WO2022023206A1 - Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine - Google Patents

Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine Download PDF

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Publication number
WO2022023206A1
WO2022023206A1 PCT/EP2021/070680 EP2021070680W WO2022023206A1 WO 2022023206 A1 WO2022023206 A1 WO 2022023206A1 EP 2021070680 W EP2021070680 W EP 2021070680W WO 2022023206 A1 WO2022023206 A1 WO 2022023206A1
Authority
WO
WIPO (PCT)
Prior art keywords
layer
ezetimibe
dosage form
atorvastatin
form according
Prior art date
Application number
PCT/EP2021/070680
Other languages
English (en)
Inventor
Danijel Videc
Polona Bukovec
Kristina DEBELJAK SIMONCIC
Grega Hudovornik
Klemen KORASA
Maja OMERZU
Original Assignee
Krka, D.D., Novo Mesto
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 Krka, D.D., Novo Mesto filed Critical Krka, D.D., Novo Mesto
Priority to EP21755380.9A priority Critical patent/EP4188338A1/fr
Publication of WO2022023206A1 publication Critical patent/WO2022023206A1/fr

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Classifications

    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2072—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

  • solid dosage forms comprising at least two layers comprising Ezetimibe in a combination with Atorvastatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in separate layers are provided.
  • a first aspect of the invention relates to a solid pharmaceutical dosage form comprising
  • an Ezetimibe layer comprising (i) Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; (ii) a first diluent; (iii) optionally, a second diluent; and (iv) optionally, a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extra- granular phase; and
  • the Ezetimibe layer comprises a first diluent, optionally, a second diluent and optionally, a first binder.
  • the Ezetimibe layer may further comprise one or more pharmaceutically acceptable excipients that may be for example selected from diluents, lubricants, glidants, disintegrants, binders, wetting agents, colorants, and the like.
  • the pharmaceutically acceptable excipients of the solid dosage form according to the invention present in the Ezetimibe layer may be present in relative amounts as shown in the following table 1. Amount indications in the following tables may be understood as indications in parts by weight of the Ezetimibe layer.
  • the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise one or more any other active substances suitable for the treatment of abnormal lipid levels and/or any other one or more active substances that show beneficial effect on said patient, such as for example bempedoic acid, fibrates (e.g. Fenofibrate, Pemafibrate), bile acid sequestrants (e.g. Colestyramine, Colestipol, Colesevelam), nicotinic acid and its derivatives, omega-3 -triglycerides incl. other esters and acids (e.g.
  • lactose preferably anhydrous lactose, lactose hydrate, partially amorphous lactose, completely amor phous lactose;
  • Atorvastatin layer At least a fraction or essentially the total amount of the third diluent is comprised in the intragranular phase of the Atorvastatin layer.
  • croscarmellose so dium and/or croscarmellose calcium polacrilin potassium, alginic acid or alginates, sodium and/or cal cium alginate, polyacrylates, docusate sodium, methylcellulose, agar, guar gum, chitosan, gums and mixtures thereof.
  • Preferred disintegrants are croscarmellose sodium, crospovidone and mixtures thereof.
  • croscarmellose sodium crospovidone and mixtures thereof; more preferably croscarmellose sodium.
  • the weight content of the second wetting agent is
  • the Ezetimibe layer of the solid pharmaceutical dosage form accord ing to the invention comprises ferric oxide, preferably ferric oxide yellow.
  • the weight content of colorant in the Ezetimibe layer is within the range of 0.05 to 0.2 wt.-%, relative to the total weight of the Ezetimibe layer.
  • 6.0 ⁇ 5.5 wt.-% preferably 6.0 ⁇ 5.0 wt.-%, more preferably 6.0 ⁇ 4.5 wt.-%, still more preferably 6.0 ⁇ 4.0 wt.-%, yet more preferably 6.0 ⁇ 3.5 wt.-%, even more preferably 6.0 ⁇ 3.0 wt.-%, most pref erably 6.0 ⁇ 2.5 wt.-%, and in particular 6.0 ⁇ 2.0 wt.-% of third disintegrant; preferably sodium croscarmellose; preferably in the intragranular phase of the Atorvastatin layer; and/or
  • sub-step i) involves dispersing the second wetting agent and/or the second binder in an organic liquid or water.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein the diluent used in lg is different than diluent used in step le and disintegrant used in lg is the same as disintegrant used in step le.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein Atorvastatin is present in the form of its any pharmaceutically ac ceptable salts, solvates, hydrates, enantiomers and any mixture thereof in any pharmaceutically accepta ble polymorphic form, preferably Atorvastatin is present in the form of Atorvastatin calcium (2: 1) tri hydrate.
  • Table 7 Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/ Atorvas tatin 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg film coated tablets
  • the dissolution profile of Atorvastatin released from the bilayer tablet of Example 3g according to the invention satisfies the similarity requirements compared to the dissolution profile of Atorvastatin released from Atozet ® 10/80 mg (B.No: S034177) and from Sortis ® 80 mg (B.No: CK1527).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formes posologiques pharmaceutiques solides comprenant de l'ézétimibe et de l'atorvastatine dans des couches séparées, ainsi que leurs procédés de fabrication. Les formes posologiques solides sont des comprimés multicouches, de préférence des comprimés bicouches, appropriés pour une administration orale.
PCT/EP2021/070680 2020-07-27 2021-07-23 Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine WO2022023206A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP21755380.9A EP4188338A1 (fr) 2020-07-27 2021-07-23 Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SI202000126 2020-07-27
SIP-202000126 2020-07-27

Publications (1)

Publication Number Publication Date
WO2022023206A1 true WO2022023206A1 (fr) 2022-02-03

Family

ID=77358210

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/070680 WO2022023206A1 (fr) 2020-07-27 2021-07-23 Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine

Country Status (2)

Country Link
EP (1) EP4188338A1 (fr)
WO (1) WO2022023206A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4374855A1 (fr) * 2022-11-22 2024-05-29 KRKA, D.D., Novo Mesto Forme pharmaceutique de dosage de candesartan et d'indapamide

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409281A1 (fr) 1989-07-21 1991-01-23 Warner-Lambert Company Acide [(R-(R'R')]-2-(4-fluorophényl)-bêta,delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)-carbonyl]-1H-pyrrole-1-heptanoique, sa forme lactonique et ses sels
EP0720599A1 (fr) 1993-09-21 1996-07-10 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
EP1741427A1 (fr) * 2005-07-06 2007-01-10 KRKA, D.D., Novo Mesto Composition pharmaceutique comprenant la simvastatin et l'ezetimibe
US20070014854A1 (en) 2005-07-15 2007-01-18 Ilan Zalit Novel granulation process
US20070014864A1 (en) 2005-07-15 2007-01-18 Teva Pharmaceutical Industries, Ltd. Novel pharmaceutical granulate
US20100209495A1 (en) 2008-09-17 2010-08-19 Mylan Laboratories, Inc. Granulates, process for preparing them and pharmaceutical products containing them
WO2011002422A2 (fr) 2009-07-02 2011-01-06 Bilgic Mahmut Formulation pharmaceutique améliorant la solubilité
WO2013166114A1 (fr) 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe d'atorvastatine et d'ézétimibe
WO2018041282A1 (fr) * 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
EP3360541A1 (fr) 2017-02-13 2018-08-15 Sanovel Ilac Sanayi ve Ticaret A.S. Composition de comprimés bicouche pharmaceutiques de calcium d'atorvastatine et d'ézétimibe
WO2020139237A2 (fr) 2018-12-25 2020-07-02 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de comprimé bicouche d'atorvastatine calcique et d'ézétimibe

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409281A1 (fr) 1989-07-21 1991-01-23 Warner-Lambert Company Acide [(R-(R'R')]-2-(4-fluorophényl)-bêta,delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)-carbonyl]-1H-pyrrole-1-heptanoique, sa forme lactonique et ses sels
EP0720599A1 (fr) 1993-09-21 1996-07-10 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
EP1741427A1 (fr) * 2005-07-06 2007-01-10 KRKA, D.D., Novo Mesto Composition pharmaceutique comprenant la simvastatin et l'ezetimibe
US20070014854A1 (en) 2005-07-15 2007-01-18 Ilan Zalit Novel granulation process
US20070014864A1 (en) 2005-07-15 2007-01-18 Teva Pharmaceutical Industries, Ltd. Novel pharmaceutical granulate
US20100209495A1 (en) 2008-09-17 2010-08-19 Mylan Laboratories, Inc. Granulates, process for preparing them and pharmaceutical products containing them
WO2011002422A2 (fr) 2009-07-02 2011-01-06 Bilgic Mahmut Formulation pharmaceutique améliorant la solubilité
WO2013166114A1 (fr) 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe d'atorvastatine et d'ézétimibe
WO2018041282A1 (fr) * 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
EP3360541A1 (fr) 2017-02-13 2018-08-15 Sanovel Ilac Sanayi ve Ticaret A.S. Composition de comprimés bicouche pharmaceutiques de calcium d'atorvastatine et d'ézétimibe
WO2020139237A2 (fr) 2018-12-25 2020-07-02 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de comprimé bicouche d'atorvastatine calcique et d'ézétimibe

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2012, PHARMACEUTICAL PRESS
FOODY JMTOTH PPTOMASSINI JE ET AL.: "Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy", VASC HEALTH RISK MANAG, vol. 9, 2013, pages 719 - 727
STEHBENS WE: "Coronary heart disease, hypercholesterolemia, and atherosclerosis. II. Misrepresented data", EXP MOL PATHOL, vol. 70, 2001, pages 120 - 139
TOTH PPFOODY JMTOMASSINI JE ET AL.: "Therapeutic practice patterns related to statin potency and Ezetimibe/simvastatin combination therapies in lowering LDL-C in patients with high-risk cardiovascular disease.", J CLIN LIPIDOL, vol. 8, 2014, pages 107 - 116
WENG TCYANG YHLIN SJTAI SH: "A systematic review and meta-analysis on the therapeutic equivalence ofstatins", J CLIN PHARM THER, vol. 35, 2010, pages 139 - 151
WHAYNE TF., JR: "Assessment of low-density lipoprotein targets", ANGIOLOGY, vol. 64, 2013, pages 411 - 416

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4374855A1 (fr) * 2022-11-22 2024-05-29 KRKA, D.D., Novo Mesto Forme pharmaceutique de dosage de candesartan et d'indapamide

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Publication number Publication date
EP4188338A1 (fr) 2023-06-07

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