WO2019132833A1 - Combinaison à libération modifiée comprenant de la linagliptine et de la metformine - Google Patents

Combinaison à libération modifiée comprenant de la linagliptine et de la metformine Download PDF

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Publication number
WO2019132833A1
WO2019132833A1 PCT/TR2018/050870 TR2018050870W WO2019132833A1 WO 2019132833 A1 WO2019132833 A1 WO 2019132833A1 TR 2018050870 W TR2018050870 W TR 2018050870W WO 2019132833 A1 WO2019132833 A1 WO 2019132833A1
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WO
WIPO (PCT)
Prior art keywords
weight
tablet formulation
pharmaceutical tablet
layer
metformin
Prior art date
Application number
PCT/TR2018/050870
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English (en)
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Merve ERGUN DONMEZ
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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
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Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2019132833A1 publication Critical patent/WO2019132833A1/fr

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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
    • A61K31/13—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

  • the present invention relates to a pharmaceutical tablet formulation comprising linagliptin, metformin and at least one modified release agent. Further the present invention provides a method for the preparation of said formulation.
  • 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 overweighed. 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.
  • Linagliptin is used for type 2 or non-insulin dependent diabetes. It is a selective, orally administered, xanthine based dipeptidyl peptidase-4 (DPP-4) inhibitor used as an adjunct to diet and exercise to improve glycemic control. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • Linagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
  • linagliptin 8-[(3R)-3-aminopiperidin-1 -yl]-7-but-2-yn-1 -yl)-3- methyl-1 -[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1 H-purine-2,6-dione and its chemical structure is shown in the Formula I.
  • Metformin is an antidiabetic 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 singly or in combination with sulfonylureas, alpha- glucosidase inhibitors, or insulin.
  • metformin hydrochloride is 1 ,1 -dimethylbiguanide hydrochloride, has the following chemical structure of Formula II.
  • Metformin has been widely prescribed for lowering blood glucose in patients. However, being a short acting drug, metformin requires twice-daily or three-times-a-day dosing. The side effects of metformin in this dose are often gastrointestinal in nature (anorexia, nausea, vomiting and occasionally diarrhea, etc.). These side effects may be partially avoided by either reducing the initial and/or maintenance dose or using a modified release form. Another clear advantage of a modified release form is a reduction in the frequency of administration. All of these findings suggest that a modified release form of metformin may provide greater convenience and the safety profile relative to a conventional dosage form.
  • the patent application WO2017093419 A1 discloses a formulation, comprising metformin HCI, linagliptin and basic amino acid as stabilizer in extended release form. Furthermore, said basic amino acid is L-arginine and modified release agents of the formulation are HPMC and polyethylene oxide.
  • modified release agents In the prior art, very high amount of modified release agents was used. This amount was more than 40% in the total formulation. Especially, using very high amount of polyethylene oxide as modified release agents causes the problem of tablet’s flowability and its compressibility.
  • the present invention is aimed to obtain a stable formulation with synergistic effect for use in the treatment of type-2 diabetes. Also, this invention provides more effective treatment and at the same time shows similar release profile for active agents. The present invention is aimed to ensure the desired content uniformity without the addition of significant side effect.
  • Another object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art and problem of compressibility which overcomes the above described problems in the prior art.
  • modified release agent refers to a pharmaceutical agent that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active agents gradually and predictably over a 12-hour to 24-hour period.
  • coating agent refers to a pharmaceutical agent that disintegrate rapidly after administration with enhanced rate of dissolution and get dissolved to release the medicaments.
  • linagliptin refers to not only linagliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
  • the linagliptin is present as amorphous linagliptin, crystalline linagliptin having polymorphic form A, crystalline linagliptin having polymorphic form B and crystalline linagliptin having polymorphic form C or mixtures of 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 or pharmaceutically acceptable prodrugs thereof.
  • combining more than one molecule in one dosage form increases the patient’s compliance. However, while this combination is increasing the patients’ quality of life, combining more than one molecule in one dosage form also reduces side effects.
  • modified release formulations are to make the plasma concentration level stable by maintaining the drug in the blood stream for a longer time period.
  • the formulation of this invention is designed as modified release to prevent the changes in drug plasma concentration levels and can be administered only once or twice a day for drugs that would otherwise have to be taken more frequently to maintain required blood levels.
  • modified release tablet forms may help to treat with reduced dosage regimens. Using lower dosages of active agents provide greater convenience and reduced side effects and toxicity.
  • the pharmaceutical tablet formulation comprises;
  • a core comprising metformin and at least one modified release agent
  • the first layer comprising at least one coating agent
  • the second layer comprising linagliptin and at least one coating agent wherein the core and the second layer are separated by the first layer.
  • the advantages of the present invention are even more significant, as the problem of homogeneity is even more likely to occur when two active substances are incorporated in one final dosage form, especially when two actives is used very different regarding the amount. Improved content uniformity efficiently contributes to a marked increase in bioavailability. Improved content uniformity also favors to avoid toxicity in the otherwise possible event that the amount of drug substance would be too high.
  • Linagliptin is used small proportion that can lead to important problems during the process of the formulation, because of problems uniformity of the content, the active substance may interact with several excipients so, it is necessary to separate linagliptin from other excipients especially metformin.
  • the first layer separates linagliptin and metformin. Using the first layer is ensured uniformity of the content.
  • the amount of linagliptin in the total composition is between 0.05% and 10.0%, preferably 0.05% and 3.0% or 3.0% and 6.0% or 6.0% and 10.0% by weight.
  • the amount of metformin in the total composition is between 50.0% and 80.0%, preferably 50.0% and 55.0%, or 55.0% and 61.0%, or 61.0% and 70.0%, or 70.0% and 75.0%, or 75.0% and 80.0% by weight.
  • the amount of linagliptin in the total composition is between 0.05% and 10.0% by weight, the amount of metformin in the total composition is 50.0% to 80.0% by weight.
  • the formulation of the invention can be developed into tablet form comprising immediate release, extended release, sustained release, controlled release, modified release and delayed release or mixtures thereof.
  • Modified release formulations are preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof. In this invention, the formulation is prepared using modified release agents.
  • Suitable modified release agents are selected from the group comprising glyceryl behenate, polymethacrylates (Eudragit), ethyl acrylate, ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, polygalacturonic acid, polymer of acrylic acid, agar, gum, nitrocellulose, methylcellulose, glycerol, propylene glycol, phfchalate esters, dibutyl sebacetate, citrate esters, castor oil
  • the amount of modified release agents in the total composition is between 10.0% and 40.0% by weight. Also, the amount of modified release agents in the total composition is between 10.0% and 15.0% by weight, 15.0% and 20.0% by weight, 20.0% and 25.0% by weight, 25.0% and 30.0% by weight, 30.0% and 35.0% by weight, 35.0% and 40.0% by weight. This amount of modified release agents provides desired modified release of metformin.
  • the modified release agents are selected from glyceryl behenate, polymethacrylates or mixtures thereof.
  • the amount of glyceryl behenate in the total composition is between 7.0% and 25.0% by weight. Also, the amount of glyceryl behenate in the total composition is between 7.0% and 10.0%, 10.0% and 14.0%, 14.0% and 19.0%, 19.0% and 25.0% by weight.
  • the amount of polymethacrylates in the total composition is between 3.0% and 15.0% by weight. Also, the amount of polymethacrylates in the total composition is between 3.0% and 6.0%, 6.0% and 10.0%, 10.0% and 15.0% by weight.
  • the weight ratio of polymethacrylates to glyceryl behenate is in the range of 1 :1 to 1 :7 by weight, preferably 1 :1 to 1 :5 by weight. While this ratio helps to protect improved stability in the present formulation, at the same time provide desired modified release of metformin.
  • the pharmaceutical tablet formulation comprises
  • a core comprising metformin and at least one modified release agent
  • the first layer comprising at least one coating agent
  • the second layer comprising linagliptin and at least one coating agent wherein the core surrounded by the first layer and the first layer surrounded by the second layer.
  • Suitable coating agents are selected from the group comprising hydroxypropyl methylcellulose, titanium dioxide, talc, polymethacrylates, triacetin, glycerol triacetin, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, macrogol, coloring agents or mixtures thereof.
  • PVA polyvinyl alcohol
  • PEG polyethylene glycol
  • Kollicoat® IR polyvinyl alcohol-polyethylene glycol copolymers
  • Surelease® ethylcellulose dispersions
  • PVP-VA polyvinylprolidone, polyvinylprolidone-vinyl
  • the coating agent is hydroxypropyl methylcellulose or titanium dioxide or talc or mixtures thereof.
  • Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
  • FD&C Food, Drug & Cosmetic
  • the formulation further comprises pharmaceutical acceptable excipients which are selected from disintegrants, lubricants or mixtures thereof.
  • Suitable disintegrants are selected from the group comprising microcrystalline cellulose, lactose monohydrate, starch, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium starch glycolate, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose, alginates, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, ion-exchange resins or mixtures thereof.
  • disintegrant that is neither too much nor too little to detrimentally alter the release of the active agents should be used to form tablet form provided herein.
  • disintegrants can be mixed with other excipient to increase effective disintegration of the tablet into smaller fragments.
  • the amount of disintegrant in the total composition is between 0.5% and 10.0% by weight, preferably 1 .0% and 8.0% by weight, more preferably 2.0% and 6.0% by weight.
  • the disintegrant is microcrystalline cellulose and the amount of microcrystalline cellulose is between 0.5% and 10.0% by weight and thus desired level of dissolution rate is provided.
  • Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or mixtures thereof.
  • the pharmaceutical combination is formulated as tablets comprising compressed tablets, coated or uncoated tablets, inlay tablet, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.
  • the pharmaceutical combination is tablet form.
  • Tablet comprises at least one type of particle, for example; mini-tablet, pellets, core, agglomerates, granules, powder, liposomes, sphericles or mixtures thereof.
  • each type of particle comprises at least one active agent.
  • the pharmaceutical formulation is formulated as tablet-in-tablet or core-in tablet.
  • linagliptin and metformin combination are stable.
  • the combination does not show incompatibilities, degradation problems, or extraction problems with certain excipients such as linagliptin, metformin, glyceryl behenate, polymethacrylates, microcrystalline cellulose, sodium stearyl fumarate and coating agents.
  • the formulation comprises;
  • Process for preparing the pharmaceutical tablet formulation comprises the following steps;
  • Example 1 Tablet comprising linagliptin and metformin
  • Example 2 Tablet comprising linagliptin and metformin
  • Process for preparing the pharmaceutical tablet formulation comprises the following steps;
  • Example 3 The core-in-tablet comprising linagliptin and metformin
  • Process for preparing the pharmaceutical tablet formulation comprises the following steps;
  • Example 4 The core-in-tablet comprising linagliptin and metformin
  • Process for preparing the pharmaceutical tablet formulation comprises the following steps;

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

Abstract

La présente invention concerne une formulation de comprimé pharmaceutique comprenant de la linagliptine, de la metformine et au moins un agent à libération modifiée. La présente invention concerne en outre un procédé pour la préparation de ladite formulation.
PCT/TR2018/050870 2017-12-26 2018-12-24 Combinaison à libération modifiée comprenant de la linagliptine et de la metformine WO2019132833A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/21824 2017-12-26
TR2017/21824A TR201721824A2 (tr) 2017-12-26 2017-12-26 Li̇nagli̇pti̇n ve metformi̇n i̇çeren modi̇fi̇ye salim sağlayan kombi̇nasyon

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WO2019132833A1 true WO2019132833A1 (fr) 2019-07-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023163510A1 (fr) * 2022-02-23 2023-08-31 주식회사 제뉴원사이언스 Formulation d'un complexe pharmaceutique à libération contrôlée de médicament comprenant de la linagliptine ou un sel de qualité pharmaceutique de celle-ci et de la metformine ou un sel de qualité pharmaceutique de celle-ci

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012031124A2 (fr) * 2010-09-03 2012-03-08 Bristol-Myers Squibb Company Formulations de médicament au moyen d'antioxydants hydrosolubles
WO2012120040A1 (fr) * 2011-03-07 2012-09-13 Boehringer Ingelheim International Gmbh Compositions pharmaceutiques comprenant de la metformine et un inhibiteur de dpp-4 ou un inhibiteur de sglt-2
WO2015107536A2 (fr) * 2013-12-09 2015-07-23 Intas Pharmaceuticals Limited Combinaison de doses fixes contenant de la linagliptine et de la metformine hcl
WO2016059219A1 (fr) * 2014-10-17 2016-04-21 Boehringer Ingelheim International Gmbh Composition pharmaceutique et utilisations de celle-ci
WO2016105084A2 (fr) * 2014-12-23 2016-06-30 주식회사 한독 Composition pharmaceutique pour le traitement du diabète
WO2017093419A1 (fr) 2015-12-04 2017-06-08 Boehringer Ingelheim International Gmbh Composition pharmaceutique, méthodes de traitement et leurs utilisations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012031124A2 (fr) * 2010-09-03 2012-03-08 Bristol-Myers Squibb Company Formulations de médicament au moyen d'antioxydants hydrosolubles
WO2012120040A1 (fr) * 2011-03-07 2012-09-13 Boehringer Ingelheim International Gmbh Compositions pharmaceutiques comprenant de la metformine et un inhibiteur de dpp-4 ou un inhibiteur de sglt-2
WO2015107536A2 (fr) * 2013-12-09 2015-07-23 Intas Pharmaceuticals Limited Combinaison de doses fixes contenant de la linagliptine et de la metformine hcl
WO2016059219A1 (fr) * 2014-10-17 2016-04-21 Boehringer Ingelheim International Gmbh Composition pharmaceutique et utilisations de celle-ci
WO2016105084A2 (fr) * 2014-12-23 2016-06-30 주식회사 한독 Composition pharmaceutique pour le traitement du diabète
WO2017093419A1 (fr) 2015-12-04 2017-06-08 Boehringer Ingelheim International Gmbh Composition pharmaceutique, méthodes de traitement et leurs utilisations

Non-Patent Citations (1)

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Title
GRAEFE-MODY E U ET AL: "Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects", CURRENT MEDICAL RESEARCH AND OPI, INFORMA HEALTHCARE, GB, vol. 25, no. 8, 1 August 2009 (2009-08-01), pages 1963 - 1972, XP008129937, ISSN: 0300-7995, DOI: 10.1185/03007990903094361 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023163510A1 (fr) * 2022-02-23 2023-08-31 주식회사 제뉴원사이언스 Formulation d'un complexe pharmaceutique à libération contrôlée de médicament comprenant de la linagliptine ou un sel de qualité pharmaceutique de celle-ci et de la metformine ou un sel de qualité pharmaceutique de celle-ci

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