EP3856162A1 - Composition pharmaceutique comprenant de la vildagliptine et de la metformine et son procédé de préparation - Google Patents

Composition pharmaceutique comprenant de la vildagliptine et de la metformine et son procédé de préparation

Info

Publication number
EP3856162A1
EP3856162A1 EP19790134.1A EP19790134A EP3856162A1 EP 3856162 A1 EP3856162 A1 EP 3856162A1 EP 19790134 A EP19790134 A EP 19790134A EP 3856162 A1 EP3856162 A1 EP 3856162A1
Authority
EP
European Patent Office
Prior art keywords
metformin
vildagliptin
pharmaceutical composition
pharmaceutically acceptable
lubricant
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
EP19790134.1A
Other languages
German (de)
English (en)
Inventor
Evangelots KARAVAS
Efthymios KOUTRI
Vasiliki SAMARA
Loanna KOUTRI
Anastasia Kalaskani
Andreas KAKOURIS
Vasilis MPENEKIS
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.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Publication of EP3856162A1 publication Critical patent/EP3856162A1/fr
Pending legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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)

Definitions

  • the present invention relates to a solid pharmaceutical formulation of Vildagliptin or a pharmaceutically acceptable salt thereof in combination with Metformin or a pharmaceutically acceptable salt thereof, to be used for the treatment of Type 2 diabetes.
  • the main objective of the present invention is to provide a formulation that is stable and robust and it overcomes the difficulties encountered in formulating combination products.
  • Diabetes mellitus is a common disorder with higher prevalence in developed countries. It is considered a metabolic disease wherein the patient has high blood sugar level over a prolonged period of time.
  • the disease has three different types. Type 1 diabetes, wherein the pancreas fails to produce enough insulin, therefore it requires immediate and life-long treatment with insulin.
  • Type 2 diabetes a chronic and progressive disease with a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. Typical treatment begins with diet and exercise, however, it will be followed by oral antidiabetic monotherapy, before moving into a combination regime. Most patients find it hard to sufficiently control glycaemia during long-term treatment with diet and exercise alone.
  • gestational diabetes occurs when pregnant women develop high blood sugar levels and is treated with diet and exercise and in some cases insulin.
  • Drugs of choice for therapy include biguanides, Dipepidyl peptidase-IV (DPP-IV) inhibitors, sulfonylurea, thiazolidinedione, alphaglucosidase inhibitor, amylin analog, glucagon-like peptide- 1 (GLP-l) or incretin mimetic, meglitinide and insulin.
  • DPP-IV inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes.
  • Vildagliptin also known as LAF-237 is the generic name for (S)-l -[(3-hydroxy- l-adamantyl)amino]acetyl-2-cyano-pyrrolidine has been disclosed specifically in US patent no 6,166,063; it was introduced in 2006, it is easy to use and does not require regular glucose monitoring or dose adjustments.
  • Vildagliptin has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbAu levels. It is well known in the art that DPP-IV inhibitors with primary or secondary amino group show incompatibilities, degradation problems or extraction problems with some excipients especially excipients that have acidic properties.
  • Vildagliptin has also a secondary amino group on its chemical structure. In solid dosage forms, it may react with many excipients or impurities of excipients, although it is very stable it has high susceptibility to air and humidity. This leads to formation of impurities and incorporation of undesired components into the composition.
  • EP 2468361 discloses a pharmaceutical composition, comprising Vildagliptin granules which are coated with at least one coating layer and one or more than one excipients.
  • direct compression is used to develop tablet formulation of DPP-IV inhibitor compounds, especially Vildagliptin or an acid addition salt thereof.
  • Metformin has also been widely prescribed for lowering blood glucose in patients with Type 2 diabetes and is marketed in 500, 750, 850 and 1000 mg strengths. However, because it is a short acting drug, metformin requires twice-daily or three- times-daily dosing (500 - 850 mg tab 2-3/day or 1000 mg bid with meals). Metformin is disclosed in U.S. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage ® , BMS), The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794 .
  • Metformin increases the sensitivity to insulin in peripheral tissues of the hosts and it is also involved in inhibition of glucose absorption from the intestine, suppression of hepatic gluconeogenesis, and inhibition of fatty acid oxidation.
  • Suitable dosage regimens of Metformin include unit doses of 500 mg two to three time's daily and can even be build up to five times daily or 850 mg once or twice daily.
  • Combination products offer several advantages. First, they have concentrations for the active agents that are consistently maintained within an optimal therapeutic range for both active agents. Second, combination products have been shown to improve patient compliance. Most healthcare practitioners now agree that within an ageing population, compliance becomes less certain and, therefore, more important. Third, particularly for treatment of Type 2 diabetes where single treatment along with diet and exercise fails quickly a combination product can have more advantages.
  • the present invention relates to a combination product comprising Vildagliptin and Metformin that overcomes the difficulties in the manufacturing process of such product, and a process for preparation thereof
  • an object of the present invention to provide an immediate release pharmaceutical formulation comprising a combination of Vildagliptin or a pharmaceutically acceptable salt thereof and Metformin or pharmaceutically acceptable salt thereof
  • a further object of the present invention is to provide a manufacturing process that is easy and cost effective and overcomes the added problems of impurities due to reaction of Vildagliptin with excipients present in the formulation.
  • Metformin granules are formed after granulation with an appropriate binder and Vildagliptin is then added in order to avoid formation of impurities.
  • the main objective of the present invention is to provide a composition comprising the combination of Vildagliptin or pharmaceutical acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof, prepared by a suitable manufacturing process in order to obtain a stable and efficacious dosage form with good physicochemical characteristics.
  • a process for the preparation of a stable dosage form of Vildagliptin and Metformin comprising the following steps:
  • the dry granulation method may be used where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted.
  • the method consists of blending, slugging the ingredients, dry screening, lubrication and compression.
  • the wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting.
  • the procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation.
  • the damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill.
  • the overall process includes weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.
  • powders do not have sufficient adhesive or cohesive properties to form hard, strong granules.
  • a binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders.
  • Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation. The large number of processing steps and time create problems due to high level manufacturing costs.
  • Wet granulation has also been known to reduce the compressibility of some pharmaceutical excipients, such as microcrystalline cellulose.
  • Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug.
  • the active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.
  • lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulation can materially affect hardness and disintegration time for the resulting tablets. Excessive blending of lubricants with the granulate ingredients can cause water proofing of the granule and reduces tablet hardness or strength of the compressed tablet. For these reasons, high-shear mixing conditions have not been used to prepare direct compression dosage forms.
  • wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances.
  • hydrophilic excipients makes the surface of the hydrophobic drug more hydrophilic, reducing disintegration and dissolution problems.
  • the content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug. easily, the segregation of drug(s) from excipients is avoided.
  • Segregation could be a potential problem with direct compression.
  • the size and shape of particles comprising the granulate to be compressed are optimized through the wet granulation process. This is because when a dry solid is wet granulated the binder "glues" particles together, so that they agglomerate into spherical granules.
  • the size and shape of the resulting tablet should be considered since an easy oral administration to a patient is required, as well as an easy tablet manufacturing process which meets all the herein described requirements.
  • the high-dose Vildagliptin and Metformin tablets have to meet all the herein listed requirements with preferably a limited number and amount of pharmaceutical excipients to reduce the size of the tablet.
  • Pre-formulation testing was the first step in the development of dosage forms for the drug substance. The physical and chemical properties of the drug substance combined with excipients were investigated. Pre-formulation testing generated useful information in developing stable and bioavailable dosage forms that can be scaled up. Based on compatibility and pre-formulation studies the selected commonly used Ph.Eur grade excipients were shown compatible with the active substance.
  • the main objective of the present invention is to develop a robust and stable immediate release film-coated tablet comprising Vildagliptin/Metformin HC1 in two strengths 50/850mg and 50/l000mg respectivelly.
  • the excipients were selected to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the APIs.
  • Binders such as Hydroxypropylcellulose, Hydroxypropylmethylcellulose Copovidone, vinylpyrrolidone-vinyl acetate copolymer and Povidone were tested in order to promote granules during granulation and to provide mechanical strength to the tablet.
  • Colloidal silicon dioxide was tested as glidant to improve the flow property of the formulation due to the reduction of the friction between the particles during granulation and compaction.
  • Magnesium Stearate was used in formulations as lubricant to prevent any sticking during compression. Wet (aqueous and solvent) granulation and melt granulation were tested in manufacturing process.
  • Formulation trials were performed in order to study the physicochemical properties of the tablets as well as dissolution properties and result in the final drug product with the optimum quality.
  • the target characteristics were set to hardness from 150 to 25 ON, disintegration time from 12 ⁇ 0” to 17 ⁇ 0” and dissolution was set to >85% at 30 minutes.
  • the preferred formulation of this invention comprises the following: Vildagliptin and Metformin HC1 as the active ingredients, one or more binders, optionally a diluent, one or more lubricants, optionally a disintegrant and a lubricant which is magnesium stearate.
  • the excipients have been carefully selected after many optimization steps.
  • Binder excipients are formulated to act as an adhesive, to literally“bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. Binders are added to create a more effective and predictable granule formation.
  • pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, e.g., vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; com syrup; polysaccharides; and gelatin.
  • the binder e.g., may be present in an amount from about 10% to about 40% by weight of the composition.
  • Polyvinylpyrrolidone VA64 (PVP VA64), also known as Kollidon® VA 64, is a vinylpyrrolidone-vinyl acetate copolymer. It is used in a variety of manufacturing processes such as a dry binder for direct compression, as s granulating agent, as s retarding and as a film forming agent as well as in taste-masking applications. Kollidon® VA 64 can be used as a dry binder for direct compression tableting and as a soluble binder for granulation and it is ideal as a solubilizer in hot-melt extrusion processes because of its excellent binding capacity. Another important property of Kollidon® VA 64 is the plasticity, which distinguishes the products from povidone (e.g.
  • Kollidon® 30 This property often gives granules and mixtures that are less susceptible to capping during tableting, and tablets that are less brittle. These properties in total make it an attractive and cost-effective alternative to natural binders. In addition,. Kollidon® VA 64 is especially suitable for processes with higher humidity exposure.
  • Kollidon® VA 64 is an excellent binder in wet granulation for the production of tablets and granules, since it is readily soluble in all the usual solvents. It can then be added either as a solution during granulation, or dry to the other ingredients, in which case the solvent is added alone during granulation. Trials so far conducted with both methods, using equal quantities of liquid, produced tablets of much the same hardness. A combination of the two methods, i.e. mixing some of the Kollidon® VA 64 with the active ingredient, and dissolving the rest in the solvent, sometimes gives the best results. This is particularly recommended if the active ingredient does not readily absorb the solvent. Since it is less hygroscopic than povidone (e.g. Kollidon® 25 or Kollidon® 30), Kollidon® VA 64 gives granules that have less tendency to stick to the punches of the tableting machine, when operating under humid conditions.
  • povidone e.g. Kollidon® 25 or Kollidon® 30
  • Kollidon VA64 as binder showed the best results when used in an amount from about 5% to about 25% by weight of the composition, more preferably from about 10% to about 20%.
  • Aerosil ® when added during the external phase protects Vildagliptin and minimizes its degradation. This is most likely due to the formation of a protective film around Vildagliptin and minimization of its interaction with the Metformin granules.
  • the preferred amount of Aerosil ® in the present invention is from about 0.1% to about 7% of the total weight of the composition and most preferably from about 1% to about 5% of the total weight of the composition.
  • the formulation may contain diluents.
  • diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent may be present in an amount from about 15% to about 40% by weight of the composition.
  • the preferred diluent is microcrystalline cellulose which is manufactured by the controlled hydrolysis of alpha- cellulose, obtained as a pulp from fibrous plant materials, with dilute mineral acid solutions.
  • a disintegrant is also an optional but useful component of the tablet formulation. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. One, two, three or more disintegrants can be selected.
  • examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium or croscarmellose); soy polysaccharides; and guar gum, sodium starch glycolate.
  • the disintegrant may be present preferably in an amount from about 2% to about 20%, more preferably from about 5% to about 10%, and most preferably from 7% to about 9% by weight of the composition.
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight.
  • the lubricant component may be hydrophobic or hydrophilic. One, two, three or more lubricants can be selected.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant may be present in an amount preferably from about 0.1% to about 5% by weight of the composition and most preferably from about 0.1% to about 2% by weight of the composition.
  • Magnesium stearate was the choice for the present invention. It reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die. It has a particle size range of 450-550 microns and a density range of 1.00-1.80 g/mL. It is stable and does not polymerize within the tableting mix.
  • the inventors of the invention have surprisingly found that it is possible to formulate a stable pharmaceutical composition comprising a combination of Vildagliptin or pharmaceutically acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof, which can exhibit superior chemical and physical stability by wet granulation, a manufacturing process that is easy and cost effective.
  • the tablet as described in the present invention is obtained by wet granulation of the Metformin granules in the presence of a binder, drying and subsequent addition of a lubricant and Vildagliptin and optionally at least one pharmaceutically acceptable excipient.
  • the tablet as described in the present invention comprises as active ingredients,
  • the process for the preparation of a stable dosage form of Vildagliptin and Metformin HC1 comprising the following steps:
  • a lubricant which is Magnesium stearate and mixing
  • the main objective of the present invention was to develop a robust and stable immediate release film-coated tablet comprising Vildagliptin/Metformin HC1 in two strengths 50/850mg and 50/1000 mg with respect to both active ingredients.
  • excipients were selected to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the active ingredients.
  • Formulation trials were performed in order to study the physicochemical properties of the tablets as well as dissolution properties and result in the final drug product with the optimum quality below.
  • compositions 1.2 - 1.4 show a rather stable behavior except from formulation 1.3 with the ethanol granulation where the total impurities after the six months are above the limit. Based upon the stability data and the physical attributes of the studied compositions, the manufacturing process of formulation 1.3 was not further utilized, while the process of formulations 1.2 and 1.4 were qualified as more appropriate for the development.
  • melt granulation is a standard and cost-effective manufacturing process that incorporates common raw materials and requires standard equipment.
  • melt granulation may require non-typical equipment i.e. hot melt extruder (HME) which means that the potential excipients for such process are limited. For that reason, melt granulation was not further utilized and wet granulation remained as the prevalent manufacturing process
  • the next step of the formulation development incorporated the use of alternative excipients (PVP/K30, PVP/VA64, MCC, Aerosil and HPMC) with different proportions in each composition, in order to study any effect on the physical attributes of the final tablet.
  • Wet granulation in a high shear granulator performed as the selected manufacturing process to form metformin granulates for all formulations.
  • the composition, for each compression mixture categorized by the binder type and the internal phase excipients, is tabulated below (Table 4). Hardness and disintegration time for each formulation after compression and coating were measured and listed in Table 4.
  • Formulations 2.5, 2.6 and 2.7 presented the best hardness value in combination with an acceptable disintegration time for a high load drug combination. Flowability of the said formulations 2.5, 2.6 and 2.7 was measured by the Carr’s index and found to be 26, 19 and 23, respectively. In conclusion, PVP/VA64 performed well as a binding agent, to form a Metformin granulate that provides adequate physical properties to the final tablet.
  • the in-vitro Vildagliptin and Metformin release from film-coated tablets was evaluated using apparatus II (rotating paddle method) of the USP 2 on a dissolution tester.
  • the test for the film- coated tablets was performed at 37 ⁇ 0.5°C with a rotation speed of 100 rpm using as dissolution medium 900 mL of buffer solution at pH 6.8 for 60 mins.
  • Formulation 2.6.1 with 8.4% PVP/VA64 and 2% Aerosil showed Metformin and Vildagliptin release rates that were satisfying. Although, Metformin release rate for formulations 3.6.1 and 3.7.1 exhibited similar behaviour, the respective Vildagliptin release rate showed a slower profile.
  • the Carr’s index for formulations 2.6.1 and 3.7.1 characterized the bulk flowability as good and for formulation 3.6.1 as poor.
  • Example 6 According to the results from the previous experiments the inventors determined that the PVP/VA64 and Aerosil percentages are defined at around 15.5% and 3.4%, respectively. Finally, formulation 4.5 was tested that was manufactured according to these findings shown in table 12.
  • the manufacturing process comprises wet granulation of Metformin HC1 with a kneading aqueous solution of PVP/VA64. Then, for the external phase Vildagliptin and Aerosil are added successively and Magnesium Stearate for the lubrication.
  • the drug release profile is similar for formulations 4.5 compared to 2.6.1, a fact that underlines the unchangeable in-vitro behaviour even in case of different final tablet weight.
  • the 6 months stability data for the final composition 4.5 are shown below in Table 13 and 14. Regarding the final composition 4.5, the stability data are within the specified limits for both active ingredients Table 13. Vildagliptin stability data in zero time and after 6 months for Comp 4.5
  • Metformin HC1 and Vildagliptin sustain their crystallinity form after the manufacturing process.

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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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique solide de vildagliptine ou d'un sel pharmaceutiquement acceptable de celle-ci en combinaison avec de la metformine ou un sel pharmaceutiquement acceptable de celle-ci, destinée à être utilisée pour le traitement du diabète de type 2.
EP19790134.1A 2018-09-25 2019-09-24 Composition pharmaceutique comprenant de la vildagliptine et de la metformine et son procédé de préparation Pending EP3856162A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20180100438A GR1009644B (el) 2018-09-25 2018-09-25 Φαρμακευτικο σκευασμα που περιλαμβανει βιλνταγλιπτινη και μετφορμινη και μεθοδος για την παρασκευη αυτου
PCT/EP2019/025314 WO2020064145A1 (fr) 2018-09-25 2019-09-24 Composition pharmaceutique comprenant de la vildagliptine et de la metformine et son procédé de préparation

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EP3856162A1 true EP3856162A1 (fr) 2021-08-04

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TR202009949A1 (tr) * 2020-06-25 2022-01-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Vi̇ldagli̇pti̇n ve metformi̇n hci i̇çeren bi̇r fi̇lm kapli tablet
EP4066820A1 (fr) * 2021-03-29 2022-10-05 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé revêtu d'un film de vildagliptine et de chlorhydrate de metformine
CN114886862B (zh) * 2022-05-17 2024-02-02 北京悦康科创医药科技股份有限公司 一种复方降糖药物制剂及其制备方法

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US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
CO5150173A1 (es) 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
BRPI0507007A (pt) 2004-01-20 2007-06-05 Novartis Ag formulação e processo de compressão direta
GT200600008A (es) 2005-01-18 2006-08-09 Formulacion de compresion directa y proceso
JOP20180109A1 (ar) * 2005-09-29 2019-01-30 Novartis Ag تركيبة جديدة
AR071175A1 (es) * 2008-04-03 2010-06-02 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante
SI2459531T1 (sl) * 2009-07-31 2020-02-28 Krka, D.D., Novo Mesto Granulat, ki obsega vildagliptin, in postopek njegove priprave
TR201010683A1 (tr) 2010-12-21 2012-07-23 Sanovel İlaç San. Ve Ti̇c. A.Ş. Vildagliptin formülasyonları.
WO2014101986A1 (fr) * 2012-12-27 2014-07-03 Zentiva Sağlik Ürünleri San. Ve Tic. A.Ş. Procédé de granulation à sec pour la production de compositions de comprimés de metformine et compositions associées
WO2015097234A1 (fr) * 2013-12-23 2015-07-02 Krka, D. D. Novo Mesto Composition pharmaceutique d'un inhibiteur de la dpp iv en combinaison avec la metformine

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