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WO2024116198A1 - Oral liquid formulation of empagliflozin or its pharmaceutically acceptable salt thereof - Google Patents

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

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Publication number
WO2024116198A1
WO2024116198A1 PCT/IN2023/051096 IN2023051096W WO2024116198A1 WO 2024116198 A1 WO2024116198 A1 WO 2024116198A1 IN 2023051096 W IN2023051096 W IN 2023051096W WO 2024116198 A1 WO2024116198 A1 WO 2024116198A1
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WO
WIPO (PCT)
Prior art keywords
liquid formulation
pharmaceutically acceptable
empagliflozin
solution
acceptable salt
Prior art date
Application number
PCT/IN2023/051096
Other languages
French (fr)
Inventor
Girish Shantilal Achliya
Piyush Kishor Mundada
Mayur Dilip KAPADIA
Dipak Rameshbhai Faldu
Original Assignee
Syri Research Private Limited
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 Syri Research Private Limited filed Critical Syri Research Private Limited
Publication of WO2024116198A1 publication Critical patent/WO2024116198A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof.
  • the present invention is more particularly related to an oral liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.
  • This invention also related to a process for preparing the liquid formulation and its application in the treatment of type 2 diabetes mellitus, symptomatic chronic heart failure and chronic kidney disease.
  • Type 2 diabetes mellitus is a chronic, progressive metabolic condition that is not fully understood. Hyperglycemia represents the primary characteristic of diabetes mellitus, which is a chronic, progressive and inadequately understood metabolic disorder. Type 2 diabetes mellitus (T2DM) which encompasses a range of conditions, initially arising from tissue insulin resistance and gradually advances to a state characterized by the complete loss of secretory activity in the beta cells of the pancreas. It is believed to result from impaired insulin secretion, insulin resistance in tissues, or a combination of both factors.
  • sulfonylureas like glipizide, glyburide, gliclazide, and glimepiride
  • meglitinides like repaglinide and nateglinide
  • biguanides like metformin
  • thiazolidinediones such as rosiglitazone and pioglitazone
  • a-glucosidase inhibitors like acarbose, miglitol, and voglibose
  • DPP-4 inhibitors like sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, or combinations thereof.
  • Sodium glucose co-transporter-2 (SGLT2) inhibitors are relatively new additions to the class of antidiabetic agents.
  • the SGLT2 inhibitors are recognised for glycemic control and have reduced the risk of kidney disease for those with diabetes and can reduce the risk of being hospitalized or dying from heart failure.
  • Empagliflozin is a widely recognized SGLT2 inhibitor that has received approval in the United State (USA) and Europe for its use in enhancing glycemic control among adults with type 2 diabetes mellitus (T2DM).
  • T2DM type 2 diabetes mellitus
  • These drugs reduce plasma glucose (PG) levels by decreasing the renal threshold for glucose excretion (RTG) and inhibiting renal glucose reabsorption, leading to an increase in urinary glucose excretion (UGE).
  • the IUPAC name of Empagliflozin is (lS)-l,5-anhydro-l-(4-chloro-3- ⁇ 4-[(3S)- tetrahydrofuran-3-yloxy]benzyl ⁇ phenyl)-D-glucitol and has the following structure:
  • Empagliflozin is a white to yellowish non-hygroscopic crystalline solid; it is chiral, possesses 6 stereogenic centres and a single polymorphic form has been observed.
  • the patent US7579449B2 discloses Empagliflozin, or the stereoisomers thereof, the mixtures thereof and the salts thereof generically and specifically.
  • the invention further relates to pharmaceutical compositions and the use for preparing a pharmaceutical composition for the treatment of metabolic disorders.
  • the patent US7713938B2 discloses a crystalline form of Empagliflozin having an X-ray diffraction pattern, to a method for the preparation and use thereof for preparing medicaments.
  • the patent US9949997B2 discloses a method to reduce the risk of cardiovascular death in a patient with type 2 diabetes mellitus comprising administering Empagliflozin to the patient, wherein Empagliflozin is administered orally in a total daily amount of 10 mg or 25 mg.
  • the patent application CN112618495 A discloses Empagliflozin dry suspension and a preparation method thereof.
  • the Empagliflozin dry suspension is prepared from the components in percentage by weight: 1-10% of Empagliflozin, 55-80% of filler, 10-20% of a suspending aid, 0.1-2% of a lubricant, 8-15% of a disintegrating agent and 0.05-1% of a flavoring agent.
  • the Empagliflozin is classified under the biopharmaceutics classification system (BCS) class III due to its characteristics of high solubility but low permeability.
  • BCS biopharmaceutics classification system
  • the inventors of the present invention solved the problems associated with extemporaneous preparation and the challenges in dose adjustment.
  • the present invention provides simple manufacturing process, enhances patient compliance by offering acceptable taste-masking, improved drug solubility and enhanced stability.
  • the present invention provides a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.
  • the present invention provides a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
  • the present invention provides a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Empagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 10% w/v in the liquid formulation.
  • the present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of suspension or solution or the like.
  • the present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
  • the present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is stable under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
  • the present invention provides a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; d) 0.5-15% w/v of a solubilizer or solubilizing agent; and e) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
  • the present invention provides a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
  • the present invention provides a process for the preparation of a liquid formulation, comprising: a) separately taking part quantity of vehicle in beaker, heating and adding preservative and dissolving to get clear solution and cool; b) adding slowly solubilizing agent and dissolving in another part of vehicle, stirring to get clear solution; c) adding slowly Empagliflozin and dissolving in above solution of step b) and mixing using stirrer to get clear solution; d) adding and dissolving viscosity enhancer in above solution of step c) and mixing using stirrer to get clear solution; e) adding solution of step d) in solution of step a) using stirring to get clear solution; f) adding sweetener in above solution using stirring to get clear solution; g) adding flavour in above solution using stirring to get clear solution; and h) making up the volume with vehicle and mixing using stirrer to get clear solution.
  • the present invention provides a process for the preparation of a liquid formulation, comprising: a) adding preservatives into vehicle under continue stirring for desired time to get clear solution; b) soaking viscosity enhancer into vehicle and keep for desired time; c) adding soaked viscosity enhancer of step-b) into step-a) solution under homogenizer for desired time and speed; d) adding Empagliflozin into step-c) solution under homogenizer for desired time and speed; e) adding sweetener and mixing flavour into step-d) under homogenizer for desired time; f) making up final volume of step-e) suspension with vehicle and homogenizing for desired time and speed; and g) recording pH of step-f) suspension and adjusting pH with buffering agents.
  • the present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as monotherapy, also used for the treatment of symptomatic chronic heart failure and chronic kidney disease.
  • Empagliflozin as used herein is not limited to the Empagliflozin, but includes its solvates, hydrates, solvate-hydrate, all pharmaceutically acceptable salts, esters, amides, isomers and stereo isomers and polymorphic form including amorphous form.
  • terapéuticaally effective amount is defined to mean the amount or quantity of the active drug (e.g. Empagliflozin or a pharmaceutical acceptable salt thereof), which is sufficient to elicit an appreciable biological response when administered to the patient.
  • active drug e.g. Empagliflozin or a pharmaceutical acceptable salt thereof
  • 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 solution, suspension and the like.
  • excipient or “excipients” or “ingredient” means a pharmacologically inactive component that are useful in preparing a liquid formulation which are generally safe, nontoxic and are acceptable for human pharmaceutical use.
  • stable or “stability” encompass any characteristic of the liquid formulation which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, appearance, viscosity and colour and clarity.
  • the storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.
  • the Empagliflozin may be present in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include, without being restricted thereto hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, glutamic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • the present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.
  • the present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
  • the present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Empagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 10% w/v in the liquid formulation.
  • the present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of solution or suspension or the like.
  • the present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of solution.
  • the present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of suspension.
  • the present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8 with a particularly preferred range of about 4.5 to about 7.5.
  • the pH of the liquid formulation can be adjusted to a pH of about 4, about 4.5, about 5, about 5.5, about 6, about 6.5 or about 7 or about 7.5 or about 8.
  • the present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is stable for at least one month under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
  • the one or more pharmaceutically acceptable excipient which are selected from the group consisting of preservatives, viscosity enhancers or viscosity enhancing agents, solubilizers or solubilizing agents, buffers or buffering agents, sweeteners or sweetening agents, flavors or flavours, vehicles/solvents, wetting agents, cosolvents, suspending agents, antifoaming agents, taste masking agents, antioxidants, chelating agents, stabilizers, colorants and any other excipient known to the art for making liquid formulations.
  • compositions are the components that are added to the liquid formulation other than the active ingredient Empagliflozin or pharmaceutically acceptable salt thereof. Excipient may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc.
  • preservatives include but not limited to group comprising parabens (p-hydroxybenzoate) including methyl p-hydroxybenzoate (methylparaben or MHB), ethyl p-hydroxybenzoate (ethylparaben), propyl p- hydroxybenzoate (propylparaben) and butyl p-hydroxybenzoate (butylparaben) and their salts such as sodium methyl parahydroxybenzoate (Sodium MHB), sodium propyl parahydroxybenzoate (Sodium PHB),
  • Other suitable preservatives include sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), halogenated diphenyl ether (e.g.
  • the preferred preservative is methyl p-hydroxybenzoate (MHB), sodium benzoate and sorbic acid.
  • the preservatives are present in an amount of about 0.001% w/v to about 4% w/v of the liquid formulation. Particularly, the preservative is present in an amount of about 0.015 % w/v to about 3% w/v of the liquid formulation.
  • viscosity enhancers or viscosity enhancing agents include but not limited to group comprising of glycerol, polyethylene glycol, polyethylene oxide, dextrin, liquid maltitol, liquid sorbitol, cellulose derivatives such as hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives e.g., carboxymethyl cellulose sodium (carmellose sodium), microcrystalline cellulose, microcrystalline cellulose and carboxymethyl cellulose sodium, carbomers, gums such as xanthan gum, locust bean gum, tragacanth gum, pectin, propylene glycol alginate, gelatin, pectin, alginates, starches, chitosan, povidone, copovidone, polyvinyl compounds, sugar alcohols, colloidal silica; maltodextrin, starch; and mixtures thereof.
  • glycerol poly
  • the preferred viscosity enhancer or viscosity enhancing agents are carboxymethyl cellulose sodium (carmellose sodium).
  • the viscosity enhancers are present in an amount of about 0.01 to about 15% w/v of the liquid formulation. Particularly, the viscosity enhancers are present in an amount of about 0.015% to about 12% w/v of the liquid formulation. More particularly, the viscosity enhancers are present in an amount of about 0.1% to about 10% w/v of the liquid formulation.
  • solubilizers or solubilizing agents include but not limited to group comprising glycol, acetone, alcohol (ethanol), benzyl alcohol, benzyl benzoate, butylene glycol, dibutyl phthalate, sorbitol, poloxamer, polysorbates, polyoxyethylene fatty acid esters, sodium lauryl sulphate, diethyl phthalate, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, glycofurol, glycerin, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, propylene glycol, polyethylene glycol, propylene carbonate, pyrrolidone, triacetin, triethyl citrate and triolein, the cyclodextrin includes a- cyclodextrin, P-cyclodextrin, 6-cyclodextrin, y-cyclodextrin, or combinations thereof,
  • substituted cyclodextrins include hydroxypropyl-P-cyclodextrin (HP-P-CD) and sulfobutylether-P-cyclodextrin (SBE-P-CD), and the like.
  • the preferred solubilizers are hydroxypropyl-P-cyclodextrin (HP-P-CD).
  • the solubilizers are present in an amount of about 0.01% to about 40% w/v of the liquid formulation. Particularly, the solubilizers are present in an amount of about 0.1% to about 20% w/v of the liquid formulation. More particularly, the solubilizers are present in an amount of about 0.5% to about 15% w/v of the liquid formulation.
  • buffering agents or buffers include but not limited to group comprising sodium dihydrogen phosphate, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate precipitate, citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts and/or combinations thereof.
  • the preferred Buffering agent is sodium dihydrogen phosphate.
  • sweeteners or sweetening agents include but not limited to group comprising sucralose, glucose, maltose, sucrose, aspartame, mannitol, sorbitol, xylitol, acesulfame, neotame, stevia, dextrose, saccharin, saccharin sodium, mannose, glycerol or glycerin and/or combinations thereof.
  • the preferred sweetener is sucralose.
  • sweetener is present in an amount of from about 0.01 to about 20% w/v, more preferably from about 0.1 to 3% w/v of the liquid formulation.
  • flavouring agents or flavours according to the present invention include but not limited to group comprising mix fruit flavour, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grapes, banana, spearmint, peppermint, eucalyptus, and/or combinations thereof, the preferred flavour is mix fruit flavour.
  • vehicles or solvents according to the present invention include but not limited to group comprising water, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, and/or combinations thereof.
  • antioxidants include but not limited to group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates and/or combinations thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • propyl gallate vitamin E
  • hydroquinone hydroxycoumarins
  • ethanolamine lecithin
  • cephalin ascorbic acid
  • malic acid malic acid
  • sorbitol phosphoric acid
  • thiodipropionic acid and its esters and dithiocarbamates and/or combinations thereof.
  • chelating agents include but not limited to group comprising disodium edentate salt (EDTA), tartaric acid, malic acid, citric acid and/or combinations thereof.
  • EDTA disodium edentate salt
  • colorants include but are not limited to caramel colorant, red colorant Enocianin, Indigo yellow, Quinoline yellow, Quinizarine Green, FD&C Blue #1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide and/or combinations thereof.
  • 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 under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
  • the present invention relates to a liquid formulation
  • a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity enhancer or viscosity enhancing agent; d) 0.5-15% w/v of a solubilizer or solubilizing agent; and e) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
  • the present invention relates to a liquid formulation
  • a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
  • the present invention relates to a process for the preparation of a liquid formulation, comprising: a) separately taking part quantity of vehicle in beaker, heating and adding preservative and dissolving to get clear solution and cool; b) adding slowly solubilizing agent and dissolving in another part of vehicle, stirring to get clear solution; c) adding slowly Empagliflozin and dissolving in above solution of step b) and mixing using stirrer to get clear solution; d) adding and dissolving viscosity enhancer in above solution of step c) and mixing using stirrer to get clear solution; e) adding solution of step d) in solution of step a) using stirring to get clear solution; f) adding sweetener in above solution using stirring to get clear solution; g) adding flavour in above solution using stirring to get clear solution; and h) making up the volume with vehicle and mixing using stirrer to get clear solution.
  • the present invention relates to a process for the preparation of a liquid formulation, comprising: a) adding preservatives into vehicle under continue stirring for desired time to get clear solution; b) soaking viscosity enhancer into vehicle and keep for desired time; c) adding soaked viscosity enhancer of step-b) into step-a) solution under homogenizer for desired time and speed; d) adding Empagliflozin into step-c) solution under homogenizer for desired time and speed; e) adding sweetener and mixing flavour into step-d) under homogenizer for desired time; f) making up final volume of step-e) suspension with vehicle and homogenizing for desired time and speed; and g) recording pH of step-f) suspension and adjusting pH with buffering agents.
  • the present invention relates to the liquid formulation that comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as monotherapy, also used for the treatment of symptomatic chronic heart failure and chronic kidney disease.
  • the present invention relates to the liquid formulation that comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient that enhances patient compliance by providing acceptable taste-masking, improves drug solubility and storage stability.
  • the liquid formulation can be conveniently packaged in various pharmaceutically acceptable containers, such as bottles, depending on the required dosage form.
  • Empagliflozin 10mg/5ml Oral Solution Manufacturing Process: a) separately taken part quantity of water in a beaker, heated to a temperature range of 80- 90°C, methyl parahydroxybenzoate, sodium benzoate and sorbic acid were added and dissolved to get a clear solution and allowed to cool up to 40°C; b) hydroxypropyl beta-cyclodextrin was slowly added and dissolved in another portion of water using a stirrer at a speed of 1500 - 2500 RPM for 30 minutes to get a clear solution; c) Empagliflozin was slowly added and dissolved to the above solution and mixed using stirrer at the speed of 1500 - 2500 RPM for 30 minutes to get clear solution; d) carmellose sodium was added and dissolved in the above solution, and the mixture is stirred using a stirrer at a speed of 1500 - 2500 RPM for 30 minutes to get clear solution; e) step-d) solution was added to the step-a) solution using

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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Abstract

The present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient, its process for preparation and its application in the treatment of type 2 diabetes mellitus, symptomatic chronic heart failure and chronic kidney disease.

Description

Oral liquid formulation of Empagliflozin or its pharmaceutically acceptable salt thereof
Field of the Invention
The present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof. The present invention is more particularly related to an oral liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient. This invention also related to a process for preparing the liquid formulation and its application in the treatment of type 2 diabetes mellitus, symptomatic chronic heart failure and chronic kidney disease.
Background of the Invention
Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic condition that is not fully understood. Hyperglycemia represents the primary characteristic of diabetes mellitus, which is a chronic, progressive and inadequately understood metabolic disorder. Type 2 diabetes mellitus (T2DM) which encompasses a range of conditions, initially arising from tissue insulin resistance and gradually advances to a state characterized by the complete loss of secretory activity in the beta cells of the pancreas. It is believed to result from impaired insulin secretion, insulin resistance in tissues, or a combination of both factors.
Numerous treatment approaches for diabetes mellitus have been discovered and are well- established for the management of hyperglycemia. Common treatments include therapeutic agents such as sulfonylureas like glipizide, glyburide, gliclazide, and glimepiride; meglitinides like repaglinide and nateglinide; biguanides like metformin; thiazolidinediones such as rosiglitazone and pioglitazone; a-glucosidase inhibitors like acarbose, miglitol, and voglibose; and DPP-4 inhibitors like sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, or combinations thereof.
Since diabetes mellitus is a chronic metabolic condition, patients typically require lifelong medication. This is often associated with the severe adverse effects of antidiabetic drugs. The spectrum of these undesired effects spans from minor issues such as gastric discomfort, nausea, diarrhoea, and weight gain to more severe, life-threatening conditions like cardiovascular complications and lactic acidosis. Therefore, there is a continual need for the development of novel antihyperglycemic agents that can provide improved control over blood sugar levels with minimal adverse effects.
Sodium glucose co-transporter-2 (SGLT2) inhibitors are relatively new additions to the class of antidiabetic agents. The SGLT2 inhibitors are recognised for glycemic control and have reduced the risk of kidney disease for those with diabetes and can reduce the risk of being hospitalized or dying from heart failure. Empagliflozin is a widely recognized SGLT2 inhibitor that has received approval in the United State (USA) and Europe for its use in enhancing glycemic control among adults with type 2 diabetes mellitus (T2DM). These drugs reduce plasma glucose (PG) levels by decreasing the renal threshold for glucose excretion (RTG) and inhibiting renal glucose reabsorption, leading to an increase in urinary glucose excretion (UGE).
Empagliflozin is marketed in USA, Europe and other countries under the brand name Jardiance which is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as monotherapy when metformin is considered inappropriate due to intolerance, in addition to other medicinal products for the treatment of diabetes. It is also indicated in adults for the treatment of symptomatic chronic heart failure and chronic kidney disease.
The IUPAC name of Empagliflozin is (lS)-l,5-anhydro-l-(4-chloro-3-{4-[(3S)- tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol and has the following structure:
Figure imgf000003_0001
Empagliflozin is a white to yellowish non-hygroscopic crystalline solid; it is chiral, possesses 6 stereogenic centres and a single polymorphic form has been observed.
The patent US7579449B2 discloses Empagliflozin, or the stereoisomers thereof, the mixtures thereof and the salts thereof generically and specifically. The invention further relates to pharmaceutical compositions and the use for preparing a pharmaceutical composition for the treatment of metabolic disorders. The patent US7713938B2 discloses a crystalline form of Empagliflozin having an X-ray diffraction pattern, to a method for the preparation and use thereof for preparing medicaments.
The patent US9949997B2 discloses a method to reduce the risk of cardiovascular death in a patient with type 2 diabetes mellitus comprising administering Empagliflozin to the patient, wherein Empagliflozin is administered orally in a total daily amount of 10 mg or 25 mg.
The patent application CN112618495 A discloses Empagliflozin dry suspension and a preparation method thereof. The Empagliflozin dry suspension is prepared from the components in percentage by weight: 1-10% of Empagliflozin, 55-80% of filler, 10-20% of a suspending aid, 0.1-2% of a lubricant, 8-15% of a disintegrating agent and 0.05-1% of a flavoring agent.
The Empagliflozin is classified under the biopharmaceutics classification system (BCS) class III due to its characteristics of high solubility but low permeability.
The inventor has encountered challenges in ensuring acceptable oral bio availability and low solubility. In such cases, choosing an alternative formulation becomes necessary to overcome difficulties appears in the existing marketed formulation. Under these circumstances, choosing for an oral liquid formulation is advisable. This choice facilitates ease of administration, particularly benefiting paediatric and geriatric patients, as well as individuals with swallowing difficulties (dysphagia), those recovering from a stroke, individuals with unstable psychological conditions, and patients unwilling to take medication due to polytherapy or other factors. For the aforementioned patient groups, the common practice involves crushing one or more Empagliflozin tablets into a powder, which is then dissolved in a liquid, preferably water. However, a significant drawback arises due to the bitter taste of the product, makes a challenge to patient compliance. While this method simplifies administration, it introduces potential inaccuracies in dosing and difficulties in making necessary dose adjustments.
The inventors of the present invention solved the problems associated with extemporaneous preparation and the challenges in dose adjustment. The present invention provides simple manufacturing process, enhances patient compliance by offering acceptable taste-masking, improved drug solubility and enhanced stability.
Summary of the Invention
The present invention provides a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.
The present invention provides a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
The present invention provides a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Empagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 10% w/v in the liquid formulation.
The present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of suspension or solution or the like.
The present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
The present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is stable under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
The present invention provides a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; d) 0.5-15% w/v of a solubilizer or solubilizing agent; and e) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
The present invention provides a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
The present invention provides a process for the preparation of a liquid formulation, comprising: a) separately taking part quantity of vehicle in beaker, heating and adding preservative and dissolving to get clear solution and cool; b) adding slowly solubilizing agent and dissolving in another part of vehicle, stirring to get clear solution; c) adding slowly Empagliflozin and dissolving in above solution of step b) and mixing using stirrer to get clear solution; d) adding and dissolving viscosity enhancer in above solution of step c) and mixing using stirrer to get clear solution; e) adding solution of step d) in solution of step a) using stirring to get clear solution; f) adding sweetener in above solution using stirring to get clear solution; g) adding flavour in above solution using stirring to get clear solution; and h) making up the volume with vehicle and mixing using stirrer to get clear solution.
The present invention provides a process for the preparation of a liquid formulation, comprising: a) adding preservatives into vehicle under continue stirring for desired time to get clear solution; b) soaking viscosity enhancer into vehicle and keep for desired time; c) adding soaked viscosity enhancer of step-b) into step-a) solution under homogenizer for desired time and speed; d) adding Empagliflozin into step-c) solution under homogenizer for desired time and speed; e) adding sweetener and mixing flavour into step-d) under homogenizer for desired time; f) making up final volume of step-e) suspension with vehicle and homogenizing for desired time and speed; and g) recording pH of step-f) suspension and adjusting pH with buffering agents.
The present invention provides the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as monotherapy, also used for the treatment of symptomatic chronic heart failure and chronic kidney disease.
Detailed Description of the Invention
The term “Empagliflozin” as used herein is not limited to the Empagliflozin, but includes its solvates, hydrates, solvate-hydrate, all pharmaceutically acceptable salts, esters, amides, isomers and stereo isomers and polymorphic form including amorphous form.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g. Empagliflozin or a pharmaceutical acceptable salt thereof), which is sufficient to elicit an appreciable biological response when administered to the patient.
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 solution, suspension and the like.
The term “excipient” or “excipients” or “ingredient” means a pharmacologically inactive component that are useful in preparing a liquid formulation which are generally safe, nontoxic and are acceptable for human pharmaceutical use.
As used herein, the terms “stable” or “stability” encompass any characteristic of the liquid formulation which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, appearance, viscosity and colour and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.
The Empagliflozin may be present in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, without being restricted thereto hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, glutamic acid, methanesulfonic acid and p-toluenesulfonic acid.
The present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient.
The present invention relates to a liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is suitable for oral administration.
The present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein Empagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 10% w/v in the liquid formulation.
The present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of solution or suspension or the like.
The present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of solution.
The present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulations is in the form of suspension. The present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8 with a particularly preferred range of about 4.5 to about 7.5. For example, the pH of the liquid formulation can be adjusted to a pH of about 4, about 4.5, about 5, about 5.5, about 6, about 6.5 or about 7 or about 7.5 or about 8.
The present invention relates to the liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient, wherein the liquid formulation is stable for at least one month under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
The one or more pharmaceutically acceptable excipient which are selected from the group consisting of preservatives, viscosity enhancers or viscosity enhancing agents, solubilizers or solubilizing agents, buffers or buffering agents, sweeteners or sweetening agents, flavors or flavours, vehicles/solvents, wetting agents, cosolvents, suspending agents, antifoaming agents, taste masking agents, antioxidants, chelating agents, stabilizers, colorants and any other excipient known to the art for making liquid formulations.
Pharmaceutically acceptable excipient(s) are the components that are added to the liquid formulation other than the active ingredient Empagliflozin or pharmaceutically acceptable salt thereof. Excipient may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc.
The examples of preservatives according to the present invention include but not limited to group comprising parabens (p-hydroxybenzoate) including methyl p-hydroxybenzoate (methylparaben or MHB), ethyl p-hydroxybenzoate (ethylparaben), propyl p- hydroxybenzoate (propylparaben) and butyl p-hydroxybenzoate (butylparaben) and their salts such as sodium methyl parahydroxybenzoate (Sodium MHB), sodium propyl parahydroxybenzoate (Sodium PHB), Other suitable preservatives include sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), halogenated diphenyl ether (e.g. triclosan), herbal extracts, essential oils, bisguanide antiseptics, quaternary ammonium compounds and/or combinations thereof. The preferred preservative is methyl p-hydroxybenzoate (MHB), sodium benzoate and sorbic acid. The preservatives are present in an amount of about 0.001% w/v to about 4% w/v of the liquid formulation. Particularly, the preservative is present in an amount of about 0.015 % w/v to about 3% w/v of the liquid formulation.
The examples of viscosity enhancers or viscosity enhancing agents according to the present invention include but not limited to group comprising of glycerol, polyethylene glycol, polyethylene oxide, dextrin, liquid maltitol, liquid sorbitol, cellulose derivatives such as hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives e.g., carboxymethyl cellulose sodium (carmellose sodium), microcrystalline cellulose, microcrystalline cellulose and carboxymethyl cellulose sodium, carbomers, gums such as xanthan gum, locust bean gum, tragacanth gum, pectin, propylene glycol alginate, gelatin, pectin, alginates, starches, chitosan, povidone, copovidone, polyvinyl compounds, sugar alcohols, colloidal silica; maltodextrin, starch; and mixtures thereof. The preferred viscosity enhancer or viscosity enhancing agents are carboxymethyl cellulose sodium (carmellose sodium). The viscosity enhancers are present in an amount of about 0.01 to about 15% w/v of the liquid formulation. Particularly, the viscosity enhancers are present in an amount of about 0.015% to about 12% w/v of the liquid formulation. More particularly, the viscosity enhancers are present in an amount of about 0.1% to about 10% w/v of the liquid formulation.
The examples of solubilizers or solubilizing agents according to the present invention include but not limited to group comprising glycol, acetone, alcohol (ethanol), benzyl alcohol, benzyl benzoate, butylene glycol, dibutyl phthalate, sorbitol, poloxamer, polysorbates, polyoxyethylene fatty acid esters, sodium lauryl sulphate, diethyl phthalate, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, glycofurol, glycerin, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, propylene glycol, polyethylene glycol, propylene carbonate, pyrrolidone, triacetin, triethyl citrate and triolein, the cyclodextrin includes a- cyclodextrin, P-cyclodextrin, 6-cyclodextrin, y-cyclodextrin, or combinations thereof, the cyclodextrin preferably includes either a substituted or non- substituted P-cyclodextrin. Examples of substituted cyclodextrins include hydroxypropyl-P-cyclodextrin (HP-P-CD) and sulfobutylether-P-cyclodextrin (SBE-P-CD), and the like. The preferred solubilizers are hydroxypropyl-P-cyclodextrin (HP-P-CD). The solubilizers are present in an amount of about 0.01% to about 40% w/v of the liquid formulation. Particularly, the solubilizers are present in an amount of about 0.1% to about 20% w/v of the liquid formulation. More particularly, the solubilizers are present in an amount of about 0.5% to about 15% w/v of the liquid formulation.
The examples of buffering agents or buffers according to the present invention include but not limited to group comprising sodium dihydrogen phosphate, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate precipitate, citric acid, sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts and/or combinations thereof. The preferred Buffering agent is sodium dihydrogen phosphate.
The examples of sweeteners or sweetening agents according to the present invention include but not limited to group comprising sucralose, glucose, maltose, sucrose, aspartame, mannitol, sorbitol, xylitol, acesulfame, neotame, stevia, dextrose, saccharin, saccharin sodium, mannose, glycerol or glycerin and/or combinations thereof. The preferred sweetener is sucralose. Preferably, sweetener is present in an amount of from about 0.01 to about 20% w/v, more preferably from about 0.1 to 3% w/v of the liquid formulation.
The examples of flavouring agents or flavours according to the present invention include but not limited to group comprising mix fruit flavour, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grapes, banana, spearmint, peppermint, eucalyptus, and/or combinations thereof, the preferred flavour is mix fruit flavour.
The examples of vehicles or solvents according to the present invention include but not limited to group comprising water, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, and/or combinations thereof. The examples of antioxidants according to the present invention include but not limited to group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates and/or combinations thereof.
The examples of chelating agents according to the present invention include but not limited to group comprising disodium edentate salt (EDTA), tartaric acid, malic acid, citric acid and/or combinations thereof.
The examples of colorants include but are not limited to caramel colorant, red colorant Enocianin, Indigo yellow, Quinoline yellow, Quinizarine Green, FD&C Blue #1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide and/or combinations thereof.
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 preferred embodiment of the present invention, the liquid formulation is stable for at least two months under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
The present invention relates to a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity enhancer or viscosity enhancing agent; d) 0.5-15% w/v of a solubilizer or solubilizing agent; and e) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
The present invention relates to a liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.1-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
The present invention relates to a process for the preparation of a liquid formulation, comprising: a) separately taking part quantity of vehicle in beaker, heating and adding preservative and dissolving to get clear solution and cool; b) adding slowly solubilizing agent and dissolving in another part of vehicle, stirring to get clear solution; c) adding slowly Empagliflozin and dissolving in above solution of step b) and mixing using stirrer to get clear solution; d) adding and dissolving viscosity enhancer in above solution of step c) and mixing using stirrer to get clear solution; e) adding solution of step d) in solution of step a) using stirring to get clear solution; f) adding sweetener in above solution using stirring to get clear solution; g) adding flavour in above solution using stirring to get clear solution; and h) making up the volume with vehicle and mixing using stirrer to get clear solution.
The present invention relates to a process for the preparation of a liquid formulation, comprising: a) adding preservatives into vehicle under continue stirring for desired time to get clear solution; b) soaking viscosity enhancer into vehicle and keep for desired time; c) adding soaked viscosity enhancer of step-b) into step-a) solution under homogenizer for desired time and speed; d) adding Empagliflozin into step-c) solution under homogenizer for desired time and speed; e) adding sweetener and mixing flavour into step-d) under homogenizer for desired time; f) making up final volume of step-e) suspension with vehicle and homogenizing for desired time and speed; and g) recording pH of step-f) suspension and adjusting pH with buffering agents.
The present invention relates to the liquid formulation that comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise as monotherapy, also used for the treatment of symptomatic chronic heart failure and chronic kidney disease.
The present invention relates to the liquid formulation that comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient that enhances patient compliance by providing acceptable taste-masking, improves drug solubility and storage stability.
The liquid formulation can be conveniently packaged in various pharmaceutically acceptable containers, such as bottles, depending on the required dosage form.
The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the present invention.
Examples
Example 1
Empagliflozin 10mg/5ml Oral Solution:
Figure imgf000014_0001
Manufacturing Process: a) separately taken part quantity of water in a beaker, heated to a temperature range of 80- 90°C, methyl parahydroxybenzoate, sodium benzoate and sorbic acid were added and dissolved to get a clear solution and allowed to cool up to 40°C; b) hydroxypropyl beta-cyclodextrin was slowly added and dissolved in another portion of water using a stirrer at a speed of 1500 - 2500 RPM for 30 minutes to get a clear solution; c) Empagliflozin was slowly added and dissolved to the above solution and mixed using stirrer at the speed of 1500 - 2500 RPM for 30 minutes to get clear solution; d) carmellose sodium was added and dissolved in the above solution, and the mixture is stirred using a stirrer at a speed of 1500 - 2500 RPM for 30 minutes to get clear solution; e) step-d) solution was added to the step-a) solution using a stirrer operating at a speed of 1500 - 2500 RPM for 15 minutes to get a clear solution, The Step-d) solution was rinsed with 100 g of water; f) sucralose was added to the above solution and mixed using a stirrer at a speed of 1500 - 2500 RPM for 10 minutes to get a clear solution. g) mix fruit flavor was added into the above solution and mixed using a stirrer at a speed of 1500 - 2500 RPM for 5 minutes to get a clear solution; and h) The volume is made up with water and the mixture is stirred for 10 minutes using a stirrer at a speed of 1500 - 2500 RPM to obtain a clear solution.
Example 2
Empagliflozin 10mg/5ml Oral Suspension:
Figure imgf000015_0001
q.s.: Quantity sufficient Manufacturing Process: a) The sodium methyl p-hydroxy benzoate (sodium MHB) and sodium propyl p-hydroxy benzoate (sodium PHB) were added into 300 g purified water under continued stirring for 30 minutes to get clear solution; b) carmellose sodium was soaked into 100 g purified water and keep for 30 minutes; c) soaked carmellose sodium of step-b) was added into step-a) solution under homogenizer and homogenized it for 30 minutes at 4000-5000 RPM; d) Empagliflozin was added into step-c) solution under homogenizer and homogenized it for 30 minutes at 2800-3200 RPM; e) sucralose and mix fruit flavour was added into step-d) under homogenizer and homogenized it for 10-15 minutes; f) the volume of step-e) suspension is made up with water and homogenized it for 30 minutes at 2800-3200 RPM, and g) recorded pH of step-f) suspension and adjusted pH at 7.00 with sodium dihydrogen phosphate dihydrate.
Example 3
Stability study of formulation from Example- 1:
Stability data of oral solution from example 1, packed in glass bottle is shown below.
Figure imgf000016_0001

Claims

Claims:
1. An oral liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient, wherein Empagliflozin or its pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 10% w/v in the liquid formulation.
2. The liquid formulation according to claim 1, wherein the liquid formulation is in the form of solution or suspension or the like.
3. The liquid formulation according to claim 2, wherein the liquid formulation is in the form of solution.
4. The liquid formulation according to claim 2, wherein the liquid formulation is in the form of suspension.
5. The liquid formulation according to claim 1, wherein the liquid formulation has a pH ranging from about 4 to about 8.
6. The liquid formulation according to claim 5, wherein the liquid formulation has a pH ranging from about 4.5 to about 7.5.
7. The liquid formulation according to claim 1, wherein the liquid formulation is stable under storage conditions of 25°C/60% RH, 30°C/65% RH, 40°C/75% RH, and/or 2-8°C.
8. The liquid formulation according to claim 1, wherein the one or more pharmaceutically acceptable excipient which are selected from the group consisting of preservatives, viscosity enhancers or viscosity enhancing agents, solubilizers or solubilizing agents, buffers or buffering agents, sweetener or sweetening agent, flavors or flavours, vehicles or solvents, wetting agents, cosolvent, suspending agents, antifoaming agents, taste masking agents, antioxidants, chelating agents, stabilizers and colorants.
9. The liquid formulation according to claim 8, wherein the viscosity enhancers or viscosity enhancing agents is selected from cellulose derivatives, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or methylcellulose, carboxymethyl cellulose and its salts/derivatives e.g., carboxymethyl cellulose sodium (carmellose sodium), microcrystalline cellulose, co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, poloxamers, from gums, guar gum, tragacanth gum, acacia gum, xanthan gum, gellan gums, alginic derivatives, alginic acid, sodium alginate, polyvinylpyrrolidone, from silicates, bentonite, laponite, veegum, and/or combinations thereof.
10. The liquid formulation according to claim 8, wherein the solubilizers or solubilizing agents is selected from cyclodextrin or its derivatives, a-cyclodextrin, P-cyclodextrin, 6- cyclodextrin, y-cyclodextrin, hydroxypropyl- P-cyclodextrin (HP-P-CD), polyethylene glycol (PEG), propylene glycol, poloxamer, polysorbates, alcohol (ethanol), sorbitol, sodium lauryl sulfates, glycerin, sorbitan monooleate, vitamin E TPGS (tocophersolan), olive oil, peppermint oil, castor oil, beeswax, d-alpha-tocopherol, hydrogenated soy phosphatidylcholine, 1-alpha-dimyristoyl phosphatidylglycerol and/or combinations thereof.
11. A liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; d) 0.5-15% w/v of a solubilizer or solubilizing agent; and e) one or more pharmaceutically acceptable excipient.
12. A liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient.
13. An oral liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; d) 0.5-15% w/v of a solubilizer or solubilizing agent; and e) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
14. An oral liquid formulation comprising: a) 0.1-10% w/v of Empagliflozin or its pharmaceutically acceptable salt thereof; b) 0.015-3% w/v of a preservative; c) 0.01-10% w/v of a viscosity enhancer or viscosity enhancing agent; and d) one or more pharmaceutically acceptable excipient, wherein the liquid formulation has a pH ranging from about 4 to about 8.
15. A process for the preparation of an oral solution formulation, comprising: a) separately taking part quantity of vehicle in beaker, heating and adding preservative and dissolving to get clear solution and cool; b) adding slowly solubilizing agent and dissolving in another part of vehicle, stirring to get clear solution; c) adding slowly Empagliflozin and dissolving in above solution of step b) and mixing using stirrer to get clear solution; d) adding and dissolving viscosity enhancer in above solution of step c) and mixing using stirrer to get clear solution; e) adding solution of step d) in solution of step a) using stirring to get clear solution; f) adding sweetener in above solution using stirring to get clear solution; g) adding flavour in above solution using stirring to get clear solution; and h) making up the volume with vehicle and mixing using stirrer to get clear solution.
16. A process for the preparation of an oral suspension formulation, comprising: a) adding preservatives into vehicle under continue stirring for desired time to get clear solution; b) soaking viscosity enhancer into vehicle and keep for desired time; c) adding soaked viscosity enhancer of step-b) into step-a) solution under homogenizer for desired time and speed; d) adding Empagliflozin into step-c) solution under homogenizer for desired time and speed; e) adding sweetener and mixing flavour into step-d) under homogenizer for desired time; f) making up final volume of step-e) suspension with vehicle and homogenizing for desired time and speed; and, g) recording pH of step-f) suspension and adjusting pH with buffering agents.
17. The method of using the liquid formulation according to claim 1, wherein said liquid formulation comprising Empagliflozin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipient for the treatment of type 2 diabetes mellitus, symptomatic chronic heart failure and chronic kidney disease.
PCT/IN2023/051096 2022-12-02 2023-11-25 Oral liquid formulation of empagliflozin or its pharmaceutically acceptable salt thereof WO2024116198A1 (en)

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US20200069713A1 (en) * 2009-02-13 2020-03-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20200237794A1 (en) * 2014-04-01 2020-07-30 Boehringer Ingelheim Vetmedica Gmbh Treatment of metabolic disorders in equine animals
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