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EP3784672A2 - Formulations de comprimés comprenant de la metformine et de la sitagliptine - Google Patents

Formulations de comprimés comprenant de la metformine et de la sitagliptine

Info

Publication number
EP3784672A2
EP3784672A2 EP19834733.8A EP19834733A EP3784672A2 EP 3784672 A2 EP3784672 A2 EP 3784672A2 EP 19834733 A EP19834733 A EP 19834733A EP 3784672 A2 EP3784672 A2 EP 3784672A2
Authority
EP
European Patent Office
Prior art keywords
weight
formulation according
tablet formulation
pharmaceutical tablet
compartment
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
EP19834733.8A
Other languages
German (de)
English (en)
Other versions
EP3784672A4 (fr
Inventor
Ali Turkyilmaz
Seval Ataman
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
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP3784672A2 publication Critical patent/EP3784672A2/fr
Publication of EP3784672A4 publication Critical patent/EP3784672A4/fr
Pending legal-status Critical Current

Links

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
    • A61K31/4985—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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical tablet formulation comprising metformin and sitagliptin and at least one surfactant. 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. 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 overweight. 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.
  • Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 250 to 1000 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 I.
  • metformin Although 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.
  • Gl gastrointestinal
  • 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 insulin tropic 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 patent US 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 are available which shows their efficacy and safety in therapies/medication are available.
  • the single sitagliptin alone does not provide adequate glycemic control.
  • 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.
  • a tablet formulation for metformin and sitagliptin combination is commercially available under the trade name Janumet®. It contains either 500 or 1000 mg metformin, and 50 mg sitagliptin.
  • Pharmaceutical compositions comprising fixed-dose combinations of immediate- release sitagliptin and metformin are disclosed in WO 2007/078726 patent application which published on July 12, 2007.
  • U.S. publication number 2012/0202820 discloses pharmaceutical compositions comprising sitagliptin and metformin in combination with a lubricant wherein the lubricant is polyethylene glycol or mixtures of polyethylene glycol with one or more other lubricants and comprises more than 10% by weight of the total weight of the composition.
  • Sitagliptin and metformin combination has incompatibility and stability problems due to interactions between drug substances.
  • the tablet in which sitagliptin and metformin are in different compartments is formulated so as to overcome the problems.
  • metformin and sitagliptin do not interact with each other, but also this provides easy and cost-effective process.
  • the main object of the present invention is to avoid incompatibility problems between metformin and sitagliptin using the tablet having different compartments.
  • Another object of the present invention is to provide improved stability and desired dissolution rate in tablet formulation.
  • Another object of the present invention is to provide compressible property of metformin.
  • metformin includes metformin and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts include 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 include hydrochloride, hydrobromide, phosphate, sulphate, mesylate, besylate, 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 malate is used.
  • the term "compartment” used herein throughout the specification is used to intend a part of the dosage form comprising one or both of metformin and sitagliptin, and optionally together with pharmaceutical excipients.
  • the part of the dosage form may be in the form of a layer or core or tablet.
  • the forms may be formed by coating or compression.
  • core refers to a compact mass having a definite geometric shape such as tablets, granules, pellets, capsules.
  • Sitagliptin and metformin combination has incompatibility and stability problems due to interactions between drug substances. Separating metformin and sitagliptin in such a way that their interaction is eliminated is an effective solution so as to overcome these problems.
  • the tablet is designed by placing these two drug substances in different compartments that solves the interaction problems. Furthermore, this is an easy and cost-effective process and this provides improvement in dissolution profile with using certain excipients.
  • the pharmaceutical tablet formulation comprises sitagliptin, metformin and at least one surfactant, wherein the active agents are in different compartments.
  • the compartments are in direct contact with each other or the compartments are separated by a coating layer.
  • each compartment at least one type of active ingredient is contained.
  • the first compartment comprises metformin.
  • the second compartment comprises sitagliptin.
  • the ratio of the first compartment to the second compartment is in the range of between 25:1 to 1 :25 by weight, preferably between 19:1 and 1 :19 by weight. This ratio provides desired dissolution profile of active agents and desired combination efficacy.
  • the amount of metformin in total composition is between 45.0% and 82.0% or between 60.0% and 80.0% or between 45% and 76% or between 55.0% and 76.0%.
  • the amount of sitagliptin in total composition is between 3.0% and 16.0% or between 3.0% and 12.0% or between 3.0% and 10.0%.
  • Surfactants offer many advantages. One of these is the use of surfactants becomes inevitable to reduce the interfacial tension between the medium and the drug and to increase solubility of drugs so also, surfactants help to maintain stability in combination formulations.
  • Suitable surfactants are selected from the group comprising polyoxyethylene sorbitan esters (polysorbate), sodium lauryl sulphate, propylene glycol, glyceryl oleate, tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil, sorbitan esters, docusate sodium, nonoxynol or mixtures thereof.
  • the surfactants are present in the first compartment or the second compartment or both.
  • the amounts of surfactants in the tablet is between 0.0001% and 10.0% or between 0.001 % and 7.0% or between 0.001 % and 2.0% by weight of the total composition.
  • the surfactant is polyoxyethylene sorbitan esters (polysorbate) or sodium lauryl sulphate or mixtures thereof.
  • each active ingredient is combined with suitable excipients that enable desired dissolution profile in each compartment. So, the formulation is free of disintegrant.
  • said disintegrant is crospovidone or dibasic calcium phosphate or croscarmellose sodium or sodium starch glycolate or alginic acid or sodium alginate or calcium alginate.
  • the composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, pore formers, lubricants, glidants, coating agents, coloring agents, solvents or mixtures thereof.
  • Suitable fillers or binders are selected from group comprising microcrystalline cellulose, polyvinylpyrrolidone, lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, carboxymethyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof.
  • the amount of fillers or binders in the tablet is between 1.0% and 40.0% or between 4.0% and 32.0% or between 1.0% and 10.0% by weight of the total composition.
  • the filler or binder is microcrystalline cellulose or polyvinylpyrrolidone or mixtures thereof.
  • fillers or binders are present in the first compartment or the second compartment or both.
  • fillers or binders are present in the first compartment.
  • the pore former may be used.
  • the speed of the drug release will consequently increase.
  • Pore formers dissolve or disperse away without swelling and the pore formed by this way, provides improved drug release.
  • Suitable pore formers are selected from group comprising sodium chloride, talc, silicon dioxide, lactose, sucralose, copovidone, maltodextrin, xylitol, poloxamers, polydextrose or mixtures thereof.
  • the amount of pore formers in the tablet is between 0.5% and 6.0%, preferably it is between 0.1% and 4.0% by weight of total composition.
  • pore former is sodium chloride. It may be in the first compartment or the second compartment or both. Preferably sodium chloride is in the second compartment.
  • Suitable lubricants or glidants 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, polyethylene glycol, paraffin or mixtures thereof.
  • the amount of glidants in the tablet is between 0.1% and 5.0%, preferably it is between 0.2% and 4.0% by weight of total composition.
  • the glidant is hydrophobic silicon dioxide.
  • the amount of lubricants in the tablet is between 0.1% and 5.0%, preferably it is between 0.2% and 4.0% by weight of total composition.
  • effective amount of lubricant is used in the tablet.
  • the lubricant is magnesium stearate.
  • the pharmaceutical combination is formulated as tablets comprising compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, inlay tablets, effervescent tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles.
  • coating layers does not comprise an active pharmaceutical agent and typically will rapidly disperse or dissolves in water.
  • coating layers comprise at least one coating agent.
  • the amount of coating layers in the tablet is between 1.0% and 12.0%, preferably it is between 3.0% and 7.0% by weight of total composition.
  • Suitable coating agents are selected from the group comprising polyvinyl alcohol (PVA), titanium dioxide, polyethylene glycol (PEG), talc, candelilla wax, hydroxypropyl methylcellulose, polymethacrylates, triacetin, glycerol triacetin, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, macrogol, coloring agents or mixtures thereof.
  • PVA polyvinyl alcohol
  • PEG polyethylene glycol
  • talc candelilla wax
  • hydroxypropyl methylcellulose polymethacrylates
  • triacetin glycerol triacetin
  • hydroxypropyl cellulose polyvinyl alcohol-polyethylene glycol copolymers
  • Suitable coloring agents are selected from the group comprising ferric oxide, 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
  • D&C Drug & Cosmetic
  • D&C indigotine FD&C blue
  • carmoisine indigotine indigotine
  • iron oxides such as; iron oxide red, yellow, black
  • quinoline yellow flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
  • the coating agents are polyvinyl alcohol (PVA), titanium dioxide, polyethylene glycol (PEG), talc, candelilla wax or mixtures thereof.
  • PVA polyvinyl alcohol
  • PEG polyethylene glycol
  • talc polyethylene glycol
  • candelilla wax candelilla wax or mixtures thereof.
  • Metformin is known to be very poorly compressible active substance for tableting process. As it is highly crystalline and has poor compaction properties, it is difficult to form tablets by direct compression or dry granulation. Metformin further, is a high dose drug that is hard to compress directly into tablets. On the other hand, it is known that conventional methods of dry granulation fail to provide a satisfactory solution to poor compaction properties of metformin. It has been found that desired stability and improved dissolution may be obtained when metformin and sitagliptin are formulated in wet granulation process.
  • the tablet comprising metformin and sitagliptin are formed by wet granulation.
  • the compartments then may be processed with compression or coating process.
  • wet granulation method is used for elimination of compressibility problems related to metformin.
  • solvents are used. Suitable solvents are selected from the group comprising pure water, isopropyl alcohol, propylene glycol, polyethylene glycol, glycerin, ethanol, or mixtures thereof.
  • the solvent is pure water or isopropyl alcohol or mixtures thereof.
  • the resulting formulation may also possess enhanced formulation robustness and stability.
  • sitagliptin and metformin combination are stable.
  • the combination does not show incompatibilities, degradation problems or extraction problems with certain excipients such as microcrystalline cellulose, polyvinylpyrrolidone, hydrophobic silicon dioxide, magnesium stearate, polyoxyethylene sorbitan esters, hydroxypropyl methyl cellulose, isopropyl alcohol, coating agents, pure water or mixtures thereof.
  • sitagliptin and metformin combination are stable.
  • the combination does not show significant incompatibilities, degradation problems or extraction problems with certain excipients such as polyvinylpyrrolidone, sodium lauryl sulphate, magnesium stearate, polyoxyethylene sorbitan esters, sodium chloride, coating agents, candelilla wax, pure water or mixtures thereof.
  • compartments or coating layers may be coated or it may be compressed as a layer.
  • a process for preparing the tablet in example 1 comprises the following steps:
  • a process for preparing the tablet in example 2 comprises the following steps:

Landscapes

  • 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 comprimés comprenant de la metformine et de la sitagliptine et au moins un tensioactif. La présente invention concerne également un procédé de préparation de ladite composition.
EP19834733.8A 2018-04-27 2019-03-25 Formulations de comprimés comprenant de la metformine et de la sitagliptine Pending EP3784672A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201806019 2018-04-27
PCT/TR2019/050190 WO2020013777A2 (fr) 2018-04-27 2019-03-25 Formulations de comprimés comprenant de la metformine et de la sitagliptine

Publications (2)

Publication Number Publication Date
EP3784672A2 true EP3784672A2 (fr) 2021-03-03
EP3784672A4 EP3784672A4 (fr) 2022-03-30

Family

ID=69141601

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19834733.8A Pending EP3784672A4 (fr) 2018-04-27 2019-03-25 Formulations de comprimés comprenant de la metformine et de la sitagliptine

Country Status (2)

Country Link
EP (1) EP3784672A4 (fr)
WO (1) WO2020013777A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022074664A1 (fr) * 2020-10-05 2022-04-14 V-Ensure Pharma Technologies Private Limited Composition à libération immédiate de chlorhydrate de sitagliptine
KR102853692B1 (ko) * 2021-07-08 2025-09-02 한미약품 주식회사 시타글립틴, 다파글리플로진 및 메트포르민을 포함하는 경구용 복합정제
CN114010612B (zh) * 2021-11-24 2022-06-28 上海普康药业有限公司 一种西格列汀二甲双胍双层缓释片及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080064701A1 (en) * 2007-04-24 2008-03-13 Ramesh Sesha Anti-diabetic combinations
GEP20125672B (en) 2007-07-19 2012-10-25 Takeda Pharmaceuticals Co ) solid composition containing alogliptin and metformin hydrochloride
EP2259676A4 (fr) * 2008-03-04 2011-03-16 Merck Sharp & Dohme Compositions pharmaceutiques d'une combinaison de metformine et d'un inhibiteur de dipeptidyl peptidase-iv
PE20140960A1 (es) 2008-04-03 2014-08-15 Boehringer Ingelheim Int Formulaciones que comprenden un inhibidor de dpp4
WO2013110085A1 (fr) 2012-01-20 2013-07-25 Handa Pharmaceuticals, Llc Formes pharmaceutiques destinées à l'administration par voie orale de metformine et de sitagliptine
TR201722603A2 (tr) 2017-12-28 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Metformi̇n ve si̇tagli̇pti̇n i̇çeren sicak eri̇tme ekstrüzyonu i̇le gerçekleşti̇ri̇len tablet formülasyonlari

Also Published As

Publication number Publication date
EP3784672A4 (fr) 2022-03-30
WO2020013777A2 (fr) 2020-01-16
WO2020013777A3 (fr) 2020-04-09

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