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WO2025116860A1 - Comprimé comprenant une formulation à libération prolongée pour metformine et formulation à libération immédiate comprenant de la sitagliptine - Google Patents

Comprimé comprenant une formulation à libération prolongée pour metformine et formulation à libération immédiate comprenant de la sitagliptine Download PDF

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Publication number
WO2025116860A1
WO2025116860A1 PCT/TR2024/051370 TR2024051370W WO2025116860A1 WO 2025116860 A1 WO2025116860 A1 WO 2025116860A1 TR 2024051370 W TR2024051370 W TR 2024051370W WO 2025116860 A1 WO2025116860 A1 WO 2025116860A1
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WO
WIPO (PCT)
Prior art keywords
tablet
sitagliptin
formulation according
metformin
tablet formulation
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
PCT/TR2024/051370
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English (en)
Inventor
Fatih Sunel
Nur PEHLIVAN AKALIN
Guldeniz TUNC
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
Priority claimed from TR2023/016131 external-priority patent/TR2023016131A1/tr
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of WO2025116860A1 publication Critical patent/WO2025116860A1/fr
Pending legal-status Critical Current
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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a tablet formulation comprising a core tablet having metformin and at least one matrix agent and a coating solution having sitagliptin surrounding the core tablet and a film coating wherein the coating solution further comprises at least one antioxidant and at least one coating agent. Further, the present invention provides a method for the preparation of said composition.
  • 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.
  • Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly.
  • 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.
  • 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.
  • the chemical name of metformin is 1 ,1 -dimethyl biguanide, has the following chemical structure of Formula I.
  • metformin is effective at lowering blood glucose levels, its use is associated with gastrointestinal (Gl) adverse effects, particularly diarrhea and nausea. These adverse effects may limit the tolerated dose of metformin and cause patients to discontinue the therapy.
  • Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is an oral antihyperglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 dipeptidyl peptidase-4
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • Sitagliptin 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.
  • sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H- [1 ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one or (2R)-4-oxo-4- [3- (trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1 -(2,4,5trifluorophenyl) butan-2-amine) and its chemical structure is shown in the Formula II.
  • Sitagliptin is disclosed in the U.S. Patent No. 6699871.
  • a crystal phosphate monohydrate form of sitagliptin is disclosed in the patent WO 2005003135.
  • DPP-4 inhibitors especially sitagliptin have a novel mechanism of action and many studies showing their efficacy and safety in medication are available.
  • Sitagliptin increases plasma GLP-1 concentration and elevates cellular cAMP levels in pancreatic beta-cells leading to potentiate insulin secretion, whereas metformin improves glucose tolerance in patients with Type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents in that metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Therefore, they both help to reduce blood glucose levels in different pathways in type 2 diabetes patients.
  • Extended-release formulations of metformin have advantages over immediate release in terms of affording a more uniform maintenance of blood plasma active drug concentrations and providing better patient compliance by reducing the frequency of administration required.
  • a tablet formulation for sitagliptin and extended-release metformin combination is commercially available under the trade name Janumet XR®.
  • PCT publication WO 2009111200 discloses the tablet comprising the combinations of an extended-release form of metformin, or a pharmaceutically acceptable salt thereof, coated with an immediate-release form of sitagliptin, or a pharmaceutically acceptable salt thereof.
  • WO 2009099734 discloses pharmaceutical compositions providing an extended release of metformin and an immediate release of sitagliptin.
  • the tablet core is comprised of metformin and an extended release polymer (HPMC).
  • HPMC extended release polymer
  • the tablet core is then coated with immediate release polymer comprising sitagliptin.
  • the dosage form of pharmaceutical combination is a core tablet coating with a solution comprising the active ingredient to overcome the problem of incompatibility and dissolution rate with a formulation appropriate to the characteristics of the active ingredients.
  • the main object of the present invention is to avoid incompatibility problems between metformin and sitagliptin, and adding additional advantages to the prior art.
  • Another object of the present invention is to provide a process for preparing a tablet comprising metformin and sitagliptin. The process is a simple, rapid, cost effective, timesaving, and industrially convenient method.
  • metformin includes metformin and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts comprise hydrochloride, hydrobromide, fumarate, malonate, malate, succinate, lactate, glycolate, maleate, citrate, and aspartate.
  • the pharmaceutically acceptable salts of metformin may be present in hydrous or anhydrous forms. They may also be present in crystalline or amorphous forms. In this invention, preferably metformin hydrochloride is used.
  • sitagliptin includes sitagliptin and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts comprise hydrochloride, hydrobromide, phosphate, sulphate, mesylate, besylate, tosylate, fumarate, malonate, malate, succinate, lactate, glycolate, maleate, citrate, and aspartate.
  • the pharmaceutically acceptable salts of sitagliptin may be present in hydrous or anhydrous forms.
  • the hydrate forms may be monohydrate or dihydrate forms.
  • the pharmaceutically acceptable salts of sitagliptin may also be present in crystalline or amorphous forms. In this invention, preferably sitagliptin phosphate monohydrate is used.
  • core refers to a compact mass having a definite geometric shape such as tablets, granules, pellets, capsules.
  • the pharmaceutical combination comprises metformin and sitagliptin wherein the pharmaceutical composition has compartments comprising active agents with different release profiles.
  • Sitagliptin and metformin combination has incompatibility and stability problems due to interactions between active agents. Separating metformin and sitagliptin in such a way that their interaction is eliminated is an effective solution so as to overcome these problems.
  • sitagliptin or a pharmaceutically acceptable salts thereof and at least one coating agent and at least one antioxidant is dissolved in a coating solvent, a solution comprising a higher proportion and homogenity of sitagliptin or a pharmaceutically acceptable salts thereof is obtained, this minimizes active substance losses during granulation and provides more homogeneous (content uniformity) and efficient tablet formulation.
  • metformin is a very poorly compressible active substance and in the present invention, metformin presents in high amounts in the core tablet. It was surprisingly found that when prepared the core tablet with a coating solution comprising sitagliptin or a pharmaceutically acceptable salts thereof, it was observed that the desired tablet hardness and compressibility of metformin HCI is provided. So, an easy method was created to eliminate the disadvantages of both active ingredients. The provides the desired stability.
  • a tablet formulation comprises;
  • a core tablet comprising metformin and at least one matrix agent
  • a coating solution comprising sitagliptin surrounding the core tablet, A film coating
  • the coating solution further comprises at least one antioxidant and at least one coating agent.
  • metformin is present metformin hydrochloride form in the tablet
  • sitagliptin is present sitagliptin phosphate monohydrate in the tablet.
  • the compartments are in direct contact with each other.
  • the compartments are in the form of core or coating.
  • the first compartment is a tablet core which comprises metformin.
  • the second compartment is sitagliptin solution coating, the third compartment is the film coating.
  • the amount of metformin is between 50.0% and 75.0% by weight of the total tablet.
  • the amount of sitagliptin is between 3.0% and 15.0% by weight of the total tablet.
  • the amount of metformin is between 55.0% and 63.0% by weight of the total tablet and the amount of sitagliptin is between 6.0% and 9.5% by weight of the total tablet.
  • Said matrix agent is selected from the group comprising hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, polyvinylacetate, acrylic acid polymers, polyethylene oxide, white wax, bees wax, carnauba wax, stearic acid, palmitic acid, lauric acid, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, ethyl cellulose, acrylic acid polymers and copolymers (available commercially under Eudragit ⁇ ®>brand) or mixtures thereof.
  • the matrix agent is hydroxypropyl methyl cellulose K100 MCR/ K100M/ CN10T.
  • the flowability and compressibility of metformin is poor.
  • granulating metformin with the help of selected matrix agent provides desired flowability and compressibility of metformin.
  • the amount of matrix agent is between 8.0% and 25.0%, preferably it is between 12.0% and 20.0% by weight of the total tablet.
  • Suitable antioxidants are selected from the group comprising propyl gallate, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), erythorbic acid, monothioglycerol, potassium metabisulfite, sodium ascorbate, sodium metabisulfite, sodium sulfite, thymol or mixtures thereof.
  • used antioxidant in the coating solution comprising sitagliptin is propyl gallate.
  • used the coating agents in the coating solution comprising sitagliptin are polyethylene glycol, hydroxypropyl methyl cellulose, kaolin or mixture thereof.
  • the core further comprises at least one binder.
  • Suitable binders are selected from group comprising carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, microcrystalline cellulose, lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof.
  • the amount of binders is between 1 .0% and 15.0%, preferably it is between 1 .0% and 8.0%, more preferably it is between 2.0% and 6.0% by weight of the total tablet.
  • the binder is carboxymethyl cellulose or hydroxypropyl methyl cellulose (K100 LV) or mixtures thereof.
  • the core further comprises at least one lubricant.
  • Suitable lubricants are selected from group comprising magnesium stearate, hydrophobic silicon dioxide, talc, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, stearic acid, paraffin or mixtures thereof.
  • the amount of lubricants is between 0.1% and 4.0% by weight, preferably 0.1% and 2.0% by weight of the total tablet.
  • the lubricant is sodium stearyl fumarate.
  • Suitable coating agents are selected from the group comprising polymethacrylates, polydextrose, polyalkylacrylates copolymers, triacetin, hydroxylpropyl methyl cellulose, medium chain triglycerides, kaolin, hydroxypropyl cellulose, carnauba wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, red iron oxide, black iron oxide or mixtures thereof.
  • the film coating is prepared with coating agents.
  • coating agents used the coating agents in the film coating are polyethylene glycol, hydroxypropyl cellulose, titanium dioxide, indigo dye, carnauba wax, or mixture thereof.
  • the ratio of the core tablet to the coating solution comprising sitagliptin is in the range of between 1 and 10, preferably between 2.5 and 8.0 by weight. This ratio provides desired dissolution profile of active agents and desired combination efficacy.
  • the core tablet is between 75.0% and 85.0%, preferably between 77.0% and 82.0% by weight of the total tablet.
  • the coating solution comprising sitagliptin is between 12.0% and 24.0%, preferably between 15.0% and 20.0% by weight of the total tablet.
  • the film coating is between 1.5% and 4.0% by weight of the total tablet.
  • sitagliptin and metformin combination are stable. The combination does not show incompatibilities, degradation problems, or extraction problems.
  • a tablet formulation comprises;
  • a core tablet comprising metformin HCI having carboxymethylcellulose sodium and hydroxypropyl methylcellulose (K100 LV) as binders, hydroxypropyl methylcellulose K100 MCR/ K100M/ CN10T as matrix agent, sodium stearyl fumarate as lubricant,
  • a coating solution comprising sitagliptin phosphate monohydrate surrounding the core tablet having propyl gallate as antioxidant and coating agents,
  • a tablet formulation comprises;
  • a core tablet comprising metformin HCI having hydroxypropyl methylcellulose K100 MCR/ K100M/ CN10T as matrix agent, sodium stearyl fumarate as lubricant,
  • a coating solution comprising sitagliptin phosphate monohydrate surrounding the core tablet having propyl gallate as antioxidant and coating agents,
  • a process for preparation of the tablet formulation comprising metformin and sitagliptin wherein the tablet is prepared by a process comprising the steps of: a) preparing a core comprising metformin HCI which is obtained wet granulation or direct compression, b) applying a coating solution comprising sitagliptin phosphate monohydrate surrounding the core which is obtained wet granulation, c) applying a film coating.
  • Example 1 a) Mixing Metformin HCI, carboxymethylcellulose sodium and hydroxypropyl methylcellulose (K100 LV), b) Adding pure water and granulating, c) Drying the granules, then sieving, d) Adding hydroxypropyl methylcellulose K100 MCR/ K100M/ CN10T into the mixture and mixing, e) Then, adding sodium stearyl fumarate and mixing, f) Compressing the mixture to form a core.
  • Sitagliptin solution coating g) Preparing a coating solution with a coating material (preferably, Opadry Clear comprising polyethylene glycol and kaolin and hydroxypropyl methyl cellulose), h) Adding propyl gallate into the coating solution and mixing, i) Adding sitagliptin and then obtained the coating solution comprising sitagliptin, j) Coating the core tablet with the solution coating comprising sitagliptin.
  • a coating material preferably, Opadry Clear comprising polyethylene glycol and kaolin and hydroxypropyl methyl cellulose
  • a process for preparing the tablet in example 2 comprises the following steps: Core tablet a) Sieving Metformin HCI DC %95 into 1 .5 mm, b) Adding hydroxypropyl methylcellulose K100 MCR/ K100M/ CN10T into the mixture and mixing, c) Then, adding sodium stearyl fumarate and mixing, d) Compressing the mixture to form a core.
  • Sitagliptin solution coating e) Preparing a coating solution with a coating material (preferably, Opadry Clear comprising polyethylene glycol and kaolin and hydroxypropyl methyl cellulose) and pure water, f) Dissolving propyl gallate into ethanol and adding the mixture into the coating solution and mixing, g) Adding sitagliptin and then obtained the coating solution comprising sitagliptin, h) Coating the core tablet with the solution coating comprising sitagliptin.
  • a coating material preferably, Opadry Clear comprising polyethylene glycol and kaolin and hydroxypropyl methyl cellulose

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

Abstract

La présente invention concerne une formulation de comprimé comprenant un comprimé à noyau contenant de la metformine et au moins un agent de matrice et une solution d'enrobage contenant de la sitagliptine entourant le comprimé à noyau et un enrobage de film, la solution d'enrobage comprenant en outre au moins un antioxydant et au moins un agent d'enrobage. La présente invention concerne en outre un procédé de préparation de ladite composition.
PCT/TR2024/051370 2023-11-30 2024-11-20 Comprimé comprenant une formulation à libération prolongée pour metformine et formulation à libération immédiate comprenant de la sitagliptine Pending WO2025116860A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2023/016131 TR2023016131A1 (tr) 2023-11-30 Metformi̇n i̇çi̇n uzatilmiş salimli bi̇r formülasyon ve si̇tagli̇pti̇n i̇çeren hemen salimli formülasyon i̇çeren bi̇r tablet
TR2023016131 2023-11-30

Publications (1)

Publication Number Publication Date
WO2025116860A1 true WO2025116860A1 (fr) 2025-06-05

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PCT/TR2024/051370 Pending WO2025116860A1 (fr) 2023-11-30 2024-11-20 Comprimé comprenant une formulation à libération prolongée pour metformine et formulation à libération immédiate comprenant de la sitagliptine

Country Status (1)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099734A1 (fr) * 2008-02-05 2009-08-13 Merck & Co., Inc. Compositions pharmaceutiques d'une association de metformine et d'un inhibiteur de la dipeptidyle peptidase-iv
WO2009111200A1 (fr) * 2008-03-04 2009-09-11 Merck & Co., Inc. Compositions pharmaceutiques d'une combinaison de metformine et d'un inhibiteur de dipeptidyl peptidase-iv
KR20160111237A (ko) * 2015-03-16 2016-09-26 한미약품 주식회사 메트포르민 및 시타글립틴을 포함하는 경구용 복합제제

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099734A1 (fr) * 2008-02-05 2009-08-13 Merck & Co., Inc. Compositions pharmaceutiques d'une association de metformine et d'un inhibiteur de la dipeptidyle peptidase-iv
WO2009111200A1 (fr) * 2008-03-04 2009-09-11 Merck & Co., Inc. Compositions pharmaceutiques d'une combinaison de metformine et d'un inhibiteur de dipeptidyl peptidase-iv
KR20160111237A (ko) * 2015-03-16 2016-09-26 한미약품 주식회사 메트포르민 및 시타글립틴을 포함하는 경구용 복합제제

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