Pharmaceutical formulations of phenylephrine and process of making the same

Abstract

The present disclosure relates to a pharmaceutical batch solution or a pharmaceutical formulation of phenylephrine and method for preparing the same.

Description

PHARMACEUTICAL FORMULATIONS OF PHENYLEPHRINE AND PROCESS OF MAKING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application 63 / 627,360 filed on January 31, 2024, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to a pharmaceutical batch solution or a pharmaceutical formulation of phenylephrine, the drug product or pharmaceutical formulation comprising phenylephrine as an active ingredient, and methods for preparing the same.BACKGROUND

[0003] 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.

[0004] The structure of phenylephrine is given below.

[0005] Phenylephrine is sensitive to oxidation and will normally degrade into several oxidation-related impurities during its shelf life. One such impurity is epinephrine.

[0006] A change of color and / or appearance of particles in the phenylephrine solutions is also an indication of the degradation.

[0007] A change of color of phenylephrine is accelerated by light, but it can occur over time even in light-protected phenylephrine solutions.

[0008] Phenylephrine may also degrade during the process of preparing the phenylephrine formulation, i.e., the compounding process. It has been shown that variouscompounding processes may result in pharmaceutical batch solutions having different impurity profiles. Various compounding processes may also affect the stability of the final phenylephrine formulation. It has been further shown that contact with equipment comprising stainless steel, a material commonly used in pharmaceutical manufacturing plants, during the compounding process, may increase the content of metal induced oxidation impurities in the pharmaceutical batch solution and respective phenylephrine formulation.

[0009] Therefore, there is a need for development of a compounding process for phenylephrine that generates pharmaceutical batches and phenylephrine formulations having low degradation.SUMMARY

[0010] The present disclosure relates to a compounding process for preparing a pharmaceutical batch solution of a drug product or a pharmaceutical formulation, the drug product or pharmaceutical formulation comprising phenylephrine as an active ingredient.

[0011] In certain embodiments, the compounding process comprises (i) dissolving phenylephrine and an optional excipient in water to provide a pharmaceutical batch solution; (ii) adjusting pH with a pH adjusting agent; (iii) holding the pharmaceutical batch solution for a period of time until filling the pharmaceutical batch solution into containers; and (iv) filling the pharmaceutical batch solution into the containers, wherein at least one of steps i) to iii) is performed in cold conditions.

[0012] In an aspect, the compounding process is completed in less than 7 days.

[0013] In an aspect, cold conditions are defined by a temperature of the pharmaceutical batch solution lower than 20°C.

[0014] In an aspect, cold conditions are defined by a temperature of the pharmaceutical batch solution not exceeding 15°C.

[0015] In an aspect, the present disclosure relates to a pharmaceutical batch solution or a pharmaceutical formulation comprising phenylephrine, prepared by the process described herein.DETAILED DISCLOSURE (INCLUDING DEFINITIONS)

[0016] Various embodiments of the present disclosure relate to a compounding process for preparing a pharmaceutical batch solution of a drug product or a pharmaceutical formulation, the drug product or pharmaceutical formulation comprising phenylephrine as an active ingredient.

[0017] In an aspect, the compounding process for preparing a pharmaceutical batch solution of a drug product or a pharmaceutical formulation comprising phenylephrine comprises: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution; b) adjusting pH to reach a targeted pH; and c) holding the pharmaceutical batch solution until filling into a container; wherein at least one of steps a), b) and c) is done under cold conditions.

[0018] In another aspect, the compounding process for preparing a pharmaceutical batch solution of a drug product or a pharmaceutical formulation comprising phenylephrine comprises: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH; and b) holding the pharmaceutical batch solution until filling into a container; wherein at least one of steps a) and b) is done under cold conditions.

[0019] In an aspect, the compounding process comprises: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution; b) adjusting pH to reach a targeted pH; c) holding the pharmaceutical batch solution for a period of time until filling into a container; and d) filling the pharmaceutical batch solution into the container; wherein at least one of steps a), b) and c) is done under cold conditions.

[0020] In an aspect, the compounding process comprises: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH;b) holding the pharmaceutical batch solution for a period of time until fdling into a container; and c) filling the pharmaceutical batch solution into the container; wherein at least one of steps a) and b) is done under cold conditions.

[0021] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution; b) adjusting pH to reach a targeted pH; c) holding the pharmaceutical batch solution for a period of time until filtering the pharmaceutical batch solution; and d) filling the pharmaceutical batch solution into a container; wherein the pharmaceutical batch solution at least in step c) is in contact with stainless steel, and wherein at least one of steps a), b) and c) is done under cold conditions.

[0022] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH; b) holding the pharmaceutical batch solution for a period of time until filtering the pharmaceutical batch solution; and c) filling the pharmaceutical batch solution into a container; wherein the solution at least in step c) is in contact with stainless steel, and wherein at least one of steps a) and b) is done under cold conditions.

[0023] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution; b) adjusting pH to reach a targeted pH; c) filtering the pharmaceutical batch solution; d) holding the pharmaceutical batch solution for a period of time until filing the pharmaceutical batch solution into a container; and d) filling the pharmaceutical batch solution into a container;wherein the pharmaceutical batch solution at least in step d) is in contact with stainless steel, and wherein at least one of steps a), b), c) and d) is done under cold conditions.

[0024] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH; b) fdtering the pharmaceutical batch solution; c) holding the pharmaceutical batch solution for a period of time until filing the pharmaceutical batch solution into a container; and d) filling the pharmaceutical batch solution into a container; wherein the solution at least in step c) is in contact with stainless steel, and wherein at least one of steps a), b) and c) is done under cold conditions.

[0025] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution; b) adjusting pH to reach a targeted pH; c) making up to the final batch volume of the pharmaceutical batch solution; and d) holding the pharmaceutical batch solution for a period of time until filling into a container; wherein at least one of steps a), b), c) and d) is done under cold conditions.

[0026] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH; b) making up to the final batch volume of the pharmaceutical batch solution; and c) holding the pharmaceutical batch solution for a period of time until filling into a container; wherein at least one of steps a), b) and c)is done under cold conditions.

[0027] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution;b) adjusting pH to reach a targeted pH; c) optionally, making up to a final batch volume of the pharmaceutical batch solution; d) holding the pharmaceutical batch solution for a period of time until filling into a container; and e) filling the pharmaceutical batch solution into the container; wherein at least one of steps a), b), c) and d) is done under cold conditions.

[0028] In an aspect, the compounding process consists of the following steps: a) dissolving phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH; b) optionally, making up to a final batch volume of the pharmaceutical batch solution; c) holding the pharmaceutical batch solution for a period of time until filling into a container; and d) filling the pharmaceutical batch solution into the container; wherein at least one of steps a), b) and c) is done under cold conditions.

[0029] Adjusting the pH may be done before or after the step of dissolving phenylephrine and / or optional excipients in water. Making up the final batch volume can be also performed when dissolving phenylephrine and an optional excipient in water or when adjusting the pH.

[0030] In an aspect, the compounding process is performed in such a way that in at least in one step of the compounding process the solution is in contact with stainless steel or any other material comprising or consisting of iron. In an aspect, the holding step of the compounding process is performed in such way that the solution is in contact with stainless steel or any other material comprising or consisting of iron. In an aspect, the compounding process is performed in such a way that the solution is in contact with stainless steel. Typically, stainless steel used in pharmaceutical compounding processes is 316 stainless steel.

[0031] In an aspect, the compounding process is completed in less than one week. In an aspect, the compounding process is completed in less than 7 days, less than 6 days, less than 5 days, or less than 4 days. In an aspect, the compounding process is completed in less than 72 hours, less than 60 hours, less than 48 hours, less than 36 hours, less than 24 hours, or less than 12 hours.

[0032] In an aspect, during the compounding process, the solution is in contact with stainless steel for not more than one week. In an aspect, during the compounding process, the solution is in contact with stainless steel for not more than 6 days, not more than 5 days, or not more than 4 days. In an aspect, during the compounding process, the solution is in contact with stainless steel for not more than 72 hours, not more than 60 hours, not more than 48 hours, not more than 36 hours, not more than 24 hours, not more than 12 hours, not more than 4 hours, not more than 2 hours, and not more than 1 hour. In an aspect, during the compounding process, the solution is in contact with stainless steel for not more than 24 hours.

[0033] In an aspect, the compounding process may include filtering the pharmaceutical batch solution. Filtering may be performed after the holding step of the compounding process and before filling of the pharmaceutical batch formulation into a container.

[0034] In an aspect, the pharmaceutical batch solution is filtered and then held in the equipment comprising stainless steel for a period of time before being filled into a container. In an aspect, the pharmaceutical batch solution is held in the equipment comprising stainless steel for a period of time and is then only filtered and filled into containers.

[0035] In an aspect, filtering is performed using gas to pressurize the pharmaceutical batch solution and pass it through a filter. In an aspect, the pressurizing gas may be an inert gas. In an aspect, the inert gas may be nitrogen.

[0036] In an aspect, filtering may be performed by passing the pharmaceutical batch solution through a filter. In an aspect, the filter through which the pharmaceutical batch solution is passed has pore size in the range from 0.1 micrometers to 1.0 micrometers.

[0037] In an aspect, filtering may be performed in such a way that the pharmaceutical batch solution is in contact with stainless steel.

[0038] In an aspect, the step of holding (hold time) of the pharmaceutical batch solution before filling into a container may be from 0 minutes to 72 hours. In an aspect, the hold time may be 24 hours. In an aspect, the hold time before filling the solution into a container may be not more than 0 minutes, 0.5 minutes, 1 minute, 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 18 hours, 22 hours, or 24 hours. In an aspect, the hold time before filling the solution into a container is not more than 24 hours. In an aspect, the hold time before filling the solution into a container is not more than 36 hours. In an aspect, the hold time before filling thesolution into a container is not more than 48 hours. In an aspect, the hold time between filtering the pharmaceutical batch solution and filling the solution into a container is not more than 60 hours. In an aspect, the hold time between filtering the pharmaceutical batch solution and filling the solution into a container is not more than 72 hours. In an aspect, the hold time before filling the solution into a container is not more than 165 hours. In an aspect, the hold time between filtering the pharmaceutical batch solution and filling the solution into a container is not more than 165 hours.

[0039] In an aspect, cold conditions are defined by a temperature of solution lower than 20°C. In an aspect, cold conditions are defined by a temperature of solution not exceeding 18°C. In an aspect, cold conditions are defined by a temperature of solution not exceeding 15°C. In an aspect, cold conditions are defined by temperature of solution not exceeding 18°C, 17°C, 16°C, I5°C, 14°C, 13°C, 12°C, 11°C, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C. In an aspect cold condition is defined as refrigerated conditions, i.e., 2- 8°C.

[0040] In an aspect, all steps of the compounding process are done under cold conditions.

[0041] In an aspect, in at least one step of the compounding processes, the exposure to oxygen or oxygen content in the pharmaceutical batch solution may be reduced. The oxygen content in the pharmaceutical batch solution may be reduced compared to normal atmosphere of about 8 ppm. For example, the oxygen exposure or content might be reduced by overlaying the pharmaceutical batch solution with an inert gas or by purging the pharmaceutical batch solution with an inert gas or by applying a vacuum to the solution. In an aspect, the oxygen content might be reduced under the nitrogen purging of the solution. In an aspect, the oxygen content may be reduced to less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than, 3 ppm, less than 2 ppm, or less than 1 ppm.

[0042] In an aspect, the oxygen content in the pharmaceutical batch solution is reduced compared to normal atmosphere of about 8 ppm during the entire compounding process.

[0043] In an aspect, the dissolving step of the compounding process is performed in such way that the solution is in contact with the stainless steel.

[0044] The term “solution” as used herein means any solution included in the compounding process. The term “pharmaceutical batch solution” as used herein meanscompounded solution of phenylephrine formulation by the compounding process herein described.

[0045] The term “phenylephrine” as used herein means phenylephrine or a pharmaceutically acceptable salt of phenylephrine.

[0046] In an aspect, phenylephrine is phenylephrine hydrochloride.

[0047] When specific amounts or ranges of amounts of phenylephrine are given in this application, all values are calculated based on phenylephrine hydrochloride.

[0048] In an aspect, the concentration of phenylephrine in the pharmaceutical batch solution is from 0.05 to 0.5 mg / ml.

[0049] In an aspect, the concentration of phenylephrine may 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.

[0050] In an aspect, the concentration of phenylephrine in the pharmaceutical batch solution is 0.08 mg / ml.

[0051] In an aspect, the concentration of phenylephrine in the pharmaceutical batch solution is 0.16 mg / ml. In an aspect, the concentration of phenylephrine in the pharmaceutical batch solution is 0.20 mg / ml. In an aspect, the concentration of phenylephrine in the pharmaceutical batch solution is 0.40 mg / ml.

[0052] Excipients that may be optionally added during the compounding process, may include, but are not limited to, stabilizing agents, pH adjusting agents, buffering agents, antioxidants, chelating agents, osmolality adjusting agents, solvents, and combinations thereof.

[0053] In an aspect, an excipient may be an osmolality adjusting agent. In an aspect, an exemplary osmolality adjusting agent may be, but is not limited to, sodium chloride and / or dextrose.

[0054] In an aspect, sodium chloride is used as an osmolality adjusting agent.

[0055] In an aspect, the concentration of sodium chloride is not more than 10 mg / ml.

[0056] In an aspect, the concentration of sodium chloride is in the range of 8 to 10 mg / ml.

[0057] 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.

[0058] In an aspect, the concentration of sodium chloride is 9 mg / ml.

[0059] Phenylephrine and an optional excipient may be mixed with water in different orders. In an aspect, phenylephrine is first added to water and mixed until dissolved and an optional excipient is then added to solution and mixed.

[0060] In another aspect, an optional excipient is added to water and mixed and then phenylephrine is added to the solution and mixed until dissolved.

[0061] In an aspect, phenylephrine and an optional excipient may be added together to water and mixed. In another aspect, at least one of the optional excipients may be added to water and mixed then phenylephrine may be added to the solution and mixed until dissolved and then at least one optional excipient may be added to the solution and mixed.

[0062] In an aspect, during the step of dissolving phenylephrine in the water (dissolving step), the oxygen content in solution is reduced compared to normal atmosphere of about 8 ppm. For example, the oxygen content may be controlled by overlaying the solution with an inert gas or by purging the solution with an inert gas or by applying a vacuum to the solution. In an aspect the dissolving step of phenylephrine and optional excipient may be done under a nitrogen purging of the solution. In an aspect, the oxygen content in the solution may be reduced to less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than, 3 ppm, less than 2 ppm, or less than Ippm.

[0063] In an aspect, cold conditions during the dissolving step are defined by a temperature not exceeding 15°C. In an aspect, cold conditions are defined by a temperature not exceeding I5°C, 14°C, 13°C, 12°C, 11°C, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C. In an aspect cold condition is defined as refrigerated conditions, i.e., 2- 8°C.

[0064] In an aspect, the pH adjusting step of the compounding process is performed in such way that the solution is in contact with stainless steel.

[0065] In an aspect, the pH adjusting step may be performed before dissolving phenylephrine in the solution. In an aspect, the pH adjusting step may be done after dissolvingphenylephrine and optional excipient into the solution. In an aspect, the pH adjusting step may be done before dissolving at least one optional excipient into the solution. In an aspect, the pH adjusting step may be done after dissolving phenylephrine and optional excipients into the solution.

[0066] In an aspect, the pH of the pharmaceutical batch solution is in the range of 3.5 to 4.5. In another aspect, the pH is in the range of 3.7-4.4. In another 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, 3.9-4.2 or 3.9-4.1. In yet another aspect, the pH is 4.0.

[0067] In an aspect, the pH of the pharmaceutical batch solution may be 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4 or 4.5.

[0068] “pH” is the conventional measurement unit of hydrogen ion activity in a solution at room temperature unless another temperature is specified.

[0069] In an aspect, the disclosed pH values are targeted pH values of the pharmaceutical batch solution after completing the compounding process.

[0070] In an aspect, the concentration of the pH adjusting agent should be in a range to adjust the pH of the pharmaceutical batch solution in the specific range.

[0071] In an aspect, the pH of the pharmaceutical batch solution should be adjusted to a pH within the range from 3.5 to 4.5. In an aspect, the pH of the pharmaceutical batch solution should be adjusted to a pH within the range from 3.7 to 4.2.

[0072] In an aspect, the pharmaceutical batch solution comprises a pH adjusting agent.

[0073] In an aspect, the concentration of the pH adjusting agent 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.

[0074] In an aspect, the pH adjusting agent may be a mineral acid or base, or a carboxylic acid or a salt thereof. In an aspect, the pH adjusting agent may be hydrochloric acid, sodium hydroxide, tartaric acid, phosphoric acid, or a mixture thereof.

[0075] In an aspect, the pH adjusting agent is tartaric acid.

[0076] In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to 0.05 mg / ml. In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to 0.035 mg / ml.

[0077] In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to 0.03 mg / ml. In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to 0.025 mg / ml. In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to0.024 mg / ml. In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to0.023 mg / ml. In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to0.022 mg / ml. In an aspect, the concentration of tartaric acid is in the range of 0.001 mg / ml to0.020 mg / ml.

[0078] In an aspect, compounding process comprises:-a step of dissolving an osmolality agent in water;-a step of adjusting the pH to reach a targeted pH of the solution;-a step of dissolving phenylephrine in the solution,-a step of holding the pharmaceutical batch solution for a period of time until fdling into a container; and-a step of filling the pharmaceutical batch solution into containers, where at least one step of the compounding process is done under cold conditions.

[0079] In an aspect, during the pH adjusting step, the oxygen content in the solution may be reduced compared to normal atmosphere of about 8 ppm. For example, the oxygen content might be controlled or reduced by overlaying the solution with an inert gas or by purging the solution with an inert gas or by applying a vacuum to the solution. In an aspect, the oxygen content in the solution may be reduced under nitrogen purging of the solution. In an aspect, the oxygen content may be reduced to less than 8 ppm, less than 7ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than, 3 ppm, less than 2 ppm, or less than 1 ppm.

[0080] In an aspect, after dissolving all components of the pharmaceutical batch solution and pH adjustment, if necessary, additional water is added to make up the final volume.

[0081] In an aspect, making up the final batch volume step of the compounding process is performed in such way that the solution is in contact with stainless steel.

[0082] In an aspect, during making up the final batch volume step, the oxygen content in solution may be reduced compared to normal atmosphere of about 8 ppm. For example, the oxygen content might be reduced by overlaying the solution with an inert gas or by purging the solution with an inert gas or by applying a vacuum to the solution. In an aspect, the oxygencontent may be reduced under nitrogen purging of the solution. In an aspect, the oxygen content may be reduced to less than 8 ppm, less than 7ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than, 3 ppm, less than 2 ppm, or less than 1 ppm.

[0083] In an aspect, holding the pharmaceutical batch solution until filling into the container is performed in such way that the pharmaceutical batch solution is in contact with stainless steel.

[0084] In an aspect, during holding of the pharmaceutical batch solution for a period of time until filling into the container, the oxygen content in the solution may be reduced compared to normal atmosphere of about 8 ppm. For example, the oxygen content might be reduced by overlaying the pharmaceutical batch solution with an inert gas or by purging the pharmaceutical batch solution with an inert gas or by applying a vacuum to the pharmaceutical batch solution. In an aspect, the oxygen content may be reduced under nitrogen purging of the solution. In an aspect, the oxygen content may be reduced to less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than, 3 ppm, less than 2 ppm, or less than 1 ppm.

[0085] In an aspect, the pharmaceutical batch solution may be filled into containers.

[0086] In an aspect, the pharmaceutical batch solution may be in contact with a stainless steel material during filling of pharmaceutical batch solution into containers.

[0087] In an aspect, filling of the pharmaceutical batch solution into containers may be done under nitrogen purging.

[0088] In one aspect, the pharmaceutical batch solution is filled into a suitable container. In one aspect, the container may be a vial or a bag. In one aspect, the container is a single unit dose container. In one aspect, the container is a single unit dosage container suitable or ready for intravenous (IV) administration. In an aspect, the ready-to-administer phenylephrine formulation is stored in a container used for intravenous administration, which is preferably plastic based. In an aspect, the formulation is filled in a flexible plastic bag fitted with an administration port.

[0089] Ready-to-administer means a formulation that does not need any dilution prior to administration to the patient. A ready-to-administer formulation 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 term “flexible plastic container” means flexible polymeric infusion bags or other polymeric containers. Exemplary flexible plastic containers are made of polyolefins, such aspolyethylene, polypropylene, copolymers and derivatives thereof, with or without other additives. Examples of marketed films used for manufacture of said plastic containers, e.g., films that could be used are the Nexcel™ M312A, Infuflex 7233, Polycine APP114, Inerta® or MF518.

[0090] In an aspect, the phenylephrine formulation is contained in a plastic container having one or more polymer layers.

[0091] In another aspect, the phenylephrine formulation is contained in a plastic container having 3-6 polymer layers, wherein the inner layer comprises polypropylene or co-polymers thereof.

[0092] In an aspect, the polypropylene may be chemically modified.

[0093] In an aspect, the phenylephrine formulation is contained in a plastic container, wherein the inner polymer layer consists of an ethylene-propylene copolymer.

[0094] In an aspect, the phenylephrine formulation is contained in a plastic container, wherein the inner polymer layer comprises an ethylene-propylene copolymer.

[0095] In an aspect, the phenylephrine formulation is contained in a plastic container, wherein the inner polymer layer consists of polypropylene.

[0096] In an aspect, the polypropylene may be chemically modified.

[0097] In an aspect, the phenylephrine formulation is contained in a plastic container, wherein the inner polymer layer comprises a polypropylene.

[0098] In an aspect, the polypropylene may be chemically modified.

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

[0100] In an aspect, the formulation is contained in a plastic container, where the inner polymer layer comprises a polyolefin, and / or a styrene-block copolymer.

[0101] In one aspect, the formulation is packaged in a container produced by blow-fill-seal technology or form-fill-seal technology. In one aspect, the material of the container is PVC-free. In one aspect, the formulation is not in contact with the PVC material of the container.

[0102] In an aspect, the pharmaceutical batch solution may be sterilized by different sterilization methods, such as terminal sterilization or sterilizing filtration.

[0103] In one aspect, pharmaceutical batch solutions according to the disclosure may be aseptically filled into sterilized containers. Aseptic manufacture of the sterile product means that the packaging material is sterilized and then a sterile product is filled into the packaging material under aseptic conditions. Sterilization of flexible plastic containers may be done by different irradiation techniques for example electron beam (beta irradiation), gamma- and X-ray irradiation.

[0104] In one aspect, the pharmaceutical batch solution may be sterilized by filtration through a 0.2 pm filter followed by aseptic filling of the pharmaceutical batch solution into sterilized flexible plastic containers.

[0105] In terminal sterilization, autoclaving is normally used. In an aspect, autoclaving is a technique where the product is placed under pressurized saturated steam having set temperature of up to 121 degrees Celsius, for a period of time that can vary but would normally be up to 15 minutes, in some cases even more.

[0106] In an aspect, the flexible plastic container may be overwrapped. In an aspect, the overwrap is an aluminum pouch in which the flexible plastic container containing the ready-to- administer phenylephrine formulation, is placed. After placement of the container inside the aluminum pouch, the aluminum pouch is sealed. In one aspect, the ready -to-administer phenylephrine formulation is contained in a flexible plastic container that is overwrapped with an overwrap, wherein the overwrap comprises no oxygen absorber or scavenger.

[0107] In one aspect, the ready -to-administer phenylephrine formulation is contained in a flexible plastic container that is overwrapped with an overwrap, wherein the overwrap comprises an oxygen absorber.

[0108] In an aspect, the flexible plastic container containing the ready-to-administer phenylephrine formulation is not overwrapped.

[0109] In an aspect, the headspace of the container is purged with an inert gas. In an aspect the headspace of the container is filled with nitrogen.

[0110] In another aspect, no measures are taken to reduce the amount of oxygen in the formulation or in the headspace of the container.

[0111] If not stated otherwise, a time period of stability is calculated from the time point in which the compounding process is completed until a predetermined time period. In an aspect,the time point in which the compounding process is completed is equal to the start of fdling of the pharmaceutical batch solution into the container.

[0112] In an aspect, the present disclosure relates to a pharmaceutical batch solution or a ready -to-administer pharmaceutical phenylephrine formulation, where the pharmaceutical batch solution or the ready -to-administer pharmaceutical phenylephrine formulation is prepared by the process described herein.

[0113] As used herein, the terms “pharmaceutical batch solution”, “pharmaceutical composition”, “pharmaceutical formulation”, “composition” and “formulation” are used interchangeably.

[0114] The pharmaceutical batch solution or pharmaceutical formulation prepared by the compounding process described herein may be characterized by a single degradation impurity level not exceeding 0.2%, not exceeding 0.15%, not exceeding 0.1%, not exceeding 0.09%, not exceeding 0.08%, not exceeding 0.07%, not exceeding 0.06%, not exceeding 0.05%, not exceeding 0.04%, not exceeding 0.03%, not exceeding 0.02%, or not exceeding 0.01%, as determined by HPLC.

[0115] Exemplary single degradation impurities of phenylephrine include RRT 0.66 (epinephrine impurity), RRT 0.8, RRT 3.85, and the like.

[0116] The pharmaceutical batch solution or the pharmaceutical formulation prepared by the compounding process may be characterized by a total impurity level not exceeding 1%, not exceeding 0.9%, not exceeding 0.8%, not exceeding 0.7%, not exceeding 0.6%, not exceeding 0.5%, not exceeding 0.4%, not exceeding 0.3%, not exceeding 0.2%, not exceeding 0.1%, not exceeding 0.09%, not exceeding 0.08%, not exceeding 0.07%, not exceeding 0.06%, or not exceeding 0.05%, as determined by HPLC.

[0117] “Total impurity level” refers to the combined total of all measurable degradation impurities in the pharmaceutical batch solution or the pharmaceutical formulation.

[0118] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein does not comprise citric acid.

[0119] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation does not comprise citrate.

[0120] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation does not comprise an acetate buffer.

[0121] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein does not comprise sodium metabisulfite.

[0122] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein does not comprise edetate disodium (EDTA).

[0123] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein does not comprise a chelating agent.

[0124] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein does not comprise an antioxidant.

[0125] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein is stable under room temperature conditions for a certain period of time. The term “room temperature” used herein, is from 20°C to 27°C.

[0126] In an aspect, the pharmaceutical batch solution or ready-to-administer phenylephrine formulation prepared by the process described herein is stable at 40°C for a certain period of time.

[0127] In an aspect, a ready-to-administer phenylephrine formulation prepared by the process described herein is stable over time periods of 7 days (1 week), 14 days (2 weeks), 30 days (1 month), not less than 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, or 24 months or more at certain specified temperature conditions. For example, a stable composition may be one which has not more than 5.0 % of total impurities after a predetermined period of storage at certain specified temperature condition, determined by liquid chromatography. A stable composition may be one which has not more than 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05% of total or in specific individual degradationYlimpurities of phenylephrine after a predetermined time period, determined by liquid chromatography, e.g., HPLC, UPLC, LC / MS. As used herein, an increase in total or in specific impurities is measured from the time of preparation of the formulation to the specified time, e.g., 3 months and 6 months under specified storage conditions.

[0128] In an aspect, a composition has not more than 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05 % of total or specific individual degradation impurities of phenylephrine after a predetermined time period at room temperature.

[0129] In an aspect, a composition has not more than 0.5% of total impurities of phenylephrine after 9 months at room temperature.

[0130] In an aspect, a stable composition is one which has an assay of phenylephrine not less than 90.0% after a predetermined time at predetermined storage conditions, determined by liquid chromatography (e.g., HPLC, UPLC, LC / MS). In an aspect, a stable composition is one which has an assay of phenylephrine not less than 90.0% after 6 months at 40°C determined by liquid chromatography (e.g., HPLC, UPLC, LC / MS). In an aspect, a stable composition shows a reduction of phenylephrine assay during 6 months storage at 40°C of not more than 10.0%, as determined from the difference in assay at the start of the stability study and the assay at a specific stability time point.

[0131] In an aspect, a stable composition shows a reduction of phenylephrine assay during 9 months storage at 25°C of not more than 2.0%, as determined from the difference in assay at the start of the stability study and the assay at a specific stability time point. In yet another aspect, a stable composition shows a reduction of phenylephrine assay during 9 months storage at 25°C of not more than 1.0%, as determined from the difference in assay at the start of the stability study and the assay at a specific stability time point.

[0132] In an aspect, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius is not more than 1% as determined by HPLC.

[0133] In an aspect, the amount of impurity RRT 0.66 in the formulation after 6 months at 40 degrees Celsius is not more than 0.25%, not more than 0.30%, not more than 0.35%, not more than 0.40%, not more than 0.45%, or not more than 0.50% as determined by HPLC.

[0134] In an aspect, the amount of impurity RRT 0.66 in the formulation after 3 months at 40 degrees Celsius is not more than 0.2% as determined by HPLC.

[0135] In an aspect, the amount of impurity RRT 3.85 in the formulation after 6 months at 30 degrees Celsius is not more than 0.25%, not more than 0.30%, not more than 0.35%, not more than 0.40%, not more than 0.45%, not more than 0.50%, not more than 0.60%, not more than 0.70%, not more than 0.8%, not more than 0.9%, not more than 1.0% or not more than 1.5% as determined by HPLC.

[0136] In an aspect, the amount of impurity RRT 0.8 in the formulation after 6 months at 40 degrees Celsius is not more than 0.25%, not more than 0.30%, not more than 0.35%, not more than 0.40%, not more than 0.45%, or not more than 0.50% as determined by HPLC.

[0137] In addition to chemical stability, the appearance of the pharmaceutical batch solution or formulation comprising phenylephrine may be monitored. Appearance includes visual or instrumental inspection of precipitation, clarity, and color of the formulation.

[0138] Color may be determined spectrophotometrically by using the L*a*b* color space method and calculating the AE in accordance with USP <1061>.

[0139] In an aspect AE in not more than 0.5.

[0140] “Pharmaceutically acceptable” indicates that the substance or composition must be compatible, physically, chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0141] In an aspect, the pharmaceutical batch solution or a ready -to-administer phenylephrine formulation prepared by herein described process is administered parenterally.

[0142] In an aspect, the pharmaceutical batch solution or a ready -to-administer phenylephrine formulation prepared by herein described process 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

[0143] The preparation of the pharmaceutical batch solutions and formulations comprising phenylephrine HC1 are described herein.

[0144] The invention is further illustrated by the following non-limiting examples.EXAMPLES 1 - 5

[0145] Pharmaceutical batch solutions comprising phenylephrine were prepared by dissolving phenylephrine and optional excipient(s) in Purified water or Water for Injection under predefined conditions, with a 30 L batch volume in an SS (stainless steel) 316 compounding vessel, having a maximum capacity of 40 L.

[0146] One set of solutions was manufactured at room temperature, while another was manufactured with cooling of the compounding tank to reduce the temperature of the solution in the compounding process. If necessary, the pH was adjusted to a pH of about 4.0 using tartaric acid and / or hydrochloric acid. Sodium chloride was used as the osmolality agent, to adjust to isotonicity. The solution was mixed to ensure homogeneity and water was added to make up to a predefined volume. The pharmaceutical batch solution was then held for a period of 24 hours to 72 hours in the compounding tank. After the holding period, the pharmaceutical batch solution was filtered through a 0.2 pm filter and then filled into flexible bags as unit containers. The filled containers were sterilized in an autoclave, overwrapped, and placed in a suitable stability test chamber for monitoring of product stability at predefined temperatures.

[0147] Assay and level of impurities in the pharmaceutical batch solution were determined after the compounding process was completed. If not otherwise stated, the same point is also characterized as a starting point for monitoring stability of the phenylephrine formulation on different conditions.

[0148] Formulations were then stored at 25°C (room temperature), at 30°C, and at 40°C, and stability was determined at time points such as 1 month, 2 months, 3 months, 6 months, 9 months and further.

[0149] It was expected that the formulations are stable for 1 month, for 2 months, and preferably for not less than 3 months or 6 months at elevated temperature such as up to and including 40°C.

[0150] It was expected that the formulations are stable for not less than 3 and 6 months under room temperature and that this can be extrapolated to indicate that the formulations are stable or stabilized for at least 12 months.ANALYTICAL METHODS

[0151] HPLC Assay methodMobile phase A: Phosphoric acid and water (1 : 1000)Mobile phase B: AcetonitrileThe gradient of mobile phases is shown below.Standard solution: 0. Img / mL of phenylephrine hydrochloride RS in water.Sample solution: Nominally O. lmg / mL of phenylephrine hydrochlorideChromatographic systemMode: LCDetector: UV 273nm.Column: 4.6 x 15cm; 2.6pm packing LIColumn temperature: 35°CFlow rate: 1.0 mL / minCALCULATIONCalculate the percentage of the labeled amount of phenylephrine hydrochloride.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)

[0141] HPLC IMPURITIES METHODMobile 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: O. lmg / 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 HC1 RS in waterStandard Solution: 0.0002 mg / mL of phenylephrine HC1 RS in waterThe chromatographic system is the same as 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 products.CALCULATIONCalculate 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.

[0142] COLOR SPECTROPHOTOMETRIC METHOD (L*A*B* COLOR SPACE METHOD)The different formulations are measured by UV / VIS spectrometer such as, for example, a Perkin Elmer 650. The different formulations are measured as is without any further preparation.The total Color Difference AE* isAE* = [(AL*)2 + (Aa*)2 + (Ab*)2]' / 2 in which AL*, Aa*, and Ab* are the differences in color coordinates of the specimens being compared.COLOR COORDINATESThe Color coordinates, L*, a*, and b* are defined byL* = l lb Y / YOy / s - 16, a* = SOOKX / XOy / s - (Y / Y0)’ / 3], and b* = 200[(Y / Y0)1 / 3- (Z / Z0)‘ / 3] in which X0, Y0, and Z0 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.RESULTS

[0143] Tables 1-2 show the stability of phenylephrine formulations stored at 40°C or 30°C for 6 months. During compounding, for the formulations of the present disclosure, the temperature did not exceed 15 degrees Celsius. The control compounding process has been performed under the room temperature conditions. As shown in tables 1 and 2, reducing the temperature during the compounding steps resulted in a decrease in both individual and total impurities.Table 1 . Stability of phenylephrine formulations stored for 6 months at 40°C, depending on temperature conditions during compounding process.Table 2. Stability of phenylephrine formulations stored for 6 months at 30°C, depending on temperature conditions during compounding process.

[0144] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers. The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if itwere individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein.

[0145] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

Patent claims1. A compounding process of preparing a pharmaceutical batch solution of a drug product or a pharmaceutical formulation, the drug product or pharmaceutical formulation comprising phenylephrine as an active ingredient, wherein the compounding process comprises the following steps: a) dissolving the phenylephrine and an optional excipient in water to provide the pharmaceutical batch solution, wherein the pharmaceutical batch solution has a targeted pH; b) holding the pharmaceutical batch solution for a period of time; wherein at least one of steps a) to b) is done under cold conditions.

2. The compounding process according to claim 1, where the process further comprises a step of filling a container with the pharmaceutical batch solution after the holding step c).

3. The compounding process according to claim 1 or 2, where the process further comprises a step of filtering the pharmaceutical batch solution, where filtering is performed before, during or after the holding step b).

4. The compounding process according to any of claims 1 to 3, where the compounding process is completed in not more than 72 hours.

5. The compounding process according to any of claims 1 to 3, where the period of time in step b) in not more than 72 hours.

6. The compounding process according to any of claims 1 to 5, where the holding step b) of the compounding process is done under cold conditions.

7. The compounding process according to any of claims 1 to 5, where the holding step b) of the compounding process is done under a temperature of not more than 15°C.

8. The compounding process according to any of claims 1 to 5, where steps a) to c) are done under cold conditions.