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WO2025068937A1 - Formulation liquide orale de métoprolol - Google Patents

Formulation liquide orale de métoprolol Download PDF

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Publication number
WO2025068937A1
WO2025068937A1 PCT/IB2024/059407 IB2024059407W WO2025068937A1 WO 2025068937 A1 WO2025068937 A1 WO 2025068937A1 IB 2024059407 W IB2024059407 W IB 2024059407W WO 2025068937 A1 WO2025068937 A1 WO 2025068937A1
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WO
WIPO (PCT)
Prior art keywords
metoprolol
liquid formulation
oral liquid
pharmaceutically acceptable
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/059407
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English (en)
Inventor
Manish UMRETHIA
Chintan PANSARA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Liqmeds Worldwide Ltd
Original Assignee
Liqmeds Worldwide Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liqmeds Worldwide Ltd filed Critical Liqmeds Worldwide Ltd
Priority to GB2416809.8A priority Critical patent/GB2635613A/en
Publication of WO2025068937A1 publication Critical patent/WO2025068937A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • cellulose derivatives like hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or methyl
  • metoprolol tartrate 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).
  • 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.
  • antioxidants like sodium metabisulphite
  • 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.
  • the main objective of the present invention is to develop an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof.
  • 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.
  • 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.
  • 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”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the formulation includes at least the recited features or components, but may also include additional features or components.
  • 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.
  • active can be understood 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.
  • therapeutically effective amount includes, for example, a prophylactically effective amount.
  • 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.
  • dose and “dosage” can be understood to mean a specific amount of active or therapeutic agents for administration.
  • liquid formulation refers to liquid oral formulation like solution, suspension, or emulsion, more preferably in the form of solution.
  • 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.
  • pH 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.
  • glycosylin can be interchangeably used with the term “glycerol” as both are the same.
  • active excipients can be interchangeably used with the term “pharmaceutically acceptable excipients” as both are the same.
  • viscosifying agent can be interchangeably used with the term “viscosity increasing agent” as both are the same.
  • ready-to-use is defined as the solution that can administered directly to a patient for a treatment without the steps such as reconstitution or dilution.
  • RTU refers to ready-to-use and can interchangeably use for the “ready-to-use” phrase.
  • 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
  • preservatives for example
  • 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.
  • 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.
  • the pharmaceutically acceptable salts of metoprolol can be selected from tartrate, succinate, citrate, acetate, maleate, and fumarate.
  • the pharmaceutically acceptable salt is tartrate.
  • the pharmaceutically acceptable salt is succinate.
  • 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.
  • 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.
  • 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.
  • glycerin is used as a viscosifying agent.
  • 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.
  • GRAS generally recognized as safe
  • the pH of the liquid formulation of the present invention can be adjusted in the range from about 3 to about 5.
  • 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.
  • one or more buffering agent preferably a combination of two buffering agents.
  • citrate buffer is used as a buffering agent which contains combination of sodium citrate, and citric acid.
  • 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.
  • 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.
  • 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.
  • one or more pharmaceutically acceptable excipients can be selected from a sweetening agent, a preservative, and a flavouring agent.
  • 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.
  • 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.
  • sucralose is used as a sweetening agent.
  • 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.
  • 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.
  • sodium benzoate is used as a preservative.
  • 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.
  • 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.
  • frozen peppermint flavor is used as a flavouring agent.
  • 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.
  • at least one vehicle can be selected from purified water, glycerin, propylene glycol, glycerin containing buffers, or any combination thereof.
  • purified water is used as vehicle.
  • the amount of vehicle may present in sufficient quantity to make up the final volume.
  • the amount of vehicle may present in an amount sufficient to make 100 % w/v.
  • the liquid formulation can be selected from solution, suspension, or emulsion.
  • the liquid formulation is a solution.
  • 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.
  • 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.
  • the process includes adding of purified water in manufacturing vessel.
  • the process includes adding of glycerin.
  • the process includes adding of citric acid anhydrous.
  • the process includes adding of tri-sodium citrate dihydrate.
  • the process includes adding of sodium benzoate.
  • the process includes adding of sucralose.
  • the process includes adding of metoprolol or pharmaceutically acceptable salts thereof.
  • the process includes adding of frozen peppermint flavor.
  • the process includes to make up the final volume with purified water.
  • the process includes filling the solution in the suitable container i.e. bottle.
  • the process includes sealing and packing the bottle.
  • 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) Adjust
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention can be taken orally and ready - to-use (RTU).
  • RTU ready - to-use
  • an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is an immediate-release formulation.
  • an oral liquid formulation of metoprolol or pharmaceutically acceptable salts thereof is stable and provides better patient compliance.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • cardiovascular diseases like angina pectoris, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension.
  • NMT Not more than; M: Month; RH: Relative humidity; BQL: Below quantification limit; ND:
  • NMT Not more than; M: Month; RH: Relative humidity; BQL: Below quantification limit; ND:
  • NMT Not more than; M: Month; RH: Relative humidity; BQL: Below quantification limit; ND: Not Detected
  • 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.
  • Table 12 Dissolution profile comparison of metoprolol tartrate oral solution 10 mg/mL & LOPRESSOR 100 mg in 0.1N HCL
  • Table 13 Dissolution profile comparison of metoprolol tartrate oral solution 10 mg/mL & LOPRESSOR 100 mg in pH 4.5 acetate buffer media
  • NMT Not more than; M: Month; RH: Relative humidity; BQL: Below quantification limit; ND:
  • 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.
  • PET Polyethylene Terephthalate Table 15: Results of the photostability study
  • 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.
  • NMT Not more than
  • BQL Below quantification limit
  • HDPE High-Density Poly Ethylene

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Abstract

La présente invention concerne une formulation liquide orale de métoprolol. La présente invention concerne également une formulation liquide orale de métoprolol qui comprend du métoprolol ou des sels pharmaceutiquement acceptables de celui-ci; un ou plusieurs agents tampons; au moins un véhicule et un ou plusieurs excipients pharmaceutiquement acceptables. La présente invention concerne également le procédé de préparation d'une formulation liquide orale de métoprolol.
PCT/IB2024/059407 2023-09-30 2024-09-26 Formulation liquide orale de métoprolol Pending WO2025068937A1 (fr)

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GB2416809.8A GB2635613A (en) 2023-09-30 2024-09-26 An oral liquid formulation of metoprolol

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IN202321065858 2023-09-30
IN202321065858 2023-09-30

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5484776A (en) 1992-03-13 1996-01-16 Synepos Aktiengesellschaft Process for the production of stable liquid form of beta-blocker-containing medicaments with controlled release of the active constituent for oral administration
WO2010122442A1 (fr) 2009-04-21 2010-10-28 Pierre Fabre Dermo-Cosmetique Solutions pédiatriques comprenant un bétabloquant
US9629920B2 (en) * 2009-12-18 2017-04-25 Exodos Life Sciences Limited Partnership Methods and compositions for stable liquid drug formulations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5484776A (en) 1992-03-13 1996-01-16 Synepos Aktiengesellschaft Process for the production of stable liquid form of beta-blocker-containing medicaments with controlled release of the active constituent for oral administration
WO2010122442A1 (fr) 2009-04-21 2010-10-28 Pierre Fabre Dermo-Cosmetique Solutions pédiatriques comprenant un bétabloquant
US9629920B2 (en) * 2009-12-18 2017-04-25 Exodos Life Sciences Limited Partnership Methods and compositions for stable liquid drug formulations

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