EP4031122A1 - Effervescent tablet formulations comprising dapagliflozin and metformin - Google Patents

Effervescent tablet formulations comprising dapagliflozin and metformin

Info

Publication number
EP4031122A1
EP4031122A1 EP20866500.0A EP20866500A EP4031122A1 EP 4031122 A1 EP4031122 A1 EP 4031122A1 EP 20866500 A EP20866500 A EP 20866500A EP 4031122 A1 EP4031122 A1 EP 4031122A1
Authority
EP
European Patent Office
Prior art keywords
weight
effervescent tablet
composition according
sodium
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20866500.0A
Other languages
German (de)
French (fr)
Other versions
EP4031122A4 (en
Inventor
Abdullah TASKIN
Yavuz Dedeoglu
Muge ULUSOY BOZYEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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 Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4031122A1 publication Critical patent/EP4031122A1/en
Publication of EP4031122A4 publication Critical patent/EP4031122A4/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers

Definitions

  • the invention relates to formulations comprising dapagliflozin or a pharmaceutically acceptable salt thereof combined with metformin or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to the effervescent formulation of dapagliflozin and metformin with the desired properties.
  • Diabetes mellitus is a lifelong chronic disease resulting from the pancreas's inability to produce enough insulin or the body's ability to use insulin effectively and it continues with the reduction of insulin-producing cells. Blood glucose rises with absent or non-functioning insulin hormone. The resulting high blood sugar causes classical symptoms such as polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
  • type 1 diabetes type 1
  • type 2 diabetes type 2 diabetes
  • gestational diabetes is seen in pregnant women who develop high blood sugar levels.
  • Type 1 diabetes is caused by the body's inability to produce insulin, requiring insulin injection.
  • type 2 diabetes the body either resists the effects of insulin or does not produce enough insulin to maintain a normal glucose level.
  • type 2 diabetes is the most common type, affecting more than 171 million people worldwide.
  • Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2).
  • SGLT2 is a carrier responsible for the reabsorption of most of the glucose from the lumen of the renal tubule.
  • SGLT2 is expressed in proximal renal tubules.
  • dapagliflozin reduces the reabsorption of the filtered glucose and lowers the renal threshold for glucose. This improves urinary glucose excretion and blood glucose control.
  • Dapagliflozin also known as (1S)-1 ,5-Anhydro-1-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-D-glucitol or (2S,3R,4R,5S,6R)-2-(3-(4-etoxybenzyl)-4- chlorophenyl)-6-hydroxymethyltetrahydro-2FI-pyran-3,4,5-triol is represented by the structure of Formula I.
  • Dapagliflozin was first disclosed in patent US 6515117 (2003, Bristol-Myers Squibb).
  • Metformin is an antihyperglycemic agent that improves glucose tolerance and lowers both basal and postprandial plasma glucose levels by different mechanisms than other oral antidiabetic agents. Metformin decreases hepatic gluconeogenesis, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
  • Metformin also known as N, N- dimethylimidodicarbonimidic diamide or 1 ,1 -Dimethylbiguanide or N, N- dimethyldiguanide or N, N-Dimethylguanylguanidine, is represented by the chemical structure in Formula II.
  • EP2498758B1 discloses bilayer tablets comprising metformin and dapagliflozin.
  • EP2498759B1 discloses a process for the preparation of an immediate release formulation comprising a combination of dapagliflozin and metformin.
  • WO 2017/098481 discloses an effervescent combination comprising metformin with retained carbon dioxide content of at least 90% of the input blend and a different antidiabetic agent.
  • Unexamined patent TR2012/02948 discloses a tablet form comprising a combination of metformin hydrochloride and dapagliflozin and a core tablet coated with a coating solution containing extended release metformin and dapagliflozin.
  • the main object of effervescent tablet formulations comprising dapagliflozin or a pharmaceutically acceptable salt thereof with metformin or a pharmaceutically acceptable salt thereof is to obtain a stable formulation with good flowability and that does not adhere to the manufacturing apparatus. Another object is to obtain an effervescent formulation that is well dispersed and dissolved in water, thereby having high bioavailability. Effervescent tablet formulations with good solubility provide a homogeneous mixture, which increases patient compliance.
  • effervescent tablet formulations are becoming an increasingly important issue in patient compliance, compared to traditional solid dosage forms such as capsules and tablets for oral administration. Compliance is even more important, especially in patients having difficulty in swallowing.
  • effervescent tablet formulations are one of the advantageous ways of delivering drugs comprising dapagliflozin and metformin, providing better patient compliance along with the recommended pharmaceutical treatments. It is known that it is difficult to develop effervescent tablet formulations for several different reasons. First, it can cause non-compliance problems if it leaves an unpleasant and bitter taste when dispersed in water. Moreover, these tablets should be very porous and not too hard.
  • Effervescent tablets should ensure rapid dissolution of the drug to provide a neutral, clear solution with a pleasant taste, without leaving any residues or precipitates behind. Therefore, there is a need for the development of an effervescent formulation that has a desired dissolution time and a desired solubility without leaving any residues and precipitates after dissolution and has an acceptable taste for patients. Dissolution problems of the drug and formulation, unpleasant and bitter taste arising from water dissolution are problems that need to be overcome. Finally, any effervescent tablet with appropriate organoleptic and pharmacokinetic properties should also be produced in commercially appropriate quantities and yields and simpler methods. When evaluated within the framework of the mentioned problem, it is clear that an innovation in the art is needed for effervescent formulations comprising dapagliflozin and metformin.
  • the object of the present invention is to provide an improved effervescent tablet formulation comprising dapagliflozin or a pharmaceutically acceptable salt thereof combined with metformin or a pharmaceutically acceptable salt thereof that overcomes the above mentioned problems and beneficial in the treatment of type 2 diabetes using suitable excipients.
  • the object of the present invention is to overcome the above-mentioned problems related to effervescent formulations such as obtaining the desired solubility of the drug or formulation without leaving any residues or precipitates after dissolution and providing a better flavor for patients, by using suitable excipients together and in specific proportions.
  • Another aim of the present invention is to increase flowability during manufacture and to eliminate the problem of adhesion to the manufacturing apparatus thanks to the formulation obtained.
  • another object is to provide effervescent tablet formulations that is water-soluble and remain stable throughout their shelf life.
  • Main difficulties when two or more molecules are combined in the same pharmaceutical dosage form are a) ensuring compatibility between different active substances and / or excipients used with active substances, (b) ensuring therapeutic compatibility between the active ingredients, taking into account the pharmacokinetic and / or biopharmaceutical properties, such as the posology of the combination, to obtain effective and safe plasma levels of both active ingredients. Therefore, the selection of the active ingredients and suitable excipients to be used together and the amounts at which they are used are very important.
  • a pharmaceutical formulation comprising a combination of dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.
  • the effervescent tablet formulation comprising dapagliflozin and metformin that is stable and has very good dissolution and solubility rate, thereby high bioavailability is obtained by the present invention.
  • the present invention is an effervescent tablet formulation comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.
  • dapagliflozin or a pharmaceutically acceptable salt thereof being present in the ratio of 0,001 to 5%, preferably 0,01 to 1%, and more preferably 0,05 to 0,2% by weight of the total formulation and metformin or a pharmaceutically acceptable salt thereof being present in the ratio of 1 to 50%, preferably 5 to 30%, and more preferably 10 to 20% by weight of the total formulation has enabled both active substances to reach an effective and safe plasma level, ensured therapeutic compatibility between the active ingredients and compatibility between active ingredients and excipients.
  • Pharmaceutical formulations of the present invention may also comprise one or more pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include, but are not limited to fillers, alkali agents, acidic agents, sweeteners, aromatic agents, disintegrants, lubricants, or mixtures thereof.
  • the amount of filler in the formulation according to the invention is 1 to 80%, preferably 3 to 70%, more preferably 5 to 60% by weight in the total composition.
  • the filler is sugars, mannitol, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose or mixtures thereof.
  • mannitol is used in the invention.
  • the use of the total active ingredient to the filler at the ratio of 0,01 to 30, preferably 0,015 to 20, more preferably 0,05 to 10, and most preferably 0,1 to 5 allowed a more stable effervescent tablet formulation of dapagliflozin and metformin.
  • metformin active ingredient with low compressibility rate to the filler in the ratio of 0,01 - 30, preferably 0,05 - 20, more preferably 0,07 - 10 and most preferably 0,16 - 4 allowed a more stable effervescent tablet formulation of dapagliflozin and metformin.
  • effervescent formulations comprise acidic agents and alkali agents that react quickly in the presence of water by releasing carbon dioxide such as carbonates or bicarbonates.
  • the choice of acidic-alkali agent and their ratio to each other is important in terms of stability, disintegration time and water solubility.
  • the ratio of the acidic agent to the alkaline agent should be carefully determined to obtain a neutral solution that doesn’t leave any residues or precipitates after dissolution.
  • the high amount of acidic agent can adversely affect the gastrointestinal tract.
  • high amounts of alkaline agents (especially hydrophobic agents) lead to blurry and precipitated solution and damage the gastrointestinal tract.
  • the amount of alkali agent in the formulation of the invention is 0,5 to 60%, preferably 1 to 50%, more preferably 2 to 40% by weight in the total composition.
  • alkali agent is selected from sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, trolamine or mixtures thereof.
  • sodium bicarbonate is used in the invention.
  • the amount of acidic agent in the formulation of the invention is between 0,5 and 60% by weight, preferably between 1 and 50%, more preferably between 2 and 40% by weight in the total composition
  • the acidic agent is selected from the group comprising malic acid, fumaric acid, citric acid, adipic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid or mixtures thereof.
  • citric acid is used in the invention.
  • the amount of sweetener in the formulation of the invention is in the ratio of 0,01 to 30%, preferably 0,05 to 20%, more preferably 0,1 to 10% by weight of the total composition.
  • sweeteners comprise, but are not limited to, saccharin sodium, aspartame, sucralose, glucose, lactose, fructose and other sugars, or taumatin, mogroside, inulin, mannitol, sorbitol, xylitol, erythritol and other sugar alcohols or mixtures thereof.
  • sucralose is used in the invention.
  • the amount of the aroma in the formulation of the invention is in the ratio of 0,01 to 30%, preferably 0,05 to 20%, more preferably 0,1 to 10% by weight of the total composition.
  • aromatic agents of the invention comprise, but are not limited to, fruit flavors such as orange, banana, strawberry, cherry, bird cherry, lemon, and other flavors such as cardamom, anise, peppermint, menthol, vanillin and ethyl vanillin, and mixtures thereof.
  • disintegrant is selected from alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium, doucat sodium, guar gum, low substitute hydroxypropyl cellulose, polyacrylene potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof.
  • crospovidone is used in the invention.
  • crospovidone as a disintegrant in the ratio of 0,1% to 15%, preferably 1% to 8%, more preferably 2% to 4% by weight in the total composition allowed for a formulation with the desired water solubility time and improved patient compliance.
  • the ratio of the active ingredient dapagliflozin with low solubility to the disintegrant in the range of 0,001 - 5, preferably 0,00125 - 1 , more preferably 0,01 - 0,5, more preferably 0,0125 - 0,1 by weight in the formulation allowed for an effervescent tablet formulation of dapagliflozin and metformin with very good dissolution and solubility ratio, thereby high bioavailability, forming a neutral and clear solution that doesn’t leave any residues or precipitates after dissolution.
  • Polyethylene glycol is a water-soluble lubricant and is stable. Polyethylene glycol also does not cause over-mixing problems and is not hygroscopic. Since it is not hygroscopic, it does not harm the manufacture apparatus. Furthermore, polyethylene glycol can perform more than one function in the formulation of the present invention. For example, it can function both as a lubricant and as a stabilizer. This helps the formulation to remain stable throughout its shelf life.
  • PEG 6000 is used in the invention.
  • the amount of lubricant is 0,1 to 30%, preferably 0,5 to 15%, more preferably 1 to 5% by weight in the total composition.
  • Another embodiment of the present invention is a method for the preparation of effervescent tablet formulation, comprising the following steps; a. Granulating, drying and sieving dapagliflozin, metformin and mannitol using alcohol b. Mixing the granules with sodium bicarbonate, citric acid, sucralose, aroma and crospovidone to obtain homogeneity c. Adding PEG 6000 and mixing further for a short period of time to obtain a homogeneous mixture. d. Finalising the mixture and pressing into the tablets under low humidity conditions adimlarini igermektedir.
  • the above-mentioned pharmaceutical formulation is prepared as follows:
  • the above-mentioned pharmaceutical formulation is prepared as follows:
  • the above-mentioned pharmaceutical formulation is prepared as follows:
  • this invention provides an effervescent tablet formulation of dapagliflozin and metformin that is stable and has very good dissolution and solubility ratio, thereby high bioavailability, that does not stick to the manufacture apparatus during production, creates a stable, neutral and clear solution against moisture, does not leave any residues or precipitates after dissolution and provides a delicious taste, does not leave an unpleasant and bitter taste.

Abstract

The invention relates to effervescent tablet formulations comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.

Description

EFFERVESCENT TABLET FORMULATIONS COMPRISING DAPAGLIFLOZIN
AND METFORMIN
Field of the Invention
The invention relates to formulations comprising dapagliflozin or a pharmaceutically acceptable salt thereof combined with metformin or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to the effervescent formulation of dapagliflozin and metformin with the desired properties.
Background of the Invention
Diabetes mellitus, known as diabetes, is a lifelong chronic disease resulting from the pancreas's inability to produce enough insulin or the body's ability to use insulin effectively and it continues with the reduction of insulin-producing cells. Blood glucose rises with absent or non-functioning insulin hormone. The resulting high blood sugar causes classical symptoms such as polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Currently, there are three types of diabetes: type 1 diabetes (type 1), type 2 diabetes (type 2) and gestational diabetes. Gestational diabetes is seen in pregnant women who develop high blood sugar levels. Type 1 diabetes is caused by the body's inability to produce insulin, requiring insulin injection. Finally, with type 2 diabetes, the body either resists the effects of insulin or does not produce enough insulin to maintain a normal glucose level. Of these three types of diabetes, type 2 diabetes is the most common type, affecting more than 171 million people worldwide.
Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2). SGLT2 is a carrier responsible for the reabsorption of most of the glucose from the lumen of the renal tubule. SGLT2 is expressed in proximal renal tubules. By inhibiting SGLT2, dapagliflozin reduces the reabsorption of the filtered glucose and lowers the renal threshold for glucose. This improves urinary glucose excretion and blood glucose control. Dapagliflozin, also known as (1S)-1 ,5-Anhydro-1-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-D-glucitol or (2S,3R,4R,5S,6R)-2-(3-(4-etoxybenzyl)-4- chlorophenyl)-6-hydroxymethyltetrahydro-2FI-pyran-3,4,5-triol is represented by the structure of Formula I.
Formula I
Dapagliflozin was first disclosed in patent US 6515117 (2003, Bristol-Myers Squibb). Metformin is an antihyperglycemic agent that improves glucose tolerance and lowers both basal and postprandial plasma glucose levels by different mechanisms than other oral antidiabetic agents. Metformin decreases hepatic gluconeogenesis, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin, also known as N, N- dimethylimidodicarbonimidic diamide or 1 ,1 -Dimethylbiguanide or N, N- dimethyldiguanide or N, N-Dimethylguanylguanidine, is represented by the chemical structure in Formula II.
Formula II Metformin was first disclosed in patent US 3174901 (1965, Jan Marcel Didier Aron- Samuel).
EP2498758B1 discloses bilayer tablets comprising metformin and dapagliflozin.
EP2498759B1 discloses a process for the preparation of an immediate release formulation comprising a combination of dapagliflozin and metformin.
WO 2017/098481 discloses an effervescent combination comprising metformin with retained carbon dioxide content of at least 90% of the input blend and a different antidiabetic agent.
Unexamined patent TR2012/02948 discloses a tablet form comprising a combination of metformin hydrochloride and dapagliflozin and a core tablet coated with a coating solution containing extended release metformin and dapagliflozin.
The main object of effervescent tablet formulations comprising dapagliflozin or a pharmaceutically acceptable salt thereof with metformin or a pharmaceutically acceptable salt thereof is to obtain a stable formulation with good flowability and that does not adhere to the manufacturing apparatus. Another object is to obtain an effervescent formulation that is well dispersed and dissolved in water, thereby having high bioavailability. Effervescent tablet formulations with good solubility provide a homogeneous mixture, which increases patient compliance.
Various formulations and methods are known in the art for the preparation of effervescent tablet formulations. However, effervescent tablet formulations are becoming an increasingly important issue in patient compliance, compared to traditional solid dosage forms such as capsules and tablets for oral administration. Compliance is even more important, especially in patients having difficulty in swallowing. For these reasons, effervescent tablet formulations are one of the advantageous ways of delivering drugs comprising dapagliflozin and metformin, providing better patient compliance along with the recommended pharmaceutical treatments. It is known that it is difficult to develop effervescent tablet formulations for several different reasons. First, it can cause non-compliance problems if it leaves an unpleasant and bitter taste when dispersed in water. Moreover, these tablets should be very porous and not too hard. These porous tablets tend to be quite sensitive to moisture. As a result, they may carry some stability issues. Effervescent tablets should ensure rapid dissolution of the drug to provide a neutral, clear solution with a pleasant taste, without leaving any residues or precipitates behind. Therefore, there is a need for the development of an effervescent formulation that has a desired dissolution time and a desired solubility without leaving any residues and precipitates after dissolution and has an acceptable taste for patients. Dissolution problems of the drug and formulation, unpleasant and bitter taste arising from water dissolution are problems that need to be overcome. Finally, any effervescent tablet with appropriate organoleptic and pharmacokinetic properties should also be produced in commercially appropriate quantities and yields and simpler methods. When evaluated within the framework of the mentioned problem, it is clear that an innovation in the art is needed for effervescent formulations comprising dapagliflozin and metformin.
Background and Description of the Invention
The object of the present invention is to provide an improved effervescent tablet formulation comprising dapagliflozin or a pharmaceutically acceptable salt thereof combined with metformin or a pharmaceutically acceptable salt thereof that overcomes the above mentioned problems and beneficial in the treatment of type 2 diabetes using suitable excipients.
The object of the present invention is to overcome the above-mentioned problems related to effervescent formulations such as obtaining the desired solubility of the drug or formulation without leaving any residues or precipitates after dissolution and providing a better flavor for patients, by using suitable excipients together and in specific proportions.
Another aim of the present invention is to increase flowability during manufacture and to eliminate the problem of adhesion to the manufacturing apparatus thanks to the formulation obtained. In addition, another object is to provide effervescent tablet formulations that is water-soluble and remain stable throughout their shelf life.
Main difficulties when two or more molecules are combined in the same pharmaceutical dosage form are a) ensuring compatibility between different active substances and / or excipients used with active substances, (b) ensuring therapeutic compatibility between the active ingredients, taking into account the pharmacokinetic and / or biopharmaceutical properties, such as the posology of the combination, to obtain effective and safe plasma levels of both active ingredients. Therefore, the selection of the active ingredients and suitable excipients to be used together and the amounts at which they are used are very important.
In order to achieve all the objectives mentioned above and those that may emerge from the detailed description below, a pharmaceutical formulation has been developed comprising a combination of dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.
The effervescent tablet formulation comprising dapagliflozin and metformin that is stable and has very good dissolution and solubility rate, thereby high bioavailability is obtained by the present invention. The present invention is an effervescent tablet formulation comprising dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.
Surprisingly, it has been found that, according to this embodiment of the present invention, dapagliflozin or a pharmaceutically acceptable salt thereof being present in the ratio of 0,001 to 5%, preferably 0,01 to 1%, and more preferably 0,05 to 0,2% by weight of the total formulation and metformin or a pharmaceutically acceptable salt thereof being present in the ratio of 1 to 50%, preferably 5 to 30%, and more preferably 10 to 20% by weight of the total formulation has enabled both active substances to reach an effective and safe plasma level, ensured therapeutic compatibility between the active ingredients and compatibility between active ingredients and excipients. Pharmaceutical formulations of the present invention may also comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to fillers, alkali agents, acidic agents, sweeteners, aromatic agents, disintegrants, lubricants, or mixtures thereof.
The amount of filler in the formulation according to the invention is 1 to 80%, preferably 3 to 70%, more preferably 5 to 60% by weight in the total composition.
In the formulation of the invention, the filler is sugars, mannitol, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose or mixtures thereof. Preferably mannitol is used in the invention.
Surprisingly, according to this embodiment of the present invention, the use of the total active ingredient to the filler at the ratio of 0,01 to 30, preferably 0,015 to 20, more preferably 0,05 to 10, and most preferably 0,1 to 5 allowed a more stable effervescent tablet formulation of dapagliflozin and metformin.
Surprisingly, according to this embodiment of the present invention, the use of metformin active ingredient with low compressibility rate to the filler in the ratio of 0,01 - 30, preferably 0,05 - 20, more preferably 0,07 - 10 and most preferably 0,16 - 4 allowed a more stable effervescent tablet formulation of dapagliflozin and metformin.
In general, effervescent formulations comprise acidic agents and alkali agents that react quickly in the presence of water by releasing carbon dioxide such as carbonates or bicarbonates. The choice of acidic-alkali agent and their ratio to each other is important in terms of stability, disintegration time and water solubility. The ratio of the acidic agent to the alkaline agent should be carefully determined to obtain a neutral solution that doesn’t leave any residues or precipitates after dissolution. The high amount of acidic agent can adversely affect the gastrointestinal tract. In addition, high amounts of alkaline agents (especially hydrophobic agents) lead to blurry and precipitated solution and damage the gastrointestinal tract. The amount of alkali agent in the formulation of the invention is 0,5 to 60%, preferably 1 to 50%, more preferably 2 to 40% by weight in the total composition.
In the formulation of the invention, alkali agent is selected from sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, trolamine or mixtures thereof. Preferably, sodium bicarbonate is used in the invention.
The amount of acidic agent in the formulation of the invention is between 0,5 and 60% by weight, preferably between 1 and 50%, more preferably between 2 and 40% by weight in the total composition
In the formulation of e invention, the acidic agent is selected from the group comprising malic acid, fumaric acid, citric acid, adipic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid or mixtures thereof. Preferably, citric acid is used in the invention.
The amount of sweetener in the formulation of the invention is in the ratio of 0,01 to 30%, preferably 0,05 to 20%, more preferably 0,1 to 10% by weight of the total composition.
In the formulation of the invention, sweeteners comprise, but are not limited to, saccharin sodium, aspartame, sucralose, glucose, lactose, fructose and other sugars, or taumatin, mogroside, inulin, mannitol, sorbitol, xylitol, erythritol and other sugar alcohols or mixtures thereof. Preferably, sucralose is used in the invention.
The amount of the aroma in the formulation of the invention is in the ratio of 0,01 to 30%, preferably 0,05 to 20%, more preferably 0,1 to 10% by weight of the total composition.
The aromatic agents of the invention comprise, but are not limited to, fruit flavors such as orange, banana, strawberry, cherry, bird cherry, lemon, and other flavors such as cardamom, anise, peppermint, menthol, vanillin and ethyl vanillin, and mixtures thereof.
In the formulation of the invention, disintegrant is selected from alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium, doucat sodium, guar gum, low substitute hydroxypropyl cellulose, polyacrylene potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof. Preferably, crospovidone is used in the invention.
Surprisingly, according to this embodiment of the present invention, the use of crospovidone as a disintegrant in the ratio of 0,1% to 15%, preferably 1% to 8%, more preferably 2% to 4% by weight in the total composition allowed for a formulation with the desired water solubility time and improved patient compliance.
Surprisingly, according to this embodiment of the present invention, the ratio of the total active ingredient to the disintegrant in the range of 0,1 - 50, preferably 0,125 - 40, more preferably 0,125 - 30, more preferably 0,5 - 30, more preferably 1 - 20 and most preferably 2,5 - 10 by weight in the formulation allowed for an effervescent tablet formulation of dapagliflozin and metformin with very good dissolution and solubility ratio, thereby high bioavailability, forming a neutral and clear solution that doesn’t leave any residues or precipitates after dissolution.
Surprisingly, according to this embodiment of the present invention, the ratio of the active ingredient dapagliflozin with low solubility to the disintegrant in the range of 0,001 - 5, preferably 0,00125 - 1 , more preferably 0,01 - 0,5, more preferably 0,0125 - 0,1 by weight in the formulation allowed for an effervescent tablet formulation of dapagliflozin and metformin with very good dissolution and solubility ratio, thereby high bioavailability, forming a neutral and clear solution that doesn’t leave any residues or precipitates after dissolution.
Polyethylene glycol (PEG) is a water-soluble lubricant and is stable. Polyethylene glycol also does not cause over-mixing problems and is not hygroscopic. Since it is not hygroscopic, it does not harm the manufacture apparatus. Furthermore, polyethylene glycol can perform more than one function in the formulation of the present invention. For example, it can function both as a lubricant and as a stabilizer. This helps the formulation to remain stable throughout its shelf life. Preferably, PEG 6000 is used in the invention.
According to this embodiment of the present invention, the amount of lubricant is 0,1 to 30%, preferably 0,5 to 15%, more preferably 1 to 5% by weight in the total composition.
Another embodiment of the present invention is a method for the preparation of effervescent tablet formulation, comprising the following steps; a. Granulating, drying and sieving dapagliflozin, metformin and mannitol using alcohol b. Mixing the granules with sodium bicarbonate, citric acid, sucralose, aroma and crospovidone to obtain homogeneity c. Adding PEG 6000 and mixing further for a short period of time to obtain a homogeneous mixture. d. Finalising the mixture and pressing into the tablets under low humidity conditions adimlarini igermektedir.
The present invention is described in more detail by the following examples. The example is not to limit the scope of the invention, but should be considered in the light of the details described above.
Example 1 :
The above-mentioned pharmaceutical formulation is prepared as follows:
Granulating, drying and sieving dapagliflozin, metformin and mannitol using alcohol. Mixing this granule with sodium bicarbonate, citric acid, sucralose, aroma and crospovidone to obtain homogeneity. Adding polyethylene glycol (PEG 6000) and mixing further for a short period of time to obtain a homogeneous mixture. Obtaining the final mixture and pressing into the tablets under low humidity conditions Pressing to form 4-5 g tablet. Example 2:
The above-mentioned pharmaceutical formulation is prepared as follows:
Granulating, drying and sieving dapagliflozin, metformin and mannitol using alcohol. Mixing this granule with sodium bicarbonate, citric acid, sucralose, aroma and crospovidone to obtain homogeneity. Adding polyethylene glycol (PEG 6000) and mixing further for a short period of time to obtain a homogeneous mixture. Obtaining the final mixture and pressing into the tablets under low humidity conditions Pressing to form 4-5 g tablet.
Example 3:
The above-mentioned pharmaceutical formulation is prepared as follows:
Granulating, drying and sieving dapagliflozin, metformin and mannitol using alcohol. Mixing this granule with sodium bicarbonate, citric acid, sucralose, aroma and crospovidone to obtain homogeneity. Adding polyethylene glycol (PEG 6000) and mixing further for a short period of time to obtain a homogeneous mixture. Obtaining the final mixture and pressing into the tablets under low humidity conditions pressing to form 4-5 g tablet.
Suprisingly, this invention provides an effervescent tablet formulation of dapagliflozin and metformin that is stable and has very good dissolution and solubility ratio, thereby high bioavailability, that does not stick to the manufacture apparatus during production, creates a stable, neutral and clear solution against moisture, does not leave any residues or precipitates after dissolution and provides a delicious taste, does not leave an unpleasant and bitter taste.

Claims

1. An effervescent tablet formulation, comprising a combination of dapagliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
2. The effervescent tablet composition according to Claim 1 , wherein the composition comprises dapagliflozin or a pharmaceutically acceptable salt thereof in the ratio of 0,001 to 5%, preferably 0,01 to 1%, and more preferably 0,05 to 0,2% by weight of the total formulation and metformin or a pharmaceutically acceptable salt thereof being present in the ratio of 1 to 50%, preferably 5 to 30%, and more preferably 10 to 20% by weight of the total formulation.
3. The effervescent tablet composition according to Claim 1 or 2, wherein more than one pharmaceutically acceptable excipients are selected from the group consisting of fillers, alkali agents, acidic agents, sweeteners, aromatic agents, disintegrants, lubricants, or mixtures thereof.
4. The effervescent tablet composition according to Claim 3, wherein the amount of the disintegrant is present in the ratio of 0,1% to 15%, preferably 1% to 8%, more preferably 2% to 4% by weight in the total composition.
5. The effervescent tablet composition according to Claim 3, wherein the ratio of the total active ingredient to the disintegrant is in the range of 0,1 - 50, preferably 0,125 - 40, more preferably 0,125 - 30 by weight.
6. The effervescent tablet composition according to Claim 4 or 5, wherein the disintegrant is selected from alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium, doucat sodium, guar gum, low substitute hydroxypropyl cellulose, polyacrylene potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof, which is preferably crospovidone.
7. The effervescent tablet composition according to Claim 3, wherein the amount of the filler is present in the ratio of 1% to 80%, preferably 3% to 70% and more preferably 5% to 60% by weight in the total composition.
8. The effervescent tablet composition according to Claim 3, wherein the ratio of the total active ingredient to the filler is in the ratio of 0,01 to 30, preferably 0,015 to 20, more preferably 0,05 to 10.
9. The effervescent tablet composition according to Claim 7 and 8, wherein the filler is selected from sugars, mannitol, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose or mixtures thereof, which is preferably mannitol.
10. The effervescent tablet composition according to Claim 3, wherein the alkali agent is present in the range of 0,5 to 60%, preferably 1 to 50%, more preferably 2 to 40% by weight in the total composition.
11. The effervescent tablet composition according to Claim 10, wherein the alkali agent is selected from sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, trolamine or mixtures thereof, which is preferably sodium bicarbonate.
12. The effervescent tablet composition according to Claim 3, wherein the acidic agent is present between 0,5 and 60% by weight, preferably between 1 and 50%, more preferably between 2 and 40% by weight in the total composition.
13. The effervescent tablet composition according to Claim 12, wherein, the acidic agent is selected from the group comprising malic acid, fumaric acid, citric acid, adipic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid or mixtures thereof, which is preferably citric acid.
14. The effervescent tablet composition according to Claim 3, wherein the lubricant is present in the range of 0,1 to 30%, preferably 0,5 to 15%, more preferably 1 to 5% by weight in the total composition.
15. The effervescent tablet composition according to Claim 14, wherein the lubricant is polyethylene glycol.
16. The effervescent tablet composition according to the preceding claims, wherein the composition comprising the following; a. 0,001 to 5% by weight of dapagliflozin or a pharmaceutically acceptable salt thereof b. 1 - 50% by weight of metformin or a pharmaceutically acceptable salt thereof c. 1 - 80% by weight of mannitol d. 0,5 - 60% by weight of sodium bicarbonate e. 0,5 - 60% by weight of citric acid f. 0,01 - 30% by weight of sucralose g. 0,01 - 30% by weight of aroma h. 0,1 - 15% by weight of crospovidone i. 0,1 - 30% by weight of polyethylene glycol
17. The effervescent composition according to the preceding claims, wherein the composition comprising the following production method; a. Granulating, drying and sieving dapagliflozin, metformin and mannitol using alcohol. b. Mixing the granules with sodium bicarbonate, citric acid, sucralose, aroma and crospovidone to obtain homogeneity. c. Adding polyethylene glycol and mixing further for a short period of time to obtain a homogeneous mixture. d. Finalising the mixture and pressing into the tablets under low humidity conditions.
EP20866500.0A 2019-09-16 2020-08-05 Effervescent tablet formulations comprising dapagliflozin and metformin Pending EP4031122A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/14043A TR201914043A1 (en) 2019-09-16 2019-09-16 EFERVESAN TABLET FORMULATIONS CONTAINING DAPAGLYFLOZIN AND METFORMIN
PCT/TR2020/050687 WO2021054912A1 (en) 2019-09-16 2020-08-05 Effervescent tablet formulations comprising dapagliflozin and metformin

Publications (2)

Publication Number Publication Date
EP4031122A1 true EP4031122A1 (en) 2022-07-27
EP4031122A4 EP4031122A4 (en) 2023-08-30

Family

ID=74883168

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20866500.0A Pending EP4031122A4 (en) 2019-09-16 2020-08-05 Effervescent tablet formulations comprising dapagliflozin and metformin

Country Status (3)

Country Link
EP (1) EP4031122A4 (en)
TR (1) TR201914043A1 (en)
WO (1) WO2021054912A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4079296A1 (en) * 2021-04-21 2022-10-26 Sanovel Ilac Sanayi Ve Ticaret A.S. A bilayer tablet formulation comprising amorphous dapagliflozin and metformin

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007038979A1 (en) * 2005-09-22 2007-04-12 Swissco Development Ag Effervescent metformin composition and tablets and granules made therefrom
PL2498758T3 (en) * 2009-11-13 2019-02-28 Astrazeneca Ab Bilayer tablet formulations
WO2013115743A1 (en) * 2012-01-31 2013-08-08 Mahmut Bilgic Effervescent tablet formulations comprising the combination of voglibose and metformin
WO2017098481A1 (en) * 2015-12-12 2017-06-15 Steerlife India Private Limited Effervescent compositions of metformin and processes for preparation thereof
WO2018185669A1 (en) * 2017-04-07 2018-10-11 Zenvision Pharma Llp Effervescent compositions comprising saxagliptin or salt thereof

Also Published As

Publication number Publication date
EP4031122A4 (en) 2023-08-30
WO2021054912A1 (en) 2021-03-25
TR201914043A1 (en) 2021-04-21

Similar Documents

Publication Publication Date Title
KR20100126266A (en) Pharmaceutical compositions
US20130274342A1 (en) Compositions and methods for treating cough
EP2661252A1 (en) Water soluble dosage forms
EP2848242A1 (en) Orally disintegrating formulations of Linagliptin
EP4031122A1 (en) Effervescent tablet formulations comprising dapagliflozin and metformin
US20110257159A1 (en) Orally disintegrating tablet formulations of mirtazapine and process for preparing the same
EP2563340A2 (en) Water soluble pharmaceutical composition
JP4814636B2 (en) Biguanide drugs for internal use
US10016359B2 (en) Solid forms containing meloxicam with improved buccal taste and process for their preparation
WO2018185669A1 (en) Effervescent compositions comprising saxagliptin or salt thereof
KR101046789B1 (en) Amlodipine quick disintegrating tablet with improved stability and preparation method thereof
EP2248516A1 (en) Orally disintegrating compositions of emoxypine
WO2004089343A1 (en) Water soluble tablets
CN104434860A (en) Ambroxol hydrochloride osmotic pump type pharmaceutical composition prepared by inclusion process
DK3174521T3 (en) PEDIATRIC CHEESE TABLE CONTAINING ANTIVIRAL AGENT AND METHOD OF PRODUCING THEREOF
JP2010053048A (en) Irbesartan-containing pharmaceutical composition having mitigated bitter taste
WO2024023786A1 (en) Orally disintegrating palatable formulations of drotaverine and method of preparation thereof
CN103282038A (en) Phosphomycin pharmaceutical composition
US9849147B2 (en) Pharmaceutical composition containing phosphate binding polymer
JP2022135317A (en) Linagliptin preparation
WO2023247949A1 (en) An orodispersible pharmaceutical composition of baclofen and its process of preparation
EP4125824A1 (en) A sachet formulation comprising metformin and dapagliflozin
WO2004082664A1 (en) Water-soluble tablets of metformin
JP2022170891A (en) Oral solid preparation
EP3968955A1 (en) Pharmaceutical oral liquid solution of ivacaftor

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20220315

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230708

A4 Supplementary search report drawn up and despatched

Effective date: 20230727

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 3/10 20060101ALI20230721BHEP

Ipc: A61K 9/20 20060101ALI20230721BHEP

Ipc: A61K 31/351 20060101ALI20230721BHEP

Ipc: A61K 31/155 20060101AFI20230721BHEP