Apixaban suspension and preparation method

1. A buffered oral aqueous apixaban suspension comprising a buffering agent and 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. The buffered oral aqueous apixaban suspension of claim 1 ,

wherein the apixaban particles in the suspension have a D10 of at least 1.0 μm.

3. The buffered oral aqueous apixaban suspension of claim 1 ,

wherein the apixaban particles in the suspension have a D90 of 20 μm or less.

4. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising 0.10-0.15 w/v % apixaban.

5. The buffered oral aqueous apixaban suspension of claim 1 ,

wherein at least 95% w/w % of the apixaban present in the suspension is in crystalline Form I.

6. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising at least 80 w/v % water.

7. The buffered oral aqueous apixaban suspension of claim 1 ,

wherein said buffering agent is selected from the group consisting 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, sodium hydroxide, and combinations thereof.

8. The buffered oral aqueous apixaban suspension of claim 7 , the buffering agent comprising citric acid and a citrate salt, in an amount of 0.05-2.0 w/v %.

9. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising one or more thickening agents, the one or more thickening agents 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.

10. The buffered oral aqueous apixaban suspension of claim 9 , the one or more thickening agents comprising xanthan gum in an amount of 0.20-0.30 w/v %.

11. The buffered oral aqueous apixaban suspension of claim 1 , further comprising one or more preservatives, 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 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.

12. The buffered oral aqueous apixaban suspension of claim 11 ,

wherein the one or more preservatives comprise benzoic acid or sodium benzoate, or a combination thereof, in an amount of 0.02-0.10 w/v %.

13. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising one or more antioxidants, 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.

14. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising one or more sweetening agents, the amount of the one or more sweetening agents in the composition having a sweetening power that corresponds with the sweetening power of 60-600 w/v % saccharose.

15. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising one or more sweetening agents in an amount of 0.1-10 w/v %.

16. The buffered oral aqueous apixaban suspension of claim 1 ,

comprising one or more artificial sweetening agents, chosen from the group consisting of sucralose, sodium saccharin, aspartame, alitame, acesulfame-K, cyclamate, stevioside, glycyrrhizin, neohesperidin, dihydrochalcone, thaumatin, and combinations thereof.

17. The buffered oral aqueous apixaban suspension of claim 16 ,

wherein the one or more sweetening agents comprise sucralose and sodium saccharin, in an amount of 0.3-1.0 w/v %, the weight ratio between sucralose and sodium saccharin being 1:0.3-0.5.

18. The buffered oral aqueous apixaban suspension of claim 1 , further comprising one or more flavouring agents, 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.

19. The buffered oral aqueous apixaban suspension of claim 1 ,

wherein at least 98 w/w % of the solid form of apixaban in the suspension, is in crystalline Form I, and 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.

20. A method for the preparation of the buffered oral aqueous apixaban suspension of claim 1 , 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 homogenizing,

(ix) if present, admixing the thickener and homogenizing,

(x) if present, admixing the co-solvent,

(xi) if necessary, adjusting pH at 1.5-6.5 with ingredients of step (v),

(xii) if necessary, adjusting to the final volume by adding purified water,

(xiii) optionally, filtering through a 10 μm pore sieve or higher, and

(xiv) filling into an appropriate container.