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EP-4412586-B1 - APIXABAN SUSPENSION AND PREPARATION METHOD

EP4412586B1EP 4412586 B1EP4412586 B1EP 4412586B1EP-4412586-B1

Inventors

  • PSARRAKIS, IOANNIS
  • LIOUMIS, KONSTANTINOS

Dates

Publication Date
20260513
Application Date
20221025

Claims (15)

  1. Buffered oral aqueous apixaban suspension comprising 0.08 - 0.20 w/v% micronized apixaban having a pH of 1.5 - 6.5, the suspension being void of emulsifier and surfactant.
  2. Buffered oral aqueous apixaban suspension of claim 1, wherein the apixaban particles in the suspension: - have a D10 of at least 1.0 µm, and/or - have a D90 of 20 µm or less.
  3. Buffered oral aqueous apixaban suspension of any of the preceding claims, comprising 0.10 - 0.15 w/v% apixaban.
  4. Buffered oral aqueous apixaban suspension of any of the preceding claims, wherein at least 95% w/w% of the apixaban present in the suspension is in crystalline Form I.
  5. Buffered oral aqueous apixaban suspension of any of the preceding claims, comprising at least 80 w/v% water, preferably at least 90 w/v% water, even more preferably at least 95 w/v% water.
  6. Buffered oral aqueous apixaban suspension of any of the preceding claims, having a pH of 3.0 - 5.0, preferably 3.5 - 4.5, most preferably 3.7 - 4.3.
  7. Buffered oral aqueous apixaban suspension of any of the preceding claims, comprising one or more buffering agents, preferably: - in an amount of 0.05 - 2.0 w/v%, more preferably in an amount of 0.5 - 1.0 w/v%, and/or - comprising any of acetic acid, ammonia solutions, monoethanolamine, diethanolamine, triethanolamine, meglumine, sodium citrate, citric acid, lactic acid, phosphoric acid, propionic acid, sulphuric acid, tartaric acid, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, and sodium hydroxide, the buffering agent preferably comprising citric acid, preferably anhydrous, and a citrate salt, preferably sodium citrate, more preferably sodium dihydrate citrate.
  8. Buffered oral aqueous apixaban suspension of any of the preceding claims, comprising one or more thickening agents, preferably: - in an amount of 0.15 - 0.5 w/v%, more preferably in an amount of 0.2 - 0.3 w/v%, and/or - being chosen from the group, consisting of xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, gellan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate, sodium carboxy methylcellulose, starch, carbopols, methylcellulose, polyethylene oxide polymer and combinations thereof, the thickening agent preferably being xanthan gum, and/or - the one or more thickening agents comprise xanthan gum, preferably in an amount of 0.20 - 0.30 w/v%.
  9. Buffered oral aqueous apixaban suspension of any of the preceding claims, further comprising one or more preservatives, preferably: - in an amount of 0.01 - 0.40 w/v%, preferably 0.02 - 0.10 w/v%, - being chosen from the group, consisting of benzoic acid, sodium benzoate, potassium sorbate, benzyl benzoate, benzalkonium chloride, benzethonium chloride, boric acid and salts thereof, cetrimide, chlorocresol, thimerosal, imidurea, glycerine, monothioglycerol, propylene glycol, propionic acid and salts thereof, acetic acid and salts thereof, lactic acid and salts thereof, alkyl acids like sorbic acid and salts thereof, pentetic acid and salts thereof, sodium sulphite, sodium metabisulphite, benzyl alcohol, ethylalcohol, potassium sorbate, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, and combinations thereof, and/or - comprising benzoic acid and/or sodium benzoate, in particular in an amount of 0.02 - 0.10 w/v%.
  10. Buffered oral aqueous apixaban suspension of any of the preceding claims, comprising one or more antioxidants, preferably: - in an amount of 0.01 - 2.5 w/v%, more preferably in an amount of 0.5 - 1.0 w/v%, and/or - being chosen from the group, consisting of sodium metabisulphite, sodium sulphite, sodium thiosulfate, propyl gallate, butylated hydroxyl anisole, butylated hydroxyl toluene, tocopherol, ascorbyl palmitate, ascorbic acid and combinations thereof, the antioxidant preferably comprising sodium metabisulphite or propylgallate.
  11. Buffered oral aqueous apixaban suspension of any of the preceding claims, comprising one or more sweetening agents, preferably: - having sweetening agents in the composition has a sweetening power that corresponds with the sweetening power of 60 - 600 w/v% saccharose, and/or - the one or more sweetening agents being present in the suspension in an amount of 0.1 - 10 w/v%, and/or - being artificial sweetening agents, preferably chosen from the group consisting of sucralose, sodium saccharin, aspartame, alitame, acesulfame-K, cyclamate, stevioside, glycyrrhizin, neohesperidin, dihydrochalcone, thaumatin, and combinations thereof, and/or - comprising sucralose and/or sodium saccharin, preferably in an amount of 0.3 - 1.0 w/v%, more preferably 0.4 - 0.8 w/v%, the weight ratio between sucralose and sodium saccharin preferably being 1 : 0.3 - 0.5.
  12. Buffered oral aqueous apixaban suspension of any of the preceding claims, further comprising one or more flavouring agents, preferably: - present in an amount of 0.05 - 0.2 w/v%, and/or - being selected from the group consisting of peppermint, spearmint, eucalyptus, vanilla, forest fruits flavour, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grapes, banana, cranberry, blueberry, black currant, red currant, gooseberry, lingonberries, cumin, thyme, basil, camomile, valerian, fennel, parsley, tarragon, lavender, dill, bergamot, salvia, aloe vera balsam and combinations of two or more thereof, the one or more flavouring agents preferably comprising peppermint or vanilla flavour.
  13. Buffered oral aqueous apixaban suspension of any of the preceding claims, wherein, at least 98 w/w% of the solid form of apixaban in the suspension, in particular form I, is still present after storage of 30 ml of the suspension for 10 months in a closed 30 ml amber glass vial at 25°C, 60% humidity in the dark.
  14. Use of micronized apixaban for the preparation of a buffered oral aqueous apixaban suspension of any of the preceding claims.
  15. Method for the preparation of a buffered oral aqueous apixaban suspension of any of the preceding claims, comprising the steps of: (i) providing purified water, (ii) if present, admixing the preservative, (iii) if present, admixing the sweeteners (iv) if present, admixing the antioxidant, (v) if present, a chelating agent, (vi) admixing the pH buffer agent, (vii) if present, admixing the flavour, (viii) admixing the apixaban to the mixture of steps (i) - (vii) and homogenise (ix) if present, admixing the thickener and homogenise (x) if present, admixing the co-solvent, (xi) if necessary, adjust pH at 1.5 - 6.5 with ingredients of step (v), (xii) if necessary, adjust to the final volume by adding purified water, (xiii) optionally, filter through a 10 µm pore sieve or higher, and (xiv) filling into an appropriate container.

Description

The invention relates to a stable buffered apixaban suspension and to a method for the preparation thereof, as defined by the claims. Apixaban (CAS 503612-47-3, C25H25N5O4) is a pyrazolopyridine that is 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide substituted at position 1 by a 4-methoxyphenyl group and at position 6 by a 4-(2-oxopiperidin-1-yl)phenyl group, having the following structural formula: Apixaban is a highly selective and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyses the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation. Apixaban has no direct effect on platelet aggregation, but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin an oral anticoagulant which helps prevent the formation of harmful blood clots. It prevents the formation of blood clots in the legs, lungs, brain, and heart. In the EU, apixaban is indicated for the prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery, the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults, and for the prevention of recurrent DVT and PE in adults. The compound apixaban has been firstly described in EP1427415 and tablets are marketed under the trade name Eliquis by Bristol-Meyers Squibb and Pfizer. Liquid preparations are known in the art. In order to provide a stable pharmaceutical liquid formulation for oral delivery, it is known to combine apixaban with an organic (co-)solvent, or to prepare a nano-emulsion where the particle size of apixaban is below 1000 nm. In all formulations for oral delivery emulsifiers are included as well. EP2900217 describes such a liquid formulation comprising 20 - 30% water and over 30 w/w% of a polyhydric alcohol and an emulsifier. WO2022/123074 describes a pharmaceutical liquid formulation for oral delivery, wherein apixaban is a solution in polypropylene glycol. CN109010273A describes a nanosuspension of apixaban with improved solubility and dissolution rate, with a particle size of less than 1000nm, further comprising an emulsifier. EP1924291 describes an injectable aqueous solution of neutral pH, comprising beta cyclodextrine as solubilizing agent. US2021/0299059 describes an injectable pharmaceutical composition comprising apixaban nanoparticles and an emulsifier. WO2017/182908 describes a solid apixaban formulation, wherein a suspension of micronized apixaban in an aqueous solution of hydroxypropylcellulose and sodium lauryl sulphate is sprayed onto a carrier mixture followed by fluidised bed granulation. CN109793715A also describes an oral solid apixaban preparation, wherein a suspension of apixaban and hypromellose is subjected to wet granulation. It has now surprisingly been found that buffered aqueous suspensions of micronized apixaban having an acid pH has advantageous physicochemical properties rendering such suspensions very suitable for oral administration. The suspensions of the invention thereto comprise 0.08 - 0.20 w/v% micronized apixaban and have a pH of 1.5 - 6.5 and are void of emulsifier and surfactant. The suspensions of the invention are form stable, have good dissolution profiles and have a good stability, i.e. low impurity formation in time. The term 'form stable' herein means that the crystal form of the apixaban in the suspension is not significantly converted to another form, or from a crystal form to the amorphous form or vice versa. It was further found that a micronized apixaban suspension in an aqueous buffer of the invention was stable even in absence of an emulsifier, surfactant, dispersant or solubiliser. Indeed, a true suspension is a heterogenous mixture of a liquid (in casu water) containing solid particles that not have settled. In contrast, a dispersion is a biphasic system in which distributed particles of one material are dispersed in a continuous phase of another material. An emulsion is a such a system wherein the two liquid phases are immiscible; by the presence of an emulsifier, one of the phases (discontinuous phase) can be present as droplets in the other continuous phase. The apixaban suspension of the present invention appears to be a true suspension, i.e. particles suspended in a continuous liquid phase without the need for an emulsifier, surfactant, dispersant, or solubiliser. The term 'oral suspension' means a pharmaceutical liquid suspension for oral delivery. The term 'aqueous' herein means that the suspension comprises at least 70 w/w% water, in particular in particular at least 75 w/w%, preferably at least 80 w/w% water, more preferably at least 85 w/w%, even more preferably at least 90 w/w%, and most preferably at least 95 w/w%, 96 w/w% or 97 w/w%. The term 'micronized' mean