WO2020139237A2 - Formulation de comprimé bicouche d'atorvastatine calcique et d'ézétimibe - Google Patents

Formulation de comprimé bicouche d'atorvastatine calcique et d'ézétimibe Download PDF

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Publication number
WO2020139237A2
WO2020139237A2 PCT/TR2019/051006 TR2019051006W WO2020139237A2 WO 2020139237 A2 WO2020139237 A2 WO 2020139237A2 TR 2019051006 W TR2019051006 W TR 2019051006W WO 2020139237 A2 WO2020139237 A2 WO 2020139237A2
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Prior art keywords
weight
bilayer tablet
layer
pharmaceutical
tablet according
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Ceased
Application number
PCT/TR2019/051006
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English (en)
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WO2020139237A3 (fr
Inventor
Selin KOKSAL UZUN
Ediz Yildirim
Ali Turkyilmaz
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Sanovel Ilac Sanayi ve Ticaret AS
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Sanovel Ilac Sanayi ve Ticaret AS
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Publication of WO2020139237A3 publication Critical patent/WO2020139237A3/fr
Anticipated expiration legal-status Critical
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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
    • A61K9/2072—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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers

Definitions

  • the present invention relates to a pharmaceutical bilayer tablet formulation comprising atorvastatin calcium and ezetimibe. Further, the present invention provides a process that eliminates disadvantages of active agents.
  • atorvastatin is (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4- (phenylcarbamoyl)-5-propan-2-ylpyrrol-1 -yl]-3,5-dihydroxyheptanoic acid and has a chemical structure which is shown in Formula I.
  • Atorvastatin belongs to the statin lipid regulating drugs, it is a FIMG-CoA reductase inhibitors. Atorvastatin is reductase competitively in the body, reducing the synthesis of cholesterol, but also low-density lipoprotein (LDL) receptor synthesis the main site of action in the liver, resulting in blood cholesterol and low-density lipoprotein cholesterol levels, a moderate decrease in serum triglyceride levels, and elevated blood levels of high-density lipoprotein (HDL).
  • LDL low-density lipoprotein
  • Ezetimibe is in a class of compounds known as lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Its chemical name is as(3R,4S)-1 -(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4hydroxyphenyl) azetidin-2-one and has a chemical structure which is shown in Formula II. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. Its mechanism of action differs from those of other classes of cholesterol-reducing compounds, such as HMG-CoA reductase inhibitors.
  • atorvastatin combined with ezetimibe When atorvastatin combined with ezetimibe, it is effective than atorvastatin alone, so that the plasma levels of LDL-C was significantly reduced, the difference was statistically significant, and atorvastatin and ezetimibe combined with the use of a double dose atorvastatin compared the efficacy of lowering LDL-C similar difference was statistically significant.
  • atorvastatin combined with ezetimibe and atorvastatin alone compared can reduce LDL-C to obtain additional benefits, can make more high-risk or very high risk of coronary heart disease (CHD) patients with blood lipid standards.
  • CHD coronary heart disease
  • Statins likely to cause liver function, myopathy and gastrointestinal (Gl) and the like.
  • Chinese patent CN103340852 A discloses a pharmaceutical composition comprising ezetimibe and atorvastatin, characterized in that the two active ingredients are present in separate solid dosage forms in a single solid dosage form.
  • the preparation method of the two-layer sheet is used to improve the stability of the active ingredient.
  • the patent application WO20131661 14 (A1 ) discloses a combination comprising atorvastatin calcium, ezetimibe and a process for the preparation of the combination.
  • the ezetimibe substance is low water-soluble, low permeable, incompatible with most of the excipients usually used in formulation, presents stability problems, and is not inherently compressible. Therefore, there is a need to provide a stable composition with an acceptable dissolution profile. This also affects its bioavailability negatively.
  • formulation overcomes the above problems challenges and enables a fixed combination formulation that has simultaneously: a) a better dissolution profile to individual active ingredients, b) a stable formulation despite the incompatibilities of two component molecules - atorvastatin calcium and ezetimibe c) eliminates especially the low solubility problem of ezetimibe and the stability problem of atorvastatin calcium to enhance the good dissolution profile and good shelf-life of the final pharmaceutical product.
  • the main object of the present invention is to provide a bilayer tablet comprising atorvastatin calcium and ezetimibe to provide high stability and solubility.
  • Another object of the present invention is to provide desired level of dissolution rate and compressibility which overcomes the above described problems in prior art and have additive advantages over them.
  • a further object of the present invention is to provide a process that eliminates the above- mentioned disadvantages of ezetimibe.
  • formulations of ezetimibe can be provided in a more robust and economical way and can display a good balance of properties including chemical and physical stability and compressibility and particularly acceptable to good dissolution profiles.
  • At least one binder is used in the second layer of the bilayer tablet which comprises ezetimibe, so this overcomes the problems of stability problems and solubility problems of ezetimibe.
  • the total amount of binder in the second layer is 1.1 % to 10.0% by weight of the bilayer tablet.
  • the pharmaceutical bilayer tablet comprises; a. a first layer comprising atorvastatin calcium and
  • a second layer comprising ezetimibe wherein the tablet comprising at least one binder in each layer.
  • the amount of atorvastatin calcium in the tablet is 0.5% to 10.0% by weight and the amount of ezetimibe in the tablet is 0.5% to 8.0% by weight.
  • the total amount of binder in the first layer is 1 .1% to 10.0% by weight and the total amount of binder in the second layer is 1.1% to 10.0% by weight.
  • the total amount of binder in the first layer is 1 .1% to 7.0% by weight
  • the total amount of binder in the second layer is 3.0% to 9.0% by weight.
  • Suitable binders are selected from the group comprising polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropylcellulose, sugars, alginates, polyvinylpyrrolidone, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, pregelatinized starch, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, maltodextrin, methylcellulose, poloxamer, polydextrose, polyethylene oxide, polymethacrylates, cetostearyl alcohol, polyoxyethylene-alkyl ethers or mixtures thereof.
  • binders do not help to reduce the disadvantages of active substances.
  • disadvantages of ezetimibe are low water-soluble, low permeable, incompatible with most of the excipients usually used in formulation, presents stability problems, and is not inherently compressible.
  • the binders are selected from the group comprising polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropylcellulose or mixtures thereof.
  • the first layer comprises a binder which is hydroxypropylcellulose.
  • the second layer comprises two binders.
  • the binders are polyethylene glycol and hydroxypropyl methyl cellulose.
  • binder especially polyethylene glycol (PEG) is very effective excipient in the preparation of the tablet.
  • PEG polyethylene glycol
  • the object of the present invention is achieved when polyethylene glycol is used in a certain ratio in the second layer.
  • the amountof the polyethylene glycol in the second layer is between 1 .0% and 6.0% by weight. Said amount provides desired dissolution profile and stability of the bilayer tablet.
  • excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, i.e. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
  • the formulations should have no physicochemical incompatibility between the active ingredients and the excipients.
  • the pharmaceutical bilayer tablet further comprises pharmaceutically acceptable excipients which are selected from the group comprising fillers, surface active agents, disintegrants, lubricants, glidants, stabilizers or mixtures thereof.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, lactose monohydrate, starch, sucrose, glucose, dextrose, maltodextrin, natural and synthetic gums (e.g. acacia tree), gelatin, pregelatinized starch, polyvinylpyrrolidone, cellulose derivatives or mixtures thereof, preferably fillers are microcrystalline cellulose and lactose monohydrate. They maintain the stability of the active ingredients during shelf-life.
  • the amount of the fillers in the first layer is between 40.0% and 75.0% by weight.
  • the amount of the fillers in the second layer is between 55.0% and 80.0% by weight.
  • Suitable surface active agents are selected from the group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene glycol esters, sulphate or mixtures thereof.
  • the agent in the second layer is sodium lauryl sulphate which avoids crystallization of ezetimibe, and thus the dissolution of ezetimibe is not affected adversely.
  • the agent in the first layer is polysorbate.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, alginic acid, crospovidone, sodium alginate, starch (e.g., corn, potato) or mixtures thereof, preferably disintegrant is crosscarmellose sodium.
  • Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, polyethylene glycol, stearic acid or mixtures thereof.
  • lubricants of this invention are sodium stearyl fumarate and magnesium stearate.
  • Suitable glidants are selected from the group comprising silica colloidal anhydrous, talc, aluminium silicate or mixtures thereof.
  • the glidant of this invention is silica colloidal anhydrous.
  • Suitable stabilizers are selected from the group comprising calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerol phosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate or mixtures thereof.
  • the stabilizer is calcium carbonate. It is used only in the first layer and the amount of the calcium carbonate in the first layer is between 17.0% and 26.0% by weight of the bilayer tablet.
  • each individual layer compressed into a tablet.
  • the composition is more stable when the tablet is coated with film coating.
  • the pharmaceutical bilayer tablet composition comprises film coating to protect the composition against the moisture and light to maintain the stability.
  • Suitable coating agents are selected from the group comprising hydroxypropylmethylcellulose, polyethylene glycol (PEG), talc, lecithin, titanium dioxide, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol copolymers, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes, iron oxide or mixtures thereof.
  • the amount of the film coating in the bilayer tablet is 0.5%-5.0% by weight.
  • Another aspect of the present invention is the manufacturing process of the pharmaceutical tablet compositions of atorvastatin calcium and ezetimibe.
  • the pharmaceutical tablet compositions of atorvastatin calcium and ezetimibe of the present invention can be prepared in a fast, efficient and commercially cost low manufacturing process.
  • the tablets may be prepared by a granulation process.
  • a characteristic of the methods is given below based on wet granulation and spray granulation used for the production of the formulations of the invention.
  • Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol, or mixtures thereof, preferably granulation solution is pure water or ethyl alcohol.
  • Granulation process comprises wet, dry or spray granulation.
  • at least one granulation process is used for the bilayer tablet.
  • Another embodiment of the present invention is to provide a process for preparing the pharmaceutical bilayer tablet composition comprising the following steps:
  • 1 st layer a) mixing atorvastatin calcium, microcrystalline cellulose, calcium carbonate, lactose monohydrate, a part of croscarmellose sodium,
  • step (d) adding the remaining part of croscarmellose sodium, silica colloidal anhydrous to step (d) mixture and mixing them
  • step (e) adding magnesium stearate to step (e) mixture and mixing them.
  • 2 nd layer a) mixing microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, a part of croscarmellose sodium,
  • Example 1 Bilayer 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation de comprimé pharmaceutique bicouche comprenant de l'atorvastatine calcique et de l'ézétimibe. En outre, la présente invention concerne un procédé qui élimine les inconvénients des agents actifs.
PCT/TR2019/051006 2018-12-25 2019-11-28 Formulation de comprimé bicouche d'atorvastatine calcique et d'ézétimibe Ceased WO2020139237A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2018/20324A TR201820324A2 (en) 2018-12-25 2018-12-25 ATORVASTATIN CALCIUM AND EZETİMİBİN PHARMACEUTICAL DOUBLE LAYER TABLET FORMULATION
TR2018/20324 2018-12-25

Publications (2)

Publication Number Publication Date
WO2020139237A2 true WO2020139237A2 (fr) 2020-07-02
WO2020139237A3 WO2020139237A3 (fr) 2020-07-30

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PCT/TR2019/051006 Ceased WO2020139237A2 (fr) 2018-12-25 2019-11-28 Formulation de comprimé bicouche d'atorvastatine calcique et d'ézétimibe

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TR (1) TR201820324A2 (fr)
WO (1) WO2020139237A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022023206A1 (fr) 2020-07-27 2022-02-03 Krka, D.D., Novo Mesto Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine
GR1010981B (el) * 2024-04-09 2025-06-23 Pharmaplot Private Company, Φαρμακευτικη συνθεση που περιεχει ατορβαστατινη και εζετιμιμπη
WO2025226020A1 (fr) * 2024-04-24 2025-10-30 Chong Kun Dang Pharmaceutical Corp. Formulation de combinaison pharmaceutique comprenant de l'atorvastatine et de l'ézétimibe

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
TR201702101A2 (tr) * 2017-02-13 2018-08-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Atorvastati̇n kalsi̇yum ve ezeti̇mi̇bi̇n farmasöti̇k i̇ki̇ katmanli tablet bi̇leşi̇mi̇

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022023206A1 (fr) 2020-07-27 2022-02-03 Krka, D.D., Novo Mesto Comprimé bicouche comprenant de l'ézétimibe et de l'atorvastatine
GR1010981B (el) * 2024-04-09 2025-06-23 Pharmaplot Private Company, Φαρμακευτικη συνθεση που περιεχει ατορβαστατινη και εζετιμιμπη
WO2025226020A1 (fr) * 2024-04-24 2025-10-30 Chong Kun Dang Pharmaceutical Corp. Formulation de combinaison pharmaceutique comprenant de l'atorvastatine et de l'ézétimibe

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TR201820324A2 (en) 2020-07-21
WO2020139237A3 (fr) 2020-07-30

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