Classifications

• • 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
• • 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
  • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole

Definitions

• the present invention provides a novel amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
• Saxagliptin chemically (15 , ,35 , ,5 l S -2-[(2.S)-2-amino-2-(3-hydroxy- l -adamantyl) acetyl]-2-azabicyclo[3.1 .0]hexane-3-carbonitrile and has the structure formula:
• Saxagliptin previously identified as BMS-4771 18, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP -4) inhibitor class of drugs.
• 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.
• Saxagliptin can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
• U.S. patent no. 7,943,656 disclosed crystalline Form H-l (MonoHydrate), Form HO.5-2 (hemihydrate) and Form N-3 (Anhydrous) of saxagliptin.
• a novel amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier is stable, reproducible and so, the amorphous solid dispersion of saxagliptin is suitable for formulating saxagliptin.
• Normally amorphous Forms are hygroscopic.
• Amorphous solid dispersion of saxagliptin is found to be non-hygroscopic.
• an object of the present invention is to provide amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
• the present invention provides amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier.
• the present invention there is provided a process for the preparation of amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier, which comprises: a) preparing a solution comprising a mixture of saxagliptin and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier.
• compositions comprising a therapeutically effective amount of amorphous solid dispersion of saxagliptin 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 saxagliptin 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 m A.
• room temperature refers to temperature at about 25 to 35°C.
• amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier there is provided amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier.
• the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of saxagliptin in combination with a pharmaceutically acceptable carrier is shown in figure 1.
• Amorphous solid dispersion of saxagliptin 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 saxagliptin in combination with a pharmaceutically acceptable carrier which comprises:
• Saxagliptin used in step (a) may preferably be saxagliptin 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 and methanol.
• 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.
• compositions comprising a therapeutically effective amount of amorphous solid dispersion of saxagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
• the amorphous solid dispersion of saxagliptin may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.
• binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
• diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar . compressible, sugar confectioners, and the like and mixtures thereof.
• Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monol
• disintegrants include low-substituted hydroxypropylcellulose
• L-HPC sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
• lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
• Coloring agents include any FDA approved colors for oral use.
• Example 2 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with copovidone.
• Example 2 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with copovidone.
• Example 2 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with copovidone.
• Example 2 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with copovidone.
• Example 7 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 7 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 7 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 7 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with hydroxypropyl methylcellulose.
• Example 12 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with hydroxypropyl methylcellulose.
• a mixture of saxagliptin (10 gm) and soluplus (20 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and stirred for 1 hour. The solution was filtered through celite bed and the solvent was distilled off under reduced pressure at below 50°C to obtain 29 gm of amorphous saxagliptin solid dispersion with soluplus.
• Example 12 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with soluplus.
• Example 12 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with soluplus.
• Example 15 . . . .
• Example 12 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with soluplus.
• Example 12 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous saxagliptin solid dispersion with soluplus.
• a mixture of saxagliptin ( 10 gm) and ethyl cellulose ( 10 gm) was dissolved in methanol (150 ml) at room temperature. The contents were heated to 45 to 50°C and stirred for 1 hour. The solution was filtered through celite bed and the solvent was distilled off under reduced pressure at below 50°C to obtain 18 gm of amorphous saxagliptin solid dispersion with ethyl cellulose.
• the contents were heated to 45 to 50°C and stirred for 1 hour.
• the solution was filtered through celite bed and the solvent was distilled off under reduced pressure at below 50°C to obtain 94 gm of amorphous saxagliptin solid dispersion with hydroxypropyl methylcellulose.

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• 2013
  • 2013-05-13 WO PCT/IN2013/000311 patent/WO2013171766A2/fr not_active Ceased

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