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WO2018033808A1 - Composition améliorée de ténéligliptine et de metformine et procédé pour sa préparation - Google Patents

Composition améliorée de ténéligliptine et de metformine et procédé pour sa préparation Download PDF

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Publication number
WO2018033808A1
WO2018033808A1 PCT/IB2017/053749 IB2017053749W WO2018033808A1 WO 2018033808 A1 WO2018033808 A1 WO 2018033808A1 IB 2017053749 W IB2017053749 W IB 2017053749W WO 2018033808 A1 WO2018033808 A1 WO 2018033808A1
Authority
WO
WIPO (PCT)
Prior art keywords
metformin
pharmaceutical composition
therapeutically effective
teneligliptin
effective amount
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.)
Ceased
Application number
PCT/IB2017/053749
Other languages
English (en)
Spanish (es)
Inventor
Esteban Alejandro Fiore
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.)
Siegfried Rhein SA de CV
Original Assignee
Siegfried Rhein SA de CV
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=61196457&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2018033808(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Siegfried Rhein SA de CV filed Critical Siegfried Rhein SA de CV
Priority to BR112019002909-5A priority Critical patent/BR112019002909B1/pt
Publication of WO2018033808A1 publication Critical patent/WO2018033808A1/fr
Priority to CONC2019/0001110A priority patent/CO2019001110A2/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to an improved fixed dose composition
  • an improved fixed dose composition comprising the combination of two hypoglycemic active ingredients, one of the gliptin family, Teneliglipt ina and the other of the biguanide family, Metformin, for treatment by Oral route of diabetes mellitus type 2 (DM2) in humans, the process to obtain such an improved composition, and its uses.
  • DM2 diabetes mellitus type 2
  • the Teneligliptin compound whose IUPAC nomenclature is Methanone, [(2S, 4S) -4- [4- (3-meti 1-1-phenyl-lH-pyrazol-5-i 1) -1-piperazinyl] -2-pyrrolidinyl ] -3-thiazolidini 1, represented by formula (I), was disclosed as a product in European patent EP 1 308439 Bl and its equivalents, the holder of which is MITSUBISHI TANABE PHARMA and the priority date is 10-8-00 and 28 -12-00 (JP).
  • Teneligliptin is an oral hypoglycemic agent, a dipeptidyl peptidase 4 (DPP-4) inhibitor.
  • DPP-4 dipeptidyl peptidase 4
  • the pharmacological action of Teneligliptin is described as follows: the glucagon-like peptide type 1 (GLP-1) is secreted by the gastrointestinal tract in response to food, promotes insulin secretion from the pancreas and, by suppression of glucagon secretion, adjust postprandial glycemia.
  • GLP-1 glucagon-like peptide type 1
  • DPP-4 dipeptidyl peptidase 4
  • Metformin is an antihyperglycemic agent belonging to the group of biguanides, which lowers basal and postprandial glycemia. It does not stimulate insulin secretion, thus not producing hypoglycemia.
  • the mechanism of action is not known exactly and it is considered that it could act: 1) decreasing hepatic glucose production by inhibition of glycogenolysis and gluconeogenesis, 2) in the muscle, increasing the sensitivity or amount of insulin receptors, improving glucose uptake and utilization and 3) decreasing the intestinal absorption of glucose.
  • Metformin has been shown to produce a favorable effect on lipid metabolism, independent of its effect on blood glucose.
  • Administered in therapeutic doses Metformin lowers total cholesterol, LDL cholesterol and plasma t-riglycerides.
  • the usual initial dose of treatment is 500 mg or 850 mg two or three times per day administered during or after meals. Increased doses can be evaluated based on tolerance and blood glucose levels. The dose can be increased to 3000 mg per day, always divided every 8 or 12 hours.
  • the object of the present invention relates to an improved formulation in the form of a coated tablet, in a unit dose, comprising two agents.
  • hypoglycemic agents namely Teneliglipt ina or any of its pharmaceutically acceptable salts, and Metformin, such as Metformin hydrochloride, in a therapeutically effective amount, for the treatment of type 2 diabetes mellitus (DM2), further comprising a low content of excipients.
  • Metformin such as Metformin hydrochloride
  • the obtained tablets were highly friable, took very low hardness working with high compression force, and also pickled (they opened in sheets).
  • the physical characteristics of Metformin hydrochloride were studied thoroughly, observing that it was usually acicular crystalline powder, which tended to form lumps and compact into the container container.
  • tests were carried out, reducing the granulometry of Metformin hydrochloride by calibrating it in the Fitz Mili mill, varying the meshes and speeds. Although the compressibility improved, the hardness obtained was not optimal and the process was far from reproducible.
  • the granulate was then calibrated by a 2 mm mesh, and subsequently, dried by using a fluid bed until a residual humidity between 1.5 and 2% was obtained, taken at 105 2 C. Then the dry granulate was calibrated. using a 1 mm mesh, and after adding a small aliquot of Magnesium Stearate, it was mixed for 2 minutes at 12 rpm. It was subsequently compressed with a rotary compressor, obtaining very good hardness tablets (around 20 kp), with brightness, low friability (less than 1% P / P), without presence of decape or laminate working with standard compression force. Also, the disintegration time was less than 15 minutes. The tablets obtained perfectly complied with the content uniformity test of both active ingredients.
  • the usual methodology when developing a tablet formulation To vehicle one or more active ingredients it is to use one or more diluents, a binder, a disintegrant, a lubricant, and it is expected that as we increase the amount of excipients, compressibility improves. In the case object of this patent, the opposite happened, the compressibility decreased, that is why we affirm that it was an unexpected event.
  • the invention relates to an improved pharmaceutical composition for oral administration, in the form of a coated tablet, for the treatment of DM2, which comprises the combination of a therapeutically effective amount of the antidiabetic Teneliglipt ina or its pharmaceutically salts. acceptable, with a therapeutically effective amount of the antidiabetic Metformin hydrochloride, with a low content of pharmaceutically acceptable excipients.
  • the invention also relates to the therapeutically effective doses of Teneliglipt ina or its pharmaceutically acceptable salts, which may be in the range of 10 mg to 20 mg and the therapeutically effective doses of Metformin hydrochloride, which may be in the range of 500 to 2000 mg
  • the invention relates to processes for obtaining an improved pharmaceutical composition of oral administration, in the form of a coated tablet, for the treatment of DM2, which comprises grinding Metformin, mixing, granulating, mixing again and compressing therapeutically effective amounts of the active ingredients Teneliglipt ina or its pharmaceutically acceptable salts and Metformin hydrochloride together with low content of pharmaceutically acceptable excipients and coating, the tablets obtained.
  • DM2 a pharmaceutically acceptable pharmaceutically acceptable salts and Metformin hydrochloride
  • Teneliglipt ina mixed with Metformin in another variant, it includes dissolved in the binder solution, and finally, in another variant, incorporates Teneligliptin from the suspension of the coating.
  • the industrial lot is per 200 kg, it was kneaded in two aliquots of 100 kg each, in a Zanchetta rotator with a capacity of 300 liters.
  • Titanium dioxide 9.00 0.81
  • Weight of the coated tablet 1112 mg
  • the industrial batch is for 200 kg, it was kneaded in two aliquots of 100 kg each, in a Zanchetta rotogranuladora of 300 liters of capacity.
  • the industrial lot is for 200 kg, and was mixed in two aliquots of 100 kg each, in a Zanchetta rotogranuladora of 300 liters of capacity.
  • the process for preparing a formulation of coated tablets for administration every 12 hours comprising 10 mg of Teneliglipt ina its pharmaceutically acceptable salts and 500 mg of Metformin, in which, Metformin hydrochloride will be compressed and Teneligliptin will be applied together with the covering.
  • Metformin hydrochloride will be compressed and Teneligliptin will be applied together with the covering.
  • the formula described below is per unit of Dosing, the industrial batch is per 100 kg, and it was kneaded in a Zanchetta rotogranuladora of 300 Liters of capacity.
  • Example 5 The methodology described in Example 5 is applicable for doses of 10 mg of Teneliglipt ina its pharmaceutically acceptable salts, combined with 850 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride (to be administered every 12 hr.) , and 20 mg of Teneliglipt ina combined with 850 mg of Metformin hydrochloride (to be administered every 24 hr).
  • the industrial batch is 200 kg, Knead in two aliquots of 100 kg each,
  • Example 7 The methodology applied in Example 7, is applicable for the doses of 10 mg of Teneliglipt ina or its pharmaceutically acceptable salts combined with 500 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride, and 10 mg of Teneligliptin combined with 850 mg of Metformin hydrochloride.
  • EXAMPLE 9 The methodology applied in Example 7, is applicable for the doses of 10 mg of Teneliglipt ina or its pharmaceutically acceptable salts combined with 500 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride, and 10 mg of Teneligliptin combined with 850 mg of Metformin hydrochloride.
  • Titanium dioxide 3.75 6, 25 7.00
  • Friability Friabilómet ro type "ROCHE” equipment, according to USP General Tests and Assays ⁇ 1216>
  • composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 500 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride.
  • composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 1000 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 1000 mg of Metformin hydrochloride.
  • hydrochloride Q 70% Average: 99.3% Average: 100%
  • composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 850 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride.
  • composition in the form of a coated tablet comprising Teneligliptin 20 mg and Metformin hydrochloride 850 mg, compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride.
  • composition in the form of a coated tablet comprising Teneligliptin 10 mg in the coating and Metformin hydrochloride 500 mg, in the core compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride.
  • composition in the form of a coated tablet comprising Teneligliptin 20 mg added dissolved in the binder solution and Metformin hydrochloride 850 mg, granulated in a similar manner to the previous examples, compared with coated tablets containing 20 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride .
  • composition in the form of a coated tablet comprising Teneligliptin 20 mg in the coating and Metformin hydrochloride 500 mg, in the core prolonged deliberation compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride extended release.
  • Parameters Example 1 Teneligliptin 20 mg Metformin
  • composition in the form of a coated tablet comprising Teneligliptin 20 mg in the coating and Metformin hydrochloride 1000 mg, in the core prolonged deliberation compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 1000 mg of Metformin hydrochloride extended release.

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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)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique améliorée sous la forme de comprimé oral revêtu, à l'aide de ténéligliptine ou de ses sels pharmaceutiquement acceptables et de metformine ou de ses sels pharmaceutiquement acceptables pour le traitement du diabète sucré de type 2. Ladite composition pharmaceutique est obtenue par granulation humide, à l'aide de metformine moulue en poudre fine et d'une faible charge d'excipients, constitués d'un agglutinant, ici de la povidone et du stéarate de magnésium comme lubrifiant pendant la compression. Le fait d'utiliser la metformine moulue améliore notablement la compressibilité de cette dernière, ce qui permet à son tour d'optimiser les conditions d'utilisation. La composition pharmaceutique améliorée, comprenant la combinaison de ténéligliptine et de metformine, comparée aux deux principes actifs séparés, véhiculés sous la forme de comprimés revêtus, n'a pas démontré de différences dans la libération in vitro (dissolution), et d'autre part a amélioré la compressibilité du granulat et la friabilité des comprimés. Les aspects mentionnés font que la composition améliorée se différencie d'autres compositions contenant les mêmes actifs et qui utilisent un plus grand nombre d'excipients, et est par conséquent, l'objet principal de la présente invention.
PCT/IB2017/053749 2016-08-17 2017-06-23 Composition améliorée de ténéligliptine et de metformine et procédé pour sa préparation Ceased WO2018033808A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR112019002909-5A BR112019002909B1 (pt) 2016-08-17 2017-06-23 Composição melhorada de teneligliptina e metformina, e processo para preparação da mesma
CONC2019/0001110A CO2019001110A2 (es) 2016-08-17 2019-02-05 Composición mejorada de teneligliptina y metformina y proceso para prepararla

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2016010682A MX384961B (es) 2016-08-17 2016-08-17 Composición mejorada de teneligliptina y metformina y proceso para prepararla.
MXMX/A/2016/010682 2016-08-17

Publications (1)

Publication Number Publication Date
WO2018033808A1 true WO2018033808A1 (fr) 2018-02-22

Family

ID=61196457

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/053749 Ceased WO2018033808A1 (fr) 2016-08-17 2017-06-23 Composition améliorée de ténéligliptine et de metformine et procédé pour sa préparation

Country Status (8)

Country Link
AR (1) AR109253A1 (fr)
CL (1) CL2019000273A1 (fr)
CO (1) CO2019001110A2 (fr)
DO (1) DOP2019000035A (fr)
EC (2) ECSP19010066A (fr)
MX (1) MX384961B (fr)
PE (1) PE20190402A1 (fr)
WO (1) WO2018033808A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080383A1 (fr) * 2012-11-26 2014-05-30 Ranbaxy Laboratories Limited Composition pharmaceutique d'inhibiteurs de la dipeptidyl-peptidase-iv (dpp-iv) en association avec d'autres antidiabétiques
WO2015132679A1 (fr) * 2014-03-05 2015-09-11 Glenmark Pharmaceuticals Ltd Compositions de ténéligliptine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080383A1 (fr) * 2012-11-26 2014-05-30 Ranbaxy Laboratories Limited Composition pharmaceutique d'inhibiteurs de la dipeptidyl-peptidase-iv (dpp-iv) en association avec d'autres antidiabétiques
WO2015132679A1 (fr) * 2014-03-05 2015-09-11 Glenmark Pharmaceuticals Ltd Compositions de ténéligliptine

Also Published As

Publication number Publication date
BR112019002909A2 (pt) 2019-05-21
AR109253A1 (es) 2018-11-14
DOP2019000035A (es) 2019-06-30
MX384961B (es) 2025-03-14
CO2019001110A2 (es) 2019-04-12
CL2019000273A1 (es) 2019-06-28
MX2016010682A (es) 2018-02-16
PE20190402A1 (es) 2019-03-13
ECSP19044926A (es) 2019-07-31
ECSP19010066A (es) 2019-11-30

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