ORALLY DISINTEGRATING TABLET COMPRISING AMORPHOUS SOLID DISPERSION OF NILOTINIB AND IN VITRO CHARACTERIZATION THEREOF
Amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor nilotinib. The pharmaceutical compositions may be used in methods of treating a proliferative disorder such as cancer. In particular, the present disclosure provides a pharmaceutical composition in the form of an orally disintegrating tablet. In some embodiments, the pharmaceutical compositions can be administered without regard to food consumption. In other embodiments, the pharmaceutical compositions can be administered at a significantly lower dose as compared to a commercially available immediate-release nilotinib formulation, while providing a comparable therapeutic effect. The disclosure further provides a discriminating in vitro dissolution characterization method.
1 . A pharmaceutical composition in the form of an orally disintegrating tablet and comprising an amorphous solid dispersion, the amorphous solid dispersion comprising nilotinib free base and one or more polymers;
wherein the nilotinib and the one or more polymers are present in the amorphous solid dispersion in a w/w ratio of 35:65 to 80:20 (nilotinib:polymer);
wherein the one or more polymers comprises a hydroxypropyl methylcellulose acetate succinate;
wherein the orally disintegrating tablet is characterized by a disintegration time of 40 seconds or less, as determined according to USP <701> Disintegration, using a basket-rack apparatus with disks in a medium of distilled water; and
characterized in that, when the orally disintegrating tablet is subjected to dissolution testing according to USP <711> Dissolution using Apparatus 2 at 75 rpm and a dissolution medium at pH 3.1 consisting of 10 mM citrate buffer and 1.5% Triton X-100, not less than 75% of the nilotinib is released into the dissolution medium within 30 minutes.
2 . The pharmaceutical composition of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib free base and the hydroxypropyl methylcellulose acetate succinate.
3 . The pharmaceutical composition of claim 1 , wherein the amorphous solid dispersion consists essentially of nilotinib free base, the hydroxypropyl methylcellulose acetate succinate, and an antioxidant.
4 . The pharmaceutical composition of claim 1 , wherein the nilotinib and the hydroxypropyl methylcellulose acetate succinate are present in the amorphous solid dispersion in a w/w ratio of 40:60 to 70:30 (nilotinib:polymer).
5 . The pharmaceutical composition of claim 1 , wherein the disintegration time is 30 seconds or less.
6 . The pharmaceutical composition of claim 1 , wherein in the dissolution testing not less than 85% of the nilotinib is released into the dissolution medium within 30 minutes.
7 . The pharmaceutical composition of claim 1 , wherein the orally disintegrating tablet comprises 20 mg, 60 mg, or 80 mg nilotinib free base.
8 . The pharmaceutical composition of claim 1 , wherein the orally disintegrating tablet comprises:
a) 10% to 75% of the amorphous solid dispersion, by weight of the tablet;
b) 20% to 75% of one or more fillers, by weight of the tablet; and
c) 5% to 15% of one or more disintegrants, by weight of the tablet.
9 . The pharmaceutical composition of claim 8 , wherein the one or more fillers comprises at least one of mannitol and microcrystalline cellulose.
10 . The pharmaceutical composition of claim 8 , wherein the one or more fillers comprises a combination of mannitol and microcrystalline cellulose.
11 . The pharmaceutical composition of claim 8 , wherein the one or more disintegrants comprises at least one of crospovidone and croscarmellose sodium.
12 . The pharmaceutical composition of claim 8 , wherein the one or more disintegrants comprises a combination of crospovidone and croscarmellose sodium.
13 . The pharmaceutical composition of claim 1 , wherein the orally disintegrating tablet comprises granules, the granules comprising:
a) 20% to 80% of the amorphous solid dispersion, by weight of the granule;
b) 15% to 60% of one or more granulation fillers, by weight of the granule; and
c) 2% to 20% of one or more granulation disintegrants, by weight of the granule.
14 . The pharmaceutical composition of claim 13 , wherein the one or more granulation fillers comprises mannitol.
15 . The pharmaceutical composition of claim 13 , wherein the one or more granulation disintegrants comprises croscarmellose sodium.
16 . The pharmaceutical composition of claim 1 , wherein the orally disintegrating tablet comprises granules, the granules comprising:
a) 20% to 60% of the amorphous solid dispersion, by weight of the granule;
b) 40% to 80% of one or more granulation fillers, by weight of the granule; and
c) 2% to 10% of one or more granulation disintegrants, by weight of the granule.
17 . The pharmaceutical composition of claim 16 , wherein the one or more granulation fillers comprises co-processed mannitol starch.
18 . The pharmaceutical composition of claim 16 , wherein the one or more granulation fillers comprises microcrystalline cellulose.
19 . The pharmaceutical composition of claim 16 , wherein the one or more granulation fillers comprises a combination of co-processed mannitol starch and microcrystalline cellulose.
20 . The pharmaceutical composition of claim 16 , wherein the one or more granulation disintegrants comprises crospovidone.
21 . The pharmaceutical composition of claim 1 , wherein the orally disintegrating tablet comprises granules and extra-granular excipients.
22 . The pharmaceutical composition of claim 21 , wherein the extra-granular excipients comprise one or more tablet disintegrants.
23 . The pharmaceutical composition of claim 21 , wherein the orally disintegrating tablet comprises:
a) 20% to 80% of the granules, by weight of the tablet; and
b) 20% to 80% of the extra-granular excipients, by weight of the tablet.
24 . The pharmaceutical composition of claim 23 , wherein the extra-granular excipients comprise one or more tablet fillers and one or more tablet disintegrants.
25 . The pharmaceutical composition of claim 24 , wherein the one or more tablet fillers comprises mannitol.
26 . The pharmaceutical composition of claim 24 , wherein the one or more tablet fillers comprises a combination of mannitol and microcrystalline cellulose.
27 . The pharmaceutical composition of claim 24 , wherein the one or more tablet disintegrants comprises a combination of crospovidone and croscarmellose sodium.
28 . The pharmaceutical composition of claim 21 , wherein the orally disintegrating tablet comprises:
a) 80% to 99.5% of the granules, by weight of the tablet; and
b) 0.5% to 20% of the extra-granular excipients, by weight of the tablet.
29 . The pharmaceutical composition of claim 28 , wherein the extra-granular excipients comprise one or more tablet disintegrants, wherein the one or more tablet disintegrants comprises crospovidone.
30 . The pharmaceutical composition of claim 1 , wherein the orally disintegrating tablet can be successfully administered by swallowing the tablet intact.