A ready-to-administer product containing a norepinephrine preparation

Abstract

Described herein is a ready-to-administer product comprising a liquid norepinephrine formulation contained in a flexible plastic container.

Description

Technical Field

[0001] The present disclosure relates to a ready-to-administer product comprising a flexible plastic container and a norepinephrine formulation stored within the plastic container. Such products provide good stability over time.

Background Art

[0002] Norepinephrine is a catecholamine prescribed for blood pressure control in certain acute hypotensive states (e.g., pheochromocytoma resection; sympathectomy; acute poliomyelitis; spinal anesthesia; myocardial infarction; sepsis; transfusion and drug reactions), and serves as an adjunct in the treatment of cardiac arrest and severe hypotension.

[0003] The structure of norepinephrine is given below.

[0004]

Chemical Formula

[0005] Since norepinephrine is sensitive to oxidation, it usually degrades to several oxidation-related impurities. Thus, norepinephrine is often protected from oxygen by degassing the solution used to manufacture its norepinephrine formulation and / or to contain an antioxidant in its final formulation.

[0006] Norepinephrine also tends to degrade more easily when present at low concentrations. One degradation impurity that may be found in norepinephrine formulations is 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol.

[0007] The structure of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol is shown below.

[0008]

Chemical Formula

SUMMARY OF THE INVENTION

[0009] Described herein is a ready-to-administer product comprising a liquid norepinephrine formulation contained in a plastic container, wherein the ratio of the surface area of the plastic container to the volume of the formulation in the plastic container is less than 3.0 cm -1 less.

[0010] In a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation, it has been found that when the ratio of the surface area of the plastic container to the volume of the formulation in the plastic container is less than 3.0 cm -1 less, the amount of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the formulation is minimized.

[0011] The inventors have found that during storage, the formation of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the product can be improved by controlling the surface area of the plastic container in relation to the volume of the formulation filled in the plastic container.

[0012] Due to their enhanced storage stability, the products disclosed herein can be stored advantageously for a relatively long period. All of the foregoing description and the subsequent further description are illustrative and explanatory only and do not limit the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]

Figure 1

Figure 2

Figure 3

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure relates to a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container. Ready-to-administer means a formulation that does not require any dilution prior to administration to a patient. A ready-to-administer composition is synonymous with ready-to-inject, ready-to-inject, or ready-to-use and is suitable for direct administration to a patient.

[0015] As used herein, the terms "pharmaceutical composition", "pharmaceutical formulation", "composition", and "formulation" are used interchangeably.

[0016] The term "aqueous solution" is understood to mean any solution in which water is present in an amount of 50% v / v or more, for example, a solution containing from about 50% v / v to about 100% v / v of water. Thus, aqueous solutions include solutions containing about 50% v / v or more, about 60% v / v or more, about 70% v / v or more, about 75% v / v or more, about 80% v / v or more, about 85% v / v or more, about 90% v / v or more, about 95% v / v or more, or about 100% v / v of water.

[0017] All numbers used herein, except for pH, are modified by the term "about". That is, each number includes a small variation such that it is defined as ±10% of the numerical value or range. As used herein, the term "norepinephrine" means norepinephrine or a pharmaceutically acceptable norepinephrine salt.

[0018] In one aspect, this norepinephrine salt is norepinephrine tartrate. When a specific amount or a specific range of amounts of norepinephrine is provided in this application, all values are calculated based on norepinephrine base.

[0019] In one aspect, the norepinephrine concentration in the liquid norepinephrine preparation is 0.01 - 0.1 mg / mL. In another aspect, the concentration of norepinephrine in this liquid norepinephrine preparation is 0.01 mg / mL; 0.02 mg / mL; 0.03 mg / mL; 0.04 mg / mL; 0.05 mg / mL; 0.06 mg / mL; 0.07 mg / mL; 0.08 mg / mL; 0.09 mg / mL; 0.1 mg / mL.

[0020] In yet another aspect, the concentration of norepinephrine in this liquid norepinephrine preparation is 0.016 mg / mL, 0.032 mg / mL, 0.064 mg / mL. For an infusion product to be approved for human use, such a product must meet the isotonicity requirement. As used herein, the term "isotonic" or "isotonicity" conforms to the definition of USP<785>.

[0021] The liquid norepinephrine preparation contained in the ready - to - administer product optionally contains an isotonicity agent. This isotonicity agent can be selected from sodium chloride, potassium chloride, mannitol, glycerin, dextrose, and mixtures thereof.

[0022] In one aspect, the isotonicity agent is sodium chloride. In one aspect, the concentration of the isotonicity agent in the product is an amount that provides an isotonic ready - to - administer product, where isotonicity conforms to USP<785>.

[0023] In one aspect, the norepinephrine preparation contained in the ready - to - administer product has an osmotic pressure within the range of the physiological osmotic pressure of blood. According to the literature, when used herein, the physiological osmotic pressure of blood is within the range of 270 - 340 mOsmol / kg.

[0024] In one aspect, the concentration of the tonicity agent in the norepinephrine preparation contained in the ready-to-administer product should be an amount that achieves the osmotic pressure of the product within the target range of 270 to 340 mOsmol / kg.

[0025] In one aspect, the liquid norepinephrine preparation contained in the ready-to-administer product is isotonic and has an osmotic pressure within the range of the physiological osmotic pressure of blood as described above. In addition, the liquid norepinephrine preparation contained in the ready-to-administer product described herein may further contain one or more pharmaceutically acceptable excipients, such as pH adjusters, antioxidants, chelating agents, surfactants, complexing agents, preservatives, fillers, vehicles, solubilizers, thickeners, and combinations thereof.

[0026] The pH of the liquid norepinephrine preparation is within the range of 3.0 to 5.0. In one aspect, this pH is within the range of 3.0 to 4.5. In another aspect, this pH is within the range of 3.5 to 4.5 or 3.6 to 4.2. In another aspect, this pH is 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5. In yet another aspect, this pH is 3.8.

[0027] "pH" is the conventional unit of measurement for hydrogen ion activity in solution at room temperature unless another temperature is specified. As used herein, the "pH" in the composition is defined as ±0.1 of the numerical value or range.

[0028] In one aspect, the pH value is described only for the preparation after preparation (meaning the starting point of the storage period). The pH of the formulation may be adjusted in any suitable manner. This pH may be adjusted with one or more pH adjusters, which may be selected from inorganic acids, organic acids, weak bases, strong bases, and their salts and derivatives. 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, etc., and combinations thereof.

[0029] As described herein, the ready-to-administer product comprises a plastic container containing the liquid norepinephrine formulation. In one aspect, the plastic container may be a flexible plastic container. As used herein, the term "flexible plastic container" means an infusion bag made of a flexible polymer or other polymer container manufactured, for example, by a molding and filling technique. Exemplary flexible plastic containers are made of polyolefins such as polyethylene, polypropylene, copolymers, and their derivatives, with or without other additives. An infusion bag is an example of a flexible plastic container. The available sizes of the flexible plastic container range from 50 mL to 2000 mL, such as 50 mL, 100 mL, 200 mL, 250 mL, 500 mL, 750 mL, 1000 mL, 1500 mL, and 2000 mL, etc.

[0030] In one aspect, the ready-to-administer product according to the present disclosure is stable over a certain period of time at a temperature of 2°C to 8°C. In one aspect, the ready-to-administer product according to the present disclosure is stable over a certain period of time under room temperature conditions. As used herein, the term "room temperature" is 20°C to 26°C. In one aspect, the ready-to-administer product according to the present disclosure is stable over a certain period of time at 40°C. In one aspect, the ready-to-administer product described herein is stable for 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 3 months, 4 months, 180 days (6 months), 9 months, 12 months (1 year), 14 months, 16 months, 18 months, 20 months, 24 months, or more at a certain temperature condition.

[0031] The terms "stability", "chemical stability" or "stable" are intended to indicate that the product, composition or formulation contains an acceptable amount of norepinephrine, or that at most a certain amount of norepinephrine decomposes after a certain period. Thus, in a stable product, stable solution or stable formulation, unacceptable degradation of the norepinephrine API is avoided.

[0032] As used herein, stability includes the purity or assay of norepinephrine in a product according to the present disclosure. If the product, formulation or composition contains norepinephrine at an initially determined purity or assay, the stability of the product, formulation or composition will be reflected over time by a decrease in the chromatographic purity or chromatographic assay of norepinephrine in the product, formulation or composition, and in this case, a stable product, stable solution or stable composition will contain norepinephrine at a specific chromatographic purity or chromatographic assay after a defined period.

[0033] For example, a stable composition may have at most a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% decrease in norepinephrine purity or norepinephrine assay after a predetermined period, which is determined by high pressure liquid chromatography, for example, using the methods described herein. This stability with respect to the decrease in the overall purity or overall assay of norepinephrine after a defined period may be referred to as the overall stability of norepinephrine in the formulation.

[0034] When describing the stability of a pharmaceutical product, pharmaceutical formulation or pharmaceutical composition, of course, the low degradation of the active ingredient is an important factor as much as possible. Also important are the impurities that may be formed by the degradation of the active ingredient. The composition of the formulation, and even its container, can contribute to the formation of impurities.

[0035] In an example, an impurity of norepinephrine (1,2,3,4-tetrahydroisoquinoline-4,6,7-triol) identified based on the relative retention time (RRT) in the HPLC chromatogram is considered to be a degradation product related to the contact of norepinephrine with the plastic material of the container housing the liquid norepinephrine preparation.

[0036] Therefore, instead of the overall stability described above, "stability" may also be determined by the amount of one or more specific impurities produced after a certain period. The abundance of a specific impurity may be expressed as a percentage, for example, as a percentage of the peak area in the HPLC chromatogram, or may be calculated according to a standard solution.

[0037] As used herein, particularly when focusing on the impurity 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol, "stable" with respect to the formation of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol is defined as the formation of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol increasing by only 1% after a specified period.

[0038] In one aspect, a stable composition may be one in which the formation of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol increases by at most 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% after a predetermined period.

[0039] In one aspect, the ready-to-use product is an infusion product, that is, a product for intravenous administration of the preparation contained in the product. Since the infusion product is injected into the patient's body, it generally must be sterile. There are several methods by which such a product is sterilized; the most common methods are either by final sterilization of the ready-to-use product or by aseptically filling the liquid preparation into a sterile plastic container after sterile filtration of the liquid preparation through a 0.2 μm filter.

[0040] For terminal sterilization, autoclaving is commonly used. In one aspect, autoclaving is a technique in which the product is placed under pressurized saturated steam up to a maximum of 121° C. for a period of time, which varies but is typically up to 15 minutes, and may be longer.

[0041] The aseptic manufacture of an aseptic product means that the packaging material is sterilized and then the aseptic product is filled into the packaging material under aseptic conditions. Sterilization of plastic containers may be carried out by various radiation techniques, such as electron beam (beta irradiation), gamma - or X - ray irradiation.

[0042] Without being bound by any theory, the inventors believe that the formation of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol is triggered by the contact of norepinephrine in solution with the plastic material of the container. Without being constrained by theory, the surface area of the plastic container is considered to be a parameter that determines the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol formed. Thus, the surface area of the plastic is considered to be a limiting factor for the formation of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol.

[0043] Unless otherwise specified, "the volume of the formulation in the plastic container" is intended to be the volume of the formulation filled into the plastic container during manufacture. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 3.0 cm -1 In one aspect, the ratio of the surface area of the plastic container to the volume of the formulation in the plastic container is less than 2.0 cm -1 In another aspect, the ratio of the surface area of the plastic container to the volume of the formulation in the plastic container is 1.8 cm -1is less than. In yet another aspect, the ratio of the surface area of the plastic container to the volume of the formulation in the plastic container is 1.6 cm -1 less than, or 1.5 cm -1 less than.

[0044] Unless otherwise specified, the ratio of the surface area of the plastic container to the volume of the formulation filled in the plastic container is calculated as follows. In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 0.3 cm -1 to 3.0 cm -1 within the range. In another aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 0.5 cm -1 to 2.5 cm -1 within the range. In yet another aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.0 cm -1 to 2.0 cm -1 within the range or 1.2 cm -1 to 1.8 cm -1 within the range.

[0045] In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container less than 3.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the formulation is less than 1.0%. In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container less than 3.0 cm -1is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.8%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 3.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.5%.

[0046] In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 3.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60 °C for 3 days is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 3.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60 °C for 3 days is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 3.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60 °C for 3 days is less than 0.4%.

[0047] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 3.0 cm -1is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 3.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 3.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.4%.

[0048] In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 2.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 1.0%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the bag to the volume of the formulation in the plastic container of less than 2.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.8%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 2.0 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.5%.

[0049] In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 60 °C for 3 days is less than 0.7%. In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 60 °C for 3 days is less than 0.5%. In another aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 60 °C for 3 days is less than 0.4%.

[0050] In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 40 °C for 1 month is less than 0.7%. In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 2.0 cm -1Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 2.0 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.3%.

[0051] In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.8 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 1.0%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.8 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.8%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.8 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.5%.

[0052] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.8 cm -1is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60°C for 3 days is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.8 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60°C for 3 days is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.8 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60°C for 3 days is less than 0.4%.

[0053] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.8 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.8 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.8 cm -1is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the preparation after storage at 40°C for 1 month is less than 0.3%.

[0054] In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 1.6 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the preparation is less than 1.0%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 1.6 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the preparation is less than 0.8%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 1.6 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the preparation is less than 0.5%.

[0055] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 1.6 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the preparation after storage at 60°C for 3 days is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of less than 1.6 cm -1Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60°C for 3 days is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.6 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60°C for 3 days is less than 0.4%.

[0056] In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.6 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.6 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.6 cm -1 Less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 40°C for 1 month is less than 0.3%.

[0057] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.5 cm -1less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 1.0%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.5 cm -1 less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.8%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.5 cm -1 less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation is less than 0.5%.

[0058] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.5 cm -1 less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60 °C for 3 days is less than 0.7%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.5 cm -1 less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60 °C for 3 days is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.5 cm -1 less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 60 °C for 3 days is less than 0.4%.

[0059] In another aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.5 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the formulation after storage at 40 °C for 1 month is less than 0.7%. In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.5 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the formulation after storage at 40 °C for 1 month is less than 0.5%. In another aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.5 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the formulation after storage at 40 °C for 1 month is less than 0.4%.

[0060] In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.5 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the formulation after storage at 25 °C for 2 months is less than 0.6%. In one aspect, an administration-ready product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of less than 1.5 cm -1is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the flexible plastic container of 1.5 cm -1 is less than, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.4%.

[0061] In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.6%. In one aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.4%.

[0062] In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.0 cm -1 ~2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.6%. In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.0 cm -1 ~2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.0 cm -1 ~2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.4%.

[0063] In one aspect, a ready-to-administer product consisting essentially of a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.6%. In one aspect, a ready-to-administer product consisting essentially of a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.2 cm -1 ~1.8 cm -1within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready - to - administer product consisting essentially of a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.2 cm -1 ~1.8 cm -1 within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.4%.

[0064] In one aspect, a ready - to - administer product consisting essentially of a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.0 cm -1 ~2.0 cm -1 within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.6%. In one aspect, a ready - to - administer product consisting essentially of a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.0 cm -1 ~2.0 cm -1 within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready - to - administer product consisting essentially of a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.0 cm -1 ~2.0 cm -1 within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.4%.

[0065] In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.6%. In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.2 cm -1 ~1.8 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.4%.

[0066] In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.0 cm -1 ~2.0 cm -1 and the level of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol in the preparation after storage at 25°C for 2 months is less than 0.6%. In one aspect, a ready-to-administer product comprising a plastic container and a liquid norepinephrine preparation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the preparation in the plastic container of 1.0 cm -1 ~2.0 cm -1within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.5%. In another aspect, a ready - to - administer product comprising a plastic container and a liquid norepinephrine formulation stored in the plastic container has a ratio of the surface area of the plastic container to the volume of the formulation in the plastic container of 1.0 cm -1 ~2.0 cm -1 within the range, and the level of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol in the formulation after storage at 25°C for 2 months is less than 0.4%.

[0067] In one aspect, the plastic container may be further packaged from the outside. In one aspect, this packaging may include a gas - barrier material and / or a light - shielding material. In one aspect, the space between the container and the packaging is filled with an inert gas or any other suitable gas. In one aspect, the space between the container and the packaging is filled with nitrogen, argon, or any combination thereof.

[0068] In one aspect, the space between the container and the packaging is under reduced pressure. In one aspect, the space between the container and the packaging contains an oxygen scavenger. In one aspect, the ready - to - administer product may be used to control blood pressure in certain acute hypotensive conditions (e.g., pheochromocytoma resection; sympathectomy; acute poliomyelitis; spinal anesthesia; myocardial infarction; sepsis; blood transfusion and drug reaction).

[0069] In one aspect, the ready - to - administer product is used to raise blood pressure in adults suffering from clinically significant hypotension mainly due to vasodilation in the context of anesthesia and septic shock. In one aspect, the ready - to - administer product can be used as an adjuvant in the treatment of cardiac arrest and severe hypotension.

[0070] Examples (Methods, Results, Discussion) HPLC Assay Method Mobile Phase A: 1.13 g sodium 1-heptanesulfonate + 900 mL H2O + 100 mL MeOH, adjusted to pH 3 ± 0.2 with H3PO4.

[0071] Mobile Phase B: Methanol The gradient of the mobile phase is shown below. JPEG2025524088000003.jpg53170

[0072] Standard Solution: 0.032 mg / mL aqueous solution of norepinephrine tartrate monohydrate (equivalent to 0.016 mg / mL norepinephrine base). Sample Solution: Nominally 0.032 mg / mL norepinephrine tartrate monohydrate (equivalent to 0.016 mg / mL norepinephrine base).

[0073] Chromatography System Mode: LC Detector: UV215 nm Column: 4.6 x 25 cm; 5 μm packing L1 Column Temperature: 25 °C Flow Rate: 1.0 mL / min Calculation Calculate the percentage of the labeled amount of norepinephrine.

[0074]

Equation

[0075] As - Peak response of norepinephrine from the sample solution A std - Peak response of norepinephrine from the standard solution c std - Concentration of norepinephrine base in the standard solution (mg / mL) c s - Nominal norepinephrine concentration in the sample solution (mg / mL) HPLC Impurity Measurement Method Mobile Phase A, Mobile Phase B, and the gradient of the mobile phase are the same as those described in the above HPLC assay method.

[0076] The chromatographic system is the same as that described in the HPLC assay method above. Calculation The impurity content is given as the area % of the total area and is calculated using the following equation:

[0077]

Number

[0078] Impurity% = area % of individual peaks A i = peak area of individual peaks A tot = total peak area of the sample Ratio of surface area to volume The ratio of surface area to volume (also referred to herein as SA.V or SAV) is calculated by dividing the inner surface area of the container by "the volume of the formulation in the plastic container". The inner surface area of a container is equal to the total available inner surface area of the container available for containing the solution. (That is, the parts of the container used for the movement or delivery of the solution, even if they may come into direct contact with the solution, such as tubes, ports, stoppers, delivery sets, and the like, are not considered.) The inner surface area of a container can be calculated from the known dimensions of the container by simple mathematical calculations depending on the shape of the container. In the example of a rectangular flexible bag, the inner surface area of a container consists of two sides. To calculate the total inner surface area (SA) of a rectangular bag, x and y are measured prior to filling the bag as shown in Figure 1, and this surface area was calculated by the following equation: SA = 2xy.

[0079] The ratio between this surface area and the volume was calculated by the following equation: Ratio of surface area to volume = surface area / volume of the solution filled in the bag JPEG2025524088000006.jpg54170

[0080] Preparation of an Exemplary Norepinephrine Preparation To prepare a concentrated solution of norepinephrine, norepinephrine was dissolved in water for injection until a concentration of 0.8 - 2 mg / mL was reached. A second solution was prepared by dissolving a selected preservative, sodium chloride, and citric acid in water for injection. This solution was purged with nitrogen to remove oxygen from the solution. Its pH was adjusted with sodium hydroxide to provide a target pH within the range of 3.0 - 5.0. Norepinephrine was added into the second solution by adding an appropriate amount of the concentrated norepinephrine, giving a final concentration of norepinephrine of 0.01 - 0.1 mg / mL. These solutions were mixed and their volume was made up to the final volume by adding water. This final solution of norepinephrine was filtered through a 0.2 μm filter and aseptically filled directly into the flexible plastic container. This filled container was placed within an overwrap of aluminum, and an oxygen scavenger was provided between the container and the package.

[0081] Results Example 1: All bags were sterilized using beta-ray irradiation technology. This bag was aseptically filled with an aqueous norepinephrine solution containing 0.016 mg norepinephrine / mL and the pH was about 3.5. This bag was packaged from the outside and an oxygen scavenger was provided between the bag and the package.

[0082] The amount of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol was measured after storage at 60 °C for 3 days. The results are shown in Table 1. JPEG2025524088000007.jpg61170

[0083] The amount of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol was measured after storage at 40 °C for 1 month, 2 months, and 6 months. The results are shown in Table 2. JPEG2025524088000008.jpg59170

[0084] The amount of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol was measured after storage at 25°C for 1 month, 2 months, 3 months, 6 months, and 12 months. The results are shown in Table 3. JPEG2025524088000009.jpg83170

[0085] Example 2 All container bags were sterilized using β - ray irradiation technology. The bags were aseptically filled with aqueous norepinephrine solutions containing norepinephrine at three different concentrations (0.016 mg / mL, 0.032 mg / mL, and 0.064 mg / mL), and the pH was approximately 3.5. The bags were packaged from the outside, and an oxygen scavenger was provided between the bag and the packaging.

[0086] The amount of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol was measured after storage at 60°C for 3 days. The results are shown in Table 4. JPEG2025524088000010.jpg46170

[0087] The amount of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol was measured after storage at 40°C for 3 months and 6 months. The results are shown in Table 5. JPEG2025524088000011.jpg61170

[0088] The amount of 1,2,3,4 - tetrahydroisoquinoline - 4,6,7 - triol was measured after storage at 25°C for 3 months, 6 months, and 12 months. The results are shown in Table 6. JPEG2025524088000012.jpg77170

Claims

1. A ready-to-administer product comprising a plastic container and a liquid formulation stored in the plastic container, wherein the liquid formulation contains norepinephrine. The ratio of the inner surface area of ​​the plastic container to the volume of the liquid formulation is 3.0 cm². －１ The amount of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol is less than 0.5% when measured by HPLC after storage at 25°C for two months. Pre-processed product.

2. The product according to claim 1, wherein the concentration of norepinephrine is in the range of 0.01 mg / mL to 0.1 mg / mL.

3. The product according to claim 2, wherein the concentration of norepinephrine is 0.016 mg / mL, 0.032 mg / mL, or 0.064 mg / mL.

4. The product according to any one of claims 1 to 3, wherein the liquid formulation contains an isotonic agent.

5. The product according to claim 4, wherein the isotonic agent is selected from the group consisting of sodium chloride, potassium chloride, mannitol, glycerin, dextrose, and mixtures thereof.

6. The product according to any one of claims 1 to 3, wherein the pH of the liquid formulation is in the range of 3.0 to 5.

0.

7. The product according to claim 6, wherein the pH of the liquid formulation is in the range of 3.5 to 4.

5.

8. The ratio of the surface area of ​​the container to the volume of the liquid formulation is 0.3 cm². －１ ~3.0cm －１ A product according to any one of claims 1 to 3, which is within the range of the specified product.

9. The ratio of the surface area of ​​the container to the volume of the liquid formulation is 0.5 cm². －１ ~2.5cm －１ The product according to claim 8, which is within the range.

10. The ratio of the surface area of ​​the container to the volume of the liquid formulation is 1.0 cm². －１ ~2.0cm －１ The product according to claim 9, which is within the range.

11. The ratio of the surface area of the container to the volume of the liquid preparation is 1.2 cm －１ to 1.8 cm －１ within the range, and the product according to claim 10.

12. The product according to any one of claims 1 to 3, wherein the liquid formulation is an aqueous formulation.

13. The product according to any one of claims 1 to 3, wherein the liquid formulation does not contain a sulfite antioxidant.

14. The product according to any one of claims 1 to 3, wherein the inner surface of the plastic container contains polyolefin.

15. The product according to any one of claims 1 to 3, wherein the plastic container is a flexible plastic container.

16. The liquid preparation is an isotonic aqueous solution containing norepinephrine tartrate and citric acid, with a pH in the range of 3.5 to 4.

5. The aforementioned preparation contains norepinephrine in a concentration of 0.01 mg / mL to 0.1 mg / mL. The container is an infusion bag type product containing 50 to 500 mL of the liquid formulation, The inner surface of the injection bag contains polyolefin, and the ratio of the inner surface area of ​​the container to the volume of the formulation is 1.0 cm². －１ ~2.0cm －１ A product according to any one of claims 1 to 3, which is within the range of the specified product.

17. The product according to claim 16, wherein the amount of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol is less than 0.5% when measured by HPLC after storage at 25°C for two months.

18. The product according to any one of claims 1 to 3, manufactured by aseptic filling of the liquid formulation into a plastic container that has been sterilized in advance by irradiation.

19. The product according to claim 18, wherein the radiation irradiation is beta-ray irradiation, gamma-ray irradiation, or X-ray irradiation.

20. The product according to any one of claims 1 to 3, wherein the product is sterilized by autoclave treatment.

21. A use of the product according to claims 1 to 3 in a method for raising the blood pressure of an adult suffering from clinically significant hypotension primarily due to vasodilation under the circumstances of anesthesia and septic shock, wherein the method comprises administering the product to a patient in need of an increase in blood pressure.

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