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
  • A61K31/495—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
  • 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
  • A61K9/2095—Tabletting processes
• • 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

Definitions

• the invention relates to film-coated tablet compositions containing Linagliptin.
• DPP-4 inhibitors are used to treat Type 2 diabetes mellitus by increasing insulin secretion after glucose uptake.
• DPP-4 inhibitors block the DPP-4 enzyme, an enzyme that breaks down the incretin hormone.
• incretin hormone There are two types of incretin hormone in the body as glucagon-like peptide-1 (GLP-1 ) and glucose-dependent insulinotropic peptide (GIP). The level of these hormones increases under the effect of linagliptin, and their effects on glucose control increase.
• GLP-1 glucagon-like peptide-1
• GIP glucose-dependent insulinotropic peptide
• Linagliptin a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, was first described in patent no. EP1532149. It has a molecular weight of 472.54 g/mol and has the following chemical structure: Formula 1
• Linagliptin is used orally as tablets of 5 mg. It has double and triple combinations with metformin and empagliflozin.
• EP1786401 suggests microcrystalline cellulose as a diluent, and magnesium and calcium stearate as a lubricant as moisture sensitive formulations.
• EP2023902 discloses that mannitol and pregelatinized starch are used instead of microcrystalline cellulose to prevent incompatibility.
• EP2853257 relates to a patent application containing croscarmellose sodium as a disintegrant. Dibasic calcium phosphate is used as a diluent in the formulation.
• TR2021/011580 relates to a tablet containing sorbitol as a diluent and crospovidone as a disintegrant.
• WO2017/060398 relates to a tablet containing dibasic calcium phosphate as a diluent and prepared by direct compression, wherein the tablet does not comprise a binder.
• Fig. 1 A comparative dissolution profile of the composition of the invention and a reference product.
• An embodiment of the invention relates to film-coated tablet compositions containing Linagliptin.
• the composition may contain excipients that act as binders, fillers, disintegrants and lubricants.
• cellulose derivatives such as microcrystalline cellulose, powdered cellulose as a filler
• starch compounds such as lactose, glucose, sorbitol, dextrose, mannitol, dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, pregelatinized starch
• natural polymers such as gelatin, acacia, alginic acid, sodium alginate, starch and pregelatinized starch as binders
• synthetic polymers such as povidone, polyvinyl acetate
• cellulose derivatives such as methyl cellulose, HPMC, sodium carboxymethylcellulose, ethyl cellulose
• carbohydrate derivatives such as glucose, sucrose
• sugar alcohols such as sorbitol
• starch pregelatinized starch, microcrystalline cellulose, calcium carbonate, methyl cellulose, alginic acid, veegum, kaolin, bentonite as a
• composition of the invention produced by wet granulation contains a linagliptin granule comprising linagliptin, a binder and a diluent in its inner phase, and a lubricant and a dispersant in its outer phase.
• a linagliptin granule comprising linagliptin, a binder and a diluent in its inner phase
• a lubricant and a dispersant in its outer phase.
• hydroxypropylmethyl cellulose as a binder microcrystalline cellulose and lactose as a diluent are used in the inner phase
• croscarmellose sodium and sodium stearylfumate as a disintegrant are used.
• Dissolution is important for the effect to be seen rapidly in tablets containing Linagliptin. Therefore, dissolution is predicted to be rapid.
• at least 40% linagliptin dissolution should be achieved in 5 minutes, at least 75%, preferably 80%, more preferably 85% linagliptin dissolution in 10 minutes.
• the predicted rapid dissolution effect was achieved by using microcrystalline cellulose and lactose as a filler in the specified proportions.
• microcrystalline cellulose can be used as microcrystalline cellulose in the composition.
• the use of microcrystalline cellulose with particle size below 150 microns was preferred as a filler, and dissolution was ensured to be rapid as a technical effect.
• lactose as a filler has also contributed to the rapid dissolution.
• the composition preferably contains hydroxypropylmethyl cellulose as a binder.
• the composition contains a disintegrant.
• the ratio of the disintegrant in the composition is preferably between 1 -10% by weight.
• Croscarmellose sodium was selected as the disintegrant.
• the composition contains a lubricant.
• the ratio of the lubricant in the composition is preferably between 0.5-5% by weight. Cetyl stearyl fumarate was chosen as the lubricant.
• the amount of linagliptin in the composition of the invention is preferably 5 mg.
• the ratio of linagliptin in the composition of the invention may be between 2-5% (m/m) by weight.
• microcrystalline cellulose is preferably used at a rate of 40-80% (m/m) and lactose at a rate of 10-60% (m/m) by weight, as a filler.
• the ratio of microcrystalline cellulose:lactose used as a filler in the composition of the invention is between 1.50:1.00 and 1.00:1.00 (w/w) by weight, preferably between 1.30:1.00 and 1.10:1.00 (w/w), and between 1.20:1.00 and 1.15:1.00, most preferably 1 :1.
• a rapid dissolution as well as an excellent content uniformity was achieved with the specified ratio of microcrystalline cellulose:lactose filler mixture.
• the ratio of the microcrystalline cellulose:lactose as a filler may be 1 .50:1 .00 (w/w), 1 .30:1 .10 (w/w), or 1 .20:1 .15 (w/w) by weight.
• composition of the invention with the specified ratios of binders and diluents in the inner phase and outer phase was found to be more suitable in terms of dissolution and stability.
• composition of the invention can be used in the treatment of type 2 diabetes mellitus.
• Tablets containing linagliptin as the active ingredient, lactose monohydrate as the first filler, microcrystalline cellulose as the second filler, hydroxypropylmethyl cellulose as the binder, croscarmellose sodium as the disintegrant and sodium stearyl fumarate as the lubricant were prepared.
• wet granulation manufacturing method which is widely used in pharmaceutical technology, was preferred.

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• Health & Medical Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Diabetes (AREA)
• Hematology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Obesity (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
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• 2023
  • 2023-05-08 EP EP23803955.6A patent/EP4522138A4/de active Pending

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