EP3976014A1 - A combination comprising alogliptin and metformin - Google Patents

A combination comprising alogliptin and metformin

Info

Publication number
EP3976014A1
EP3976014A1 EP20815329.6A EP20815329A EP3976014A1 EP 3976014 A1 EP3976014 A1 EP 3976014A1 EP 20815329 A EP20815329 A EP 20815329A EP 3976014 A1 EP3976014 A1 EP 3976014A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
solid oral
formulation
oral pharmaceutical
composition according
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
EP20815329.6A
Other languages
German (de)
French (fr)
Other versions
EP3976014A4 (en
Inventor
Gulcin TOK
Ediz Yildirim
Ali Turkyilmaz
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 EP3976014A1 publication Critical patent/EP3976014A1/en
Publication of EP3976014A4 publication Critical patent/EP3976014A4/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
    • A61K9/20—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Definitions

  • the present invention relates to a solid oral pharmaceutical composition comprising alogliptin and metformin fixed dose combination and to a process for preparation thereof. More particularly, it relates to a solid oral preparation of alogliptin and metformin fixed dose combination formulation which is stable and easy to manufacture.
  • Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
  • Type 1 and Type 2 There are two main types of diabetes; Type 1 and Type 2:
  • Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.
  • Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
  • Alogliptin, 2-[ [6- [(3R)-3-aminopiperidin -1 -yl]-3- methyl-2,4- dioxopyrimidin-1 -yl ] methyl] benzonitrile, is an orally administered anti-diabetic drug has a chemical structure which is shown in the Formula I.
  • alogliptin disclosed in US 2005/261271 , EP 1586571 and in WO 2005/095381 is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt.
  • Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372.
  • a process for preparing alogliptin is disclosed in WO 2007/1 12368 and, WO 2007/035629.
  • Metformin is antidiabetics having an orally-administrated biguanide structure.
  • Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform.
  • Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. It is used as single or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
  • the lUPAC name of metformin is 3-(diaminomethylidene)-1 ,1 -dimethylguanidine, has the following chemical structure of Formula II.
  • U.S. Pat. No. 8,900,638 disclose stability related concerns with the fixed dose combinations of alogliptin and metformin when alogliptin was combined with metformin.
  • US2018235966 patent application discloses pharmaceutical compositions comprising alogliptin and metformin with suitable pharmaceutically acceptable excipient/s by one or more processes selected from direct compression, dry granulation and wet granulation. In this application, more process steps are used with the use of excess excipients.
  • the combination comprises alogliptin and metformin, the combination uses many ways to overcome the described above the problems. For example; using a bilayer tablet or multilayer tablet or adding unnecessary excipients. But the process and formulation described in the prior art are complex, time consuming and costs are high.
  • the main object of the present invention is to obtain a solid oral pharmaceutical composition comprising stable and compatible combination of alogliptin and metformin with a desired dissolution and stability.
  • Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition.
  • analogliptin refers to not only alogliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
  • metalformin refers to not only metformin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
  • the solid oral pharmaceutical composition comprises;
  • formulations are present as a single granulated mass.
  • single granulated mass means that the first formulation and the second formulation are granulated together.
  • alogliptin is in the form of alogliptin benzoate.
  • metformin is in the form of metformin free base.
  • the active ingredients are formulated separately with the polymers to provide the desired dissolution profile of the solid oral pharmaceutical composition.
  • Suitable polymers are selected from the group comprising microcrystalline cellulose, amino methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol and polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, copolymer of ethyl acrylate or methyl methacrylate, polyvinyl acetal diethylaminoacetate, polyoxyl 40 hydrogenated castor oil, hydrogenated castor oil, polyoxyl 15 hydroxystearate, polyoxyl castor oil, polyethylene oxide, poloxamer, polyvinyl alcohol/polyethylene glycol graft copolymer, cetearyl ethyl hexanone/isopropyl myristate, glyceryl monostearate or mixtures thereof.
  • polymers are microcrystalline cellulose, amino methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol and polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, polyvinylpyrrolidone or mixtures thereof.
  • the weight ratio of the second formulation to the first formulation is 1 .0-25.0, preferably the ratio is 5.0-20.0, more preferably 8.0-18.0. This ratio provides the desired efficacy of active agents.
  • the first formulation or the second formulation of the present invention can be prepared using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • Hot-melt extrusion (HME) technology is prominent in the pharmaceutical industry. HME offers the potential of shorter and more efficient times to the final product, through reduction of the processing steps involved. HME is used to disperse an active agent in a matrix at the molecular level, thus forming solid solutions.
  • Hot-melt extrusion is a technique for manufacturing amorphous solid dispersions in which the active agent is melted or dissolved within a dispersion carrier and mixed to produce and stabilize. Functional excipients are often added to further aid in processability or improve the dissolution rate of an active agent.
  • the first formulation is obtained with hot melt extrusion method.
  • the second formulation is obtained with hot melt extrusion method.
  • the solid oral pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, lubricants or mixtures thereof.
  • Suitable fillers are selected from the group comprising mannitol, lactose monohydrate, starch, sucrose, glucose, dextrose, maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, pregelatinized starch or mixtures thereof.
  • the amount of fillers is between 3.0% and 20.0%, between 3.0% and 12.0% by weight of the total composition.
  • the filler is mannitol.
  • the amount of mannitol is between 3.0% and 20.0%, between 3.0% and 12.0%, between 4.0% and 10.0% by weight of the total composition.
  • Suitable binders are selected from the group comprising crospovidone, sugars, natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, alumina hydroxide, stearic acid, sucrose, bentonite, cetostearyl alcohol, polyoxyethilene-alkyl ethers or mixtures thereof.
  • the amount of binders is between 1 .0% and 10.0%, between 1 .0% and 7.0% by weight of the total composition.
  • the binder is crospovidone.
  • the amount of crospovidone is 1 .0% and 10.0%, between 1.0% and 7.0%, between 1 .5% and 6.0% by weight of the total composition.
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fumaric acid, glyceryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • the amount of lubricants is between 0.01 % and 3.0%, between 0.05% and 2.0% by weight of the total composition.
  • the lubricant is magnesium stearate.
  • the amount of magnesium stearate is between 0.01% and 3.0%, between 0.05% and 2.0% by weight of the total composition.
  • the solid oral pharmaceutical composition is in the form of a tablet or a capsule.
  • the composition is in the form of a tablet.
  • a tablet is selected from the group comprising mono-layer tablet, inlay tablets, orally disintegrating tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets.
  • the composition is in the form of a mono-layer tablet.
  • mono-layer tablet comprises film coating which is selected from the group comprising hydroxypropylmethylcellulose, talc, titanium dioxide, iron oxides, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol copolymers, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes or mixtures thereof.
  • the amount of film coating is between 0.01 % and 5.0%, between 0.5% and 4.0% by weight of the total composition.
  • the first formulation comprises 1 .2% by weight of alogliptin benzoate and 1.2% by weight of polymers in the solid oral pharmaceutical composition.
  • the first formulation comprises 1 .5% by weight of alogliptin benzoate and 1.5% by weight of polymers in the solid oral pharmaceutical composition.
  • the first formulation comprises 3.4% by weight of alogliptin benzoate and 3.4% by weight of polymers in the solid oral pharmaceutical composition.
  • the second formulation comprises 76.0% by weight of metformin and 8.4% by weight of polymers in the solid oral pharmaceutical composition.
  • the second formulation comprises 75.8% by weight of metformin and 8.4% by weight of polymers in the solid oral pharmaceutical composition.
  • the second formulation comprises 70.3% by weight of metformin and 7.8% by weight of polymers in the solid oral pharmaceutical composition.
  • the composition comprising the first formulation and the second formulation, mannitol, crospovidone, magnesium stearate.
  • Example 1 Film coated mono-layer tablet
  • Example 2 Film coated mono-layer tablet
  • Example 3 Film coated mono-layer tablet

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a solid oral pharmaceutical composition comprising alogliptin and metformin fixed dose combination and to a process for preparation thereof. More particularly, it relates to a solid oral preparation of alogliptin and metformin fixed dose combination formulation which is stable and easy to manufacture.

Description

A COMBINATION COMPRISING ALOGLIPTIN AND METFORMIN
Field of the Invention
The present invention relates to a solid oral pharmaceutical composition comprising alogliptin and metformin fixed dose combination and to a process for preparation thereof. More particularly, it relates to a solid oral preparation of alogliptin and metformin fixed dose combination formulation which is stable and easy to manufacture.
Background of the Invention
Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2:
Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.
In Type 2 diabetes, the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
Alogliptin, 2-[ [6- [(3R)-3-aminopiperidin -1 -yl]-3- methyl-2,4- dioxopyrimidin-1 -yl ] methyl] benzonitrile, is an orally administered anti-diabetic drug has a chemical structure which is shown in the Formula I.
Formula I Alogliptin disclosed in US 2005/261271 , EP 1586571 and in WO 2005/095381 . WO 2007/035629, disclosed alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt. Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372. A process for preparing alogliptin is disclosed in WO 2007/1 12368 and, WO 2007/035629.
Metformin is antidiabetics having an orally-administrated biguanide structure. Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. It is used as single or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
The lUPAC name of metformin is 3-(diaminomethylidene)-1 ,1 -dimethylguanidine, has the following chemical structure of Formula II.
Formula II
It had been surprisingly observed that an unexpected therapeutic effect and especially a synergistic therapeutic effect can be obtained in the treatment of type-2 diabetes when a combination therapy comprising alogliptin and metformin are used together.
U.S. Pat. No. 8,900,638 disclose stability related concerns with the fixed dose combinations of alogliptin and metformin when alogliptin was combined with metformin.
It was observed that the fixed dose combination of alogliptin and metformin was not chemically stable as the primary and tertiary amino group of alogliptin show incompatibilities, degradation problems or extraction problems.
US2018235966 patent application discloses pharmaceutical compositions comprising alogliptin and metformin with suitable pharmaceutically acceptable excipient/s by one or more processes selected from direct compression, dry granulation and wet granulation. In this application, more process steps are used with the use of excess excipients. In the prior art, there is the combination comprising alogliptin and metformin, the combination uses many ways to overcome the described above the problems. For example; using a bilayer tablet or multilayer tablet or adding unnecessary excipients. But the process and formulation described in the prior art are complex, time consuming and costs are high.
There is still a need for a physically and chemically stable composition.
In the present invention, physically and chemically stable pharmaceutical composition comprising alogliptin and metformin has been found surprisingly overcomes the above- mentioned problems.
Detailed Description of the Invention
The main object of the present invention is to obtain a solid oral pharmaceutical composition comprising stable and compatible combination of alogliptin and metformin with a desired dissolution and stability.
Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition.
The term "alogliptin" as used throughout the specification refers to not only alogliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
The term "metformin" as used throughout the specification refers to not only metformin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
According to one embodiment of the present invention, the solid oral pharmaceutical composition comprises;
-a first formulation comprising alogliptin free base or pharmaceutically acceptable salts thereof and at least one polymer,
-a second formulation comprising metformin free base or pharmaceutically acceptable salts thereof and at least one polymer,
wherein the formulations are present as a single granulated mass. The term ‘single granulated mass’ means that the first formulation and the second formulation are granulated together.
According to one embodiment of the present invention, alogliptin is in the form of alogliptin benzoate.
According to one embodiment of the present invention, metformin is in the form of metformin free base.
Surprisingly, it has been found that the active ingredients are formulated separately with the polymers to provide the desired dissolution profile of the solid oral pharmaceutical composition.
Suitable polymers are selected from the group comprising microcrystalline cellulose, amino methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol and polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, copolymer of ethyl acrylate or methyl methacrylate, polyvinyl acetal diethylaminoacetate, polyoxyl 40 hydrogenated castor oil, hydrogenated castor oil, polyoxyl 15 hydroxystearate, polyoxyl castor oil, polyethylene oxide, poloxamer, polyvinyl alcohol/polyethylene glycol graft copolymer, cetearyl ethyl hexanone/isopropyl myristate, glyceryl monostearate or mixtures thereof.
According to one embodiment of the present invention, preferably polymers are microcrystalline cellulose, amino methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol and polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, polyvinylpyrrolidone or mixtures thereof.
The fact that the formulations were formed into a single mass after being separately formed with said polymer completely eliminated the incompatibilities between the active ingredients. So, it provides desired stability.
According to one embodiment of the present invention, the weight ratio of the second formulation to the first formulation is 1 .0-25.0, preferably the ratio is 5.0-20.0, more preferably 8.0-18.0. This ratio provides the desired efficacy of active agents.
The first formulation or the second formulation of the present invention can be prepared using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation. Hot-melt extrusion (HME) technology is prominent in the pharmaceutical industry. HME offers the potential of shorter and more efficient times to the final product, through reduction of the processing steps involved. HME is used to disperse an active agent in a matrix at the molecular level, thus forming solid solutions.
Hot-melt extrusion is a technique for manufacturing amorphous solid dispersions in which the active agent is melted or dissolved within a dispersion carrier and mixed to produce and stabilize. Functional excipients are often added to further aid in processability or improve the dissolution rate of an active agent.
According to one embodiment of the present invention, the first formulation is obtained with hot melt extrusion method.
According to one embodiment of the present invention, the second formulation is obtained with hot melt extrusion method.
The use of this hot melt extrusion helped to achieve the desired stability of the composition. The method is easy to use and practical and most importantly it works well.
According to one embodiment of the present invention, the solid oral pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, lubricants or mixtures thereof.
Suitable fillers are selected from the group comprising mannitol, lactose monohydrate, starch, sucrose, glucose, dextrose, maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, pregelatinized starch or mixtures thereof.
According to one embodiment of the present invention, the amount of fillers is between 3.0% and 20.0%, between 3.0% and 12.0% by weight of the total composition.
According to one embodiment of the present invention, the filler is mannitol. The amount of mannitol is between 3.0% and 20.0%, between 3.0% and 12.0%, between 4.0% and 10.0% by weight of the total composition.
Suitable binders are selected from the group comprising crospovidone, sugars, natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, alumina hydroxide, stearic acid, sucrose, bentonite, cetostearyl alcohol, polyoxyethilene-alkyl ethers or mixtures thereof. According to one embodiment of the present invention, the amount of binders is between 1 .0% and 10.0%, between 1 .0% and 7.0% by weight of the total composition.
According to one embodiment of the present invention, the binder is crospovidone. The amount of crospovidone is 1 .0% and 10.0%, between 1.0% and 7.0%, between 1 .5% and 6.0% by weight of the total composition.
Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fumaric acid, glyceryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
According to one embodiment of the present invention, the amount of lubricants is between 0.01 % and 3.0%, between 0.05% and 2.0% by weight of the total composition.
According to one embodiment of the present invention, the lubricant is magnesium stearate. The amount of magnesium stearate is between 0.01% and 3.0%, between 0.05% and 2.0% by weight of the total composition.
According to one embodiment of the present invention, the solid oral pharmaceutical composition is in the form of a tablet or a capsule.
According to one embodiment of the present invention, the composition is in the form of a tablet. A tablet is selected from the group comprising mono-layer tablet, inlay tablets, orally disintegrating tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets.
According to one embodiment of the present invention, the composition is in the form of a mono-layer tablet. Preferably, mono-layer tablet comprises film coating which is selected from the group comprising hydroxypropylmethylcellulose, talc, titanium dioxide, iron oxides, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol copolymers, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes or mixtures thereof.
According to one embodiment of the present invention, the amount of film coating is between 0.01 % and 5.0%, between 0.5% and 4.0% by weight of the total composition. According to one embodiment of the present invention, the first formulation comprises 1 .2% by weight of alogliptin benzoate and 1.2% by weight of polymers in the solid oral pharmaceutical composition.
According to one embodiment of the present invention, the first formulation comprises 1 .5% by weight of alogliptin benzoate and 1.5% by weight of polymers in the solid oral pharmaceutical composition.
According to one embodiment of the present invention, the first formulation comprises 3.4% by weight of alogliptin benzoate and 3.4% by weight of polymers in the solid oral pharmaceutical composition.
According to one embodiment of the present invention, the second formulation comprises 76.0% by weight of metformin and 8.4% by weight of polymers in the solid oral pharmaceutical composition.
According to one embodiment of the present invention, the second formulation comprises 75.8% by weight of metformin and 8.4% by weight of polymers in the solid oral pharmaceutical composition.
According to one embodiment of the present invention, the second formulation comprises 70.3% by weight of metformin and 7.8% by weight of polymers in the solid oral pharmaceutical composition.
According to one embodiment of the present invention, the composition comprising the first formulation and the second formulation, mannitol, crospovidone, magnesium stearate.
Example 1 : Film coated mono-layer tablet
Process for example 1 ;
First formulation;
a. Dry mixing a polymer and alogliptin until a homogeneous mixture is obtained, b. Heating the mixture prepared at step(a) thereby forming a melt,
c. Cooling the melt formed at step(b) thereby forming extrudates
d. Converting extrudates form to granules
Second formulation
e. Dry mixing a polymer and metformin until a homogeneous mixture is obtained, f. Heating the mixture prepared at step(a) thereby forming a melt, g. Cooling the melt formed at step(b) thereby forming extrudates h. Converting extrudates form to granules, i. Mixing the first formulation, the second formulation, binders and fillers j. Then, adding lubricants and mixing,
k. Pressing the mixture to form tablets,
L. Coating the tablets with film-coating. Example 2: Film coated mono-layer tablet
Example 3: Film coated mono-layer tablet
Process for example 2 or example 3;
First formulation;
a. Dry mixing a polymer and alogliptin until a homogeneous mixture is obtained, b. Heating the mixture prepared at step (a) thereby forming a melt,
c. Cooling the melt, formed at step (b) thereby forming extrudates,
d. Converting extrudates form to granules
Second formulation
e. Dry mixing a polymer and metformin until a homogeneous mixture is obtained, f. Heating the mixture prepared at step(a) thereby forming a melt, g. Cooling the melt formed at step(b) thereby forming extrudates,
h. Converting extrudates form to granules, i. Mixing the first formulation, the second formulation, mannitol and crospovidone, j. Then, adding magnesium stearate and mixing,
k. Pressing the mixture to form tablets,
L. Coating the tablets with film-coating.
Example 4: Film coating

Claims

1 . A solid oral pharmaceutical composition comprising;
- A first formulation comprising alogliptin free base or pharmaceutically acceptable salts thereof and at least one polymer,
A second formulation comprising metformin free base or pharmaceutically acceptable salts thereof and at least one polymer,
wherein the formulations are present as a single granulated mass.
2. The solid oral pharmaceutical composition according to claim 1 , wherein the polymers are selected from the group comprising microcrystalline cellulose, amino methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol and polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose , hydroxypropyl methylcellulose , copolymer of ethyl acrylate or methyl methacrylate, polyvinyl acetal diethylaminoacetate, polyoxyl 40 hydrogenated castor oil, hydrogenated castor oil, polyoxyl 15 hydroxystearate, polyoxyl castor oil, polyethylene oxide, poloxamer , polyvinyl alcohol/polyethylene glycol graft copolymer, cetearyl ethyl hexanone/isopropyl myristate, glyceryl monostearate or mixtures thereof.
3. The solid oral pharmaceutical composition according to claim 2, wherein the polymers are microcrystalline cellulose, amino methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol and polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, polyvinylpyrrolidone or mixtures thereof.
4. The solid oral pharmaceutical composition according to claim 1 , wherein the weight ratio of the second formulation to the first formulation is 1.0-25.0, preferably the ratio is 5.0-20.0.
5. The solid oral pharmaceutical composition according to claim 1 , wherein the first formulation is obtained with hot melt extrusion method.
6. The solid oral pharmaceutical composition according to claim 1 , wherein the second formulation is obtained with hot melt extrusion method.
7. The solid oral pharmaceutical composition according to claim 1 , further comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, lubricants or mixtures thereof.
8. The solid oral pharmaceutical composition according to claim 7, wherein the fillers are selected from the group comprising mannitol, lactose monohydrate, starch, sucrose, glucose, dextrose, maltodexrin, natural and synthetic gums, gelatin, pregelatinized starch or mixtures thereof.
9. The solid oral pharmaceutical composition according to claim 7, wherein the binders are selected from the group comprising crospovidone, sugars, natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, alumina hydroxide, stearic acid, sucrose, bentonite, cetostearyl alcohol, polyoxyethilene-alkyl ethers or mixtures thereof.
10. The solid oral pharmaceutical composition according to claim 7, wherein the lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fumaric acid, glyceryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
1 1. The solid oral pharmaceutical composition according to claim 1 , wherein the composition is in the form of a tablet or a capsule.
12. The solid oral pharmaceutical composition according to claim 1 1 , wherein the composition is in the form of a tablet.
13. The solid oral pharmaceutical composition according to claim 12, wherein the composition comprising a film-coating which is selected from the group comprising hydroxypropylmethylcellulose, talc, titanium dioxide, iron oxides, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer , pigments, dyes or mixtures thereof.
14. The solid oral pharmaceutical composition according to claim 1 , wherein the composition comprising the first formulation and the second formulation, mannitol, crospovidone, magnesium stearate.
15. A process for preparing the solid oral pharmaceutical composition according to any preceding claim, comprising the following steps:
First formulation;
a. Dry mixing a polymer and alogliptin until a homogeneous mixture is obtained, b. Heating the mixture prepared at step (a) thereby forming a melt,
c. Cooling the melt, formed at step (b) thereby forming extrudates,
d. Converting extrudates form to granules
Second formulation
e. Dry mixing a polymer and metformin until a homogeneous mixture is obtained, f. Heating the mixture prepared at step(a) thereby forming a melt,
g. Cooling the melt formed at step(b) thereby forming extrudates,
h. Converting extrudates form to granules, i. Mixing the first formulation, the second formulation, mannitol and crospovidone, j. Then, adding magnesium stearate and mixing,
k. Pressing the mixture to form tablets,
L. Coating the tablets with film-coating.
EP20815329.6A 2019-05-24 2020-04-15 A combination comprising alogliptin and metformin Pending EP3976014A4 (en)

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TR2019/07905A TR201907905A1 (en) 2019-05-24 2019-05-24 A COMBINATION WITH ALOGLIPTIN AND METFORMIN
PCT/TR2020/050317 WO2020242413A1 (en) 2019-05-24 2020-04-15 A combination comprising alogliptin and metformin

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TR202022144A1 (en) * 2020-12-29 2022-07-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi PHARMACEUTICAL COMPOSITIONS CONTAINING ALOGLIPTINE
CN113081973A (en) * 2021-05-07 2021-07-09 郑州泰丰制药有限公司 Metformin hydrochloride composition and preparation method thereof
WO2023059118A1 (en) * 2021-10-08 2023-04-13 (주)셀트리온 Stability-improved pharmaceutical composition for treatment of diabetes mellitus

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MY159203A (en) * 2007-07-19 2016-12-30 Takeda Pharmaceuticals Co Solid preparation comprising alogliptin and metformin hydrochloride
AR071175A1 (en) * 2008-04-03 2010-06-02 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INHIBITOR OF DIPEPTIDIL-PEPTIDASA-4 (DPP4) AND A COMPARING PHARMACO
WO2013179307A2 (en) 2012-05-29 2013-12-05 Mylan Laboratories Limited Stabilized pharmaceutical compositions of saxagliptin
KR20150059166A (en) * 2015-05-12 2015-05-29 씨제이헬스케어 주식회사 Pharmaceutical combination comprising sustained-release type metformin and immediate-release type HMG-CoA reductase inhibitor
WO2017029609A1 (en) * 2015-08-20 2017-02-23 Torrent Pharmaceuticals Limited Pharmaceutical composition of alogliptin and metformin
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