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, said modified cyclodextrin being selected such that the modified cyclodextrin results in the pK a of pazopanib with said modified cyclodextrin in water being lower than the pK a of pazopanib alone in water;
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 stable for at 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 modified cyclodextrin is selected such that the modified cyclodextrin results in the pK a of pazopanib with said modified cyclodextrin in water being at least 0.4 lower than the pK a of pazopanib alone in water the modified cyclodextrin results in the pK a of pazopanib in a 10 mg pazopanib/mL water solution.
5 . The pharmaceutical composition according to claim 1 , wherein the modified cyclodextrin is selected such that the modified cyclodextrin results in the pK a of pazopanib with said modified cyclodextrin in water being at least 0.8 lower than the pK a of pazopanib alone in water.
6 . The pharmaceutical composition according to claim 1 , wherein the amount of modified cyclodextrin is from about 6.0 to about 10.0% w/w.
7 . The pharmaceutical composition according to claim 1 , wherein the modified cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, β-cyclodextrin sulfobutylether and combinations thereof.
8 . The pharmaceutical composition according to claim 1 , wherein the modified cyclodextrin is β-cyclodextrin sulfobutylether.
9 . The pharmaceutical composition according to claim 1 , wherein the composition is stable for at least 6 months.
10 . The pharmaceutical composition according to claim 1 , wherein the composition is stable for at least 12 months.
11 . The pharmaceutical composition according to claim 1 , further comprising a buffering agent.
12 . The pharmaceutical composition according to claim 11 , wherein said buffering agent is a phosphate buffering agent.
13 . 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.
14 . The pharmaceutical composition according to claim 1 , wherein the modified cyclodextrin is suitable for administration to the eye of a human.
15 . The pharmaceutical composition according to claim 1 , wherein the composition is an eye drop formulation suitable for administration to a human.
16 . A pharmaceutical composition comprising:
about 10 mg pazopanib/mL of the composition;
about 2.0 to about 13.0% w/w of a modified cyclodextrin; and
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 has a U CD value in the range of 0.0002 to 0.6 at a temperature of 25° C., and wherein the composition is stable for at least 2 months.
17 . The pharmaceutical composition according to claim 16 , wherein the modified cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, β-cyclodextrin sulfobutylether and combinations thereof.
18 . The pharmaceutical composition according to claim 16 , wherein the modified cyclodextrin is β-cyclodextrin sulfobutylether.
19 . The pharmaceutical composition according to claim 16 , wherein the amount of the modified cyclodextrin is in the range of about 6.0% to about 10.0% w/w.
20 . The pharmaceutical composition according to claim 16 , wherein the osmolality of the composition is in the range of 270 to 330 mOsm.
22 . The pharmaceutical composition according to claim 16 , further comprising a buffering agent.
23 . The pharmaceutical composition according to claim 22 , wherein said buffering agent is a phosphate buffering agent.
24 . The pharmaceutical composition according to claim 16 , wherein the pH adjusting agent is selected from the group consisting of sodium hydroxide, hydrochloric acid and combinations thereof.
25 . The pharmaceutical composition according to claim 16 , wherein the pH of said ophthalmic composition is in the range of 4.0 to 4.5.
26 . The pharmaceutical composition according to claim 16 , wherein the composition is stable for at least 6 months.
27 . The pharmaceutical composition according to claim 16 , wherein the composition is stable for at least 12 months.
28 . The pharmaceutical composition according to claim 16 , wherein the modified cyclodextrin is suitable for administration to the eye of a human.
29 . The pharmaceutical composition according to claim 16 , wherein the composition is an eye drop formulation suitable for administration to a human.
30 . A pharmaceutical composition comprising:
about 10 mg pazopanib/mL of the composition;
about 2.0 to about 13.0% w/w of a modified cyclodextrin; and
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 a super-saturated aqueous solution of pazopanib, and wherein the composition is stable for at least 2 months.
31 . The pharmaceutical composition according to claim 30 , wherein the modified cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, β-cyclodextrin sulfobutylether and combinations thereof.
32 . The pharmaceutical composition according to claim 30 , wherein the modified cyclodextrin is β-cyclodextrin sulfobutylether.
33 . The pharmaceutical composition according to claim 30 , wherein the amount of the modified cyclodextrin is in the range of about 6.0% to about 10.0% w/w.
34 . The pharmaceutical composition according to claim 30 , wherein the osmolality of the composition is in the range of 270 to 330 mOsm.
35 . The pharmaceutical composition according to claim 30 , further comprising a buffering agent.
36 . The pharmaceutical composition according to claim 35 , wherein said buffering agent is a phosphate buffering agent.
37 . The pharmaceutical composition according to claim 30 , wherein the pH adjusting agent is selected from the group consisting of sodium hydroxide, hydrochloric acid and combinations thereof.
38 . The pharmaceutical composition according to claim 30 , wherein the pH of the ophthalmic composition is in the range of about 4.0 to about 4.5.
39 . The pharmaceutical composition according to claim 30 , wherein the composition is stable for at least 6 months.
40 . The pharmaceutical composition according to claim 30 , wherein the composition is stable for at least 12 months.
41 . The pharmaceutical composition according to claim 30 , wherein the modified cyclodextrin is suitable for administration to the eye of a human.
42 . The pharmaceutical composition according to claim 30 , wherein the composition is an eye drop formulation suitable for administration to a human.
43 . A pharmaceutical composition comprising:
about 10 mg pazopanib/mL of the composition;
about 2.0 to about 13.0% w/w of a modified cyclodextrin;
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.
44 . The pharmaceutical composition according to claim 43 , wherein the modified cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, β-cyclodextrin sulfobutylether and combinations thereof.
45 . The pharmaceutical composition according to claim 43 , wherein the modified cyclodextrin is β-cyclodextrin sulfobutylether.
46 . The pharmaceutical composition according to claim 43 , wherein the amount of the modified cyclodextrin is in the range of about 6.0% to about 10.0% w/w.
47 . The pharmaceutical composition according to claim 43 , wherein the osmolality of the composition is in the range of 270 to 330 mOsm.
48 . The pharmaceutical composition according to claim 43 , further comprising a buffering agent.
49 . The pharmaceutical composition according to claim 48 , wherein said buffering agent is a phosphate buffering agent.
50 . The pharmaceutical composition according to claim 43 , wherein the pH adjusting agent is selected from the group consisting of sodium hydroxide, hydrochloric acid and combinations thereof.
51 . The pharmaceutical composition according to claim 43 , wherein the pH of the ophthalmic composition is in the range of about 4.0 to about 4.5.
52 . The pharmaceutical composition according to claim 43 , wherein the modified cyclodextrin is suitable for administration to the eye of a human.
53 . The pharmaceutical composition according to claim 43 , wherein the composition is an eye drop formulation suitable for administration to a human.
54 . 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.
55 . The pharmaceutical composition of claim 54 , wherein the composition is an eye drop formulation suitable for administration to a human.
56 . 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.
57 . The method according to claim 56 , wherein the acid addition salt of pazopanib is pazopanib hydrochloride.
58 . The method according to claim 56 , wherein the modified cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, β-cyclodextrin sulfobutylether and combinations thereof.
59 . The method according to claim 56 , wherein the modified cyclodextrin is β-cyclodextrin sulfobutylether.
60 . The method according to claim 56 , wherein the amount of the modified cyclodextrin is in the range of about 2.0% to about 13.0% w/w.
61 . The method according to claim 56 , wherein the amount of the modified cyclodextrin is in the range of about 6.0% to about 10.0% w/w.