EP4188352A1 - Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine - Google Patents

Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine

Info

Publication number
EP4188352A1
EP4188352A1 EP21749796.5A EP21749796A EP4188352A1 EP 4188352 A1 EP4188352 A1 EP 4188352A1 EP 21749796 A EP21749796 A EP 21749796A EP 4188352 A1 EP4188352 A1 EP 4188352A1
Authority
EP
European Patent Office
Prior art keywords
metformin
dosage form
acceptable salt
pharmaceutical dosage
physiologically acceptable
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
EP21749796.5A
Other languages
German (de)
English (en)
Inventor
Luka ZNIDERSIC
Luka SENICA
Alen GABRIC
Sergeja Bombek
Klemen KORASA
Matej REPIC
Gasper VRHUNC
Ziga HODNIK
Ilija BUZAR
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.)
KRKA dd
Original Assignee
KRKA dd
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 KRKA dd filed Critical KRKA dd
Publication of EP4188352A1 publication Critical patent/EP4188352A1/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
    • A61K31/13—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
    • A61K31/40—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
    • A61K31/33—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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • Metformin is marketed in immediate-release formulations and extended-release formulations and is available in several products in combination with other active pharmaceutical ingredients, espe cially antidiabetic agents.
  • US 8,414,921 B2 relates to pharmaceutical compositions comprising fixed-dose combinations of a dipeptidyl peptidase-4 inhibitor and metformin, methods of preparing such pharmaceutical compo sitions, and methods of treating Type 2 diabetes with such pharmaceutical compositions.
  • metformin is most labile in alkaline and oxidative environments.
  • ammonia and DMA are formed, which can react by one of the possible reaction pathways to form N,N-dime- thylhydrazine. The latter can then be oxidized to NDMA.
  • DMA can react to NDMA in alkaline envi ronment even in the simultaneous presence of nitrite ions and formaldehyde.
  • the invention relates to a pharmaceutical composition and pharmaceutical dosage forms of metformin hydrochloride or combinations of metformin hydrochloride with any other pharma ceutically active ingredient that provides an NDMA (N-nitroso dimethylamine) content below the per missible limit of 48 ppb.
  • NDMA N-nitroso dimethylamine
  • the pharmaceutical dosage form is typically devoted for administering a therapeutically effec tive amount of metformin (ATC A10BA02) or a physiologically acceptable salt thereof to a subject in need thereof.
  • the dose of metformin or a physiologically acceptable salt thereof that is contained in the pharmaceutical dosage form preferably amounts to 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg, in each case expressed as equivalent dose relative to metformin hydrochloride.
  • metformin or the physiologically acceptable salt thereof as contained in the pharma ceutical dosage form or in metformin starting material is a solid, crystalline or amorphous material. It may comprise any polymorph, solvate, cocrystal, and the like of metformin or the physiologically ac ceptable salt thereof.
  • the content of metformin or the physiologically acceptable salt thereof is within the range of from 60 to 90 wt.-%, relative to the total weight of the pharmaceutical dosage form and the weight of metformin or the physiologically acceptable salt thereof.
  • the additional active pharmaceutical ingredient is an antidiabetic agent.
  • the pharmaceutical dosage form according to the invention is a tablet.
  • the pharmaceutical dosage form according to the invention has been prepared by wet granulation.
  • step (b) among the one or more excipients employed in step (vii);
  • the diabetes is type 2 diabetes mellitus (T2DM).
  • the pharmaceutical dosage form comprising metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb - 72 ppb);
  • the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range 30 ppb to 300 ppb);
  • the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof / metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm).
  • a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof and having a content of N-nitroso dimethylamine of not more than 48 ppb, relative to the total weight of metformin in the pharmaceutical dosage form.
  • step (b) among the one or more excipients employed in step (vii);
  • a metformin starting material for incorporation into a pharmaceutical dosage form according to clause 42 wherein the metformin or a physiologically acceptable salt thereof is present as a pow der having a median diameter D(50), determined laser diffraction analysis, of not more than 200 pm; preferably not more than 100 pm.
  • step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.
  • Values D(10), D(50) and D(90) indicate that 10%, 50% and 90% of the particles, respectively, are smaller than the specified values.
  • Ph. Eur. 10.4, 2.9.31 Particle size analysis by laser light diffraction
  • the finely milled metformin preferably has an average and median particle size D(50) of less than 100 pm, preferably less than 80 pm. Further, the finely milled metformin preferably has a particle size distribution of D(10) less than 30 pm, D(50) less than 100 pm, and D(90) less than 150 pm; preferably D(10) is less than 20 pm, D(50) less than 80 pm, and D(90) less than 120 pm.
  • Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • Metformin granulation Hydroxypropylcellulose and are added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained.
  • the granulation liquid for metformin granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations.
  • Metformin hydrochloride is delumped and sieved on sieve size 0.6 - 2.0 mm.
  • the blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous.
  • the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.
  • Blending compression mixture preparation: Sodium stearyl fiimarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.
  • Metformin drying Metformin hydrochloride is de lumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is dried in fluid bed dryer at product temper ature of 70°C for one hour.
  • Blending compression mixture preparation: Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.
  • f) Tableting Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • g) Film-coating Coating mixture and colorant ferric oxide yellow (E 172) are homogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.
  • Packaging procedure Packaging process is being carried out under the same conditions as manufacturing process.
  • DMA content of the metformin hydrochloride that was employed as staring material was determined by the LC-MS method according to the invention as described above.
  • DMA content after treatment was also determined.
  • Metformin hydrochloride was treated under various conditions (with and without milling, dry ing at 50°C and 70°C) and the influence on DMA content over time was investigated. DMA content was determined by the LC-MS method according to the invention as described above.

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

Abstract

L'invention concerne une matière de départ à base de metformine destinée à être incorporée dans une forme pharmaceutique comprenant de la metformine ou un sel physiologiquement acceptable de celle-ci, la teneur en metformine étant d'au moins 99,0 % en poids par rapport au poids total de matière de départ à base de metformine, la matière ayant une teneur en diméthylamine ne dépassant pas 180 ppm par rapport au poids de metformine, et la metformine étant présente sous forme d'une poudre ayant un diamètre D(50) médian en volume inférieur ou égal à 200 µm, déterminé par analyse de diffraction laser. L'invention concerne également un procédé de préparation d'une matière de départ à base de metformine, le procédé comprenant les étapes consistant à : (i) fournir de la metformine ou un sel physiologiquement acceptable de celle-ci ; (ii) broyer la metformine ou un sel physiologiquement acceptable de celle-ci, ce qui permet d'obtenir de la metformine ou un sel physiologiquement acceptable de celle-ci sous forme broyée ; et (iii) soumettre la metformine ou un sel physiologiquement acceptable de celle-ci, ou la metformine ou un sel physiologiquement acceptable de celle-ci sous forme broyée, à une température élevée et/ou à une pression réduite, ce qui permet d'obtenir de la metformine ou un sel physiologiquement acceptable de celle-ci sous forme séchée. L'invention concerne en outre un procédé de préparation d'une forme pharmaceutique comprenant de la metformine ou un sel physiologiquement acceptable de celle-ci et ayant une teneur en N-nitrosodiméthylamine ne dépassant pas 48 ppb par rapport au poids total de metformine dans la forme pharmaceutique, ledit procédé comprenant le procédé mentionné ci-dessus.
EP21749796.5A 2020-07-31 2021-07-23 Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine Pending EP4188352A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SI202000132 2020-07-31
EP20209718 2020-11-25
PCT/EP2021/070703 WO2022023213A1 (fr) 2020-07-31 2021-07-23 Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine

Publications (1)

Publication Number Publication Date
EP4188352A1 true EP4188352A1 (fr) 2023-06-07

Family

ID=77207154

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21749796.5A Pending EP4188352A1 (fr) 2020-07-31 2021-07-23 Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine

Country Status (2)

Country Link
EP (1) EP4188352A1 (fr)
WO (1) WO2022023213A1 (fr)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1559419A1 (fr) * 2004-01-23 2005-08-03 Fournier Laboratories Ireland Limited Composition pharmaceutique contenant une combinaison de mefformine et d'un fibrate et les procédés pour les obtenir
CA2633167A1 (fr) * 2005-12-16 2007-07-12 Merck & Co., Inc. Compositions pharmaceutiques contenant des combinaisons d'inhibiteurs de la dipeptidylpeptidase 4 avec de la metformine
ITFI20070042A1 (it) * 2007-02-21 2008-08-22 Laboratori Guidotti Spa Formulazione farmaceutica e compressa comprendente detta formulazione.
US20110021634A1 (en) * 2009-06-18 2011-01-27 Patel Pranav Dushyant Processes for preparing metformin hydrochloride
AU2011295837B2 (en) * 2010-09-03 2015-06-18 Astrazeneca Uk Limited Drug formulations using water soluble antioxidants
US11510886B2 (en) * 2016-09-30 2022-11-29 Laboratorios Silanes, S.A. De C.V. Metformin amino acid compounds and methods of using the same

Also Published As

Publication number Publication date
WO2022023213A1 (fr) 2022-02-03

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