Description:FIELD OF THE INVENTION

The present invention relates to a stable ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

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 is used topically in the eye as a mydriatic agent. Phenylephrine Hydrochloride Eye Drops are indicated to dilate the pupil for diagnostic or therapeutic procedures.

U.S. Patent No. 8,859,623 discloses a method of using an ophthalmic composition for pupil dilation, the composition comprising R-phenylephrine hydrochloride having an initial chiral purity of at least 95% and an aqueous buffer, wherein the chiral purity of R-phenylephrine hydrochloride is at least 95% of the initial chiral purity after 6 months, the method comprising: administering the composition into an eye of an individual in need thereof, wherein the composition is stored between -10 to +10 degree Celsius prior to administration, and wherein the composition comprises R-phenylephrine hydrochloride having a chiral purity of at least 95% when administered after storage.

U.S. Patent No. 6,982,079 discloses a composition comprising an ophthalmically acceptable carrier component; a vasoconstrictor component in an amount effective to treat hyperemia; and a polyanionic component in an amount effective to provide lubrication to an eye when the composition is administered.

U.S. Patent No. 7,612,115 discloses an aqueous pharmaceutical composition, which comprises 2.3 to 8 w/v % of methylcellulose, wherein a 2 w/v % aqueous solution of said methylcellulose has a viscosity of 12 mPas or below at 20 °C.; 0.14 to 4 w/v % of at least one kind of acid selected from the group consisting of multivalent carboxylic acid, lactic acid and gluconic acid; and an effective amount of a pharmaceutical agent, wherein said pharmaceutical agent is at least one member selected from the group consisting of phenylephrine hydrochloride and others.

Indian Patent No. 2,72,804 discloses an ophthalmic composition comprising phenylephrine, a viscoelastic agent, an osmolality agent, a buffering agent and water, wherein phenylephrine is present in a range of 0.15% w/v-10%w/v, the viscoelastic agent is 0.1-3%, osmolality is 300-400 mOsm, and pH is 4-5.5.

Indian Patent Application No. 201817031430 discloses a composition comprising: a) from 0.0005% w/v to 0.1000 % w/v, of the total composition, of polyquaternium-42; b) optionally, from 0.2 %w/v to 2.0 % w/v, of the total composition, of an amount of a polyol or combination polyols, wherein the term polyol refers to any compound having at least two -OH groups; c) from 0.02% w/v to 1.5% w/v, of the total composition, of a borate; and d) an antimicrobial mixture comprising: i. one or more nutrients, wherein the nutrients comprise a mixture of glucose and lactate; and ii. Optionally, one or more electrolytes such that: a. the total nutrient concentration, in the total composition, is from 1.0 mMol/L to 4.0 mMol/L of the composition; and b. when present, the total electrolyte concentration, in the total composition, is from 20.0 mMol/L to 80.0 mMol/L of the composition.

PCT Publication No. 2019014380 discloses a composition for topical application onto the mammalian body surface, the composition comprising: at least one active pharmaceutical ingredient (API); a penetration enhancer: a gelling agent; and an aqueous carrier, wherein the at least one API is selected from the group consisting of phenylephrine and others.

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. It is known in the art that a Phenylephrine Hydrochloride solution when stored at ambient conditions turns brown and the brown solution must not be used and discarded.

The present invention provides stable ophthalmic compositions of phenylephrine and process for preparation of such compositions.

SUMMARY OF THE INVENTION

The present invention provides a stable ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

One aspect of the present invention provides a stable ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is an aqueous solution.

Another aspect of the present invention provides a stable ophthalmic 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.

Another aspect of the present invention provides a stable ophthalmic 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 4.0 - 7.5.

Another aspect of the present invention provides a stable ophthalmic 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 5.0 - 6.5.

Another aspect of the present invention provides a stable ophthalmic 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 an initial pH adjusted in the range of 5.5 - 6.0.

Another aspect of the present invention provides a stable ophthalmic 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 an initial pH of 5.8 ± 0.2.

Another aspect of the present invention provides a stable ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from buffering agent(s), pH adjusting agent(s), preservative(s), and solvent(s); wherein the composition is an aqueous solution having an initial pH of 5.8 ± 0.2.

Another aspect of the present invention provides a stable ophthalmic composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- phosphate buffer or citrate buffer;
- optionally pH adjusting agents selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof,
wherein the composition is an aqueous solution having an initial pH of 5.8 ± 0.2.

Another aspect of the present invention provides a stable ophthalmic composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- optionally phosphate buffer or citrate buffer;
- pH adjusting agent(s) selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof,
wherein the composition is an aqueous solution having an initial pH of 5.8 ± 0.2.

Another aspect of the present invention provides a process for preparing a stable ophthalmic composition comprising:
a) Adding and mixing buffer in water to get a clear solution;
b) Adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to the solution of step a) under stirring to obtain a clear solution;
c) Optionally, adding benzalkoniun chloride;
d) Adding pH adjusting agents selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof, if required, to adjust the initial pH of the composition to 5.8 ± 0.2;
e) Making up the volume to 100% with water;
f) Filtering the solution of step (e) and filling aseptically in vials.

The present invention further relates to a stable ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, which is useful for dilating the pupil for diagnostic or therapeutic procedures.

DESCRIPTION OF THE INVENTION

The present invention provides a stable ophthalmic 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 ascribed 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 “ophthalmic composition” or “dosage form” or “pharmaceutical formulation” or “formulation” as used herein synonymously include the pharmaceutical compositions in a form suitable for ophthalmic administration such as but not limited to sterile aqueous, hydro-alcoholic, or non-aqueous solution, sterile aqueous, hydro-alcoholic, or non-aqueous suspension, emulsion, liposomes, microparticles, gel, gel forming suspension (in-situ gels), ointment, lotion or the like or any other suitable dosage form meant for ophthalmic administration. The ophthalmic pharmaceutical composition includes ready-to-use composition and concentrates to be used post dilution for irrigation purposes during eye surgery. 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 as 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 agents 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 solvents selected from 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 buffers include, 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. When present, 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%. In a preferred embodiment, the buffer is phosphate buffer comprising monobasic and dibasic sodium phosphate or citrate buffer comprising citric acid and sodium citrate.

Suitable tonicity agent 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. When present, 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.

Suitable antioxidants include, but are not limited to, 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.

The pH adjusting agent is typically a mineral acid or metal hydroxide base preferably selected from the group of potassium hydroxide, sodium hydroxide, hydrochloric acid, phosphoric acid or mixtures thereof, and preferably sodium hydroxide and/or phosphoric acid. 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 4 to 7.5, preferably 5.0 to 6.5. In more specific embodiment, the initial pH of the composition is adjusted to 5.5 to 6.0, more preferably about 5.8 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 ophthalmic 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%.

According to one embodiment of the present invention, there is provided a stable ophthalmic composition comprising about 0.1% w/v to about 15.0% w/v phenylephrine or a pharmaceutically acceptable salt thereof. More specifically comprising about 1% w/v, about 2.5% w/v, and about 10% w/v phenylephrine or pharmaceutically acceptable salts thereof, i.e., phenylephrine hydrochloride.

Another embodiment of the present invention provides a stable ophthalmic composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- phosphate buffer or citrate buffer;
- optionally pH adjusting agents selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof,
wherein the composition is an aqueous solution having an initial pH of 5.8 ± 0.2.

Another embodiment of the present invention provides a stable ophthalmic composition comprising:
- therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof;
- optionally a buffer;
- pH adjusting agent(s) selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof,
wherein the composition is an aqueous solution having an initial pH of 5.8 ± 0.2.

In a preferred embodiment of the present invention, the pharmaceutical composition comprises of about 2.5% and 10% of Phenylephrine hydrochloride, about 2.5mg/ml to about 7.0 mg/ml of buffer, water for injection, and preservative 0.1 mg/ml.

Another embodiment of the present invention provides a process for preparing a stable ophthalmic composition comprising:
a) Adding and mixing buffer in water to get a clear solution;
b) Adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof to the solution of step a) under stirring to obtain a clear solution;
c) Optionally adding benzalkonium chloride;
d) Adding pH adjusting agents selected from sodium hydroxide, phosphoric acid, or combinations thereof, if required, to adjust the initial pH of the composition to 5.8 ± 0.2;
e) Making up the volume to 100% with water;
f) Filtering the solution of step (e) and filling aseptically in vials.

Another aspect of the present invention provides a process for preparing a stable ophthalmic composition comprising:
a) Adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof, in water under stirring to obtain a clear solution;
b) Optionally, adding buffers and preservatives;
c) Adding pH adjusting agent selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof, to adjust the initial pH of the composition to 5.8 ± 0.2;
d) Making up the volume to 100% with water;
e) Filtering the solution of step (d) and filling aseptically in vials.

In one embodiment, the composition of the present invention can be prepared aseptically and terminally sterilized.

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 one 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 of a stable ophthalmic 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 ophthalmic 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 pharmaceutical 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.

In another embodiment of the present invention, there is provided a stable ophthalmic 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 ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, which is useful for dilating the pupil for diagnostic or therapeutic procedures.

The present invention further relates to a stable ophthalmic composition comprising therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients and one or more additional active agents selected from ketorolac, bromofenac, timolol, brimonidine, dorzolamide, brinzolamide, latanoprost, moxifloxacin, dexamethasone, prednisolone, gatifloxacin, lidocaine, and the like.

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 0.5-10%
Suspending Agent 0-10%
Viscosity modifier 0-10%
Preservative 0-5%
Chelating Agent 0-5%
Tonicity Agent 0-10%
Surfactant 0-5%
Buffer 0-10%??
Water as Diluent q.s. to 100%
pH Adjusting agents q.s. to pH of 4-7.5

Example 1: Phenylephrine Hydrochloride Ophthalmic Solution 2.5%w/v and 10%w/v
Ingredients Amount (%w/v)
Phenylephrine HCl 2.5 or 10
Sodium Phosphate Monobasic 0.25-0.35
Sodium Phosphate, Dibasic 0.5-0.75
Water for injection q.s.
Phosphoric Acid and / Sodium Hydroxide q.s
Benzalkonium Chloride 0.005-0.1
pH q.s. to pH 5.5 to 6.5
Tonicity 300-400 mOsm/kg (2.5%)
900-1100 mOsm/kg (10%)

Example 2: Phenylephrine Hydrochloride Ophthalmic Solution 2.5%w/v and 10%w/v
Ingredients 2.5%w/v 10%w/v
mg/ml %w/v mg/ml %w/v
Phenylephrine Hydrochloride 25 2.5 100 10
Dibasic Sodium Phosphate heptahydrate 3.4 0.34 2.84 0.284
Monobasic Sodium Phosphate monohydrate 6.4 0.64 6.4 0.64
Benzalkonium Chloride 0.1 0.01 0.1 0.01
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 – 5.6-6.0

Process:
1. Collected 90% of batch quantity of water for injection (WFI).
2. Dispensed and added Dibasic sodium phosphate heptahydrate in WFI under stirring till clear solution is obtained.
3. Dispensed and added Monobasic sodium phosphate monohydrate in above solution under stirring till clear solution is obtained.
4. Dispensed and added Phenylephrine HCl in above solution under stirring till clear solution is obtained.
5. Added Benzalkonium Chloride in above solution under continue stirring till homogenous solution obtained.
6. Adjust to pH 5.8 (5.6-6.0) using sodium hydroxide/phosphoric acid.
7. Made the volume using WFI.
8. Sterilized filtration using 0.22µm filter.
9. Filled aseptically in vials and sealed.

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 3-5: Phenylephrine Hydrochloride Ophthalmic Solution 1%
Ingredients Exp. 3 Exp. 4 Exp. 5
%w/v mg/mL %w/v mg/mL %w/v mg/mL
Phenylephrine hydrochloride equivalent to Phenylephrine 1.02 10.16 1.02 10.16 1.02 10.16
Citric acid monohydrate 0.03 0.3 0.029 0.285 0.027 0.27
Sodium citrate dihydrate 0.55 5.5 0.523 5.225 0.495 4.95
Hydrochloric acid q.s. to adjust pH
Sodium Hydroxide
Water for Injection q.s. to
100% q.s. to
1ml q.s. to
100% q.s. to
1ml q.s. to
100% q.s. to 1ml
pH - 5.5-6.6

Example 6: Phenylephrine Hydrochloride Ophthalmic Solution 1%
Ingredients Exp. 6
%w/v mg/mL
Phenylephrine hydrochloride equivalent to Phenylephrine 1.02 10.16
Hydrochloric acid q.s. to adjust pH
Sodium Hydroxide
Water for Injection q.s. to 100% q.s. to 1ml
pH - 5.5-6.6

Stability Studies: The pharmaceutical compositions of the Example 2 (2.5% and 10%) were tested for stability at 25°C ± 5°C /40% ± 5% RH for 12 months and 40°C ± 5°C /25% ± 5% RH for a period of six months. The amount of impurity is provided in Table 1 (2.5% w/v) and Table 2 (10% w/v) below:

Table 1:
Parameter
Initial
40°C ± 5°C/
25% ± 5% RH 25°C ± 5°C/
40% ± 5% RH
3M 6M 3M 6M 9M 12M
3-Hydroxy acetophenone ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND BDL ND ND ND ND
Phenylephrine related compound E ND ND ND ND ND BDL BDL
2-Naphthaleneacetic acid, 6-methoxy-Alpha-methyl-, (S)-/(+)-(S)-6-methoxy-Alpha-methyl-2-naphthaleneacetic acid ND ND ND ND ND ND ND
Any unspecified degradation product BDL BQL 0.03 BDL BDL BQL 0.02
Total degradation products BDL BQL 0.03 BDL BDL BQL 0.02
S-isomer 0.4 0.5 0.4 0.5 0.4 0.5 0.5
pH - 5.4 - - -- 5.2

Table 2:
Parameter Initial 40°C ± 5°C/
25% ± 5% RH 25°C ± 5°C and
40% ± 5% RH
3M 6M 3M 6M 9M 12M
3-Hydroxy acetophenone ND ND ND ND ND ND ND
Phenylephrine related compound C ND ND BDL ND ND ND ND
Phenylephrine related compound E ND BDL BDL BDL BDL BDL BDL
2-Naphthaleneacetic acid, 6-methoxy-Alpha-methyl-, (S)-/(+)-(S)-6-methoxy-Alpha-methyl-2-naphthaleneacetic acid ND ND ND ND ND ND ND
Any unspecified degradation product BQL BDL 0.04 BDL BDL BDL 0.02
Total degradation products BQL BQL 0.08 BDL BDL BDL 0.02
S-isomer 0.4 0.4 0.5 0.5 0.5 0.6 0.4
pH - 5.3 - - - - 5.5
BDL is Below Detection Limit
BQL is Below Quantification Limit

10% solution of phenylephrine hydrochloride prepared according to example 2 and having an initial pH of 4.5 was tested for stability at 25°C ± 5°C /40% ± 5% RH for 12 months and 40°C ± 5°C/25% ± 5% RH for a period of six months. The amount of impurity is provided in Table 3
Table 3:
Parameter
Initial
40°C ± 5°C/
25% ± 5% RH 25°C ± 5°C/
40% ± 5% RH
3M 6M 3M 6M 9M 12M
Initial pH 4.0 ± 0.5
Total degradation products BDL 0.89 1.03 0.67 0.83 0.96 1.1
S-isomer 0.4 1.6 2.3 1.2 1.6 2.2 2.3
, C , C , C , C , Claims:We Claim:

1. A stable ophthalmic 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 5.0 - 6.5.

2. The stable ophthalmic composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients is 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.

3. The stable ophthalmic composition as claimed in claim 1, wherein the composition is an aqueous solution having an initial pH adjusted in the range of 5.5 - 6.0.

4. The stable ophthalmic composition as claimed in claim 1, wherein the composition comprises:
- about 1% w/v to about 10% w/v phenylephrine;
- a phosphate buffer or a citrate buffer;
- optionally, pH adjusting agents to adjust the pH.

5. The stable ophthalmic composition as claimed in claim 4, wherein the composition comprises:
- about 2.5 % w/v or about 10% w/v phenylephrine;
- a phosphate buffer comprising dibasic sodium phosphate and monobasic sodium phosphate;
- benzalkonium chloride;
- optionally, Sodium hydroxide and/or phosphoric acid to adjust the pH.

6. The stable ophthalmic composition as claimed in claim 1, wherein the composition comprises:
- about 1% w/v to about 10% w/v phenylephrine;
- optionally a phosphate buffer or a citrate buffer;
- pH adjusting agent(s) to adjust the pH.

7. The stable ophthalmic composition as claimed in claim 6, wherein the composition comprises:
- about 1 % w/v phenylephrine;
- optionally a citrate buffer comprising citric acid and sodium citrate;
- Sodium hydroxide and/or Hydrochloric acid to adjust the pH.

8. The stable ophthalmic composition as claimed in claim 1, wherein the composition has an initial pH of 5.8 ± 0.2 and the pH of the composition upon storage of the composition at 40°C ± 5°C / 25% ± 5 % RH for a period of six months or 25 °C ± 5 °C and 40% ± 5 % RH for a period of at least twelve months is within 0.5 pH units of an initial pH level.

9. The stable ophthalmic composition as claimed in claim 8, wherein the composition contains less than 5% of total impurities and chiral purity of R-phenylephrine hydrochloride is at least 95% of the initial chiral purity upon storage of the composition at 40°C ± 5°C /25% ± 5 % RH for a period of six months or 25 °C ± 5 °C and 40% ± 5 % RH for a period of at least twelve months.

10. A process for preparing a stable ophthalmic composition comprising:
a) adding and mixing buffer(s) in water to get a clear solution;
b) adding therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof, to the above solution under stirring to obtain a clear solution;
c) optionally adding benzalkonium chloride to above solution;
d) adding pH adjusting agents selected from sodium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof, to adjust the initial pH of the composition in the range of 5.5 – 6.0;
e) making up the volume of the solution to 100% with water; and
f) filtering the solution of step (e) and filling aseptically in vials.

Dated this the 12th day of May 2023. For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer