WO2025068937A1

WO2025068937A1 - An oral liquid formulation of metoprolol

Info

Publication number: WO2025068937A1
Application number: PCT/IB2024/059407
Authority: WO
Inventors: Manish UMRETHIA; Chintan PANSARA
Original assignee: Liqmeds Worldwide Ltd
Current assignee: Liqmeds Worldwide Ltd
Priority date: 2023-09-30
Filing date: 2024-09-26
Publication date: 2025-04-03
Anticipated expiration: 2026-03-30

Abstract

The present invention is related to an oral liquid formulation of metoprolol. The present invention is also related to an oral liquid formulation of metoprolol which comprises metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutically acceptable excipients. The present invention is also related to the process of preparation of an oral liquid formulation of metoprolol.

Description

AN ORAL LIQUID FORMULATION OF METOPROLOL

RELATED APPLICATION

This application claims priority to IN Patent Application No. 202321065858 filed on September 30, 2023, the subject matter of which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is related to an oral liquid formulation of metoprolol. The present invention is specifically related to an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutically acceptable excipients. The present invention is also related to the process of preparation of an oral liquid formulation of metoprolol.

BACKGROUND OF THE INVENTION

Cardiovascular disease is a group of diseases affecting your heart and blood vessels. These diseases can affect one or many parts of your heart and/or blood vessels. A person may be symptomatic or asymptomatic. Cardiovascular disease is the leading cause of death worldwide. The symptoms can vary depending on the cause. The symptoms of heart problems include angina (chest pain), heaviness or discomfort in the chest, shortness of breath (dyspnea), dizziness, and fatigue. Betablockers are a class of medicines commonly used to treat a wide range of problems involving your heart and your circulatory system.

Beta-blockers are beta receptor antagonists, meaning they block beta-adrenergic receptors and slow down certain types of cell activity. Selective beta-1 blockers are a subclass of beta-blockers that are commonly used to treat high blood pressure. Beta-1 receptors are mainly found in the cardiac tissues and kidneys. Selective beta- 1 -blockers bind to the beta-1 receptor sites and inhibit the action of hormones norepinephrine and epinephrine. Norepinephrine and epinephrine are the hormones that are produced by the adrenal gland and also by the nerve cells and are released inside the circulatory system when a person is emotionally stressed. Beta-1 receptors upon activation, increase the intracellular calcium concentration in heart muscles, leading to increased heart muscle contractions and heart rate. The enzyme renin is released into the circulation by the kidneys when the smooth muscles are activated and this triggers the production of sodium and water regulatory hormones, angiotensin II and aldosterone. These hormones cause retention of sodium and water and increase blood pressure.

Metoprolol is a selective pi receptor blocker that is FDA-approved to treat angina, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension. Metoprolol is available in different dosage forms like immediate-release, extended-release tablet, and capsule formulations that can be taken by mouth or injection formulation that can be given intravenously.

Though tablets are the dosage form having great popularity in their use as simple, economical in manufacturing, most stable, and most convenient in packaging, shipping, and transportation. However, they are also having some disadvantages like they are difficult to swallow by children and old age patients and the bioavailability of the drug is lesser due to slower absorption.

Absorption is the process of drug movement from the site of drug administration to systemic circulation. Drug absorption is quantified in terms of bioavailability. Bioavailability is the fraction of the administered drug that reaches the systemic circulation. The rate of drug absorption determines its onset of action. Tablet dosage forms take time for absorption as first they need to disintegrate and then dissolution followed by absorption. However, liquid dosage forms have a faster absorption rate than tablet dosage forms and ultimately bioavailability is more in liquid dosage form than tablet dosage form. Additionally, liquid dosage forms provide better patient compliance as it is easy to administer by children, geriatric patients, and patients who are not able to swallow tablets. US5484776A discloses a process for the production of orally administrable solution forms of medicaments containing high-molecular polysaccharides with controlled release of beta-blocking agents. The examples disclose solution of metoprolol tartrate with polysaccharides like xanthan gum, dextran, and amylodextrin, antioxidants like sodium metabisulphite, and ethanol.

WO2010122442A1 discloses an aqueous nonalcoholic solutions comprising a beta-blocker propranolol, a non-sugar type sweetener and being substantially free of an aromatic preservative agent and at least one viscosity increasing agent which is selected from cellulose derivatives like hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or methylcellulose, poloxamers, from gums, guar gum, tragacanth gum, acacia gum, xanthan gum, gellan gums, alginic derivatives, alginic acid, sodium alginate, polyvinylpyrrolidone, from silicates, bentonite, laponite, magnesium aluminum silicate, more particularly from nonionic poloxamers, polyvinylpyrrolidone, and cellulose ethers.

Extemporaneous solutions of metoprolol tartrate are also known. They were prepared by dissolving crushed tablets of metoprolol tartrate in Ora-blend. Indeed, their use is provided by SickKids®, a major pediatric teaching hospital located on University Avenue in Toronto, Ontario, Canada. Another known extemporaneous solution for the oral administration of metoprolol is suspension types which is prepared by triturating tablets in a mixture of Ora-Plus® and Ora-Sweet® (by Pharmaceutical Society of New Zealand).

There are many factors associated with the risk of currently approved product, like a) materials required for the reconstitution or dilution may be available at home but it may difficult to remember during travel to obtain all the listed items like if any lack of items may result in postponed or omission of the dose and substitutions may result in exposure to verify the complete dissolution of the powder or may further difficulty in reconstituting or measuring a correct dose, b) incorrect volume of reconstitution liquid, c) incomplete dissolution of powder, d) incorrect dosage, e) may choose different solution while taking the dose, and f) chances of contamination and product degradation is high. Further, for injectable dosage forms there were many disadvantages like its expensive and need instrument like syringes, need a skilled person, once given to patients cannot be controlled if any adverse effect occurs, sterilization is required, etc.

In light of the existing prior arts, it can be concluded that metoprolol is available either in tablet, capsule, or injection forms, and currently there is no liquid formulation of metoprolol present in the market that can be consumed directly by patients in need. The prior art disclosing liquid formulations includes use of high- molecular polysaccharides like xanthan gum, dextran, and amylodextrin, and antioxidants like sodium metabisulphite, and ethanol. There are several drawbacks of this formulation like microbial contamination, decreasing viscosity with longterm storage, and uncontrollable rate of hydration, and stability.

Hence, there is a need to develop an oral liquid formulation of metoprolol which will overcome the above stated disadvantages of solid dosage form and will also provide faster onset of action in life-threatening heart disease.

Therefore, the inventors of the present invention have arrived at an oral liquid formulation of metoprolol with the aim to overcome the problems cited above by preparing an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof as described herein.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to develop an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof.

Another objective of this invention is to provide an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof which is stable. Yet another objective of this invention is to provide an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof which is ready-to-use.

Yet another objective of this invention is to provide an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof which provides better patient compliance.

Yet another objective of this invention is to provide an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof which is easy to manufacture at large scale.

Yet another objective of this invention is to provide an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof which gives faster absorption and quicker onset of action.

SUMMARY OF THE INVENTION

The present invention is all about to provide an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof.

The main aspect of the present invention is to provide an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides a process for the preparation of an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Before elaborating on the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified examples or process parameters that may, of course, vary. It is also to be understood that the terminology used herein is to describe particular embodiments of the invention only, and is not intended to limit the scope of the invention in any manner.

The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and/or utilized. The description sets forth the functions and the sequence of steps for constructing and/or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences that may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the invention.

As defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

As stated in the present invention herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer unless the content clearly dictates otherwise.

The term “about” is used synonymously with the term “approximately.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the formulation. Illustratively, the use of the term “about” indicates that values slightly outside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe. Thus, formulations slightly outside of the cited ranges are also encompassed by the scope of the present claims. However, when the term “about” is used in connection with pH, it should be considered as plus, or minus 2 unit of the pH value.

As stated herein, that it follows in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a formulation, the term “comprising” means that the formulation includes at least the recited features or components, but may also include additional features or components.

As stated herein, that follows in a transitional phrase or in the body of a claim, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim or description. “Consisting of’ is defined as “closing the claim or description to the inclusion of materials other than those recited except for impurities ordinarily associated therewith”.

As stated herein, that it follows in a transitional phrase or in the body of a claim, the term “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.

As used herein, the term “active agent” can be understood to include any substance or formulation or combination of substances or formulations of matter when administered to a human or animal subject, induces a desired pharmacologic and/or physiologic effect by local and/or systemic action. The terms are used interchangeably herein: "active", "drug", “therapeutic agent”, “active pharmaceutical agent” and "active ingredient". A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount.

As used herein, the term “therapeutically effective amount” can be understood to include an amount of metoprolol or pharmaceutically acceptable salts thereof that is effective in preventing or ameliorating a condition requiring antihypertensive therapy.

As used herein, the terms “dose” and “dosage” can be understood to mean a specific amount of active or therapeutic agents for administration.

As used herein the term “liquid formulation” refers to liquid oral formulation like solution, suspension, or emulsion, more preferably in the form of solution.

As per one preferred embodiment, the “oral solution” as mentioned herein is defined as the liquid dosage form that has no suspended particles and it’s a clear liquid solution.

The term "pH", as used herein, is meant "apparent pH" wherein the pH measurement is carried out on the metoprolol or pharmaceutically acceptable salts thereof containing formulation in the final form, for example, by measuring the pH of the solution.

As used herein, the term “glycerin” can be interchangeably used with the term “glycerol” as both are the same.

As used herein, the term “inactive excipients” can be interchangeably used with the term “pharmaceutically acceptable excipients” as both are the same. As used herein, the term “viscosifying agent” can be interchangeably used with the term “viscosity increasing agent” as both are the same.

As per one preferred embodiment, the term “ready-to-use” used herein is defined as the solution that can administered directly to a patient for a treatment without the steps such as reconstitution or dilution.

As stated herein the term “RTU” refers to ready-to-use and can interchangeably use for the “ready-to-use” phrase.

As per one embodiment of the present invention, the present invention does not include preservatives (For example, alkyl esters of p-hydroxybenzoic acid which includes methyl paraben, propyl paraben, ethyl paraben, and sorbic acid etc.), polysaccharide polymers (For example, xanthan gum, dextran, amylodextrin etc.), oligosaccharides (For example, hydroxypropyl beta-cyclodextrin, sulfobutylether- beta-cyclodextrin, methyl-beta-cyclodextrin etc.), anti-oxidants (For example, sodium metabisulphite etc.), alcohol or ethanol, sweetener (For example, saccharin sodium), viscosity increasing agent (For example, hydroxy ethyl cellulose, cellulose derivatives like hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or methylcellulose, poloxamers, from gums, guar gum, tragacanth gum, acacia gum, xanthan gum, gellan gums, alginic derivatives, alginic acid, sodium alginate, polyvinylpyrrolidone, from silicates, bentonite, laponite, magnesium aluminum silicate, more particularly from non-ionic poloxamers, polyvinylpyrrolidone and cellulose ethers etc.).

The main embodiment of the present invention is to provide an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutically acceptable excipients. As per one preferred embodiment of the present invention provides an oral liquid formulation of metoprolol comprising a therapeutically effective amount of metoprolol or pharmaceutically acceptable salts thereof for the treatment of cardiovascular diseases like angina pectoris, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension, wherein metoprolol or pharmaceutically acceptable salts thereof may be used alone or in combination with other antihypertensive agents.

As per one embodiment of the present invention, the pharmaceutically acceptable salts of metoprolol can be selected from tartrate, succinate, citrate, acetate, maleate, and fumarate.

As per one preferred embodiment of the present invention, the pharmaceutically acceptable salt is tartrate.

As per one preferred embodiment of the present invention, the pharmaceutically acceptable salt is succinate.

As per one embodiment of the present invention, metoprolol or pharmaceutically acceptable salts thereof can be present in the formulation of present invention in an amount from about 0.1 mg/mL to about 500 mg/mL, preferably in the range from about 0.5 mg/mL to about 200 mg/mL, preferably in the range from about 0.5 mg/mL to about 150 mg/mL, more preferably in the range from about 0.5 mg/mL to about 100 mg/mL, more preferably in the range from about 0.5 mg/mL to about 50 mg/mL, more preferably in the range from about 0.5 mg/mL to about 40 mg/mL, more preferably in the range from about 0.5 mg/mL to about 30 mg/mL, most preferably in the range from about 0.5 mg/mL to about 20 mg/mL, or any other value in between thereof. As per one embodiment, the “viscosifying agent” used in the present invention is defined as an agent which can increase the viscosity of a liquid without substantially changing its other properties.

As per one embodiment of the present invention, at least one viscosifying agent can be selected from liquid sorbitol, liquid maltitol, sucrose, fructose, dextrose, maltodextrin, polyethylene glycol, glycerin, polydextrose, or any combination thereof.

As per preferred embodiment of the present invention, glycerin is used as a viscosifying agent.

As per one embodiment of the present invention, glycerin or at least one viscosifying agent can be used in the range from about 1 mg/mL to about 500 mg/mL, preferably in the range from about 10 mg/mL to about 500 mg/mL, more preferably in the range from about 50 mg/mL to about 500 mg/mL, more preferably in the range from about 100 mg/mL to about 500 mg/mL, and most preferably in the range from about 200 mg/mL to about 500 mg/mL, or any other value in between thereof.

The buffers used in the present invention are generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. The pH of the liquid formulation of the present invention can be adjusted in the range from about 3 to about 5.

As per one embodiment of the present invention, one or more buffering agent can be selected from sodium acetate trihydrate, phosphate, citrate, sodium citrate, citric acid, tris, succinate, histidine, glycine, arginine, malic, tartaric, acetic, benzoic, gluconic, glyceric, lactic, adipic, ascorbic, carbonic, glutamic, ammonium chloride, triethanolamine, and salts or acids thereof, or any combination thereof. As per the preferred embodiment of the present invention, one or more buffering agent, preferably a combination of two buffering agents. As per the preferred embodiment of the present invention, citrate buffer is used as a buffering agent which contains combination of sodium citrate, and citric acid.

As per one embodiment of the present invention, sodium citrate can be used in the range from about 0.5 mg/mL to about 30 mg/mL, preferably in the range from about 1 mg/mL to about 30 mg/mL, more preferably in the range from about 1 mg/mL to about 20 mg/mL, and most preferably in the range from about 1 mg/mL to about 15 mg/mL, or any other value in between thereof.

As per one embodiment of the present invention, citric acid can be used in the range from about 0.5 mg/mL to about 30 mg/mL, preferably in the range from about 1 mg/mL to about 30 mg/mL, more preferably in the range from about 1 mg/mL to about 20 mg/mL, and most preferably in the range from about 1 mg/mL to about 20 mg/mL, or any other value in between thereof.

As per one embodiment of the present invention, one or more pharmaceutically acceptable excipients can be selected from a viscosifying agent, a buffering agent, a sweetening agent, a preservative, and a flavouring agent.

As per one embodiment of the present invention, one or more pharmaceutically acceptable excipients can be selected from a viscosifying agent, a buffering agent, a sweetening agent, a preservative, and a flavouring agent in an amount from about 0.01 mg/ml to about 500 mg/mL, or any other value in between thereof.

As per one embodiment of the present invention, one or more pharmaceutically acceptable excipients can be selected from a sweetening agent, a preservative, and a flavouring agent. As per one embodiment, the “sweetening agent” is added to additives that are used or intended to be used either to impart a sweet taste to a pharmaceutical formulation.

As per one embodiment of the present invention, at least one sweetening agent can be selected from but not limited to glucose, sucralose, trehalose, fructose, xylose, dextrose, galactose, tagatose, maltose, sucrose, glycerol, dulcitol, mannitol, lactitol, sorbitol, xylitol, cyclamate or the corresponding sodium or calcium salt, aspartame, or acesulfame or the potassium salt thereof, ammonium glycyrrhizinate, alitame, inulin, isomalt, neohesperidin dihydrochalcone, neotame, thaumatin, or any combination thereof.

As per the preferred embodiment of the present invention, sucralose is used as a sweetening agent.

As per one embodiment of the present invention, sucralose or at least one sweetening agent can be used in the range from about 0.1 mg/mL to about 20 mg/mL, preferably in the range from about 0.1 mg/mL to about 15 mg/mL, preferably in the range from about 0.1 mg/mL to about 10 mg/mL, more preferably in the range from about 0.5 mg/mL to about 10 mg/mL, and most preferably in the range from about 0.5 mg/mL to about 5 mg/mL, or any other value in between thereof.

As per one embodiment of the present invention, at least one preservative can be selected from but not limited to benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, myristyl gamma picolinium chloride, phenol, 2- phenoxyethanol, phenyl mercuric nitrate, phenyl ethyl alcohol, ethylenediaminetetraacetic acid (EDTA), or any combination thereof. As per the preferred embodiment of the present invention, sodium benzoate is used as a preservative.

As per one embodiment of the present invention, sodium benzoate or at least one preservative can be used in the range from about 0.01 mg/mL to about 10 mg/mL, preferably about 0.01 mg/mL to about 8 mg/mL, preferably about 0.01 mg/mL to about 6 mg/mL, more preferably about 0.05 mg/mL to about 5 mg/mL, and most preferably about 0.05 mg/mL to about 3 mg/mL, or any other value in between thereof.

As per one embodiment of the present invention, at least one flavouring agent can be selected from but not limited to vanilla, citrus oil, including lemon, orange, grape, lime, and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums, pineapple, apricot, frozen peppermint, tutti frutti flavor, and so forth and the like, or any combination thereof.

As per the preferred embodiment of the present invention, frozen peppermint flavor is used as a flavouring agent.

As per one embodiment of the present invention, frozen peppermint or at least one flavouring agent can be used in the range from about 0.01 mg/mL to about 2 mg/mL, preferably about 0.01 mg/mL to about 1 mg/mL, preferably about 0.05 mg/mL to about 1 mg/mL, more preferably about 0.05 mg/mL to about 0.8 mg/mL, and most preferably about 0.05 mg/mL to about 0.5 mg/mL, or any other value in between thereof.

Vehicle can be considered as any inert substance, or mixture of substances, added to increase the volume of the liquid formulation of present invention in order to make the liquid formulation of the present invention suitable form. As per one embodiment of the present invention, at least one vehicle can be selected from purified water, glycerin, propylene glycol, glycerin containing buffers, or any combination thereof.

As per preferred embodiment of the present invention, purified water is used as vehicle.

According to one preferred embodiment, the amount of vehicle may present in sufficient quantity to make up the final volume.

According to one preferred embodiment, the amount of vehicle may present in an amount sufficient to make 100 % w/v.

As per one embodiment of the present invention, the liquid formulation can be selected from solution, suspension, or emulsion.

As per the preferred embodiment of the present invention, the liquid formulation is a solution.

As per one embodiment, the pH of an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is in the range from about 2 to about 7, preferably in the range from about 3 to about 6, more preferably in the range from about 3 to about 5, and most preferably in the range from about 3.5 to about 4.5, or any other value in between thereof.

As per another main embodiment of the present invention, the process of preparation of an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof comprises steps of: mixing together a metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutically acceptable excipients. Preferably the process includes adding of purified water in manufacturing vessel.

Preferably the process includes adding of glycerin.

Preferably the process includes adding of citric acid anhydrous.

Preferably the process includes adding of tri-sodium citrate dihydrate.

Preferably the process includes adding of sodium benzoate.

Preferably the process includes adding of sucralose.

Preferably the process includes adding of metoprolol or pharmaceutically acceptable salts thereof.

Preferably the process includes adding of frozen peppermint flavor.

Preferably the process includes to make up the final volume with purified water.

Preferably the process includes filling the solution in the suitable container i.e. bottle.

Preferably the process includes sealing and packing the bottle.

As per another embodiment of the present invention, the process of preparation of an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof comprises step of: a) Mixing glycerin in purified water with stirrer at 900 - 1400 rpm till completely solubilized; b) Adding citric acid in solution of step (a) with stirring at 900 - 1400 rpm till completely solubilized; c) Adding sodium citrate in solution of step (b) with stirring at 900 - 1400 rpm till completely solubilized; d) Adding sucralose in solution of step (c) with stirring at 900 - 1400 rpm till completely solubilized; e) Adding metoprolol or pharmaceutically acceptable salts thereof in solution of step (d) with stirring at 900 - 1400 rpm till completely solubilized; f) Adding frozen peppermint flavour in solution of step (e) with stirring at 900 - 1400 rpm till completely solubilized; g) Adjusting the final volume with purified water. As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 500 mg/mL; at least one viscosifying agent; one or more buffering agent; at least one sweetening agent; at least one preservative; at least one flavoring agent, and at least one vehicle.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 50 mg/mL; at least one viscosifying agent in an amount from about 200 mg/mL to about 400 mg/mL; at least one vehicle, and one or more pharmaceutically acceptable excipients.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 50 mg/mL; one or more buffering agent in an amount from about 5 mg/mL to about 30 mg/mL; at least one vehicle, and one or more pharmaceutically acceptable excipients.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 50 mg/mL; at least one viscosifying agent in an amount from about 200 mg/mL to about 400 mg/mL; one or more buffering agent in an amount from about 5 mg/mL to about 30 mg/mL; at least one vehicle, and one or more pharmaceutically acceptable excipients.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 50 mg/mL; at least one viscosifying agent in an amount from about 200 mg/mL to about 400 mg/mL; one or more buffering agent in an amount from about 5 mg/mL to about 30 mg/mL; at least one vehicle, and one or more pharmaceutically acceptable excipients; wherein the said formulation is free or void of alkyl esters of p-hydroxybenzoic acid, polysaccharide polymers, alcohol, and anti-oxidant.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.01 % w/v to about 5 % w/v; one or more pharmaceutically acceptable excipients in an amount from about 0.01 % w/v to about 99 % w/v, and at least one vehicle; wherein one or more pharmaceutically acceptable excipient is selected from group consisting of a viscosifying agent; a buffering agent; a sweetening agent; a preservative, and a flavoring agent.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 500 mg/mL; at least one viscosifying agent in an amount from about 1 mg/mL to about 500 mg/mL; one or more buffering agent in an amount from about 0.5 mg/mL to about 30 mg/mL; at least one sweetening agent in an amount from about 0.1 mg/mL to about 20 mg/mL; at least one preservative in an amount from about 0.01 mg/mL to 10 mg/mL; at least one flavoring agent in an amount from about 0.01 mg/mL to about 2 mg/mL, and at least one vehicle; wherein the said formulation is free or void of alkyl esters of p-hydroxybenzoic acid, polysaccharide polymers, oligosaccharides, alcohol, and anti-oxidants.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 500 mg/mL; at least one viscosifying agent in an amount from about 1 mg/mL to about 500 mg/mL; one or more buffering agent in an amount from about 0.5 mg/mL to about 30 mg/mL; at least one sweetening agent in an amount from about 0.1 mg/mL to about 20 mg/mL; at least one preservative in an amount from about 0.01 mg/mL to 10 mg/mL; at least one flavoring agent in an amount from about 0.01 mg/mL to about 2 mg/mL, and at least one vehicle.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.1 mg/mL to about 500 mg/mL; at least one viscosifying agent glycerin in an amount from about 1 mg/mL to about 500 mg/mL; a combination of buffering agent sodium citrate, and citric acid in an amount from about 0.5 mg/mL to about 30 mg/mL; at least one sweetening agent sucralose in an amount from about 0.1 mg/mL to about 20 mg/mL; at least one preservative sodium benzoate in an amount from about 0.01 mg/mL to 10 mg/mL; at least one flavoring agent frozen peppermint in an amount from about 0.01 mg/mL to about 2 mg/mL, and at least one vehicle purified water.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.5 mg/mL to about 20 mg/mL; at least one viscosifying agent glycerin in an amount from about 200 mg/mL to about 500 mg/mL; a combination of buffering agent sodium citrate, and citric acid in an amount from about 5 mg/mL to about 25 mg/mL; at least one sweetening agent sucralose in an amount from about 0.5 mg/mL to about 5 mg/mL; at least one preservative sodium benzoate in an amount from about 0.05 mg/mL to about 3 mg/mL; at least one flavoring agent frozen peppermint in an amount from about 0.05 mg/mL to about 0.5 mg/mL, and at least one vehicle purified water.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol comprising metoprolol or pharmaceutically acceptable salts thereof in an amount of about 10 mg/mL; at least one viscosifying agent glycerin in an amount of about 315 mg/mL; a combination of buffering agent sodium citrate in an amount of about 9.84 mg/mL, and citric acid in an amount of about 12.78 mg/mL; at least one sweetening agent sucralose in an amount of about 1 mg/mL; at least one preservative sodium benzoate in an amount of about 1 mg/mL; at least one flavoring agent frozen peppermint in an amount of about 0.1 mg/mL, and at least one vehicle purified water.

According to one embodiment, the present invention can be taken orally and ready - to-use (RTU).

As per the preferred embodiment of the present invention, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is an immediate-release formulation.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is stable and provides better patient compliance.

As per the preferred embodiment of the present invention, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is dissolved more than 50 % in 10 minutes, dissolved more than 60 % in 10 minutes, dissolved more than 70 % in 10 minutes; dissolved more than 80 % in 10 minutes, or dissolved more than 90 % in 10 minutes.

According to one embodiment, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is stable for 1 month, 3 months, and 6 months at 40 °C ± 2 °C / NMT 25 % RH or 25 °C ± 2 °C / 60 % RH ± 5 % RH.

According to one embodiment, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is stable for 1 month, 3 months, 6 months, 12 months, 18 months, 24 months or longer time at 40 °C ± 2 °C / NMT 25 % RH or 25 °C ± 2 °C / 60 % RH ± 5 % RH. According to one embodiment, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is stable at 40 °C ± 2 °C /NMT 25 % RH or 25 °C ± 2 °C / 60 % RH ± 5 % RH for at least 6 months.

According to one embodiment, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is stable under stress conditions like light exposure of illumination of 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200-watt hours/square meter.

According to one embodiment, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof has a total impurities are less than 1.0 % and any single unspecified impurities are less than 0.2 % after 1 month, 3 months, and 6 months of storage at 40 °C ± 2 °C / NMT 25 % RH or 25 °C ± 2 °C / 60 % RH ± 5 % RH.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof can be useful in the treatment of cardiovascular diseases like angina pectoris, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension.

As per one embodiment of the present invention, an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof for use as a medicament for the treatment of cardiovascular diseases like angina pectoris, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, 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. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for illustrative discussion of preferred embodiments of the invention.

EXAMPLES

EXAMPLE 1: THE EFFECT OF GLYCERIN IN PRESENCE OF BUFFER

ON FORMULATION

To evaluate how glycerin affects the stability of metoprolol tartrate in different buffer environments, trials were conducted using purified water, citrate buffer at pH 4, and phosphate buffer at pH 7, all containing glycerin. Formulations are summarized in below table:

Q.S.: Quantity Sufficient; mM: Millimolar

Table 1: Effect of glycerin in the presence of buffer on the stability of metoprolol tartrate Result:

Table 2: Results of effect of glycerin in the presence of buffer on the stability of metoprolol tartrate

Based on the above data it was concluded that the batch having the presence of phosphate buffer or purified water in combination with glycerin showed an increase in level of impurities as compared to the batch with citrate buffer with glycerin. Therefore, citrate buffer pH 4 with glycerin was finalized.

EXAMPLE 2: THE EFFECT OF DIFFERENT CONCENTRATION OF GLYCERIN ON FORMULATION

To assess how varying concentrations of glycerin impact the stability of metoprolol tartrate, trials were conducted using citrate buffer at pH 4 with different levels of glycerin concentration. Formulations are summarized in below table:

Q.S.: Quantity Sufficient

Table 3: Effect of different concentrations of glycerin on the stability of metoprolol tartrate

Result:

NMT: Not more than; M: Month; RH: Relative humidity; BQL: Below quantification limit; ND:

Not Detected Table 4: Results of the effect of 189 mg/mL concentration of glycerin on the stability of metoprolol tartrate (Batch No.: METL/260521/1013)

Not Detected

Table 5: Results of effect of 315 mg/mL concentration of glycerin on the stability of metoprolol tartrate (Batch No.: METL/260521/1014)

NMT: Not more than; M: Month; RH: Relative humidity; BQL: Below quantification limit; ND: Not Detected

Table 6: Results of effect of 441 mg/mL concentration of glycerin on the stability of metoprolol tartrate (Batch No.: METL/260521/1015)

Based on the data from the tables above, it was concluded that the batches prepared with varying concentrations of glycerin remained stable when combined with citrate buffer. The optimal glycerin concentration determined was 315 mg/ml, as this level provided the best consistency for the final product. Concentrations of 189 mg/ml resulted in a slightly runny consistency, while 441 mg/ml produced a more viscous texture. Consequently, further studies were conducted using the product with citrate buffer and glycerin as a viscosifying agent.

EXAMPLE 3: FORMULATION OF AN ORAL LIQUID SOLUTION OF METOPROLOL TARTRATE (B)

Table 7: Formulation of an oral liquid solution of metoprolol tartrate (B)

EXAMPLE 4: FORMULATION OF AN ORAL LIQUID SOLUTION OF METOPROLOL TARTRATE (Bl)

Table 8: Formulation of an oral liquid solution of metoprolol tartrate (Bl)

EXAMPLE 5: FORMULATION OF AN ORAL LIQUID SOLUTION OF METOPROLOL TARTRATE (B2)

Table 9: Formulation of an oral liquid solution of metoprolol tartrate (B2) EXAMPLE 6: FORMULATION OF AN ORAL LIQUID SOLUTION OF

METOPROLOL TARTRATE (B3)

Table 10: Formulation of an oral liquid solution of metoprolol tartrate (B3)

Procedure: a) The glycerin was mixed in purified water with stirrer at 900 - 1400 rpm till completely solubilized; b) The citric acid was added in the solution of step (a) with stirring at 900 - 1400 rpm till completely solubilized; c) The sodium citrate was added in the solution of step (b) with stirring at 900 - 1400 rpm till completely solubilized; d) The sodium benzoate was added in the solution of step (c) with stirring at 900 - 1400 rpm till completely solubilized; e) The sucralose was added in the solution of step (d) with stirring at 900 - 1400 rpm till completely solubilized; f) The Metoprolol tartrate was added in the solution of step (e) with stirring at 900 - 1400 rpm till completely solubilized; g) The frozen peppermint flavour was added in the solution of step (f) with stirring at 900 - 1400 rpm till completely solubilized; h) The final volume was adjusted with purified water.

EXAMPLE 7: DISSOLUTION STUDY OF AN ORAL LIQUID FORMULATION OF METOPROLOL TARTRATE WITH MARKETED TABLET FORMULATION (B3)

The marketed tablet formulation (LOPRESSOR 100 mg tablets), and oral solution as per the present invention, were assessed for their dissolution profiles using phosphate buffer at pH 6.8, 0.01 N HC1, and pH 4.5 acetate buffer as dissolution media.

Result:

RSD: Relative Standard Deviation

Table 11: Dissolution profile comparison of metoprolol tartrate oral solution

10 mg/mL & LOPRESSOR 100 mg in phosphate buffer pH 6.8

RSD: Relative Standard Deviation

Table 12: Dissolution profile comparison of metoprolol tartrate oral solution 10 mg/mL & LOPRESSOR 100 mg in 0.1N HCL

RSD: Relative Standard Deviation

Table 13: Dissolution profile comparison of metoprolol tartrate oral solution 10 mg/mL & LOPRESSOR 100 mg in pH 4.5 acetate buffer media

Based on the dissolution data, it was concluded that batch B3 shows a faster dissolution profile than the marketed tablet formulation. EXAMPLE 8: THERMAL STABILITY DATA OF FORMULATION (B3)

The thermal stability study was conducted for formulation at accelerated stability

5 conditions 40°C±2°C/NMT 75% RH and 25°C±2°C/60±5%RH.

Result:

Not Detected

10

Table 14: Results of the stability study Based on the above data, it was concluded that the product is stable up to 6M at accelerated and real temperature stability conditions.

EXAMPLE 9: STRESS STUDIES

Stress studies (photostability and freeze-thaw) were performed to evaluate and verify the product processing and handling during storage and transportation to establish controlled storage and handling. 9.1: PHOTOSTABILITY STUDIES

The B3 formulation was filled into the 185 mL HDPE bottle and subjected to a photostability study. The total light exposure of an overall illumination of 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200- watt hours/ square meter was provided.

Result:

NMT: Not more than; BQL: Below quantification limit; HDPE: High Density Poly Ethylene;

PET: Polyethylene Terephthalate Table 15: Results of the photostability study

As per the results in the above table, when the product was exposed to light in a clear bottle single maximum impurity was detected at 0.15%. Therefore, it was concluded that the product was getting affected by exposure to light in a clear PET bottle and not getting affected in an HDPE bottle.

9.2: FREEZE-THAW STUDIES

The B3 formulation bottles were subjected to a temperature cycle of -20°C ± 5°C for 2 days followed by 40°C ± 2°C for 2 days. The product bottles were subjected to three such cycles.

Result:

NMT: Not more than; BQL: Below quantification limit; HDPE: High-Density Poly Ethylene

Table 16: Results of freeze-thaw study

The results indicated that the product stability was not affected by the extreme temperature conditions encountered by the drug product and the product can withstand limited temperature excursions during the transportation process.

Claims

1. An oral liquid formulation of metoprolol comprising: metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutical acceptable excipients.

2. The oral liquid formulation of metoprolol as claimed in claim 1, wherein said pharmaceutically acceptable salts can be selected from succinate, citrate, acetate, maleate, tartrate, and fumarate, more preferably, tartrate.

3. The oral liquid formulation of metoprolol as claimed in claim 1, wherein said metoprolol tartrate used in the range from about 0.1 mg/mL to about 500 mg/mL, more preferably from about 0.5 mg/mL to about 30 mg/mL, and most preferably from about 0.5 mg/mL to 20 mg/mL.

4. The oral liquid formulation of metoprolol as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from a group consisting of a viscosifying agent; a sweetening agent; a preservative, and a flavoring agent.

5. The oral liquid formulation of metoprolol as claimed in claim 1, wherein the said formulation is free or void of alkyl esters of p-hydroxybenzoic acid, polysaccharide polymers, oligosaccharides, alcohol, and anti-oxidants.

6. The oral liquid formulation of metoprolol as claimed in claim 1, wherein the said liquid formulation has a pH range from about 3 to about 5.

7. The oral liquid formulation of metoprolol as claimed in claim 1, wherein said liquid formulation can be selected from solution, suspension or emulsion, more preferably, solution.

8. The oral liquid formulation of metoprolol as claimed in claim 1, wherein said solution is stable at 40 °C ± 2 °C / NMT 25 % RH or 25 °C ± 2 °C / 60 % RH ± 5 % RH for at least 6 months.

9. The oral liquid formulation of metoprolol as claimed in claim 1, wherein the said solution contains total impurities less than 1.0 % and any single impurities less than 0.2 % after 1 month, 3 months, and 6 months storage at 40 °C ± 2 °C / NMT 25 % RH or 25 °C ± 2 °C / 60 % RH ± 5 % RH.

10. The oral liquid formulation of metoprolol as claimed in claim 1, can be useful in the treatment of cardiovascular diseases like angina pectoris, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension.

11. An oral liquid formulation of metoprolol comprising: metoprolol or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 500 mg/mL; at least one viscosifying agent glycerin in an amount from about 1 mg/mL to about 500 mg/mL; a combination of buffering agent sodium citrate and citric acid in an amount from about 0.5 mg/ml to about 30 mg/mL; at least one sweetening agent sucralose in an amount from about 0.1 mg/mL to about 20 mg/mL; at least one preservative sodium benzoate in an amount from about 0.01 mg/mL to 10 mg/mL; at least one flavoring agent frozen peppermint in an amount from about 0.01 mg/mL to about 2 mg/mL, and at least one vehicle purified water.

12. An oral liquid formulation of metoprolol comprising: metoprolol or pharmaceutically acceptable salts thereof in an amount from about 0.01 % w/v to about 5 % w/v; one or more pharmaceutically acceptable excipients, and at least one vehicle; wherein one or more pharmaceutically acceptable excipient is selected from group consisting of a viscosifying agent; a buffering agent; a sweetening agent; a preservative, and a flavoring agent.

13. A process of preparation of an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof comprises steps of: mixing together a metoprolol or pharmaceutically acceptable salts thereof; one or more buffering agent; at least one vehicle, and one or more pharmaceutically acceptable excipients.

14. The process of preparation of an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof as claimed in claim 13, comprising the steps of: the said process includes adding of purified water in the manufacturing vessel; the said process includes adding of glycerin; the said process includes adding of citric acid anhydrous; the said process includes adding of tri-sodium citrate dihydrate; the said process includes adding of sodium benzoate; the said process includes adding of sucralose; the said process includes adding of metoprolol or pharmaceutically acceptable salt thereof; the said process includes adding of frozen peppermint flavor; the said process includes to make up the final volume with purified water; the said process includes filling the solution in the suitable container i.e. bottle; the said process includes sealing and packing the bottle.