EP2958548A1 - Verfahren zur herstellung von gliclazid-formulierungen - Google Patents

Verfahren zur herstellung von gliclazid-formulierungen

Info

Publication number
EP2958548A1
EP2958548A1 EP14705166.8A EP14705166A EP2958548A1 EP 2958548 A1 EP2958548 A1 EP 2958548A1 EP 14705166 A EP14705166 A EP 14705166A EP 2958548 A1 EP2958548 A1 EP 2958548A1
Authority
EP
European Patent Office
Prior art keywords
formulation
process according
gliclazide
produced
formulation produced
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.)
Withdrawn
Application number
EP14705166.8A
Other languages
English (en)
French (fr)
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Esra Sucuoglu
Zekiye Basak HATIRNAZ
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 EP2958548A1 publication Critical patent/EP2958548A1/de
Withdrawn legal-status Critical Current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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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

Definitions

  • the present invention relates to improving the stability of formulations comprising gliclazide.
  • the present invention more particularly relates to a process for producing stable gliclazide formulations comprising an impurity in a pharmaceutically acceptable level.
  • Diabetes mellitus is an abnormality of the glucose metabolism, which occurs due to causes like insufficient insulin secretion and decreased sensitivity of target cells to insulin and is characterized by hyperglycemia.
  • hyperglycemia severe harmful complications such as retinopathy, nephropathy, and neuropathy occur as a result of vascular lesions in various organs and nerves.
  • anti-diabetic medicaments including sulfonylureas, have been administered orally in the treatment of diabetics so far.
  • Sulfonylurea is a name defining a group of orally administered anti-diabetic medicaments used in the treatment of type II diabetes mellitus.
  • Diabetes mellitus is a disorder of the carbohydrate metabolism, in which insulin secretion is diminished, or which occurs due to a varying insulation secretion or decreased insulin activity or a combination of both factors.
  • sulfonylureas stimulate the insulin secretion from pancreatic islet cells in the mediation of receptors which were reported as adenosine 5'-triphosphate-sensitive potassium channels (KATP). For this reason, sulfonylureas basically increase the endogenous insulin secretion so that an efficient control is provided in the blood sugar levels, not controllable via diets, of the diabetics and particularly of the type II diabetics.
  • KATP adenosine 5'-triphosphate-sensitive potassium channels
  • Sulfonylureas are considered to be divided into two categories: first generation agents, e.g. tolbutamide, chlorpropamide, tolazamide, acetohexamide; and second generation agents, e.g. glyburide (glibenclamide), glipizide, gliclazide.
  • first generation agents e.g. tolbutamide, chlorpropamide, tolazamide, acetohexamide
  • second generation agents e.g. glyburide (glibenclamide), glipizide, gliclazide.
  • second generation sulfonylureas is an active agent with antidiabetic properties at typical doses administered to humans (its chemical structure is illustrated in Formula 1 )-
  • Gliclazide has been administered in the form of 30, 60, 80 mg tablets until today. It is usually administrated twice a day, making a total of two tablets per day. It may be altered, however, to 1 - 4 tablets per day, as required by the severity of the diabetes case. 30 mg and 60 mg modified-release dosage forms are also available at the markets.
  • the patent US 4,696,815 discloses immediate-release tablets comprising sulfonylurea, formulated using an acidified and/or alkalized excipient and an inert polar solvent like polyethylene glycol.
  • An analogous immediate-release formulation comprising an acidified and/or alkalized excipient, an inert polar solvent, and polyvinylpyrrolidone is also described in that patent.
  • the patent US 6,733,782 discloses a core tablet for the controlled-release of gliclazide, ensuring a sustained and constant release of the active agent by making use of hydroxypropylmethyl cellulose (HPMC) which is not influenced from the pH variations of the solubilizing medium following oral administration.
  • HPMC hydroxypropylmethyl cellulose
  • the main target of that invention is to obtain an oral dosage form, which can be administered once a day and provides extended release.
  • That US patent provides information on using a glucose syrup, e.g. maltodextrin, together with cellulosic polymers in order to obtain a controlled and full release from a gliclazide formulation.
  • the patent document WO2008/062470 in turn, relates to a stabilized controlled release dosage form of gliclazide, having one or more release controlling polymer, calcium hydrogen phosphate anhydrous and free from saccharide component. It is further stated in that patent document that calcium hydrogen phosphate dihydrate is the reason for the high impurity A.
  • gliclazide formulations After gliclazide formulations are formulated, the formation of various impurities and particularly of impurity B are observed. Obtaining gliclazide formulations using processes involving heat leads to impurities of various types. Having said that, the poor water-solubility of gliclazide is another problem. In order to achieve desirable release profiles, those processes involving heat, such as wet granulation and hot melting method, are preferred. These preferences, in turn, make it necessary to apply heat during the process and drying steps. Heat application, however, particularly results in the formation of 2-nitroso-octahydrocyclopenta[c]pyrrole, i.e. the impurity B. This, in turn, is unfavorable in terms of pharmaceutics. Therefore, a special formulation and process embodiment is needed that would overcome this problem.
  • the present invention provides a gliclazide formulation, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
  • the main object of the present invention is to obtain a gliclazide formulation, which is stable, comprises an impurity in a pharmaceutically acceptable level, and has a desirable level of solubility and dissolution rate.
  • Another object of the present invention is to obtain a controlled-release formulation comprising impurity B in a pharmaceutically acceptable level.
  • a further object of the present invention is to obtain a stable controlled-release formulation having high bioavailability.
  • a production process for a gliclazide formulation comprising not more than 3 ppm impurity B has been developed to carry out all objects, referred to above and to emerge from the following detailed description.
  • said novelty is characterized in that the formulation is exposed to heat at a temperature not higher than 60 ' ⁇ during any of the productions steps.
  • the formulation is exposed to heat preferably at a temperature not higher than ⁇ ' ⁇ , and more preferably at a temperature between 40 - 45 ⁇ during any of the productions steps.
  • said process is a wet granulation process or a hot melting process.
  • heat is applied during the granulation phase or the drying phase of granules of the wet granulation process. According to a preferred embodiment of the present invention, heat is applied during the melting phase of the hot melting process.
  • the formulation is in the form of a solid formulation, liquid formulation, or a gel formulation.
  • the formulation is in the form of a controlled-release solid formulation or an immediate-release solid formulation.
  • the formulation is in the form of a 30 mg, 60 mg, or 80 mg dosage form.
  • the solid dosage form does not have a breaking notch, a breaking surface or a breaking line.
  • the d 90 particle size of gliclazide is 75 ⁇ .
  • the d 5 o particle size of gliclazide is 20 ⁇ .
  • the di 0 particle size of gliclazide is 5 ⁇ .
  • the formulation comprises a polymer which controls the release rate.
  • the polymer that controls the release rate is selected from a group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl cellulose (EC), methyl cellulose (MC), sodium carboxymethyl cellulose, and cellulose acetate butyrate, or a mixture thereof.
  • the polymer that controls the release rate is hydroxypropyl methylcellulose.
  • the viscosity of the hydroxypropyl methylcellulose polymer that controls the release rate is 100 cP.
  • the viscosity of the hydroxypropyl methylcellulose polymer that controls the release rate is 4000 cP.
  • the viscosity of hydroxypropyl methylcellulose present in the internal phase is 4000 cP.
  • the total amount of the polymer that controls the release rate is between 10 and 30% of the tablet weight.
  • Another preferred embodiment according to the present invention further comprises at least one or a mixture of fillers, glidants, and lubricants as an excipient.
  • said filler comprises at least one or a mixture of calcium hydrogen phosphate dihydrate, calcium hydrogen phosphate anhydrous, and mannitol.
  • said glidant is colloidal silicon dioxide.
  • said lubricant magnesium stearate is said lubricant magnesium stearate.
  • said formulation comprises the following ingredients only:
  • This example describes a controlled-release pharmaceutical tablet formulation comprising gliclazide or a pharmaceutically-acceptable salt thereof.
  • the active ingredient and excipients of the tablet are given below:
  • Magnesium stearate 0.25 - 1 .0 Gliclazide, calcium hydrogen phosphate dihydrate, mannitol, and some part of hydroxypropyl methylcellulose (4000 cP) (E4M) are mixed together in a granulator. Water is sprayed onto the resulting mixture and is thus granulated.
  • the wet granules prepared are directly transferred to a fluidized bed dryer.
  • the granules are dried in the fluidized bed dryer until the humidity thereof is reduced to 1 % or below, and dried granules are sieved and passed to a mixer.
  • hydroxypropyl methylcellulose E4M
  • the entire amount of 10 hydroxypropyl methylcellulose K100LV
  • colloidal silicon dioxide colloidal silicon dioxide
  • Gliclazide calcium hydrogen phosphate dihydrate, mannitol, and some part of hydroxypropyl methylcellulose (4000 cP) (E4M) are mixed together in a granulator. 20 Water is sprayed onto the resulting mixture and is thus granulated.
  • d 90 , d 50 , and di 0 particle sizes of gliclazide are 75 ⁇ , 20 ⁇ , and 5 ⁇ , respectively.
  • the wet granules prepared are directly transferred to a fluidized bed dryer.
  • heat is applied at a temperature not higher than 60 °C, preferably not more than 50 'C, and more
  • the granules are dried in the fluidized bed dryer until the humidity thereof is reduced to 1 % or below, preferably 0.7% or below, and dried granules are sieved and passed to a mixer.
  • the remaining part of hydroxypropyl methylcellulose (E4M), the entire amount of hydroxypropyl methylcellulose (K100LV), and colloidal silicon dioxide are added to the sieved dry granules and mixed together.
  • magnesium stearate is added to the resulting mixture and mixing is continued.
  • the mixture is filled into capsules or compressed into tablets.
  • a gliclazide formulation is obtained with the present invention, showing improved stability and comprising impurity B in a pharmaceutically acceptable amount, not more than 3 ppm.
  • the formulation according to the present invention may be in the form of a solid, liquid, or gel. It was determined that the temperature applied during the solving, drying, and similar phases of the wet granulation process or during the hot melting process had a direct influence of the formation of the B-type impurity. However, in order to provide acceptable levels of solubility and dissolution rate, the active agents should be dissolved under the influence of temperature.
  • the present invention provides a heterogeneous matrix, which comprises active agent particles, at least some part thereof being dissolved under heat and the remaining part thereof left undissolved, by virtue of a formulation having a balanced content.
  • the particle size of the active agent and the influence of temperature are directly effective.
  • a heterogeneous matrix is obtained in which not more than 20% of gliclazide is completely dissolved, and the remaining part thereof is left undissolved in a particulate form.
  • such formulations can be obtained according to the present invention, which comprise a pharmaceutically acceptable amount of impurity and show a desirable dissolution rate and solubility.
  • a controlled-release formulation can be obtained as mentioned above. It is further possible to easily carry out a conventional tablet production.
  • mannitol in the formulation according to the present invention is effective in preventing the formation of impurity B.
  • the ratio of mannitol in the total formulation is above 55% and it can prevent the formation of impurity in an amount above 55%.
  • the formulation comprises mannitol more than 55% and a temperature is applied in any of the production steps of this formulation which is not more than 60 'C, preferably not more than 50 'C, and more preferably between 40-45 °C, the amount of impurity B 5 drops down below 3 ppm and is observed at around 0.7 ppm.
  • the impurity B of the formulation is determined by HPLC (High-Performance Liquid Chromatography).
  • the pH of the buffer 6.00
  • a desirable dissolution profile and dissolution rate can be achieved using hydroxypropyl methylcellulose E4M and hydroxypropyl methylcellulose K100LV, when gliclazide with a d 90 particle size of 75 ⁇ , a d 50 particle size of 20 ⁇ , and a di 0 particle size of 5 ⁇ is used and a temperature is applied in any of the production steps which is not more than 25 60 'C, preferably not more than 50 °C, and more preferably in between 40-45 ⁇ .
  • the particle size of the active agent is measured by MALVERN MASTERSIZER 2000 by using dry dispersion method.
  • the process according to the present invention makes it possible to obtain a 60 mg controlled-release tablet formulation.
  • the process according to the present invention makes it possible to obtain a 80 mg controlled-release tablet formulation.
  • This formulation is used for preventing or treating diabetes mellitus in mammalians, particularly in humans.
  • Polymers can be used to form a matrix in which the active agent is dispersed.
  • the release rate of the active agent depends on the properties of the polymer used.
  • the cellulose derivates thereof are particularly hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC), see “Handbook of Pharmaceutical Excipients (Ed. A Wade and P. J. Weller, Pharmaceutical Press, London 1994).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • the properties of a polymer when it contacts an aqueous medium and particularly a physiological medium can be used for controlling the release rate of an active agent from a controlled-release formulation. For instance, polymers like HPMC frequently develop a gel-like outer layer that is dissolved or worn away and thus control the permeation of water into the interior of the controlled-release formulation.
  • the present invention makes use of mannitol as a binder and a hydrophilic diluent with a low glycemic index.
  • a preferred embodiment of this invention is a controlled-release pharmaceutical tablet formulation, comprising (a) a therapeutically-effective amount of gliclazide or a pharmaceutically-acceptable salt thereof, (b) mannitol as a binder and hydrophilic diluent, not increasing the blood glucose level in human patients who are in the need of a non-insulin dependent diabetes mellitus (NIDDM) treatment, (c) calcium hydrogen phosphate dihydrate or calcium hydrogen phosphate anhydrous as a diluent, (d) two different types of pharmaceutically-acceptable cellulosic polymers as a release rate- controlling polymer, wherein not more than 25% of the total amount of gliclazide or a pharmaceutically-acceptable salt thereof is dissolved in a shorter time than two hours and wherein the blood glucose level is not increased.
  • NIDDM non-
  • the pharmaceutically-acceptable cellulosic polymer controlling the release rate include, but is not limited to HPMC, HPC, hydroxyethyl cellulose (HEC), ethyl cellulose (EC), methyl cellulose (MC), sodium carboxymethyl cellulose and cellulose acetate butyrate or a mixture thereof.
  • HPMC hydroxyethyl cellulose
  • EC ethyl cellulose
  • MC methyl cellulose
  • sodium carboxymethyl cellulose and cellulose acetate butyrate or a mixture thereof The preferred polymer according to the present invention is HPMC, used as a release rate-controlling polymer. According to a most preferred embodiment, the viscosity of HPMC is 1 00 cP and 4000 cP.
  • the amount of the release rate-controlling polymer is 10 - 30%, the amount of calcium hydrogen phosphate dihydrate or calcium hydrogen phosphate anhydrous is 12 - 25%, and the amount of mannitol is above 55% in the controlled-release pharmaceutical tablet formulation according to the present invention.
  • the controlled- release pharmaceutical tablet formulation further comprises at least one excipient.
  • This excipient is selected from a group consisting of glidants and lubricants.
  • the glidant may be selected from a group consisting of colloidal silicon dioxide, silica, calcium silicate, magnesium trisilicate, sodium stearyl fumarate, talk, etc..
  • the glidant is preferably colloidal silicon dioxide used in an amount of 0.05 - 0.5%.
  • the lubricant is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, vegetable-derived fatty acids, etc..
  • the lubricant is preferably magnesium stearate used in an amount of 0.25 - 1 .0%
  • conducting an in vitro dissolution test using a USP paddle method in a 900 ml medium (0.05 M pH 7.5 phosphate buffer) at 75 rpm and 37°C should provide a dissolution rate for calcium hydrogen phosphate dihydrate or calcium hydrogen phosphate anhydrous and mannitol, together with HPMC, gliclazide or a pharmaceutically-acceptable salt thereof not more than 25% in 2 hours, 30 - 65% in 6 hours, and not less than 85% in 24 hours.
  • the cellulosic polymer is hydroxypropyl methylcellulose 100 cP or 4000 cP used in an amount of 10 - 30%, the amount of calcium hydrogen phosphate dihydrate or calcium hydrogen phosphate anhydrous is 12 - 25% and the amount of mannitol is above 55%.
  • the present invention is hereby disclosed by referring to exemplary embodiments hereinabove. These exemplary embodiments do not restrict the object of the present invention and must be evaluated under the light of the foregoing detailed description.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP14705166.8A 2013-02-19 2014-02-18 Verfahren zur herstellung von gliclazid-formulierungen Withdrawn EP2958548A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201301951 2013-02-19
PCT/EP2014/053109 WO2014128116A1 (en) 2013-02-19 2014-02-18 A production process for gliclazide formulations

Publications (1)

Publication Number Publication Date
EP2958548A1 true EP2958548A1 (de) 2015-12-30

Family

ID=49223837

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14705166.8A Withdrawn EP2958548A1 (de) 2013-02-19 2014-02-18 Verfahren zur herstellung von gliclazid-formulierungen

Country Status (2)

Country Link
EP (1) EP2958548A1 (de)
WO (1) WO2014128116A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107375224B (zh) * 2017-08-02 2019-09-13 浙江康德药业集团股份有限公司 一种格列齐特缓释片

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL132376C (de) 1966-02-10
DE3320582A1 (de) 1983-06-08 1984-12-13 Dr. Karl Thomae Gmbh, 7950 Biberach Gliquidonhaltige zubereitungsformen und verfahren zu ihrer herstellung
CZ20011629A3 (cs) * 1998-11-12 2001-12-12 Smithkline Beecham Plc Farmaceutický prostředek pro upravené uvolňování senzitizéru inzulínu a jiných antidiabetických přípravků
AP1243A (en) 1999-02-01 2004-02-02 Servier Lab Core tablet for controlled release of gliclazide after oral administration.
US20060002998A1 (en) * 2002-11-15 2006-01-05 Anupam Trehan Pharmaceutical dosage forms of biguanide-sulfonylurea combinations
ES2545589T3 (es) * 2005-04-08 2015-09-14 Abbott Laboratories Formulaciones farmacéuticas orales que comprenden sales de ácido fenofíbrico
WO2008062470A2 (en) 2006-10-19 2008-05-29 Torrent Pharmaceuticals Limited Stabilized controlled release dosage form of gliclazide
US20090312302A1 (en) * 2008-06-17 2009-12-17 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating nonalcoholic fatty liver disease-associated disorders
EP2468268B1 (de) * 2010-12-21 2017-12-13 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Kombinationszusammensetzung aus Vildagliptin und Gliclazid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014128116A1 *

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