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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a solid oral dosage form comprising linagliptin and at least one binder.
• Linagliptin is used for type 2 or non-insulin dependent diabetes. It is a selective, orally administered, xanthine based dipeptidyl peptidase-4 (DPP-4) inhibitor used as an adjunct to diet and exercise to improve glycemic control. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
• DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
• DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
• GLP-1 glucagon-like peptide-1
• GIP glucose-dependent insulinotropic peptide
• Linagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
• linagliptin 8-[(3R)-3-aminopiperidin-1 -yl]-7-but-2-yn-1 -yl)-3-methyl-1 - [(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1 H-purine-2,6-dione and its chemical structure is shown in the Formula I.
• WO2014/026939 patent application discloses a pharmaceutical composition comprising linagliptin or salts thereof with mannitol, copovidone, and magnesium stearate, a process for the preparation of the pharmaceutical composition.
• a pharmaceutical composition comprising linagliptin or salts thereof with mannitol, copovidone, and magnesium stearate, a process for the preparation of the pharmaceutical composition.
• mannitol, copovidone, and magnesium stearate a process for the preparation of the pharmaceutical composition.
• the main object of the present invention is to provide high stability of linagliptin and a long shelf life by the help of selection of excipients in a certain ratio.
• Another aim of the present invention is to provide a pharmaceutical dosage form comprising linagliptin which has a long shelf life, a short disintegration time, desired dissolution properties and enables a high bioavailability of linaglitpin in a patient.
• linagliptin refers to not only linagliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
• the linagliptin is present as amorphous linagliptin, crystalline linagliptin having polymorphic form A, crystalline linagliptin having polymorphic form B and/or crystalline linagliptin having polymorphic form C or mixtures thereof.
• the linagliptin is present as a mixture of crystalline linagliptin having polymorphic form A and crystalline linagliptin having polymorphic form B.
• the pharmaceutical solid oral dosage form comprises linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to binder is between 0.1 and 6.0. This ratio is important in order to providing high stability of linagliptin and improved flow properties.
• the weight ratio of linagliptin to binder is between 0.3 and 3.0 or between 0.5 and 2.0.
• the amount of linagliptin in the composition is between 1 .0% and 10.0% by weight, preferably it is between 2.0% and 7.0%, more preferably it is between 2.5% and 6.0%.
• particle size means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern Mastersizer 2000 analysis).
• d (0.9) means the size at which %90 by volume of the particles are finer.
• linagliptin has a d (0.9) particle size less than 100 pm, preferably linagliptin has a d (0.9) particle size less than 50 pm. This property provides improved flow properties.
• Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, mannitol, gelatin, pullulan, sodium alginate or mixtures thereof.
• the present invention comprises one or more binders in an amount of from about 1% to about 20% by weight of the composition.
• DPP-4 inhibitors are not very stable compounds.
• amine group containing DPP-4 inhibitors like linagliptin may react with many excipients or impurities of excipients.
• binder ensures high stability of linagliptin in a solid oral dosage composition.
• povidone is used as binder in the present invention. Povidone has also disintegration property and it is used to enhance dissolution of poorly soluble drugs from solid-dosage forms.
• binder is povidone and the amount of povidone in the composition is 1.0% and 5.0% by weight.
• the pharmaceutical acceptable excipients used in the present invention are selected from the group consisting of fillers, disintegrants, lubricants, and film coating agents.
• Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
• microcrystalline cellulose is a filler which has the best flowability properties among the other fillers. In this invention, it further improves the disintegration of compositon as well as being a filler. In addition, it further enhances the compressibility by increasing the hardness of the tablet.
• the amount of microcrystalline cellulose is in the range of 70.0 to 90 %, preferably 76.0 to 88.0 %, more preferably it is 80.0 to 85.0 % by weight of total composition.
• Suitable disintegrants are selected from the group comprising sodium starch glycolate, cross- linked polyvinil pyrrolidone (crospovidone), povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, sodium dodecyl sulphate, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
• crospovidone cross- linked polyvinil pyrrolidone
• povidone povidone
• croscarmellose sodium low-substituted hydroxypropyl cellulose
• pregelatinized starch sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, gu
• disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient should be used to form solid oral dosage forms provided herein.
• disintegrants can be mixed with other excipient to increase effective disintegration of the tablet into smaller fragments.
• disintegrant is sodium starch glycolate, is also known as superdisintegrant, and the amount of sodium starch glycolate is in the range of 3.0% to 8.0% and thus desired level of dissolution rate is provided.
• povidone and sodium starch glycolate provides desired short disintegration time and desired dissolution properties in composition.
• the weight ratio of sodium starch glycolate to povidone is between 0.2 and 10.0 or 0.6 and 8.0.
• the lubricant is selected from the group comprising sodium stearyl fumarate, magnesium stearate, polyethylene glycol (PEG), sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, paraffin or mixtures thereof, preferably sodium stearyl fumarate. Coating may also preferably be used for moisture protection.
• Suitable coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, glycerine, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.
• Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
• FD&C Food, Drug & Cosmetic
• the pharmaceutical composition of the present invention comprises linagliptin or a pharmaceutically acceptable salt thereof, povidone, sodium stearyl fumarate, sodium starch glycolate, microcrystalline cellulose.
• Solid oral dosage is used for having effective stability and bioavailability.
• Another embodiment of the present invention is a pharmaceutical composition in the form of a solid oral dosage form.
• the solid oral dosage form is tablet or capsule or pastilles or strip.
• the solid oral dosage form is tablet. Tablet may be consisted of separated compartments or layer.
• the pharmaceutical combination is formulated as tablets comprising film-coated tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.
• the pharmaceutical combination is formulated as film coated tablet.
• the pharmaceutical combination can be prepared in tablet form. Tablet comprises at least one type of particle, for example; mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
• each type of particle comprises at least one active agent.
• pharmaceutical combination may comprise a film coating if necessary.
• Capsule comprises of at least one type of particle, for example; mini-capsules, mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
• the dosage unit form of composition is mini capsules in capsule wherein the mini-capsules comprise at least one active agent.
• the dosage unit form of composition is mini-tablets in capsule wherein a mini-tablets comprise at least one active agent.
• the dosage unit form of composition is pellets in capsule wherein pellets comprise at least one active agent.
• the composition comprises;
• the composition comprises;
• the pharmaceutical composition of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet and dry granulation.
• the formulation when the formulation is prepared with wet granulation, the formulation has desired stability and desired dissolution rate.
• Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol or mixtures thereof, preferably the granulation solution is pure water.
• the process for preparation of the pharmaceutical composition comprises the following steps:
• Example 1 Film coated tablet comprising linagliptin
• Example 2 Solid oral dosage form comprising linagliptin
• the process for preparation of the pharmaceutical composition comprises the following steps:

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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)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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Citations (4)

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• 2017
  • 2017-12-15 TR TR2017/20515A patent/TR201720515A2/tr unknown
• 2018
  • 2018-12-14 EP EP18914956.0A patent/EP3723761A4/de active Pending
  • 2018-12-14 WO PCT/TR2018/050812 patent/WO2019203755A2/en unknown
  • 2018-12-14 CA CA3085455A patent/CA3085455C/en active Active

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Non-Patent Citations (2)

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