Pharmaceutical formulation containing thienotriazolodiazepine compounds
A method of treating lymphoblastic leukemia, acute myeloid leukemia, BCR-ABL positive acute lymphoblastic leukemia or CD34 positive acute myeloid leukemia comprising the step of administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound according to Formula (1) as a solid dispersion wherein X is a halogen, R 1 is C 1 -C 4 alkyl, R 2 is C 1 -C 4 alkyl, a is an integer of 1-4, R 3 is C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, phenyl optionally having substituent(s), or heteroaryl optionally having substituent(s), a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer. In one embodiment, the pharmaceutically acceptable polymer is HPMCAS.
1. A method of treating an acute lymphoblastic leukemia comprising administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound which is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide or a dihydrate thereof, wherein the thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound, and a pharmaceutically acceptable polymer which is hydroxypropylmethylcellulose acetate succinate having a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate weight ratio of 1:3 to 1:1.
2. The method of claim 1 , wherein the thienotriazolodiazepine compound is (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
3. The method according to claim 1 , wherein the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130° C. to about 140° C.
4. A method of treating an acute myeloid leukemia comprising administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound which is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide or a dihydrate thereof, wherein the thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound and a pharmaceutically acceptable polymer which is hydroxypropylmethylcellulose acetate succinate having a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate weight ratio of 1:3 to 1:1.
5. The method of claim 4 , wherein the thienotriazolodiazepine compound is (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
6. The method according to claim 4 , wherein the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130° C. to about 140° C.
7. A method of treating a BCR-ABL positive acute lymphoblastic leukemia comprising administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound which is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide or a dihydrate thereof.
8. The method of claim 7 , wherein the thienotriazolodiazepine compound is (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
9. The method according to claim 8 , wherein the thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound and a pharmaceutically acceptable polymer which is hydroxypropylmethylcellulose acetate succinate having a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate weight ratio of 1:3 to 1:1.
10. The method according to claim 9 , wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound.
11. The method according to claim 10 , wherein the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130° C. to about 140° C.
12. A method of treating a CD34 positive acute myeloid leukemia comprising administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound which is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide or a dihydrate thereof.
13. The method of claim 12 , wherein the thienotriazolodiazepine compound is (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
14. The method according to claim 13 , wherein the thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound and a pharmaceutically acceptable polymer which is hydroxypropylmethylcellulose acetate succinate having a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate weight ratio of 1:3 to 1:1.
15. The method according to claim 14 , wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound.
16. The method according to claim 14 , wherein the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130° C. to about 140° C.