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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

• the present invention provides a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
• Linagliptin chemically 8-[(3i?)-3-aminopiperidin- 1 -yl]-7-(but-2-yn- 1 -yl)-3 methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione and has the structure formula:
• Linagliptin (BI-1356) is a DPP-IV inhibitor. Linagliptin is useful for the prevention or treatment of diabetes mellitus, prediabetes or reduced glucose tolerance.
• the generic name linagliptin is marketed by BOEHRINGER INGELHEIM under the brand name Tradjenta ® .
• Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
• polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
• Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
• Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
• XRD X-ray diffraction
• DSC Differential Scanning Calorimetry
• IR Infrared spectrometry
• Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
• Linagliptin can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
• amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
• the amorphous solid dispersion of linagliptin is stable, reproducible and so, the amorphous solid dispersion of linagliptin is suitable for formulating linagliptin.
• Normally amorphous Forms are hygroscopic.
• Amorphous solid dispersion of linagliptin is found to be non-hygroscopic.
• an object of the present invention is to provide amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
• the present invention provides amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
• the present invention there is provided a process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, which comprises:
• compositions comprising a therapeutically effective amount of amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
• Figure 1 is a powder X-ray diffractogram patterns of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
• Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
• room temperature refers to temperature at about 25 to 35°C.
• amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier there is provided amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier.
• the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier is shown in figure 1.
• Amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier is found to be stable.
• the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
• a process for the preparation of amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier which comprises:
• Linagliptin used in step (a) may preferably be linagliptin obtained by the known process.
• the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol and ethanol.
• the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
• the solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.
• the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
• the distillation may preferably be carried out until the solvent is almost completely distilled off.
• reduced pressure refers to a pressure of less than 100 mmHg.
• pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of linagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
• the amorphous solid dispersion of linagliptin may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• a mixture of linagliptin (25 gm) and hydroxypropyl methylcellulose (12.5 gm) was dissolved in ethanol (750 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 36 gm of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 3 Preparation of amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose
• Example 2 was repeated using dimethylformamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 2 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 2 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 2 was repeated using methanol solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 7 was repeated using dimethylformamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
• Example 7 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
• Example 7 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
• Example 7 was repeated using methanol solvent instead of ethanol solvent to provide amorphous linagliptin solid dispersion with copovidone.
• a mixture of linagliptin (20 gm) and soluplus (20 gm) was dissolved in ethanol (300 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 37 gm of amorphous linagliptin solid dispersion with soluplus.
• Example 13 Preparation of amorphous linagliptin solid dispersion with polyethylene glycol

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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2013
  • 2013-07-08 WO PCT/IN2013/000417 patent/WO2014009970A2/fr not_active Ceased

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