Amorphous solid dispersions
The disclosure provides new, stable, pharmaceutically acceptable amorphous solid dispersions of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.
1. 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base in the form of an amorphous solid dispersion comprising:
(a) cellulose acetate excipient in a ratio of 5:95 to 50:50 ITI-007 free base to cellulose acetate; or
(b) cellulose acetate phthalate excipient in a ratio of 25:75 to 75:25 ITI-007 free base to cellulose acetate phthalate; or
(c) hydroxypropyl methyl cellulose phthalate (HPMC-P) excipient in a ratio of 25:75 to 75:25 ITI-007 free base to HPMC-P;
wherein the X-ray diffraction pattern of the amorphous solid dispersion is free of peaks characteristic of the excipient.
2. The dispersion of claim 1 , wherein the dispersion comprises cellulose acetate excipient in a ratio of 5:95 to 50:50 ITI-007 free base to cellulose acetate.
3. The dispersion of claim 2 , wherein the dispersion comprises ITI-007 free base and cellulose acetate in a weight ratio of 5:95 up to 50:50, but excluding the ratio 50:50.
4. The dispersion of claim 1 , wherein the dispersion comprises cellulose acetate phthalate excipient in a ratio of 25:75 to 75:25 ITI-007 free base to cellulose acetate phthalate.
5. The dispersion of claim 4 , wherein the dispersion comprises ITI-007 free base and cellulose acetate phthalate in a weight ratio of from 25:75 up to 75:25, but excluding the ratios 25:75 and 75:25.
6. The dispersion of claim 1 , wherein the dispersion comprises HPMC-P excipient in a ratio of 25:75 to 75:25 ITI-007 free base to HPMC-P.
7. The dispersion of claim 6 , wherein the dispersion comprises ITI-007 free base and HPMC-P in a weight ratio of from 25:75 up to 75:25, but excluding the ratios 25:75 and 75:25.
8. The dispersion of claim 1 , wherein the dispersion is x-ray amorphous.
9. The dispersion of claim 1 , wherein the dispersion shows a single glass transition temperature (T g ) above 75° C.
10. The dispersion of claim 1 , wherein the dispersion shows less than 10% weight loss up to a temperature of 100° C.
11. The dispersion of claim 1 , wherein the dispersion shows no changes in appearance or texture after 7 days at 75% relative humidity at 40° C.
12. The dispersion of claim 1 , wherein the dispersion shows greater than 90% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40° C.
13. The dispersion of claim 1 , wherein the dispersion is manufactured by a method comprising dissolving ITI-007 free base and the selected excipient in a suitable solvent or mixture of solvents and removing the solvent to obtain the amorphous solid dispersion.
14. The dispersion of claim 13 , wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
15. The dispersion of claim 13 , wherein the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture.
16. The dispersion of claim 15 , wherein the solvent or mixture of solvents is dioxane and methanol in a 90:10 to 98:2 ratio of dioxane to methanol, or a 92:8 to 95:5 ratio, or a 93:7 ratio of dioxane to methanol.
17. A process for the production of the dispersion of claim 1 , comprising the steps of:
(a) combining 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base with the selected excipient in a suitable solvent or mixture of solvents; and
(b) removing the solvent and recovering the amorphous solid dispersion thus formed.
18. A pharmaceutical composition comprising the dispersion of claim 1 , in combination or association with a pharmaceutically acceptable diluent or carrier.
19. The composition of claim 18 , wherein the composition is in the form of a tablet or capsule for oral administration.
20. The composition of claim 18 , wherein the composition is in the form of a depot formulation for use as a long-acting injectable (LAI).