Solid dispersions of a ERB2 (HER2) inhibitor
A solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and processes for preparing the solid dispersion are provided herein. Also, a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and uses thereof are provided herein.
1. A solid dispersion comprising amorphous N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, wherein the dispersion polymer is PVP-VA.
2. The solid dispersion of claim 1 , wherein the N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is present in an amount of from about 0.1% to about 50% by weight relative to the dispersion polymer.
3. The solid dispersion of claim 1 , wherein the N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is present in an amount of from about 5% to about 35% by weight relative to the dispersion polymer.
4. The solid dispersion of claim 1 , wherein the N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is present in an amount of from about 25% to about 35% by weight relative to the dispersion polymer.
5. The solid dispersion of claim 1 , wherein at least 80% of the N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is in amorphous form.
6. The solid dispersion of claim 1 , wherein at least 95% of the N4-(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is in amorphous form.
7. A pharmaceutical composition comprising a solid dispersion according to claim 1 and one or more pharmaceutically acceptable excipients.
8. The pharmaceutical composition of claim 7 , wherein the composition is a tablet.
9. A pharmaceutical composition comprising:
(a) about 1 to about 70 weight % of the solid dispersion of claim 1 ;
(b) about 0.1 to 20 weight % of a disintegrant;
(c) about 0.1 to 25 weight % of an osmogen;
(d) about 0.1 to 10 weight % of a glidant;
(e) about 0.1 to 10 weight % of a lubricant; and
(f) about 0.1 to 25 weight % of a binder.
10. A pharmaceutical composition comprising:
(a) about 1 to about 70 weight % of the solid dispersion of claim 1 ;
(b) about 0.1 to 20 weight % of a disintegrant;
(c) about 0.1 to 25 weight % of an osmogen;
(d) about 0.1 to 10 weight % of a glidant;
(e) about 0.1 to 10 weight % of a lubricant; and
(f) about 0.1 to 25 weight % of a filler.
11. The pharmaceutical composition of claim 9 , wherein the binder is about 10 to 25 weight %.
12. The pharmaceutical composition of claim 9 , wherein the disintegrant is about 5 to 15 weight %.
13. The pharmaceutical composition of claim 10 , wherein the filler is about 10 to 25 weight %.
14. The pharmaceutical composition of claim 9 , wherein the disintegrant is about 1 to 10 weight %.
15. The pharmaceutical composition of claim 9 , wherein the osmogen is about 15 to 25 weight %.
16. The pharmaceutical composition of claim 9 , wherein the glidant is about 0.1 to 3 weight %.
17. The pharmaceutical composition of claim 9 , wherein the lubricant is about 0.1 to 3 weight %.
18. A pharmaceutical composition comprising:
(a) solid dispersion of claim 1 ; and
(b) sodium bicarbonate.
19. A pharmaceutical composition comprising:
(a) about 1 to about 70 weight % of the solid dispersion of claim 1 ; and
(b) about 0.1 to about 30 weight % sodium bicarbonate.
20. The pharmaceutical composition of claim 9 , wherein the solid dispersion is about 25 to about 60 weight %.
21. The pharmaceutical composition of claim 9 , wherein the solid dispersion is about 40 to about 60 weight %.
22. The pharmaceutical composition of claim 9 , wherein the composition is a tablet.
23. A method for the treatment of ErbB2 positive breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of the solid dispersion of claim 1 .
24. A process of preparing the solid dispersion of claim 1 comprising the steps of:
(a) dissolving N4-(4-(1,2,4]triazolo[1,5-α]pyridine-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymer in a suitable solvent to form a feed solution; and
(b) evaporating the solvent by spray drying the feed solution to form the solid dispersion.