WO2023233422A1 - Oral liquid formulation of tranexamic acid or its pharmaceutically acceptable salt thereof - Google Patents

Oral liquid formulation of tranexamic acid or its pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2023233422A1
WO2023233422A1 PCT/IN2023/050509 IN2023050509W WO2023233422A1 WO 2023233422 A1 WO2023233422 A1 WO 2023233422A1 IN 2023050509 W IN2023050509 W IN 2023050509W WO 2023233422 A1 WO2023233422 A1 WO 2023233422A1
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Prior art keywords
liquid formulation
pharmaceutically acceptable
tranexamic acid
formulation
acceptable salt
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PCT/IN2023/050509
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French (fr)
Inventor
Girish Shantilal Achliya
Mayur Dilip KAPADIA
Gaurav Sureshkumar MISTRY
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Syri Research Private Limited
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Publication of WO2023233422A1 publication Critical patent/WO2023233422A1/en

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to an oral liquid formulation of Tranexamic acid or pharmaceutically acceptable salt thereof.
  • the present invention particularly relates to stable suspension formulation of Tranexamic acid or pharmaceutically acceptable salt thereof.
  • This invention also relates to the process for the preparation of said formulation.
  • Fibrinolysis is a physiological process where the activated plasminogen removes excess fibrin and promotes better fibrin clot formation and wound healing.
  • Tissue plasminogen activator (t-PA) and other activators of plasminogen are first line agents in lysis therapy.
  • Inhibitors of this process act at the step where plasminogen is converted to plasmin, by reversely blocking the lysine binding sites of plasmin or by active inhibition of plasmin via serine protease inhibition.
  • the drugs used for inhibition of fibrinolysis are the lysine analogues, tranexamic acid and s-aminocaproic acid, and the serine protease inhibitor, aprotinin. Aprotinin also inhibits trypsin, and decreases the activation of neutrophils and platelets.
  • Tranexamic acid is an ant ifibrino lytic agent in the treatment of major bleeding. It is synthetic derivative of lysine.
  • the mechanism of action of tranexamic acid involves competitive and reversible inhibition of plasminogen activation via binding at several distinct sites, including four or five low-affinity sites and one high-affinity site, the latter of which is involved in its binding to fibrin.
  • the binding of plasminogen to fibrin induces fibrinolysis - by occupying the necessary binding sites tranexamic acid prevents this dissolution of fibrin, thereby stabilizing the clot and preventing hemorrhage.
  • Tranexamic acid has wide range of clinical applications in obstetric as well as surgical conditions. Obstetric conditions involve postpartum haemorrhage, abnormal uterine bleeding. While, surgical application involves cardiothoracic surgeries like coronary artery bypass grafting, loss of blood during orthopaedic surgery etc. Along with that, it also has therapeutic indication in conditions associated with heavy menstrual bleeding (menorrhagia), trauma, and dental surgeries. Tranexamic acid has more affinity for receptor binding as when compared with other fibrinolytic agents and the risk associated with bleeding is quite lower.
  • Tranexamic acid is chemically known as 4-(amino methyl) cyclohexane- 1 -carboxylic acid while GB 1097313 A discloses its process for preparation.
  • US8968777B2 discloses delayed release solid dosage form of Tranexamic acid wherein the delayed release material comprises a copolymer of methacrylic acid with an acrylate or methacrylate ester.
  • Patent application US20040006021A1 discloses the injection or infusion comprising Tranexamic acid and factor Vll-related polypeptide.
  • the present invention provides solution for above mentioned prior arts with respect to difficulty in administration of solid dosage form and administration of injection or infusion. Additionally Tranexamic acid has a bitter taste and unstable in case of liquid formulation.
  • the objective of the invention is to provide a stability for a longer period of time, easy to administer, palatable, patient compliance and easy to manufacture oral liquid formulation of Tranexamic acid.
  • the present invention relates to a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient.
  • the present invention provides a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
  • the present invention provides a stable liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the formulation is stable for at least one month or two month or three month or six month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
  • the present invention provides a stable liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
  • the present invention provides a stable liquid formulation comprising: a) Tranexamic acid or pharmaceutically acceptable salt thereof; b) suspending agent; c) preservative; d) sweetener; and e) one or more pharmaceutically acceptable excipient.
  • the present invention provides a stable liquid formulation comprising: a) 0.01-20% w/v of Tranexamic acid or pharmaceutically acceptable salt thereof; b) 0.01-15% w/v of suspending agent; c) 0.001- 3% w/v of preservative; d) 0.001-5% w/v of sweetener; and e) one or more pharmaceutically acceptable excipient.
  • the present invention provides a process for the preparation of liquid formulation, comprising a) adding preservative in vehicle and dissolving to obtain a clear solution; b) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; c) adding suspending agent in the above mixture and mixing to achieve a lump free uniform suspension; d) adding flavouring agent to the above suspension; e) adding buffering agent to the above suspension to adjust the pH; and f) adding vehicle to make up the volume.
  • the present invention provides a process for the preparation of liquid formulation, comprising a) adding suspending agent in vehicle and mixing to obtain a clear solution; b) adding preservative in the above mixture to obtain a clear solution; c) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; and d) adding vehicle to make up the volume.
  • the present invention provides a method for using liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof for treating bleeding disorder, preventing or treating hemorrhage under general or local fibrinolysis for pre/post- operative hemorrhage, used for dental extraction in patients with haemophilia, used to prevent excess bleeding in patients with menorrhagia (heavy menstrual bleeding) and hereditary angioneurotic edema.
  • terapéuticaally effective amount is defined to mean the amount or quantity of the active drug (e.g. Tranexamic acid or a pharmaceutically acceptable salt), which is sufficient to elicit an appreciable biological response when administered to the patient.
  • active drug e.g. Tranexamic acid or a pharmaceutically acceptable salt
  • excipient or “ingredient” means a pharmacologically inactive component such as a vehicle, suspending agent, preservative, sweetener, or the like.
  • the excipient that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.
  • formulation or “composition” or “pharmaceutical composition” or “dosage form” or “liquid formulation” or “liquid pharmaceutical composition” as used herein synonymously include dosage forms such as suspension, solution and the like.
  • stable or “stability” encompass any characteristic of the liquid compositions which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and colour and clarity.
  • the storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.
  • “Pharmaceutically acceptable excipient (s)” are components that are added to the pharmaceutical composition other than the active ingredient Tranexamic acid. Excipient may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc.
  • Pharmaceutically acceptable excipient(s) includes, but not limited to suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents, suitable vehicle, isotonizing agent, anticaking agent and any other excipient known to the art for making pharmaceutical formulation. According to the present invention a particular excipient may perform multiple roles in the pharmaceutical formulation, for example, it can act both as a preservative and/or as a pH adjusting agents.
  • the present invention is related to a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient.
  • the present invention is related to a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
  • the present inventors have surprisingly found that the suspension formulations of Tranexamic acid can be administered effectively in the paediatric population and adults who are unable to swallow a solid dosage form. It is an object of the present invention to provide a stable oral suspension formulation of Tranexamic acid or pharmaceutically acceptable salt thereof.
  • the present invention related to a stable liquid formulation of Tranexamic acid comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
  • the storage conditions used in the present invention are 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
  • the ‘storage condition of 25°C/60% RH’ means storage at a temperature of 25°C and 60% relative humidity.
  • the ‘storage condition of 30°C/65% RH’ means storage at a temperature of 30°C and 65% relative humidity
  • the ‘storage condition of 40°C/75% RH’ means storage at a temperature of 40°C and 75% relative humidity.
  • the ‘storage condition of 2-8°C’ means storage at a temperature of 2 to 8°C.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 25°C/60% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 25°C/60% RH.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 30°C/65% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 30°C/65% RH.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 40°C/75% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 40°C/75% RH.
  • the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 2-8°C. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 2- 8 °C.
  • an invention provides a stable oral liquid formulation comprising: a) Tranexamic acid or pharmaceutically acceptable salt thereof; b) suspending agent; c) preservative; d) sweetener; and e) one or more pharmaceutically acceptable excipient.
  • an invention provides a stable oral liquid formulation comprising: a) 0.01 -20% w/v of Tranexamic acid or pharmaceutically acceptable salt thereof; b) 0.01%-15% w/v of suspending agent; c) 0.001-3% w/v of preservative; d) 0.001-5% w/v of sweetener; and e) one or more pharmaceutically acceptable excipient.
  • Another embodiment of an invention provides the process for the preparation of stable oral liquid formulation comprising: a) adding preservative in vehicle and dissolving to obtain a clear solution; b) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; c) adding suspending agent in the above mixture and mixing to achieve a lump free uniform suspension; d) adding flavouring agent to the above suspension; e) adding buffering agent to the above suspension to adjust the pH; and f) adding vehicle to make up the volume.
  • Another embodiment of an invention provides the process for the preparation of stable oral liquid formulation comprising: a) adding suspending agent in vehicle and mixing to obtain a clear solution; b) adding preservative in the above mixture to obtain a clear solution; c) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; and d) adding vehicle to make up the volume.
  • Tranexamic Acid as used herein comprises trans-4- ( Amino methyljcyclo hexanecarboxy lie acid with a molecular weight of 157.21 g/mol. Further the term “Tranexamic Acid” means all varieties or forms of Tranexamic Acid including, but not limited to all pharmaceutically acceptable salts, esters, amides, isomers, stereo isomers, crystalline and amorphous forms.
  • the amount of Tranexamic Acid in the formulation of the invention may vary depending on the total volume of formulation and the concentration of the other components.
  • the amount of Tranexamic Acid according to the invention may be present at a concentration of from 0.01 to 20% w/v, and preferably from 0.05 to 18% w/v and more particularly from 0.1 to 15% w/v.
  • the one or more pharmaceutically acceptable excipient are selected from group consisting of buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents, suitable vehicle, isotonizing agent, viscosity modifying agent, anticaking agent and any other excipient known to the art for making formulation.
  • buffers pH adjusting agents
  • preservatives antioxidants
  • solubilizers complexing agents
  • antifoaming agents sweeteners
  • flavouring agents suitable vehicle
  • isotonizing agent viscosity modifying agent
  • anticaking agent any other excipient known to the art for making formulation.
  • Suspending agents include, but are not limited to xanthan gum, gellan gum, guar gum, microcrystalline cellulose, sodium carbo xymethylcellulose, a mixture of carbo xymethylcellulose and microcrystalline cellulose, colloidal silicon dioxide, propylene glycol alginate and combinations thereof.
  • the suspending agent is a mixture of carbo xymethylcellulose and microcrystalline cellulose, sodium carbo xymethylcellulose and colloidal silicon dioxide.
  • the amount of the suspending agents in the formulation generally ranges from about 0.01 to 15% w/v, preferably about 0.01 to 12% w/v, and more particularly from about 0.1 to about 10% w/v.
  • Buffers/pH Adjuster which may be used, according to the present invention, include suitable buffers that are not chemically reactive with the other excipient, and which may be present in an amount sufficient to provide the desired degree of pH buffering.
  • a buffer system comprising of an aqueous mixture of an acid, wherein the acid is citric, succinic, tartaric, lactic, or phosphoric acid, and a base, wherein the base is sodium citrate dihydrate, sodium hydroxide, or disodium hydrogen phosphate, is for maintaining the pH in the range from 5 to 9.
  • Preservatives which may be used according to the present invention, include, but are not limited to, benzoic acid, sodium benzoate, potassium sorbate, cresol, cetrimide, citric acid and sodium citrate, and alkyl hydroxybenzoates (parabens).
  • the preservative is selected from an alkyl hydroxybenzoate, such as methyl hydroxybenzoate (MHB), ethyl hydroxybenzoate (EHB), propyl hydroxybenzoate (PHB) (as base or sodium salt) or a combination thereof.
  • the preservative is combination of MHB and PHB. More preferably, the preservative is combination of Na MHB and Na PHB.
  • the amount of the preservatives in the formulation generally ranges from about 0.001 to 3% w/v, preferably about 0.01 to 2% w/v, and more particularly from about 0.01 to about 1.5% w/v.
  • Solubilizers which may be used according to the present invention, include, but are not limited to polyhydric alcohol, ethanol, polyethylene glycol, non-ionic surfactant, an ionic surfactant, a hydrophilic polymer and a carbohydrate.
  • Non-limiting examples of non-ionic surfactants that can be used in the liquid formulation are polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers, polyoxyethylene castor oil derivatives, polyoxyglycerides, vitamin E polyethylene glycol succinate, and macrogol 15 hydroxystearate.
  • Non-limiting examples of ionic surfactants that can be used in the liquid formulation are sodium lauryl sulfate and docusate sodium.
  • Non-limiting examples of hydrophilic polymers that can be used in the liquid formulation are povidone (for example PVPK 12, Povidone K30), copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.
  • Non-limiting examples of polyhydric alcohols that can be used in the liquid formulation are glycerin, propylene glycol, sorbitol, and mannitol.
  • Non-limiting examples of polyethylene glycols that can be used in the liquid formulation are polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400.
  • Non-limiting examples of carbohydrates that can be used in the liquid formulation are fructose, sucrose, and lactose.
  • Anti-foaming agent can be a silicone based antifoam.
  • Antifoaming agent is preferably simethicone emulsion.
  • Antioxidants which may be used according to the present invention, include, but are not limited to sodium metabisulfate, ascorbic acid, sodium formaldehyde, sulfoxylate, or mixtures thereof.
  • Complexing agents which may be used according to the present invention, include, but are not limited to a-cyclodextrin, P-cyclodextrin, y-cyclodextrin and their derivatives such as, for example, hydroxypropyl- P-cyclodextrin.
  • Sweeteners or sweetening agents may be any natural or artificial sweetener.
  • natural sweeteners or sweetening agents these include, but are not limited to, glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins, and mixtures thereof.
  • artificial sweeteners these include, but are not limited to, sucralose, aspartame and saccharin. In one embodiment, the artificial sweetener is sucralose.
  • the amount of the sweetener or sweetening agents in the formulation generally ranges from about 0.001 to 5% w/v, preferably about 0.01 to 4% w/v, and more particularly from about 0.01 to about 2% w/v.
  • Flavouring agents or flavorant incorporated in the liquid formulation may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits, and so forth and combinations thereof. Other useful flavors are vanilla, citrus oils, including lemon, orange, lime and grapefruit, and fruit essence, including apple, grape, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth.
  • the amount of the flavouring agent or flavorant in the formulation generally ranges from about 0.001 to 2% w/v, preferably about 0.01 to 1.5% w/v, and more particularly from about 0.01 to about 1% w/v.
  • the vehicle used in the formulation of the invention is selected from glycerin, propylene glycol, water or combination thereof.
  • the vehicle used in the formulation of the invention is preferably purified water, although other suitable water-containing (aqueous) vehicles known to the skilled person may also be used.
  • the amount of water can be present from about 70% to about 99% w/v of the liquid formulation.
  • the present invention related a stable liquid formulation of Tranexamic acid comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient.
  • liquid formulation suitable for oral administration includes suspension, solution or the like and any combination thereof.
  • the stable liquid formulation of Tranexamic acid is in the form of a suspension.
  • the stable liquid formulation of Tranexamic acid is in the form of a solution.
  • the liquid formulation of Tranexamic acid is oral aqueous suspension or powder for oral suspension which meant to be administered after reconstitution in a suitable solvent.
  • a method for treating bleeding disorder preventing or treating hemorrhage under general or local fibrinolysis for pre/po st-operative hemorrhage, used for dental extraction in patients with haemophilia, used to prevent excess bleeding in patients with menorrhagia (heavy menstrual bleeding) and hereditary angioneurotic edema.
  • Tranexamic acid has a particle size distribution D(90) less than about 200pm, preferably less than about 180pm, more preferably less than about 150pm.
  • the present inventors have surprisingly found that the liquid formulations of Tranexamic acid can be administered effectively in the paediatric population and adults who are unable to swallow a solid dosage form. It is an object of the present invention to provide a stable liquid formulation of Tranexamic acid. Further object of the present invention is to provide a stable aqueous suspension formulation of Tranexamic acid.
  • the liquid formulation comprising Tranexamic acid provide improved or comparable bio availability as compared to known or marketed formulation.
  • the liquid formulation comprising Tranexamic acid provide faster absorption than solid, palatable, better choice especially for children and old age patients, more flexibility in achieving the proper dosage of medication and provides ease for the patients having difficulty in swallowing other oral dosage forms.
  • the liquid formulation comprising Tranexamic acid provides better chemical stability and larger surface area and is often more bioavailable than aqueous solutions, tablets, and capsules.
  • the liquid formulation comprising Tranexamic acid provides better palatability with increasing the patient compliance and patient acceptability towards the formulation.
  • the liquid formulation of Tranexamic acid is administered two or three or four times daily.
  • the liquid formulation may be packaged within any type of pharmaceutically acceptable package, bottles, container depending upon the quantity of the final dosage form.
  • Methyl paraben sodium and Propylparaben sodium were added in above solution mixing using silverson mixer for 15 min at 3000 RPM to obtain clear solution.
  • the suspension formulation of example 1 found to be stable for 3 months at storage conditions 25°C/60% RH, 30°C/65% RH and 40°C/75% RH.

Abstract

The present invention relates to an oral liquid formulation of Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration. The present invention particularly relates to a stable suspension formulation comprising Tranexamic acid or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient and also relates to the process for preparation of said formulation and its use in the treatment of bleeding disorder.

Description

Oral liquid formulation of Tranexamic acid or its pharmaceutically acceptable salt thereof
FIELD OF THE INVENTION
The present invention relates to an oral liquid formulation of Tranexamic acid or pharmaceutically acceptable salt thereof. The present invention particularly relates to stable suspension formulation of Tranexamic acid or pharmaceutically acceptable salt thereof. This invention also relates to the process for the preparation of said formulation.
BACKGROUND OF THE INVENTION
Fibrinolysis is a physiological process where the activated plasminogen removes excess fibrin and promotes better fibrin clot formation and wound healing. Tissue plasminogen activator (t-PA) and other activators of plasminogen are first line agents in lysis therapy. Inhibitors of this process act at the step where plasminogen is converted to plasmin, by reversely blocking the lysine binding sites of plasmin or by active inhibition of plasmin via serine protease inhibition. The drugs used for inhibition of fibrinolysis are the lysine analogues, tranexamic acid and s-aminocaproic acid, and the serine protease inhibitor, aprotinin. Aprotinin also inhibits trypsin, and decreases the activation of neutrophils and platelets.
Tranexamic acid is an ant ifibrino lytic agent in the treatment of major bleeding. It is synthetic derivative of lysine. The mechanism of action of tranexamic acid involves competitive and reversible inhibition of plasminogen activation via binding at several distinct sites, including four or five low-affinity sites and one high-affinity site, the latter of which is involved in its binding to fibrin. The binding of plasminogen to fibrin induces fibrinolysis - by occupying the necessary binding sites tranexamic acid prevents this dissolution of fibrin, thereby stabilizing the clot and preventing hemorrhage.
Tranexamic acid has wide range of clinical applications in obstetric as well as surgical conditions. Obstetric conditions involve postpartum haemorrhage, abnormal uterine bleeding. While, surgical application involves cardiothoracic surgeries like coronary artery bypass grafting, loss of blood during orthopaedic surgery etc. Along with that, it also has therapeutic indication in conditions associated with heavy menstrual bleeding (menorrhagia), trauma, and dental surgeries. Tranexamic acid has more affinity for receptor binding as when compared with other fibrinolytic agents and the risk associated with bleeding is quite lower.
Tranexamic acid is chemically known as 4-(amino methyl) cyclohexane- 1 -carboxylic acid while GB 1097313 A discloses its process for preparation.
US8968777B2 discloses delayed release solid dosage form of Tranexamic acid wherein the delayed release material comprises a copolymer of methacrylic acid with an acrylate or methacrylate ester.
Patent application US20040006021A1 discloses the injection or infusion comprising Tranexamic acid and factor Vll-related polypeptide.
A. P. H. Lee et al. (2005) in British Dental Journal reported use of tranexamic acid mouthwash after dental scaling is well tolerated by patients and is as effective as using factor replacement therapy before dental scaling in controlling gingival bleeding for people with haemophilia.
Currently, solid dosage form containing Tranexamic acid is available but difficulty in swallowing persists due to large size of tablet. This creates swallowing difficulty in paediatric and geriatric patient population. There are no oral liquid formulations available for Tranexamic acid or pharmaceutically acceptable salt thereof and in such circumstances; the practice of compounding the liquid dosage form from marketed solid dosage form is very conventional and well known for patients who have swallowing difficulties, where administration of accurate dose is compromised. For these patients, Tranexamic acid 500 mg tablets placed into 20 mL of water and stirred until the tablets are completely disintegrated to form suspension, but it has only five days of expiry if the solution is refrigerated and protected from light.
As per as wide range of therapeutic applications of Tranexamic acid in cases like trauma, obstetric and surgical conditions are considered, opting for an alternate formulation with ease of administration is one of the ways to cope with the difficulties. The present invention provides solution for above mentioned prior arts with respect to difficulty in administration of solid dosage form and administration of injection or infusion. Additionally Tranexamic acid has a bitter taste and unstable in case of liquid formulation. The objective of the invention is to provide a stability for a longer period of time, easy to administer, palatable, patient compliance and easy to manufacture oral liquid formulation of Tranexamic acid.
SUMMARY OF THE INVENTION
The present invention relates to a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient.
In another aspect, the present invention provides a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
In another aspect, the present invention provides a stable liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the formulation is stable for at least one month or two month or three month or six month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
In another aspect, the present invention provides a stable liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
In another aspect, the present invention provides a stable liquid formulation comprising: a) Tranexamic acid or pharmaceutically acceptable salt thereof; b) suspending agent; c) preservative; d) sweetener; and e) one or more pharmaceutically acceptable excipient.
In another aspect, the present invention provides a stable liquid formulation comprising: a) 0.01-20% w/v of Tranexamic acid or pharmaceutically acceptable salt thereof; b) 0.01-15% w/v of suspending agent; c) 0.001- 3% w/v of preservative; d) 0.001-5% w/v of sweetener; and e) one or more pharmaceutically acceptable excipient.
In another aspect, the present invention provides a process for the preparation of liquid formulation, comprising a) adding preservative in vehicle and dissolving to obtain a clear solution; b) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; c) adding suspending agent in the above mixture and mixing to achieve a lump free uniform suspension; d) adding flavouring agent to the above suspension; e) adding buffering agent to the above suspension to adjust the pH; and f) adding vehicle to make up the volume.
In another aspect, the present invention provides a process for the preparation of liquid formulation, comprising a) adding suspending agent in vehicle and mixing to obtain a clear solution; b) adding preservative in the above mixture to obtain a clear solution; c) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; and d) adding vehicle to make up the volume.
In another aspect, the present invention provides a method for using liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof for treating bleeding disorder, preventing or treating hemorrhage under general or local fibrinolysis for pre/post- operative hemorrhage, used for dental extraction in patients with haemophilia, used to prevent excess bleeding in patients with menorrhagia (heavy menstrual bleeding) and hereditary angioneurotic edema.
DETAILED DESCRIPTION OF THE INVENTION
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g. Tranexamic acid or a pharmaceutically acceptable salt), which is sufficient to elicit an appreciable biological response when administered to the patient. The term “excipient” or “ingredient” means a pharmacologically inactive component such as a vehicle, suspending agent, preservative, sweetener, or the like. The excipient that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.
The term “formulation” or “composition” or “pharmaceutical composition” or “dosage form” or “liquid formulation” or “liquid pharmaceutical composition” as used herein synonymously include dosage forms such as suspension, solution and the like.
As used herein, the terms “stable” or “stability” encompass any characteristic of the liquid compositions which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and colour and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.
“Pharmaceutically acceptable excipient (s)” are components that are added to the pharmaceutical composition other than the active ingredient Tranexamic acid. Excipient may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc. Pharmaceutically acceptable excipient(s) includes, but not limited to suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents, suitable vehicle, isotonizing agent, anticaking agent and any other excipient known to the art for making pharmaceutical formulation. According to the present invention a particular excipient may perform multiple roles in the pharmaceutical formulation, for example, it can act both as a preservative and/or as a pH adjusting agents.
The present invention is related to a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient. The present invention is related to a liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
The present inventors have surprisingly found that the suspension formulations of Tranexamic acid can be administered effectively in the paediatric population and adults who are unable to swallow a solid dosage form. It is an object of the present invention to provide a stable oral suspension formulation of Tranexamic acid or pharmaceutically acceptable salt thereof.
The present invention related to a stable liquid formulation of Tranexamic acid comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
The storage conditions used in the present invention are 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C. The ‘storage condition of 25°C/60% RH’ means storage at a temperature of 25°C and 60% relative humidity. Likewise the ‘storage condition of 30°C/65% RH’ means storage at a temperature of 30°C and 65% relative humidity, the ‘storage condition of 40°C/75% RH’ means storage at a temperature of 40°C and 75% relative humidity. The ‘storage condition of 2-8°C’ means storage at a temperature of 2 to 8°C.
In an embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 25°C/60% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 25°C/60% RH.
In yet another embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 30°C/65% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 30°C/65% RH.
In further embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 40°C/75% RH. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 40°C/75% RH.
In another embodiment of the present invention, the liquid formulation is stable for at least two months, preferably for at least three months, preferably for at least four months, more preferably for at least five months under storage condition of 2-8°C. In another embodiment of the present invention, the liquid formulation is stable for at least six months under storage condition of 2- 8 °C.
In another embodiment, an invention provides a stable oral liquid formulation comprising: a) Tranexamic acid or pharmaceutically acceptable salt thereof; b) suspending agent; c) preservative; d) sweetener; and e) one or more pharmaceutically acceptable excipient.
In another embodiment, an invention provides a stable oral liquid formulation comprising: a) 0.01 -20% w/v of Tranexamic acid or pharmaceutically acceptable salt thereof; b) 0.01%-15% w/v of suspending agent; c) 0.001-3% w/v of preservative; d) 0.001-5% w/v of sweetener; and e) one or more pharmaceutically acceptable excipient.
Another embodiment of an invention provides the process for the preparation of stable oral liquid formulation comprising: a) adding preservative in vehicle and dissolving to obtain a clear solution; b) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; c) adding suspending agent in the above mixture and mixing to achieve a lump free uniform suspension; d) adding flavouring agent to the above suspension; e) adding buffering agent to the above suspension to adjust the pH; and f) adding vehicle to make up the volume.
Another embodiment of an invention provides the process for the preparation of stable oral liquid formulation comprising: a) adding suspending agent in vehicle and mixing to obtain a clear solution; b) adding preservative in the above mixture to obtain a clear solution; c) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; and d) adding vehicle to make up the volume.
The term “Tranexamic Acid” as used herein comprises trans-4- ( Amino methyljcyclo hexanecarboxy lie acid with a molecular weight of 157.21 g/mol. Further the term “Tranexamic Acid” means all varieties or forms of Tranexamic Acid including, but not limited to all pharmaceutically acceptable salts, esters, amides, isomers, stereo isomers, crystalline and amorphous forms.
The amount of Tranexamic Acid in the formulation of the invention may vary depending on the total volume of formulation and the concentration of the other components. The amount of Tranexamic Acid according to the invention may be present at a concentration of from 0.01 to 20% w/v, and preferably from 0.05 to 18% w/v and more particularly from 0.1 to 15% w/v.
The one or more pharmaceutically acceptable excipient are selected from group consisting of buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents, suitable vehicle, isotonizing agent, viscosity modifying agent, anticaking agent and any other excipient known to the art for making formulation.
Suspending agents, which may be used according to the present invention, include, but are not limited to xanthan gum, gellan gum, guar gum, microcrystalline cellulose, sodium carbo xymethylcellulose, a mixture of carbo xymethylcellulose and microcrystalline cellulose, colloidal silicon dioxide, propylene glycol alginate and combinations thereof. Preferably, the suspending agent is a mixture of carbo xymethylcellulose and microcrystalline cellulose, sodium carbo xymethylcellulose and colloidal silicon dioxide. The amount of the suspending agents in the formulation generally ranges from about 0.01 to 15% w/v, preferably about 0.01 to 12% w/v, and more particularly from about 0.1 to about 10% w/v.
Buffers/pH Adjuster which may be used, according to the present invention, include suitable buffers that are not chemically reactive with the other excipient, and which may be present in an amount sufficient to provide the desired degree of pH buffering. In this regard, a buffer system comprising of an aqueous mixture of an acid, wherein the acid is citric, succinic, tartaric, lactic, or phosphoric acid, and a base, wherein the base is sodium citrate dihydrate, sodium hydroxide, or disodium hydrogen phosphate, is for maintaining the pH in the range from 5 to 9.
Preservatives, which may be used according to the present invention, include, but are not limited to, benzoic acid, sodium benzoate, potassium sorbate, cresol, cetrimide, citric acid and sodium citrate, and alkyl hydroxybenzoates (parabens). Preferably, the preservative is selected from an alkyl hydroxybenzoate, such as methyl hydroxybenzoate (MHB), ethyl hydroxybenzoate (EHB), propyl hydroxybenzoate (PHB) (as base or sodium salt) or a combination thereof. Preferably, the preservative is combination of MHB and PHB. More preferably, the preservative is combination of Na MHB and Na PHB. The amount of the preservatives in the formulation generally ranges from about 0.001 to 3% w/v, preferably about 0.01 to 2% w/v, and more particularly from about 0.01 to about 1.5% w/v.
Solubilizers, which may be used according to the present invention, include, but are not limited to polyhydric alcohol, ethanol, polyethylene glycol, non-ionic surfactant, an ionic surfactant, a hydrophilic polymer and a carbohydrate.
Non-limiting examples of non-ionic surfactants that can be used in the liquid formulation are polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers, polyoxyethylene castor oil derivatives, polyoxyglycerides, vitamin E polyethylene glycol succinate, and macrogol 15 hydroxystearate.
Non-limiting examples of ionic surfactants that can be used in the liquid formulation are sodium lauryl sulfate and docusate sodium. Non- limiting examples of hydrophilic polymers that can be used in the liquid formulation are povidone (for example PVPK 12, Povidone K30), copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.
Non-limiting examples of polyhydric alcohols that can be used in the liquid formulation are glycerin, propylene glycol, sorbitol, and mannitol.
Non-limiting examples of polyethylene glycols that can be used in the liquid formulation are polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400.
Non-limiting examples of carbohydrates that can be used in the liquid formulation are fructose, sucrose, and lactose.
Anti-foaming agent can be a silicone based antifoam. Antifoaming agent is preferably simethicone emulsion.
Antioxidants, which may be used according to the present invention, include, but are not limited to sodium metabisulfate, ascorbic acid, sodium formaldehyde, sulfoxylate, or mixtures thereof.
Complexing agents, which may be used according to the present invention, include, but are not limited to a-cyclodextrin, P-cyclodextrin, y-cyclodextrin and their derivatives such as, for example, hydroxypropyl- P-cyclodextrin.
Sweeteners or sweetening agents, which may be used according to the present invention, may be any natural or artificial sweetener. In terms of natural sweeteners or sweetening agents, these include, but are not limited to, glucose, fructose, invert sugar, sorbitol, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, xylitol, mannitol, maltodextrins, and mixtures thereof. In terms of artificial sweeteners, these include, but are not limited to, sucralose, aspartame and saccharin. In one embodiment, the artificial sweetener is sucralose. The amount of the sweetener or sweetening agents in the formulation generally ranges from about 0.001 to 5% w/v, preferably about 0.01 to 4% w/v, and more particularly from about 0.01 to about 2% w/v. Flavouring agents or flavorant incorporated in the liquid formulation may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits, and so forth and combinations thereof. Other useful flavors are vanilla, citrus oils, including lemon, orange, lime and grapefruit, and fruit essence, including apple, grape, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. The amount of the flavouring agent or flavorant in the formulation generally ranges from about 0.001 to 2% w/v, preferably about 0.01 to 1.5% w/v, and more particularly from about 0.01 to about 1% w/v.
The vehicle used in the formulation of the invention is selected from glycerin, propylene glycol, water or combination thereof. The vehicle used in the formulation of the invention is preferably purified water, although other suitable water-containing (aqueous) vehicles known to the skilled person may also be used. The amount of water can be present from about 70% to about 99% w/v of the liquid formulation.
The present invention related a stable liquid formulation of Tranexamic acid comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient.
In another embodiment of the present invention, the non limiting example of liquid formulation suitable for oral administration includes suspension, solution or the like and any combination thereof.
In another embodiment of the present invention, the stable liquid formulation of Tranexamic acid is in the form of a suspension.
In another embodiment of the present invention, the stable liquid formulation of Tranexamic acid is in the form of a solution.
In another embodiment of the present invention, the liquid formulation of Tranexamic acid is oral aqueous suspension or powder for oral suspension which meant to be administered after reconstitution in a suitable solvent. In another embodiment of the present invention is a method for treating bleeding disorder, preventing or treating hemorrhage under general or local fibrinolysis for pre/po st-operative hemorrhage, used for dental extraction in patients with haemophilia, used to prevent excess bleeding in patients with menorrhagia (heavy menstrual bleeding) and hereditary angioneurotic edema.
According to another embodiment of the present invention, Tranexamic acid has a particle size distribution D(90) less than about 200pm, preferably less than about 180pm, more preferably less than about 150pm.
The present inventors have surprisingly found that the liquid formulations of Tranexamic acid can be administered effectively in the paediatric population and adults who are unable to swallow a solid dosage form. It is an object of the present invention to provide a stable liquid formulation of Tranexamic acid. Further object of the present invention is to provide a stable aqueous suspension formulation of Tranexamic acid.
In another embodiments, the liquid formulation comprising Tranexamic acid provide improved or comparable bio availability as compared to known or marketed formulation.
In another embodiments, the liquid formulation comprising Tranexamic acid provide faster absorption than solid, palatable, better choice especially for children and old age patients, more flexibility in achieving the proper dosage of medication and provides ease for the patients having difficulty in swallowing other oral dosage forms.
In another embodiments, the liquid formulation comprising Tranexamic acid provides better chemical stability and larger surface area and is often more bioavailable than aqueous solutions, tablets, and capsules.
In another embodiments, the liquid formulation comprising Tranexamic acid provides better palatability with increasing the patient compliance and patient acceptability towards the formulation.
In another embodiment of the present invention, the liquid formulation of Tranexamic acid is administered two or three or four times daily. The liquid formulation may be packaged within any type of pharmaceutically acceptable package, bottles, container depending upon the quantity of the final dosage form.
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 invention is further illustrated by the following non-limiting examples which are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments. These examples should not be construed to limit any of the embodiments described in the present specification.
Examples:
Example 1 -
Tranexamic acid 500mg/5ml Oral Suspension
Figure imgf000014_0001
Procedure:
1. Adding Sodium MHB and Sodium PHB in 80% of purified water and dissolving using silverson mixer for 15 min at 3000 RPM to obtain a clear solution.
2. Adding Tranexamic acid and sucralose in the above mixture and mixing it using silverson mixer for 15 min. at 3000 RPM to obtain a clear solution. 3. Adding mixture of carboxymethylcellulose and microcrystalline cellulose in the above solution and mixing using silverson mixer for 30 min. at 3000 RPM until a lump free uniform suspension was obtained.
4. Adding orange flavour to the above suspension and mixing it using silverson mixer and measure the pH.
5. Adding citric acid to the above suspension to adjust the pH to 7
6. Adding purified water to make up the volume to 100 ml.
Example 2 -
Tranexamic acid 500mg/5ml Oral Suspension
Figure imgf000015_0001
Procedure:
1. Taking sodium carbo xymethylcellulose added in 65% of water mixing using silverson mixer for 15min at 3000 RPM to obtain clear solution.
2. Methyl paraben sodium and Propylparaben sodium were added in above solution mixing using silverson mixer for 15 min at 3000 RPM to obtain clear solution.
3. Tranexamic acid, sucralose and colloidal silicon dioxide were added in the above solution mixture using silverson mixer for 15 min at 3000 RPM until suspension was obtained.
4. Finally purified water was added to make up final volume to 100 ml and pH was measured. Example 3: Stability study:
Stability data of suspension formulation of example 1, packed in glass bottle is shown below.
Figure imgf000016_0001
The suspension formulation of example 1 found to be stable for 3 months at storage conditions 25°C/60% RH, 30°C/65% RH and 40°C/75% RH.
Example 4: Stability study:
Stability data of suspension formulation of example 2, packed in glass bottle is shown below.
Figure imgf000016_0002

Claims

Claims:
1. A stable liquid formulation comprising Tranexamic acid or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
2. The stable liquid formulation as claimed in claim 1, wherein the formulation is stable for at least one month under storage condition of 25°C/60% RH and/or 30°C/65% RH and/or 40°C/75% and/or 2-8°C.
3. The stable liquid formulation as claimed in claim 1, wherein the amount of Tranexamic acid is present from 0.01% w/v to 20% w/v to the total volume of formulation.
4. The stable liquid formulation as claimed in claim 1, wherein the liquid formulation is in the form of suspension, solution or the like and any combination thereof.
5. The stable liquid formulation as claimed in claim 1, wherein the liquid formulation has a pH of about 5 to about 9.
6. The stable liquid formulation as claimed in claim 1, wherein Tranexamic acid has a particle size distribution D(90) less than about 200pm.
7. The stable liquid formulation as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipient are selected from group consisting of suspending agents, buffers (pH adjusting agents), preservatives, antioxidants, solubilizers, complexing agents, antifoaming agents, sweeteners, flavouring agents, suitable vehicle, isotonizing agent, viscosity modifying agent, anticaking agent and any other excipient known to the art for making formulation.
8. A stable liquid formulation comprising: a) Tranexamic acid or pharmaceutically acceptable salt thereof; b) suspending agent; c) preservative; d) sweetener; and e) one or more pharmaceutically acceptable excipients
9. A stable liquid formulation comprising: a) 0.01 -20% w/v of Tranexamic acid or pharmaceutically acceptable salt thereof; b) 0.01%- 15% w/v of suspending agent; c) 0.001- 3% w/v of preservative; d) 0.001- 5% w/v of sweetener; and e) one or more pharmaceutically acceptable excipient. A process for preparation of stable liquid formulation comprising: a) adding preservative in vehicle and dissolving to obtain a clear solution; b) adding Tranexamic acid or pharmaceutically acceptable salt thereof in the above mixture and mixing to obtain a clear solution; c) adding suspending agent in the above mixture and mixing to achieve a lump free uniform suspension; d) adding flavouring agent to the above suspension; e) adding buffering agent to the above suspension to adjust the pH; and f) adding vehicle to make up the volume. A process for preparation of stable liquid formulation comprising: a) adding suspending agent in vehicle and mixing to obtain a clear solution; b) adding preservative in the above mixture to obtain a clear solution; c) adding Tranexamic acid or pharmaceutically acceptable salt thereof and sweetener in the above mixture and mixing to obtain a clear solution; and d) adding vehicle to make up the volume.
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US20100143468A1 (en) * 2004-03-04 2010-06-10 Xanodyne Pharmaceuticals, Inc. Tranexamic Acid Formulations
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US20090048341A1 (en) * 2004-03-04 2009-02-19 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US20100143468A1 (en) * 2004-03-04 2010-06-10 Xanodyne Pharmaceuticals, Inc. Tranexamic Acid Formulations
WO2006023000A1 (en) * 2004-07-30 2006-03-02 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US20120302640A1 (en) * 2009-12-17 2012-11-29 Don Macalister Oral formulations
WO2017123653A1 (en) * 2016-01-11 2017-07-20 Leading BioSciences, Inc. Compositions and methods for treating and preventing adhesions and ileus
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