WO2024008293A1

WO2024008293A1 - Injectable phenylephrine compositions

Info

Publication number: WO2024008293A1
Application number: PCT/EP2022/068891
Authority: WO
Inventors: Matija SIMAC
Original assignee: Xellia Pharmaceuticals Aps
Priority date: 2022-07-07
Filing date: 2022-07-07
Publication date: 2024-01-11

Abstract

Described herein is a product including a ready-to-administer injectable formulation, the formulation including phenylephrine or a pharmaceutically acceptable salt thereof, a tonicity agent and a pH adjusting agent, wherein the pH adjusting agent is selected from hydrochloric acid, tartaric acid, and mixtures thereof; and wherein the formulation is contained in a flexible PVC-free plastic container.

Description

TITLE

INJECTABLE PHENYLEPHRINE COMPOSITIONS

FIELD OF THE INVENTION The present disclosure relates to a ready-to-administer formulation comprising phenylephrine that is stable in a flexible PVC-free plastic container. Such compositions provide good stability over time.

BACKGROUND.

Phenylephrine is an alpha-1 adrenergic receptor agonist indicated for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation, in such settings as septic shock or anesthesia.

The structure of phenylephrine is given below.

Phenylephrine is sensitive to oxidation and will normally degrade into several oxidation related impurities.

A pathway for phenylephrine oxidative degradation suggested by Rezk et al,; Journal of AOAC International, Vol. 100, No.2, pp. 434-444, 2017 is shown in Scheme 1.

Scheme 1 . Suggested pathway for phenylephrine oxidative degradation.

Phenylephrine products that are available in the market are normally stored in glass vials, glass ampules or pre-filled syringes to protect phenylephrine from oxygen and consequently oxidation. Often these products need to be diluted prior to administering into the patient.

Jansen et al, Hosp Pharm; 49(5):455-457, 2014 has studied the stability of phenylephrine compositions with a phenylephrine HCI concentration of 400 pg/ml and 200 pg/ml stored in polyvinyl chloride (PVC) bags. As seen in the results, the phenylephrine has degraded by around 4-5 % after 60 days at room temperature.

SUMMARY

It has been found that a ready-to-administer injectable formulation comprising phenylephrine or a pharmaceutically acceptable salt thereof, a tonicity agent, and a pH adjusting agent selected from hydrochloric acid, tartaric acid, and mixtures thereof, possesses surprisingly enhanced stability when stored in a flexible PVC-free plastic container. Described herein are the formulations and products comprising the formulations contained in a flexible PVC-free plastic container.

The inventors have also found that the color and stability of the products described herein can be further improved by overwrapping the flexible PVC-free plastic container with an overwrap.

The inventors have also found that the ready-to-administer injectable formulation mentioned above could be further secured, although not necessary, by overwrapping the flexible PVC- free plastic container with an overwrap. This provides the beneficial effect that should secondary packaging break during handling the initially enhanced product stability of the product described herein is retained.

Because of their enhanced storage stability, the products and formulations disclosed herein can be advantageously stored for relatively long periods.

DETAILED DISCLOSURE (including definitions)

The disclosure relates to ready-to-administer injectable formulations of phenylephrine contained or stored in a flexible PVC-free plastic container. An injectable product includes an injectable formulation contained or stored in a flexible PVC-free plastic container.

The ready-to-administer phenylephrine formulations comprise a tonicity agent. The tonicity agent can be chosen from pharmaceutically acceptable tonicity agents, such as, for example sodium chloride, dextrose, and the like.

The ready-to-administer phenylephrine formulations comprise an aqueous solvent.

By the term “aqueous solvent” is understood any composition/ solvent in which water is present in or above 50% v/v, such as, e.g., a composition comprising from 50% v/v to 99.5% v/v water, from 50 % v/v to 90% v/v water, from 60% v/v to 85% v/v water, from 70% v/v to 80 % v/v water. Accordingly, aqueous compositions include compositions comprising 50% v/v or more water, 60% v/v or more water, 70% v/v or more water, 75% v/v or more water, 80% v/v or more water, 85% v/v or more water, 90% v/v or more water, 95% v/v or more water, or 99% v/v or more water. The aqueous composition can additionally comprise pharmaceutically acceptable organic solvents. The aqueous composition may further comprise standard diluents for parenteral use, such as water for injection, 0.9% sodium chloride for injection, Sterile water for injection, Dextrose 5% injection or other suitable diluents.

The term “phenylephrine” as used herein means phenylephrine or a pharmaceutically acceptable salt of phenylephrine.

In an aspect, phenylephrine is phenylephrine HCL

When specific amounts or ranges of amounts of phenylephrine are given in this application, all values are calculated based on phenylephrine HCL

In an aspect, the concentration of phenylephrine is from 0.15 to 0.25 mg/ml.

In an aspect, the concentration of phenylephrine may be 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, or 0.25 mg/ml.

In an aspect, the concentration of phenylephrine is 0.16 mg/ml.

In an aspect, the concentration of phenylephrine is 0.20 mg/ml.

The pH of the formulations is in the range from 3.7-4.4. In an aspect the pH is in the range of 3.8-4.3. In another aspect the pH is in the range of 3.8-4.2 or 3.9-4.2. In yet another aspect the pH is 4.0.

In an aspect, pH of the formulations may be 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3 or 4.4.

“pH” is the conventional measurement unit of hydrogen ion activity in a solution at room temperature, unless another temperature is specified.

In an aspect, pH values are given for the formulations just after preparation, which means at the start of the shelf life.

In an aspect, pH values are given for the formulations after 3 months of storage at 40°C.

In one aspect, pH values are given for the formulations after 6 months of storage at 40°C. As used herein, the months of storage are calculated from the time of preparation.

In another aspect, pH values are given for the formulation after certain period of time in predetermined temperature conditions.

The pH of the formulation may be adjusted in any suitable manner. The pH may be adjusted with one or more pH adjusting agents disclosed herein.

For formulations to be accepted for use in humans, such formulations must meet the requirements of isotonicity. By the term of “isotonic” or “isotonicity” as used herein, is meant as defined in USP <785>.

In an aspect, the concentration of a tonicity agent in the formulation is in the amount to give the formulation isotonicity in accordance with USP <785>.

In an aspect, the formulation has an osmolality within the physiological osmolality of blood. According to the literature, and as used herein, the physiological osmolality of blood is in range of 270 to 340 mOsmol/kg.

In an aspect, the concentration of a tonicity agent in the formulation should be in the amount to achieve an osmolality of the formulation within the targeted range of 270 to 340 mOsmol/kg.

In an aspect, sodium chloride is used as a tonicity agent.

In an aspect, the concentration of sodium chloride is in the range of 8 to 10 mg/ml.

In an aspect, the concentration of sodium chloride may be 8 mg/ml, 8.5 mg/ml, 9 mg/ml, 9.5 mg/ml or 10 mg/ml.

In an aspect, the concentration of sodium chloride is 9 mg/ml.

In an aspect, the formulation comprises a pH adjusting agent selected from hydrochloric acid, tartaric acid, and mixtures thereof.

In an aspect, the concentration of the pH adjusting agent should be in range to adjust the pH of the formulation in the specific range. In an aspect, the pH in the formulations should be adjusted to a pH within the range from 3.7 to 4.4.

In an aspect, pH adjusting agent is hydrochloric acid.

In an aspect, pH adjusting agent is tartaric acid. The concentration of tartaric acid in the formulation may be in the range of 0.005 to 0.035 mg/ml.

In an aspect, the concentration of tartaric acid is from 0.01 to 0.025 mg/ml.

In another aspect, the concentration of tartaric acid is from 0.015 to 0.023 mg/ml.

In another aspect, the concentration of tartaric acid is from 0.016 to 0.022 mg/ml.

In another aspect, the concentration of tartaric acid is from 0.017 to 0.020 mg/ml

In another aspect, the concentration of tartaric acid is 0.019 mg/ml.

In an aspect, pH adjusting agent is mixture of tartaric acid and hydrochloric acid.

Unless otherwise is specified, the amount of pH adjusting agent needed to adjust the pH within the range of 3.7-4.4 would be known to the person skilled in the art.

In an aspect, a ready-to-administer injectable product comprises a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, a tonicity agent, an aqueous solvent, and a pH adjusting agent selected from hydrochloric acid, tartaric acid, and mixtures thereof, contained in a flexible PVC-free plastic container.

In an aspect, a ready-to-administer injectable product consists essentially of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, a tonicity agent, an aqueous solvent, and a pH adjusting agent selected from hydrochloric acid, tartaric acid, and mixtures thereof, contained in a flexible PVC-free plastic container.

In an aspect, a ready-to-administer injectable product consists of a formulation of phenylephrine or a pharmaceutically acceptable salt thereof, a tonicity agent, an aqueous solvent, and a pH adjusting agent selected from hydrochloric acid, tartaric acid, and mixtures thereof, contained in a flexible PVC-free plastic container.

In an aspect, a ready-to-administer injectable product consists of phenylephrine or a pharmaceutically acceptable salt thereof, sodium chloride, tartaric acid, and an aqueous solvent, contained in a flexible PVC-free plastic container. In an aspect, the ready-to-administer formulation does not comprise citric acid.

In an aspect, the ready-to-administer formulation does not comprise citrate.

In an aspect, the ready-to-administer formulation does not comprise an acetate buffer.

In an aspect, the ready-to-administer formulation does not comprise sodium metabisulfite.

Ready-to-administer means a formulation that does not need any dilution prior to administration to the patient. A ready-to-administer composition is synonymous with ready-to- infuse or ready-to-inject and it is suitable to be administered directly to the patient.

As used herein, the terms “pharmaceutical composition”, “pharmaceutical formulation”, “composition” and “formulation” are used interchangeably.

In an aspect, a ready-to-administer product/formulation according to the present disclosure is stable at a temperature of from 2°C to 8°C for a certain period of time.

In an aspect, a ready-to-administer product/formulation according to the present disclosure is stable under room temperature conditions for a certain period of time. The term “room temperature” used herein, is from 20 °C to 26 °C.

In an aspect, a ready-to-administer product/formulation according to the present disclosure is stable at 40°C for a certain period of time.

In an aspect, the product/formulation described herein is stable over time periods of 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 certain specified temperature conditions. The skilled person will acknowledge that a composition comprising an active pharmaceutical ingredient may be stored at refrigerated conditions or at about room temperature conditions. When referring to “certain specified temperature conditions”, it is to be understood to include refrigerated conditions at 2-8°C and room temperature conditions at 20°C to 26°C.

The term “certain period of time” or “relatively long periods” used herein covers the above time periods.

The term “stability”, “chemical stability” or “stable” intends to mean that the product, composition or formulation exhibits an acceptable amount of phenylephrine being present, or not more than a certain amount of phenylephrine has degraded after a certain period of time. Accordingly, in a stable product, solution or formulation unacceptable degradation of API is avoided.

Stability can be presented as the purity of phenylephrine in a product/composition according to the disclosure. If the product, formulation or composition initially contains phenylephrine in a certain purity, the stability of the product, formulation or composition will be reflected by a decrease in the chromatographic purity of phenylephrine in the product, formulation or composition over time, where a stable product, solution or composition would contain the phenylephrine in a specified chromatographic purity after a predetermined time period.

In an aspect no more than 10% of purity decrease/drop of phenylephrine in the pharmaceutical formulation, determined by liquid chromatography, e.g., HPLC, UPLC, LC/MS.

For example, a stable composition can be one which has not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, of purity decrease/drop of phenylephrine after a predetermined time period.

When describing stability of a pharmaceutical product, formulation or composition, as little degradation of the active ingredient as possible is of course an important factor and aimed for. However, another important factor is the formation of impurities, which may be formed by degradation of the active ingredient.

In the tables below, some degradation impurities of phenylephrine are identified based on their relative retention time (RRT) in the HPLC chromatogram, these impurities are believed to be degradation products related to oxidation of phenylephrine. The inventors have found that the main oxidative impurities are the impurity RRT 0.66 and impurity RRT 0.85 shown in the examples below.

Accordingly, “stability” may also be defined by the amount of total or specific impurities generated after a certain period of time. The amount of impurities being present may be expressed as a percentage, for example as a peak-area percentage of a HPLC chromatogram or calculated according to standard solution. As used herein, a drop in phenylephrine purity is measured from the time of preparation of the formulation and storage in a container through the specified time, e.g., 3 months and 6 months. In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.80 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.7, 0.75 or 0.80 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.60 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.60 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.35, 0.40, 0.45, 0.50, 0.55 or 0.60 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.45 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 1 .50 %.

In an aspect the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45 or 1.50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.95 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 1 .50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45 or 1.50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.60 %. In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.80 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.40 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.55 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.25, 0.30, 0.35, 0.40, 0.45, 0.50 or 0.55 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.30 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 1 .50 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1 .00, 1 .05, 1 .10, 1 .15, 1 .20, 1 .25, 1 .30, 1 .35, 1 .40, 1 .45 or 1 .50 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.80 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 1 .00 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95 or 1 .00 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, is not more than 0.50 %. In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.80 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.7, 0.75 or 0.80 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.60 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.60 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.35, 0.4, 0.45, 0.50, 0.55 or 0.60 %.

In an aspect, the drop in phenylephrine purity in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.45 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 1 .50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45 or 1.50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.95 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 1 .50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1 .00, 1 .05, 1 .10, 1 .15, 1 .20, 1 .25, 1 .30, 1 .35, 1 .40, 1 .45 or 1 .50 %.

In an aspect, the drop in phenylephrine purity in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.60 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.80 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80 %.

In an aspect, the amount total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.40 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.55 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.25, 0.30, 0.35, 0.40, 0.45, 0.50 or 0.55 %.

In an aspect, the amount of total impurities in the formulation after 3 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.30 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 1 .50 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1 .25, 1 .30, 1 .35, 1 .40, 1 .45 or 1 .50 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.80 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 1 .00 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95 or 1 .00 %.

In an aspect, the amount of total impurities in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers with an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.50 %.

The stability of the solutions, formulations and compositions may also be expressed in terms of concentration or absolute amount of an impurity or combinations of impurities.

In an aspect, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.50 %.

In an aspect, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, is not more than 0.25, 0.30, 0.35,0.40, 0.45 or 0.50 %.

In an aspect, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.50 %.

In an aspect, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius, in PVC-free plastic containers without an overwrap, in a formulation where the phenylephrine concentration is from 0.15 to 0.25 mg/ml or the concentration is 0.16 mg/ml or 0.20 mg/ml, is not more than 0.25, 0.30, 0.35,0.40, 0.45 or 0.50 %.

In addition to chemical stability, the appearance of the formulation may be monitored.

Appearance includes visual inspection of precipitation, clarity, and color of the formulation. Color can also be determined spectrophotometrically by using the L*a*b* color space method and calculating the AE in accordance with USP <1061 >.

As used herein, the terms “secondary packaging” and “overwrap” are used interchangeably.

To further improve the stability and/or the appearance of the formulations, especially reducing the formation of impurities and formation of color, of the formulations described herein, the bags may be overwrapped with a secondary packaging.

In an aspect, the overwrap comprises a material that provides an oxygen barrier effect. That is, the overwrap on the flexible PVC-free plastic container protects the formulation stored in the container from oxygen.

Thus, in an aspect, the flexible PVC-free plastic container is overwrapped with a secondary packaging. The material for the overwrap may be one that has a low oxygen permeability. In an aspect, the overwrap is an aluminum pouch in which the flexible PVC-free plastic container containing the ready-to-administer injectable formulation, is placed. After placement of the container inside the aluminum pouch, the aluminum pouch is sealed. Prior to sealing, the amount of oxygen in the secondary packaging, e.g., the aluminum pouch, may be removed or significantly reduced by applying a vacuum to the secondary packaging. Alternatively, an oxygen absorber or scavenger may be placed in the secondary packaging to help remove or decrease the level of dissolved oxygen in the packaging. There are many types of oxygen absorbers available on the market. The oxygen absorber or scavenger may be enclosed in a porous sachet or packet, but it may also be part of the secondary packaging, in which case the placing of the oxygen absorber in the secondary packaging is of course not needed.

In an aspect, the flexible PVC-free container comprises a degassed/deaerated composition. In an aspect, the flexible PVC-free plastic container is overwrapped with an overwrap in which an oxygen absorber or scavenger is placed.

In one aspect, the ready-to-administer formulation is contained in a flexible PVC plastic container that is overwrapped with an overwrap in which an oxygen absorber or scavenger is placed.

In an aspect, the flexible PVC-free plastic container is overwrapped with an overwrap wherein there is no oxygen absorber or scavenger placed. In one aspect, the ready-to-administer formulation is contained in a flexible PVC plastic container that is overwrapped with an overwrap, wherein there is no oxygen absorber or scavenger is placed.

In an aspect, the flexible PVC-free plastic container containing the ready-to-administer formulation is not overwrapped.

As described herein the ready-to-administer phenylephrine formulations are contained in a flexible PVC-free plastic container. Exemplary flexible PVC-free plastic containers are made of PVC-free polyolefins, such as polyethylene, polypropylene, copolymers and derivatives thereof, with or without other additives. Examples of marketed PVC-free plastic containers, e.g., bags that could be used are the Nexcel™ M312A or Infuflex 7233 bag.

In an aspect, the formulation is contained in a PVC-free plastic container having 3-6 layers of different polymers, wherein the inner layer comprises an ethylene-propylene copolymer.

In another aspect, the formulation is contained in a PVC-free plastic container having 3-6 layers of different polymers, wherein the inner layer comprises polypropylene.

In an aspect the polypropylene may be chemically modified.

In an aspect, the formulation is contained in a PVC-free plastic container, wherein the inner layer consists of ethylene-propylene copolymer.

In an aspect, the formulation is contained in a PVC-free plastic container, wherein the inner layer comprises an ethylene-propylene copolymer.

In an aspect, the formulation is contained in a PVC-free plastic container, wherein the inner layer consists of polypropylene.

In an aspect the polypropylene may be chemically modified.

In an aspect, the formulation is contained in a PVC-free plastic container, wherein the inner layer comprises a polypropylene.

In an aspect the polypropylene may be chemically modified.

In an aspect, the formulation is contained in a PVC-free plastic container, where the inner layer consists of polyolefin, styrene-block copolymer.

In an aspect, the formulation is contained in a PVC-free plastic container, where the inner layer comprises a polyolefin, styrene-block copolymer.

In an aspect, the products and formulations are produced under conditions in which dissolved oxygen in the formulation is removed or significantly reduced to levels in the range of parts per billions (ppb). The dissolved oxygen in the formulation may be removed prior to filling the formulation into the flexible PVC-free plastic container. This removal of oxygen may be performed by deaerating or degassing the formulation by bubbling or blowing the composition with a modified atmosphere, such as, e.g., an inert gas. Examples of inert gasses include nitrogen, argon, and mixtures thereof. The removal or reduction of oxygen by deaeration or degassing may also be performed on the aqueous solvent before the phenylephrine, tonicity agent and pH adjusting agent are added to the aqueous solvent.

In an aspect, the level of dissolved oxygen in the formulation is 2.0 ppm or lower.

The disclosure also provides processes for manufacturing or preparing product comprising phenylephrine or a pharmaceutically acceptable salt of phenylephrine. The process comprises a) providing water in a tank; b) adding excipients such as a tonicity agent, a pH adjusting agent, or a combination thereof, to the solution; c) adding the phenylephrine or salt thereof to the solution and mixing until the phenylephrine is dissolved; d) measuring the pH and if needed further adjusting the pH to reach the targeted pH of the formulation; e) making up the final batch volume by adding in more water to the solution; f) filtering the solution and filling the solution into flexible PVC-free plastic containers; g) sealing the flexible PVC-free plastic containers, and h) sterilizing the flexible PVC-free plastic containers. Sterilization can for example be done by autoclaving.

If a filtration step is applied to the aqueous formulation before filling it into the flexible PVC- free plastic container, this step may be performed by passing the aqueous formulation through a sterilizing grade filter. Passage may be performed by pressurizing the solution with inert gas.

Before the composition is filled into a flexible PVC-free plastic container, the container may be flushed with an inert gas such as, e.g., nitrogen, argon, or a mixture thereof, to remove oxygen, or a vacuum may be applied to the container to remove oxygen.

After filing the aqueous formulation into a flexible PVC-free plastic container, the formulation may be overlaid with a modified atmosphere in order to minimize the volume of residual oxygen in the headspace of the container, before closure of the container. Closure of the container is done either by sealing or plugging the port of the container. In an aspect, the atmosphere of the flexible PVC-free plastic container is not exchanged with an inert atmosphere prior to filling the composition into the flexible PVC-free plastic container.

The steps of preparing and filtering the composition and filling it into a flexible PVC-free plastic container may all be performed in a modified atmosphere, such as, e.g., in nitrogen, argon, or a mixture thereof.

Optionally, the PVC-free bag comprising the aqueous phenylephrine formulation can be overwrapped with a secondary packaging. The overwrap can for example be a tube wherein the PVC-free bag comprising the aqueous phenylephrine formulation is placed and the tube is sealed in both ends. The overwrap can also be two sheets wherein the PVC-free bag comprising the aqueous phenylephrine formulation is placed in between the two sheets and the two sheets are sealed on all four edges.

Optionally the amount of oxygen in the secondary packaging, is removed or significantly reduced by applying a vacuum to the secondary packaging prior to sealing. Alternatively, an oxygen absorber or scavenger is placed in the secondary packaging to help remove or decrease the level of dissolved oxygen in the packaging.

"Pharmaceutically acceptable" indicates that the substance or composition must be compatible, chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

All of the numbers used herein are modified by the term “about.” This means that each number includes minor variations as defined ±10% of the numerical value or range in question.

In an aspect, the formulation in the product is administered parenterally.

In an aspect, the formulation is used to increase blood pressure in adults with clinically important hypotension resulting primarily from vasodilation, in such settings as septic shock or anesthesia.

EXAMPLES

The preparation of the formulations is described for formulations having a phenylephrine HCI content of 0.2 mg/ml, however formulations having other concentrations of phenylephrine, such as for example 0.16 mg/ml are prepared in a similar manner. Formulation 1 :

900 mL of water was purged with nitrogen to a dissolved oxygen level of 2.0 ppm or lower. 9 g of sodium chloride was added to the purged water and mixed until dissolved. The pH was adjusted to a target pH of 4.0 using 1 M solution of HCL

0.200 g of phenylephrine hydrochloride was then added to the solution and mixed until dissolved.

The pH was measured and, if needed, the pH was further adjusted with 1 M hydrochloric acid to reach the target pH of 4.0. If needed, more water was added to the solution to make up the volume to a total of 1000 ml.

The solution was filtered through a 0.22 pm filter and filled into flexible PVC-free plastic bags. The bags were sealed and autoclaved in an autoclave under conditions of 121 °C/15min with an overpressure of 0.7 bar.

Formulation 2:

900 mL of water was purged with nitrogen to a dissolved oxygen level of 2.0 ppm or lower.9 g of sodium chloride was added to the purged water and mixed until dissolved. The pH was adjusted to a target pH of 4.0 by using 1 M solution of tartaric acid.

The pH was measured and if needed, the pH was further adjusted with 1 M tartaric acid to reach the target pH of 4.0. If needed, more water was added to the solution to make up the volume to a total of 1000 ml.

The solution was filtered through a 0.22 pm filter and filled into PVC-free plastic bags.

The bags were sealed and autoclaved in an autoclave under conditions of 121 °C/15min with an overpressure of 0.7 bar.

Comparison formulation:

900 mL of water was purged with nitrogen to a dissolved oxygen level of 2.0 ppm or lower.9 g of sodium chloride was added to the purged water and mixed until dissolved. The pH was adjusted to a target pH of 4.0 by using 1 M solution of citric acid.

0.200 g of phenylephrine hydrochloride was then added to the solution and mixed until dissolved. The pH was measured and if needed, the pH was further adjusted with 1 M citric acid to reach the target pH of 4.0. If needed, more water was added to the solution to make up the volume to a total of 1000 ml.

The solution was filtered through a 0.22 pm filter and filled in PVC-free plastic bags.

The bags were sealed and autoclave in an autoclave under conditions of 121 °C/15min with an overpressure of 0.7 bar.

Analytical methods

1 . HPLC Assay method

Mobile phase A: Phosphoric acid and water (1 :1000)

Mobile phase B: Acetonitrile

The gradient of mobile phases is shown below.

Standard solution: 0.1 mg/mL of Phenylephrine Hydrochloride RS in water.

Sample solution: Nominally 0.1 mg/mL of phenylephrine hydrochloride

Chromatographic system

Mode: LC

Detector: UV 273nm.

Column: 4.6 x 15cm; 2.6pm packing L1

Column temperature: 35°C

Flow rate: 1 .0 mL/min

Calculation

Calculate the percentage of the labeled amount of phenylephrine hydrochloride. 100

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)

2. HPLC Impurities method

Mobile phase A, Mobile phase b, gradient of mobile phases and Sample solution are the same as mentioned above in the HPLC Assay method

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 pg/mL of Phenylephrine HCI RS in water

Standard Solution: 0.0002 mg/mL of Phenylephrine HCI RS in water

Chromatographic system is the same a mentioned above in the HPLC Assay method except that the detector is UV 215nm.

In the formulations including tartaric acid a UV detector of 273nm was used to calculate the degradation product at RRT 0.66.

Calculation

Calculate the percentage of each degradation product (see *UV 273nm above):

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 factor, see Table 2.

3. Color spectrophotometric method (L*a*b* color space method) The different formulations are measured by UV/VIS spectrometer like for example Perkin Elmer 650. The different formulations are measured as is without any further preparation.

The total Color Difference AE* is

AE* = [(AL*)2 + (Aa*)2 + (Ab*)2]¹/₂ in which AL*, Aa*, and Ab* are the differences in color coordinates of the specimens being compared.

Color Coordinates

The Color Coordinates, L*, a*, and b* are defined by

L* = 116(Y/Y0)7₃ - 16, a* = 500[(X/X0)¹/₃ - (Y/Y0)¹/₃], and b* = 200[(Y/Y0)¹/₃ - (Z/Z0)¹/₃] in which X0, Y0, and ZO are the tristimulus values of the nominally white or colorless standard, and Y/YO > 0.01 . Usually they are equal to the tristimulus values of the standard illuminant, with Y0 set equal to 100.0. In this case X0 = 98.0 and Z0 = 118.1.

Example 1

Tables 1 a and 1 b show the effect of HCI and tartaric acid on stability compared with citric acid when the formulation is contained in a flexible PVC-free bag with no overwrap.

Table 1 a shows results at 40°C

Table lb shows results at 25°C

Example 2

Table 2 shows the effect of color formation of the formulations when the PVC-free plastic container bags have been overwrapped with a multilayer of polypropylene and polyethylene film with a layer of aluminum foil. In this example the Infuflex 7233 bag has been used as the

PVC-free plastic container.

Table 2

Claims

1 . A product comprising a ready-to-administer injectable formulation, the formulation comprising phenylephrine or a pharmaceutically acceptable salt thereof, a tonicity agent and a pH adjusting agent, wherein the pH adjusting agent is selected from hydrochloric acid, tartaric acid, and mixtures thereof; and wherein the formulation is contained in a flexible PVC-free plastic container.

2. The formulation according to claim 1 , wherein the tonicity agent is sodium chloride.

3. The formulation according to claim 1 , wherein the pH of the formulation is 3.7 to 4.4.

4. The formulation according to claim 3 wherein the pH of the formulation is 4.0.

5. The formulation according to claim 1 wherein the phenylephrine is phenylephrine hydrochloride.

6. The formulation according to claim 1 , wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.15 to 0.25 mg/ml.

7. The formulation according to claim 6, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.16 mg/ml.

8. The formulation according to claim 6 wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.20 mg/ml.

9. The formulation according to claim 2, wherein the concentration of sodium chloride is 9 mg/ml.

10. The formulation according to claim 1 , wherein the pH adjusting agent is hydrochloric acid.

11 . The formulation according to claim 1 , wherein the pH adjusting agent is tartaric acid.

12. The formulation according to claim 1 , wherein the pH adjusting agent is a mixture of tartaric acid and hydrochloric acid.

13. A product comprising a ready-to-administer injectable formulation, the ready-to- administer injectable formulation consisting of phenylephrine or a pharmaceutically acceptable salt thereof, tonicity agent, and a pH adjusting agent, wherein the pH adjusting agent is selected from hydrochloric acid, tartaric acid, and mixtures thereof; and wherein the formulation is contained in a flexible PVC-free plastic container.

14. The formulation according to claim 13, wherein the tonicity agent is sodium chloride.

15. The formulation according to claim 13, wherein the pH of the formulation is 3.7 to 4.4.

16. The formulation according to claim 14, wherein the pH of the formulation is 4.0.

17. The formulation according to claim 13, wherein the phenylephrine is phenylephrine hydrochloride.

18. The formulation according to claim 13, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.15 to 0.25 mg/ml.

19. The formulation according to claim 18, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.16 mg/ml.

20. The formulation according to 18, wherein the concentration of phenylephrine as phenylephrine hydrochloride is 0.20 mg/ml.

21 . The formulation according to claim 14, wherein the concentration of sodium chloride is 9 mg/ml.

22. The formulation according to claim 13, wherein the pH adjusting agent is hydrochloric acid.

23. The formulation according to claim 13, wherein the pH adjusting agent is tartaric acid.

24. The formulation according to claim 13, wherein the pH adjusting agent is a mixture of tartaric acid and hydrochloric acid.