable salt thereof as the active ingredient, In some embodiments, the composition preferably contain vasopressin or any pharmaceutically acceptable salt thereof as the sole active ingredient.
In an embodiment, the stable liquid pharmaceutical composition, comprising vasopressin or a pharmaceutically-acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of ready to use composition.
In an embodiment, the stable liquid pharmaceutical composition, comprising vasopressin or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of aqueous solution or a lyophilized powder, which can be diluted or reconstituted just prior to use.
In a preferred embodiment of the present subject matter, the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.01 mg/mL to about 0.07 mg/mL, acetic acid as a preferred buffer, pH is adjusted from about 3.0 to about 3.6 using sodium hydroxide and hydrochloric acid as pH adjustment agent and supplied as single dose vial.
In another preferred embodiment of the present subject matter, the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.01 mg/mL to about 0.07 mg/mL, acetic acid as a buffer, chlorobutanol as preservative, pH is adjusted in the range of about 3.0 to about 3.6 using sodium hydroxide and hydrochloric acid as pH adjustment agent and supplied as multiple dose vial.
In another preferred embodiment of the present subject matter, the stable liquid pharmaceutical composition comprising vasopressin in an amount of about 0.1 unit/mL to about 1 unit/mL, histidine or citric acid or combinations thereof as a buffer, pH is adjusted in the range of about 3.5 to about 4.0 more specifically 3.8, using sodium hydroxide and hydrochloric acid as pH adjustment agent, dextrose as a tonicity agent and supplied as single dose vial.
In an embodiment, the stable liquid pharmaceutical composition of the present subject matter are suitable for intravenous administration, for example, to a mammal to treat or prevent a disease or condition. Preferably, the mammal is a human. The disease or condition is treatable by the administration of vasopressin or a pharmaceutically acceptable salt thereof. In an example, the pharmaceutical composition is administered to increase blood pressure in a patient. In particular, the formulations of the present disclosure can be administered to patients with vasodilatory shock requiring an increase in blood pressure.
In an embodiment of the present subject matter related to a process for preparation of the stable pharmaceutical composition comprising vasopressin or pharmaceutically acceptable salts thereof as an active ingredient and, suitable buffer, wherein the formulations for intravenous use.
In an embodiment of the present subject matter related to, a process for preparation of the stable liquid pharmaceutical composition comprising
(a) 90% vehicle was collected in a vessel and was cooled down,
(b) Buffer was added to step (a) under continuous stirring until uniform solution was achieved,
(c) Optionally pH was adjusted using pH adjusting agents and stirred well to get the stable pH,
(d) Optionally preservative was added under continuous stirring condition and solution was cooled down,
(e) Vasopressin was added under continuous stirring until it get dissolved,
(f) pH of the solution was measured and adjusted using pH adjusting agents, further it was stirred well to get the stable pH and again pH was measured,
g) Final volume was adjusted with vehicle and stirred well,
(i) The solution was filtered and filled in vial, sealed it with pre and post nitrogen purging.

The present subject matter is further illustrated by the following examples which are provided merely to be exemplary of the subject matter and don't limit the scope of the subject matter. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present subject matter.
Examples
Examples 1 to 4
Table 1 - Single dose vial composition (Ready to dilute - 20 units/mL Vasopressin):
Ingredients Concentration %w/v
Examples Example 1 Example 2 Example 3 Example 4
Vasopressin 0.00377 0.00377 0.00377 0.00377
Glacial acetic acid 0.024 - - -
Citric acid - 0.024 - -
Histidine - - 0.024
Lactic acid - - - 0.024
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 5 to 8
Table 2 - Multiple dose vial composition (Ready to dilute -200 units/10mL Vasopressin):
Ingredients Concentration %w/v
Example 5 Example 6 Example 7 Example 8
Vasopressin 0.00377 0.00377 0.00377 0.00377
Chlorobutanol 0.50 0.50 0.50 0.50
Glacial acetic acid 0.024 - - -
Citric acid - 0.024 - -
Histidine - - 0.024
Lactic acid - - - 0.024
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 9
Table 3 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Citric acid anhydrous 0.0035 % 0.0035 % 0.0035 % 0.0035 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 10
Table 4 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Histidine 0.02 % 0.02 % 0.02 % 0.02 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid 0.0118 %v/v 0.0118 %v/v 0.0118 %v/v 0.0118 %v/v
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 11
Table 5 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Glycine 0.02 % 0.02 % 0.02 % 0.02 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid 0.0023 %v/v 0.0023 %v/v 0.0023 %v/v 0.0023 %v/v
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 12
Table 6 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Aspartic acid 0.0025 % 0.0025 % 0.0025 % 0.0025 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid 0.0008%v/v 0.0008%v/v 0.0008%v/v 0.0008%v/v
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Example 13
Table 7 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Lactic acid/ Sodium lactate 0.0163 %/0.0107 % 0.0163 %/0.0107 % 0.0163 %/0.0107 % 0.0163 %/0.0107 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 14
Table 8 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Tartaric acid 0.0027% 0.0027% 0.0027% 0.0027%
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 15
Table 9 -Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Cysteine-Hydrochloride 0.0035% 0.0035% 0.0035% 0.0035%
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 16
Table 10 - Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Tri-sodium citrate dihydrate 0.0024 % 0.0024 % 0.0024 % 0.0024 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 17
Table 11 -Single dose vial composition (Ready to use):
Ingredients Concentration (% w/v)
20units/100mL 40units/100mL 60units/100mL 50units/50mL
Vasopressin 0.2 units/mL 0.4 units/mL 0.6 units/mL 1 unit/mL
Sodium dihydrogen phosphate dihydrate 0.0234 % 0.0234 % 0.0234 % 0.0234 %
Phosphoric acid 0.0023 % 0.0023 % 0.0023 % 0.0023 %
Dextrose anhydrous 5.0 % 5.0 % 5.0 % 5.0 %
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 18 - Stability Experiments:
HPLC was used to determine the concentration of vasopressin and Total degradation products in vasopressin composition similar to those outlined in TABLES 12-17 below. Experiment conducted after the sample stored at temperature 5°C±3°C and accelerated condition of temperature 25°C and Relative Humidity of 60% (25°C/60% RH) for time in months as 1 month, 3 months or 6 months. The results of the experiment illustrated in Table 12-17 below.
Table 12: Stability data of Example 1 - Single dose composition
Tests Initial 5°C±3°C 25°C/60% RH
1 Month 3 Month 6 Month 1 Month 3 Month 6 Month
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of vasopressin
102.1
100.5
100.3
98.3
99.7
99.2
96.5
Total degradation products (%)
0.37
0.43
0.63
0.61
1.00
1.85
2.51

Table 13: Stability data of Example 5 - Multiple dose composition
Tests Initial 5°C±3°C 25°C/60% RH
1 Month 3 Month 6 Month 1 Month 3 Month 6 Month
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of vasopressin 103.2 101.1 100.8 99.4 100.5 98.4 96.7
Total degradation products (%) 0.36 0.57 0.67 0.63 0.96 1.99 3.18

Table 14: Stability data of Example 9 - Single dose composition - Batch A
Tests Initial 5°C±3°C
1 Month 3 Month 6 Month
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of vasopressin 100.90 100.95 99.80 96.60
Total degradation products (%) ND ND ND 0.418
ND: Not detected

Table 15: Stability data of Example 9 - Single dose composition - Batch B
Tests Initial 5°C±3°C
1 Month 3 Month 6 Month
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of vasopressin 103.40 105.85 106.1 100.45
Total degradation products (%) 0.543 0.213 1.751 1.457

Table 16: Stability data of Example 10 - Single dose composition - Batch A
Tests Initial 5°C±3°C (1 Month)
Description Clear, colorless solution Clear, colorless solution
Assay of vasopressin 103.50 104.70
Total degradation products (%) 1.065 2.112
ND: Not detected

Table 17: Stability data of Example 10 - Single dose composition - Batch B
Tests Initial 5°C±3°C (1 Month)
Description Clear, colorless solution Clear, colorless solution
Assay of vasopressin 90.0 88.00
Total degradation products (%) 0.629 0.562

Above experiments’ result demonstrated that the composition of the present subject matter is stable at stress conditions.

,CLAIMS:We Claim:

1. A stable liquid pharmaceutical composition comprising vasopressin or a pharmaceutically acceptable salt thereof and a buffer, wherein the pharmaceutical composition is for intravenous use.

2. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is ready to dilute.

3. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is ready to use.

4. The stable liquid pharmaceutical composition according to claim 2, comprising vasopressin in an amount of about 10 units/mL to about 30 units/mL, a buffer selected from acetic acid, citric acid and histidine or combinations thereof and optionally chlorobutanol as a preservative.

5. The stable liquid pharmaceutical composition according to claim 2, comprising vasopressin in an amount of about 20 units/mL, a buffer selected from acetic acid, citric acid and histidine or combinations thereof and optionally chlorobutanol as a preservative.

6. The stable liquid pharmaceutical composition according to claim 2, wherein the pH of the composition is adjusted from about 3.0 to 3.6.

7. The stable liquid pharmaceutical composition according to claim 3, comprising vasopressin in an amount of about 0.1 units/mL to about 2 units/mL, a buffer selected from acetic acid, citric acid and histidine or combinations thereof.

8. The stable liquid pharmaceutical composition according to claim 3, comprising vasopressin in an amount of about 0.2 units/mL, about 0.4 units/mL, about 0.6 units/mL or about 1 unit/mL and a buffer selected from acetic acid, citric acid and histidine or combinations thereof.

9. The stable liquid pharmaceutical composition according to claim 2, wherein the pH of the composition is adjusted from about 3.5 to about 4.0.

10. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is supplied as single dose vials or multiple dose vials.