Oxytocin preparation

Abstract

The present disclosure relates to an immediately administrable formulation of oxytocin, a pharmaceutically acceptable salt thereof, or a derivative thereof, and a product containing such a formulation. Specifically, the present disclosure relates to an oxytocin formulation having storage stability and being immediately administrable, a method for producing such a formulation, and its use.

Description

Technical Field

[0001] The present disclosure relates to ready-to-administer oxytocin formulations and their use. Specifically, the present disclosure generally relates to formulations of oxytocin with storage stability.

Background Art

[0002] Oxytocin is a cyclic nonapeptide hormone having the following structural formula: Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2, or CYIQNCPLG-NH2.

[0003] Oxytocin is prepared synthetically to avoid the possibility of contamination by vasopressin and other small polypeptides having biological activity. Oxytocin injection is indicated for the induction of labor in patients with a medical indication for the onset of labor, such as patients with Rh problems, maternal diabetes, preeclampsia during or near term, when delivery is in the best interests of the mother and fetus, or when the membranes have ruptured prematurely and delivery is indicated; for the promotion or augmentation of labor in selected cases of uterine inertia; as an adjuvant therapy in the management of incomplete or inevitable abortion; to promote uterine contractions in the third stage of labor; and to suppress postpartum hemorrhage or bleeding.

[0004] Currently, oxytocin is available as single-use vials at a concentration of 10 US Pharmacopeia (USP) units / ml. The formulation is typically stored in 1 mL glass vials. The available formulation contains 0.5 percent (5 mg / ml) chlorobutanol as a preservative and has a pH of 3.0 - 5.0.

[0005] The currently approved method of oxytocin administration for labor induction or augmentation is by intravenous (IV) infusion. To prepare a normal IV infusion solution, it is typically necessary to dilute a 1 mL oxytocin injection, a 10 USP unit / mL product, to 10 mU / mL before administration to the patient.

[0006] Therefore, one of the drawbacks of existing oxytocin formulations is that, in the case of IV injection, a dilution step is required before administration to the patient, resulting in an increased risk of mismedication. Furthermore, after the initial closed puncture and subsequent dilution, such diluted formulations can only be used for a short period of time, and any unused portion must be discarded.

[0007] Another drawback of existing formulations is the use of chlorobutanol as a preservative. However, chlorobutanol is skin-irritating and highly toxic to the liver. Therefore, it is desirable to avoid chlorobutanol in oxytocin formulations. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0008] Therefore, there is a need in the art for an immediately administrable oxytocin formulation that is stable for a specific long period under storage conditions and can be delivered to patients without the need for dilution.

[0009] Furthermore, there is a need for a stable, immediately administrable oxytocin formulation that does not contain chlorobutanol. MEANS FOR SOLVING THE PROBLEM

[0010] The present disclosure relates to an immediately administrable formulation of oxytocin, its pharmaceutically acceptable salts, or derivatives thereof, and a product containing such formulation. According to the present disclosure, the degradation of oxytocin is delayed, and the shelf life of the stable formulation is extended.

[0011] In one aspect, the pH of the formulation is 3.2 to 5.5. In one aspect, the immediately administrable formulation is in unit dosage form. In one aspect, the concentration of oxytocin in the formulation is 5 mU / ml to 100 mU / ml.

[0012] In one aspect, the pharmaceutical formulation of the present disclosure is in an aqueous form. Unexpectedly, the inventors of the present application have found that when oxytocin is formulated into the formulations according to the present disclosure, the formation of degradation products is delayed, and thus such formulations exhibit long-term stability and provide more flexible storage conditions and handling when stored under controlled room temperature conditions.

[0013] The present disclosure also provides a process for manufacturing the disclosed pharmaceutical formulations. The pharmaceutical formulations according to the present disclosure can be used to initiate or improve uterine contractions in a subject in need thereof.

[0014] It should be understood that the foregoing description and the following further description are merely illustrative and explanatory and do not limit the claims.

Embodiments for Carrying Out the Invention

[0015] The present disclosure relates to an oxytocin formulation that can be administered immediately and products containing such a formulation. According to the present disclosure, the degradation of oxytocin can be retarded, and the shelf life of such products containing the formulation can be extended.

[0016] According to the present specification, oxytocin is synthetically produced. In one aspect, the pH of the formulation is 3.2 to 5.5. In one aspect, the pH of the formulation is 3.4 to 5.0.

[0017] In one aspect, the pH of the formulation is 3.6 to 4.5. In one aspect, the pH of the formulation is 3.8 to 4.5. In one aspect, 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 or 5.0.

[0018] "pH" is the conventional measure of the hydrogen ion activity in solution at controlled room temperature, unless another temperature is specified. As used herein, the term "pH" in a composition is defined as ±0.1 of the numerical value or range.

[0019] In one aspect, the composition is in unit dosage form. When oxytocin is formulated into a formulation according to the present disclosure, the formation of degradation products is delayed, and thus such a formulation exhibits long-term chemical stability and provides more flexible storage conditions and handling when stored under controlled room temperature conditions.

[0020] The term "controlled room temperature" as used herein means the controlled room temperature set in USP <659>, i.e., 20 - 25°C. Furthermore, the formulations according to the present disclosure have improved stability at a temperature of 40°C.

[0021] The term "stable" means that the composition meets one or more of the following criteria: (i) The composition shows that after a certain period, an acceptable amount of the active ingredient is decomposed compared to the amount of oxytocin present at the start of that period; and / or (ii) The composition shows that after a certain period, an acceptable amount of impurities is formed compared to the amount of impurities present at the start of that period; and / or (iii) The composition retains a desirable appearance such as transparency, improved color, and the absence of visible particles (i.e., a composition without precipitates or particles) over a certain period. Visual inspection of visible particles can be carried out as follows: Gently rotate and invert the container being inspected, confirm that no bubbles are generated, and inspect using the naked eye and / or a magnifying glass for a certain period (about 5 - 20 seconds). Visual inspection regarding color change can be performed as follows: Visually inspect the container and assign a color to the composition. The color can also be measured with a UV / VIS spectrometer, and the color difference between two samples can be expressed as delta E.

[0022] As used herein, the acceptable amount of the active ingredient decomposed after a certain period (i.e., the decrease in the oxytocin assay) is calculated as the difference in the oxytocin assay between the assay measured immediately after formulation preparation and the assay measured at a specific stability test time point (e.g., after 1 month, 2 months, 3 months, etc.). The oxytocin assay is analyzed, for example, by liquid chromatography (e.g., HPLC, UHPLC, LC / MS).

[0023] In one aspect, the oxytocin assay is analyzed by UHPLC. In one aspect, the oxytocin assay is analyzed by UHPLC-FLD, UHPLC-DAD or UHPLC-MS methods.

[0024] In one aspect, the ready-to-use composition according to the present disclosure is stable for a certain period under controlled room temperature conditions. In one aspect, the composition 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.

[0025] In one aspect, the composition is stable for at least 3 months when stored under controlled room temperature conditions. The formulations according to the present disclosure showed surprising stability over a reasonable period when stored at a temperature of 30°C.

[0026] In one aspect, the composition is stable for at least 14 days, at least 1 month, at least 2 months, at least 3 months, or more when stored at a temperature of 30°C. The formulations according to the present disclosure showed surprising stability over a reasonable period when stored at a temperature of 40°C.

[0027] In one aspect, the composition is stable for at least 14 days, at least 1 month, at least 2 months, at least 3 months, or more when stored at a temperature of 40 °C. In one aspect, "stability" can be defined by the total amount of impurities or the amount of individual impurities in the formulation after a certain period. Stability can also be defined by the increase in the total amount of impurities or individual impurities produced after a suitable period.

[0028] Stability can be determined by measuring the amount of individual impurities in the formulation according to the present disclosure after a predetermined period, and is preferably expressed as a percentage or area percentage analyzed by HPLC or UHPLC. In one aspect, the amount of individual impurities in the formulation is analyzed by UHPLC. In one aspect, the amount of individual impurities in the formulation is expressed as a percentage or area percentage analyzed by the UHPLC-FLD method or the UHPLC-DAD method. In one aspect, the amount of individual impurities in the formulation is expressed as a percentage or area percentage analyzed by the UHPLC-MS method.

[0029] As used herein, the term "impurities" means degradation impurities of the active pharmaceutical ingredient in a pharmaceutical formulation. Individual impurities related to oxytocin mainly mean the following impurities: oxytocin trisulfide and monodeamidated oxytocin.

[0030] The structure of oxytocin trisulfide is shown below as Structure 1.

[0031]

Chemical formula

[0032] The structure of monodeaminated oxytocin is shown below as Structure 2.

[0033]

Chemical formula

[0034] Structure 2. A representative formula of mono-deamidated oxytocin, wherein one of A is an OH group and the other two As are NH2 groups, and the OH group and the NH2 groups can be located at all three A positions (three possible structures).

[0035] In one aspect, the disclosed formulations also minimize the degradation of the active pharmaceutical ingredient into impurities. In one aspect, the disclosed formulations retain a pharmaceutically desirable appearance, such as being free of visible particles.

[0036] In a specific aspect, "stable" is defined as a decrease in the oxytocin assay in the pharmaceutical formulation of 10% or less as analyzed by liquid chromatography, such as HPLC, UHPLC, LC / MS.

[0037] For example, a stable composition may be one in which the decrease in the oxytocin assay after a predetermined period is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or less as analyzed by liquid chromatography, such as HPLC, UHPLC, LC / MS.

[0038] For example, a stable composition may be one in which the decrease in the oxytocin assay after a predetermined period is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or less as analyzed by liquid chromatography, such as HPLC, UHPLC, LC / MS.

[0039] In one aspect, a stable composition may be one in which the decrease in the oxytocin assay after a predetermined period is 8% or less. In one aspect, a stable or stabilized composition may be one in which the decrease in the oxytocin assay after a certain period is 10% or less.

[0040] In one aspect, a stable or stabilized composition may be analyzed by liquid chromatography, such as HPLC, UHPLC, LC / MS, and have a decrease in oxytocin assay of 8% or less after one month at a temperature of 40°C.

[0041] In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 10% or less after two months at a controlled room temperature. In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 10% or less after three months at a controlled room temperature.

[0042] In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 10% or less after four months at a controlled room temperature. In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 8% or less after four months at a controlled room temperature.

[0043] In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 8% or less after three months at a controlled room temperature. In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 10% or less after six months at a controlled room temperature.

[0044] In one aspect, a stable or stabilized composition may be analyzed by UHPLC and have a decrease in oxytocin assay of 8% or less after six months at a controlled room temperature. As used herein, when two or more impurities of an individual active pharmaceutical ingredient can be formed over time, "stable" is defined as an increase in the formation of each individual impurity of 5% or less after a predetermined time, as analyzed by UHPLC.

[0045] In one aspect, when two or more impurities of an individual active pharmaceutical ingredient can be formed over time, a stable composition can be one in which the increase in the formation of individual impurities after a predetermined time is 1%, 2%, 3%, 4%, or 5% or less, as analyzed by liquid chromatography, for example, HPLC, UHPLC, LC / MS.

[0046] In one aspect, the pharmaceutical composition described herein is stable at a temperature of 40 °C for at least 14 days. In one aspect, the pharmaceutical composition described herein is stable at a temperature of 40 °C for at least 1 month.

[0047] In one aspect, a stable composition can be one in which the increase in the formation of individual impurities after 1 month at a temperature of 40 °C, as analyzed by UHPLC, is 2% or less. In one aspect, a stable composition can be one in which the increase in the formation of individual impurities after 3 months at a controlled room temperature, as analyzed by UHPLC, is 2% or less.

[0048] In one aspect, a stable composition can be one in which the increase in each of oxytocin trisulfide and mono-deamidated oxytocin after 1 month at a temperature of 40 °C, as analyzed by UHPLC, is 2% or less.

[0049] In one aspect, a stable composition can be one in which the increase in oxytocin trisulfide after 1 month at a temperature of 40 °C, as analyzed by UHPLC, is 2% or less. In one aspect, a stable composition can be one in which the increase in mono-deamidated oxytocin after 1 month at a temperature of 40 °C, as analyzed by UHPLC, is 2% or less.

[0050] In one aspect, a stable composition can be one in which the increase in the formation of individual impurities after 1 month at a temperature of 40 °C, as analyzed by UHPLC, is 4% or less. In one aspect, a stable composition can be one in which the increase in each of oxytocin trisulfide and mono-deamidated oxytocin after 3 months at a controlled room temperature, as analyzed by UHPLC, is 2% or less.

[0051] In one aspect, a stable composition can be one in which the increase in oxytocin trisulfide after 3 months at controlled room temperature, analyzed by UHPLC, is 2% or less. In one aspect, a stable composition can be one in which the increase in oxytocin trisulfide after 6 months at controlled room temperature, analyzed by UHPLC, is 2% or less.

[0052] In one aspect, a stable composition can be one in which the increase in mono-deamidated oxytocin after 1 month at controlled room temperature, analyzed by UHPLC, is 2% or less. In one aspect, a stable composition can be one in which the increase in mono-deamidated oxytocin after 3 months at controlled room temperature, analyzed by UHPLC, is 2% or less.

[0053] In one aspect, a stable composition can be one in which the increase in mono-deamidated oxytocin after 6 months at controlled room temperature, analyzed by UHPLC, is 3% or less. In one aspect, a stable composition can be one in which the increase in the formation of individual impurities after 3 months at controlled room temperature, analyzed by UHPLC, is 3% or less.

[0054] As used herein, "stable" can be defined as being free of visible particles (particle-free, or free of particles / precipitates) in a pharmaceutical formulation after a given time. In one aspect, the composition is particle-free when stored at 40 °C for at least 1 month.

[0055] In one aspect, the composition is particle-free when stored at controlled room temperature for at least 3 months. As used herein, the terms "pharmaceutical composition" or "pharmaceutically acceptable composition" mean any composition suitable for in vivo use, e.g., administration to a patient or subject, and intended for that purpose. As used herein, the terms "patient" and "subject" are interchangeable and refer to any human or animal individual to whom a composition as described herein is administered.

[0056] As used herein, the terms "pharmaceutical composition", "pharmaceutically acceptable composition", "pharmaceutical preparation", "composition", and "preparation" are used interchangeably. In one aspect, the concentration of oxytocin in the preparation is 5 mU / ml to 100 mU / ml.

[0057] In one aspect, the concentration of oxytocin in the preparation is 10 mU / ml to 60 mU / ml. In one aspect, the concentration of oxytocin in the preparation is 10 mU / ml, 20 mU / ml, 30 mU / ml, 40 mU / ml, 50 mU / ml, or 60 mU / ml.

[0058] In one aspect, the concentration of oxytocin in the preparation is 60 mU / ml. In one aspect, oxytocin is in the form of a salt. The oxytocin salt can be selected from succinate, maleate, citrate, tartrate, aspartate, gluconate, and acetate. In one aspect, oxytocin is in the form of acetate.

[0059] In one aspect, oxytocin is in the form of oxytocin acetate hydrate. In one aspect, the pharmaceutical preparation is aqueous. The terms "aqueous composition", "aqueous solution", or "aqueous" are understood to mean any composition in which water is present at 50% v / v or more, for example, a composition containing 50% v / v to 99.5% v / v of water, 50% v / v to 90% v / v, 60% v / v to 85% v / v, 70% v / v to 80% v / v of water, etc. Thus, an aqueous composition includes a composition containing 50% v / v or more, 60% v / v or more, 70% v / v or more, 75% v / v or more, 80% v / v or more, 85% v / v or more, 90% v / v or more, 95% v / v or more, or 99% v / v or more of water.

[0060] In one aspect, the aqueous composition of oxytocin contains 90% or more water. In one aspect, the pharmaceutical preparation may contain water or a standard diluent for parenteral use, such as water for injection, 0.9% sodium chloride for injection, sterile water for injection, 5% dextrose injection, or other suitable diluents.

[0061] In one aspect, the preparation contains 0.9% sodium chloride for injection. In one aspect, the composition of oxytocin contains at least one cyclodextrin.

[0062] In one aspect, the liquid composition of oxytocin contains at least one β-cyclodextrin. In one aspect, exemplary cyclodextrins are 2-hydroxypropyl-β-cyclodextrin (HPBCD) and sulfobutyl ether-β-cyclodextrin (SBEBCD).

[0063] In one aspect, the β-cyclodextrin is SBECD. Sulfobutyl ether-β-cyclodextrin (SBECD) is an anionic β-cyclodextrin derivative of sodium sulfonate salt separated from the hydrophobic cavity by a spacer group of butyl ether. The sulfobutyl ether substituents are introduced at the 2, 3, and 6 positions of one or more glucopyranose units in the cyclodextrin structure.

[0064] In one aspect, the average degree of substitution of SBECD is 5.9 - 7.1. In one aspect, the average degree of substitution of 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, or 7.1.

[0065] The degree of substitution can be expressed as the average degree of substitution understood as the number of substituents per cyclodextrin ring. The degree of substitution can also be expressed as the molar degree of substitution, which is the number of substituents per glucose unit of cyclodextrin.

[0066] In one aspect, the β-cyclodextrin is HPBCD. Hydroxypropyl-β-cyclodextrin is a poly(2-hydroxypropyl) ether in which β-cyclodextrin is partially substituted. In one aspect, the molar substitution degree of HPBCD is 0.4 to 1.5.

[0067] In one aspect, the molar substitution degree of HPBCD is 0.5 to 1.1. In another aspect, the molar substitution degree of HPBCD is 0.6 to 1.0. In another aspect, the molar substitution degree of HPBCD is 0.6 to 0.9.

[0068] In another aspect, the molar substitution degree of HPBCD is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 or 1.1. In one aspect, at least one cyclodextrin has a concentration of 0.01 mM to 5 mM.

[0069] In other aspects, at least one cyclodextrin has a concentration of 0.1 mM to 1 mM. In one aspect, at least one cyclodextrin has a concentration of 0.05 mM, 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM or 1.0 mM.

[0070] In some aspects, the formulation contains at least one amino acid. The term "amino acid" means any amino acid, including but not limited to the 20 amino acids that occur naturally in peptides, and is also intended to include any salts thereof, particularly pharmaceutically acceptable salts. 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 and ornithine, and salts thereof.

[0071] In one embodiment, the amino acid is aspartic acid, serine, glutamic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the formulation comprises at least two amino acids.

[0072] In one embodiment, the formulation comprises at least three amino acids. In one embodiment, the amino acid is glutamic acid. In one embodiment, the amino acid is serine.

[0073] In one embodiment, the amino acid is aspartic acid. In some embodiments, the amino acid can be in the L-configuration, and in some other embodiments, it can be in the D-configuration.

[0074] In one embodiment, glutamic acid is L-glutamic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the amino acid is L-serine.

[0075] In one embodiment, the amino acid is L-aspartic acid. In one embodiment, the formulation comprises HPBCD and L-aspartic acid. In one embodiment, the formulation comprises HPBCD and L-serine.

[0076] In one embodiment, the formulation comprises HPBCD and L-glutamic acid. In one embodiment, the formulation comprises L-glutamic acid and serine. In one embodiment, the formulation comprises L-serine and L-aspartic acid.

[0077] In one embodiment, the formulation comprises L-glutamic acid and L-aspartic acid. In one embodiment, the concentration of at least one amino acid is from 0.5 mM to 200 mM.

[0078] In one embodiment, the concentration of at least one amino acid is from 5.5 mM to 50 mM. In one embodiment, the concentration of at least one amino acid is 5.5 mM to 15 mM. In one embodiment, the concentration of at least one amino acid is 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.

[0079] In one embodiment, the concentration of L-glutamic acid is 0.1 mg / ml to 5 mg / ml. In one embodiment, the concentration of L-glutamic acid is 0.8 mg / ml to 2 mg / ml.

[0080] In one embodiment, oxytocin and at least one amino acid are in a molar ratio of 1:0.5 to 1:20. In one embodiment, oxytocin and at least one amino acid are in a molar ratio of 1:0.5, 1:1, 1:1, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20.

[0081] In one embodiment, the pharmaceutical preparation contains at least one organic acid or a pharmaceutically acceptable salt thereof, and the organic acid is not an amino acid. In one embodiment, the at least one organic acid can be selected from aldonic acids such as lactobionic acid and gluconic acid; dicarboxylic acids, especially α,ω-dicarboxylic acids such as adipic acid; and / or carboxylic acids such as picolinic acid. In one embodiment, the at least one organic acid can be selected from adipic acid, lactobionic acid, gluconic acid, picolinic acid, or a pharmaceutically acceptable salt thereof. Combinations of organic acids can also be used.

[0082] In one embodiment, the preparation contains at least two organic acids. In one embodiment, the preparation contains at least three organic acids. In one aspect, the formulation comprises an aldonic acid or a pharmaceutically acceptable salt thereof.

[0083] In one aspect, the formulation comprises gluconic acid or a pharmaceutically acceptable salt thereof. In one aspect, the formulation comprises sodium gluconate. As used herein, the term "sodium gluconate" means sodium D-gluconate.

[0084] In one aspect, the formulation comprises lactobionic acid or a pharmaceutically acceptable salt thereof. As used herein, the term "lactobionic acid" means 4-O-β-D-galactopyranosyl-D-gluconic acid.

[0085] In one aspect, the formulation comprises adipic acid. In one aspect, the formulation comprises HPBCD and sodium gluconate. In one aspect, the formulation comprises HPBCD and lactobionic acid.

[0086] In one aspect, the formulation comprises HPBCD and adipic acid. In one aspect, the formulation comprises sodium gluconate and lactobionic acid. In one aspect, the formulation comprises gluconic acid and lactobionic acid or a pharmaceutically acceptable salt thereof.

[0087] In one aspect, the formulation comprises gluconic acid and adipic acid or a pharmaceutically acceptable salt thereof. In one aspect, the formulation comprises gluconic acid and L-glutamic acid or a pharmaceutically acceptable salt thereof.

[0088] In one aspect, the formulation comprises sodium gluconate and adipic acid. In one aspect, the formulation comprises sodium gluconate and L-glutamic acid. In one aspect, the formulation comprises sodium gluconate and L-serine.

[0089] In one aspect, the formulation contains sodium gluconate and L-aspartic acid. In one aspect, the formulation contains lactobionic acid and adipic acid. In one aspect, the formulation contains lactobionic acid and L-glutamic acid.

[0090] In one aspect, the formulation contains lactobionic acid and L-serine. In one aspect, the formulation contains lactobionic acid and L-aspartic acid. In one aspect, the formulation contains adipic acid and L-glutamic acid.

[0091] In one aspect, the formulation contains adipic acid and L-serine. In one aspect, the formulation contains adipic acid and L-aspartic acid. In one aspect, the concentration of at least one organic acid is 0.5 mM to 200 mM.

[0092] In one aspect, the concentration of at least one organic acid is 5.5 mM to 50 mM. In one aspect, the concentration of at least one organic acid is 5.5 mM to 15 mM. In one aspect, the concentration of at least one organic acid is 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.

[0093] In one aspect, the concentration of gluconic acid is 0.1 mg / ml to 5 mg / ml. In one aspect, the concentration of gluconic acid is 1.3 mg / ml to 2 mg / ml. In one aspect, the concentration of sodium gluconate is 0.1 mg / ml to 5 mg / ml.

[0094] In one aspect, the concentration of sodium gluconate is 0.8 mg / ml to 2 mg / ml. In one aspect, the concentration of sodium gluconate is 1.3 mg / ml to 2 mg / ml.

[0095] In one aspect, the concentration of sodium gluconate is 1.3 mg / ml to 1.5 mg / ml. In one aspect, the concentration of lactobionic acid is 0.1 mg / ml to 5 mg / ml.

[0096] In one aspect, the concentration of lactobionic acid is 0.5 mg / ml to 2 mg / ml. In one aspect, the formulation contains magnesium or a pharmaceutically acceptable salt thereof. In one aspect, the formulation contains magnesium chloride.

[0097] In one aspect, the pharmaceutical formulation does not contain a chelating agent. In one aspect, the pharmaceutical formulation does not contain EDTA. In one aspect, the pharmaceutical formulation does not contain chlorobutanol.

[0098] In one aspect, the pharmaceutical formulation does not contain cyclodextrin. In one aspect, the pharmaceutical formulation does not contain sodium acetate. In one aspect, the pharmaceutical formulation does not contain magnesium or a pharmaceutically acceptable salt thereof.

[0099] The pH of the solution can be adjusted by any suitable method. The pH can be adjusted with one or more pH adjusters selected from mineral acids, organic acids, weak bases, and strong bases, as well as salts and derivatives thereof. Examples of pH adjusters include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, succinic acid, lactic acid, citric acid, phenolic acid, sodium hydroxide, ammonium hydroxide, sodium bicarbonate, and the like.

[0100] In one aspect, the pH is adjusted with sodium hydroxide and hydrochloric acid. In one aspect, the pH is adjusted with hydrochloric acid. In one aspect, the formulation is in the form of an immediately administrable composition.

[0101] An “immediately administrable” composition is synonymous with an “immediately injectable” or “immediately infusible” composition. An “immediately administrable” composition is suitable for direct administration to a patient and requires no dilution steps.

[0102] The immediately administrable formulations according to the present disclosure can be used by administering oxytocin to a subject in need thereof. The immediately administrable formulations according to the present disclosure can be used for the initiation or improvement of uterine contractions by administering oxytocin to a subject in need thereof.

[0103] In one aspect, the immediately administrable formulation is used for induction of labor in patients with a medical indication for the onset of labor, such as Rh problems, maternal diabetes, pre-eclampsia during or near labor, and can be used when delivery is in the best interest of the mother and fetus, or when the membranes have ruptured early and delivery is indicated.

[0104] In one aspect, the immediately administrable formulation can be used for promoting or intensifying labor, such as in selected cases of uterine inertia in a subject. In one aspect, the immediately administrable formulation can be used as an adjuvant therapy in the management of incomplete or inevitable abortion.

[0105] In one aspect, the immediately administrable formulation can be used to effect uterine contractions during the third stage of labor and to suppress post-partum hemorrhage or bleeding. The present disclosure also provides a method for manufacturing any of the disclosed pharmaceutical formulations. In various embodiments, the method can include dissolving a predetermined excipient and oxytocin in water or a predetermined standard diluent for parenteral use, and filling the formulation into a predetermined container. If necessary, the pH is adjusted to achieve the desired pH range.

[0106] In one aspect, an immediately administrable formulation of oxytocin can be prepared by dissolving an excipient in water for injection or a predetermined standard diluent for parenteral use under predetermined conditions until a clear solution is obtained. Oxytocin is added to the solution containing the dissolved excipient, and the solution is mixed until the oxytocin 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 volume to a predetermined value. The prepared formulation is then mixed to ensure homogeneity, filtered through a 0.2 μm filter, and dispensed into predetermined packages.

[0107] In another aspect, the pharmaceutical formulation can be manufactured by any method known to those skilled in the art. In one aspect, the liquid formulation of oxytocin is packaged in a suitable container. Accordingly, products containing the oxytocin formulations described herein are included herein. The container can be a vial, an ampoule, or a bag. In one aspect, the container is a single unit dose container. In one aspect, the container is a single unit dose container for IV administration.

[0108] In one aspect, the volume of the container is from 50 mL to 1000 mL. In one aspect, the volume of the container is from 100 mL to 1000 mL. In one aspect, 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.

[0109] In one aspect, the volume of the container is 500 mL. In one aspect, the formulation is stored in a container for intravenous administration, which is preferably plastic-based. In one aspect, the formulation is packaged in a flexible plastic bag. In one aspect, the formulation is packaged in a container produced by a blow-fill-seal technique. In one aspect, the material of the container does not contain PVC. In one aspect, the formulation is not in contact with the PVC material of the container.

[0110] In one aspect, the plastic material can be a polyolefin, such as polyethylene (PE), polypropylene (PP), ethylene vinyl acetate (EVA), ethylene vinyl alcohol (EVOH), polyolefin / styrene block copolymers, and their derivatives with or without other additives, and at least two combinations of such polymeric materials, particularly blends, composites or laminates.

[0111] In one aspect, the plastic material of the container contains polyethylene (PE). In one aspect, the plastic material of the container contains ethylene vinyl alcohol (EVOH).

[0112] In one aspect, the container is a single-layer or multi-layer container. In one aspect, the inner layer of the container in contact with the formulation contains polyethylene. In one aspect, the inner layer of the plastic material in contact with the formulation is polyethylene.

[0113] In one aspect, the barrier layer of the plastic material is EVOH. In one aspect, an immediately administrable injectable formulation does not require the removal of oxygen from the container in which the formulation is stored. That is, there is no need to remove oxygen from the headspace of the container and no need to purge the solution with an inert gas.

[0114] In one aspect, the container may optionally further include an overwrap. In one aspect, the overwrap may include a gas barrier and / or a light barrier material.

[0115] In one aspect, the overwrap is made of aluminum. In one aspect, the space between the container and the overwrap is filled with an inert gas or any other suitable gas. In one aspect, the space between the container and the overwrap is filled with nitrogen (N2), argon, or any combination thereof.

[0116] In one aspect, the space between the container and the overlap is evacuated. In one aspect, the space between the container and the overlap contains an oxygen scavenger. In one aspect, the container is overlapped with a water vapor barrier overlap. In one aspect, the container is overlapped with a water vapor barrier overlap, and the space between the container and the overlap is not filled with nitrogen or any other inert gas. In one aspect, the container is overlapped with a water vapor barrier overlap, and the space between the container and the overlap is not filled with nitrogen or any other inert gas and does not contain an oxygen scavenger.

[0117] In one aspect, the container is overlapped with an overlap, and the space between the container and the overlap is not filled with nitrogen or any other inert gas. In one aspect, the container is overlapped with an overlap, and the space between the container and the overlap is not filled with nitrogen or any other inert gas and does not contain an oxygen scavenger.

[0118] In one aspect, the formulation need not be overlapped. Also, the formulation does not require any atmosphere control method to reduce the oxygen content between the product and the overlap.

[0119] The formulations disclosed herein can be sterilized by known means. Such known means in the art include sterile filtration, heat treatment and / or irradiation. In one aspect, the present disclosure provides a method of treating a human by administering an effective dose of oxytocin via the IV route.

[0120] In one aspect, the present disclosure provides a method of treating a human by administering an effective dose of an oxytocin formulation that is immediately administrable by IV injection. In one aspect, the formulations described herein are intended to be administered, for example, intravenously or intramuscularly via injection or infusion.

[0121] In one aspect, the present disclosure provides a method of treating a human with an effective dose of oxytocin, comprising directly intravenously administering to a human, from a unit dosage form, an immediately administrable pharmaceutical composition disclosed herein, wherein the unit dosage form comprises oxytocin at 10 mU / ml to 60 mU / ml or a pharmaceutically acceptable salt thereof.

[0122] In one aspect, the present disclosure provides a method of treating a human with an effective dose of oxytocin, comprising directly intravenously administering to a human, from a unit dosage form, an immediately administrable pharmaceutical composition disclosed herein, wherein the unit dosage form comprises oxytocin at 60 mU / ml or a pharmaceutically acceptable salt thereof.

[0123] All numerical values used herein, except for pH values, are modified by the term "about". This means that each numerical value includes a small variation defined as ±10% of that numerical value or range.

[0124] In one aspect, the composition is an isotonic composition. The term "isotonic" as used in the present disclosure is to be understood as having an osmotic pressure similar to the physiological osmotic pressure of blood. Typically, the immediately administrable pharmaceutical composition has an osmotic pressure of 250 to 350 mOsm / kg.

[0125] In one aspect, the composition has an osmotic pressure of 240 to 600 mOsm / kg. In one aspect, the immediately administrable formulation comprised in the immediately administrable product is isotonic and has an osmotic pressure similar to the physiological osmotic pressure of blood as described above.

[0126] In some embodiments, the immediately administrable pharmaceutical composition further comprises one or more osmotic agents. Exemplary osmotic agents for use in the immediately administrable pharmaceutical composition include, but are not limited to, sodium chloride and dextrose.

[0127] Unless otherwise specified, the calculation of the molar ratio or concentration of oxytocin in the present disclosure is performed based on the oxytocin free base. Unless otherwise specified, the calculation of the molar ratio or concentration of the excipient in the present disclosure is performed based on the free base of the excipient.

[0128] 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.

[0129] Accordingly, the present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 5 mU / ml to 100 mU / ml and having a pH in the range of 3.2 to 5.5.

[0130] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 5 mU / ml to 100 mU / ml and having a pH in the range of 3.8 to 4.5.

[0131] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.2 to 5.5.

[0132] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.8 to 4.5.

[0133] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml, sodium gluconate, and having a pH in the range of 3.2 to 5.5. The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml, sodium gluconate, and having a pH in the range of 3.8 to 4.5.

[0134] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and having a pH in the range of 3.2 to 5.5. The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and having a pH in the range of 3.6 to 4.5.

[0135] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and having a pH in the range of 3.8 to 4.5. The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml, gluconic acid or a pharmaceutically acceptable salt thereof, wherein the gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0136] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml, gluconic acid or a pharmaceutically acceptable salt thereof, wherein the gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0137] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, gluconic acid or a pharmaceutically acceptable salt thereof, wherein the gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0138] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH ranges from 3.8 to 4.5.

[0139] The present disclosure provides an immediately administrable formulation comprising oxytocin and sodium gluconate at a concentration of 5 mU / ml to 100 mU / ml, wherein sodium gluconate is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH ranges from 3.2 to 5.5.

[0140] The present disclosure provides an immediately administrable formulation comprising oxytocin and sodium gluconate at a concentration of 5 mU / ml to 100 mU / ml, wherein sodium gluconate is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH ranges from 3.8 to 4.5.

[0141] The present disclosure provides an immediately administrable formulation comprising oxytocin and sodium gluconate at a concentration of 10 mU / ml to 60 mU / ml, wherein sodium gluconate is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH ranges from 3.2 to 5.5.

[0142] The present disclosure provides an immediately administrable formulation comprising oxytocin and sodium gluconate at a concentration of 10 mU / ml to 60 mU / ml, wherein sodium gluconate is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH ranges from 3.8 to 4.5.

[0143] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 5 mU / ml to 100 mU / ml, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0144] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 5 mU / ml to 100 mU / ml, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.8 to 4.5.

[0145] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0146] The present disclosure provides an immediately administrable formulation comprising oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.8 to 4.5.

[0147] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and sodium gluconate, wherein sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0148] The present disclosure provides an immediately administrable formulation comprising oxytocin and sodium gluconate at a concentration of 5 mU / ml to 100 mU / ml, wherein sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.8 to 4.5.

[0149] The present disclosure provides an immediately administrable formulation comprising oxytocin and sodium gluconate at a concentration of 10 mU / ml to 60 mU / ml, wherein sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0150] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, wherein the sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.6 to 4.5.

[0151] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, wherein the sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0152] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, wherein the sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.6 to 4.5, and the formulation is stable for at least 3 months at controlled room temperature, with the decrease in the oxytocin assay being 8% or less as measured by UHPLC.

[0153] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, wherein the sodium gluconate is at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.8 to 4.5, and the formulation is stable for at least 3 months at controlled room temperature, with the decrease in the oxytocin assay being 8% or less as measured by UHPLC.

[0154] The present disclosure provides an immediately administrable formulation consisting essentially of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, 0.8 mg / ml to 2 mg / ml of sodium gluconate, 9 mg / ml of sodium chloride, optionally a pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0155] The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, an optional pH adjuster, and water, and having a pH in the range of 3.6 to 4.5.

[0156] The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, an optional pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0157] Accordingly, the present disclosure provides an immediately administrable preparation comprising oxytocin at 5 mU / ml to 100 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, and having a pH in the range of 3.2 to 5.5.

[0158] The present disclosure provides an immediately administrable preparation comprising oxytocin at 5 mU / ml to 100 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, and having a pH in the range of 3.8 to 4.5.

[0159] The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, and having a pH in the range of 3.2 to 5.5.

[0160] The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, and having a pH in the range of 3.8 to 4.5.

[0161] The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and L-glutamic acid, and having a pH in the range of 3.2 to 5.5. The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and L-glutamic acid, and having a pH in the range of 3.8 to 4.5.

[0162] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, and having a pH in the range of 3.2 to 5.5. The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, and having a pH in the range of 3.8 to 4.5.

[0163] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, wherein L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0164] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, wherein L-L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0165] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, wherein L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0166] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, wherein L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0167] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, L-glutamic acid, where L-glutamic acid is at a concentration of 0.1 mg / ml to 5 mg / ml, and the pH ranges from 3.2 to 5.5.

[0168] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, L-glutamic acid, where L-glutamic acid is at a concentration of 0.1 mg / ml to 5 mg / ml, and the pH ranges from 3.8 to 4.5.

[0169] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, where L-glutamic acid is at a concentration of 0.1 mg / ml to 5 mg / ml, and the pH ranges from 3.2 to 5.5.

[0170] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, where L-glutamic acid is at a concentration of 0.1 mg / ml to 5 mg / ml, and the pH ranges from 3.8 to 4.5.

[0171] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, where L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH ranges from 3.2 to 5.5.

[0172] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, L-glutamic acid or a pharmaceutically acceptable salt thereof, where L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH ranges from 3.8 to 4.5.

[0173] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0174] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.8 to 4.5.

[0175] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and L-glutamic acid, wherein L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0176] The present disclosure provides an immediately administrable formulation comprising 5 mU / ml to 100 mU / ml of oxytocin and L-glutamic acid, wherein L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.8 to 4.5.

[0177] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml and L-glutamic acid, wherein L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.2 to 5.5.

[0178] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml and L-glutamic acid, wherein L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml and the pH ranges from 3.6 to 5.5.

[0179] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, wherein the L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.8 to 5.5.

[0180] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, wherein the L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.6 to 5.5, the formulation being stable for at least 3 months at controlled room temperature, and having a decrease in oxytocin assay of 8% or less as measured by UHPLC.

[0181] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid, wherein the L-glutamic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.8 to 5.5, the formulation being stable for at least 3 months at controlled room temperature, and having a decrease in oxytocin assay of 8% or less as measured by UHPLC.

[0182] The present disclosure provides an immediately administrable formulation consisting essentially of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0183] The present disclosure provides an immediately administrable formulation consisting of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and having a pH in the range of 3.6 to 4.5.

[0184] The present disclosure provides an immediately administrable preparation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, an optional pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0185] Accordingly, the present disclosure provides an immediately administrable preparation comprising oxytocin, L-glutamic acid, and sodium gluconate at 5 mU / ml to 100 mU / ml and having a pH in the range of 3.2 to 5.5.

[0186] The present disclosure provides an immediately administrable preparation comprising oxytocin, L-glutamic acid, and sodium gluconate at 5 mU / ml to 100 mU / ml and having a pH in the range of 3.8 to 5.5.

[0187] The present disclosure provides an immediately administrable preparation comprising oxytocin, L-glutamic acid, and sodium gluconate at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.2 to 5.5.

[0188] The present disclosure provides an immediately administrable preparation comprising oxytocin, L-glutamic acid, and sodium gluconate at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.8 to 5.5.

[0189] The present disclosure provides an immediately administrable preparation comprising oxytocin, L-glutamic acid, and sodium gluconate at 5 mU / ml to 100 mU / ml, wherein each of L-glutamic acid and sodium gluconate is at a concentration of 0.1 mg / ml to 5 mg / ml and having a pH in the range of 3.2 to 5.5.

[0190] The present disclosure provides an immediately administrable preparation comprising oxytocin, L-glutamic acid, and sodium gluconate at 5 mU / ml to 100 mU / ml, wherein each of L-glutamic acid and sodium gluconate is at a concentration of 0.1 mg / ml to 5 mg / ml and having a pH in the range of 3.8 to 5.5.

[0191] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0192] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.8 to 5.5.

[0193] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 5 mU / ml to 100 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0194] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 5 mU / ml to 100 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.8 to 5.5.

[0195] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0196] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.6 to 5.5, being stable at least for 3 months at controlled room temperature, and having a decrease in oxytocin assay of 8% or less as measured by UHPLC.

[0197] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid, and sodium gluconate at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and sodium gluconate being at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.8 to 5.5, being stable at least for 3 months at controlled room temperature, and having a decrease in oxytocin assay of 8% or less as measured by UHPLC.

[0198] The present disclosure provides an immediately administrable formulation consisting essentially of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, sodium gluconate at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0199] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and having a pH in the range of 3.6 to 4.5.

[0200] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, L-glutamic acid at 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0201] Therefore, the present disclosure provides an immediately administrable formulation comprising oxytocin, lactobionic acid or a pharmaceutically acceptable salt thereof at a concentration of 5 mU / ml to 100 mU / ml and having a pH in the range of 3.2 to 5.5.

[0202] The present disclosure provides an immediately administrable formulation comprising oxytocin, lactobionic acid or a pharmaceutically acceptable salt thereof at a concentration of 5 mU / ml to 100 mU / ml and having a pH in the range of 3.8 to 5.5.

[0203] The present disclosure provides an immediately administrable formulation comprising oxytocin, lactobionic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.2 to 5.5.

[0204] The present disclosure provides an immediately administrable formulation comprising oxytocin, lactobionic acid or a pharmaceutically acceptable salt thereof at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.8 to 5.5.

[0205] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and lactobionic acid and having a pH in the range of 3.2 to 5.5. The present disclosure provides an immediately administrable formulation comprising oxytocin and lactobionic acid at a concentration of 5 mU / ml to 100 mU / ml and having a pH in the range of 3.8 to 5.5.

[0206] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml and lactobionic acid and having a pH in the range of 3.2 to 5.5. The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml and lactobionic acid and having a pH in the range of 3.8 to 5.5.

[0207] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, wherein the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH is in the range of 3.2 to 5.5.

[0208] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, wherein the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH is in the range of 3.8 to 5.5.

[0209] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, wherein the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH is in the range of 3.2 to 5.5.

[0210] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, wherein the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH is in the range of 3.8 to 5.5.

[0211] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and lactobionic acid, wherein the lactobionic acid is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH is in the range of 3.2 to 5.5.

[0212] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 5 mU / ml to 100 mU / ml and lactobionic acid, wherein the lactobionic acid is at a concentration of 0.1 mg / ml to 5 mg / ml and the pH is in the range of 3.8 to 5.5.

[0213] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, where the lactobionic acid is at a concentration of 0.1 mg / ml to 5 mg / ml, and the pH is in the range of 3.2 to 5.5.

[0214] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, where the lactobionic acid is at a concentration of 0.1 mg / ml to 5 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0215] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, where the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.2 to 5.5.

[0216] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, where the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0217] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, where the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.2 to 5.5.

[0218] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid or a pharmaceutically acceptable salt thereof, where the lactobionic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0219] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.2 to 5.5.

[0220] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.6 to 5.5.

[0221] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0222] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 5 mU / ml to 100 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0223] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.2 to 5.5.

[0224] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.6 to 5.5.

[0225] The present disclosure provides an immediately administrable formulation containing oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0226] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.6 to 5.5, and being stable at least for 3 months at a controlled room temperature with a decrease in oxytocin assay of 8% or less as measured by UHPLC.

[0227] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, lactobionic acid, wherein the lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.8 to 5.5, and being stable at least for 3 months at a controlled room temperature with a decrease in oxytocin assay of 8% or less as measured by UHPLC.

[0228] The present disclosure provides an immediately administrable formulation consisting essentially of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, 0.8 mg / ml to 2 mg / ml of lactobionic acid, 9 mg / ml of sodium chloride, optionally a pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0229] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, 0.8 mg / ml to 2 mg / ml of lactobionic acid, 9 mg / ml of sodium chloride, optionally a pH adjuster, and water, and having a pH in the range of 3.6 to 4.5.

[0230] The present disclosure provides an immediately administrable formulation comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, 0.8 mg / ml to 2 mg / ml of lactobionic acid, 9 mg / ml of sodium chloride, optionally a pH adjuster, and water, and having a pH in the range of 3.8 to 4.5.

[0231] Accordingly, the present disclosure provides an immediately administrable formulation comprising oxytocin at 5 mU / ml to 100 mU / ml, L-glutamic acid, and lactobionic acid, and having a pH in the range of 3.2 to 5.5.

[0232] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid and lactobionic acid at concentrations of 5 mU / ml to 100 mU / ml and having a pH in the range of 3.8 to 5.5.

[0233] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid and sodium gluconate at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.2 to 5.5.

[0234] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid and lactobionic acid at a concentration of 10 mU / ml to 60 mU / ml and having a pH in the range of 3.8 to 5.5.

[0235] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid, and lactobionic acid at 5 mU / ml to 100 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0236] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid, and lactobionic acid at 5 mU / ml to 100 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.8 to 5.5.

[0237] The present disclosure provides an immediately administrable formulation comprising oxytocin, L-glutamic acid, and lactobionic acid at a concentration of 10 mU / ml to 60 mU / ml, each of L-L-glutamic acid and lactobionic acid being at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0238] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.1 mg / ml to 5 mg / ml, and having a pH in the range of 3.8 to 5.5.

[0239] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 5 mU / ml to 100 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0240] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 5 mU / ml to 100 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0241] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.2 to 5.5.

[0242] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.6 to 4.5.

[0243] The present disclosure provides an immediately administrable formulation containing oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, each of L-glutamic acid and lactobionic acid being at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0244] The present disclosure provides an immediately administrable formulation that contains oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein each of L-glutamic acid and lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, the pH ranges from 3.6 to 4.5, the formulation is stable at least for 3 months at a controlled room temperature, and the decrease in the oxytocin assay is 8% or less as measured by UHPLC.

[0245] The present disclosure provides an immediately administrable formulation that contains oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein each of L-glutamic acid and lactobionic acid is at a concentration of 0.8 mg / ml to 2 mg / ml, the pH ranges from 3.8 to 4.5, the formulation is stable at least for 3 months at a controlled room temperature, and the decrease in the oxytocin assay is 8% or less as measured by UHPLC.

[0246] The present disclosure provides an immediately administrable formulation that consists essentially of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.8 mg / ml to 2 mg / ml, lactobionic acid at a concentration of 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and the pH ranges from 3.8 to 4.5.

[0247] The present disclosure provides an immediately administrable formulation that consists of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at a concentration of 0.8 mg / ml to 2 mg / ml, lactobionic acid at a concentration of 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and the pH ranges from 3.6 to 4.5.

[0248] The present disclosure provides an immediately administrable formulation that consists of oxytocin at a concentration of 10 mU / ml to 60 mU / ml, L-glutamic acid at a concentration of 0.8 mg / ml to 2 mg / ml, lactobionic acid at a concentration of 0.8 mg / ml to 2 mg / ml, sodium chloride at 9 mg / ml, optionally a pH adjuster, and water, and the pH ranges from 3.8 to 4.5.

[0249] The present disclosure provides an immediately administrable preparation in a plastic container, which contains oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and has a pH in the range of 3.8 to 4.5.

[0250] The present disclosure provides an immediately administrable preparation in a plastic container, which contains oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.8 mg / ml to 2 mg / ml, and has a pH in the range of 3.8 to 4.5.

[0251] The present disclosure provides an immediately administrable preparation in a plastic bag, which contains oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.8 mg / ml to 2 mg / ml, the pH of the preparation is in the range of 3.8 to 4.5, and the plastic bag is overwrapped.

[0252] The present disclosure provides an immediately administrable preparation in a plastic bag, which contains oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.8 mg / ml to 2 mg / ml, the pH of the preparation is in the range of 3.8 to 4.5, the plastic bag is overwrapped, and the space between the plastic bag and the overwrap is not filled with nitrogen.

[0253] The present disclosure provides an immediately administrable preparation in a plastic bag, which contains oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.8 mg / ml to 2 mg / ml, the pH of the preparation is in the range of 3.8 to 4.5, the plastic bag contains an EVOH barrier, the plastic bag is overwrapped, and the space between the plastic bag and the overwrap is not filled with nitrogen.

[0254] The present disclosure provides an immediately administrable preparation contained in a plastic bag, comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, having a pH in the range of 3.8 to 4.5, and the plastic bag contains an EVOH barrier.

[0255] The present disclosure provides an immediately administrable preparation contained in a plastic bag, comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.1 mg / ml to 5 mg / ml, having a pH in the range of 3.8 to 4.5, and the plastic bag contains an EVOH barrier.

[0256] The present disclosure provides an immediately administrable preparation contained in a plastic bag, comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate at a concentration of 0.8 mg / ml to 2 mg / ml, having a pH in the range of 3.8 to 4.5, and the plastic container is filled with an EVOH barrier.

[0257] The present disclosure provides an immediately administrable preparation contained in a plastic container, comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and L-glutamic acid, having a pH in the range of 3.8 to 4.5.

[0258] The present disclosure provides an immediately administrable preparation contained in a plastic container, comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and L-glutamic acid, wherein sodium gluconate and L-glutamic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, and having a pH in the range of 3.8 to 4.5.

[0259] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, sodium gluconate, and L-glutamic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein sodium gluconate and L-glutamic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 4.5, and the plastic bag is overlapped.

[0260] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, sodium gluconate, and L-glutamic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein sodium gluconate and L-glutamic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 4.5, the plastic bag is overlapped, and the space between the plastic bag and the overlap is not filled with nitrogen.

[0261] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, sodium gluconate, and L-glutamic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein sodium gluconate and L-glutamic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 5.5, the plastic bag contains an EVOH barrier, the plastic bag is overlapped, and the space between the plastic bag and the overlap is not filled with nitrogen.

[0262] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, sodium gluconate, and L-glutamic acid at concentrations of 10 mU / ml to 60 mU / ml, the pH is in the range of 3.8 to 4.5, and the plastic bag contains an EVOH barrier.

[0263] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin at a concentration of 10 mU / ml to 60 mU / ml, sodium gluconate, and L-glutamic acid, wherein sodium gluconate and L-glutamic acid are each at a concentration of 0.1 mg / ml to 5 mg / ml, the pH is in the range of 3.8 to 4.5, and the plastic bag contains an EVOH barrier.

[0264] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, sodium gluconate, and L-glutamic acid at a concentration of 10 mU / ml to 60 mU / ml, wherein sodium gluconate and L-glutamic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 5.5, and the plastic container is filled with an EVOH barrier (bag).

[0265] The present disclosure provides an immediately administrable formulation in a plastic container, comprising oxytocin, L-glutamic acid, and lactobionic acid at a concentration of 10 mU / ml to 60 mU / ml, and the pH is in the range of 3.8 to 5.5.

[0266] The present disclosure provides an immediately administrable formulation in a plastic container, comprising oxytocin, L-glutamic acid, and lactobionic acid at a concentration of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid and lactobionic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, and the pH is in the range of 3.8 to 5.5.

[0267] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, L-glutamic acid, and lactobionic acid at a concentration of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid and lactobionic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 5.5, and the plastic bag is overlapped.

[0268] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid and lactobionic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 5.5, the plastic bag is overlapped, and the space between the plastic bag and the overlap is not filled with nitrogen.

[0269] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid and lactobionic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH is in the range of 3.8 to 5.5, the plastic bag contains an EVOH barrier, the plastic bag is overlapped, and the space between the plastic bag and the overlap is not filled with nitrogen.

[0270] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, the pH is in the range of 3.8 to 5.5, and the plastic bag contains an EVOH barrier.

[0271] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising 10 mU / ml to 60 mU / ml of oxytocin, L-glutamic acid, and lactobionic acid, wherein L-glutamic acid and lactobionic acid are each at a concentration of 0.1 mg / ml to 5 mg / ml, the pH is in the range of 3.8 to 5.5, and the plastic bag contains an EVOH barrier.

[0272] The present disclosure provides an immediately administrable formulation in a plastic bag, comprising oxytocin, L-glutamic acid, and lactobionic acid at concentrations of 10 mU / ml to 60 mU / ml, wherein L-glutamic acid and lactobionic acid are each at a concentration of 0.8 mg / ml to 2 mg / ml, the pH ranges from 3.8 to 5.5, and the plastic container is filled with an EVOH barrier, an immediately administrable formulation.

[0273] Other objects, features, and advantages will become apparent from the following forms and examples for carrying out the invention. However, it should be understood that the "forms for carrying out the invention" and examples show specific embodiments, but are shown for illustrative purposes only and are not intended to limit the scope or range of the concept in any way.

[0274] The stabilizing effect of different factors in an immediately administrable state was evaluated. General technology All the formulations shown in the following examples were prepared by providing a liquid solution of oxytocin and at least one excipient. If necessary, the pH was adjusted to achieve the desired pH range.

[0275] The prepared composition was transferred to containers such as vials and bags to achieve the desired amount of active ingredient per container. Formulations of oxytocin stored in different packages using 0.9% NaCl with the desired pH were prepared and shown for comparison.

[0276] Analysis method After preparation, the initial levels of the active pharmaceutical ingredient and impurities were analyzed by ultra-high performance liquid chromatography (UHPLC), and then the containers were loaded into a stability chamber at different storage conditions, 40 °C and 25 °C.

[0277] To determine the stability of the active pharmaceutical ingredient in the formulation according to the present disclosure, the containers were taken out of the stability chamber at various time points such as 14 days, 1 month, 2 months, 3 months, 4 months, 6 months, etc. and analyzed by UHPLC.

[0278] The assay for the active pharmaceutical ingredient was analyzed by separation using UHPLC and measurement using a fluorescence detector (FLD), a mass spectrometer (MS) with added internal standard, and / or a diode array detector (DAD). Impurities were separated by UHPLC and measured by coupled MS or DAD. In all cases, a reverse-phase C18 column was used. The conditions for each method are listed below.

[0279] Assay Procedure I (Fluorescence Detector) Chromatography System: Detector: Fluorescence detector, excitation 228 nm, emission 310 nm Column: 2.1 mm; 15 cm; 1.7 μm packing L1, stationary phase: octadecylsilyl silica gel for chromatography R Column temperature: 50 °C Autosampler: 5 °C Flow rate: 0.5 mL / min Injection volume: 100 μL Diluent: 5 g of chlorobutanol, 5.0 mL of acetic acid, 1.1 g of sodium acetate, and 4.7 g of ethanol in 1 L of ultrapure water.

[0280] Solution A: 100 mM monobasic sodium phosphate, pH approximately 4.5. Solution B: Water and acetonitrile (50:50).

[0281] [Table 1]

[0282] Preparation of the formulation sample solution: Direct injection into the system Preparation of the standard solution: Oxytocin standard at 0.06 IU / mL in the diluent Assay Procedure IIA (Mass Spectrometer) Chromatography System: Detector: Electrospray ionization - triple quadrupole mass spectrometer. Gas temperature 300 °C, gas flow rate 6 L / min, nebulizer 20 psi (137.9 kPa), sheath gas temperature 350 °C, sheath gas flow rate 12 L / min, capillary 4000 V, operated in positive ion mode. Acquisition: Multiple reaction monitoring. For the quantification of oxytocin, precursor m / z 1007.1 was selected, while the m / z of the monitored product was 723. The internal standard (IS) deuterated oxytocin was monitored with precursor m / z 1021.1, while the m / z of the product was 723 (or, if otherwise observed, the most abundant product ion in the spectrum). In both cases, the retention time, fragmentor voltage and collision energy were 200 ms, 238 V and 40 eV, respectively.

[0283] Column: 2.1 mm; 15 cm; 1.7 μm packing L1, stationary phase: octadecylsilyl silica gel for chromatography R Column temperature: 50 °C Autosampler: 10 °C Flow rate: 0.4 mL / min Injection volume: 10 μL Preparation of diluent: 0.5 g of chlorobutanol, 5.0 mL of acetic acid, 1.1 g of sodium acetate and 4.7 g of ethanol in 1 L of ultrapure water.

[0284] Preparation of IS: Dissolve 25 nmol of deuterated oxytocin in 2.0 mL of ultrapure water. Transfer 1.0 mL of the resulting solution to a 20 mL volumetric flask and dilute with ultrapure water to the appropriate volume. Solution A: 10 mM ammonium formate, pH = 4.5 Solution B: Acetonitrile, MS grade

[0285]

Table 2

[0286] Preparation of sample solution for formulation: Add 50 μL of the IS solution to 250 μL of the sample solution, mix and inject into the system. Preparation of Standard Solution: Oxytocin standard at 0.06 IU / mL in the diluent. Add 50 μL of the IS solution to 250 μL of the oxytocin standard solution, mix, and inject into the system.

[0287] Assay Procedure IIB (Mass Spectrometer) Chromatography System: Detector: Electrospray ionization - single quadrupole mass spectrometer. Gas temperature 300 °C, gas flow rate 6 L / min, nebulizer 20 psi (137.9 kPa), sheath gas temperature 350 °C, sheath gas flow rate 12 L / min, capillary 4000 V, nozzle voltage 0 V, operating in positive ion mode. For quantification of oxytocin, 1007.5 m / z was selected, while the IS deuterated oxytocin was monitored at 1012.5 m / z.

[0288] Column: 2.1 mm; 5 cm; 1.7 μm packing L1, stationary phase: octadecylsilyl silica gel for chromatography R Column Temperature: 40 °C Flow Rate: 0.4 mL / min Injection Volume: 20 μL Preparation of Diluent: 0.5 g of chlorobutanol, 5.0 mL of acetic acid, 1.1 g of sodium acetate, and 4.7 g of ethanol in 1 L of ultrapure water.

[0289] Preparation of IS: Dissolve 25 nmol of deuterated oxytocin in 2.0 mL of ultrapure water. Transfer 1.0 mL of the resulting solution to a 20 mL volumetric flask and dilute with ultrapure water to the appropriate volume. Solution A: 10 mM ammonium formate, pH = 4.5 Solution B: Acetonitrile, MS grade

[0290]

Table 3

[0291] Preparation of Sample Solution for the Formulation: Add 50 μL of the IS solution to 250 μL of the sample solution, mix, and inject into the system. Preparation of Standard Solution: Oxytocin standard at 0.06 IU / mL in the diluent. Add 50 μL of the IS solution to 250 μL of the oxytocin standard solution, mix, and inject into the system.

[0292] Assay Procedure III (Diode Array Detector) Chromatography System: Detector: Diode array detector at 205 nm, bandwidth 4 nm, no reference wavelength Column: 2.1 mm; 15 cm; 1.7 μm packing L1, stationary phase: octadecylsilyl silica gel for chromatography R Column Temperature: 40 °C Autosampler: 5 °C Flow Rate: 0.4 mL / min Injection Volume: 40 μL Diluent: 5 g of chlorobutanol, 5.0 mL of acetic acid, 1.1 g of sodium acetate and 4.7 g of ethanol in 1 L of ultrapure water.

[0293] Solution A: 10 mM sodium dihydrogen phosphate, pH = 4.50 Solution B: Acetonitrile

[0294]

Table 4

[0295] Preparation of Sample Solution for Formulation: Inject directly into the system Preparation of Standard Solution: Oxytocin standard at 0.06 IU / mL in the diluent Impurity Procedure (Mass Spectrometer) Chromatography System: Detector: Electrospray ionization - quadrupole - time - of - flight mass spectrometer. Capillary voltage 3000 V, sampling cone voltage 40 V, source temperature 120 °C, desolvation temperature 350 °C, desolvation gas flow rate 600 L / hour, operate in positive ion mode in resolution mode. Acquisition: Scan from 100 m / z to 1500 m / z at a frequency of 1 Hz.

[0296] Column: 2.1 mm; 10 cm; 1.7 μm packing L1, stationary phase: octadecylsilyl silica gel for chromatography R Column temperature: 50 °C Autosampler: 10 °C Flow rate: 0.4 mL / min Injection volume: 10 μL Solution A: 10 mM ammonium formate, pH = 4.5 Solution B: acetonitrile, MS grade

[0297]

Table 5

[0298] Preparation of sample solution for preparation: solid phase extraction. Calculation of assay of active compound using assay procedure I (fluorescence detector) and III (diode array detector) The assay of the active compound is calculated using the following formula: Assay (%) = (Amps / Ampstd) × (cstd / cs) × 100% In the formula, Amps = peak area of oxytocin peak in the sample solution Ampstd = peak area of oxytocin peak in the standard solution cs = concentration of oxytocin in the sample solution (IU / mL) cstd = concentration of oxytocin in the standard solution (IU / mL) Calculation of assay of active compound using assay procedure II (mass spectrometer) The assay of the active compound is calculated using the following formula: Assay (%) = [(AOs / AHs) / (AOstd / AHstd)] × cstd / cs × 100% In the formula, AOs = peak area of oxytocin peak in the sample solution AHs = peak area of IS peak in the sample solution AOstd = peak area of oxytocin peak in the standard solution AHstd = Peak area of the IS peak in the standard solution cs = Concentration of oxytocin in the sample solution (IU / mL) cstd = Concentration of oxytocin in the standard solution (IU / mL) Calculation of the assay decrease of the main peak Assay(tp) (%) Assay value of the main peak at different time points (tp) (e.g., 7 days, 1 month, 2 months, etc.) different from the initial time point under different storage conditions such as 25 °C and 40 °C analyzed by UHPLC Assay(st) (%) Assay value of the main peak at the initial time point ΔAssay Decrease in the calculated assay of the main compound: (%) ΔAssay (%) = Assay(st) (%) - Assay(tp) (%) Calculation of individual impurities The content of impurities monitored using the scanning mode of the mass spectrometer is given as the area % of the total area.

[0299] Visual particle inspection At the start of the visual inspection at each stability time point, check whether there is any precipitate formed at the bottom of the container. Then, gently rotate and invert the container to confirm the visual particle inspection and check that no bubbles are generated. The container was inspected visually with the naked eye for about 15 seconds. For the samples inspected, the observations regarding the visual inspection were recorded.

[0300] List of abbreviations used: HPBCD: 2-Hydroxypropyl-β-cyclodextrin M: Month MonO: Mono-deaminated oxytocin OTris: Oxytocin trisulfide N / A: Not applicable

Example

[0301] In the following examples, oxytocin is added in the form of acetate. Example 1 For parenteral use under defined conditions, a ready-to-administer formulation of oxytocin was prepared by separately dissolving the excipient and oxytocin in water or a defined standard diluent. The contents were stirred using a magnetic stirrer. If necessary, the pH was adjusted to a defined pH. The solutions were mixed, homogeneity was ensured, filtered through a 0.2 μm filter, transferred to the same container, and WFI or a defined diluent was added to bring to a defined volume. The prepared formulation was then aliquoted into defined packages.

[0302] The formulation was then stored at a controlled room temperature and the stability was determined at time points such as 1 month, 2 months, 3 months, 6 months and longer. The formulations of the present disclosure are expected to be stable for 3 and 6 months at a controlled room temperature and by extrapolation, it can be shown that the formulations are stable or stabilized for up to about 12 months.

[0303] Table 1 shows the chemical stability of ready-to-administer formulations containing oxytocin and different excipients. Unless otherwise specified, the formulations were stored in glass vials. The assays were analyzed using the UHPLC-FLD method.

[0304]

Table 6

[0305] Table 2 shows the chemical stability of ready-to-administer formulations containing oxytocin and different excipients. For comparison, a formulation of oxytocin dissolved in 0.9% NaCl and adjusted to pH 4.0 was prepared. Unless otherwise specified, the formulations were stored in plastic bags containing PE and EVOH and then overlapped without using a nitrogen blanket or an oxygen scavenger. The assays were analyzed using the UHPLC-DAD method.

[0306]

Table 7

[0307] Table 3 shows the chemical stability of an immediate - administrable formulation containing oxytocin and different excipients in bags and glass vials. The plastic bags used in this example contain polyethylene and EVOH. The bags were overlapped without using a nitrogen blanket or oxygen scavenger. The assay was analyzed using the UHPLC - DAD method and the impurities were analyzed by the UHPLC - MS method.

[0308]

Table 8

[0309] Example 2 An immediate - administrable formulation of oxytocin is prepared by dissolving the excipient under predetermined conditions in water for injection or a predetermined standard diluent for parenteral use until a clear solution (free of visible particles) is obtained. Then oxytocin is added and the solution is mixed until the oxytocin is dissolved. If necessary, the pH is adjusted to a predetermined pH value and then WFI or an appropriate diluent is added to a predetermined volume. The solution is mixed to ensure homogeneity, then filtered through a 0.2 μm filter and dispensed into predetermined packages.

Claims

**Claim 1** An immediately administrable preparation containing oxytocin, gluconic acid or a pharmaceutically acceptable salt thereof, wherein the pH of the immediately administrable preparation is in the range of 3.2 to 5.

5. **Claim 2** The immediately administrable preparation according to claim 1, wherein the gluconate is sodium gluconate. **Claim 3** The immediately administrable preparation according to claim 1, wherein the concentration of oxytocin is 5 mU / ml to 100 mU / ml. **Claim 4** The immediately administrable preparation according to claim 3, wherein the concentration of oxytocin is 10 mU / ml to 60 mU / ml. **Claim 5** The immediately administrable preparation according to claim 1, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.5 mM to 200 mM. **Claim 6** The immediately administrable preparation according to claim 1, wherein gluconic acid or a pharmaceutically acceptable salt thereof is at a concentration of 0.5 mM to 200 mM. **Claim 7** The immediately administrable preparation according to claim 1, further comprising glutamic acid or a pharmaceutically acceptable salt thereof. **Claim 8** The immediately administrable preparation according to claim 1, wherein the glutamic acid is L-glutamic acid. **Claim 9** The immediately administrable preparation according to claim 1, further comprising lactobionic acid or a pharmaceutically acceptable salt thereof. **Claim 10** The immediately administrable preparation according to claim 1, wherein the preparation is stored in a plastic bag. **Claim 11** The immediately administrable preparation according to claim 1, wherein the preparation is stable for 3 months under room temperature conditions and the decrease in oxytocin assay measured by UHPLC is 8% or less.

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