DESC:STABLE READY-TO-USE PARENTERAL COMPOSITIONS OF PHENYLEPHRINE

FIELD OF THE INVENTION
The present invention relates to a stable ready-to-use parenteral composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Furthermore, the present invention also provides a process for the preparation of the stable ready-to-use parental composition.

BACKGROUND OF THE INVENTION
Phenylephrine is a selective a1 receptor agonist medication. Phenylephrine is a member of the class of phenylethanolamines. Chemically, Phenylephrine is (R)-3-[-1-hydroxy-2-(methylamino) ethyl] phenol.

Phenylephrine hydrochloride is used in injection form to increase blood pressure in adults with clinically important hypotension resulting primarily from vasodilation, in such settings as septic shock or anesthesia.

Phenylephrine hydrochloride in injection form is approved for marketing in the United States as a 10 mg/mL concentrated solution. At this concentration, phenylephrine hydrochloride must be diluted before administration as a bolus intravenous infusion or a continuous intravenous infusion. The need to dilute the solution is inconvenient and introduces opportunities for calculation and compounding confusion that can lead to dosing errors including over dosage. Dilution can also lead to concerns for the stability and introduces opportunities for contamination and the need to preserve the solution from microorganisms. Once diluted, the solution should not be held for more than 4 hours at room temperature or 24 hours under refrigerated conditions.

Several attempts have been made to achieve a stable ready-to-use (RTU) parenteral composition of phenylephrine which are described in various patent and non-patent literature such as:

U. S. Patent No. 11,213,480 discloses a stable, ready-to-use sterile intravenous injection solution of phenylephrine hydrochloride consisting essentially of about 0.05 mg/mL to about 0.15 mg/mL phenylephrine hydrochloride as the only active pharmaceutical ingredient in the solution; about 0.1 mg/mL to about 0.3 mg/mL of edetate disodium (EDTA); sodium chloride; and water; wherein the solution is free of bisulfites or other antioxidants.

U. S. Patent Application Publication No. 20210228507 A discloses a ready-to-administer sterile antioxidant free phenylephrine composition, comprising: phenylephrine or salt thereof at a concentration of equal or less than 0.4 mg/ml; an acetate buffer, wherein the composition has a pH of between 4.5 and 5.5; and an optional metal ion chelator.

U. S. Patent Application Publication No. 20070249566 A1 discloses a phenylephrine solution that includes edetate disodium. The solution has a pH range of approximately 2 to 4.75, with a preferred range from 3 to 4.5 and is substantially free of aldehydes.

The above references disclose that in the course of developing dilute, stable ready-to-use (“RTU”) formulations of phenylephrine hydrochloride, it has been found that anti-oxidants, such as sodium metabisulfite which stabilize the formulation when used in the marketed concentrated formulations do not protect the more dilute RTU formulations from oxidation but actually destabilize the formulation. For example, simply diluting a currently marketed sodium metabisulfite containing 10 mg/mL phenylephrine hydrochloride solution to a ready-to-use concentration does not result in a sufficiently stable formulation. These references disclaim the presence of conventional antioxidants and emphasizes the inclusion of ethylenediaminetetraacetic acid (EDTA) and metal salts thereof.

EDTA inhibits the binding of dihydropyridines-like compounds to calcium channels and also the binding of dihydropyridines-like compounds to brain and cardiac microsomes is inhibited by EDTA indicating both chelating agent and the drug regulate the calcium channels. Intravenous formulations using disodium EDTA can lead to a decline in the concentration of calcium since disodium EDTA binds to soluble calcium ions causing a reduction of calcium. A rapid decline in blood calcium can lead to muscle spasms. It can cause severe hypocalcemia, brachiopods, bronchial spasms, seizures, and even apnea. Also, the specific [3H] nitrendipine (a dihydropyridine calcium channel blocker) binding was reduced by 70-95% due to EDTA treatment to the ileal and aortic smooth muscle and cardiac muscle. Effects on the cardiovascular system, mainly for the conduction block and other arrhythmias, can occur in severe ventricular fibrillation.

Aqueous formulations of phenylephrine are susceptible to degradation through a number of different mechanisms and as a result of several types of stress conditions like agitation, long term storage, pumping, filtration, or unrefrigerated storage. The benzylic hydrogen is acidic and can be deprotonated easily. The hydroxyl group may be oxidized to form a carbonyl moiety conjugated with phenyl group, especially with help of the adjacent basic amino group. Thus, even though various phenylephrine hydrochloride formulations are known in the art, extended stability at low and ready-to-use concentrations is problematic.

There is still a need to design a ready-to-use parenteral composition of phenylephrine that has prolonged stability, efficacy, and reduced side effects. After extensive experimentation and lots of efforts, the inventors of the present invention have developed formulations that are free of harmful ethylenediaminetetraacetic acid and metal salts thereof and comprises safer antioxidants that are optimal, economical, and commercially viable. The formulations of the present invention exhibit excellent storage stability and good tolerance.

OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a stable ready-to-use parental composition comprising therapeutically effective amount of phenylephrine or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a stable ready-to-use parental composition for increasing blood pressure in adults with clinically important hypotension in particular resulting primarily from vasodilation.

Another objective of the present invention is to provide a process for the preparation of the stable ready-to-use parental composition.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof; and
- one or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof; and
- one or more pharmaceutically acceptable excipients selected form the group comprising solubilizing agent(s), cosolvent(s), preservative(s), tonicity agent(s), pH adjusting agent(s), buffering agent(s), viscosity modifying agent(s), antioxidant(s), chelating agent(s), stabilizer(s), solvent(s), bulking agent(s), or combinations thereof,
wherein the pharmaceutical composition is an aqueous solution.

Another aspect of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is an aqueous solution having a pH in the range of 3.0 - 7.0 and is free from EDTA or its pharmaceutically acceptable salts.

Another aspect of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- antioxidant(s); and
- one or more pharmaceutically acceptable excipients,
wherein the composition is an aqueous solution having a pH in the range of 4.5 – 6.5 and is free from EDTA or its pharmaceutically acceptable salts.

Another aspect of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- antioxidant(s); and
- one or more pharmaceutically acceptable excipients,
wherein the composition is an aqueous solution having an initial pH of 5.5 ± 0.5 and is free from EDTA or its pharmaceutically acceptable salts.

Another aspect of the present invention provides a process for preparing a stable ready-to-use parenteral composition comprising:
- adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to water under stirring to obtain a clear solution;
- adding antioxidant to the above solution;
- optionally, adding buffering agent(s), chelating agent(s), tonicity agent(s) and/or preservative(s);
- adding pH adjusting agent(s), if required, to adjust the initial pH of the composition to 5.5 ± 0.5;
- making up the volume to 100% with water;
- filtering and filling aseptically in vials.

Another aspect of the present invention provides a process for preparing a stable ready-to-use parenteral composition comprising:
- adding buffer and antioxidant in water to get a clear solution;
- adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to the solution under stirring to obtain a clear solution;
- optionally, adding tonicity agent(s) and/or preservative(s);
- adding pH adjusting agent(s) to adjust the initial pH of the composition to 5.5 ± 0.5;
- making up the volume to 100% with water;
- filtering and filling aseptically in vials.

The present invention further relates to a stable ready-to-use parenteral composition comprising therapeutically effective amount of phenylephrine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, which is useful for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation, in such settings as septic shock or anaesthesia.

DETAIL DESCRIPTION OF THE INVENTION
The present invention provides a stable ready-to-use parenteral composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” or “a process” includes one or more methods, one or more processes and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

As used herein the term “about” in reference to a numerical value means that variations of 10% above or below the numerical value are within the range as described to the specified value.

The term “therapeutically effective amount” or “effective amount” used interchangeably, is defined to mean the amount or quantity of the active drug, which is sufficient to elicit an appreciable biological response when administered to the patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The term “composition” or “pharmaceutical composition” or “parenteral composition” or “dosage form” or “pharmaceutical formulation” or “formulation” or “parenteral formulation” as used herein synonymously include the pharmaceutical compositions in a form suitable for parenteral administration such as but not limited to sterile aqueous, hydro-alcoholic, or non-aqueous suspension, aqueous, hydro-alcoholic, or non-aqueous solution, or emulsion, liposomes, microparticles, or the like or any other suitable dosage form meant for parenteral administration. Further, parenteral pharmaceutical composition includes pharmaceutical composition for intramuscular, intravenous, sub-cutaneous, and intrathecal administration. In one embodiment, the pharmaceutical composition may be in the form of a unit dose composition or multi-dose composition.

The term “pharmaceutically acceptable” refers to what is physiologically well tolerated by mammals or humans.

The term “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further include alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like. In a preferred embodiment, the salt is hydrochloride salt, i.e., phenylephrine hydrochloride.

The term “stable” according to present invention refers to a composition which is stable on exposure to 40 °C ± 5 °C and 25% ± 5 % RH for a period of six months or 25 °C ± 5 °C and 40% ± 5 % RH for a period of at least 12 months with no signs of degradation such impurities, precipitation, discoloration etc.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component. As pharmaceutical excipients have various functions and contribute to the pharmaceutical composition in many different ways, e.g., solubilisation, dilution, thickening, stabilization, and preservation. The properties that are commonly considered when formulating an active drug substance include bioavailability, ease of manufacture, ease of administration, and stability of the dosage form. Due to the varying properties of the active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored for the active drug substance in order to achieve advantageous physical and pharmaceutical properties.

Suitable “pharmaceutically acceptable excipients” include, without limitation, solubilizing agent(s), cosolvent(s), preservative(s), tonicity agent(s), pH adjusting agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), solvent(s), bulking agent(s), or combinations thereof.

Suitable solubilizing agent(s) include, without limitation, surfactants, lipids, organic liquids/semi-solids, cyclic oligosaccharides/cyclodextrins, phospholipids, or mixtures thereof. When present the solubilizing agent(s) may be employed in an amount ranging from about 0.01% w/v to about 80% w/v of the pharmaceutical composition.

Suitable co-solvent(s) include, without limitation, organic or inorganic solvents selected from the group, but not limited to monohydric or polyhydric alcohols including ethanol, isopropyl alcohol, polyethylene glycol (PEG), propylene glycol (PG), sorbitol, glycerine, acetone, benzyl alcohol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, solketal, glycerol formal, or combinations thereof. When present, cosolvent(s) may be employed in an amount ranging from about 0.01% v/v to about 80% v/v of the pharmaceutical composition or equivalent weight conversion based on the density of the solvent.

The buffering agent(s) may be included in the formulation to prevent pH change/shift under storage conditions. Suitable buffering agent(s) includes, without limitation, to phosphate buffer, acetate buffer, citrate buffer, succinate buffer, borate buffers, tris HCl and amino acids such as glycine, aspartate, histidine, cysteine, tyrosine, phenylalanine, proline, arginine, threonine, serine, valine, isoleucine, lycine, and glutamine. The particular concentration of the buffer will differ, depending on the specific agent employed. Wherein in the present invention, the buffering agent(s) is preferably used in an amount of about 0.01% w/v to about 20% w/v of the pharmaceutical composition more preferably about 0.05 w/v to about 5%.

According to one embodiment of the present invention, the composition is free of buffering agent. In one embodiment, the composition, in particular is free of citrate or acetate buffer.

Suitable tonicity agent(s) includes, without limitation, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, non-ionic diols such as glycerol and propylene glycol, dextrose and/or mannitol, sorbitol. Amount of tonicity agent will vary, depending on the certain agent to be added. When present, the tonicity agent(s) is preferably used in an amount of about 0.01% w/v to about 10% w/v of the pharmaceutical composition.

The compositions of the present invention may include a preservative. Suitable preservative includes, without limitation, benzalkonium chloride (BAC), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, benzyl alcohol, ethanol, phenylmercury nitrate, phenylmercury acetate, thiomerosal, merthiolate, phenylmercuryborate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, butyl-p-hydroxybenzoate, chlorobutanol, sorbic acid, polyquaternary ammonium compounds, or mixtures thereof. Wherein in the present invention, the preservative(s) may be used in an amount of about 0.001% w/v to about 20.0% w/v of the pharmaceutical composition, more preferably about 0.005% w/v to about 1.0% w/v of the pharmaceutical composition.

According to one embodiment of the present invention the composition is free of preservative.

As to chelating agents, any suitable pharmaceutically acceptable chelating agent can be used. Examples include but not limited ethylenediaminetetraacetic acid and metal salts thereof, such as disodium edetate, trisodium edetate, tetrasodium edetate or mixtures thereof. When present, the chelating agent(s) may be added in an amount of about 0.001% w/v to about 10.0% w/v of the pharmaceutical composition.

According to one embodiment of the present invention, the composition is free of chelating agent(s). In one embodiment of the present invention, the composition, in particular is free of ethylenediaminetetraacetic acid and metal salts thereof, such as disodium edetate, trisodium edetate, tetrasodium edetate or mixtures thereof.

Suitable antioxidants includes, without limitation, sodium thiosulfate, sodium bisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, esters of gallic acid, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, tartaric acid, citric acid, fumaric acid, malic acid, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, sodium metabisufite, sodium sulphite, sodium pyrosulphate, methionine, glutamine, thiamine, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof. In a preferred embodiment, the ready-to-use parentral composition comprises antioxidant(s).

The pH adjusting agent is typically a mineral acid or metal hydroxide base including, without limitation, potassium hydroxide, sodium hydroxide, hydrochloric acid, phosphoric acid, or mixtures thereof. These acidic and/or basic pH adjusting agents are added to adjust the formulation to the target pharmaceutically acceptable pH range. Hence, it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

The compositions will typically have a pH in the range of 3.0 to 7.0, preferably 4.5 to 6.5. In more specific embodiment, the initial pH of the composition is adjusted in the range of 5.0 to 6.0, more preferably 5.5 ± 0.2 and the pH of the composition on long term storage, i. e, for shelf life or on exposure to 40°C ± 5 °C and 25% ± 5 % RH for a period of at least 1 month, at least 3 months, at least six months or 25 °C ± 5 °C and 40% ± 5 % RH for a period of at least 3 months, at least six months, at least 12 months is within 0.5 pH units of an initial pH level.

Suitable solvent(s) includes, without limitation, aqueous, hydroalcoholic, or non-aqueous solvent such as purified water, water for injection, bacteriostatic water for injection, sterile water, isotonic saline water, buffered aqueous solution, ethanol, glycerine, or combinations thereof.

The stable ready-to-use parenteral composition of the present invention may further comprise viscosity modifiers.

The viscosity modifier includes but is not limited to glycerol, propylene glycol, polymeric polyols, such as, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 6000), dextrans such as dextran 70, water soluble proteins such as gelatin, polyvinyl alcohols, polyvinylpyrrolidones, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, carbomers, gums such as gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid, agar, carrageenan, shellac, and hyaluronic acid derivatives, dextrans, polyvinyl alcohol, polyacrylic acids, polysaccharides, or combinations thereof. The viscosity modifiers may be present in an amount of about 0.05 to about 10 wt%.

In one embodiment of the present invention, there is a stable ready-to-use parenteral composition comprising equal to or less than 0.1% w/v phenylephrine or a pharmaceutically acceptable salt thereof. More specifically comprising equal to or less than 0.05% w/v, equal to or less than 0.025% w/v, phenylephrine or pharmaceutically acceptable salts thereof, i.e., phenylephrine hydrochloride.

According to another embodiment of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof; and
- one or more pharmaceutically acceptable excipients,
wherein the composition is an aqueous solution having a pH in the range of 3.0 - 7.0 and is free from EDTA or its pharmaceutically acceptable salts.

According to another embodiment of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- antioxidant(s); and
- one or more pharmaceutically acceptable excipients,
wherein the composition is an aqueous solution having a pH in the range of 4.5 – 6.5 and is free from EDTA or its pharmaceutically acceptable salts.

According to another embodiment of the present invention provides a stable ready-to-use parenteral composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- antioxidant(s); and
- one or more pharmaceutically acceptable excipients,
wherein the composition is an aqueous solution having an initial pH of 5.5 ± 0.5 and is free from EDTA or its pharmaceutically acceptable salts.

According to another embodiment of the present invention provides a process for preparing a stable ready-to-use parenteral composition comprising:
- adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to water under stirring to obtain a clear solution;
- adding antioxidant to the above solution;
- optionally, adding buffering agent(s), chelating agent(s), tonicity agent(s) and/or preservative(s);
- adding pH adjusting agent(s), if required, to adjust the initial pH of the composition to 5.5 ± 0.5;
- making up the volume to 100% with water;
- filtering and filling aseptically in vials.

According to another embodiment of the present invention provides a process for preparing a stable ready-to-use parenteral composition comprising:
- adding buffer and antioxidant in water to get a clear solution;
- adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to the solution under stirring to obtain a clear solution;
- optionally, adding tonicity agent(s) and/or preservative(s);
- adding pH adjusting agent(s) to adjust the initial pH of the composition to 5.5 ± 0.5;
- making up the volume to 100% with water;
- filtering and filling aseptically in vials.

According to another embodiment of the present invention, the composition of the present invention can be prepared aseptically and terminally sterilized.

According to another embodiment, the present invention provides a stable ready-to-use parenteral composition comprising phenylephrine, wherein the parenteral composition is having total phenylephrine impurity is less than 0.2%, when stored at 40°C ± 2°C & 75% ± 5% RH for a period of at least six months.

According to another embodiment, the present invention provides a stable ready-to-use parenteral composition comprising phenylephrine, one or more impurity selected from the group comprising 3-Hydroxy acetophenone, Phenylephrine related compound C, Phenylephrine related compound E and/or Naproxen and one or more pharmaceutically acceptable excipients.

According to another embodiment, the present invention provides a stable ready-to-use parenteral composition comprising therapeutically effective amount of phenylephrine or its pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients, wherein the said composition is free from EDTA or its pharmaceutically acceptable salts, wherein the said composition is an aqueous solution having an initial pH of 5.5 ± 0.5.

According to another embodiment, the present invention provides a stable ready-to-use parenteral composition comprising phenylephrine or pharmaceutically acceptable salts thereof, one or more impurity selected from the group comprising 3-Hydroxy acetophenone, Phenylephrine related compound C, Phenylephrine related compound E and/or Naproxen and one or more pharmaceutically acceptable excipients, wherein the total phenylephrine impurity is less than 0.2%, when stored at 40°C ± 2°C & 75% ± 5% RH for a period of at least six months.

According to another embodiment, the present invention provides a stable ready-to-use parenteral composition comprising phenylephrine and one or more pharmaceutically acceptable excipient, wherein the ready to use composition has pH in the range of about 5 to about 6.

Stringent control of the oxygen levels in the headspace and the dissolved oxygen that is absorbed into the composition provide beneficial effects for decreasing the total impurities of the drug product. Purging a sufficient amount of inert gas during manufacturing of composition and flushing nitrogen during filling operation affords an overall more stable composition.

According to another embodiment of the present invention, the composition prepared by the process of the invention is having less than or equal to 5ppm oxygen in formulation, more preferably less than or equal to 2 ppm, and/or is stored in a container having less than or equal to 5% head space oxygen content, preferably less than or equal to 2%.

The present invention further relates to a process for preparation a stable ready-to-use parenteral composition of phenylephrine, wherein the process comprises inert gas purging such as Nitrogen purging to reduce the oxygen concentration or flushing with oxygen-free gas, substitution with oxygen-free gas, or bubbling with oxygen-free gas such as Nitrogen. The inert gas purging is done to reduce the dissolved oxygen content to less than or equal to 2ppm and headspace oxygen less than or equal to 2%.

The present invention further relates to a package or storage container for packaging or storing the ready-to-use parenteral composition, wherein the package or container is made up of material that blocks oxygen or is impervious to oxygen or comprises an oxygen scavenger.

The compositions as per the present invention can be bulk sterilized or terminally sterilized using any methods, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam). The container in which composition is filled can be sterilized using oven, autoclaving, gamma irradiation or ethylene oxide or pre-acetic acid or any other conventional method of sterilization.

According to another embodiment of the present invention, there is provided a stable ready-to-use parenteral composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition is having impurity(ies) below FDA acceptable limit on long term storage and during the shelf life. The total impurity(ies) of about 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less at 40 °C ± 5 °C and 25% ± 5% RH for a period of at least one month, at least three months, or at least six months or 25 °C ± 5 °C and 40% ± 5 % RH for a period of at least three months, at least six months, or at least 12 months. The chiral purity of R-phenylephrine hydrochloride in the composition is at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5% of the initial chiral purity after at least one month, at least three months, at least six months, or on long term storage, i.e, for shelf life at ambient/room conditions or when the composition is stored at 25 °C ± 5 °C and 40% ± 5 % RH.

The terms “FDA acceptable intake limit” of impurity(ies) as used in the present invention is the upper limit set by FDA for daily intake of impurity(ies) below which there is no harmful side-effect likely to occur on long term treatment with the therapeutically active agent.

The present invention further relates to a stable ready-to-use parenteral composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, which is useful for increasing blood pressure in adults with clinically important hypotension, in particular resulting primarily from vasodilation, in such settings as septic shock or anaesthesia.

While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

EXAMPLES

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don’t limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

A representative composition of this invention comprises following:

Ingredient Amount (% w/v)
Phenylephrine or Phenylephrine hydrochloride Less than 0.1%
Antioxidant 0.01-5%
Preservative 0-5%
Chelating Agent 0-5%
Tonicity Agent 0-10%
Buffering Agent 0-10%??
Water as Diluent q.s. to 100%
pH Adjusting agents q.s. to pH of 3.0-7.0

Example 1: Phenylephrine Hydrochloride Ready-to-Use Solution 0.01%w/v
Ingredients Amount (%w/v)
Phenylephrine HCl 0.01
Sodium Phosphate Monobasic 0.01-1.0
Sodium Phosphate, Dibasic 0.01-1.0
Sodium thiosulfate 0.001-0.5
Sodium Chloride 0.25-0.9
Water for injection q.s.
Sodium Hydroxide/HCl q.s. to pH 4.5-6.5

Process:
1. collecting 90% of batch quantity of water for injection (WFI);
2. dispensing and adding Dibasic sodium phosphate heptahydrate in WFI under stirring till clear solution is obtain;
3. dispensing and adding Monobasic sodium phosphate monohydrate in above solution under stirring till clear solution is obtain;
4. dispensing and adding Sodium thiosulfate in above solution under stirring till clear solution is obtain.;
5. dispensing and adding Sodium chloride in above solution under stirring till clear solution is obtain;
6. dispensing and adding Phenylephrine HCl in above solution under stirring till clear solution is obtain;
7. adjusting pH to 4.5-6.5 using Sodium hydroxide/HCl;
8. making the volume using WFI;
9. sterilizing filtration using 0.22µm filter;
10. filling aseptically in vials and sealing.

Example 2-3: Phenylephrine Hydrochloride Ready-to-Use Solution 0.004%w/v
Ingredients Exp. 2 Exp. 3
mg/ml %w/v mg/ml %w/v
Phenylephrine Hydrochloride 0.04 0.004 0.04 0.004
Citric acid monohydrate 0.34 0.034 0.28 0.028
Sodium citrate dihydrate 0.64 0.064 0.72 0.072
Sodium Metabisulphite 0.05 0.005 - -
EDTA Sodium 0.01 0.001 - -
Sodium Chloride 8.4 0.84 8.4 0.84
Sodium Hydroxide q.s. to adjust pH
Phosphoric Acid
Water for injection q.s. to 1 ml q.s. to 100 % q.s. to 1 ml q.s. to 100 %
pH – 5.0-6.0

Process:
1. collecting 90% of batch quantity of water for injection (WFI);
2. dispensing and adding Citric acid monohydrate in WFI under stirring till clear solution is obtain;
3. dispensing and adding Sodium citrate dihydrate in above solution under stirring till clear solution is obtain;
4. dispensing and adding Sodium Metabisulphite (Exp. 2) in above solution under stirring till clear solution is obtain.;
5. dispensing and adding EDTA Sodium (Exp. 2) in above solution under stirring till clear solution is obtain.;
6. dispensing and adding Phenylephrine HCl in above solution under stirring till clear solution is obtain.;
7. dispensing and adding Sodium chloride in above solution under stirring till clear solution is obtain;
8. adjusting pH to 5.0-6.0 using Sodium hydroxide/Phosphoric acid;
9. making the volume using WFI;
10. sterilizing filtration using 0.22µm filter;
11. filled aseptically in vials and sealing.

The process involves purging or bubbling nitrogen (0.2 µm filtered) at various stages of process to reduce the dissolved oxygen content to less than or equal to 2ppm and headspace oxygen content to less than or equal to 2%.

Example 4-5: Phenylephrine Hydrochloride Ready-to-Use Solution 0.008%w/v
Ingredients Exp. 4 Exp. 5
mg/ml %w/v mg/ml %w/v
Phenylephrine Hydrochloride 0.08 0.008 0.08 0.008
Glycine 0.35 0.035 - -
Tartaric acid - - 0.64 0.064
Sodium ascorbate 0.05 0.005 0.35 0.035
EDTA Sodium 0.05 0.005 - -
Sodium Chloride 8.4 0.84 6.0 0.60
Sodium Hydroxide q.s. to adjust pH
Glacial Acetic Acid
Water for injection q.s. to 1 ml q.s. to 100 % q.s. to 1 ml q.s. to 100 %
pH – 5.6-6.0

Process:
1. Collecting 90% of batch quantity of water for injection (WFI);
2. dispensing and adding glycine (Exp. 4) or tartaric acid (Exp. 5) in WFI under stirring till clear solution is obtain;
3. dispensing and adding Sodium ascorbate in above solution under stirring till clear solution is obtain;
4. dispensing and adding EDTA Sodium (Exp. 4) in above solution under stirring till clear solution is obtain;
5. dispensing and adding Phenylephrine HCl in above solution under stirring till clear solution is obtain;
6. adjusting pH to 5.6-6.0 using sodium hydroxide/Glacial Acetic Acid;
7. dispensing and adding sodium chloride in above solution under stirring till clear solution is obtain;
8. making the volume using WFI;
9. sterilizing filtration using 0.22µm filter;
10. filling aseptically in vials and sealing.

The process involves purging or bubbling nitrogen (0.2 µm filtered) at various stages of process to reduce the dissolved oxygen content to less than or equal to 2ppm and headspace oxygen content to less than or equal to 2%.

Inventors has formulated the different composition according to the present invention with different strength of Phenylephrine and subjected to the stability study to access the stability of composition after storage. The compositions have prepared and charged into the stability chamber with varying temperature and humidity conditions. The results are given in below table:

Stability result of composition of 0.004%w/v Phenylephrine
Parameter Initial 40°C±2°C/75%±5% RH 30°C±2°C/ 65%±5% RH 25°C±2°C/60%±5% RH
1M 3M 6M 3M 6M 3M 6M
Description Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution
pH 5.5 5.6 5.6 5.7 5.6 5.7 5.5 5.6
Assay (%) 100.6 99.2 99.7 97.9 99.8 99.2 100.3 98.7
Organic Impurities (%)
3-Hydroxy acetophenone ND ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND ND ND ND ND ND ND
Phenylephrine related compound E ND ND ND ND ND ND ND ND
Naproxen ND ND ND ND ND ND ND ND
Any unspecified degradation product ND BQL BQL 0.06 BQL BQL BQL BQL
Total degradation products ND 0.04 0.06 0.13 0.04 0.07 0.03 0.05

Stability result of composition of 0.01%w/v Phenylephrine
Parameter Initial 40°C±2°C/75%±5% RH 30°C±2°C/ 65%±5% RH 25°C±2°C/60%±5% RH
1M 3M 6M 3M 6M 3M 6M
Description Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution
pH 5.7 5.7 5.8 5.9 5.7 5.6 5.7 5.6
Assay (%) 100.4 101.3 101.4 99.4 101.4 102.3 98.9 101
Organic Impurities (%)
3-Hydroxy acetophenone ND ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND ND ND ND ND ND ND
Phenylephrine related compound E ND ND ND ND ND ND ND ND
Naproxen ND ND ND ND ND ND ND ND
Any unspecified degradation product ND ND BQL 0.06 BQL BQL BQL BQL
Total degradation products 0.02 0.04 0.07 0.13 0.06 0.08 0.04 0.07

Stability result of composition of 0.004%w/v Phenylephrine
Parameter Initial 40°C±2°C/75%±5% RH 30°C±2°C/ 65%±5% RH 25°C±2°C/60%±5% RH
1M 3M 6M 3M 6M 3M 6M
Description Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution
pH 5.6 5.5 5.6 5.7 5.7 5.7 5.5 5.6
Assay (%) 99.2 99.3 97.9 99.0 98.9 98.9 98.5 98.7
Organic Impurities (%)
3-Hydroxy acetophenone ND ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND ND ND ND ND ND ND
Phenylephrine related compound E ND ND ND ND ND ND ND ND
Naproxen ND ND ND ND ND ND ND ND
Any unspecified degradation product ND BQL BQL BQL BQL BQL BQL BQL
Total degradation products ND 0.02 0.04 0.07 0.02 0.04 0.02 0.03

Stability result of composition of 0.008%w/v Phenylephrine
Parameter Initial 40°C±2°C/75%±5% RH 30°C±2°C/ 65%±5% RH 25°C±2°C/60%±5% RH
1M 3M 6M 3M 6M 3M 6M
Description Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution
pH 5.8 5.8 5.7 5.9 5.7 5.8 5.8 5.8
Assay (%) 99.3 100.4 99.2 99.0 99.2 99.3 99.3 98.8
Organic Impurities (%)
3-Hydroxy acetophenone ND ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND ND ND ND ND ND ND
Phenylephrine related compound E ND ND ND ND ND ND ND ND
Naproxen ND ND ND ND ND ND ND ND
Any unspecified degradation product ND BQL BQL BQL BQL BQL ND BQL
Total degradation products ND 0.04 0.07 0.11 0.03 0.06 ND 0.04

Stability result of composition of 0.008%w/v Phenylephrine
Parameter Initial 40°C±2°C/75%±5% RH 30°C±2°C/ 65%±5% RH 25°C±2°C/60%±5% RH
1M 3M 6M 3M 6M 3M 6M
Description Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution Clear colorless solution
pH 5.8 5.8 5.7 5.9 5.8 5.7 5.8 5.8
Assay (%) 100.7 100.5 99.2 99.5 99.2 99.7 99.4 99.8
Organic Impurities (%)
3-Hydroxy acetophenone ND ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND ND ND ND ND ND ND
Phenylephrine related compound E ND ND ND ND ND ND ND ND
Naproxen ND ND ND ND ND ND ND ND
Any unspecified degradation product ND ND BQL BQL ND BQL ND ND
Total degradation products ND ND 0.05 0.08 ND 0.05 ND ND

Stability was measured in terms of the total impurity. From the above table, it is evident that the composition of phenylephrine is stable.
,CLAIMS:We Claim:

1. A stable ready-to-use parenteral composition comprising therapeutically effective amount of phenylephrine or its pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients, wherein the said composition is free from EDTA or its pharmaceutically acceptable salts, wherein the said composition is an aqueous solution having an initial pH of 5.5 ± 0.5.

2. The stable ready-to-use parenteral composition as claimed in claim 1, wherein the said composition further comprise viscosity modifiers.

3. The stable ready-to-use parenteral composition as claimed in claim 1, wherein the said composition can be prepared aseptically and/or terminally sterilized.

4. The stable ready-to-use parenteral composition as claimed in claim 1, wherein the parenteral composition is having total phenylephrine impurity is less than 0.2%, when stored at 40°C ± 2°C & 75% ± 5% RH for a period of at least six months.

5. The stable ready-to-use parenteral composition as claimed in claim 1, wherein the said composition is free of citrate or acetate buffer.

6. The stable ready-to-use parenteral composition as claimed in claim 1, wherein the said composition is free of preservative.

7. The stable ready-to-use parenteral composition as claimed in claim 1, wherein the said composition is having less than or equal to 2ppm oxygen in formulation.

8. A stable ready-to-use parenteral composition comprising phenylephrine or pharmaceutically acceptable salts thereof, one or more impurity selected from the group comprising 3-Hydroxy acetophenone, Phenylephrine related compound C, Phenylephrine related compound E and/or Naproxen and one or more pharmaceutically acceptable excipients, wherein the total phenylephrine impurity is less than 0.2%, when stored at 40°C ± 2°C & 75% ± 5% RH for a period of at least six months.

9. A process for preparing a stable ready-to-use parenteral composition as claimed in claim 1, wherein the process comprising the steps of:
(a) adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to water under stirring to obtain a clear solution;
(b) adding antioxidant to the above solution;
(c) optionally, adding buffering agent(s), chelating agent(s), tonicity agent(s) and/or preservative(s);
(d) adding pH adjusting agent(s), if required, to adjust the initial pH of the composition to 5.5 ± 0.5;
(e) making up the volume to 100% with water;
(f) filtering and filling aseptically in vials.

Dated this 10th day of May 2024.
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer