EP3976014A1 - Combinaison comprenant de l'alogliptine et de la metformine - Google Patents

Combinaison comprenant de l'alogliptine et de la metformine

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)
English (en)
Other versions
EP3976014A4 (fr
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/fr
Publication of EP3976014A4 publication Critical patent/EP3976014A4/fr
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

Landscapes

  • 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

La présente invention concerne une composition pharmaceutique orale solide comprenant une combinaison de dose fixe d'alogliptine et de metformine et son procédé de préparation. Plus particulièrement, l'invention concerne une préparation orale solide d'une combinaison de dose fixe d'alogliptine et de metformine qui est stable et facile à produire.
EP20815329.6A 2019-05-24 2020-04-15 Combinaison comprenant de l'alogliptine et de la metformine Pending EP3976014A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/07905A TR201907905A1 (tr) 2019-05-24 2019-05-24 Alogli̇pti̇n ve metformi̇n i̇çeren bi̇r kombi̇nasyon
PCT/TR2020/050317 WO2020242413A1 (fr) 2019-05-24 2020-04-15 Combinaison comprenant de l'alogliptine et de la metformine

Publications (2)

Publication Number Publication Date
EP3976014A1 true EP3976014A1 (fr) 2022-04-06
EP3976014A4 EP3976014A4 (fr) 2023-02-15

Family

ID=73553852

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20815329.6A Pending EP3976014A4 (fr) 2019-05-24 2020-04-15 Combinaison comprenant de l'alogliptine et de la metformine

Country Status (3)

Country Link
EP (1) EP3976014A4 (fr)
TR (1) TR201907905A1 (fr)
WO (1) WO2020242413A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR202022144A1 (tr) * 2020-12-29 2022-07-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Alogli̇pti̇n i̇çeren farmasöti̇k kompozi̇syonlar
CN113081973A (zh) * 2021-05-07 2021-07-09 郑州泰丰制药有限公司 一种盐酸二甲双胍组合物及其制备方法
WO2023059118A1 (fr) * 2021-10-08 2023-04-13 (주)셀트리온 Composition pharmaceutique à stabilité améliorée pour le traitement du diabète sucré

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20090882A1 (es) * 2007-07-19 2009-08-03 Takeda Pharmaceutical Preparacion solida que comprende alogliptina y clorhidrato de metformina
PE20140960A1 (es) * 2008-04-03 2014-08-15 Boehringer Ingelheim Int Formulaciones que comprenden un inhibidor de dpp4
WO2013179307A2 (fr) 2012-05-29 2013-12-05 Mylan Laboratories Limited Compositions pharmaceutiques stabilisées de saxagliptine
KR20150059166A (ko) * 2015-05-12 2015-05-29 씨제이헬스케어 주식회사 서방형 메트포르민과 속방형 HMG-CoA 환원효소 억제제를 포함하는 복합제제
WO2017029609A1 (fr) * 2015-08-20 2017-02-23 Torrent Pharmaceuticals Limited Composition pharmaceutique d'alogliptine et de metformine
US20180235911A1 (en) * 2015-08-21 2018-08-23 Alembic Pharmaceuticals Limited Stable pharmaceutical composition of alogliptin and metformin fixed dose combination

Also Published As

Publication number Publication date
WO2020242413A1 (fr) 2020-12-03
EP3976014A4 (fr) 2023-02-15
TR201907905A1 (tr) 2020-12-21

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