AQUEOUS FORMULATIONS OF TOFACITINIB AND TOFACITINIB SALTS
Aqueous formulations containing active pharmaceutical ingredient and cyclodextrin and their method of preparation and their uses are provided herein
1 . An aqueous formulation comprising:
tofacitinib or a pharmaceutically acceptable salt thereof; and
cyclodextrin at a concentration of at least about 10% w/w;
wherein, after extended period of time under storage condition, at least about 75% of the tofacitinib or a pharmaceutically acceptable salt remains in the aqueous formulation; or
wherein the tofacitinib or a pharmaceutically acceptable salt thereof is present in the aqueous formulation at a concentration of at least about 5 mg/mL.
2 . The aqueous formulation of claim 1 , wherein at least about 90% of the tofacitinib or a pharmaceutically acceptable salt remains in the aqueous formulation after extended period of time under storage condition.
3 . The aqueous formulation of claim 1 , wherein at least about 95% of the tofacitinib or a pharmaceutically acceptable salt remains in the aqueous formulation after extended period of time under storage condition.
4 . The aqueous formulation of claim 1 , wherein the extended period of time is about 3 months.
5 . The aqueous formulation of claim 1 , wherein the extended period of time is about 12 months.
6 . The aqueous formulation of claim 1 , wherein the storage condition has a storage temperature of about 2-8° C.
7 . The aqueous formulation of claim 1 , wherein the storage condition has a storage temperature of about 25° C.
8 . The aqueous formulation of claim 1 , wherein the tofacitinib salt is selected from the group consisting of tofacitinib citrate, oxalate, malate, tartrate and acetate.
9 . The aqueous formulation of claim 1 , wherein the tofacitinib salt is tofacitinib citrate.
10 . The aqueous formulation of claim 1 , further comprising a stabilizer selected from the group consisting of tromethamine (TRIS), glycine, a polyacrylic acid polymer, and combinations thereof.
11 . The aqueous formulation of claim 10 , wherein the polyacrylic acid polymer is a Carbopol®.
12 . The aqueous formulation of claim 10 , wherein the stabilize is TRIS, and wherein the TRIS: tofacitinib molar ratio is 3.0:1 to 2.0:1.
13 . The aqueous formulation of claim 1 , wherein the cyclodextrin concentration is at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
14 . The aqueous formulation of claim 1 , wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin; or a derivative thereof.
15 . The aqueous formulation of claim 1 , wherein the cyclodextrin is β-cyclodextrin; or a derivative thereof.
16 . The aqueous formulation of claim 15 , wherein the β-cyclodextrin or derivative thereof is hydroxypropyl-β-cyclodextrin, sulfobutylether β-cyclodextrin or methyl-beta-cyclodextrin.
17 . The aqueous formulation of claim 1 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.
18 . The aqueous formulation of claim 17 , wherein the hydroxypropyl-β-cyclodextrin is present at a concentration ranging from about 60% to about 65% (w/w).
19 . The aqueous formulation of claim 1 , wherein the cyclodextrin is sulfobutylether-p-cyclodextrin.
20 . The aqueous formulation of claim 19 , wherein the sulfobutylether-β-cyclodextrin is present at a concentration ranging from about 10% to about 40% (w/w).
21 . The aqueous formulation of claim 1 , wherein the cyclodextrin is methyl-β-cyclodextrin.
22 . The aqueous formulation of claim 21 , wherein the methyl-β-cyclodextrin is present at a concentration ranging from about 35% to about 70% (w/w).
23 . The aqueous formulation of claim 1 , wherein pH of the aqueous formulation ranges from about pH 4.0 to about pH 8.
24 . The aqueous formulation of claim 1 , wherein pH of the aqueous formulation is from about pH 6 to about pH 7.
25 . The aqueous formulation of claim 1 , wherein the tofacitinib or a pharmaceutically acceptable salt is present in the aqueous formulation at a concentration of from about 10 mg/mL to about 140 mg/mL.
26 . The aqueous formulation of claim 1 , comprising:
tofacitinib citrate at a concentration of about 10 mg/mL to about 140 mg/mL;
cyclodextrin at a concentration of about 40% w/w to about 80% w/w; and
tromethamine (TRIS) at a molar ratio of 3.5:1 to 1.5:1 (TRIS: tofacitinib).
27 . The aqueous formulation of claim 1 , comprising:
tofacitinib citrate at a concentration of about 10 mg/mL to about 130 mg/mL;
hydroxypropyl-β-cyclodextrin at a concentration of about 10% w/w to about 55% w/w; and
Carbopol® 971P at a concentration ranging from about 0.05% w/w to about 1.5% w/w, wherein the pH of the aqueous formulation ranges from about pH 4.0 to about pH 8.
28 . The aqueous formulation of claim 1 , comprising:
tofacitinib citrate at a concentration of about 10 mg/mL to about 150 mg/mL;
sulfobutylether β-cyclodextrin at a concentration of about 10% w/w to about 40% w/w; and
Carbopol® 971 at a concentration ranging from about 0.05% w/w to about 1.5% w/w, wherein the pH of the aqueous formulation ranges from about pH 4.0 to about pH 8.
29 . The aqueous formulation of claim 1 , comprising:
tofacitinib citrate at a concentration of about 20 mg/mL to about 140 mg/mL and methyl-β-cyclodextrin at a concentration of about 35% w/w to about 70% w/w, wherein the pH of the aqueous formulation ranges from about pH 4.0 to about pH 8.
30 . The aqueous formulation of claim 1 , in combination with an ingestible device configured to topically deliver the aqueous formulation to gastrointestinal tract of a subject.