EP4522138A2 - Film-coated tablet containing linagliptin - Google Patents

Film-coated tablet containing linagliptin

Info

Publication number
EP4522138A2
EP4522138A2 EP23803955.6A EP23803955A EP4522138A2 EP 4522138 A2 EP4522138 A2 EP 4522138A2 EP 23803955 A EP23803955 A EP 23803955A EP 4522138 A2 EP4522138 A2 EP 4522138A2
Authority
EP
European Patent Office
Prior art keywords
composition according
microcrystalline cellulose
linagliptin
filler
weight
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
EP23803955.6A
Other languages
German (de)
French (fr)
Other versions
EP4522138A4 (en
Inventor
Neyir Zeynep TASKENT
Muhammed Emre KARA
Demet ULKER
Isa ALBAYRAK
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.)
Atabay Kimya Sanayi Ve Tic AS
Original Assignee
Atabay Kimya Sanayi Ve Tic 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 Atabay Kimya Sanayi Ve Tic AS filed Critical Atabay Kimya Sanayi Ve Tic AS
Priority claimed from PCT/TR2023/050422 external-priority patent/WO2023219591A2/en
Publication of EP4522138A2 publication Critical patent/EP4522138A2/en
Publication of EP4522138A4 publication Critical patent/EP4522138A4/en
Pending 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
    • A61K31/33—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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • 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)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to film-coated tablet compositions containing Linagliptin. Microcrystalline cellulose and lactose are used as fillers at a ratio of 1.50:1.00 to 5 1.00:1.00 (w/w) by weight.

Description

FILM-COATED TABLET CONTAINING LINAGLIPTIN
Technical Field
The invention relates to film-coated tablet compositions containing Linagliptin.
State of the Art
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. 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.
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.
Description of Figures
Fig. 1 : A comparative dissolution profile of the composition of the invention and a reference product.
Detailed Description of the Invention
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.
In the manufacturing of a pharmaceutical tablet, the following substances may be used: 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 disintegrant, cross-linked cellulose (croscarmellose), cross-linked PVP (crospovidone), cross-linked starch (sodium starch glycolate) as a super disintegrant, ion exchange resins; metallic stearates such as magnesium stearate, fatty acid esters such as stearic acid, hydrogenated vegetable oils, sodium stearyl fumarate, glyceryl behenate, glyceryl palmitostearate, as a lubricant; tribasic calcium, colloidal silicon dioxide, talc, calcium stearate, sodium acetate, sodium benzoate, glycol, polyethylene glycol, and silica. Polyvinyl alcohol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose based agents can be selected as film forming agents.
The 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. Preferably, hydroxypropylmethyl cellulose as a binder, microcrystalline cellulose and lactose as a diluent are used in the inner phase, whereas in the outer 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. For the rapid dissolution limit, 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.
Preferably, 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.
In the composition of the invention, the use of lactose as a filler has also contributed to the rapid dissolution.
As is known, there is a color change, so-called Maillard reaction, between lactose and the primary amine group. Although the linagliptin molecule contains a primary amine group, no color change was observed as a result of the Maillard reaction using lactose, and there was no adverse effect on the stability of linagliptin, contrary to the expectations.
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.
In the composition of the invention, 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.
In another embodiment, 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.
Preparation of the 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.
The composition of the invention can be used in the treatment of type 2 diabetes mellitus.
Example Composition:
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. As the manufacturing method, wet granulation manufacturing method, which is widely used in pharmaceutical technology, was preferred.
1- Preparation of Solution: Hydroxypropylmethyl cellulose was added to pure water slowly and mixed (a Mechanical Mixer)
2- Dry Mixture: Linagliptin, microcrystalline cellulose and lactose monohydrate were dry mixed (Planetary Stirrer).
3- Wet Granulation: The prepared solution was slowly added to the dry mixture and mixed thoroughly (Planetary Stirrer).
4- Pre-Drying: The binder was dried in an oven at 50 °C.
5- Sieving: The sieving process was carried out using a 20 mesh (841 pm) sieve. (Wet Granulator)
6- Drying: The binder was continued to be dried in the oven at 50 °C. (The drying time may be adjusted depending on the humidity.)
7- Final Mixture: Dry granulated croscarmellose sodium was added and mixed. (Planetary Stirrer).
Finally, sodium stearyl fumarate was sieved, added and mixed. (Planetary Stirrer)
8- Tablet Compression: The final mixture was compressed in a tablet compression machine by controlling the hardness, brittleness and disintegration.
9- Film Coating: The core tablets were film coated. Film-coated tablets contain 2-4% of film-coating material.
The dissolution results of the product developed at pH 1 .2 are given below. (Figure 1 )

Claims

1. A tablet composition containing Linagliptin prepared by wet granulation, characterized in that the microcrystalline cellulose:lactose ratio as a filler is between 1 .50:1 .00 and 1 .00:1 .00 (w/w) by weight.
2. A composition according to claim 1 , characterized in that the microcrystalline cellulose:lactose ratio as a filler is between 1.30:1.00 and 1.10:1.00 (w/w) by weight.
3. A composition according to claim 2, characterized in that the microcrystalline cellulose:lactose ratio as a filler is between 1.20:1.00 and 1.15:1.00 (w/w) by weight.
4. A composition according to claim 1 , characterized in that the microcrystalline cellulose:lactose ratio as a filler is 1 .50:1 .00 (w/w), 1.30:1.10 (w/w), or 1.20:1 .15 (w/w) by weight.
5. A composition according to any one of the preceding claims, characterized in that it comprises hydroxypropyl methylcellulose as a binder.
6. A composition according to any one of the preceding claims, characterized in that it comprises croscarmellose sodium as a disintegrant.
7. A composition according to any one of the preceding claims, characterized in that it contains sodium stearyl fumarate as a lubricant.
8. A composition according to any one of the preceding claims, characterized in that the particle size of microcrystalline cellulose is less than 150 microns.
9. A composition according to any one of the preceding claims, characterized in that the amount of linagliptin is 5 mg.
10. A composition according to any one of the preceding claims for use in the treatment of Type 2 diabetes mellitus.
EP23803955.6A 2022-05-09 2023-05-08 Film-coated tablet containing linagliptin Pending EP4522138A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR202207542 2022-05-09
PCT/TR2023/050422 WO2023219591A2 (en) 2022-05-09 2023-05-08 Film-coated tablet containing linagliptin

Publications (2)

Publication Number Publication Date
EP4522138A2 true EP4522138A2 (en) 2025-03-19
EP4522138A4 EP4522138A4 (en) 2026-05-06

Family

ID=94686904

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23803955.6A Pending EP4522138A4 (en) 2022-05-09 2023-05-08 Film-coated tablet containing linagliptin

Country Status (1)

Country Link
EP (1) EP4522138A4 (en)

Also Published As

Publication number Publication date
EP4522138A4 (en) 2026-05-06

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