WO2013137839A1 - Tablet formulation comprising dapagliflozin and extended release metformin - Google Patents

Tablet formulation comprising dapagliflozin and extended release metformin Download PDF

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Publication number
WO2013137839A1
WO2013137839A1 PCT/TR2013/000084 TR2013000084W WO2013137839A1 WO 2013137839 A1 WO2013137839 A1 WO 2013137839A1 TR 2013000084 W TR2013000084 W TR 2013000084W WO 2013137839 A1 WO2013137839 A1 WO 2013137839A1
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WO
WIPO (PCT)
Prior art keywords
dapagliflozin
core tablet
metformin
tablet according
hydroxypropyl methylcellulose
Prior art date
Application number
PCT/TR2013/000084
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French (fr)
Inventor
Didehan KESGIN
Abdullah Bulgur
Original Assignee
Ali Raif İlaç Sanayi Ve Ticaret Anonim Şirketi
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Application filed by Ali Raif İlaç Sanayi Ve Ticaret Anonim Şirketi filed Critical Ali Raif İlaç Sanayi Ve Ticaret Anonim Şirketi
Publication of WO2013137839A1 publication Critical patent/WO2013137839A1/en

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    • 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
    • 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
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention is related to combination formulation prepared by being coated with a coating solution comprising dapagliflozin or pharmaceutically acceptable salts, solvates or hydrates thereof on the extended-release metformin tablet.
  • Type 2 diabetes More than 90% of diabetes diseases are Type 2 diabetes. More than 100 million people in the world are type 2 diabetic patients, and the said number is increasing rapidly.
  • Type 2 diabetes is a disease that develops at middle or older ages, and lasts for a lifetime.
  • Type 2 diabetes is a disease occurring as a result of relative decrease in the insulin synthesis and secretion, or sometimes a complete disappearance thereof by resistance against the insulin effect or decrease in insulin sensitivity.
  • the main reason of impairment in insulin responsiveness is the insulin receptor present at the cell membrane. However, specific impairment is unknown. Type 2 diabetes cases developed based on a known cause are classified separately.
  • Dapagliflozin among the sodium/glucose co-transporter inhibitors which is one of the treatment methods, reacts by accelerating the sugar excretion from urine.
  • Dapagliflozin is a new anti-diabetic known as sodium-glucose transporter-2 inhibitor (Formula 1). Its chemical name is (1S)-1 ,5-Anhydro-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-glucitol, its molecule formula is C21 H25CIO 6 , and its molecular weight is 408.873 g/mol.
  • Metformin is antihyperglycemic agent in the biguanide group, which heals glycose tolerance by decreasing basal and post prandial plasma glucose in type 2 diabetics (Formula 2).
  • the chemical name of metformin is " ⁇ , ⁇ -dimethylimidocarbonimidic diamide, 1 ,1- dimethylbiguanide", its closed formula is C4HHN5, and its molecular weight is 129.16 g/mol.
  • Metformin is a white substance in the shape of a crystalized powder.
  • Formula 2 There are several patents present relating to the drugs comprising dapagliflozin.
  • immediate-release pharmaceutical formulation in the form of granule or capsule and comprising dapagliflozin or pharmaceutically acceptable salt or solvates thereof and metformin or pharmaceutically acceptable salt or solvates thereof is disclosed.
  • WO 2011/060256 PCT application a double-layer tablet formulation comprising extended- release metformin at the first layer, and dapagliflozin at the second layer, is disclosed.
  • the present invention is a film tablet obtained by coating the extended-release core tablet comprising metformin hydrochloride with film coating solution comprising dapagliflozin or pharmaceutically acceptable salts, solvates or hydrates thereof.
  • Dapagliflozin (S) propylene glycol hydrate "Dapagliflozin (S) PGS" is preferred.
  • the core tablet comprises Metformin HCI as active substance, hydroxypropyl methylcellulose as agent controlling the release, colloidal silicone dioxide as flow enhancer, and magnesium stearate as lubricant.
  • the core tablet prepared is coated with aqueous solution comprising dapagliflozin (S) propylene glycol hydrate, hydroxypropyl methylcellulose, polyvinyl pyrolidone, polyethylene glycol and titanium dioxide.
  • Methocel K 100M CR 2% solution of which has a viscosity of 80000-120000 cp in 20°C water, is used as hydroxypropyl methylcellulose in the core tablet.
  • Avicel PH101 is used as microcrystalline cellulose.
  • Colloidal silicone dioxide is known as aerosil.
  • HPMC 3 cp is used as hydroxypropyl methylcellulose
  • Povidone K30 is used as polyvinyl pyrolidone
  • PEG 4000 is used as polyethylene glycol.
  • the core tablet is prepared by direct compression method. The following examples describe the invention, but do not limit it in any way.
  • Glucophage SR Tablet has been used as reference product in order to control the similarity of Metformin HCI with the original product in the tests.
  • the similarity factor (f2) used in the comparison of dissolution profiles of test formulation and reference product is the similarity measure of two dissolution graphics, and when f2 value is 50 or higher, two dissolution profiles are accepted as similar.
  • f2 value is 50 or higher, two dissolution profiles are accepted as similar.
  • Test formulations amounts are in m

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

Abstract

The present invention is related to a combination formulation coated with dapagliflozin on the extended-release core tablet comprising metformin hydrochloride.

Description

TABLET FORMULATION COMPRISING DAPAGLIFLOZIN AND EXTENDED
RELEASE METFORMIN DESCRIPTION
Technical Field:
The present invention is related to combination formulation prepared by being coated with a coating solution comprising dapagliflozin or pharmaceutically acceptable salts, solvates or hydrates thereof on the extended-release metformin tablet.
Prior Art:
More than 90% of diabetes diseases are Type 2 diabetes. More than 100 million people in the world are type 2 diabetic patients, and the said number is increasing rapidly. Type 2 diabetes is a disease that develops at middle or older ages, and lasts for a lifetime. Type 2 diabetes is a disease occurring as a result of relative decrease in the insulin synthesis and secretion, or sometimes a complete disappearance thereof by resistance against the insulin effect or decrease in insulin sensitivity. The main reason of impairment in insulin responsiveness is the insulin receptor present at the cell membrane. However, specific impairment is unknown. Type 2 diabetes cases developed based on a known cause are classified separately.
Dapagliflozin among the sodium/glucose co-transporter inhibitors, which is one of the treatment methods, reacts by accelerating the sugar excretion from urine.
Dapagliflozin is a new anti-diabetic known as sodium-glucose transporter-2 inhibitor (Formula 1). Its chemical name is (1S)-1 ,5-Anhydro-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-glucitol, its molecule formula is C21 H25CIO6, and its molecular weight is 408.873 g/mol.
Figure imgf000002_0001
Metformin is antihyperglycemic agent in the biguanide group, which heals glycose tolerance by decreasing basal and post prandial plasma glucose in type 2 diabetics (Formula 2). The chemical name of metformin is "Ν,Ν-dimethylimidocarbonimidic diamide, 1 ,1- dimethylbiguanide", its closed formula is C4HHN5, and its molecular weight is 129.16 g/mol. Metformin is a white substance in the shape of a crystalized powder.
Figure imgf000003_0001
Formula 2 There are several patents present relating to the drugs comprising dapagliflozin. In WO 2011/060290 PCT application, immediate-release pharmaceutical formulation in the form of granule or capsule and comprising dapagliflozin or pharmaceutically acceptable salt or solvates thereof and metformin or pharmaceutically acceptable salt or solvates thereof, is disclosed.
In WO 2011/060256 PCT application, a double-layer tablet formulation comprising extended- release metformin at the first layer, and dapagliflozin at the second layer, is disclosed.
Description of the Invention:
The present invention is a film tablet obtained by coating the extended-release core tablet comprising metformin hydrochloride with film coating solution comprising dapagliflozin or pharmaceutically acceptable salts, solvates or hydrates thereof. Dapagliflozin (S) propylene glycol hydrate "Dapagliflozin (S) PGS" is preferred. The core tablet comprises Metformin HCI as active substance, hydroxypropyl methylcellulose as agent controlling the release, colloidal silicone dioxide as flow enhancer, and magnesium stearate as lubricant. The core tablet prepared is coated with aqueous solution comprising dapagliflozin (S) propylene glycol hydrate, hydroxypropyl methylcellulose, polyvinyl pyrolidone, polyethylene glycol and titanium dioxide.
Methocel K 100M CR, 2% solution of which has a viscosity of 80000-120000 cp in 20°C water, is used as hydroxypropyl methylcellulose in the core tablet. Avicel PH101 is used as microcrystalline cellulose. Colloidal silicone dioxide is known as aerosil. In the coating, HPMC 3 cp is used as hydroxypropyl methylcellulose, Povidone K30 is used as polyvinyl pyrolidone, and PEG 4000 is used as polyethylene glycol. The core tablet is prepared by direct compression method. The following examples describe the invention, but do not limit it in any way.
EXAMPLES:
The following formulations have been studied according to the present invention. All the formulations have been produced by direct compression.
Glucophage SR Tablet has been used as reference product in order to control the similarity of Metformin HCI with the original product in the tests. The similarity factor (f2) used in the comparison of dissolution profiles of test formulation and reference product is the similarity measure of two dissolution graphics, and when f2 value is 50 or higher, two dissolution profiles are accepted as similar. For dapagliflozin, 80% (Q) dissolution limit for 30 minutes authorized by European Pharmacopoeia has been tried to be met.
Table 1. Test formulations (amounts are in mg)
Figure imgf000004_0001
Table 2. Test formulations amounts are in m
Figure imgf000005_0001
Table 3. Test formulations amounts are in mg)
Figure imgf000005_0002
The formulations have been tested under the dissolution conditions in accordance with long- acting Metformin HCI tablet monograph determined by US Pharmacopeia (pH 6.8 Phosphate buffer). It has been observed that f2 values of formulations are higher than 50, and therefore, they are similar to the original products. Dapagliflozin dissolution is above 80% in 30 minutes. .
Under the same conditions, the controls have been performed in 0.1 N HCI and pH 4.5 phosphate buffer, and it has been observed that the results are similar to the original product.

Claims

1. A combined tablet comprising metformin hydrochloride and dapagliflozin, characterized in that the core tablet comprises extended-release metformin and the said core tablet is coated with a coating solution comprising dapagliflozin or pharmaceutically acceptable salts, solvates or hydrates thereof.
2. A combined tablet according to Claim 1 , characterized in that the coating layer comprises dapagliflozin (S) propylene glycol hydrate.
3. A core tablet according to Claim 1 , characterized in that it comprises Metformin hydrochloride as active substance, hydroxypropyl methylcellulose as controlled release agent, colloidal silicone dioxide as flow enhancer, and magnesium stearate as lubricant.
4. A core tablet according to Claim 1 , characterized in that it is prepared by direct compression method.
5. A core tablet according to Claim 1 , characterized in that it comprises hydroxypropyl methylcellulose, 2% solution of which has a viscosity of 80000-120000 cp in 20°C water.
6. A core tablet according to Claim 1 , characterized in that it is coated with aqueous solution comprising dapagliflozin (S) propylene glycol hydrate, hydroxypropyl methylcellulose, polyvinyl pyrolidone, polyethylene glycol and titanium dioxide.
7. The coating layer according to Claim 1 , characterized in that it comprises HPMC 3 cp as hydroxypropyl methycellulose, Povidone K30 as polyvinyl pyrolidone, and PEG 4000 polyethylene glycol.
PCT/TR2013/000084 2012-03-15 2013-03-07 Tablet formulation comprising dapagliflozin and extended release metformin WO2013137839A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2012/02948 2012-03-15
TR2012/02948A TR201202948A2 (en) 2012-03-15 2012-03-15 Tablet formulation comprising dapaglyphlosin and prolonged release metaphormin.

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WO2013137839A1 true WO2013137839A1 (en) 2013-09-19

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017114227A1 (en) * 2015-12-30 2017-07-06 深圳翰宇药业股份有限公司 Dapagliflozin and metformin complex extended release tablet and preparation method thereof
KR20190038283A (en) * 2017-09-29 2019-04-08 한미약품 주식회사 Pharmaceutical combination comprising DAPAGLIFLOZIN L-PROLINE and METFORMIN
WO2020009352A1 (en) * 2018-07-06 2020-01-09 한미약품 주식회사 Pharmaceutical preparation containing amorphous dapagliflozin l-proline, and preparation method therefor
WO2022225489A1 (en) * 2021-04-21 2022-10-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A bilayer tablet formulation comprising amorphous dapagliflozin and metformin
CN115414347A (en) * 2022-08-22 2022-12-02 北京诺和德美医药科技有限公司 Sustained-release tablet and preparation method and application thereof
WO2023136797A3 (en) * 2022-01-13 2023-08-17 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A bilayer tablet composition comprising amorphous dapagliflozin and metformin

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4212150A1 (en) 2022-01-13 2023-07-19 Sanovel Ilac Sanayi Ve Ticaret A.S. A bilayer tablet composition comprising amorphous dapagliflozin and metformin

Citations (6)

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WO2009099734A1 (en) * 2008-02-05 2009-08-13 Merck & Co., Inc. Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
WO2010045656A2 (en) * 2008-10-17 2010-04-22 Nectid, Inc. Novel sglt2 inhibitor dosage forms
WO2011039337A1 (en) * 2009-10-02 2011-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2011060256A2 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Bilayer tablet formulations
WO2011060290A2 (en) 2009-11-13 2011-05-19 Bristol-Myer Squibb Company Immediate release tablet formulations
WO2012120040A1 (en) * 2011-03-07 2012-09-13 Boehringer Ingelheim International Gmbh Pharmaceutical compositions comprising metformin and a dpp-4 inhibitor or a sglt-2 inhibitor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099734A1 (en) * 2008-02-05 2009-08-13 Merck & Co., Inc. Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
WO2010045656A2 (en) * 2008-10-17 2010-04-22 Nectid, Inc. Novel sglt2 inhibitor dosage forms
WO2011039337A1 (en) * 2009-10-02 2011-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2011060256A2 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Bilayer tablet formulations
WO2011060290A2 (en) 2009-11-13 2011-05-19 Bristol-Myer Squibb Company Immediate release tablet formulations
WO2012120040A1 (en) * 2011-03-07 2012-09-13 Boehringer Ingelheim International Gmbh Pharmaceutical compositions comprising metformin and a dpp-4 inhibitor or a sglt-2 inhibitor

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017114227A1 (en) * 2015-12-30 2017-07-06 深圳翰宇药业股份有限公司 Dapagliflozin and metformin complex extended release tablet and preparation method thereof
CN106924208A (en) * 2015-12-30 2017-07-07 深圳翰宇药业股份有限公司 A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof
KR20190038283A (en) * 2017-09-29 2019-04-08 한미약품 주식회사 Pharmaceutical combination comprising DAPAGLIFLOZIN L-PROLINE and METFORMIN
KR102369679B1 (en) * 2017-09-29 2022-03-04 한미약품 주식회사 Pharmaceutical combination comprising DAPAGLIFLOZIN L-PROLINE and METFORMIN
WO2020009352A1 (en) * 2018-07-06 2020-01-09 한미약품 주식회사 Pharmaceutical preparation containing amorphous dapagliflozin l-proline, and preparation method therefor
KR20200005320A (en) * 2018-07-06 2020-01-15 한미약품 주식회사 Pharmaceutical formulation including amorphous dapagliflozin l-proline and preparation method thereof
KR102687535B1 (en) * 2018-07-06 2024-07-24 한미약품 주식회사 Pharmaceutical formulation including amorphous dapagliflozin l-proline and preparation method thereof
WO2022225489A1 (en) * 2021-04-21 2022-10-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A bilayer tablet formulation comprising amorphous dapagliflozin and metformin
WO2023136797A3 (en) * 2022-01-13 2023-08-17 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A bilayer tablet composition comprising amorphous dapagliflozin and metformin
CN115414347A (en) * 2022-08-22 2022-12-02 北京诺和德美医药科技有限公司 Sustained-release tablet and preparation method and application thereof
CN115414347B (en) * 2022-08-22 2023-09-15 北京诺和德美医药技术有限公司 Sustained release tablet and preparation method and application thereof

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