MODIFIED-RELEASE DOSAGE FORMS OF RUXOLITINIB
Modified-release pharmaceutical compositions of ruxolitinib or a pharmaceutically acceptable salt thereof are disclosed. Preferably, the invention relates to oral modified-release pharmaceutical compositions of ruxolitinib, which enable once-daily administration. Oral modified-release compositions of ruxolitinib, methods for their administration, processes for their preparation, and use of these compositions for treatment of diseases treatable by ruxolitinib are also described.
1 . A monolithic, matrix-based, extended-release pharmaceutical composition suitable for once-daily administration, said composition comprising:
a) ruxolitinib phosphate; and
b) a release-controlling polymer, which is polyethylene oxide;
wherein not less than 20% of total amount of ruxolitinib is released from said composition within 2 hours, and not more than 60% of total amount of ruxolitinib is released from said composition within 3 hours as determined by USP dissolution apparatus II (paddle) at 50 rpm in 500 ml of 0.1N HCI as dissolution medium; and
wherein the weight of polyethylene oxide in the pharmaceutical composition is not more than 30% by weight of the composition.
2 . The composition of claim 1 , further comprising at least one stabilizing agent.
3 . The composition of claim 1 , wherein a level of total impurities in said composition is less than 2.0% w/w when stored at 25° C./60% RH for at least 3 months.
4 . The composition of claim 1 , wherein said composition does not contain hydroxypropyl methyl cellulose as the release-controlling polymer.
5 . The composition of claim 1 , wherein said composition comprises: an intra-granular phase containing at least said ruxolitinib phosphate and said polyethylene oxide; and an extra-granular phase containing at least one additional excipient selected from diluents, binders, chelating agents, coating agents, disintegrating agents, lubricants, glidants, colorants, surfactants, plasticizers, or mixtures thereof.
6 . The composition of claim 5 , wherein said intra-granular phase further comprises microcrystalline cellulose.
7 . The composition of claim 5 , wherein said extra-granular phase comprises magnesium stearate as a lubricant.
8 . The composition of claim 1 , further comprising a diluent selected from group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium sulfate, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, starch, starch pregelatinized and sucrose.
9 . The composition of claim 8 , wherein the amount of said diluent ranges from about 60% to about 95% w/w of total composition.
10 . The composition of claim 1 , wherein said composition is a tablet.
11 . The composition of claim 1 , wherein said composition is prepared using wet granulation.
12 . The composition of claim 1 , wherein said ruxolitinib phosphate is present in an amount of 13.2 mg, or 26.4 mg, or 39.6 mg, or 52.8 mg, or 66 mg, or 79.2 mg.
13 . A method of treating a condition selected from myelofibrosis, polycythemia vera, aGVHD, or cGVHD, wherein said method comprises administering the composition of claim 1 to a patient in need thereof.
14 . The composition of claim 1 , wherein not more than 70% of total amount of ruxolitinib is released from said composition within 3 hours as determined by USP dissolution apparatus II (paddle) at 75 rotations per minute (rpm) in 900 ml of re-buffered dissolution medium to pH 6.8.
15 . A monolithic, matrix-based, extended-release pharmaceutical composition suitable for once-daily administration, said composition comprising:
a) ruxolitinib phosphate; and
b) a release-controlling polymer, which is polyethylene oxide;
wherein not more than 40% of total amount of ruxolitinib is released from said composition within 1 hour, 40% to 70% of total amount of ruxolitinib is released from said composition within 3 hours, and not less than 80% of total amount of ruxolitinib is released from said composition within 12 hours, as determined by USP dissolution apparatus II (paddle) at 50 rpm in 500 mL of 0.1N HCI as dissolution medium.
16 . The composition of claim 15 , further comprising at least one stabilizing agent.
17 . The composition of claim 15 , wherein a level of total impurities in said composition is less than 2.0% w/w when stored at 25° C./60% RH for at least 3 months.
18 . The composition of claim 15 , wherein said composition comprises: an intra-granular phase containing at least said ruxolitinib phosphate and said polyethylene oxide; and an extra-granular phase containing at least one additional excipient selected from diluents, binders, chelating agents, coating agents, disintegrating agents, lubricants, glidants, colorants, surfactants, plasticizers, or mixtures thereof.
19 . The composition of claim 18 , wherein said intra-granular phase further comprises microcrystalline cellulose.
20 . The composition of claim 18 , wherein the weight of polyethylene oxide in the pharmaceutical composition is not more than 30% by weight of the composition.