PHARMACEUTICAL COMPOSITIONS AND METHODS OF MAKING SAME
The present invention relates to pharmaceutical compositions that include about 10 mg pazopanib/mL of the composition and about 2 to about 13% w/w of a modified cyclodextrin as well as methods of making the same are described.
1 . A pharmaceutical composition comprising:
about 10 mg pazopanib/mL of the composition;
from about 2.0 to about 13.0% w/w of a modified cyclodextrin, which is R-cyclodextrin sulfobutylether;
a pH adjusting agent as needed to provide a pH of 3.5 to 5.7;
a tonicity adjusting agent as needed to provide an osmolality of 200 to 400 mOsm; and
water;
wherein the composition is an eye drop formulation suitable for administration to a human, has a U CD value in the range of 0.0002 to 0.6 at a temperature of 25° C., is a super-saturated aqueous solution of pazopanib, and is stable for a least 2 months.
2 . The pharmaceutical composition according to claim 1 , wherein the composition has a pH of from about 4 to about 4.5.
3 . The pharmaceutical composition according to claim 1 , wherein the osmolality of the composition is from about 270 to about 330 mOsm.
4 . The pharmaceutical composition according to claim 1 , wherein the amount of modified cyclodextrin is from about 6.0 to about 10.0% w/w.
5 . The pharmaceutical composition according to claim 1 , wherein the composition is stable for at least 6 months.
6 . The pharmaceutical composition according to claim 1 , wherein the composition is stable for at least 12 months.
7 . The pharmaceutical composition according to claim 1 , further comprising a buffering agent.
8 . The pharmaceutical composition according to claim 7 , wherein said buffering agent is a phosphate buffering agent.
9 . The pharmaceutical composition according to claim 1 , wherein the pH adjusting agent is selected from the group consisting of sodium hydroxide, hydrochloric acid and combinations thereof.
10 . The pharmaceutical composition according to claim 1 , wherein the modified cyclodextrin is suitable for administration to the eye of a human.
11 . A pharmaceutical composition comprising:
about 10 mg pazopanib/mL of the composition;
about 9%β-cyclodextrin sulfobutylether;
a pH adjusting agent as needed to provide a pH of 3.5 to 5.7;
a tonicity adjusting agent as needed to provide an osmolality of 200 to 400 mOsm; and
water
wherein the composition is an eye drop formulation suitable for administration to a human, has a U CD value in the range of 0.0002 to 0.6 at a temperature of 25° C., is a super-saturated aqueous solution of pazopanib, and is stable for at least 2 months.
12 . A method of preparation of a super-saturated solution of pazopanib, said method comprising:
forming an aqueous solution of an acid addition salt of pazopanib and a modified cyclodextrin suitable for use in an ophthalmic formulation; and
adjusting the pH of said solution to between 3.5 to 5.7 to obtain a super-saturated solution of pazopanib, wherein the concentration of the acid addition salt of pazopanib solubilized in the super-saturated solution is equivalent to about 10 mg/ml of pazopanib.
13 . The method according to claim 12 , wherein the acid addition salt of pazopanib is pazopanib hydrochloride.
14 . The method according to claim 12 , wherein the modified cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, β-cyclodextrin sulfobutylether and combinations thereof.
15 . The method according to claim 12 , wherein the modified cyclodextrin is β-cyclodextrin sulfobutylether.
16 . The method according to claim 12 , wherein the amount of the modified cyclodextrin is in the range of about 2.0% to about 13.0% w/w.
17 . The method according to claim 12 , wherein the amount of the modified cyclodextrin is in the range of about 6.0% to about 10.0% w/w.