Phenylephrine Composition for Injection

Abstract

Described herein are products containing injectable formulations that can be administered as such, the formulations containing phenylephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and a pH adjuster, the pH adjuster being tartaric acid, and the formulations of this oxygen-sensitive substance are manufactured without protection from oxygen, filled into flexible plastic containers, and remain stable over a long period even when stored without changing the air at the location by removing oxygen from the bag or package.

Description

Technical Field

[0001] The present invention relates to a ready-to-administer formulation containing phenylephrine that is stable within a flexible plastic container. Such compositions provide good stability of phenylephrine over time.

Background Art

[0002] Phenylephrine is an α1-adrenergic receptor agonist used to increase blood pressure in adults with clinically significant hypotension primarily due to vasodilation in situations such as septic shock and anesthesia.

[0003] The structure of phenylephrine is shown below.

[0004]

Chemical formula

[0005] Phenylephrine is susceptible to oxidation and is usually decomposed into several oxidation-related impurities. The oxidative degradation pathway of phenylephrine proposed by Rezk et al. (Non-Patent Document 1) is shown in Scheme 1.

[0006]

Chemical formula

[0007] Commercially available phenylephrine products are usually stored in glass vials, glass ampoules, or pre-filled syringes to prevent oxidation by protecting phenylephrine from oxygen. In many cases, these products need to be diluted before administration to the patient.

[0008] Jansen et al. (Non-Patent Document 2) studied the stability of phenylephrine compositions with phenylephrine HCl concentrations of 400 μg / ml and 200 μg / ml stored in polyvinyl chloride (PVC) bags. As can be seen from the results, phenylephrine decomposed by about 4 - 5% after 60 days at room temperature.

[0009] Patent Document 1 mentions a phenylephrine composition and also mentions that formulations with a lower concentration of phenylephrine have lower stability than those with a higher concentration of phenylephrine.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

[0012] An injectable formulation that contains phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, and a small amount of tartaric acid and is manufactured without protection from oxygen and can be administered as it is has been found to have surprisingly improved stability when stored in a flexible plastic container. This specification describes a formulation contained in a flexible plastic container and a product containing such a formulation.

[0013] The inventors have also discovered that by covering a flexible plastic container with an overwrap, the color and stability of the products described herein can be further improved. When covering the products, it has been found that it is not necessary to package and seal the products in an inert atmosphere. Also, for this product, an atmosphere control method for reducing the oxygen content between the product and the overwrap is not necessary.

[0014] The inventors have also discovered that an injectable preparation that can be administered as is, filled in a flexible plastic container as described above, can be further protected by covering the flexible plastic container with an overwrap to prevent loss of moisture. However, such protection is not essential.

[0015] The products and preparations disclosed herein have improved storage stability and can therefore be advantageously stored for a relatively long period of time. The above injectable preparation that can be administered as is has an excellent safety profile even when administered in large amounts to patients. This is due to its exceptionally low concentration and the types of excipients in the preparation.

Mode for Carrying Out the Invention

[0016] Detailed Disclosure (Including Definitions) The present disclosure relates to an injectable preparation of phenylephrine that can be administered as is and can be further contained or stored in a flexible plastic container. Injectable products include injectable preparations contained or stored in a flexible plastic container.

[0017] The phenylephrine preparation that can be administered as is contains an aqueous solvent. The term "aqueous solvent" means any composition / solvent in which water is present at 50% v / v or more, for example, compositions containing 50% v / v - 99.5% v / v of water, 50% v / v - 90% v / v of water, 60% v / v - 85% v / v of water, 70% v / v - 80% v / v of water, etc. Thus, aqueous compositions include compositions containing 50% v / v or more of water, 60% v / v or more of water, 70% v / v or more of water, 75% v / v or more of water, 80% v / v or more of water, 85% v / v or more of water, 90% v / v or more of water, 95% v / v or more of water, or 99% v / v or more of water. The aqueous composition can further contain a pharmaceutically acceptable organic solvent. The aqueous composition may further contain a standard diluent for parenteral use, such as water for injection, 0.9% sodium chloride for injection, 5% dextrose for injection, or other suitable diluents.

[0018] All numerical values used in this application, 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.

[0019] The term "phenylephrine" as used in this application means phenylephrine or a pharmaceutically acceptable salt of phenylephrine. In one aspect, phenylephrine is phenylephrine HCl.

[0020] When a specific amount or range of amounts of phenylephrine is indicated in this application, all values are calculated based on phenylephrine HCl. In one aspect, the concentration of phenylephrine in the directly administrable formulation is 0.05 - 0.5 mg / ml.

[0021] In one aspect, the concentration of phenylephrine can be 0.05 mg / ml, 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.10 mg / ml, 0.11 mg / ml, 0.12 mg / ml, 0.13 mg / ml, 0.14 mg / ml, 0.15 mg / ml, 0.16 mg / ml, 0.17 mg / ml, 0.18 mg / ml, 0.19 mg / ml, 0.20 mg / ml, 0.21 mg / ml, 0.22 mg / ml, 0.23 mg / ml, 0.24 mg / ml, 0.25 mg / ml, 0.26 mg / ml, 0.27 mg / ml, 0.28 mg / ml, 0.29 mg / ml, 0.30 mg / ml, 0.31 mg / ml, 0.32 mg / ml, 0.33 mg / ml, 0.34 mg / ml, 0.35 mg / ml, 0.36 mg / ml, 0.37 mg / ml, 0.38 mg / ml, 0.39 mg / ml, 0.40 mg / ml, 0.41 mg / ml, 0.42 mg / ml, 0.43 mg / ml, 0.44 mg / ml, 0.45 mg / ml, 0.46 mg / ml, 0.47 mg / ml, 0.48 mg / ml, 0.49 mg / ml or 0.50 mg / ml.

[0022] In one aspect, the concentration of phenylephrine in the directly administrable preparation is 0.08 mg / ml. In one aspect, the concentration of phenylephrine in the directly administrable preparation is 0.16 mg / ml.

[0023] In one aspect, the concentration of phenylephrine in the directly administrable preparation is 0.20 mg / ml. In one aspect, the concentration of phenylephrine in the directly administrable preparation is 0.40 mg / ml.

[0024] The pH of the preparation is in the range of 3.5 to 4.5. In another aspect, the pH is in the range of 3.7 to 4.4. In another aspect, the pH is in the range of 3.8 to 4.3. In another aspect, the pH is in the range of 3.8 to 4.2, 3.9 to 4.2, or 3.9 to 4.1. In yet another aspect, the pH is 4.0.

[0025] In one aspect, the pH of the formulation can be 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4 or 4.5. "pH" is the conventional unit of measurement of hydrogen ion activity in solution at room temperature, unless another temperature is specified.

[0026] As used herein, the term "pH" in a composition is defined as ±0.1 of the numerical value or range. In one aspect, the pH value of the formulation immediately after preparation, i.e., at the start of the storage period, is indicated.

[0027] In one aspect, the pH value of the formulation after storage at 40 °C for 3 months is indicated. In one aspect, the pH value of the formulation after storage at 40 °C for 6 months is indicated. As used herein, the number of months of the storage period is calculated from the time of preparation of the formulation that can be administered as such.

[0028] In another aspect, the pH value of the formulation after a certain period of time under predetermined temperature conditions is indicated. In one aspect, the composition is an isotonic composition. The term "isotonic" as used in this disclosure is understood to mean having an osmotic pressure similar to the physiological osmotic pressure of blood.

[0029] Typically, a pharmaceutical composition that can be administered as such has an osmotic pressure of 240 - 340 mOsm / kg. In one aspect, the composition has an osmotic pressure of 240 - 600 mOsm / kg.

[0030] In one aspect, the formulation that can be administered as such contained in a product that can be administered as such is isotonic and has an osmotic pressure similar to the physiological osmotic pressure of blood as described above. In some aspects, the composition that can be administered as such further comprises one or more osmotic pressure regulators. Osmotic pressure regulators suitable for use in a composition that can be administered as such include, but are not limited to, sodium chloride and dextrose.

[0031] In one aspect, sodium chloride is used as the osmotic pressure regulator. In one aspect, the concentration of sodium chloride is in the range of 8 to 10 mg / ml. In one aspect, the concentration of sodium chloride can be 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml or 10 mg / ml.

[0032] In one aspect, the concentration of sodium chloride is 9 mg / ml. In one aspect, the formulation contains a small amount of pH adjuster. The term "small amount" used in the present application means that the concentration of the pH adjuster is in the range of 0.001 mg / ml to 0.05 mg / ml, more preferably in the range of 0.005 mg / ml to 0.05 mg / ml.

[0033] In one aspect, the concentration of the pH adjuster needs to be within a range that can adjust the pH of the formulation to a specific range. In one aspect, the pH of the formulation should be adjusted to a pH within the range of 3.5 to 4.5.

[0034] In one aspect, the pH adjuster is tartaric acid. In one aspect, the concentration of tartaric acid in the formulation is in the range of 0.001 mg / ml to 0.05 mg / ml.

[0035] In one aspect, the concentration of tartaric acid in the formulation is in the range of 0.001 mg / ml to 0.04 mg / ml. In one aspect, the concentration of tartaric acid in the formulation is in the range of 0.001 mg / ml to 0.035 mg / ml.

[0036] In one aspect, the concentration of tartaric acid in the formulation is in the range of 0.001 mg / ml to 0.03 mg / ml. In one aspect, the concentration of tartaric acid in the formulation is in the range of 0.001 mg / ml to 0.025 mg / ml.

[0037] In one aspect, the concentration of tartaric acid in the formulation is in the range of 0.001 mg / ml to 0.023 mg / ml. In one aspect, the concentration of tartaric acid in the formulation ranges from 0.001 mg / ml to 0.022 mg / ml.

[0038] In one aspect, the concentration of tartaric acid in the formulation ranges from 0.001 mg / ml to 0.020 mg / ml. In one aspect, an injectable product that can be administered as is contains a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, an aqueous solvent, and a small amount of tartaric acid as a pH adjuster, contained in a flexible plastic container.

[0039] In one aspect, an injectable product that can be administered as is contains a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, an aqueous solvent, and tartaric acid as a pH adjuster in an amount less than 0.05 mg / ml, contained in a flexible plastic container.

[0040] In one aspect, an injectable product that can be administered as is contains a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container.

[0041] In one aspect, an injectable product that can be administered as is and does not require the removal of oxygen from the product contains a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure adjuster, an aqueous solvent, and a small amount of tartaric acid as a pH adjuster, contained in a flexible plastic container. As used herein, the removal of oxygen can include purging the headspace of the flexible plastic container with an inert gas and / or sparging the formulation with an inert gas, sealing the container, and / or packing the flexible plastic container containing the solution together with an oxygen absorber in another container (e.g., an aluminum pouch). In other words, no measures are taken to reduce the amount of oxygen in the formulation or in the headspace of the container.

[0042] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is comprises a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount less than 0.05 mg / ml, contained in a flexible plastic container.

[0043] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is comprises a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount less than 0.05 mg / ml, contained in a flexible plastic container, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius is less than 0.4%.

[0044] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is comprises a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container.

[0045] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is comprises a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius is less than 0.4%.

[0046] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists essentially of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a small amount of tartaric acid as a pH adjuster, contained in a flexible plastic container.

[0047] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists essentially of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a formulation of tartaric acid as a pH adjuster in an amount less than 0.05 mg / ml, contained in a flexible plastic container.

[0048] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists essentially of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a formulation of tartaric acid as a pH adjuster in an amount less than 0.05 mg / ml, contained in a flexible plastic container, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius is less than 0.4%.

[0049] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists essentially of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a formulation of tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container.

[0050] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists essentially of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a formulation of tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius is less than 0.4%.

[0051] In one aspect, an injectable product that can be administered as is consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a small amount of tartaric acid as a pH adjuster, contained in a flexible plastic container.

[0052] In one aspect, an injectable product that can be administered as is consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of less than 0.05 mg / ml, contained in a flexible plastic container.

[0053] In one aspect, an injectable product that can be administered as is consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container.

[0054] In one aspect, an injectable product that can be administered as is and does not require oxygen removal from the product consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and a small amount of tartaric acid as a pH adjuster, contained in a flexible plastic container.

[0055] In one aspect, an injectable product that can be administered as is and does not require oxygen removal from the product consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of less than 0.05 mg / ml, contained in a flexible plastic container.

[0056] In one aspect, an injectable product that can be administered as is and does not require oxygen removal from the product consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of less than 0.05 mg / ml, contained in a flexible plastic container, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius is less than 0.4%.

[0057] In one aspect, an injectable product that can be administered as is and does not require oxygen removal from the product consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, contained in a flexible plastic container.

[0058] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, an aqueous solvent, and tartaric acid as a pH adjuster in an amount of 0.001 mg / ml to 0.05 mg / ml, which is contained in a flexible plastic container, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius is less than 0.4%.

[0059] In one aspect, an injectable product that can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, a small amount of tartaric acid, and an aqueous solvent, which is contained in a flexible plastic container.

[0060] In one aspect, an injectable product that can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, tartaric acid in an amount less than 0.05 mg / ml, and an aqueous solvent, which is contained in a flexible plastic container.

[0061] In one aspect, an injectable product that can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, tartaric acid in an amount of 0.001 mg / ml to 0.05 mg / ml, and an aqueous solvent, which is contained in a flexible plastic container.

[0062] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, a small amount of tartaric acid, and an aqueous solvent, which is contained in a flexible plastic container.

[0063] In one aspect, an injectable product that does not require oxygen removal from the product and can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, tartaric acid in an amount less than 0.05 mg / ml, and an aqueous solvent, which is contained in a flexible plastic container.

[0064] In one aspect, an injectable product that does not require the removal of oxygen from the product and can be administered as is consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, tartaric acid in an amount of 0.001 mg / ml to 0.05 mg / ml, and an aqueous solvent, and is contained in a flexible plastic container.

[0065] In one aspect, the formulation that can be administered as is does not contain citric acid. In one aspect, the formulation that can be administered as is does not contain citrate. In one aspect, the formulation that can be administered as is does not contain acetate buffer.

[0066] In one aspect, the formulation that can be administered as is does not contain sodium metabisulfite. In one aspect, the formulation that can be administered as is does not contain disodium edetate (EDTA).

[0067] "Can be administered as is" means a formulation that does not need to be diluted before administration to a patient. A composition that can be administered as is is synonymous with being able to be injected as is or being able to be injected directly and is suitable for direct administration to a patient.

[0068] As used in this application, the terms "pharmaceutical composition", "pharmaceutical formulation", "composition" and "formulation" are used interchangeably. In one aspect, phenylephrine in the product and / or formulation that can be administered as is according to the present disclosure is stable at a temperature of 2°C to 8°C for a certain period of time.

[0069] In one aspect, phenylephrine in the product and / or formulation that can be administered as is according to the present disclosure is stable under room temperature conditions for a certain period of time. As used in this application, the term "room temperature" is from 20°C to 27°C.

[0070] In one aspect, phenylephrine in the product and / or formulation that can be administered as is according to the present disclosure is stable at 40°C for a certain period of time. In one aspect, phenylephrine in the products and / or formulations described herein is stable over a period of 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months) or more, 3 months or more, 4 months or more, 180 days (6 months) or more, 9 months or more, 12 months (1 year) or more, 14 months or more, 16 months or more, 18 months or more, 20 months or more, 24 months or more at specific designated temperature conditions. Those skilled in the art will recognize that compositions containing active pharmaceutical ingredients can be stored under refrigeration conditions, intermediate conditions (between refrigeration temperature and room temperature), or near room temperature conditions. The "specific designated temperature conditions" are understood to include refrigeration conditions of 2 - 8°C, intermediate conditions of 10°C - 18°C, and room temperature conditions of 20°C - 27°C.

[0071] As used herein, the "certain period" or "relatively long period" encompasses the periods described above. The terms "stability", "chemical stability", or "stable" are intended to mean that an acceptable amount of phenylephrine is present in the product, composition, or formulation, or that no more than a certain amount of phenylephrine decomposes after a certain period. Thus, in a stable product, solution, or formulation, unacceptable degradation of the API is avoided.

[0072] Stability can be presented as an assay of phenylephrine in the product in accordance with the present disclosure. If a product, formulation, or composition initially contains phenylephrine in a specific assay, the stability of that product, formulation, or composition is reflected by the decrease in the assay of phenylephrine in the product, formulation, or composition over time. A stable product, solution, or composition should contain phenylephrine in the designated assay after a predetermined period.

[0073] In one aspect, the assay decrease / degradation of phenylephrine in a pharmaceutical formulation measured by liquid chromatography, such as HPLC, UPLC, LC / MS, is 10% or less. For example, a stable composition can be a composition in which the assay decrease / reduction of phenylephrine after a predetermined period measured by liquid chromatography, for example, HPLC, UPLC, LC / MS is 1% or less, 2% or less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, 10% or less.

[0074] In the present application, the decrease in the phenylephrine assay is measured from the preparation of the formulation for a specified time under specific storage conditions, for example, up to 3 months and 6 months. When explaining the stability of a pharmaceutical, formulation, or composition, of course, minimizing the degradation of the active ingredient is an important and targeted factor. However, another important factor is the formation of impurities that can be formed by the degradation of the active ingredient.

[0075] In the following table, based on the relative retention time (RRT) of the HPLC chromatogram, one of the degradation impurities of phenylephrine is identified. This impurity is considered to be a degradation product related to the oxidation of phenylephrine. The inventors have found that one of the main oxidation impurities is impurity RRT 0.66 shown in the following examples.

[0076] Therefore, "stability" may also be defined by the total amount of impurities or the amount of a specific impurity generated after a certain period. The amount of impurities present can be expressed as a percentage (for example, as a percentage of the peak area of the HPLC chromatogram), or can be calculated according to a standard solution.

[0077] In the present application, the increase in total impurities or specific impurities is measured from the preparation of the formulation for the specified time, for example, up to 3 months and 6 months under specific storage conditions. In the following embodiments, when the product includes an overlap, it is preferable that the overlap does not include an oxygen absorber or a deoxidizer.

[0078] In one aspect, in a plastic container without overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is less than 0.80% as measured by HPLC. In one aspect, in a plastic container without overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is less than 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.7, 0.75, or 0.80% as measured by HPLC.

[0079] In one aspect, in a plastic container without overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is 0.4% or less as measured by HPLC. In one aspect, in a plastic container with overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is 0.40% or less as measured by HPLC.

[0080] In one aspect, in a plastic container with overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, or 0.40% or less as measured by HPLC.

[0081] In one aspect, in a plastic container with overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is 0.30% or less as measured by HPLC. In one aspect, in a formulation where the phenylephrine concentration is 0.05 - 0.5 mg / ml or the concentration is 0.08 mg / ml, 0.16 mg / ml, 0.20 mg / ml, or 0.40 mg / ml, in a plastic container without overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius is 0.80% or less as measured by HPLC.

[0082] In one aspect, in a formulation where the phenylephrine concentration is 0.05 to 0.5 mg / ml or the concentration is 0.08 mg / ml, 0.16 mg / ml, 0.20 mg / ml, or 0.40 mg / ml, in a plastic container without overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius, as measured by HPLC, is less than 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.7, 0.75, or 0.80%.

[0083] In one aspect, in a formulation where the phenylephrine concentration is 0.05 to 0.5 mg / ml or the concentration is 0.08 mg / ml, 0.16 mg / ml, 0.20 mg / ml, or 0.40 mg / ml, in a plastic container without overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius, as measured by HPLC, is 0.40% or less.

[0084] In one aspect, in a formulation where the phenylephrine concentration is 0.05 to 0.5 mg / ml or the concentration is 0.08 mg / ml, 0.16 mg / ml, 0.20 mg / ml, or 0.40 mg / ml, in a plastic container with overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius, as measured by HPLC, is less than 0.40%.

[0085] In one aspect, in a formulation where the phenylephrine concentration is 0.05 to 0.5 mg / ml or the concentration is 0.08 mg / ml, 0.16 mg / ml, 0.20 mg / ml, or 0.40 mg / ml, in a plastic container with overlap, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius, as measured by HPLC, is less than 0.40%, less than 0.35%, less than 0.30%, less than 0.25%, less than 0.20%, less than 0.15%, or less than 0.10%.

[0086] In one aspect, in a formulation where the phenylephrine concentration is 0.05 to 0.5 mg / ml or the concentration is 0.08 mg / ml, 0.16 mg / ml, 0.20 mg / ml, or 0.40 mg / ml, the total amount of impurities in the formulation after 3 months at 40 degrees Celsius in an overlapping plastic container is 0.30% or less as measured by HPLC.

[0087] In one aspect, in a plastic container without overlap, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius is 0.50% or less as measured by HPLC. In one aspect, in a plastic container without overlap, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius is 0.25% or less, 0.30% or less, 0.35% or less, 0.40% or less, 0.45% or less, or 0.50% or less as measured by HPLC.

[0088] In one aspect, in a formulation where the phenylephrine concentration is 0.15 to 0.25 mg / ml or the concentration is 0.16 mg / ml or 0.20 mg / ml, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius in a plastic container without overlap is 0.50% or less as measured by HPLC.

[0089] In one aspect, in a formulation where the phenylephrine concentration is 0.15 to 0.25 mg / ml or the concentration is 0.16 mg / ml or 0.20 mg / ml, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius in a plastic container without overlap is 0.25% or less, 0.30% or less, 0.35% or less, 0.40% or less, 0.45% or less, or 0.50% or less as measured by HPLC.

[0090] In addition to chemical stability, the appearance of the formulation can also be monitored. Appearance includes visual inspection of the precipitation, transparency, and color of the formulation. Color is L * a * b *It can also be determined with a spectrophotometer by using a color space method and calculating ΔE according to USP <1061>.

[0091] In the present application, the terms "secondary packaging" and "overlap" are used interchangeably. To further improve the stability and / or appearance of the formulation, particularly to reduce the formation of impurities and color in the formulations described herein, the flexible plastic container may be covered with secondary packaging.

[0092] In one aspect, the overlap includes a material that provides a barrier to the movement of water and / or gas, but does not include components for changing the air within the pouch. Thus, in one aspect, the flexible plastic container is covered with secondary packaging. In one aspect, the overlap is an aluminum pouch that contains a flexible plastic container with an injectable formulation that can be administered as is. After placing this container in the aluminum pouch, the aluminum pouch is sealed. Before sealing, no air exchange / changing or gas removal is required to ensure the stability of the formulation.

[0093] In one aspect, the flexible container contains a composition that is neither manufactured in an oxygen-free atmosphere nor manipulated to reduce the oxygen level in the product. In one aspect, the formulation that can be administered as is is contained in a flexible plastic container covered with an overlap that does not contain an oxygen absorber or a deoxidizer.

[0094] In one aspect, a flexible plastic container containing a formulation that can be administered as is is not covered with an overlap. As described herein, the phenylephrine formulation that can be administered as is is contained in a container. The container can be any container suitable for storing the phenylephrine formulation that can be administered as is. Preferably, the container is a flexible plastic container. In the present application, the term "flexible plastic container" means a flexible polymer infusion bag or other polymer container. Exemplary flexible plastic containers are manufactured from polyolefins such as polyethylene, polypropylene, their copolymers and derivatives, optionally with other additives. Examples of commercially available films used in the manufacture of the plastic container include, for example, Nexcel® M312A, Infuflex 7233, or Polycine APP114-S, etc.

[0095] In one aspect, the formulation is contained in a plastic container having multiple layers of different polymers. In another aspect, the formulation is contained in a plastic container having 3 to 6 layers of different polymers, and the inner layer contains polypropylene.

[0096] In one aspect, the polypropylene may be chemically modified. In one aspect, the formulation is contained in a plastic container, and the inner layer consists of an ethylene-propylene copolymer.

[0097] In one aspect, the formulation is contained in a plastic container, and the inner layer contains an ethylene-propylene copolymer. In one aspect, the formulation is contained in a plastic container, and the inner layer consists of polypropylene.

[0098] In one aspect, the polypropylene may be chemically modified. In one aspect, the formulation is contained in a plastic container, and the inner layer contains polypropylene. In one aspect, the polypropylene may be chemically modified.

[0099] In one aspect, the formulation is contained in a plastic container, and the inner layer consists of a polyolefin and / or a styrene block copolymer. In one aspect, the formulation is contained in a plastic container, and the inner layer contains a polyolefin and / or a styrene block copolymer.

[0100] In one aspect, the products and formulations in the aspects included are manufactured under conditions where the dissolved oxygen in the formulation is not removed and is not significantly reduced. The present disclosure also provides a method for manufacturing or preparing a product containing phenylephrine or a pharmaceutically acceptable salt of phenylephrine. This method includes: a) supplying water to a tank; b) forming a solution by adding excipients such as an osmotic pressure regulator, a pH regulator, or a combination thereof to the tank; c) adding phenylephrine or its salt to the solution and mixing until the phenylephrine is dissolved; d) measuring the pH and further adjusting the pH to reach the target pH of the formulation if necessary; e) adding more water to the solution to reach the final batch volume; f) filtering the solution and filling the solution into a flexible plastic container; g) closing the flexible plastic container; and h) optionally sterilizing the flexible plastic container. Sterilization can be performed, for example, by autoclaving.

[0101] When applying a filtration step before filling an aqueous formulation into a flexible plastic container, this step can be carried out by passing the aqueous formulation through a sterilization-grade filter. Passing may be facilitated by pressurizing the solution with a gas.

[0102] Optionally, a flexible plastic container containing an aqueous phenylephrine formulation can be covered with a secondary packaging. The overwrap may be, for example, a tube in which a flexible plastic container containing an aqueous phenylephrine formulation is placed and both ends are sealed. The overwrap may also be two sheets, in which case a bag containing an aqueous phenylephrine formulation is placed between the two sheets, and then all four ends of the two sheets are sealed.

[0103] "Pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammals to be treated thereby.

[0104] In one aspect, the formulation in the product is administered parenterally. In one aspect, this formulation is used to raise the blood pressure of adults with clinically significant hypotension mainly caused by vasodilation in situations such as septic shock and anesthesia.

[0105] Examples The preparation of the formulation is described for formulations with a phenylephrine HCl content of 0.2 mg / ml or 0.08 mg / ml, but formulations with other concentrations of phenylephrine, such as 0.16 mg / ml or 0.4 mg / ml, are also prepared in a similar manner.

[0106] Formulations 1 - 3 of the present invention 9 g of sodium chloride was added to 900 mL of water and mixed until dissolved. The pH was adjusted to a target pH of 4.0 using a 0.06 mol / L tartaric acid solution.

[0107] Next, 0.200 g of phenylephrine hydrochloride (Formulation 1 and Formulation 3) or 0.080 g of phenylephrine hydrochloride (Formulation 2) was added to the solution and mixed until dissolved. The pH was measured and, if necessary, further adjusted to the target pH of 4.0 with a 0.06 mol / L tartaric acid solution. If necessary, additional water was added to the solution to bring the total volume to 1000 ml.

[0108] The solution was filtered through a 0.22 μm filter, filled into a flexible plastic bag, and then sealed. For Formulations 1 and 2, the bags were autoclaved in an autoclave at 121°C for 15 minutes. After autoclaving, the bags were sealed with an aluminum overlap that did not contain an oxygen absorber or deoxidizer. For Formulation 3, the bag was sealed with an aluminum overlap that did not contain an oxygen absorber or deoxidizer and then autoclaved in an autoclave at 121°C for 15 minutes.

[0109] Comparative Formulation 4 The dissolved oxygen concentration was made 2.0 ppm or less by purging 900 mL of water with nitrogen. 9 g of sodium chloride was added and mixed until dissolved. The pH was adjusted to a target pH of 4.0 using 1 mol / L citric acid solution.

[0110] Next, 0.200 g of phenylephrine hydrochloride was added to the solution and mixed under a nitrogen blanket until dissolved. The pH was measured and, if necessary, further adjusted to the target pH of 4.0 with 1 mol / L citric acid solution. If necessary, additional water was added to the solution to bring the total volume to 1000 mL, and the surface of the solution was covered with nitrogen.

[0111] The solution was pump-filtered through a 0.22 μm filter, filled into a flexible plastic bag, and then sealed. The bag was sealed with an aluminum overlap that did not contain an oxygen absorber or deoxidizer and then autoclaved in an autoclave at 121°C for 15 minutes.

[0112] Analytical Method HPLC Assay Method Mobile Phase A: Phosphoric acid and water (1:1000) Mobile Phase B: Acetonitrile The gradient of the mobile phase is shown below.

[0113]

Table 1

[0114] Standard Solution: 0.1 mg / mL of phenylephrine hydrochloride RS in water. Sample solution: phenylephrine hydrochloride with a nominal concentration of 0.1 mg / mL Chromatography system Mode: LC Detector: UV 273 nm.

[0115] Column: 4.6 × 15 cm; 2.6 μm packing L1 Column temperature: 35 °C Flow rate: 1.0 mL / min Calculation Calculate the percentage relative to the declared amount of phenylephrine hydrochloride.

[0116]

Number

[0117] ru… Peak response of phenylephrine from the sample solution rs… Peak response of phenylephrine from the standard solution cs… Concentration of phenylephrine hydrochloride RS in the standard solution (mg / mL) cu… Nominal concentration of phenylephrine hydrochloride RS in the sample solution (mg / mL) 1. HPLC impurity method Mobile phase A, mobile phase B, mobile phase gradient and sample solution are the same as those described in the above HPLC assay method.

[0118] System suitability solution: 0.1 mg / mL of phenylephrine hydrochloride RS and 0.005 mg / mL of phenylephrine related compound F RS in water. Sensitivity solution: 0.1 μg / mL of phenylephrine HCl RS in water Standard solution: 0.0002 mg / mL of phenylephrine HCl RS in water The chromatography system is the same as that described in the above HPLC assay method, except that the detector is UV 215 nm.

[0119] In the preparation containing tartaric acid, the degradation product at RRT 0.66 was calculated using a UV detector at 273 nm. Calculation Calculate the percentage of each degradation product (refer to the above * UV 273 nm):

[0120]

Number

[0121] ru… Peak response of each degradation product from the sample solution rs… Peak response of phenylephrine from the standard solution cs… Concentration of phenylephrine hydrochloride RS in the standard solution (mg / mL) cu… Nominal concentration of phenylephrine hydrochloride RS in the sample solution (mg / mL) F… Relative response coefficient, refer to Table 2.

[0122] 2. Color spectrophotometry (L * A * B * Color space method) For example, various preparations are measured by a UV / VIS spectrometer such as Perkin Elmer 650. Various preparations are measured as they are without additional preparation.

[0123] Total color difference ΔE * is

[0124]

Number

[0125] and ΔL * , Δa * , and Δb * are the differences in the color coordinates of the specimens to be compared. Color coordinates Color coordinate L * , a * , and b * are

[0126]

Number

[0127]

Number

[0128] and

[0129]

Number

[0130] It is defined by. Here, X0, Y0, and Z0 are nominal standard tristimulus values that are white or colorless, and Y / Y0 > 0.01. Usually, these are equal to the tristimulus values of the standard light source, and Y0 is set to 100.0. In this case, X0 = 98.0 and Z0 = 118.1.

[0131] Example 1 Table 1 shows the effect of the concentrations of tartaric acid and phenylephrine on stability when the formulation is contained in a flexible plastic container with an overlap, compared with citric acid.

[0132]

Table 2

[0133] In Formulations 1 and 2 using tartaric acid, the total impurities decreased compared with the citric acid-containing formulation purged with N2, even without removing oxygen during production. Example 2 Table 2 shows formulations of 0.2 mg / ml phenylephrine (PEP) with an overlap. Formulation 1 was produced without nitrogen purging of the solution during production of the product, and Formulation 028 is the same as Formulation 1 but was produced with nitrogen purging to remove oxygen from the solution during formulation. Comparative Formulation 4 contains citric acid as a pH adjuster and was produced by nitrogen purging to remove oxygen from the solution during formulation.

[0134]

Table 3

[0135] As can be seen from Table 2, when tartaric acid is used as the pH adjuster, the total impurity level in Formulation 1 is significantly lower than that in Formulation 28. Also, as can be seen from Table 2, when tartaric acid is used as the pH adjuster, the stability after 6 months is improved by at least about 5-fold compared to Comparative Formulation No. 4 (i.e., the one using citric acid and purged with nitrogen).

Claims

1. A product comprising an injectable preparation that can be administered as is, said preparation comprising phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, and a pH regulator which is tartaric acid in an amount of less than 0.05 mg / ml, said preparation being contained in a flexible plastic container.

2. A product comprising an injectable preparation that can be administered as is, said preparation comprising phenylephrine or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, and a pH regulator which is tartaric acid in an amount of less than 0.05 mg / ml, said preparation being contained in a flexible plastic container, oxygen not being removed from said product, and the total amount of impurities measured by HPLC after 3 months at 40 degrees Celsius being less than 0.4%.

3. The product according to claim 1 or 2, wherein the osmotic pressure regulator is sodium chloride.

4. The product according to claim 3, wherein the concentration of sodium chloride is 8 to 10 mg / ml.

5. The product according to claim 4, wherein the concentration of sodium chloride is 9 mg / ml.

6. The product according to claim 1 or 2, wherein the pH of the preparation is 3.7 to 4.

4.

7. The product according to claim 6, wherein the pH of the preparation is 4.

0.

8. The product according to claim 1 or 2, wherein the phenylephrine is phenylephrine hydrochloride.

9. The product according to claim 1, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.05 mg / ml to 0.5 mg / ml.

10. The product according to claim 8, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.08 mg / ml.

11. The product according to claim 8, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.16 mg / ml.

12. The product according to claim 8, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.20 mg / ml.

13. The product according to claim 8, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.40 mg / ml.

14. The product according to claim 1 or 2, wherein the concentration of tartaric acid is 0.001 mg / ml to 0.05 mg / ml.

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